 Temporary urinary incontinence after radical prostatectomy  for prostate cancer remains a disadvantage of surgical treat-  ment. Though long-term continence rates after radical pros-  tatectomy are excellent, the time it takes to regain continence  has a significant impact on the patient's quality of life in the  initial postoperative period. Several technical modifications  have been proposed to promote an earlier return of conti-  nence, including bladder-neck sparing, preservation of the  puboprostatic ligaments, intussusception of the recon-  structed bladder neck, and posterior reconstruction of the  rhabdosphincter.**   Posterior reconstruction of the rhabdosphincter was ini-  tially described in 2001, by Rocco and colleagues, and con-  sisted of a two-layered reconstruction with apposition of the  free edge of Denovilliers’ fascia and the posterior bladder  with the posterior aspect of the rhabdosphincter and posterior  median raphe. The technique provides posterior support  for the sphincteric mechanism and also draws the bladder  caudally into a supported position, taking all tension of the  vesicourethral anastomosis. The same authors reported sig-  nificantly quicker times to recovery of urinary continence fol-  lowing open radical prostatectomy using this technique.”   The benefits of robotic technology are ideally suited for  such precise suturing in the confines of the male pelvis. We  adopted and modified this technique for use in RALP. The  principles are consistent with the two-layer reconstruction  originally described by Rocco with some minor technical  modifications. The reconstruction is performed utilizing a  continuous suture of two 3-0 monocryl sutures (RB1 nee-  dles) of different colors that are tied together with each indi-  vidual length being 12 cm. The free edge of the remaining  Denovilliers’ fascia is identified following prostatectomy.  This edge is approximated to the posterior aspect of the rhab-  dosphincter with a running suture using one arm of the con-  tinuous monocryl suture. Typically, four bites of Denovilliers’  fascia and the rhabdosphincter/posterior median raphe are  taken and the edges are approximated. The second layer of  the reconstruction is then commenced with the other arm of  the monocryl suture. This layer approximates the posterior    bladder (2 cm posterosuperior to the bladder neck) to the  initial reconstructed layer of posterior rhabdosphincter and  Denovilliers’ fascia. A continuous modified Van Velthoven  vesicourethral anastomosis“ is then performed with a run-  ning suture.   Our initial pilot study using this technique revealed a  complete "early continence" rate (no pads) of 5896 at 1 week  postoperatively. If the definition of continent is broadened to  also include mild urinary incontinence (0 or 1 pad per day),  the rate was 7296.? Other authors have also demonstrated  improvements in early postoperative continence rates follow-  ing LRP and RALP utilizing a similar reconstruction. 6^?    Since the first RALP was performed in 2000, the operation  has undergone significant standardization and modification.  The use of this operation has increased exponentially in the  United States and a similar pattern is likely to be seen in  other continents. Today, RALP offers men a minimally inva-  sive approach to radical prostatectomy with good oncologi-  cal and functional outcomes. Owing to refinements in  technique, the majority of patients will experience a quick  return to normal daily activities with minimal impact on their  health-related quality of life.   2. Kwoh YS, Hou J, Jonckheere EA, Hayati S. A robot with improved  absolute positioning accuracy for CT guided stereotactic brain sur-  gery. IEEE Trans Biomed Eng. 1988;35:153-160   3. Davies B. A review of robotics in surgery. 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Meng MV, Elkin EP, et al Predictors of treatment after initial sur-  veillance in men with prostate cancer: results from CaPSURE.  J Urol. 2003;170(6 Pt 1):2279-2283    . Myers RP. Radical prostatectomy: making it a better operation in    . Young HH. The early diagnosis and radical cure of carcinoma of the    prostate. Being a study of 40 cases and presentation of a radical  operation which was carried out in four cases. 1905 J Urol. 2002;  168(3):914-921   Reiner WB, Walsh PC. An anatomical approach to the surgical  management of the dorsal vein and Santorini's plexus during radi-  cal retropubic surgery. J Urol. 1979:121:198-200   Walsh PC, Donker PJ. Impotence following radical prostatectomy:  insight into etiology and prevention. J Urol. 1982;128:492-497  Oelrich TM. The urethral sphincter muscle in the male. Am J Anat.  1980;158:229-296   Schuessler WW, Schulam PG, Clayman RV, Kavoussi LR.  Laparoscopic radical prostatectomy: Initial short-term experience.  Urology. 1997;50:854—857   Guillonneau B, Vallancien G. Laparoscopic radical prostatectomy:  the Montsouris experience. J Urol. 2000;163:418-422   Rassweiler J, Sentker L, Seemann O, et al Laparoscopic radical  prostatectomy with the Heilbronn technique: an analysis of the first  180 cases. J Urol. 2001;166:2101—2108   Eden CG, Cahill D, Vass JA, et al Laparoscopic radical prostatec-  tomy: the initial UK series. BJU Int. 2002;90:876—882   Menon M, Tewari A, Baize B, et al Prospective comparison of radi-  cal retropubic prostatectomy and robot-assisted anatomic prostate-  ctomy: the Vattikuti Urology Institute experience. Urology. 2002;  60:864—868   Binder J, Kramer W. Robotically-assisted laparoscopic radical  prostatectomy. BJU Int. 2001;:87(4):408-410   Pasticier G, Rietbergen JBW, Guillonneau B, Fromont G, Menon M,  Vallancien G. Robotically assisted laparoscopic radical prostatec-  tomy: feasibility study in men. Eur Urol. 2001;40:70-74   Menon M, Shrivastava A, Tewari A, et al Laparoscopic and robot  assisted radical prostatectomy: establishment of a structured pro-  gram and preliminary analysis of outcomes. J Urol. 2002;168(3):  945-949   Ahlering TE, Skarecky D, Lee D, et al Successful transfer of open  surgical skills to a laparoscopic environment using a robotic inter-  face: Initial experience with laparoscopic radical prostatectomy.  J Urol. 2003;170:1738-1741   Bhandari A, Peabody JO, et al Does surgical robot assist in safe  learning of laparoscopic radical prostatectomy? AUA Abstract [pre-  sented 05/10/04]   Hugh JL, Thaly R, Shah K, Patel V. The advanced learning curve in  robotic prostatectomy: a multi-institutional survey. AUA abstract  [presented 05/20/07]   Berryhill R Jr, Jhaveri J, Yadav R, et al Robotic prostatectomy: a  review of outcomes compared with laparoscopic and open  approaches. Urology. 2008;72(1): 15-23   Patel VR, Palmer KJ, Coughlin G, Samavedi S. Robotic-assisted  laparoscopic radical prostatectomy: perioperative outcomes of 1500  cases. J Endourol. 2008;22(10):1—7   Ahlering TE, Skarecky D, Lee D, et al Successful transfer of open  surgical skills to a laparoscopic environment using a robotic inter-  face: initial experience with laparoscopic radical prostatectomy.  J Urol. 2003;170:1738-1741   Bentas W, Wolfram M, Jones J, et al Robotic technology and the  translation of open radical prostatectomy to laparoscopy: the early    Frankfurt experience with robotic radical prostatectomy and one  year follow-up. Eur Urol. 2003;44:175-181   Tewari A, Srivasatava A, Menon M, et al A prospective comparison  of radical retropubic and robot-assisted prostatectomy: experience  in one institution. BJU Int. 2003;92:205-210   Wolfram M, Brautigam R, Engl T, et al Robotic-assisted laparo-  scopic radical prostatectomy: the Frankfurt technique. World J  Urol. 2003;21:128-132   Ahlering TE, Woo D, Eichel L, Lee DI, Edwards R, Skarecky DW.  Robot-assisted versus open radical prostatectomy: a comparison of  one surgeon’s outcomes. Urology. 2004;63:8 19-822   Ahlering TE, Eichel L, Skarecky D. Rapid communication: early  potency outcomes with cautery-free neurovascular bundle preserva-  tion with robotic laparoscopic radical prostatectomy. J Endourol.  2005;19:715-718   Chien GW, Mikhail AA, Orvieto MA, et al Modified clipless ante-  grade nerve preservation in robotic-assisted laparoscopic radical  prostatectomy with validated sexual function evaluation. Urology.  2005;66:4 19-423   Joseph JV, Vicente I, Madeb R, et al Robot-assisted vs pure laparo-  scopic radical prostatectomy: are there any differences? BJU Int.  2005;96:39-42   Menon M, Kaul S, Bhandari A, et al Potency following robotic radi-  cal prostatectomy: a questionnaire based analysis of outcomes after  conventional nerve sparing and prostatic fascia sparing techniques.  J Urol. 2005;174:2291—2296   Patel VR, Thaly R, Shah K. Robotic radical prostatectomy: out-  comes of 500 cases. BJU Int. 2007;9(9):1109-1112   Tewari A, Jhaveri J, Rao S, et al Total reconstruction of vesicoure-  thral junction. BJU Int. 2008;101:871-877   Badani KK, Kaul S, Menon M. Evolution of robotic radical pros-  tatectomy assessment after 2766 procedures. Cancer. 2007;110(9):  1951-1958   Shah K, Palmer KJ, Coughlin G, Patel VR. Early retrograde release  of the neurovascular bundle during robotic-assisted laparoscopic  radical prostatectomy. J Endourol. 2007;21(suppl 1):27   Coughlin G, Dangle P, Palmer K, et al Athermal early retrograde release  of the neurovascular bundle during nerve sparing robotic assisted lap-  aroscopic radical prostatectomy. J Robotic Surg. 2009 Mar;3(1)   Rocco F, Gadda F, Acquati P, et al Personal research: reconstruction  of the urethral striated sphincter. Arch Ital Urol Androl. 2001;73:  127-37   Rocco F, Carmignani L, Acquati P, et al Early continence recovery  after open radical prostatectomy with restoration of the posterior  aspect of the rhabdosphincter. Eur Urol. 2007;52:376-83   Van Velthoven RF, Ahlering TE, Peltier A, Skarecky DW, Clayman  RV. Technique for laparoscopic running urethrovesical anastomo-  sis: the single knot method. Urology. 2003;61(4):699—702  Coughlin G, Dangle P, Patil N, et al Modified posterior reconstruc-  tion of the rhabdosphincter: application to robotic assisted laparo-  scopic prostatectomy. BJU Int 2008 Nov;102(10):1482—5   Rocco B, Gregori A, Stener S, et al Posterior reconstruction of the  rhabdosphincter allows a rapid recovery of continence after trans-  peritoneal videolaparoscopic radical prostatectomy. Eur Urol.  2007;51:996—1003   Nguyen MM, Kamoi K, Stein RJ, et al Early continence outcomes  of posterior musculofascial plate reconstruction during robotic and  laparoscopic prostatectomy. BJU Int. 2008;101:1135-1139    Radical cystectomy/anterior exenteration is currently  regarded as the gold standard for managing invasive blad-  der cancer, extensive uncontrollable superficial cancer, and  refractory carcinoma in situ (CIS). At specialized centers,  the 5-year recurrence-free survival for muscle invasive dis-  ease is 56-73%.' Optimum standards for this procedure  include 1046 positive surgical margins overall and 1546 in  patients with T3 and T4 tumors. The median number of  lymph nodes retrieved should be 10-14.? Although open  radical cystectomy (ORC) has become safer in expert  hands, it remains a formidable procedure with a complica-  tion rate of around 30-50%. Excessive bowel handling,  fluid loss, and opiates can lead to prolonged ileus. In spite  of improvements in surgical techniques, blood loss dur-  ing ORC is often significant. The hospital stay is conse-  quently quite prolonged with 18-21 days, quoted as the UK  average.   Urologists experienced in advanced laparoscopy have  reported promising results of laparoscopic radical cystec-  tomy (LRC) in the hope of reducing patient morbidity.  Within our own group, LRC is performed by a team consist-  ing of two experienced urologists to reduce surgical fatigue."  The procedure is sometimes difficult owing to reduced  maneuverability of laparoscopic instruments, and the com-  plication rate can be high even in expert hands. The overall  complications during hospital stay and after discharge have  been reported as 46 and 19%, respectively? Another large  LRC series of 84 patients showed that the complication rate  can be reduced to 1896, which is better than reported in most  series of ORC.‘ The da Vinci™ system (Intuitive Surgical,  CA) has the potential to overcome some of the technical dif-  ficulties of LRC. We published the first experience of UK  with this system and now review the oncological and func-  tional outcomes of robotic-assisted radical cystectomy  (RARC).    Our technique is derived from ORC and LRC and has  evolved over 5 years.’ Patients are given clear fluids orally,  an enema the day before their operation, and overnight intra-  venous normal saline to prevent dehydration. This is part of  an enhanced recovery program derived from colorectal sur-  gery, where formal bowel preparation is deliberately avoided.  Intravenous cefuroxime and metronidazole and subcutane-  ous low molecular weight heparin are administered periop-  eratively. Patients above 60 years of age are digitalized as  recommended by urologists experienced in open cystec-  tomy, to prevent atrial fibrillation.” They are placed in the  extended lithotomy position with a 45? Trendelenberg tilt  (Fig. 2.1). A disposable sigmoidoscope is introduced per  rectum in male and a methylene blue soaked swab per vagi-  num in female patients. After sterile catheterization, a six  port transperitoneal approach is used as previously described    Fig. 2.1 Position of patient during robotic cystectomy. Reprinted from  Murphy et al’, Copyright 2008, with permission from Elsevier    Fig. 2.2 Schematic diagram of port positioning. Reprinted from Murphy  et al?, Copyright 2008, with permission from Elsevier    (Fig. 2.2).'° The ports are usually placed in a fan-shaped or  W configuration (Fig. 2.3). The procedure involves three  surgeons — one at the console and one on each side of the  patient. With the da Vinci S HD, a fourth robotic arm is used  in place of the left side assistant.    The ureters are mobilized in the pelvis while keeping ade-  quate tissue around them so as not to compromise their vas-  cularity. The distal ends are clipped and cut and sent for  frozen section analysis. An inverted U-shaped incision is    made in the peritoneum of the cul-de-sac (Pouch of Douglas)  (Fig. 2.4). The posterior layer of Denonvillier's fascia is then  incised in the midline and the plane between the rectum and  the prostate developed. In patients wishing to preserve  potency, diathermy is avoided at the tips of the seminal vesi-  cles to avoid injury to the pelvic plexus. In females, the ovar-  ian vessels are controlled with Hem-o-lok clips (Weck  Closure Systems, NC) and divided. The plane between the  rectum and uterus is developed and the uterine arteries are  controlled with Hem-o-loks.    Dissection is continued medial to the external iliac veins to  carefully preserve the obturator nerves and expose the lateral  pelvic wall. This delineates the lateral pedicles to the bladder  (and uterus in females). We initially used Hem-o-lok clips  for control of the lateral pedicles but subsequently switched  to an Endopath™ATW45 linear stapler (Ethicon Endosurgery,  Livingston, UK). This was prompted by our perception that  blood loss was somewhat higher with clips. Currently, an  ACE Harmonic™ scalpel (Ethicon Endosurgery, Livingston,  UK) seems to be the most efficient (Fig. 2.5a—c) for this pur-  pose. It is also more cost effective, ~£300 for harmonic as  opposed to £1,200 for staplers, since multiple firings of car-  tridges are required.    The bladder is filled with 200 mL of formol-saline for easy  identification and dropped by an inverted U incision to    Fig. 2.5 (a) Control of lateral pedicles of the bladder with clips.  (b) Control of lateral pedicles of the bladder with harmonic scalpel.  Reprinted from Murphy et al'?, Copyright 2008, with permission from  Elsevier. (c) Control of lateral pedicles of the bladder with staples    include the urachus. The endopelvic fascia is opened and the  dorsal vein is controlled by a stitch. Nerve sparing is per-  formed in potent patients. The dorsal vein complex and    urethra are cut and a clip placed on the specimen side of the  urethra to prevent any spillage. The distal urethral margin is  sent for frozen section. In females, the urethra is dissected  fully to the external meatus. The posterior vaginal fornix is  opened. The previously placed methylene blue swab becomes  visible indicating that the correct plane had been entered.  The lateral vaginal walls are transected. The cystectomy  specimens are placed in a 15 mm EndoCatch II™ bag (Tyco  Healthcare, Hampshire, UK) for later retrieval. Leakage of  carbon dioxide from the vagina is reduced by a water proof  dressing applied externally. The vagina is then closed longi-  tudinally by continuous intracorporeal suturing.    Using robotic bipolar forceps and scissors, careful bilateral  Iymphadenectomy is performed. The limits of the dissection  are the genitofemoral nerve laterally, the bifurcation of the  common iliac artery proximally and the node of Cloquet dis-  tally. Care is taken to preserve the obturator nerve. The da  Vinci S-HD gives better quadrantic access and it is possible  to extend the lymph node dissection to the aortic bifurcation  with this new system. The lymph nodal packs are placed  in separately marked laparoscopic sacks. An Endoloop™  (Ethicon Endo-surgery, Livingston, UK) is applied on the  distal end of the left ureter, which is then transposed under  the sigmoid mesocolon to the left by pulling the Endoloop  through. The distal ends of the ureters are held together with  a laparoscopic grasper introduced through the left-sided 5  mm assistant port.    It is easier and quicker to perform urinary diversions extra-  corporeally although complete robotic-assisted intracorpo-  real diversion has been reported. For ileal conduits, a 15 cm  segment of ileum about 15 cm proximal to the ileo-caecal  junction is held in laparoscopic graspers introduced through  the most lateral right-sided 10 mm port. The robot is undocked.  The previously bagged bladder and lymph nodal specimens  are extracted through a 5-7 cm incision (Fig. 2.6). In thin  patients, an appendix muscle-splitting incision is made by  extending a lateral port while in overweight patients (BMI >  30 kg/m?) a subumbilical midline incision is preferred for  easier left ureteric access. The graspers holding the ureters  and ileal segment are brought to the surface through this inci-  sion. The ileal loop is isolated on its mesentery, bowel conti-  nuity is restored with staplers, and the mesenteric window is    closed. Uretero-ileal anastomosis is performed over 8F feed-  ing tubes by a Wallace I technique. The distal end of the con-  duit is fashioned as a stoma at a previously marked site on the  abdominal wall. A sump drain is introduced into the conduit  to prevent any anastomotic pressure and leak from subse-  quent stomal edema. Studer pouches are created through  lower midline incisions and anastomosed to the urethral  stump by six robotically placed 3-0 monocryl sutures (Fig.  2.7). Alternatively, a continuous 3-0 monocryl anastomosis  can be performed as in radical prostatectomy, after re-dock-  ing the robot. A 20 F drain is placed in the pelvis. The port  sites and wounds are closed with absorbable sutures (Fig. 2.8).  A liter oficodextrin (Adept, ML Pharmaceuticals, Warrington,  UK) is instilled into the abdomen and drained after an hour to  reduce the risk of bowel adhesions.    Fig. 2.8 Postoperative wounds. Reprinted from Murphy et al’,  Copyright 2008, with permission from Elsevier    All patients are electively managed in an overnight recovery  or high dependency unit immediately after the operation.  The naso-gastric tube is removed and oral liquids are admin-  istered based on the tolerence of the patient. Early mobiliza-  tion and chest physiotherapy are encouraged. Most patients  are discharged with their pelvic drains and ureteric catheters  in situ, which are removed at 3 weeks. Patients are seen again  at 6 weeks, have an abdominal ultrasound at 3 months, and  CT scans at 6 months and then at 6 monthly intervals. At  these visits, they also undergo clinical examination and  assessment of serum hemoglobin, electrolytes, creatinine,  chloride, and bicarbonate.    RARC and urinary diversion was initially reported in 2003."'  Similar to LRC, it involved a six-port trans-peritoneal  approach. The procedure was performed in three stages:  initially pelvic lymphadenectomy and cystoprostatectomy,  second extracorporeal formation of a neobladder, and third  intra-corporeal urethro-neovesical anastomosis following  re-docking of the robot. The operative times ranged from  260 to 308 min depending on whether an ileal conduit or  orthotopic neobladder was formed. Blood loss was «150 mL  and surgical margins were clear in all cases. One patient had  NI disease. Long-term oncological or functional results were  not reported, although a port site metastasis was subsequently  mentioned. Around the same time, Beeken et al described  robotic cystectomy and intra-corporeal Hautmann orthotopic    neobladder with an operating time of 8.5 h and a blood loss  of 200 mL," while Balaji et al successfully performed  robotic-assisted totally intracorporeal laparoscopic ileal con-  duit urinary diversion in three patients with operative time of  630-830 min and hospital stay of 5-10 days.'* The longest  operative time was in one patient who underwent concomi-  tant RARC. Menon's group has subsequently refined the  robotic technique for women with preservation of the uterus  and vagina.^ Other authors have excluded patients with  prior extensive abdominal surgery, pelvic irradiation, who  have undergone neoadjuvant chemotherapy, and extravesical  mass on CT from RARC,'^ making a selection bias quite  likely. Guru et al reported their early results on 20 RARC  with an average age of 70 and a BMI of 26 kg/m?. The mean  operative duration was 442 min, blood loss 555 mL, and hos-  pital stay of 10 days. The procedure was unsuccessful in a  patient with fixed pelvic mass and another needed conver-  sion to open surgery as the patient could not tolerate the  Trendelenburg position. There were three bowel obstruc-  tions, one of whom died of sepsis and one readmission with  pyelonephritis. Thus, the overall complication rate was 2096.  One patient had positive vaginal margins and 9 of 26 lymph  nodes were positive." The same group found that overweight  and obese patients had similar operative times, estimated  blood loss, and complications compared with patients with  normal BMI. Overweight and obese patients with bulky dis-  ease (pT3-4) had significantly higher rates of positive surgi-  cal margins.   In over 50 patients at Guy's, the operative time was  between 5.5 and 8 h depending on whether an ileal conduit  or Studer pouch was created. One patient needed blood  transfusion owing to bleeding from an inferior epigastric  artery and one patient with a large urethral adenocarcinoma  needed a colostomy for rectal injury. Delayed functional  complications occurred in three patients. One patient with a  Studer pouch developed a neovesico-urethral stricture,  which needed urethral dilatation. Another developed a left  upper ureteric stricture at 6 months. This was assumed to be  malignant and hence treated with nephroureterectomy. The  final pathology was that of a benign inflammatory stricture.  A third patient needed repair of an incisional hernia at 12  months. Serum creatinine levels were maintained in all  patients. Three of four previously potent male patients who  underwent nerve sparing were potent with Tadalafil. Our  experience was published by Murphy et al in a recent  Surgery in Motion DVD to aid urologists trying to learn  this procedure. We described our technique in 23 patients,  19 of whom had ileal loop urinary diversion while 4 had  Studer pouch reconstruction. Mean total operative time was  397 (295-600) min. Mean blood loss was 278 (100-1,150)  mL. Surgical margins were clear in all patients with a  median of 16 lymph nodes retrieved. The complication rate  was 2396. At a mean follow-up of 17 (4—40) months, 1    patient has died of metastatic disease with 1 other alive  with metastases.’   The operation has also been performed in patients with-  out cancer. Two men, 41 and 38 years old, with complete  posttraumatic C7—C8 quadriplegia underwent total intracor-  poreal cystoprostatectomy and ileal-conduit urinary diver-  sion with robotic assistance. The procedures were completed  without open conversion. The total surgical time was 9.25  and 6.75 h, respectively. There were no intraoperative com-  plications. In the postoperative period, both patients had  complications (pulmonary and urinary infections) that were  treated medically. The postoperative hospital stay was  13 days.”   The International Robotic-Assisted Cystectomy Con-  sortium (IRCC) reported on data on 369 patients from 11  centers at the American Urological Association, 2008. The  mean operative time was 397 min, estimated blood loss 390  mL, transfusion rate 10.5%, hospital stay 9 days, and posi-  tive margins 8%.    Rhee et al compared 23 ORC to seven RARC and found that  although blood loss was lower for RARC, four of seven  patients (57%) needed transfusion. The operative duration  was 638 min for RARC vs. 507 min for ORC and hospital  stay 11 and 13 days, respectively?! In another study of 37  patients, 24 (64.9%) had ORC and 13 (29.7%) were treated  with RARC. RARC resulted in significantly lower blood  loss, hospital stay, and longer operating time compared with  ORC. Four (16.7%) perioperative complications occurred in  the open group compared with 2 (15.496) in the robotic  group.” Pruthi and Wallen compared 20 men undergoing  RARC and extracorporeal urinary diversion to 24 matched  men who underwent ORC. Mean operative time for RARC  was 6.1 h as opposed to 3.8 h for ORC. Mean blood loss was  significantly less for RARC. On surgical pathology, 14  RARC cases were pT2 or less, four were pT3, and two were  N +. There were no positive surgical margins. A mean of 19  lymph nodes was removed. Mean time to flatus and bowel  movement was significantly shorter than in men undergoing  ORC. There were six postoperative complications (3096) in  five patients.” Likewise, Wang et al compared 20 ORC and  33 RARC patients and found similar complication rates  (24% open, 21% robotic). The open cohort had more patients  with extravesical disease (57 vs. 2896) and nodal metastasis  (34 vs. 19%), although this may be a reflection of small  sample size. There were three patients in the open group and  two in the robotic with positive margins. The median num-  ber of lymph nodes removed was similar between the  groups.”    Hospital stay Recovery Oncologic  (days) (weeks) follow-up  16 8 60% RES G 5year  16 3 60% RFS @4year  10.5 4 90% RFS @3year    Thirty age-matched patients (10 in each group) had ORC,  LRC, or RARC and ileal conduit diversion by three surgeons.  RARC and LRC took longer than ORC but were associated  with less blood loss and quicker recovery (Table 2.1).  Hospital stay was shortest for RARC, which also had the  lowest complication rate.”    For RARC to stand the test of time, the oncological outcomes  have to be equivalent to ORC and LRC. In their series of  1,054 patients undergoing ORC, Stein et al reported recur-  rence-free survival at 5 and 10 years of 68 and 66%, respec-  tively.” The recurrence-free survival appears to be worse for  patients with stage >pT2NO0.' Based on their results in 10  LRC patients, five of whom died, Simonato et al reported  poorer oncologic outcomes with LRC when compared with  ORC.” In a recent study of 37 patients undergoing LRC, fol-  lowed up for up to 5 years, Haber and Gill reported actuarial  overall and recurrence-free survival of 63 and 92%, respec-  tively. However, only eight patients had completed 5 years of  follow-up, and oncological data were not available in seven  patients. Assuming that all these seven patients had died  from metastatic disease, the recalculated 5-year overall and  cancer-specific survival were 58 and 6846, respectively. The  outcomes were poorer in those with concomitant CIS, extra-  organ disease, and nodal metastasis. Patients having extended  laparoscopic lymph node dissection had slightly better can-  cer-specific survival when compared with those having a  limited template lymphadenectomy, although not reaching  statistical significance? With the da Vinci S HD system,  excellent lymph node yield can be achieved during RARC.  In a cohort study, the mean number of lymph nodes retrieved  was 18 (6—43) with an operative time of 44 min. Neither  BMI nor previous major abdominal surgery affected the  nodal yield. There was one vascular injury.? With strict  adherence to oncological principles during RARC to prevent  spillage of cancer cells, we reported 10046 overall and recur-  rence-free survival at 2 years. At a maximum follow-up of  3.5 years, the actuarial overall and recurrence-free survival  were 95 and 90%, respectively. A median of 16 (6-28) lymph    nodes were removed. In our patient group, 10% had lymph  nodal disease, 10% incidental prostate cancer, and 10% pro-  static urethral CIS. There were no positive margins, no local  pelvic recurrences, and no port site metastasis. Lymph node  metastastis, higher grade, and concomitant CIS were predic-  tors of poor medium-term outcome.”   Bulky tumors removed with RARC may be associated  with an increased rate of intraoperative transfusion, higher  stage disease, and higher rate of margin positivity. In patients  with large-volume tumors on preoperative assessment, wider  dissection may decrease the margin-positive rates."!    Using quality of life questionnaires, Guru et al found that  time to normal activity was 4 weeks, time to driving 6 weeks,  and time to strenuous activity 10 weeks." Using the SF-8  validated questionnaire, we found no change in physical  quality of life scores at 6 weeks after RARC but significantly  better mental scores (Fig. 2.9). Patient satisfaction was high  (median 30 out of a maximum of 32 on a validated client  satisfaction-8 survey; range 27-32). We found that 93% of  patients read and understood the patient information leaflet  provided and 60% elected to watch a robotic patient informa-  tion video. This had been screened by the British Broadcasting  Corporation (BBC) after appropriate patient consent.    Pcs-8 post Mcs-8 pre Mcs-8 post  Fig. 2.9 Assessment of physical and mental quality of life after robotic    Fig. 2.10 Assessment of surgical fatigue by motion analysis in a gait laboratory (courtesy of Adam Shortland)    One of the advantages of RARC over ORC and LRC may  be reduced surgical fatigue during a long procedure.” This has  been studied using motion analysis and EMG recordings in a  gait lab (Fig. 2.10). These elegant experiments showed that  while laparoscopy was associated with the most fatigue and  progressive errors over time, robotics combined the best of  laparoscopy and open surgery. With robotics, the patients  enjoyed the generic benefits of minimal access, while the sur-  geon had the least fatigue and errors as in open surgery.    The medium term surgical, oncologic, and functional out-  comes of RARC are encouraging. A randomized controlled  trial of ORC, LRC, and RARC is planned and will include  detailed health economic modeling.    1. Madersbacher S, Hochreiter W, Burkhard F, et al Radical cystec-  tomy for bladder cancer today—a homogeneous series without neo-  adjuvant therapy. J Clin Oncol. 2003;21:690-696   2. Herr H, Lee C, Chang S, Lerner S; for the bladder cancer collabora-  tive group. Standardization of radical cystectomy and pelvic lymph  node dissection for bladder cancer. A collaborative group report.  J Urol. 2004;171:1823-1828   3. Nuttall MC, van der Meulen J, McIntosh G, Gillatt D, Emberton M.  Changes in patient characteristics and outcomes for radical cystec-  tomy in England. BJU Int. 2005;95:513-516   4. Rimington P, Dasgupta P. Laparoscopic and robotic radical cystec-  tomy. BJU Int. 2004;93:460-461   5. Haber G-P, Gill IS. Laparoscopic radical cystectomy for cancer:  oncological outcomes at up to 5 years. BJU Int. 2007:100:137—142   6. Cathelineau X, Arroyo C, Rozet F, Barret E, Vallancien G.  Laparoscopic assisted radical cystectomy: the Montsouris experi-  ence after 84 cases. Eur Urol. 2005;47:780—784    . Dasgupta P, Hemal A, Rose K; Guy's and St. Thomas’ Robotics  Group. Robotic urology in the UK: establishing a programme and  emerging role. BJU Int. 2005;95:723-724   . Raychaudhuri B, Khan MS, Challacombe B, Rimington P, Dasgupta P.  Minimally invasive radical cystectomy. BJU Int. 2006;98: 1064-1067   placement of ports in pelvic and upper urinary tract surgery using   Menon M, Hemal AK, Tewari A, et al Robot-assisted radical cys-   preservation of the uterus and vagina. J Am Coll Surg. 2004; 198:   Butt ZM, Perlmutter AE, Piacente PM, et al Impact of body mass   Hubert J, Chammas M, Larre S, et al Initial experience with suc-    conduit construction in tetraplegic patients: report of two cases.  J Endourol. 2006;20:139—143   Rhee JJ, Lebeau S, Smolkin M, Theodorescu D. Radical cystec-  tomy with ileal conduit diversion: early prospective evaluation of  the impact of robotic assistance. BJU Int. 2006;96:1059—1063  Galich A, Sterrett S, Nazemi T, et al Comparative analysis of early  perioperative outcomes following radical cystectomy by either the  robotic or open method. JSLS. 2006:10:145-150   Pruthi RS, Wallen EM. Robotic assisted laparoscopic radical cysto-  prostatectomy: operative and pathological outcomes. J Urol. 2007;  178(3 Pt 1):814-818   Wang GJ, Barocas DA, Raman JD, et al Robotic vs open radical  cystectomy: prospective comparison of perioperative outcomes and  pathological measures of early oncological efficacy. BJU Int. 2008;  101:89-93   Elhage O, Keegan J, Varma P, et al A comparative analysis of open,  laparoscopic and robotic radical cystectomy for bladder cancer.  J Endourol. 2007;21(S1):142A   Dasgupta P, Rimington P, Murphy D, Elhage O, Challacombe B,  Khan MS. Robotically assisted radical cystectomy. BJU Int. 2008;  101:1489—90   Stein JP, Lieskovsky G, Cote R, et al Radical cystectomy in the  treatment of invasive bladder cancer: long-term results in 1054  patients. J Clin Oncol. 2001;19:666-675   Simonato A, Gregori A, Lissiani A, et al Laparoscopic radical cys-  toprostatectomy: our experience in a consecutive series of 10  patients with a 3 years follow-up. Eur Urol. 2005;47:785—790  Guru KA, Sternberg K, Wilding GE, et al The lymph node yield dur-  ing robot-assisted radical cystectomy. BJU Int. 2008;102:231—234  Dasgupta P, Rimington P, Murphy D, et al Robot-assisted radical  cystectomy for bladder cancer and 2 year follow-up. B/UInt. 2007;  99(S1):P62   Yuh B, Padalino J, Butt ZM, et al Impact of tumour volume on  surgical and pathological outcomes after robot-assisted radical cys-  tectomy. BJU Int. 2008;102:840—843   Elhage O, Murphy D, Challacombe B, Shortland A, Dasgupta P.  Ergonomics in minimally invasive surgery. Int J Clin Pract. 2007;  61:186-188    Laparoscopic pyeloplasty was first reported in the literature  by Schuessler and colleagues in 1993.' This procedure was  developed in an attempt to duplicate the high success rates  achieved with open pyeloplasty while offering the advan-  tages of minimally invasive techniques. Their series con-  sisted of 5 patients with symptomatic ureteropelvic junction  (UPJ) obstruction. Symptoms were completely resolved in  all patients and the advantages of minimally invasive surgery  could be seen as their patients returned to normal activity  within 1 week.   The advantages of minimal invasive surgery are shorter  hospital stays, decreased perioperative pain, and faster recov-  ery times. The morbidity associated with open pyeloplasty is  due to the large incision necessary to expose the ureteropel-  vic junction. This results in pain and prolonged convales-  cence. In recent years, many groups have transitioned to  laparoscopic pyeloplasty to eliminate this unnecessary mor-  bidity. Unfortunately, the technical difficulty associated with  laparoscopic suturing has limited this procedure to highly  skilled laparoscopic surgeons.   Robotic pyeloplasty was developed in part to manage the  anatomical challenges of operating in the tight confines of  the retroperitoneum and allows for tremor filtering, move-  ment scaling, improved ergonomics, better vision of the  operative field, and increased range of motion.’ Robotic  pyeloplasty maintains the clinical advantages seen with lap-  aroscopy including a shorter hospital stay, decreased periop-  erative pain, and decrease blood loss, and its surgeon friendly  interface allows for more widespread usage.’    The classic symptom of obstruction of the upper urinary tract  is flank discomfort, which is exacerbated by the intake of  fluids. In many patients, it is not uncommon for them to be    asymptomatic. In the pediatric population, the typical pre-  sentation ranges from a palpable flank mass to an incidental  finding. Adults classically present with intermittent vague  flank pain that may be associated with nausea or vomiting.  Other manifestations of UPJ obstruction include hematuria,  hypertension, recurrent urinary tract infection (UTI), and  occasionally, azotemia. UPJ obstruction is twice as common  in males as in females, and the sex differential is most strik-  ing in infants, in whom this condition is five times more  common in the male than in the female. The left kidney is  involved twice as often as the right.   A variety of studies can be done to better identify the  obstruction and the function of the kidney. Computerized  tomography (CT) is initially used to evaluate flank pain and,  in the setting of UPJ obstruction, will demonstrate hydro-  nephrosis initiated at the level of the obstruction.   Once the diagnosis of UPJ obstruction is established,  patients generally undergo intravenous urography (IVU),  which demonstrates a dilated pelvicalyceal system and a  stenosis at the UPJ. An anatomic narrowing does not always  correlate with symptoms or a functional obstruction. Unless  distal ureteral filling occurs, the length of the obstructive  segment is difficult to determine. Although often obtained in  the evaluation of symptoms and follow-up, IVU has given  way to accurate functional studies such as the Lasix renal  scan. A CT angiogram with three-dimensional reconstruc-  tions is occasionally performed prior to operative interven-  tion to assess the presence of crossing vessels. Retrograde  urography is generally performed intraoperatively to avoid  infecting the operative field prior to intervention.   Surgical correction of the UPJ should be performed only  after adequate imaging studies have documented UPJ obstruc-  tion and have eliminated the possibility of other ureteral  abnormalities. Urine cultures must be sterile. Accepted indi-  cations for operative intervention include deteriorating renal  function, obstructive symptoms, stone formation, and infec-  tion. After all the appropriate studies have been completed  demonstrating obstruction, a variety of techniques may be  used to repair the UPJ. Operative interventions include open,  laparoscopic, and robotic pyeloplasty as well as endopyelo-  tomy. The goal of surgical intervention is to reconstitute a    nonobstructed pathway to restore renal function and alleviate  symptoms. Open pyeloplasty has classically been the opera-  tion of choice, but the morbidity associated with this proce-  dure has shifted the focus toward less invasive procedures.   Endopyelotomy is a contemporary procedure of pyelo-  plasty. This technique was brought to the United States in  1915; however, it was not until the 1940s when Davis popu-  larized this approach and renamed it “intubated ureterotomy,”  the method gained popularity. Wickham named this proce-  dure "pyelolysis With this procedure, an indwelling stent  was left for 4 weeks. It was not until 1986 when Arthur Smith  popularized this procedure in the United States. He renamed  it “endopyelotomy” as both the renal pelvis and ureter were  incised under endoscopic control. Although endopyelotomy  has many minimally invasive benefits in comparison with an  open pyeloplasty, success rates vary from 76 to 9096.5 The  potential for a second procedure is considered, as open repair  becomes more difficult in patients who have undergone  endopyelotomy. In addition to having lower success rates  than open pyeloplasty, endopyelotomy also has an increased  risk of hemorrhage in patients with a crossing vessel.   The goal of the laparoscopic pyeloplasty was to combine  the success rate of an open pyeloplasty, but in a less morbid  fashion. Laparoscopic pyeloplasty has had similar success  rates (97-98%) as open pyeloplasty; however, the popularity  of this procedure never materialized due to multiple techni-  cal challenges." The major challenge was that of laparo-  scopic suturing; this created longer operating room times  and despite repeated efforts, an effective alternative to lap-  aroscopic suturing was never developed.   Robotic pyeloplasty was first described by Sung and col-  leagues in 1995.'' The minimally invasive advantages and  success rates of laparoscopy are maintained while creating a  surgeon friendly interface that allows for more widespread  use of the procedure.’ The aforementioned advantages of  robotic pyeloplasty make it the procedure of choice in the  future.    Preoperative evaluation for patients with supposed UPJ  obstruction includes a standard history and physical exam,  laboratory examination, and imaging studies — both func-  tional and anatomic. Important preoperative findings include  any history of previous abdominal surgery, bleeding disor-  ders, recurrent urinary tract infections, adequate description  of the flank pain, and physical identification of abdominal/  flank scars and a palpable abdominal mass. It is beneficial to  thoroughly document the patient's description of pain,  including analog pain scores, particularly if this is the  patient's chief or sole complaint.    Laboratory evaluation should be undertaken to assess  overall renal function and the presence of urinary tract infec-  tion. Urinalysis and urine culture should be performed to  identify any underlying infection due to stagnation of urine.  If infection is documented, it should be treated prior to and at  the time of surgical repair. Serum chemistry should be sent  for creatinine to assess the patient's overall renal function.   A combination of diagnostic imaging studies are often  employed to assess renal and ureteral anatomy, as well as,  delineation of function and degree of obstruction. Standard  techniques include ultrasonography, intravenous urography  (IVU), retrograde/antegrade pyelogram, diuretic renography,  and computed tomographic imaging (CT). The differing  modalities have inherent benefits and limitations; therefore a  combination of studies is employed prior to undergoing  operative intervention.   Ultrasonography (US) is a rapid examination often avail-  able in clinicians’ offices. It does not subject the patient to  ionizing radiation; however, it is quite user dependent and its  yield is limited to anatomic information regarding renal  parenchyma, degree of hydronephrosis, presence of vascula-  ture, etc... It should be noted that enhancements in ultrasound  technology and techniques have improved its ability of iden-  tify vasculature. Crossing vessels have been reliably imaged  with the use of contrast-enhanced color Doppler imaging  and endoluminal ultrasonography.'*'* Imaging of associated  renal calculi is also limited with the use of ultrasound. Owing  to its limitations, ultrasound is often an initial diagnostic test  but not one on which surgical decisions are based.   Intravenous urography is informative regarding both the  anatomic and functional aspects of the kidneys. A properly  performed IVU will indicate the presence of calculi (if radio-  opaque), renal parenchymal thickness, hydronephrosis, delay/  lack of excretion, and level of obstruction. One concern with  this imaging modality is the lack of information with respect  to renal vasculature, particularly the presence or absence of  crossing vessels. One study has suggested that particular find-  ings on IVU can reliably detect crossing vessels with a sensi-  tivity of 82% and specificity of 10096.'* The authors identified  an acute posteriorly angulated ureteral deformity just below a  patent UPJ. Despite its value in evaluation of UPJ obstruc-  tion, IVU is decreasingly utilized likely due to the ubiquity of  CT scanners and the more objective data obtained from  diuretic nuclear scintigraphy. Intravenous urography remains  an important diagnostic modality and continues to play a role  in the postoperative evaluation of UPJ obstruction.   Nuclear scintigraphy (diuretic renography) documents  important information regarding differential function (right  vs. left), and clearance time but lacks anatomic detail.^ A  Lasix renal scan is the most common functional study used  in patients with UPJ obstruction. The most commonly  applied agent is 99m Tc-MAG3 owing to its more favorable  dosing and imaging characteristics. Radionuclide that is to    be excreted into the collecting system is administered intra-  venously and allowed to collect in the area of interest (col-  lecting system). Imaging determining the level ofradioactivity  (counts) is obtained at 5 min intervals until the collecting  system is filled. If the curve demonstrates obstruction  (increasing counts), intravenous Lasix (1 mg/kg) is adminis-  tered. Imaging is repeated at 5 min intervals and computer-  ized curves of the counts remaining in the collecting system  are determined. This process of uptake and excretion by the  kidneys occurs in a fairly reproducible manner. After perfu-  sion and uptake/clearance of the agent from the renal paren-  chyma, excretion of the radiopharmaceutical should occur.  The normal time it takes for half the radiotracer to leave the  collecting system (T2) is less than 10 min. A normal reno-  gram excludes significant renal obstruction. Studies with TY  between 10 and 20 min are considered equivocal and those  with TY greater than 20 min are indicative of obstruction.'^  Diuretic renography therefore provides objective data with  which to diagnose and follow patients after surgical repair.  The lack of anatomic detail, however, leads most surgeons to  combine this test with further imaging.   Currently, the most common diagnostic study is CT  because of its rapidity, ubiquity, and ability to diagnose a mul-  titude of ailments in the patient presenting with flank pain. CT  provides excellent anatomic detail with respect to renal paren-  chyma, degree of hydronephrosis, renal calculi, and level of  obstruction, and is capable of identifying crossing vessels.  Functional assessment is limited but subjective evaluation  owing to delay in contrast enhancement of renal parenchyma  and excretion of contrast dye is useful. Interestingly, a recent  analysis of CT-measured renal parenchyma area accurately  predicted and correlated with renal function assessment of  nuclear scintigraphy." These findings notwithstanding, CT  is still not the standard method of functional assessment.   Because of the limited functional assessment, CT imag-  ing does not play a routine role in the postoperative follow-  up of patients after robotic pyeloplasty.   Retrograde pyelography is a beneficial study for assessing  degree of hydronephrosis, level of ureteral obstruction, and  presence of additional ureteral anatomic abnormalities.  Retrograde studies generally require an additional visit to the  operating room if used as part of preoperative diagnostic  evaluation and therefore is often performed only at the time  of planned surgical repair. If patients require preoperative  stenting due to pain or infection, a retrograde pyelogram  should be performed. Antegrade pyelography is also uncom-  mon as a preoperative diagnostic study because it requires  placement of a percutaneous nephrostomy tube; however, if  placed, anatomic details similar to retrograde pyelography  can be obtained. Additionally, if concern remains regarding  the significance of hydronephrosis and the actual presence of  obstruction, a Whitaker test can be performed via the percu-  taneous nephrostomy tube. This is a renal collecting    system/ureteral perfusion test at a set flow rate to determine  if functional obstruction is present. Owing to its invasive  nature, it is rarely used except in equivocal cases.   A thorough review of the available clinical data is para-  mount prior to surgical intervention. Once the proper diagno-  sis is made, it is the role of the urologist to educate the patient  on the surgical risks, benefits, and alternatives.    The most common approach to robotic pyeloplasty is trans-  peritoneal. This technique is most familiar to minimally inva-  sive surgeons and provides the greatest working space for the  surgeon. The familiarity with anatomy and increased range  of motion make this approach easier to learn and therefore  more rapidly disseminated. Alternatively, a retroperitoneal  approach has been described and successful outcomes have  been demonstrated.” Though limited by a smaller working  space and less familiar anatomic landmarks, the potential  advantages of containment of potential urinoma and applica-  tion to patients with prior abdominal surgery make the retro-  peritoneal approach a fertile area of investigation. Currently,  however, the standard technique for robotic pyeloplasty  remains as transperitoneal access to the renal hilum.   Variations exist regarding ureteral stent placement.  Ureteral stents are placed prior to arrival in the operating  room (OR), retrograde in the OR just prior to positioning for  pyeloplasty, or antegrade during reconstruction of the UPJ.  Some authors advocate retrograde placement at the time of  the procedure combined with a retrograde pyelogram, which  permits assessment of length and level of anatomic obstruc-  tion.? Additionally, the retrograde pyelogram will occasion-  ally demonstrate a distal ureteral obstruction, thereby altering  surgical management. Others prefer antegrade stent place-  ment during the time of reconstruction?! Arguments for  antegrade stent placement include improved visualization of  the renal pelvis and site of obstruction, because the pelvis is  not decompressed, and the ability to start in the lateral decu-  bitus position as opposed to lithotomy for cystoscopy fol-  lowed by repositioning. The decision when to place a ureteral  stent remains a matter of surgical preference.    On arrival to the operating room, the patient has sequential  compressive devices placed on the lower extremities and  general anesthesia is induced. If the patient is to have a cys-  toscopy, retrograde pyelogram, and stent placement prior to  robotic pyeloplasty, the patient is placed in standard    lithotomy position. Routine cystoscopy and stent placement  is performed followed by Foley catheterization of the urinary  bladder. The anesthesia team places an orogastric tube for  decompression of the stomach.   Once the stent has been placed, or if it is to be placed  antegrade during reconstruction, the patient is placed on the  operating table in the lateral decubitus position with the sur-  gical side up. The decubitus positioning for robotic pyelo-  plasty has been described as ranging from 45 to 70? flank  position. Patients are secured to the table and supported with  a variety of equipment ranging from egg-crates to gel pads to  a bean bag depending upon institutional and physician pref-  erence. Typically, the umbilicus is placed at the level of the  bed's break point. The bed is then gently flexed to increase  the working space between the iliac crest and the ribs.   The equipment is placed as appropriate for the OR being  utilized. Generally, the anesthesia cart is located cephalad to  the patient's bed, the sterile surgical table is placed cephalad  and posterior to the bedside assistant, and the robotic console  is located where appropriate with respect to room space.  Importantly, the robot is located cephalad and lateral to the  surgical side. The robot can then be brought in at a 60? angle  over the posterior aspect of the patient, permitting an optimal  approach to the upper urinary tract. The assistant is stationed  anterior to the abdominal wall at the level of the lowest assis-  tant port. The surgical tech/scrub nurse is located along side  but posterior to the surgical assistant.    After the patient is properly positioned, adequately padded,  and secured, the patient is prepped and draped in a standard  sterile manner. The surgical field extends from the level of  the xyphoid to the anterior superior iliac spine. Laterally, the  field extends to the mid-axillary line for the transperitoneal  approach.   The initial incision is a semicircular peri-umbilical inci-  sion on the ipsilateral side of the surgical site. This is then  carried down to the level of the rectus fascia. A Veress needle  is inserted and the peritoneal cavity is insufflated. Securing  the rectus fascia with a suture or clamp for counter traction  can be beneficial at the time of Veress insertion. Once the  pneumoperitoneum is properly established, a 12-mm trocar  is placed through the abdominal wall. The camera can now  be inserted and the peritoneal cavity inspected. Prior to the  placement of additional ports, the abdomen should be evalu-  ated for injuries, adhesions, as well as the presence of addi-  tional intra-abdominal pathology.   The two robotic arms can now be inserted. Generally, the  goal is to triangulate the renal pelvis while maintaining ade-  quate separation to avoid the arms from hindering each    other. The camera is utilized for visualization of the reus-  able 8 mm robotic trocars during their insertion. The  cephalad arm is located 8 cm superior to the umbilicus in  the midline. The caudal arm is placed 8 cm away from the  umbilical port in line toward the ipsilateral anterior superior  iliac spine. Various locations and port sizes have been  described for the assistant port. Assistant ports have been  described in the midline both inferior and superior to the  umbilical camera port, subcostally in the ipsilateral anterior  axillay line, and in the contralateral lower abdominal  area? ^ The important point is to avoid obstruction of the  assistant's movement by the robotic arms. The assistant port  used has been reported as 5, 10, and 12 mm depending on  the surgeon's preference. The advantage of the larger tro-  cars is that they provide access for different sized instru-  ments and passage of suture material. This may lead to  decreased cosmesis and potentially require surgical closure.  For obese patients, the trocar sites are transposed laterally in  the direction of the surgical site.    Once the trocars have been safely placed and any intraab-  dominal adhesions that would limit progress of the proce-  dure have been mobilized, the dissection may begin. Some  authors prefer to perform the initial dissection of the colon  and renal pelvis with standard laparoscopic instruments and  utilize the robot for the reconstructive portion of the proce-  dure, while others prefer to perform the entire procedure  with robotic assistance.?'^ Both techniques are capable of  accomplishing the same task, thereby, making the decision  one of surgeon's preferences.   If the operative site is the right renal pelvis, the line of  Toldt is incised and the colon reflected medially from the  level of the hepatic flexure to the pelvis. The posterior peri-  toneal reflection is mobilized off the anterior surface of  Gerota's fascia, thereby exposing the renal hilum. It may be  necessary to perform a Kocher maneuver on the duodenum if  it is found to be overlying the operative site. Once the kidney  with the overlying Gerota's fascia is properly exposed, the  renal hilum and proximal ureter can be dissected out of the  peri-renal fat. Care is taken to not dissect the proximal ureter  to far distally or disturb an excessive amount of its adventitia  so as to not strip it of its blood supply.   For patients with left-sided UPJ obstruction, mobilization  of the line of Toldt from the level of the splenic flexure to the  sigmoid attachment is often necessary. Additionally, if the  site of obstruction is medially displaced, it may be necessary  to mobilize the spleen, including the splenophrenic and sple-  norenal ligaments. Alternatively, if the patient is thin and the  UPJ is laterally located, a trans-mesenteric approach has    been used. The course of the gonadal vein on the left can be  used as a guide to identification of the ureter and subse-  quently the renal pelvis.   As the dissection of the UPJ proceeds, either from the  renal pelvis toward the ureter or vice versa, care should be  taken to identify potential crossing vessels. The use of preop-  erative imaging should have indicated the presence of such  structures but will occasionally miss smaller vessels.  Extensive dissection and manipulation of the ureter should  be avoided. Grasping of the ureter should be kept to a mini-  mum or completely avoided to prevent crush injuries due to  the lack of tactile feedback when using the robot.   After exposure of the UPJ and the obstruction, some  authors advocate the use of a “hitch” stitch. This is either  passed through the abdominal wall or inserted through the  assistant's trocar. This suture is passed through the renal pel-  vis and the abdominal wall in an attempt to elevate the col-  lecting system off the retroperitoneum and out of any pooled  urine or blood.    Multiple techniques exist for performing the pyeloplasty  portion of the procedure, both dismembered and non-  dismembered — Anderson-Hynes dismembered pyeloplasty,  Fengerplasty, Y-V plasty, Heine-Mikulicz, etc... The authors  prefer the Anderson-Hynes technique of dismembered pyelo-  plasty owing to its versatility. It is applicable for the removal  of functionally or anatomically abnormal segments, as well  as transposition of the UPJ in the presence of crossing ves-  sels. It is the procedure of choice for a patient with a large  renal pelvis or a high insertion due to the need for “tailoring”  of the UPJ.   The ureter is transected caudal to the obstruction. Care is  taken to avoid damaging any previously placed ureteral stent.  The ureter is mobilized distally as necessary to allow for  spatulation and a tension-free anastamosis. If the ureteral  stent was placed earlier, it is brought out of the renal pelvis.  Close attention to anatomic landmarks or placement of a  marking stitch are important to prevent malrotation of the  ureter. The ureter is spatulated laterally, for a distance of 1  cm, using standard robotic scissors. The ureter must be mobi-  lized anteriorly if a crossing vessel is identified.   Once the ureter has been prepared, the renal pelvis is  incised on the medial aspect, cephalad to the blockage. This  incision is carried obliquely in a caudal, lateral direction  until the UPJ is free from the pelvis. The specimen is  retrieved through the assistant's trocar and sent to pathology.  If a crossing vessel is present, the renal pelvis can be trans-  posed anteriorly. The pelvis must be carefully freed of all its  attachments to the crossing vessel and retroperitoneum to    minimize tension and permit proper anterior translocation.  If the renal pelvis is redundant, additional tissue can be  resected to allow for optimal drainage through the new  anastamosis.   The posterior aspect of the anastamosis is performed first.  Either an interrupted or continuous closure can be performed.  An absorbable 4—0 monofilament suture is employed for the  anastamosis. The most caudal portion of the renal pelvis is  sutured to the most caudal aspect of the ureteral spatulation  with the knot located outside the anastamosis. Closure pro-  ceeds medially and cephalad until the posterior wall is closed.  If the ureteral stent was not placed prior to dissection, it can  be placed at this point. A guide wire is inserted through the  assistant's trocar or alternatively through a small stab inci-  sion in the abdominal wall. The wire is passed into the ureter  and down into the urinary bladder under direct vision. The  stent is advanced over the guide wire until the proximal coil  is located at the level of the renal pelvis and the wire is then  removed. The proximal coil is placed into the renal pelvis.  The anterior portion of the anastomosis can now be com-  pleted. If the renal pelvis requires further closure, further  suturing can be performed to completely close the superior  aspect of the incision.   Upon completion of the anastomosis, the intraabdominal  pressure is decreased and the operative field is inspected for  adequate hemostasis. To ensure a water-tight anastamosis, a  drain is placed through the inferior robotic trocar prior to  de-docking of the robot.    Some authors advocate reattachment of the colon to the lateral  side-wall to retroperitonealize the kidney and ureter.” Most  surgeons, however, do not bother with this step as no data  exists regarding outcomes from this technique. All trocars  are removed under direct vision to ensure adequate hemosta-  sis at the trocar sites. The 12 mm trocar sites are closed with  an absorbable suture at the fascial level. Skin is then closed  with subcuticular suture and/or skin adhesive. Sterile dress-  ings are placed and the patient can now be repositioned into  the supine position and awaken from anesthesia.    The patient is left with a Foley catheter and an indwelling  double J ureteral stent. The Foley catheter remains in place  for 24—48 h; however, if high output from the drain is encoun-  tered, it is advisable to continue urethral catheterization until  the drainage diminishes. If high drain output is identified, it    is beneficial to send the fluid for a creatinine level to assess  whether it is due to urinary leakage, peritoneal fluid, bowel  injury, or retained irrigation fluid (if used). Once the drain  output is less than 50 mL/8 h, it is generally safe to remove  the Foley catheter. The drain output should remain low at this  point. If the output increases significantly, it is advisable to  replace the Foley catheter and continue until the drainage  becomes scant. Patients can be discharged with a Foley cath-  eter and the drain in place and return to the office for removal,  once low output occurs.   Postoperative pain is managed with standard narcotics  and/or Ketorolac (renal function permitting). Patients should  be ambulating on the first postoperative day. A clear diet can  be started on postoperative day 1 and advanced as tolerated.  The average hospitalization is expected to range from 1 to 5  days.” The ureteral stent is removed at 3-6 weeks  postoperatively in the office setting. It is reasonable to follow  pain scales at the time of stent removal in an attempt to gen-  erate objective assessment of outcomes. The initial follow-  up imaging should be a diuretic renal scan or IVP at 3 months  postoperatively.    Gettman et al reported no intraoperative complications or  open conversions in their initial series of 9 patients." One  patient required an open re-exploration to repair a leaking  renal pelvis; however, all of the procedures were successful  on a subjective as well as radiographic analysis, although  follow-up was limited to 3 months.   In a series of 35 patients published in 2005, no open con-  versions or intraoperative complications were noted."!  Postoperative complications included a nephrectomy sec-  ondary to nonrecovery of renal function, and persistent pain  on the affected side. Another patient had an asymptomatic  stricture at the site of the anastomosis; this was successfully  treated with a laser incision of the stricture. Again follow up  was limited with a mean of 7.9 months.   Yee et al, retrospectively compared eight open and eight  robotic pyeloplasties in children and did not find any intraop-  erative complications in either group.*° Immediate postoper-  ative complications were limited to a prolonged ileus in one  patient who underwent robotic pyeloplasty; however, no  long-term complications were seen in the robotic arm with a  mean follow-up of 14.7 months. The open cohort had one  failure due to ureteropelvic stricture, which was diagnosed  approximately 6 months postoperatively.   A cohort of 31 patients who underwent robotic pyelo-  plasty with an average follow-up of 6 months was reported  by Weise et al?! The authors documented one febrile UTI  and one urine leak causing a postoperative ileus. Both    patients were managed nonoperatively and recovered with-  out incident. Of their robotic pyeloplasty series, five patients  continued to have partial obstruction as documented by early  postoperative renography, although none were symptomatic.  One patient had high-grade obstruction, and once imaging  confirmed no anatomical obstruction, a laparoscopic nephre-  ctomy was performed.   A series of 92 patients who underwent transperitoneal  robotic pyeloplasty were evaluated by Schwentner et al with  a mean follow-up of 39.1 months.” They reported no intra-  operative complications and all cases were completed with-  out open conversion. Three early complications were reported  including insufficient closure of the collecting system, post-  operative hemorrhage, and improper stent placement. There  were no long-term complications reported in just over 3  years of follow-up.   In the largest cohort to date, Mufarrij et al evaluated 140  patients from three medical centers." Their postoperative  complications at mean follow up of 29 months included: a  renal pelvis clot, stent migration, febrile UTI, delayed anas-  tomotic closure, and a ureteral stricture. Stent migration was  the most common major complication seen in their cohort.  Stent migration was suggested to be in part due to the  improper placement. They suggested using blue-dyed saline  and allowing it to reflux to confirm proper stent placement.  Ureteral strictures generally lead to a second procedure:  pyeloplasty or endopyelotomy. The strictures were attributed  to technical errors or ureteral ischemia. Minor complications  encountered were a febrile UTI and a delayed anastomotic  closure.   Unfortunately as seen earlier, outcomes data is limited in  caseload and follow-up time. A prospective analysis with  longer follow-up times is needed to properly assess the com-  plications associated with robotic pyeloplasty. However, ini-  tial data suggests this procedure offers the benefits of  minimally invasive surgery with complications similar in  nature and number to other laparoscopic procedures.    As previously stated, the goal of robotic pyeloplasty is to  emulate the high success rate of open pyeloplasty while  reproducing the benefits of minimally invasive surgery. The  complications, outlined previously, demonstrate that robotic  pyeloplasty is a safe procedure with a low number of compli-  cations. Once safety is documented, it is important for any  procedure to establish successful outcomes to gain accep-  tance and use. For robotic pyeloplasty, success can be  reported as peri-operative (i.e., length of hospitalization,  complications, etc...) and cure (i.e., asymptomatic and relief  of obstruction). Both sets of measures illustrate the high    Length of Mean Symptomatic Radiographic  hospitalization follow-up success  success   (days) (months)    success rate of this surgical approach to UPJ obstruction. As  illustrated in Table 3.1, operative time ranges from 108 to  300 min, with a low estimated blood loss. The length of hos-  pitalization is relatively short (1.1—5.5 days), averaging 2.5  days. The long-term outcomes of radiographic and symp-  tomatic success are comparable with the reported success  rates of both open and laparoscopic repair.” Symptomatic  success is slightly lower (92.4—100%) than radiographic suc-  cess (94-100%), both of which are the acceptable rates for  any surgical intervention.    The patient initially returns in 3-6 weeks time after robotic  pyeloplasty for cystoscopy and stent removal. Assessment of  abdominal wounds, postoperative pain, and a thorough  review of systems (i.e., return of bowel function, activity  level, etc...) should be included at this visit, as it is expected  that the patient has returned to his/her preoperative baseline.  All subsequent visits should evaluate the patient’s analog  pain scores, serum assessment of renal function, and  imaging.   Various authors advocate the use of renal ultrasound,  intravenous urography, and diuretic renography, alone or in  combination. The goal of follow-up imaging is to deter-  mine return of function and normal anatomy. Functional  assessment with diuretic renography or intravenous urog-  raphy is performed 3 months postoperatively and then  repeated at 6 and 12 months. The authors find it helpful to  alternate between renal scan and IVP at each subsequent  visit in an attempt to overcome the inherent limitations of  each study. Others have recommended diuretic renogram at  3, 6, and 12 months followed by ultrasound or renogram  annually thereafter. Adequate guidelines on the length of  follow-up do not exist; however, evidence continues to  mount indicating that long-term follow-up is imperative in  these patients.**    Nephrolithiasis is not uncommonly associated with UPJ  obstruction; this may be due to a combination of urinary sta-  sis and underlying metabolic or dietary predilection for stone  formation. The potential presence of stones should be con-  sidered preoperatively and investigated during routine work-  up with diagnostic imaging. If identified, stones can be  addressed at the time of pyeloplasty. Removal of renal cal-  culi at the time of robotic pyeloplasty has been documented  in a number of series.” Insertion of a flexible cystonephro-  scope through one of the robotic trocars sites and into the  renal pelvis is performed. Once in the collecting system, all  calyces can be readily inspected and graspers or baskets are  utilized to grasp and remove the calculi. Atug et al reported  irrigating smaller fragments into the peritoneal cavity and  using the assistant’s suction to remove these stones.”    Limited data exists regarding the application and outcome of  robotic pyeloplasty in horseshoe kidneys. To date seven  patients have been described as successfully having undergone  robotic pyeloplasty.?^?/?9^' Notably, Pe et al reported suc-  cessful repair following failed endopyelotomy.” All authors  report successful outcomes with up to 1 year follow-up.    Robotic pyeloplasty is a safe and effective treatment option  for patients who present with signs and symptoms of UPJ  obstruction. Proper documentation of patients’ preoperative    status — symptomatically, anatomically, functionally — is  imperative to optimize outcomes. As techniques and equip-  ment continue to advance, it is likely to become the “gold  standard" treatment of UPJ obstruction.    . Kletscher BA, Segura JW, LeRoy AJ, et al Percutaneous antegrade    . Moon DA, El-Shazly MA, Chang CM, et al Laparoscopic pyelo-    . Zhang DH, Yu DM, Ding GQ, et al Experience with transperitoneal    . Inagaki T, Rha KH, Ong AM, et al Laparoscopic pyeloplasty: cur-   Sung GT, Gill IS, Hsu TH. Robotic-assisted laparoscopic pyelo-  plasty: a pilot study. Urology. 1999;53:1099   Mitterberger M, Pinggera GM, Neururer R, et al Comparison of  contrast-enhanced color Doppler imaging (CDI), computed tomog-  raphy (CT), and magnetic resonance imaging (MRI) for the detec-  tion of crossing vessels in patients with ureteropelvic junction  obstruction (UPJO). Eur Urol. 2008;53:1254   Lin L, Bagley DH, Liu JB. Role of endoluminal sonography in  evaluation of obstruction of the ureteropelvic junction. AJR Am J  Roentgenol. 2008;191:1250   Wang W, LeRoy AJ, McKusick MA, et al Detection of crossing  vessels as the cause of ureteropelvic junction obstruction: the role  of antegrade pyelography prior to endopyelotomy. J Vasc Interv  Radiol. 2004;15:1435   Goldfarb CR, Srivastava NC, Grotas AB, et al Radionuclide imag-  ing in urology. Urol Clin North Am. 2006;33:319   Roarke MC, Sandler CM. Provocative imaging. Diuretic renogra-  phy. Urol Clin North Am. 1998;25:227   Feder MT, Blitstein J, Mason B, et al Predicting differential renal  function using computerized tomography measurements of renal  parenchymal area. J Urol. 2008;180:2110   Whitaker RH. Methods of assessing obstruction in dilated ureters.  Br J Urol. 1973;45:15    Kaouk JH, Hafron J, Parekattil S, et al Is retroperitoneal approach  feasible for robotic dismembered pyeloplasty: initial experience  and long-term results. J Endourol. 2008;22:2153   Canes D, Berger A, Gettman MT, et al Minimally invasive  approaches to ureteropelvic junction obstruction. Urol Clin North  Am. 2008;35:425   Palese MA, Stifelman MD, Munver R, et al Robot-assisted laparo-  scopic dismembered pyeloplasty: a combined experience. J Endourol.  2005;19:382   Schwentner C, Pelzer A, Neururer R, et al Robotic Anderson-Hynes  pyeloplasty: 5-year experience of one centre. BJU Int. 2007;  100:880   Gettman MT, Neururer R, Bartsch G, et al Anderson-Hynes dis-  membered pyeloplasty performed using the da Vinci robotic sys-  tem. Urology. 2002;60:509   Gettman MT, Peschel R, Neururer R, et al A comparison of laparo-  scopic pyeloplasty performed with the daVinci robotic system ver-  sus standard laparoscopic techniques: initial clinical results. Eur  Urol. 2002;42:453   Mendez-Torres F, Woods M, Thomas R. Technical modifications  for robot-assisted laparoscopic pyeloplasty. J Endourol. 2005;19:  393   Mufarrij PW, Woods M, Shah OD, et al Robotic dismembered  pyeloplasty: a 6-year, multi-institutional experience. J Urol. 2008;  180:1391   Bentas W, Wolfram M, Brautigam R, et al Da Vinci robot assisted  Anderson-Hynes dismembered pyeloplasty: technique and | year  follow-up. World J Urol. 2003;21:133   Siddiq FM, Leveillee RJ, Villicana P, et al Computer-assisted lap-  aroscopic pyeloplasty: University of Miami experience with the  daVinci Surgical System. J Endourol. 2005;19:387   Yee DS, Shanberg AM, Duel BP, et al Initial comparison of robotic-  assisted laparoscopic versus open pyeloplasty in children. Urology.  2006;67:599   Weise ES, Winfield HN. Robotic computer-assisted pyeloplasty ver-  sus conventional laparoscopic pyeloplasty. J Endourol. 2006;20:813  Bauer JJ, Bishoff JT, Moore RG, et al Laparoscopic versus open  pyeloplasty: assessment of objective and subjective outcome.  J Urol. 1999;162:692   Jarrett TW, Chan DY, Charambura TC, et al Laparoscopic pyelo-  plasty: the first 100 cases. J Urol. 2002;167:1253   Yanke BV, Lallas CD, Pagnani C, et al The minimally invasive  treatment of ureteropelvic junction obstruction: a review of our  experience during the last decade. J Urol. 2008;180:1397   Atug F, Castle EP, Burgess SV, et al Concomitant management of  renal calculi and pelvi-ureteric junction obstruction with robotic  laparoscopic surgery. BJU Int. 2005;96:1365   Chammas M Jr, Feuillu B, Coissard A, et al Laparoscopic robotic-  assisted management of pelvi-ureteric junction obstruction in  patients with horseshoe kidneys: technique and 1-year follow-up.  BJU Int. 2006;97:579   Pe ML, Sterious SN, Liu JB, et al Robotic dismembered pyeloplasty  in a horseshoe kidney after failed endopyelotomy. JSLS. 2008;  12:210    Laparoscopy came into existence in Urology the first time  when Kelling introduced a cystoscope into the abdomen of a  living dog via a trocar placed through the abdominal wall in  1901.' Since that time, laparoscopic surgical techniques have  been honed to allow urologic surgeons to perform the entire  gamut of urologic procedures in a minimally invasive man-  ner. With new advances in robotic technologies, the surgical  repertoire has grown to include an ever-expanding array of  complex extirpative and reconstructive procedures. While  partial nephrectomy and, to a lesser extent, laparoscopic par-  tial nephrectomy have been accepted as the gold standard  for the treatment of small incidentally found solid renal  tumors, there is only limited literature available about the  role of robotic-assisted laparoscopic partial nephrectomy  (RALPN).*° This is an emerging procedure, which has yet to  find its role in the mainstream of urologic practice; however,  it does offer several clear and intriguing advantages over cur-  rent technology when placed in the correct hands.   Between the years 1975 and 1995, the incidence of renal  cancers rose between 2 and 446 each year owing in large part  to a significant increase in the use of cross-sectional imag-  ing." The most striking increase was seen in incidentally  found, localized tumors potentially amenable to surgical  cure.” Currently, this group represents between 48 and 66%  of all renal masses in contemporary series.'* Despite the rela-  tively new development of renal ablative techniques for the  treatment of such tumors, the mainstay of treatment remains  surgical excision.   Open partial nephrectomy became the standard of care for  the treatment of T1 renal tumors, as the cancer control was  shown to be equivalent to radical nephrectomy.'**° As it  became clear that up to 20-30% of solid enhancing renal  masses in contemporary series represent benign pathol-  ogy,’ a major push to minimize morbidity through mini-  mally invasive nephron sparing surgery has advanced to the  forefront. To date, the world's literature on laparoscopic par-  tial nephrectomy includes well over 2,000 patients. Minimally  invasive nephron sparing surgery mimics the oncologic prin-  ciples of open nephron sparing surgery.^^ These include    careful identification and excision of the tumor under direct  vision with attempts at minimizing the required warm isch-  emia time (WIT) and intraoperative confirmation of negative  surgical margins.   Surgical robotics offers several distinct benefits over the  abilities available with conventional laparoscopy in perform-  ing complex urologic procedures. The prototype for reproduc-  ing an open procedure using minimally invasive techniques is  the robotic-assisted laparoscopic radical prostatectomy.”  Though more robotic systems exist, and are currently being  developed, the vast majority of the experience in the pub-  lished literature has been performed with the DaVinci system  (Intuitive Surgical, Sunnyvale, CA). This surgical system  includes a surgical console, in which the surgeon sits to con-  trol the slave surgical robotic cart through a set of hand and  foot controls. A slave robotic cart stands immediately at the  side of the patient and holds a 3-dimensional camera and artic-  ulating working instruments, which are passed through the  abdominal wall via specially designed trocars. For purposes of  this chapter, the remainder of the discussion will focus specifi-  cally on this surgical system except where otherwise stated.   The DaVinci system provides a magnified 3-dimensional  view of the entire surgical field under the direct control of the  surgeon. This provides a very stable and clear view without  the need for constant communication with the assistant regard-  ing camera distance and position. The articulating instruments  provide 6 degrees of freedom via the use of an endowrist  located near the end of the instrument. The motion of these  instruments can be both scaled down as well as set to provide  tremor reduction allowing for very precise dissection and  suturing capabilities. The current system does not, however,  provide for any tactile feedback to the surgeon. With experi-  ence, most surgeons are quickly able to compensate for this by  the use of subtle visual cues allowed by the high-level optics.    Indications for robotic-assisted minimally invasive nephron  sparing surgery are essentially identical to those seen in the  conventional laparoscopic experience. With experience, the    added benefits of improved visualization, tissue handling, and  suturing abilities, the robotic platform may allow a surgeon  with less conventional laparoscopic training and experience  to perform more complex resections in a minimally invasive  fashion. Special consideration to tumor location, size, depth  of invasion into the renal parenchyma, and proximity to the  renal hilum must be taken into account. These must also be  balanced with the surgeon's skill set to come up with an opti-  mal approach to maintain oncologic principles, while mini-  mizing morbidity from access to the site. Minimally invasive  nephron sparing approaches are particularly applicable to  patients with solitary kidneys, preexisting chronic kidney  disease, multiple or bilateral tumors, or those with a genetic  predisposition for the development of multiple renal tumors  such as von Hippel-Lindau disease, tuberous sclerosis syn-  drome, or hereditary papillary renal cell carcinoma (RCC).    Space is at a premium in most surgical suites. This space  constraint is exaggerated when a relatively large amount of  space is required for storage, movement, and function of the  robotic surgical cart. The room is set up to allow for maneu-  vering of the robotic surgical cart and ease of passage of  instruments from the scrub nurse/tech to the surgical assis-  tant, while allowing the anesthesia team room to manipulate  the airway and access sites as needed as shown in Fig. 4.1.  Monitors should be placed at an ergonomically comfortable  height and position to allow all members of the surgical team  (assistant, scrub tech, anesthesia team) to closely monitor the  progression of the procedure to insure prompt availability of  all required instruments and interventions during critical  portions of the case.    A metastatic work-up, creatinine clearance determination,  and differential function testing should be completed prior to  considering nephron sparing surgery. Informed consent  regarding the risks, benefits, expectations, and alternatives  during the preoperative, intraoperative, and postoperative  periods is obtained prior to initiating any surgical procedure.  A bowel preparation is administered to patients the day  before surgery, and NPO status is maintained during the day  of surgery. Necessary medications are allowed according to  the guidelines set forth by the department of Anesthesia at  our institution.    The patient will be positioned in such a way that access to  the endotracheal tube and vascular access sites may be lim-  ited to during surgery. For this reason, it is imperative that all  access be secured prior to positioning the patient. Dissection  during the case will be in proximity to the great vessels and,  as such, there exists the potential for significant blood loss  should there be an injury to these or nearby structures. For  this reason, it is recommended that a current specimen for  type and cross and two units of packed red blood should be  available and at least two large bore intravenous accesses are  obtained prior to positioning. Additional vascular access in  the form of arterial lines and central venous access/monitors  should be placed at the discretion of the anesthesiologist.    Pneumatic anti-embolism stockings are placed immediately  upon entering the operative suite and should be functioning  well before and during the induction of anesthesia. A first-  generation cephalosporin is typically given as prophylaxis  against surgical site infection within 60 min of the time of  incision. Repeat doses are administered at 4 h intervals dur-  ing the duration of the case.    Routine cystoscopic open-ended ureteral catheter placement  is performed prior to positioning in the flank position in all  cases of laparoscopic nephrectomy. The patient is placed in  modified lithotomy position and is padded appropriately. A  glide wire is used to obtain access to the ureteral orifice to  prevent ureteral trauma during passage of the ureteral stent.  This stent allows for retrograde injection of dilute methylene  blue/saline mixture following excision and initial parenchy-  mal closure to look for sites of entry into the renal collecting  system. Though small, peripheral, exophytic tumors may be  excised without this step, it is felt that the minimal extra  effort required for ureteral catheter placement allows for the  most conservative management when tumors require more  extensive resections than initially suspected. As such, this  has become the standard at our institution.   The patient is then repositioned into the 45-degree flank  position as shown in Fig. 4.2. The bed is flexed to allow for  optimal working space during the transperitoneal approach. An  axillary roll is placed and all pressure points are padded, taking  care to protect the legs, knees, ankles, and hip well before  securing the patient to the bed. The head and arms should be    Fig. 4.1 Room equipment  configuration during robotic-  assisted laparoscopic partial  nephrectomy with the (a) 3-arm  and (b) 4-arm DaVinci (Intuitive  Surgical, Sunnyvale, CA) robotic  surgical systems    placed in a neutral position and secured in place after the  anesthesia team has confirmed good function of all vascular  access sites and secured the airway following repositioning.   Access is then gained into the peritoneal cavity to create a  pneumoperitoneum. If the Varress needle technique is used  to obtain access, confirmatory tests (i.e., the “drop test") to    insure intraperitoneal placement must be performed prior to  insufflation with carbon dioxide gas. The initial port is  placed carefully after creation of the pneumoperitoneum to a  level of 20 cm of water to avoid inadvertent visceral injury.  This level is then decreased to 15 cm of water after all ports  have been placed and is maintained for the remainder of the    Fig. 4.2 Patient position and port placement for performing robotic-  assisted laparoscopic partial nephrectomy on both the right (a, c) and  left (b, d) sides using the 3-arm (a, b) and 4-arm (c, d) DaVinci (Intuitive    case. Additional ports are placed under direct vision. It is  important to maintain adequate distance between ports to  allow for triangulation of the instruments. This will allow  maximum range of motion for the robotic arms during dis-  section and reconstructive portions of the case. In general,  the three primary robotic ports are placed into a diamond  configuration with the pathology, in this case, the renal hilum  and/or tumor, opposite the camera and the working arms  located at the apices of the diamond on either side as shown  in Fig. 4.2.   Alternatively, some authors have supported the use of a  more lateral placement of the camera port and use of a  30-degree down lens with more medial placement of the  working arms stating that it gave better visualization of the  hilum while obviating the need for colonic retraction.? This  modification may be particularly helpful for excising more  posteriorly located tumors. A “port-in-port” technique has  been described in which the 8 mm robotic working ports are  placed through conventional laparoscopic 12 mm ports  enabling seamless transition from the laparoscopic to the  robotic portions of the case and back again as necessary."   When using a fourth assistant arm, the remaining robotic  port is placed laterally and inferiorly to allow for retraction  and stabilization of the kidney/tumor during excision and  reconstruction. An additional 12 mm port is placed between    Surgical) robotic surgical systems. C camera port; S satinsky port; A  assistant port; L liver retractor port    the camera port and the more inferior primary robotic work-  ing port to allow for passage of needles, suction, and the use  of vascular bulldog clamps if desired. En bloc clamping of  the artery and vein within the vascular pedicle can be per-  formed with a Satinsky clamp placed through a lower mid-  line 12 mm port. In thin patients, we have found that this  clamp can be placed directly through the abdominal wall  through a small skin incision without the need for an addi-  tional port that requires fascial closure. It must be placed in a  location that it will not allow external interaction with the  lower-most robotic arm while clamped in place on the renal  hilum. On the right side, a 5 mm port is placed in the sub-  xiphoid region for retraction of the liver with a locking clamp  secured to the inner aspect diaphragm laterally.    The colon and mesocolon are mobilized completely from the  anteromedial aspect of the kidney as seen in Fig. 4.3a. It is  important to find the plane between this leaflet of mesentery  and the anterior surface of Gerota's fascia, as it will allow for  an easy identification of the hilar structures. Avoidance of  the use of diathermy in this area can help to avoid inadvertent    Fig. 4.3 Surgical steps of robotic-assisted laparoscopic partial nephrectomy including mobilization of the colon (a), intraoperative ultrasono-  graphic examination to identify and score the boundaries of the tumor (b), prior to hilar clamping (c), and excision of the tumor (d)    bowel injury. Rotating the operative table away from the  robotic cart helps to allow the colon to fall medially away  from the hilum maximizing exposure.” On the left side, care  must be taken not to injure the spleen or the tail of the pan-  creas during mobilization. On the right side, the duodenum  must be carefully Kockerized off of the anterior aspect of the  hilum. Again, the use of sharp dissection without electrocau-  tery should be emphasized in this region as duodenal injuries  can be caused easily and may have devastating results.    The kidney is typically completely mobilized to facilitate  achieving the correct orientation for safe and precise exci-  sion of the tumor and renorrhaphy after excision. Mobilization  of the medial, inferior, and superior aspects of the kidney  should be performed first to allow access to the hilar struc-  tures. The lateral attachments are best left intact at this point  in the dissection to allow for hilar exposure to be maintained    without the need for further retractors. Mobilization of the  kidney can be performed in two distinct planes; outside of  Gerota’s fascia or directly on the capsule of the kidney  beneath Gerota’s fat. Mobilization within the Gerota’s fat  may facilitate nephropexy at the end of the case by allowing  simple reapproximation of the perinephric fat, thus securing  the kidney back in its original anatomic location.    The ureter is identified near the lower pole of the kidney on  the anterior aspect of the psoas muscle. It is then retracted  gently anterolaterally and followed toward the level of the  hilum. At this juncture, any lower pole accessory renal arter-  ies will be encountered and should be noted and carefully  spared. The gonadal vein is likely to be seen at this time and  can be allowed, in most cases, to simply fall medially. On the  left side, the gonadal vein enters the renal vein and may need  to be taken to allow safe en bloc clamping of the renal vein    and artery. This should be done in such a manner that if, in an  emergent situation, the hilum is needed to be stapled to pre-  vent massive blood loss; it could be performed safely while  avoiding any surgical clips interfering with the stapling  device. If en bloc clamping is not feasible, or if additional  renal arteries are encountered, the renal vascular pedicle can  be controlled with laparoscopic bulldogs as well. It is impor-  tant to have the entire hilum prepared for clamping prior to  planning the tumor excision. Doses of mannitol and furo-  semide are given approximately 30 min prior to clamping  and immediately prior to unclamping the hilum.    Strategic defatting of the kidney should be performed to  maintain fat directly over the tumor for the purpose of cancer  control as well as to allow manipulation of the tumor without  compromising the integrity of the tumor. Maintaining fat  over uninvolved portions can be helpful as well, as this can  be used as a handle for manipulating and securing the kidney  in a stable position during tumor excision and renorrhaphy.  During the defatting of the kidney, the kidney would likely  be rotated into several different orientations. During this pro-  cess, it is important to be cognizant of the relationships of the  hilar structures to the surface of the kidney. The ureter can be  easily inadvertently injured near the lower pole during these  maneuvers if care is not taken to identify it and spare it from  the area of dissection. Likewise, the renal artery will be  encountered posteriorly with aggressive mobilization after  the kidney is flipped anteriorly.    Intraoperative ultrasonographic examination is performed  routinely through the 12 mm assistant port. This allows for  accurate identification of the size, location, and depth of  invasion of the tumor. It also allows for an assessment of the  remainder of the kidney to insure that multifocal disease  does not exist. Under ultrasound guidance, the borders of the  resection are scored into the renal capsule with the electro-  cautery as shown in Fig. 4.3b.    The robotic cart is docked after the above steps have been  performed using conventional laparoscopic techniques. This  allows the surgeon to take advantage of the flexibility of    conventional laparoscopy for mobilization and orientation  of the kidney and tumor, while still taking advantage of the  precision and dexterity of the robotic assistance. The robotic  cart is docked over the ipsilateral shoulder/flank as depicted  in Fig. 4.1. It is important to insure that there is ample room  between the arms of the robot. On the first generation  DaVinci system, the elbows of the working arms should be  allowed to be spread as far to the sides as possible to provide  the largest range of motion. Positioning with the newer  4-arm DaVinci-S robotic system, it is imperative that the  numbers on the robotic working arms face directly toward  the surgical field and that the camera arm is positioned  within the "sweet spot" as indicated on the elbow joint.  When using the fourth arm for retraction, it is also helpful to  position the camera arms elbow to the side opposite the  fourth arm to allow for maximum freedom of motion of all  arms.    With the primary surgeon seated at the console, the assistant  carefully applies the Satinsky clamp to the renal pedicle as  shown in Fig. 4.3c. Prior to this crucial step, it is imperative  that the surgical team have a clear plan and vision for exci-  sion and renorrhaphy specific to the tumor involved. Care  must be taken not to avulse any posterior lumber veins or  other small branches from the main renal vein during this  maneuver. For this reason, the renal hilum should be skele-  tonized enough to allow safe passage of the clamp under  direct vision. It cannot be overemphasized that the Satinsky  clamp should not interact with the caudal-most robotic arm  while clamped to the renal hilum. Because this area will  likely be out of the surgeon's view during excision of the  tumor, the assistant must remain cognizant of this potential  interaction and monitor the proximity of the two pieces of  equipment as significant injury could potentially result.  During this time of warm ischemia, the entire surgical team  must remain focused on the task at hand. In an attempt to  minimize ischemic injury, a renal cooling protocol was  described during RALPN by Gettman et al, similar to that  used at their institution during conventional laparoscopic  partial nephrectomy.*    The tumor is excised sharply from the underlying paren-  chyma using the previously scored lines in the renal capsule  as a guide as can be seen in Fig. 4.3d. During this excision  process, the assistant should remain vigilant and provide    expert but judicious and unobtrusive suctioning to maintain a  bloodless field. Though during conventional laparoscopy it  has become our practice to apply Hem-o-lok clips (Weck  Closure Systems, Research Triangle Park, NC) to distinct  vessels during tumor excision within the bed of resection,  this is often more difficult and time-consuming with the  robotic techniques and this step is eliminated. As an alterna-  tive, the robotic Maryland bipolar electrocautery device can  be used to control these vessels during excision.^" After com-  plete excision, the specimen is placed to the side of the surgi-  cal field and renorrhaphy is performed immediately. The  specimen will be trapped in a laparoscopic specimen bag and  removed via an extended port site incision for frozen section  margin analysis immediately following renorrhaphy.    The initial closure of the renal defect is performed in a run-  ning fashion with polyglycolic acid absorbable braided  suture as in Fig. 4.4b. The choice of needle size depends on  the size of the defect to be closed, but most typically a CT-1  or CT-X is chosen. The aim of the initial closure is to control  transected vessels in the sinus fat with direct ligation and to  close the collecting system. The collecting system is identi-  fied and the edges of any calyceal/pelvis violation are care-  fully approximated. Since the robotic surgical system lacks  tactile feedback, suture breakage can be expected early in the  surgeon's robotic experience and care must be taken to avoid  suture cut-through within the parenchyma. It should also be  pointed out that unlike both open and conventional laparo-  scopic needle drivers, the needle drivers for the DaVinci sys-  tem do not have locking mechanisms when activated. With  very little experience, most surgeons make the transition  without a significant learning curve. Retrograde injection of  blue-dyed saline is then performed through the previously  placed open-ended ureteral catheter to confirm a water-tight  closure and to identify any areas that need further suturing as  seen in Fig. 4.4a.   At this point, the hilar clamp is carefully removed by the  surgical assistant as part of an “early unclamping" protocol”  during which the defect is not closed in its entirety prior to  clamp removal in an attempt to decrease WIT and to allow  for the identification of vessels, which might otherwise bleed  without further ligation prior to completely closing the defect.  This technique was developed in response to criticism that  the WITs in laparoscopic partial nephrectomy series is ^10  longer than in comparable open series.” If arterial bleeding is  identified after clamp removal, further sutures are placed,  thus providing definitive surgical hemostasis.*! The remain-  der of the defect is then closed with or without the use of an  oxidized cellulose bolster at the discretion of the surgeon. If    Fig. 4.4 Renorrhaphy technique including identification of collecting  system violation via retrograde injection of blue-dyed saline through a  previously placed open-ended ureteral catheter (a), running parenchy-  mal suture to control transected vessels in the defect bed (b), and place-  ment of an oxidized cellulose bolster (c)    a bolster is chosen, it is sized to fit well within the edges of  the defect. It should not be allowed to lie directly against the  ureteral wall within the defect, as it may cause ureteral  obstruction in this position (Fig. 4.4c). Once surgical hemo-  stasis is assured, hemostatic agents are applied to the defect  in combination with an oxidized cellulose covering.  Because the kidney has been completely mobilized for  tumor identification, excision, and reconstruction, the kidney  can theoretically torse about its hilar axis. For this reason, a   of the kidney to the lateral body wall. A closed suction drain To date, there have been eight series reported in the litera-  is then placed in the paracolic gutter and is secured to the ture detailing the experience with RALPN representing over  skin. All 12 mm port sites are then closed at the fascial level — 100 patients.^? The details of these are shown in Table 4.1.  and all ports are removed under direct vision. Complications following RALPN mimic those seen in the    Study  Variable Gettman Phillips Caruso et al Kaul et al Rogers et al Deane Aron et al Bhayani  et al et al et al et al  Type of study Case series Case series Case-control Case series Case series Case- Matched- Case Series  (technique control pair  report)  No. RALPN 13 12 10 10 8 (14 tumors) 11 12 B5  Mean(range) tumor 3.5 (2-6) 1.8 2 2.3 (1-3.5) 2.4 (0.8-6.4) 3.1 (2.5-4) 2.4 (1.4-3.8) 2.5(1-5)  size (cm)  Side (R/L) 7/6 NR NR 6/4 3/5 4/7 7/5 NR  Tumor location U3;MS; NR U3;M3;L4 U3;L3;NR4 Hilar5; U+M1; U8;L3 U2;M4;L6 NR  L5 U+L1;U1  Technique Pure robotic Robotic assisted Robotic assisted Pure robotic Pure robotic Robotic Robotic Pure robotic  11 trans, all trans all trans all trans all trans assisted all assisted all all trans  2 retro trans trans  Hilar clamping Bulldogs Bulldogs Bulldogs Bulldogs Bulldogs Bulldogs Satinsky Bulldogs or  method fourth  arm with  atraumatic  grasper  Mean (range) 215 (130-262) 265 (NR) 279 (NR) 155 (120-185) 192 (165-214) 228.7 (98-375) 242 (130-360) 142 (69-219)  operative  time (min)  EBL (ml) 170 (50-300) 240 (NR) 240 (NR) 92 (NR) 230 (100-450) 115.0 (75-500) | 329 (50-1,000) — 133 (25-500)  WIT (range) (min) (n25)22 26 (NR) 26.4 (NR) 21 (18-27) 31 24-45) 32.1 (30-45) 23 (13-36) 20 (0-40)  (15-29)  Cold IT (range) (n = 8) 33  (min) (18-43)  Positive marginon 1 NR 0 0 0 0 0 0  final pathology  Mean LOS (range) 4.3 (2-7) 2l 2.6 3.5 (1-21) 2.6 (2-3) 2.0 4.7 (2-10) 2.5 (1-7)  (days)  No. RCC (% of 10 (77) NR 8 (80) 8 (80) 7 (87) 9 (82) 9 (75) 24 (66)  tumors RCC)  Follow-up 2-11, NR NR 15 (16-28) all 3 NR, all NED 4.5 (1-8), all 7.4, all NED NR  (months) all NED NED NED  Complications Ileus, 1 Conversion to: Conversion to: Urine leak, 1; HAL Conversion to: Conversion to:  HAL 1, SL HAL 1, Re-exploration re-explora- SL 2: PE Open 1,  1, Open 1 Open 1; for bleed, 1 tion for and SL  Retention, 1 bleed 1 angio- cryoabla-  emboliza- tion, DVT  tion 1 1 AE AL,  HTN’ ive  crisis 1,  transfu-  sion 2    RALPN robotic-assisted laparoscopic partial nephrectomy; NR not reported; U upper pole; M middle pole; L lower pole; trans transperitoneal; retro retroperitoneal; EBL estimated  blood loss; WIT warm ischemia time; Cold IT cold ischemia time; LOS length of stay; RCC renal cell carcinoma; HAL hand-assisted laparoscopy; SL straight laparoscopy; PE  pulmonary embolism; DVT deep venous thrombosis; MI myocardial infarction; HTN’ive hypertensive   *Some smaller lesions were excised without hilar clamping after the index tumor was excised with the hilum clamped    conventional laparoscopic series. In the early series that  have been reported, the most commonly reported complica-  tion is conversion to a conventional or hand-assisted laparo-  scopic approach and in one case an open approach. Most of  these conversions have been required to control significant  bleeding,” although conversion due to focal positive margin  on frozen section examination and robotic camera malfunc-  tion necessitating conversion to a conventional laparoscopic  technique have also been described.^ Re-exploration for  bleeding was reported in two separate series,™ one of which  required a nephrectomy to be performed.? The remainder of  reported complications included urine leak? and postopera-  tive hemorrhage requiring transfusion? and angioembo-  lization?^ as well as ileus,* myocardial infarction (MI),  DVT*/pulmonary embolism, postoperative atrial fibrillation,  congestive heart failure,° and asymptomatic perinephric  hematoma.°°    Surgical robotics will inevitably undergo many modifica-  tions and advancements in the near future. The next genera-  tions of these systems will undoubtedly incorporate tactile  feedback in more streamlined housings with less obtrusive  maneuvering mechanisms. These may have advanced instru-  ments designed for specific procedures and working with  more freedom of movement. New systems are being devel-  oped that can integrate multiple imaging modalities in real  time to allow for more accurate location of the tumor within  the renal parenchyma. Advanced optics may be developed,  which allow for more accurate visual discrimination between  tumor and normal tissue as well as to clearly identify indi-  vidual vessels through the use of various filters with or with-  out the use of photo-pharmaceuticals. Whatever the future  brings, this remains an invigorating time rife with an oppor-  tunity for innovation.    Overall, RALPN represents an exciting and new procedure  which, while in its infancy, has demonstrated both feasibility  and safety comparable with that of contemporary series of  both open and laparoscopic partial nephrectomy series. With  continued improvements in the available and future robotic  surgical platforms, the technical difficulties of such complex  urologic procedures may continue to be diminished leading  to improved oncologic and functional outcomes for our  patients.    1. Kelling G. Die Tamponade der Bauchhohle mit Luft zur Stillung  lebensgefahrlicher Intestinalblutungen. Munch Med Wochenschr.  1901:48:1535-1538   2. Rogers CG, Singh A, Blatt AM, et al Robotic partial nephrectomy for  complex renal tumors: surgical technique. Eur Urol. 2008;53:514   3. Kaul S, Laungani R, Sarle R, et al da Vinci-assisted robotic partial  nephrectomy: technique and results at a mean of 15 months of  follow-up. Eur Urol. 2007;51:186   4. Gettman MT, Blute ML, Chow GK, et al Robotic-assisted laparo-  scopic partial nephrectomy: technique and initial clinical experi-  ence with DaVinci robotic system. Urology. 2004;,64:914   5. Deane LA, Lee HJ, Box GN, et al Robotic versus standard laparo-  scopic partial/wedge nephrectomy: a comparison of intraoperative  and perioperative results from a single institution. J Endourol.  2008;22:947   6. Aron M, Koenig P, Kaouk JH, et al Robotic and laparoscopic partial  nephrectomy: a matched-pair comparison from a high-volume cen-  tre. BJU Int. 2008;102:86   7. Phillips CK, Taneja SS, Stifelman MD. Robot-assisted laparoscopic  partial nephrectomy: the NYU technique. J Endourol. 2005;19:441   8. Caruso RP, Phillips CK, Kau E, et al Robot assisted laparoscopic  partial nephrectomy: initial experience. J Urol. 2006;176:36   9. Bhayani SB, Das N. Robotic assisted laparoscopic partial nephrec-  tomy for suspected renal cell carcinoma: retrospective review of  surgical outcomes of 35 cases. BMC Surg. 2008;8:16   10. La Vecchia C, Negri E, Levi F. Increasing incidence of renal cell  cancer. JAMA. 1999;282:2120   11. Katner HP, Baynham SA. Increasing incidence of renal cell cancer.  JAMA. 1999;282:2119   12. Chow WH, Devesa SS, Warren JL, et al Rising incidence of renal  cell cancer in the United States. JAMA. 1999;281:1628   13. Mathew A, Devesa SS, Fraumeni JF Jr, et al Global increases in kid-  ney cancer incidence, 1973-1992 Eur J Cancer Prev. 2002;11:171   14. Abaza R, Picard J. A novel technique for laparoscopic or robotic  partial nephrectomy: feasibility study. J Endourol. 2008;22:1715   15. Herr HW. Partial nephrectomy for unilateral renal carcinoma and a  normal contralateral kidney: 10-year followup. J Urol. 1999;161:33   16. Fergany AF, Hafez KS, Novick AC. Long-term results of nephron  sparing surgery for localized renal cell carcinoma: 10-year fol-  lowup. J Urol. 2000; 163:442   17. Leibovich BC, Blute ML, Cheville JC, et al Nephron sparing sur-  gery for appropriately selected renal cell carcinoma between 4 and  7 cm results in outcome similar to radical nephrectomy. J Urol.  2004;171:1066   18. Patard JJ, Shvarts O, Lam JS, et al Safety and efficacy of partial  nephrectomy for all T1 tumors based on an international multi-  center experience. J Urol. 2004;171:2181   19. Lau WK, Blute ML, VWeaver AL, et al Matched comparison of  radical nephrectomy vs nephron-sparing surgery in patients with  unilateral renal cell carcinoma and a normal contralateral kidney.  Mayo Clin Proc. 2000;75:1236   20. Lee CT, Katz J, Shi W, et al Surgical management of renal tumors 4  cm. or less in a contemporary cohort. J Urol. 2000;163:730   21. Frank I, Blute ML, Cheville JC, et al Solid renal tumors: an analysis  of pathological features related to tumor size. J Urol. 2003;170:2217   22. Fujii Y, Komai Y, Saito K, et al Incidence of benign pathologic  lesions at partial nephrectomy for presumed RCC renal masses:  Japanese dual-center experience with 176 consecutive patients.  Urology. 2008;72:598   23. Kutikov A, Fossett LK, Ramchandani P, et al Incidence of benign  pathologic findings at partial nephrectomy for solitary renal mass  presumed to be renal cell carcinoma on preoperative imaging.  Urology. 2006;68:737   Azevedo OC, Azevedo JL, Sorbello AA, et al Evaluation of tests  performed to confirm the position of the Veress needle for creation  of pneumoperitoneum in selected patients: a prospective clinical  trial. Acta Cir Bras. 2006;21:385   Azevedo JL, Guindalini RS, Sorbello AA, et al Evaluation of the  positioning of the tip of the Veress needle during creation of closed  pneumoperitoneum in pigs. Acta Cir Bras. 2006;21:26   Bemelman WA, Dunker MS, Busch OR, et al Efficacy of establish-  ment of pneumoperitoneum with the Veress needle, Hasson trocar, and    modified blunt trocar (TrocDoc): a randomized study. J Laparoendosc  Adv Surg Tech A. 2000;10:325   Phelan MW, Perry KT, Gore J, et al Laparoscopic partial nephrec-  tomy and minimally invasive nephron-sparing surgery. Curr Urol  Rep. 2003;4:13   Berger A, Crouzet S, Canes D, et al Minimally invasive nephron-  sparing surgery. Curr Opin Urol. 2008;18:462   Gill IS, Kavoussi LR, Lane BR, et al Comparison of 1,800 laparo-  scopic and open partial nephrectomies for single renal tumors.  J Urol. 2007;178:41   Nguyen MM, Gill IS. Halving ischemia time during laparoscopic  partial nephrectomy. J Urol. 2008;179:627    The demand for the repair of female pelvic organ prolapse  has increased significantly as the general population has  aged, yet remained active and focused on the quality of life.’  The majority of evidence-based studies cite the importance  of apical support in obtaining optimal and durable pro-  lapse repair.^? Although transvaginal repairs, with or with-  out the use of synthetic mesh, have demonstrated adequate  and reproducible outcomes; support of the vaginal apex is  generally not emphasized during these procedures. As a  consequence, remote objective failures and symptomatic  recurrences are not uncommon.?   Contemporary clinical trials have demonstrated the supe-  riority of abdominal-based prolapse repairs, including  abdominal sacral colpopexy (ASC), in providing durable  anatomical restoration and lower rates of dyspareunia.**  However, open ASC is associated with increased morbid-  ity and postoperative discomfort when compared with the  transvaginal route. Indeed, the morbidity of open abdominal  prolapse surgery has been a major impediment to its wide-  spread application with many patients accepting lower suc-  cess rates with vaginal surgery in exchange for improved  aesthetics and faster recovery. In response to these short-  comings, laparoscopic ASC was introduced and refined dur-  ing the last decade? Laparoscopic ASC essentially mimics  the open approach while decreasing the latter's attendant  morbidity. Cumulative outcomes with laparoscopic ASC  have been compared favorably with the open approach with  decreased blood loss and pain and faster recovery.^? Despite  these advantages, laparoscopic ASC is associated with lon-  ger operative times and a steep learning curve that has  largely limited its use.” Robotic ASC was introduced in  2004 in an attempt to overcome these limitations.!' Thus far,  outcomes have been equivalent or superior to laparoscopic  ASC with a significantly shorter learning curve. In this  chapter, we will review the preoperative evaluation for  robotic ASC, describe our operative technique, and provide  a balanced and concise review of the published literature on  the subject.    The indications for robotic ASC parallel those for laparoscopic  and open ASC and include post-hysterectomy vaginal vault  prolapse, prolapse recurrence following primary vaginal repair,  primary prolapse when concomitant abdominal surgery is  required, and, in appropriate circumstances, the repair of pri-  mary pelvic organ prolapse in females who have not undergone  prior hysterectomy (sacral uteropexy).'* Optimal candidates  demonstrate symptomatic Stage II or greater anterior, apical, or  posterior prolapse and, though not a specific contraindication,  no or minimal prior abdominal surgeries are preferred. The  goals of surgery should be the durable restoration of anatomy  and the relief of urinary, sexual, bowel, and local symptoms.  Certainly, treatment must be individualized and should con-  sider the patient's risk factors, goals for treatment, and should  optimally address all pathologies simultaneously."   All patients should undergo a thorough history and physical  examination. Specific attention should be paid to the patient's  presenting symptoms and an attempt should be made to rec-  oncile the symptom complex with physical exam findings."  In general, urinary, bowel, sexual, and other local symptoms  (vaginal pressure, heaviness, or pain) predominate, and their  impact on the quality of life should be elicited. It is often help-  ful to administer quality of life questionnaires (urogenital dis-  tress inventory (UDI-6) or Incontinence Impact Questionnaire  (IIQ-7)) to establish a baseline for later reference.!ó   Urinary symptoms are frequently encountered in women  with pelvic organ prolapse, and it is essential to elucidate the  nature and severity of these symptoms." Patients often report  urgency and frequency of urination with or without con-  comitant urge incontinence, nocturia, hesitancy of urination,  especially in the setting of severe prolapse, and stress uri-  nary incontinence.'*!* A voiding log and postvoid residual  measurement are administered to all patients and are invalu-  able in objectively translating patient complaints. Pad weight  testing is appropriate in patients with significant incontinence.  The ancillary and judicious use of urodynamic testing is fre-  quently helpful in objectively demonstrating and quantifying  symptoms, especially in the circumstance of suspected stress    urinary incontinence, in which leakage can be masked by  severe prolapse more than 80% of the time.'*°   The physical examination should be thorough, focused,  and systematic. The abdomen should be inspected for any  scars or evidence of prior surgery. A bimanual examination  should be performed to determine the size and location of the  uterus if present and to rule out the presence of any adnexal  pathology. With the use of a bivalved speculum or its equiva-  lent, the vagina is evaluated for hypoestrogenism, urethral  hypermobility (Q-tip test), prolapse, and the integrity of the  perineal body and rectal sphincter. ^^'^ Optimally, the ante-  rior, apical, and posterior walls of the vagina should be indi-  vidually inspected for the evidence of prolapse and quantified  utilizing the pelvic organ prolapse quantification (POPQ)  system.” Cystoscopic evaluation is generally not indicated  in patients with an uncomplicated clinical picture.”   Preoperative medical clearance, especially among women  of advanced age, is appropriate and should be individualized.  Similarly, preoperative formal imaging is rarely indicated.  Although magnetic resonance imaging is an accurate and  reproducible means of diagnosing and staging pelvic organ  prolapse, its utility is as yet unproven.?67*    Patients are brought to the operating room and placed in the  supine position for induction. After general anesthesia is  administered, the patient's arms are tucked and hands are  padded with the thumb in the upright position. After remov-  ing and/or lowering the foot of the bed, the patient's perineum  is centered at the distal end of the bed. Both legs are placed  in Allen stirrups with each knee facing the contralateral  shoulder (low lithotomy position). Padding is placed later-  ally to protect the peroneal nerves. An additional pad is  placed across the patient's chest, and the patient is secured to  the table with 2 in. silk tape. The abdomen and perineum are  prepped widely with betadine or chlorhexadine solution.  Particular attention should be paid to the preparation of the  vagina, as vaginal sizer will be used to reduce the apex to an  appropriate location during graft positioning. A Foley cath-  eter is placed and left to gravity drainage. A sterile drape  specifically designed for laparoscopy (pre-fabricated service  pockets and Velcro straps) is employed. When appropriately  used, these drapes can provide order during the operative  procedure and efficiency of instrument exchange.   Following the identification of relevant landmarks, an  approximate 12 mm peri-umbilical incision is made. Ideally,  this incision should be no less than 14 cm from the pubic  bone to ensure adequate intraoperative visualization. The  rectus fascia is palpated, a Veress needle is introduced through  the fascia into the peritoneal cavity, and intra-peritoneal    access confirmed with a saline drop test. The Veress needle  should always be aspirated to rule out vascular or visceral  transgression. Alternatively, an open Hasson technique can  be used. The abdomen is insufflated with CO, gas to a maxi-  mum pressure of 15 mmHg. Once adequate pneumoperito-  neum has been achieved, the Veress needle is removed and  exchanged for a 12 mm operative trocar (port 1). A standard  operative laparoscope or the robotic camera is introduced  through this initial port and the peritoneal cavity is inspected.  The patient is placed in steep Trendelenburg and the operat-  ing table is lowered maximally. Under direct vision, two  additional 8 mm robotic trocars (ports 2 and 3) are placed  approximately 9 cm lateral and just caudad to the peri-  umbilical trocar. If employing a 4-armed da Vinci? robot  (Intuitive Surgical, Sunnyvale, CA), an additional 8 mm  robotic trocar (port 6) is placed 2 cm cephalad and medial to  the left anterior superior iliac spine. If a 3-armed robot is to  be used, a 5 mm standard trocar is placed in this location for  bedside assistance. A 12 mm standard trocar (port 4) is placed  on the patient's right side for suction/irrigation and the pas-  sage of mesh/sutures. An additional 5 mm trocar (port 5) can  be placed as needed for additional assistance (Fig. 5.1).    Fig. 5.1 Schematic representation of port configuration during robotic-  assisted laparoscopic abdominal sacral colpopexy. The patient is placed  in the lithotomy position with arms tucked at the side. The robotic cam-  era is placed in port 1 and robotic instruments are placed in ports 2 and 3.  Port 4 is used by the bedside assistant for suction/irrigation and the pas-  sage of mesh/sutures. Ports 5 and 6 may be placed as needed for addi-  tional assistance. Reprinted with the permission of The Cleveland Clinic  Center for Medical Art & Photography © 2008. All Rights Reserved    The da Vinci? robot is positioned with its base equidis-  tance between the patient's legs. The base of the robot should  be far enough away from the end of the table to allow an  assistant to place a vaginal sizer during dissection of the vag-  inal cuff. The camera arm is connected to port 1 and instru-  ment arms are connected to ports 2, 3, and 6 (if a 4-armed  robot is used). A 0? scope is used. Monopolar shears or hook  cautery are applied to the right hand and atraumatic grasping  forceps are applied to arms 2 and 3. An assistant is posi-  tioned on the patient's right side to exchange instruments  (suction/irrigator or atraumatic small bowel grasper) and  introduce suture and mesh through ports 4 and 5.   The sigmoid colon is identified and retracted laterally to  the left with arm 3 to facilitate exposure of the sacral prom-  ontory. If a first generation robot is used, an assistant may  use a locking grasper to retract the colon. In either situation,  atraumatic grasping forceps should be used and the colon  should be grasped by its taenia coli and held under appropri-  ate but not excessive static tension (Fig. 5.2). Alternatively, a  silk stitch may be introduced percutaneously from the left  side and a figure-of-eight suture placed through the taenia  coli to retract the sigmoid colon.    Fig. 5.2 The sigmoid colon is reflected laterally using a ProGrasp  instrument in the left hand and the posterior peritoneum of the cul-de-  sac is incised superficially with a J-hook to expose the underlying sacral  promontory. Reprinted with the permission of The Cleveland Clinic  Center for Medical Art & Photography O 2008. AII Rights Reserved    The sacral promontory and presacral space are visualized  and its borders confirmed by the bedside assistant through  tactile feedback. The posterior peritoneum overlaying the  sacrum is incised superficially. Deep dissection is discour-  aged as sacral veins are encountered at this level. It is impor-  tant to incise the peritoneum evenly to avoid difficulty with  its eventual closure. A vaginal sizer is placed to facilitate  subsequent dissection and to reduce the vagina to a normal  anatomical position in preparation for mesh placement. The  bladder is dissected from the anterior vagina and the poste-  rior vagina is dissected from the colon. A pre-fashioned  Y-shaped polypropylene mesh is introduced by the assistant  through port 4 or 5. With the vagina appropriately reduced,  the mesh is sutured to the apex of the vagina anteriorly and  posteriorly with 0 nonabsorbable (Ethibond, Ethicon, New  Brunswick, NJ) suture (Fig. 5.3). The tail of the mesh is  affixed to the sacral promontory at the level of S1-S2 with a  laparoscopic tacking device, suture through the superficial  periosteum, or a commercially available drill designed spe-  cifically for sacral colpopexy (American Medical Systems,  Minnetonka, MN). The mesh should adequately reduce the  vagina to a normal anatomic position but should not be under    Fig. 5.3 A pre-fashioned Y-shaped portion of mesh is sutured to the  vaginal cuff and affixed under appropriate tension to the sacral promon-  tory to effect vaginal reduction. Reprinted with the permission of The  Cleveland Clinic Center for Medical Art & Photography © 2008. All  Rights Reserved    any undue tension. Cystoscopy is performed to rule out  transvesical placement of any suture material. The excess  mesh is excised and the peritoneal flaps are closed over the  graft with 2-0 absorbable suture. When necessary or at the  discretion of the operating surgeon, a culdoplasty may be  performed.   The abdomen is inspected thoroughly and the sigmoid  colon is returned to its normal anatomic position. The robot  arms are disengaged and the robot undocked. The 12 mm  ports are sequentially removed and the fascia closed with  1—0 Vicryl suture with the aid of a Carter- Thompson needle.  All skin incisions are closed with a running, subcuticular 5-0  Monocryl suture. Following skin closure, the vagina should  be reinspected and a decision is rendered regarding the need  for additional procedures including anterior plication.  Additionally, transvaginal or transobturator sling placement  for stress urinary incontinence should be performed at this  time if needed. A vaginal pack is placed and may be soaked  in betadine or estrogen cream.   Patients are admitted for 23 h following surgery. A clear  liquid diet is allowed during the night following surgery and  bed rest is prescribed. Postoperative laboratory testing is  generally unnecessary. Oral narcotics and intravenous break-  through ketorolac are used for pain control. The vaginal pack  and Foley catheter are removed in the morning of postopera-  tive day 1. The patient is ambulated and the diet is advanced  as tolerated. Once the patient has adequate pain control with  oral narcotics, is tolerating a regular diet, and is voiding  freely, she is discharged home. Patients are instructed to  avoid heavy lifting (215 pounds) and sexual intercourse for a  minimum of 4 weeks. A stool softener should be prescribed  to avoid postoperative constipation and resultant straining.  Patients are re-evaluated at the first and third month follow-  ing surgery with repeated POPQ evaluation.    First proposed in 1962, open ASC has changed little since its  inception and original description??? Cumulative outcomes  with open ASC have been excellent with reported success  rates (absence of apical prolapse) of between 80 and 100% at  a mean follow-up of 6 months to 3 years.^^' Complications  have been relatively uncommon and include hemorrhage and  hematoma (3%), injury to adjacent organs (1.6%), and the  need for re-exploration for bowel obstruction or other  abdominal pathology (3%).*' The rate of reoperation for pro-  lapse following ASC approaches 496? When compared  directly with vaginal apical restorative surgery in prospective  and retrospective trials, open ASC has consistently demon-  strated a lower objective rate of recurrent vault prolapse and    dyspareunia.” However, the anatomical superiority of open  ASC comes at the expense of increased costs, longer opera-  tive times, and higher morbidity. Patients must therefore  choose between an objectively superior abdominal proce-  dure with more discomfort and risk or a less successful vagi-  nal procedure with lower attendant morbidity. Although the  morbidity of open ASC has never been specifically identified  as an impediment to its broad application, it is generally  reserved for younger patients with better overall vitality,  those patients who have failed prior vaginal reconstruction,  and/or those with concomitant abdominal pathology."  Recognizing the limitations of open ASC, urologists and  urogynecologists described and refined laparoscopic ASC in  the mid 1990s.^? Laparoscopic ASC essentially recreates the  open procedure with some minor modifications, and ostensi-  bly offers superior visibility, less postoperative pain, and  improved cosmesis. Indeed, objective and subjective success  rates with laparoscopic ASC have rivaled or surpassed out-  comes with open ASC. Nearly 1,000 laparoscopic ASC cases  have been reported thus far with favorable outcomes in  greater than 90% (Table 5.1). Of note, one dedicated, retro-  spective comparative cohort study was performed by Paraiso  and colleagues in 2005, in which open ASC was compared  with laparoscopic ASC.’ The laparoscopic cohort demon-  strated longer operative times, decreased blood loss, and a  shorter duration of hospitalization. The objective success  and complication rates were similar between the two groups.    Despite the tangible and reproducible benefits offered by  laparoscopic ASC, this procedure has similarly experienced  limited widespread applicability owing to its generous learn-  ing curve." Much like laparoscopic radical prostatectomy  and laparoscopic partial nephrectomy, laparoscopic ASC  demands expertise in intracorporeal suturing and a resolute  commitment by the operating surgeon to develop and main-  tain this skill set.   The introduction and FDA approval of robotics in 2000  revolutionized urologic surgery by offering the advantages  of laparoscopy with a considerably shorter learning curve.  Although initially used exclusively for radical prostatectomy  by most urologists, its application and advantages in the field  of extirpative and reconstructive renal and pelvic surgery is  now being realized. The robotic platform is ideally suited for  reconstructive procedures given its superior optics, its capac-  ity to filter tremor, and its ability to operate freely and pre-  cisely in a confined field. Moreover, myriad studies have  successfully demonstrated that robotic reconstructive proce-  dures can be performed with confidence and safety even  among surgeons with little to no formal laparoscopic  experience.   Robotic ASC combines the gold standard anatomical  repair of open ASC with the decreased morbidity of laparos-  copy, and makes it accessible, feasible, and reproducible  across the entire field of urology and urogynecology. The  first published reports of robotic ASC came from Elliott and  colleagues at the Mayo Clinic in 2004.''*° Their initial expe-  rience in the treatment of 20 patients with symptomatic vagi-  nal vault prolapse was very favorable. Nineteen of 20 patients  underwent successful robotic ASC without complications.  The mean length of stay was approximately 1 day. At a mean  follow-up of 5.1 months, one patient developed recurrent  prolapse (rectocele only) and nearly all patients (9096) were  subjectively satisfied with the results of their operation. The  authors concluded that robotic ASC "facilitated precise intra-  corporeal suture placement so that the procedure could be  done in a fashion similar to the open method." Additional  studies published in 2004 and 2006 corroborated their find-  ings and documented durability of the repair.”   In 2007, a second report of robotic ASC was published by  Daneshgari and colleagues from the Cleveland Clinic.”  Twelve patients with symptomatic pelvic organ prolapse  underwent successful robotic ASC with preoperative and  postoperative POPQ examination. Mean POPQ stage preop-  eratively was 3.1. Mean estimated blood loss was 81 mL and  mean operative time was 317 min. The mean length of hos-  pitalization was 2.4 days. At a mean follow-up of 3.1 months,  the mean POPQ stage was 0. The authors concluded that  robotic ASC was safe and feasible but not without technical  limitations. They cited a longer initial learning curve than the  traditional laparoscopy owing to the increased technologi-  cal burden that is inherent to robotics (i.e., positioning of    trocars, set-up of the robotic arms and joints, etc). However,  they found that simple modifications to their initial operation  and setup yielded significantly shorter operative times and  fully exploited the ergonomic advantages of the robot,  namely complex dissection in a swift, precise manner.?   In our experience, robotic ASC is safe, expedient, and can  be easily performed by urologists who are familiar with the  robotic platform and are adept at robotic suturing. By employ-  ing our aforementioned set-up and operative technique, many  of the limitations inherent to robotic ASC should be obviated  and, as a result, the learning curve should be curtailed.  Certainly, any discussion of robotics must address not only  the technical limitations and benefits of robotics, but also  issues related to capital overhead and the cost of disposables.  One must bear in mind that although robotic ASC is, in our  opinion, a significant advance, its utility and clinical superior-  ity have yet to be proven in prospective, multi-center trials.    The essential tenet of surgery for pelvic organ prolapse is the  durable restoration and repositioning of the pelvic structures  in a fashion that relieves symptoms, treats concomitant pelvic  disease, and improves urinary, bowel, and sexual function.  The preponderance of evidence-based studies and systematic  reviews cite apical support as the cornerstone of effective and  durable treatment. Though abdominal procedures offer ana-  tomically superior apical support, patients are often reluctant  to undergo a potentially morbid and cosmetically unpleasing  procedure. Robotic ASC offers equivalent objective outcomes  with lower attendant morbidity, and makes the procedure  accessible and reproducible among junior or inexperienced  laparoscopists. Despite these advantages, future long-term  studies are needed to answer two questions: does robotic  ASC offer improved and discernable patient outcomes, and is  robotic ASC cost-effective? As the field of laparoscopy trends  further toward robotics as a whole and improved robotic  instrumentation and platforms are introduced, we believe the  answer to these two questions is yes.    1. Olsen AL, Smith VJ, Bergstrom JO, et al Epidemiology of surgically  managed pelvic organ prolapse and urinary incontinence. Obstet  Gynecol. 1997;89:501—506   2. Nygaard IE, McCreery R, Brubaker L, et al Abdominal sacrocol-  popexy: a comprehensive review. Obstet Gynecol. 2004;104:805—823   3. Maher C, Baessler K, Glazener CM, et al Surgical management of  pelvic organ prolapse in women. Cochrane Database Syst Rev.  2007;(3):CD004014    . Maher CF, Qatawneh AM, Dwyer PL, et al Abdominal sacral col-  popexy or vaginal sacrospinous colpopexy for vaginal vault pro-  lapse: a prospective randomized study. Am J Obstet Gynecol.  2004;190:20—26   . Rozet F, Mandron E, Arroyo C, et al Laparoscopic sacral colpopexy  approach for genito-urinary prolapse: experience with 363 cases.  Eur Urol. 2005;47:230-236   . Wattiez A, Canis M, Mage G, et al Promontofixation for the treat-  ment of prolapse. Urol Clin North Am. 2001;28:151—157   . Nezhat CH, Nezhat F, Nezhat C. Laparoscopic sacral colpopexy for  vaginal vault prolapse. Obstet Gynecol. 1994;84:885-888   . Antiphon P, Elard S, Benyoussef A, et al Laparoscopic promontory  sacral colpopexy: is the posterior, recto-vaginal, mesh mandatory?  Eur Urol. 2004;45:655—661   Wall LL, Versi E, Norton P, et al Evaluating the outcome of surgery   Bump RC, Mattiasson A, Bo K, et al The standardization of termi-   Donovan J, Bosch R, Gotoh M, et al Symptom and quality of life   assessment. In: Abrams P, Cardozo L, Khoury S, Wein A, eds.   Romanzi LJ, Chaikin DC, Blaivas JG. The effect of genital prolapse   Rosenzweig B, Pushkin S, Blumenfeld D, et al Prevalence of abnor-   Fantl JA, Cardozo L, McClish DK. Estrogen therapy in the manage-   plication for potential stress incontinence prophylaxis in women  undergoing vaginal reconstruction for stage III or IV pelvic organ    prolapse. The Continence Program for Women Research Group.  Am J Obstet Gynecol. 1996;175:326—333   Fantl JA, Newman DK, Colling J, et al Urinary Incontinence in  Adults: Acute and Chronic Management. Clinical Practice Guideline  No. 2 Update. Rockville, MD: U.S. Department of Health and  Human Services, Public Health Service, Agency for Health Care  Policy and Research; 1996   Vasavada SP, Comiter CV, Raz S. Cytoscopic light test to aid in the  differentiation of high-grade pelvic organ prolapse. Urology. 1999;  54:1085-1087   Yang A, Mostwin JL, Rosenshein NB, et al Pelvic floor descent in  women: dynamic evaluation with fast MR imaging and cinematic  display. Radiology. 1991;179:25—33   Singh K, Reid WM, Berger LA. Assessment and grading of pelvic  organ prolapse by use of dynamic magnetic resonance imaging. Am  J Obstet Gynecol. 2001;185:71-77   Tubaro A, Artibani W, Bartram CI, et al Imaging and other investiga-  tions. In: Abrams P, Cardozo L, Khoury S, Wein A, eds. Incontinence:  3rd International Consultation. Plymouth, UK: Health Publications;  2005:707-797   Birnbaum SJ. Rational therapy for the prolapsed vagina. Am J  Obstet Gynecol. 1973;115:411-419   Sutton GP, Addison WA, Livengood CH III, et al Life-threatening  hemorrhage complicating sacral colpopexy. Am J Obstet Gynecol.  1981;140:836-837    . Beer M, Kuhn A. Surgical techniques for vault prolapse: a review of    the literature. Eur J Obstet Gynecol Reprod Biol. 2005;119:144—155  Maher CF, Qatawneh AM, Dwyer PL, et al Abdominal sacral col-  popexy or vaginal sacrospinous colpopexy for vaginal vault pro-  lapse: a prospective randomized study. Am J Obstet Gynecol. 2004;  190:20-26   Yohannes P, Rotariu P, Pinto P, et al Comparison of robotic versus  laparoscopic skills: is there a difference in the learning curve?  Urology. 2002;60:39-45   Bentas W, Wolfram M, Brautigam R, et al daVinci robot assisted  Anderson-Hynes dismembered pyeloplasty: technique and 1 year  follow-up. World J Urol. 2003;21:133-138   Elliott DS, Frank I, DiMarco DS, et al Gynecologic use of roboti-  cally assisted laparoscopy: sacrocolpopexy for the treatment of  high-grade vaginal vault prolapse. Am J Surg. 2004;188:52-56  Elliott DS, Krambeck AE, Chow GK. Long-term results of robotic  assisted laparoscopic sacrocolpopexy for the treatment of high  grade vaginal vault prolapse. J Urol. 2006:176:655—659  Daneshgari F, Kefer JC, Moore C, et al Robotic abdominal sacro-  colpopexy/sacrouteropexy repair of advanced female pelvic organ  prolapse (POP): utilizing POP-quantification-based staging and  outcomes. BJU Int. 2007;100:875—-879   Ross JW. Laparoscopic approach for severe pelvic vault prolapse.  J Am Assoc Gynecol Laparosc. 1996;3:S43   Cosson M, Bogaert E, Narducci F, et al Laparoscopic sacral col-  popexy: short-term results and complications in 83 patients.  J Gynecol Obstet Biol Reprod. 2000;29:746—750   Rozet F, Mandron E, Arroyo C, et al Laparoscopic sacral colpopexy  approach for genito-urinary prolapse: experience with 363 cases.  Eur Urol. 2005;47:230-236    The application of intra-Iuminal endoscopy and laparoscopy  in children was virtually unknown until 1971, when Gans  and Berci reported the procedures as safe diagnostic mea-  sures.! Since then, the feasibility, safety, and benefits of ther-  apeutic endoscopy (minimal access surgery-thoracoscopy  and laparoscopy) in infants and children have been widely  reported, and the number and types of procedures performed  endoscopically have grown at a rate consistent with improve-  ments in the advances of technology, training of surgeons  and patients, and media awareness of the advantages of the  techniques. Children may be expected to have laparoscopic  nephrectomy as a day case and Nissen's fundoplication and  pyeloplasty with an overnight hospital stay and minimal, if  any, narcotic analgesia, and infants undergo colonic proce-  dures, lung resection, and esophageal atresia repair with  minimal morbidity and short hospital stay.?   Telerobotic surgery represents an advance for minimal  access surgery. Although its advantages in radical prostatec-  tomy are well documented,’ the application of the new tech-  nique in both adult and pediatric surgical practice remains in  its early infancy.   This chapter highlights the aspects of the current status of  robotic-assisted surgery in children.    In 1998, clinical robotics was introduced to the world of adult  surgery.’ In the year 2000, pediatric surgeons from Europe  and USA investigated the feasibility and potentials of robotic-  assisted surgery for fundoplication and pyeloplasty.^" Since  then, increasing numbers of surgeons have reported the suc-  cess of the new technique in a growing range of pediatric sur-  gical subspecialties, namely cervical and transoral, thoracic,  cardiovascular, gastrointestinal, and urological (Table 6.1).  In a prospective study, Lehnert et alë compared ten robotic  Thall anti-reflux procedures with ten manual laparoscopic  similar problems. The patients’ mean age was 11.4 + 1.4    years. There were no operative or postoperative complications  and the overall operating time was similar. However, the  authors concluded that the Da Vinci robotic system was supe-  rior and faster for dissection and suturing, but the setup time  was longer. Anderberg et al’ compared postoperative data from  six Da Vinci robotic Nissen’s fundoplications with historic  data from six manual laparoscopic and six open procedures in  children matched for age (2—11 years old) and severity of the  preexisting condition. They had no complications and con-  cluded that the operative time for the robot was comparable  with that of the laparoscopy but longer than open procedures  and analgesia requirements and hospital stay were similar in  the robotic and laparoscopic groups, but shorter than open.   Meehan and Sandler" reported a large series of children  who underwent robotic surgery using the Da Vinci system.  This report included 100 cases, 89% abdominal and 11%  thoracic. Although the majority of procedures had never  been performed using minimally invasive techniques by the  authors, 31 different types of procedures were attempted in  patients whose age ranged from 1 day to 23 years with the  average being 8.4 years and 22% being less than 10 kg of  body weight (range 2.27103 kg). They had a 13% conversion  rate for nonrobot-related complications. However, five of  these patients suffered significant bleeding as a result of  accessory conventional laparoscopic instrumentation. The  authors concluded that robotic surgery in infants and chil-  dren is safe and ideal for complex hepatobiliary and thoracic  conditions. Luebbe and associates! reported the first series  of 20 abdominal procedures with a total complication rate of  1596. In this report, the mean age of the patients was 8.4  years, the youngest being 4 months old. One patient devel-  oped a pneumothorax during the Morgagni diaphragmatic  hernia repair and another two suffered significant bleeding  during splenectomies, but none of the patients encountered  hemodynamic instability or required blood transfusions. The  authors concluded that even in the learning phase, complica-  tions following telerobotic surgery appear low.   In 2002, Le Bret and associates" described the success of  robotic-assisted ligation of patent ductus arteriosis in a large  series of children with an average age of 20 months using the  Zeus robotic system. Suematsu et al"? reported the use of the    retroperitoneal  Heller myotomy Cases  Hiatal repair and fundoplication Large series  Gastrostomy Short series  Cholecystectomy Large series  Biliary atresia and choledochal cyst Cases    Splenectomy Short series  Duodenal and pylorus Cases  Pancreas Cases  Small intestine — variety Cases  Large intestine Cases  Rectal pull-through and prolapse Cases  Adrenal Cases  Nephrectomy/partial nephrectomy Large series  Pyeloplasty Large series  Ureter Short series  Bladder Cases  Urinary stone Cases  Mullerian remnants Cases  Ovarian Cases  Urachus Cases  Testis Cases  Experimental Short reports  Fetal — experimental Cases    Da Vinci system in 15 children between the ages 3 and  18 who underwent closure of patent ductus arteriosis and  division of vascular ring. The authors concluded that the  system was safe and that future technologic improvement,  including miniaturization of instruments and the incorpora-  tion of tactile feedback, might allow the technique to be  applied in young infants and intracardiac procedures. Robotic  retroperitoneal and transperitoneal’ pyeloplasty in children  were reported in the early 2000s. In a retrospective case-  controlled study, Lee et al’ compared 33 robotic with 33 open    pyeloplasties in children whose age ranged from 0.2 to 19  years. There were no conversions or operative complications.  However, one patient in the robotic group required redo sur-  gery for recurrent obstruction. The mean operating time was  significantly longer in the robotic group (219 and 181 min,  p = 0.031), but the postoperative narcotic requirements  (p = 0.001) and hospital stay (2.3 and 3.5 days, P « 0.001)  were significantly less. The authors have also quoted that  with experience the robotic operating time decreased and  approached the open technique experience.   In an interesting report by Rahbar et al'* using the Da  Vinci system, the application and safety of transoral intralu-  minal robotic surgery in the pediatric airway was tested. The  authors tried four pediatric cadaver larynxes at first followed  by five children with laryngeal cleft defects (age 1—14 years).  They had two successes and three failures with the size of the  equipment and instruments being the limiting factor.   Other authors have published successful case reports of  robotic procedures covering the pediatric age groups and a  wide variety of conditions including thyroid surgery," tho-  racic,'°'' upper and lower gastrointestinal procedures,” bil-  iary including choledochal cyst, biliary atresia,'^! and renal  bladder and pelvic surgery."   The feasibility and safety of intrauterine (fetal) robotic  surgery has also been investigated in animal models with  specific reference to congenital defects such as myelomenin-  gocele and diaphragmatic hernia. 5?    From March 2006 to March 2009 (including the learning  phase), using the Da Vinci system, the author has personally  carried out 144 procedures in 115 patients involving 23 differ-  ent types of transperitoneal procedures with 4446 being gas-  trointestinal and 5696 urological. The mean age at the time of  surgery was 6.8 + 3.7 (7 months-16 years) including three  patients weighing «7 kg. At the start of the new program, our  setup and operating times were long.” Nowadays and with an  experienced theater team, the nursing setup time can be as  short as 25 min, robot docking time 4 min (robot moved into  position, arms and instruments fixed and ready to use), and  console time for pyeloplasty 120 min and fundoplication 58  min. We have had five (4.396) conversions: robotic related one  (mechanical failure) and non-robotic related four. On a few  occasions, procedures were delayed for 13-32 min owing to  the faulty signals within the system. So far, we have had no  robot-related complications, and outcomes of surgery have  been comparable with that of conventional laparoscopic and  open techniques. In our hands, the requirements for preoperative  and postoperative analgesia and duration of hospital stay were  no different from that of laparoscopic surgery.    Nursing preparation 20-45 min  Docking 10.9 min (4-20)  Console 167 min (120—200)  Total 217 min (180-280)    Table 6.2 illustrates the results of the most common  robotic procedure carried out by the author.    The complexity and reconstructive nature of many pediatric  surgical procedures, and patients’ spectrum that spans from  unborn fetuses and infants to older children and adolescents  demands high grades of operating view, dexterity, and preci-  sion. The three-dimensional panoramic high-resolution  views with depth, perception, ability to directly control a  stable visual operating field with increased magnification,  intuitive increased freedom of movements, motion scaling,  near normal restoration of eye and hand coordination, and  superior ergonomics, make the robot a near ideal tool for  pediatric and neonatal surgery.   Other, but potential, advantages of the system include: the  reduced learning curve for new and established minimal  access surgical procedures,”' and delivering safe, advanced,  and emergency procedures in smaller locations where spe-  cialist skills are absent.”   The robotic system has overcome many difficulties in the  development of minimal access surgery and enhanced the  surgeon’s ability to execute complex surgical procedures that  were previously thought to be technically demanding.^ ^.^  However, the system is not without limitations. A complete  lack of haptics necessitates surgeons to take extra care while  handling pediatric delicate tissues and microsuture materi-  als. Other disadvantages emanate from the size of the mobile    slave unit and instruments. The size discrepancy may restrict  anesthetist's access to the patient (upper abdomen and tho-  racic procedures, and small children) and allow arm and  instrument collision outside and inside the patient, respec-  tively (infants and small children). The recently developed 8  mm telescope represents an improvement over the 12 mm  telescope. The 5 mm telescope is capable of delivering two-  dimensional images. Both 5 and 8 mm instruments are effec-  tive; however, smaller instruments would undoubtedly  enhance the surgeon's ability to work in a smaller working  space and further reduce surgical trauma.   The capital and maintenance costs of the Da Vinci system  are significantly higher than conventional open and minimal  access surgery equipment. However, the cost of consumables  is comparable with that of disposable minimal access sur-  gery instruments.    The ability to perform safe and successful robotic procedures  relies greatly on the understanding of general and specific  principles of surgery/minimally invasive surgery, and appro-  priate application of the equipment and instruments as well  as safe access and the creation of an operative space. Failure  to do this produces unnecessary complications and puts  patients at risk.   The procedure is performed under general anesthesia  with intubation, full muscle relaxation and controlled ventila-  tion. There is no place for local, regional, or spinal/epidural  anesthesia in pediatric robotic surgery. During induction, gas-  eous distension of the gastrointestinal tract should be avoided  as even a slight dilatation can jeopardize safe access and  increases the risks of conversion to open method surgery. This  is particularly so in infants and small children. Nasogastric  aspiration via a tube improves access in the upper abdomen  and minimizes the risks of pulmonary aspiration. In children,  preoperative colon preparation is rarely required for lower  abdominal/pelvic surgery. A palpable bladder can be ade-  quately emptied by expression, and catheterization is required  only in prolonged lower abdominal procedures.”   In thoracic procedures, endotracheal intubation with or  without lung retraction and/or low pressure CO, (4-6 mmHg)  insufflation provides adequate exposure to all hemithoracic  compartments including the mediastinum. Double lumen  intubation, which is an ideal technique, is not suitable in  children weighing «25 kg. Selective bronchial intubation,  with or without contralateral bronchial occlusion with a  balloon catheter is technically demanding and may prove  helpful in certain circumstances.   In both thoracoscopic and laparoscopic procedures, postop-  erative analgesia is provided effectively with local anesthetic    infiltration of the port sites at the start or end of the proce-  dure. This may be supplemented with 12-24 h of Oromorph,  intravenous Opiate or Paracetamol, or epidural analgesia  depending on the age and general health of the child and the  exact nature of the procedure to be executed, e.g., patients  who undergo extensive intraperitoneal/pleural dissection or  those who are expected to ooze blood, bile, or urine during  the immediate postoperative period, or require wound exten-  sion to retrieve solid organs are more likely than not requir-  ing stronger and longer duration of postoperative analgesia.”   It is important to recognize that in children, particularly  infants, the surface area for access is small, the body wall is  thin and highly compliant, intercostal spaces are narrow, the  liver margin is below the rib cage, the bladder is largely an  intraabdominal structure, the viscera and major blood ves-  sels are close to the body surface and the working spaces are  small. In infants, only 200—500 mL of CO, may be required  to establish a pneumoperitoneum/pneumothorax. These ana-  tomical characteristics make access and manipulation in  children more difficult and complicated when compared to  adults. However, most children have well-defined anatomi-  cal landmarks owing to lack of excess fat, making recogni-  tion and dissection of structures a relatively easy exercise.   Although our system, Da Vinci, has four arms, the author  prefers the use of three robotic arms with or without an  accessory conventional laparoscopic port in most pediatric  cases. This is because:    * Many pediatric procedures can easily be performed using  two instruments within two working arms.   * The fourth arm (third working port) does not allow for  easy suction irrigation, insertion and retrieval of suturing  materials, and stapling guns, needles, and specimen bag  and has limited choice of retractors and sealing devices.   * An accessory laparoscopic/thoracoscopic port may prove  more versatile and be used for:    In pediatric abdominal procedures, open technique (modi-  fied Hasson) is the preferred method for insertion of the  primary “telescope” port and creation of a pneumoperito-  neum.?^? An incision to fit the size of the primary port is  made. A purse-string or single suture through the fascia and  peritoneum with a double throw prevents gas leak around  the port. Hitching the suture around the gas inlet port pre-  vents outward displacement of the port (Fig. 6.1). The exact  location of primary port depends on the site and nature of  the procedure to be executed. In general, a periumbilical  (transperitoneal) or mid-axillary line in fifth to seventh  intercostal space (transpleural) position serves most pur-  poses. An insuffulation pressure of 6-8 mmHg at a CO,  flow of 0.1-0.5 L/min in neonates and infants, and 8-10  mmHg at a flow 0.5-1.5 L/min in older children are ade-  quate parameters for all abdominal procedures. In the chest,  if insufflation is required, a pressure of 4-6 mmHg at a CO,  flow of 0.1-1 L/min is adequate. In children (who are nor-  mal otherwise), physiological changes that may follow CO,  insufflation are of no clinical significance provided the pres-  sure is kept below 15-18 mmHg for laparoscopy and 8-12  mmHg for thoracoscopy.”   The placement of two or three 5-8 mm robotic working  ports and one or more (if necessary) accessory conventional  laparoscopic ports under direct telescopic vision are also  modified according to the type of surgical procedure to be  completed. In general, the positions of the ports are similar  to those of equivalent conventional laparoscopic/thoraco-  scopic procedures.” However, care must be taken not to  allow for collision between:   * Robotic arms and patient's head, prominent bony land-  marks, operating table and anesthetic apparatus (Fig. 6.2).    Fig. 6.2 Position of the robotic arms in relation to the patient, operat-  ing table, and the anesthetic machine for renal and adrenal surgery    The working spaces for both instrument function and dis-  section may be reduced critically if too much of the ports are  placed inside the peritoneal/pleural space. In infants and  small children and in certain anatomical locations (e.g., retro-  peritoneal space), only 5-10 mm of the ports may be allowed  inside the working space (Fig. 6.3). The position of the Da  Vinci slave usually depends on the type of procedure to be  executed and size of the patient. The slave is placed at the  head of the table for cervical and thoracic inlet procedures,    left or right shoulders for left and right upper abdominal pro-  cedures, respectively, behind (semiprone patients) posterior  mediastinum, in front (semisupine/lateral patient) of anterior  mediastinum and left and right retroperitoneal renal surgery,  behind with a slight turn toward the foot (semi-supine patient)  for transperitoneal renal surgery, left or right (supine patient)  for small and large bowels, left or right foot of the table  (supine patient) for left and right lower abdominal proce-  dures, respectively, and direct foot of the table (supine in  infants and small children, Lloyd-Davis in older children) for  lower abdominal midline structures.   Dissection and suturing, and the use of energy sources are  carried out in a manner similar to that of a conventionally  performed open/endoscopic operation. However, pediatric  surgeons are to be particularly careful while handling tissues  and microsutures because of a complete lack of haptics.   The importance of teaching and training a dedicated pedi-  atric theater team cannot be overemphasized and probably is  more critical than they are for adults. This is because the  spectrum of patients who would benefit from robotic surgery  varies widely in terms of age, size, complexity, and pathol-  ogy (multidisciplinary) and due to the lack of specialized  equipment and instruments as a whole, including minimal  access/robotic surgery.    In children, telerobotic surgery is safe and applicable to a  wide range of pediatric surgical conditions. The technique  holds more promise for pediatric surgeons than adult sur-  geons. This is because pediatric surgery covers a wider range  of patients, age groups, and procedures, many of which are  complex and reconstructive by nature. In its current format,  it has already improved aspects of conventional minimal  access surgery. However, the system has limitations and a  smaller system and miniaturization of instruments and lower  costs are worthy investments.    1. Gans SL, Berci G. Advances in endoscopy of infants and children.  J Pediatr Surg. 1971;6:199-223   2. Najmaldin A, Rothenberg S, Crabbe D, Beasley S, eds. Operative  Endoscopy and Endoscopic Surgery in Infants and Children.  London: Hodder Arnold; 2005   3. Tewari A, Srivasatava A, Menon M. A prospective comparison of  radical retropubic and robot-assisted prostatectomy: experience in  one institution. BJU Int. 2003;92:205-210   5. Heller K, Gutt CN, Schaeff B, et al Use of the robot system da Vinci  for laparoscopic repair of gastro-oesophageal reflux in children.  Eur J Pediatr Surg. 2002;12:239—242    . Lee RS, Retik AB, Borer JG, Peters CA. Paediatric robot assisted    laparoscopic dismembered pyeloplasty: comparison with a cohort  of open surgery. 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Oxford:  Blackwell Science; 1998   Lister DR, Rudston-Brown B, Warriner CB, et al Carbon dioxide  absorption is not linearly related to intraperitoneal carbon dioxide  insufflation pressure in pigs. Anaesthesiology. 1994;80:129-136  Sfez M, Guerard A, Desruelle P. Cardiorespiratory changes during lap-  aroscopic fundoplication in children. Paediatr Anaesth. 1995;5:89-95    This is perhaps the most beautiful time in human history; it is  really pregnant with all kinds of creative possibilities made pos-  sible by science and technology which now constitute the slave  of man — if man is not enslaved by it.    We live in exciting times and the pace of change in medical  and surgical technology has never been more rapid. Gordon  Moore's 1965 law stated that the power (memory) of com-  puters would double every 18 months.' Almost every mea-  sure of the capabilities of digital electronic devices remains  linked to Moore's law: processing speed, memory capacity,  and even the number and size of pixels in digital cameras.  This law continues to be true today in the field of surgical  robotics. What have changed while technology continues to  expand are the demands and expectations of our increasingly  well-informed, demanding, and internet-literate patients.  Patients want the best for themselves and their families and  market forces themselves are driving expansion and develop-  ment in many instances.   At present, robotic urological surgery is dominated by the  da Vinci™ robotic system and the procedure of robotic-  assisted laparoscopic radical prostatectomy (RALRP),  although there is significant expansion in renal and bladder  surgical applications; however, technology does not stand still  and there are a huge and diverse number of robotic systems in  development throughout the globe. There are many systems  with enormous clinical potential in the pipeline that are likely  to be further refined and developed in the coming years before  being released into the clinical arena. Urologists have been  quick to embrace robotic surgery and other new technologies  and RALRP is easily the most common robotic procedure  performed worldwide. From 766 cases performed in 2002,  over 48,000 are projected for 2008.* This accounts for over  40% of the radical prostatectomy market in the USA.   We will look at the robotic systems being developed in  some of the premier robotic engineering institutions in the  world and assess their clinical applications.    Robotic laboratories throughout the world are attempting to  produce robotic systems that are superior to those already in  clinical use and remedy some of the problems experienced  by the current machines. The da Vinci S™ is far lighter than  the standard da Vinci system, but it remains a bulky piece of  equipment that is difficult to maneuver and store in many  standard operating theaters. Groups are looking at reducing  these issues by installing ceiling-mounted robotic devices  that swing down onto the patient when required and are eas-  ily housed above the patient when no longer required. Other  options include simply debulking the robot cart still further  by the use of lightweight polymers and downsizing the  robotic arms and instruments. Another issue presented by the  da Vinci system is the lack of force feedback and there are  now miniature robots capable of entering via a laparoscopic  port to provide the surgeon with enhanced and detailed hap-  tic feedback.   Other than trying to improve on the robotic systems  already in clinical use, various engineering teams are also  looking at percutaneous and transrectal needle placing robots  that can be used within CT/MRI scanners, robots used in  natural orifice and single port surgery, and developing nano-  robotic technology. This chapter will look more closely at  these exciting areas.    With the advent of specialized surgical robots such as the da  Vinci S™ surgical system, urological surgeons have been pro-  vided with specialist end-effectors that assist during complex  laparoscopic operations and help to improve the outcomes  including blood loss, analgesia requirements, and length of  hospital stay while reducing the overall morbidity of surgical  procedures. These highly sophisticated robotic devices incor-  porate advanced technologies such as precision mechanics,  enhanced and magnified stereo vision, and advanced motion    control algorithms enabling tremor-free handling of the oper-  ating instruments. However, there are limitations to even the  updated da Vinci S system. Most notably, the surgeon loses all  tactile sensation when operating with the aid of a robot. This  sense of touch, which is readily available during open surgery  and also present to a lesser degree in traditional laparoscopic  procedures, provides the surgeon with valuable information  about the nature of the tissues and potential extent of disease  and margins of safety. The inability to palpate organs and soft  tissues during an operation can lead to a misjudgment and  result in inadvertent injury to neighboring organs or an incom-  plete surgical resection. Recent studies have revealed that the  lack of tactile sensation during robot-aided surgery can lead to  an increase in tissue trauma and accidental tissue damage, and  surgeons provided with force feedback significantly improved  their performance.?^ This risks leaving cancer behind and get-  ting a positive surgical margin. Open surgeons often avoid this  by feeling the tumor and going wide at the suspicious areas to  obtain a negative margin and excise the cancer completely. In  urological surgery using the da Vinci robot, the lack of tactile  feedback is particularly difficult during surgery for locally  advanced T3 prostate cancer and large bulky muscle invasive  bladder cancer. In these situations, tactile feedback via an  indentation probe with an applied sense of "feel" would thus  be clinically very useful.   Current research at a number of research institutes aims at  equipping surgical robots with sensors and feedback mecha-  nisms to reestablish the surgeon with tactile perception and  feedback. Owing to advances in microtechnologies, there is  now a clear trend toward developing miniaturized sensors  that can measure the manipulation forces at the point where  the tool comes into contact with soft tissue through a laparo-  scopic port. Recently, a surgical gripper at the end of a lap-  aroscopic instrument has been integrated with a strain gauge  sensor? The sensor's hexapod structure made from an alumi-  num alloy provides a light-weight and rigid solution to  acquire force and torque signals along all six axes with a  high resolution of 0.05 and 0.25 N in the radial and axial  direction, respectively, with a range of up to 20 N. A MEMS  microgripper driven by a piezoelectric actuator integrated  with semiconductor strain gauges mounted on a microfabri-  cated elastic surface (flexure) has been developed allowing  soft tissue property characterization and realistic palpation  using a haptic interface.°   Advances have also been made in employing piezoelec-  tric materials to measure the contact forces at the tip of  surgical tools. Micromachined force array sensors have  been developed that can be mounted on surgical tools.”  The developed sensors claim to have a high sensitivity and  linear behavior over a wide range of up to 15 N, allowing  realistic palpation feedback. Very promising results have  also been achieved based on fiber-optic measuring princi-  ples. Miniature force sensors can be created using fiber-    optic cables that carry light signals — which are modulated  in response to the applied forces — from a sensing region to  an optoelectronic converter. Recently, a 5-mm diameter  force sensor integrating three fiber-optic sensor elements  into the tip of a surgical tool was developed. This sensor  can measure forces along three axes with a sensitivity of  0.04 N and a range of up to 2.5 N.°” The main advantages of  these sensors are that they are not affected by electromag-  netic interference and are compatible with magnetic reso-  nant imaging systems potentially enabling procedures to be  performed during MR imaging. Exploiting this, a three  degree-of-freedom optical fiber force sensor was used in an  MR-compatible neurosurgery robot to measure tool-tissue  interaction forces. °   Accurate sensors and appropriate actuators that recon-  struct the measured forces in the user’s hand are both neces-  sary components of haptic interfaces that provide genuine  remote touch sensing. The major problem in providing haptic  feedback to the surgeon is the difficulty in sensing the forces  during movement in multiple directions/degrees of freedom  as well as the need for sophisticated control systems to drive  the actuation mechanisms necessary to create the sensation  of touch in the hands of the surgeons. These problems are  further compounded by the miniaturization and sterilization  requirements of minimally invasive surgical instruments. ''  Attempting to avoid the complicated control systems needed  for the surgeon to "feel" the tissue interaction, smart instru-  ments are being created to measure mechanical soft tissue  properties (i.e., areas of increased stiffness or softness in tis-  sue) and transmit this information to aid the surgeon in tissue  diagnosis. A uniaxial stretching device has been used by  Brouwer et al to measure porcine tissue response both in vivo  and ex vivo." Another device was developed to investigate  the in vivo viscoelastic properties of tissue under uni axial  small deformations.'* A motorized endoscopic grasper, which  was used to test abdominal porcine tissues in vivo and in situ  with cyclic and static compressive loadings, is also described. '*  An ultrasound indentation device, which integrates an ultra-  sound transducer and a load cell, is integrated to simultane-  ously monitor the tissue strain, and the response tissue stress  under compressive load has been used for measuring breast  tissue in vivo.? The use of a transrectal probe equipped with  tactile sensors to identify prostate tumors has been described. ^  Tactile feedback systems have also been proposed for the  identification and characterization of pulmonary tumors,"  lesions in the breast," and for identifying arteries during  robotic surgery. '?   The previous research aims to estimate tissue properties  by applying an external stimulus while measuring the corre-  sponding tissue response. The difficulty is that, in many  cases, small and deep lesions are not easily detected using  this technique. To overcome this, a technique known as elas-  tography that can provide a relative stiffness image of a    target area deep inside tissue has been proposed and utilized  in soft tissue diagnosis. Sonoelastography is an imaging  technique where low-amplitude, low-frequency ultrasound  shear waves are propagated through an organ to measure tis-  sue elasticity. This has been used to measure the elasticity of  in vitro muscle? and reconstruct three-dimensional tumor  volumes of in vitro prostate samples based on the measure-  ment of tissue elasticity"! Others have used the concept of  harmonic motion imaging (HMI), which can be used to dif-  ferentiate soft tissue stiffness.” This technique applies a  radiation force produced by focused ultrasound to induce a  harmonic motion deep inside a tissue. In a further study,  HMI” has been used to measure the elastic modulus of  in vitro bovine liver using a mechanical model and computa-  tional scheme. Magnetic resonance elastography (MRE)  imaging has also been described" and this technique can  directly visualize and quantitatively measure propagating  acoustic strain waves allowing the calculation of local quan-  titative values of shear modulus and the generation of images  that depict tissue elasticity or stiffness.   Recently conducted research at King's College, London,  is aiming to develop devices that look at a series of distribu-  tions measured as either a wheeled probe (Figs. 7.1 and 7.2)  or an air-cushion spherical probe (Fig. 7.3) that slide across  a tissue surface. This approach differs from those previously  mentioned, which includes static indentations, as the wheeled  probe and spherical probe allow the assessment of larger  regions of organ tissue in a relatively short time.” Both  probes can fuse the kinaesthetic information from the wheel-  tissue rolling interaction into a pseudo-color map that can  indicate the spatial variation of tissue stiffness caused by the  differences of the internal tissue structure." These devices  have been trialed with success in excised porcine liver and    Fig. 7.1 Diagram of the force-sensitive probe with a grooved wheel  end-effector    The ability to accurately place a needle into a patient is a  feature of numerous medical procedures. In urological sur-  gery, this is particularly useful during the first stage of percu-  taneous nephrolithotomy, for radioactive seed placement in  prostate brachytherapy, in ablative renal procedures such as  cryotherapy and radiofrequency ablation, and also to accu-  rately target a biopsy for a variety of organs. Inaccuracies in  needle or electrode placement for these procedures and lack  of navigation devices to aid placement may result in increased  procedure time, morbidity, inaccurate diagnosis, or tumor  recurrence. In recent years, robot-assisted needle insertion  has attracted significant attention because of its capabilities  to provide assistance throughout a range of minimally inva-  sive procedures. These systems may provide a safer working  environment for the physician by reducing radiation expo-  sure. In addition, there is the potential to enhance outcomes  by improving repeatability and accuracy, which could allow  standardization of surgical ability.   One of the leaders in the field of percutaneous robotic  biopsy and needle placement is the Urology Robotics  Laboratory at Johns Hopkins University. This laboratory ini-  tially developed the percutaneous access to the kidney robot  (PAKY) which was used in the first randomized trial of tel-  erobotic surgery" and also successfully for PCNL in patients  where robotic insertions compared favorably with manual  insertions when time to access, number of attempts, and esti-  mated blood loss were looked at.” This robot consisted of a  seven DOF lockable manipulator, or passive arm, connected  to a three DOF active arm. The arm houses a radiolucent  needle driver and was mounted using a side rail onto the  operating table. Following on from this, they have developed  the Acubot device, which like its predecessor is based on the  remote center of motion (RCM) device. Clinical feasibility  studies in 2 patients with hepatic metastases have been  described by Solomon et al^ to develop a tumor ablation  treatment system that utilizes the AcuBot robot system for  accurate applicator placement.   The RCM is a key concept in surgical robotics (Fig. 7.4).  It consists of a fulcrum point that is located distal to the  mechanism itself, typically at the skin entry point/laparoscopic  port site in percutaneous devices. This allows the RCM to  precisely orientate a surgical instrument/needle in space  while maintaining the needle tip at the skin entry point (or  another specified location) without placing unwanted trac-  tion or pressure on this point. Current examples of RCM  robots include the da Vinci™ itself along with the Zeus™,  AESOP™, and AcuBot? devices.   When equipped with a force feedback device, the AcuBot  robot can detect changes in resistance upon successful entry  to the renal collecting system or other tissues and thus can  confirm percutaneous access.    A derivative of the AcuBot is the MrBot robot (Fig. 7.5),  a fully actuated robot for image-guided access of the prostate  gland. For MRI compatibility, this robot is exclusively con-  structed from nonmagnetic and dielectric materials such as  plastics, ceramics, and rubbers and is electricity free. The  system utilizes a new type of motor specifically designed for  this application, the pneumatic stepper motor (PneuStep)."  These uniquely provide easily controllable precise and safe  pneumatic actuation. Fiber-optical encoding is used for feed-  back, so that all electric components are distally located out-  side the imager's room.   Imager compatibility tests performed in scanners up to 7  T showed outstanding MRI compatibility, independent of the  field strength. MRI-guided needle targeting experiments  showed that the tip of the needle may be placed within 1 mm  of a desired target selected in the image. This robot has    Fig. 7.6 Revolving needle driver (RND) connected to the AcuBot  CT-guided robot for needle positioning and orientation    recently been shown in to be capable of accurate MR imag-  ing-guided prostatic needle intervention within a standard  MR imager in vivo in a canine model.”   The latest device from the Urobotics lab is the revolving  needle driver (RND). This is a fully actuated driver for needle  insertion, spinning, release, and force measurement and is  perhaps the most complex, feature-rich needle driver reported  to date (Fig. 7.6). It can be connected to the AcuBot CT-guided  robot for needle positioning and orientation. Using a novel  kinematic design for inserting the needle, the RND creates  the translation motion with a mechanism of rotary joints.  This has resulted in a compact design, so that the driver is  less tall than the needle. Beside its actuated needle insertion  mechanism, the RND is also capable of spinning the needle,  so that the needle is advanced in a drill-like motion. To  engage the needle, standard biopsy needles are placed in a  custom adapter fitted with a gear. The RND supports the nee-  dle from its head, and provides an additional needle support  guide in close proximity of the skin entry point. This is simi-  lar to holding the needle with two finger-like grippers, one  from its head and one from its barrel next to the skin.   The top one pushes the needle in and out, while the lower  holds the guide to support the direction of the needle as close  as possible to the skin. The guide or needle nozzle also encases  the sharp needle point before insertion to protect the patient  and medical personnel. Both grippers can simultaneously  release the needle automatically. Finally, the new driver is also  equipped with a set of force sensors to measure the interaction  of the nozzle with the patient and the force of needle insertion.  These can be used either with a haptic interface to reproduce    the interaction of the physician in handling the needle, or to  provide additional information that is not typically used in  the manual case, such as respiratory motion tracking. This  device has been assessed using a porcine model and been  found to be effective for lung and liver biopsy. Reduced  force was required for insertions using needle rotation.    Nanotechnology or nanotech is an emerging technology seek-  ing to exploit distinct technological advances by controlling  the structure of materials at a reduced dimensional scale  approaching that of individual molecules and their aggregates  or supramolecular structures. In the same way as the develop-  ment of microtechnology in the 1980s led to new tools for  urological and other surgery, emerging nanotechnologies will  similarly permit further advances toward better diagnosis and  new devices for medicine. Nanorobots are expected to permit  significant new capabilities for the diagnosis and treatment of  the disease, for patient monitoring, and for minimally inva-  sive surgery." ^ The ability to manufacture nanorobots results  from new methodologies in fabrication, computation, trans-  ducers, and manipulation, e.g., electrospinning techniques  for the preparation of nanofibers and macroporous scaffolds  intended for drug delivery and tissue engineering.   The hardware architecture for a medical nanorobot must  include the necessary devices for monitoring the most  important aspects of its operational workspace: the human  body. Teams of nanorobots may cooperate to perform pre-  defined complex tasks in medical procedures.? With this  goal in mind, data processing, energy supply, and data trans-  mission capabilities can be addressed through embedded  integrated circuits, using advances in technologies derived  from nanotechnology and very large system integration  (VLSI design).*   Complementary metal semi-conductor (CMOS) VLSI  design using deep ultraviolet lithography provides a high  precision and commercial way for manufacturing early nan-  odevices and nanoelectronics systems. The CMOS industry  may successfully drive the pathway for the assembly pro-  cesses needed to manufacture nanorobots, where the joint  use of nanophotonic, carbon nanotubes, and nanocrystals  may even accelerate further the actual levels of resolution  ranging from 248 to 157 nm devices.“ The appropriate inter-  disciplinary effort will impact on assembly nanodevices and  nanoeletronics to build nanorobots.** To validate designs to  achieve a successful implementation, the use of Verification  Hardware Description Language (VHDL) is the most com-  mon methodology utilized in the integrated circuit manu-  facturing industry. Nanorobots can be useful in a large  range of biomedical applications for future drug delivery    applications, such as dosage regimens based on predicted  pharmacokinetic parameters for chemotherapy in anti-cancer  treatments.^ A range of different signals are directly corre-  lated to specific medical problems. Chemical signals can  serve for medical target identification and actuation. A single  tumor cell can be characterized as a typical endothelial cell  mutation with profound consequences for patients suffering  from cancer. Endothelial cells have a large number of func-  tions and may play an important role in human health. They  also serve as part of the structure forming the inside blood  vessels, which are spread throughout every single organ or  system comprising our body.   Factors like low energy consumption and high sensitiv-  ity are among some of the advantages of nanosensors.  Nanobioelectronics using nanowires as material for cir-  cuit assembly can achieve maximal efficiency for applica-  tions involving chemical changes, enabling new medical  applications. Using chemical sensors, nanorobots can be  programmed to detect different levels of E-cadherin and  beta-catenin as medical targets in primary and metastatic  phases. Integrated nanosensors can be utilized for such a task  to find different concentrations of E-cadherin signals.  Beyond sensors, nanorobots may be designed with appropri-  ated space to carry chemotherapeutic agents for future can-  cer drug delivery. This approach enables the drug carrier to  be maintained for as long a time as necessary in the blood-  stream, and therefore avoiding the extravasation toward non-  reticuloendothelial-located cancers and the side-effects of  premature degeneration.^?    The da Vinci robot is highly unlikely to represent the ultimate  robotic surgical system and it should be seen as the current  most highly sophisticated master-slave system on a stepwise  progression of robotic development. The devices themselves  will become smaller, lighter, and integrated into telesurgical  systems, which may have fully robotic surgical theater nurses  and equipment nurses. This will allow the seamless integration  of patient data and imaging into the robotic console permitting  real-time intraoperative visualization of pathology and other  tissues. This augmented reality surgery combining laparo-  scopic images with virtual 3D images will help identify and  avoid injury to key structures. Instruments will continue to  decrease in size to true needlescopic (2 mm) end-effectors and  a haptic feedback system is likely to arrive within a few years.   Other areas of development include the snake-like or ser-  pentine robots, which are now being targeted toward the field  of natural orifice surgery. Known as NOTES™ (natural ori-  fice trans-luminal endoscopic surgery), these robots have  multiple degrees of freedom, do not fail if one joint locks/  blocks, and can be used transgastrically.°° One such device is  the CardioARM (Articulated Robotic MedProbe), a snake-  like surgical robot developed at Carnegie Mellon University,  which hopes to allow cardiac surgeons to perform procedures  through a single subxiphoid incision (Fig. 7.7). The robot  has a series of joints that automatically adjust to follow the  course plotted by the robot’s head, providing greater preci-  sion than a flexible endoscope can offer.    It is 12 mm in diameter, has 102 degrees of freedom,  three of which can be activated at once and “memory” as  device remembers its configuration as it moves, so each seg-  ment follows the previous segment's path.?' The same com-  pany is also developing a laparoARM'M, gastroARM?M, and  arthroARM™, which will provide platforms for various  endoscopic and laparoscopic procedures. These and other  similar devices open the door for single incision or external  woundless/scarless surgery and procedures including chole-  cystectomies, appendicectomies, and tubal ligations that  have already occurred. Once the ability to exchange and  manipulate a variety of end-effectors has been developed,  this type of robot may become the future of robotic surgery.  The field of surgical robotics continues to move at a rapid  pace and many of these concepts that we find difficult to  grasp at present will rapidly become standard surgical prac-  tice throughout the globe.    Acknowledgment The authors would like to acknowledge contribu-  tions from Mr. Hongbin Liu, Mr. Dinusha Zzbyszewski, Mr. David  Noonan, Professor Lakmal Seneviratne, and Dr. Adriano Cavalcanti.   2. Peplinski R. 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It is a precise, safe, versatile instrument  that can be utilized anywhere in the urinary tract. Most  importantly, it has diverse applications being able to be used  in treating the prostate, urinary calculi, strictures, and other  soft tissue disorders in the urinary tract. This makes it a  unique technology for urological practice. This chapter will  focus on the use of the holmium laser for the treatment of  benign prostatic enlargement (BPE).    The holmium laser is a pulsed solid-state laser with a wave-  length of 2,140 nm. As the prostate is 60-70% water, the  light absorption length in the prostate is very short at 0.4 mm —  the resulting energy density being high enough to create a  temperature greater than 100°C, which results in tissue  vaporization without coagulation. This enables precise cut-  ting and incision, while the dissipating heat coagulates the  small- and medium-sized vessels to a depth of 2-3 mm.' The  fact that saline can be used as the operative irrigant means  that the consequences of using hypo-osmolar solutions can  be avoided. Our unit has not had a case of TUR Syndrome in  over 5,000 cases and this means that the operating time need  not be restricted as it is for transurethral resection of prostate  (TURP).    BPE is a common cause of lower urinary tract symptoms  (LUTS). The mainstay of surgical intervention in the past  has been TURP and while this has proven efficacy, alterna-  tive techniques have been sought to avoid TURP's periopera-  tive morbidity, which occurs in up to 15% of patients.    Lasers have been at the forefront of alternative treatments  for the treatment of BPE. Early generation Neodymium: YAG  lasers were beset by several problems; only prostate coagula-  tion was able to be performed, and this created prolonged  sloughing of prostate tissue with consequent postoperative uri-  nary symptoms. The lack of tissue removal also contributed to  the procedure's lack of durability and unpredictable results.   With the advent of the high-powered holmium laser, sur-  gical techniques evolved beyond ablation. The characteris-  tics of the holmium wavelength allowed precise incision and  resection, and so for the first time there was a technique that  could mimic TURP while avoiding the perioperative mor-  bidity and shortening inpatient hospital stay. This procedure  was holmium laser resection of the prostate (HoLRP). With  the development of the tissue morcellator, however, holmium  enucleation of the prostate (HoLEP) evolved and became  an endourological equivalent of the Open Prostatectomy,  with no restriction on the size of the prostate that could be  treated. Well-designed randomized controlled trials from  several centers have proven that HoLEP has superior peri-  operative outcomes when compared with TURP or Open  Prostatectomy, as well as equivalent clinical outcomes.    The indications for HoLEP include, but are not limited to,  those for TURP. In general, anticoagulants are stopped 7  days prior to surgery, but the hemostatic properties of the  holmium laser allow patients who are unable to cease taking  these medications to undergo HoLEP In addition, the use of  normal saline rather than glycine as irrigant means that there  is no risk of TUR Syndrome, and therefore there is no limita-  tion to the size of prostate treated. The largest adenoma  retrieved at our institution is 1,100 g.   A 100 W laser is usually used (Lumenis, Yokneam, Israel).  A 550 um laser fiber is passed through an interlink injection  port (Baxter, Deerfield, IL) via a 6 F open-ended ureteric  catheter. The end of the ureteric catheter should be just visi-  ble, with the end of the laser fiber a few millimeters beyond    the ureteric catheter. The laser may require advancing at  times during the procedure to prevent damage to the ureteric  catheter, or more importantly, the scope.   The laser resectoscope is a 26 F, continuous-flow, with an  inner sheath (27040 XAL), with an incorporated stabilizing  guide (Storz, Tuttlingen, Germany). A 30? telescope (27005  BA) with a long bridge (27068CD) is also required.   An alternative setup involves a combined laser-bridge and  inner sheath (A21500A) passed through a 27 F outer sheath  (Olympus, Hamburg, Germany)?   The principles of HoLEP are sequential retrograde enucle-  ation of the three prostatic lobes in their entirety. Hemostasis is  achieved by utilizing the defocused laser on bleeding vessels.   After identifying the ureteric orifices, bladder neck inci-  sions are made at the 5 and 7 o'clock positions to define the  median lobe (Fig. 8.1). The depth of incision is made down  to the prostatic capsule, easily identifiable by the transversely  running connective tissue fibers. These incisions are vital to  ensure the effectiveness of the remainder of the operation,  particularly the enucleation of the lateral lobes. The two inci-  sions are joined just proximal to the verumontanum, and the  median lobe is enucleated in a retrograde direction. In many  cases, a single incision can be employed with the median  lobe tissue included with one of the lateral lobes and a  bi-lobed dissection taking place.   Dissection then continues from the previously made blad-  der neck incision laterally and anteriorly at the level of the  veru (Fig. 8.2). Once the limit of this dissection is achieved  (ideally at the 2 o'clock position), a further bladder neck  incision is made at the 12 o'clock position. This is continued  laterally and inferiorly (Fig. 8.3). The two incisions are then  joined at the level of the veru, and the lateral lobe is then  enucleated retrogradely off the capsule. The same process is  repeated on the contralateral side (Fig. 8.4).    8 The Holmium Laser in the Treatment of Benign Prostatic Enlargement 61    Following enucleation, morcellation is performed. This is  achieved by passing the morcellator (comprising hand piece,  reciprocating blades, and graduated foot pedal and controller  box — Versacut, Lumenis) via a long nephroscope.   The morcellator is often cited as a drawback preventing  widespread HoLEP uptake, but if simple principles are main-  tained, complications are rare. These principles are ensuring  meticulous hemostasis (which is efficiently achieved, with  blood transfusion rates much less than 1%) to allow vision to  be maintained, constant distention of the bladder, and precise  placement of the morcellator in the bladder cavity just inside  the bladder neck. Small fragments can be removed with a  retrieval loop (Storz), or Toomey syringe?   Postoperatively, 95% of patients require a standard 20 F  indwelling catheter, the remaining 5% requiring continu-  ous irrigation. The vast majority of men have their catheter  removed the next morning.    The holmium laser treatment of BPE has been extensively  and thoroughly studied; several large, well-designed, ran-  domized controlled trials have been published, and these are  in contrast to the majority of literature concerning alternative  treatments for BPE. This is particularly true for the green  light laser literature, the majority of which is single institu-  tion case series of short duration.   Three well-designed randomized controlled trials com-  paring HoLEP and TURP have demonstrated the following:  reduced perioperative complications, reduced catheter time,  and reduced hospital stay.   Tan et al* published the first prospective randomized trial  comparing TURP and HoLEP in 2003. All patients had exten-  sive preoperative workup, including video urodynamics.  HoLEP was superior with respect to catheter time (17.7 vs.  44 h) and hospitalization (27.6 vs. 49 h). Efficiency was equiv-  alent but the urodynamic findings were superior with HoLEP  in terms of relief of obstruction. There were no differences  between the two modalities with respect to maximum urinary  flow (Qmax) or IPSS scores at 12 months of follow-up.   Kuntz et al^ published results of a larger prospective  randomized trial in 2004. There were 100 patients in each  treatment arm, and again the results were consistent, with  reduced catheter time (27.6 vs. 43.4 h) and hospitalization  (53.3 vs. 85.8 h) in the HoLEP group. Up to 12 months of  follow-up, there were similar improvements in urinary flow  rates, but HoLEP was significantly superior with regard to  the reduction in both symptom scores and post void residual  volumes (PVR).   Montorsi et al published the first multi-center random-  ized trial comparing HoLEP with TURP.^ All patients had    extensive preoperative workup including urodynamics and  IPSS, QOL, and IIEF questionnaires. Though operating time  was longer in the HoLEP group (74 vs. 57 min), significantly  more tissue was removed in the HoLEP group (36.08 vs.  25.4g). Catheterization time (31 vs. 57.78 h), and Hospital  Stay (59 vs. 85.8 h) were superior in the HoLEP group. These  differences were statistically significant.   A meta-analysis of HoLEP vs. TURP trials demonstrated  that those undergoing HoLEP had reduced postoperative  blood loss, a shorter catheterization time, and a shorter hos-  pital stay. There were no differences in clinical outcomes  between the two groups at 6 and 12 months."    HoLEP's perioperative morbidity is low. Blood loss is mild,  with an average postoperative decrease in Hemoglobin just  over 1 g/dL. There were no transfusions required in the  HoLEP groups of the three randomized trials. ^ TUR  Syndrome also did not occur. The reintervention rate was 096  in Tan's paper? and 1% in both Montorsi's and Kuntz's stud-  ies.^^ Postoperative urinary retention rates are 0-896. Specific  to HoLEP, minor bladder mucosal injury caused by the mor-  cellator occurred in up to18%, but this did not prevent timely  catheter removal. Transient dysuria and urge incontinence  also occurs, but was not a feature at 6 month postoperative  follow-up and has been shown to be similar to TURP.°    Though HoLEP is often slower than TURP in treating moderate-  sized glands, significantly more prostate tissue is removed  with HoLEP and therefore the efficiency of the operation is  equivalent to TURP. As prostate volume increases, HoLEP  becomes significantly more efficient than TURP, and in very  large glands, HoLEP needs to be compared with open pros-  tatectomy, and in this comparison it compares very favorably.    Further enhancing the benefits of HoLEP, delayed morbidity  for this procedure is low and not significantly different from  TURP morbidity. In Montorsi's paper, 1 patient in the HoLEP  group developed a urethral stricture vs. 4 in the TURP group.^  This is consistent with Tan's findings. A pooled analysis of  over 1,800 patients demonstrated that incontinence occurred  in 1.1% of patients, urethral stricture in 1.9% of patients, and  bladder neck contracture in 1.5%.'    Earlier comparative studies of Holmium and TURP com-  menced prior to the establishment of standardized sexual  function questionnaires. More recently, Briganti et al spe-  cifically compared the impact of HoLEP and TURP on sex-  ual function. Apart from the expected impact on orgasmic  function (owing to postoperative retrograde ejaculation,  which was equal in both groups), there was no difference in  sexual function compared with the preoperative state. There  was no difference in outcome between the two surgical  groups.*    In Tan's paper, at 6 months of postoperative follow-up, the  HoLEP group had superior urodynamic parameters when  compared with the TURP group, with lower PdetQmax and  lower Schafer grades.* This is the first study showing a pro-  cedure to be urodynamically superior to TURP and is to be  expected given that the prostate volume has been shown to  reduce by 62-77% after HoLEP.    Several studies have shown that the reduction in PSA after  treatment correlates well with the amount of adenoma  resected. This is important indirect evidence to consider  when comparing established techniques such as TURP  and HoLEP with ablative techniques such as the KTP  laser, where no tissue is removed. After HoLEP, PSA com-  monly drops by 81—8696.? In larger prostates, it has been  proven that PSA can reduce by 90%.'° A recent study  demonstrated that PSA reduces by 71% after TURP,"  but only reduces by 30-42% after treatment with KTP  laser. ?    One concern with HoLEP was that the effect of the holmium  laser as well as mechanical morcellation would affect the  ability of the histopathologist to accurately assess the ade-  noma specimen. This was studied by Naspro et al, who con-  cluded that this was not the case and that the diagnosis of  incidental prostate cancer is not affected. '*    The reduced perioperative morbidity means that HoLEP can  be performed as day case surgery. A randomized study of  men with prostates less than 40 g demonstrated that day stay  HoLEP surgery was achievable, with a mean hospital stay of  12.3 h. In our experience and that of others, over 9096 of men  can be treated on an outpatient basis."    A large, well-designed randomized trial by Kuntz et al dem-  onstrated significant advantages for HoLEP when treating  large prostates. Blood loss and transfusion rates were signifi-  cantly lower in the HoLEP group, as was the median hospital  stay (2 vs. 10 days).'^ Significantly, there was no difference  in the amount of prostate tissue removed, vindicating state-  ments that HoLEP mimics the index finger of open prostate-  ctomy, without the perioperative morbidity.   Naspro et al performed a well-designed, prospective ran-  domized trial with 24 months of follow-up, comparing  HoLEP with open prostatectomy for men with prostate vol-  umes greater than 70 g. Though operating time was longer in  the HoLEP group (72 vs. 58 min), catheter time and hospital  stay were significantly shorter. Blood loss and transfusion  rates (4 vs. 13%) were also superior in the HoLEP group.  Symptomatically, there was no difference in the two groups  out to 24 months of follow-up. There was no difference in  the rates of late complications."    A common issue with alternative treatments for BPE is the  lack of treatment durability, with deterioration in objective  and subjective parameters and higher reoperation rates due  to lack of adequate prostate tissue removal. Quality data are  emerging supporting the sustained benefits of HoLEP.  Wilson et al published 24-month data from the random-  ized trial comparing HoLEP and TURP in urodynamically  obstructed patients with prostate volumes between 40 and  200 g. There was no difference in symptom scores, Qmax  scores, or quality of life scores between the two surgical  groups at 2 years. Two of the patients in the TURP group  required reintervention vs. none in the HoLEP group.'®  Vavassori et al have published 3-year follow-up data on  330 consecutive patients. This demonstrated that the clinical  improvement was sustained at 3 years of follow-up. The  reoperation rate for recurrent/residual adenoma was 2.7%."  Ahyai et al published the 3-year data comparing HoLEP and    8 The Holmium Laser in the Treatment of Benign Prostatic Enlargement 63    TURP in 200 patients. At 2 years, symptom scores were sig-  nificantly lower in the HoLEP group. At 3 years, there was  no difference in outcome measures or reoperation rates  between the two groups.” Elzayat et al have also published  long-term data, which at a mean follow-up of 48 months  demonstrate similar prolonged efficacy and low late compli-  cation rates. Interestingly, when analyzing their reoperation  rates, 4 of the 5 patients who required reintervention occurred  early in the HoLEP learning curve. Gilling et al have  recently published 6-year data. This demonstrated persistent  reductions in IPSS scores (8.5 vs. 25.7), QOL score (1.8 vs.  4.9), and Qmax (19 vs. 8.1). The reoperation rate was 1.4%.  Ninety-two percent of patients were satisfied or extremely  satisfied with the results of surgery.” We have also recently  presented our 7-year data from the trial comparing HoLEP  with TURP. At mean follow-up of 7.6 years, there was no  difference in outcomes between the two groups. At this dura-  tion of follow-up, no patient in the HoLEP groups required  reintervention vs. 3 patients in the TURP arm.”   These results obviously compare more favorably with  TURP but also highlight the lack of long-term data for other  alternative treatments for BPE. It is rare to find any quality  data for other alternative treatments beyond 12 months of  follow-up. In Kuntz's pooled analysis, 1.896 of 1,800 patients  required reoperation after HoLEP:!    Kuntz et al described their 5-year data comparing open pros-  tatectomy to HoLEP for prostates >100 g. At 5 years, both  groups had similar outcomes, with mean IPSS scores of 3.0,  and mean Qmax of 24.4 mL/s. There does not appear to be  any increase in complications when treating large prostates.  Reoperation rates were low, 596 in the HoLEP groups and  6.7% in the open prostatectomy group. There was no differ-  ence in the incidence of delayed urethral stricture formation  or bladder neck contracture.”    One of the commonly cited reasons that HoLEP has not  become more popular is the “learning curve.” This is com-  monly mentioned in editorials, usually by urologists who  have minimal experience or understanding of the technique.  There is no doubt that training and mentoring are required,  but there are some advantages over learning over TURP. As  there is no risk of TUR syndrome and hemostasis is much  easier to achieve, there is no restriction of vision and no  operative time constraints as there is for TURP. The    procedure is technically satisfying and uses anatomical  planes for the dissection and in our experience, is easier to  teach and learn, than TURP, for novices.   Like most facets of HoLEP, the learning curve associated  with it has been well studied. El Hakim concluded that 20  cases were required to achieve competence. Although good  outcomes are achieved early in the operative series, enucle-  ation efficiency improves with time.” Other studies demon-  strate that results equivalent to published experts can be  achieved after 50 cases when self-taught. When learning  HoLEP, a short intense period of instruction and mentoring  is important, as well as careful case selection of prostates  less than 60 g (ultrasound measurement).   This learning-curve data further support the broad appli-  cability of HoLEP; it has wide clinical applications, but also  need not be restricted to a talented few. When compared with  many other “standard” urological procedures, such as open  retropubic prostatectomy, laparoscopic nephrectomy, or  robotic-assisted prostatectomy, HoLEP is easier to master.    A study by Salonia et al, analyzing the inpatient costs of  HoLEP when compared with open prostatectomy, concluded  that there was a cost advantage for HoLEP of about 10%.”  At our institution, comparing the cost of Holmium laser  resection with that of TURP also demonstrated a cost advan-  tage for HoLRP of nearly 25%.** We would expect this cost  advantage to be maintained for HoLEP when compared with  TURP as more adenoma is removed and the addition of mor-  cellation has made the operation more efficient.    Aho et al performed a randomized study comparing HoBNI  to HoLEP as an outpatient procedure in men with prostate  volumes «40 g. HoBNI was significantly faster to perform,  but 10% of patients in the HoBNI group required recatheter-  ization. There was no significant difference in catheter time,  or more importantly hospital time (12.3 h in HoBNI group  vs. 13.7 h in HoLEP group). However, fewer patients  remained obstructed at 6 months following HoLEP, but this  appeared to be true only for prostates between 30 and 40 g.”  This study supports the fact that like other alternative treat-  ments for BPE, day-stay surgery is achievable in the vast  majority of patients with both HoBNI and HoLEP.    HoBNI as a catheterless day-stay procedure was described  by Cornford et al in 1998. Ninty-seven of 100 patients voided  successfully postoperatively. There were significant improve-  ments in symptom scores and urinary flow rates, which were  sustained at 2 years of follow-up.”    The use of the high-powered holmium laser has evolved to  the current technique of enucleation but the older techniques  of ablation and resection may still play a role for some urolo-  gists. Ablation was the first technique used with the hol-  mium laser (HoLAP), and has the advantage of being simple  to perform. A side-firing fiber is used to create a TURP-like  cavity.   HoLAP has been compared with TURP; this demon-  strated improved perioperative outcomes for ablation, with  reduced bleeding, catheter time, and hospital stay in the abla-  tion group.   In one of the very few studies to analyze the long-term  outcome of HoLAP, a paper by Tan et al reported 7-year data.  Although, like in most BPE studies, there were a significant  percentage of patients lost to follow-up, the study showed  that Qmax improved by a mean of 8396 and IPSS score  reduced by 47%. The reoperation rate was 1596.?! This high-  lights one of the several problems with the ablation tech-  nique. In addition, the technique is inefficient, and very slow  when used for treating large prostates. In common with all  ablation procedures, it is also aesthetically inferior when  compared with more refined anatomical techniques.   With the promotion of the high-powered KTP laser, abla-  tion has been repopularized.? In response, HoLAP has been  remarketed and may have a role to play in treating the smaller  prostate although data have recently been presented concern-  ing its use in large glands.    Prior to the development of a morcellator, the holmium laser  was used to resect tissue rather than enucleate whole lobes.  The prostate was resected in pieces small enough to be  removed whole (less than 1—2 g), or be resected once they  were in the bladder. Though this is a more effective use of the  holmium laser’s unique properties, it is inefficient when  compared with whole lobe enucleation and morcellation.  Nevertheless, HoLRP has been well studied. A prospec-  tive randomized trial comparing HoLRP with TURP showed  perioperative advantages for HoLRP; nursing requirements,    catheter time, and duration of hospital stay were superior.  There were no differences in outcome between the two  groups at 12 months.” Westenberg published 48-month data  for this comparative study. There was no difference in out-  comes between the two groups, with similar improvements  in symptom scores and urinary flow rates.**   While HoLEP is the mainstay of treatment, HoLRP has  an advantage of avoiding morcellation, which may appeal to  some urologists. It is also commonly employed in malignant  "channel" prostatectomy and for reoperations. However, this  is really only a viable primary option for smaller prostates, as  operating time is long.    HoLEP has been proven to be a safe and effective means of  treating BPE and can be used to treat prostates of any size. It  has reduced the burden of postoperative care with less post-  operative bleeding and reduced irrigation requirements. It  has obvious patient and economic advantages with shorter  hospitalization times when compared with the incumbent  procedure, TURP. The postoperative outcomes between the  two procedures are at least equivalent, and HoLEP has proven  durability out to 7 years of follow-up. This is in stark contrast  to other alternative treatments for BPE.    1. Kuntz RM. Current role of lasers in the treatment of BPH. Eur Urol.  2006;49(6):961—969   2. Elzayat E, Habib E, Elhilali M. Holmium laser enucleation of the  prostate in patients on anticoagulant therapy or with bleeding disor-  ders. J Urol. 2006;175(4):1428-1432   3. Gilling PJ. Holmium laser enucleation of the prostate (HoLEP).  Surgery illustrated. BJUI Int. 2008;101(1):131-142   4. Tan AHH, Gilling PJ, Kennett KM, et al Randomized trial compar-  ing holmium laser enucleation of prostate with transurethral resec-  tion of prostate for treatment of bladder outlet obstruction secondary  to benign prostatic hyperplasia in large glands (40 to 200 grams).  J Urol. 2003;170:1270   5. Kuntz R, Ahyai S, Lehrich K, Fayad A. Transurethral holmium laser  enucleation of the prostate versus transurethral electrocautery resec-  tion of the prostate: a randomized prospective trial in 200 patients.  J Urol. 2004;172(3):1012-1016   6. Montorsi F, Naspro R, Salonia A, et al Holmium laser enucleation  versus transurethral resection of the prostate: results from a 2-center  prospective randomized trial in patients with obstructive benign pro-  static hyperplasia. J Urol. 2008;179(5 suppl):S87—S90   7. Tan A, Liao C, Mo Z, et al Meta-analysis of holmium laser enucle-  ation versus transurethral resection of the prostate for symptomatic  prostatic obstruction. Br J Surg. 2007;94(10):1201-1208   8. Briganti A, Naspro R, Gallina A, et al Impact on sexual function of  holmium laser enucleation versus transurethral resection of the pros-  tate: results of a prospective, 2-center, randomized trial. J Urol.  2006;175(5):1817-1821    . Tinmouth WW, Habib E, Kim SC, et al Change in serum prostate    specific antigen concentration after holmium laser enucleation of  the prostate: a marker for completeness of adenoma resection?  J Endourol. 2005;19(5):550-554   Matlaga BR, Kim SC, Kuo RL, et al Holmium laser enucleation of  the prostate for prostates of 2125 mL. BJU Int. 2006;97(1):8 1-84  Fonseca RC, Gomes CM, Meireles EB, et al Prostate specific anti-  gen levels following transurethral resection of the prostate. Int Braz  J Urol. 2008;34(1):41-48   Sulser T, Reich O, Wyler S, et al Photoselective KTP laser vaporiza-  tion of the prostate: first experiences with 65 procedures. J Endourol.  2004;18:976—981   Volkan T, Ihsan T.A, Yilmaz O, et al Short term outcomes of high  power (80 W) potassium-titanyl-phosphate laser vaporization of the  prostate. Eur Urol. 2005;48:608-613   Naspro R, Freschi M, Salonia A, et al Holmium laser enucleation  versus transurethral resection of the prostate. Are histological find-  ings comparable? J Urol. 2004;171(3):1203-1206   Larner TR, Agarwal D, Costello AJ. Day-case holmium laser enu-  cleation of the prostate for gland volumes of «60 mL: early experi-  ence. BJU Int. 2003;91(1):61—64   Kuntz R, Ahyai S, Lehrich K. Transurethral holmium laser enucle-  ation of the prostate compared with transvesical open prostatec-  tomy: 18-month follow-up of a randomized trial. J Endourol. 2004;  18(2):189-191   Naspro R, Suardi N, Salonia A, et al Holmium laser enucleation of  the prostate versus open prostatectomy for prostates >70 g:  24-month follow-up. Eur Urol. 2006 ;50(3):563-568   Wilson LC, Gilling PJ, Williams A, et al A randomised trial com-  paring holmium laser enucleation versus transurethral resection in  the treatment of prostates larger than 40grams: results at 2 Years.  Eur Urol. 2006;50(3):569—573   Vavassori I, Valenti S, Naspro R, et al Three-year outcome follow-  ing holmium laser enucleation of the prostate combined with  mechanical morcellation in 330 consecutive patients. Eur Urol.  2008;53(3):599-604   Ahyai S, Kuntz R, Lehrich K. Holmium laser enucleation versus  transurethral resection of the prostate: 3-year follow-up results of a  randomized clinical trial. Eur Urol. 2007;52(5):1456-1463  Elzayat E, Elhilali M. Holmium laser enucleation of the prostate  (HoLEP): long-term results, reoperation rate, and possible impact  of the learning curve. Eur Urol. 2007;52(5):1465—1471   Gilling PJ, Aho TF, Frampton CM, King CJ, Fraundorfer MR.  Holmium Laser Enucleation of the prostate: results at 6 Years. Eur  Urol. 2008;53(4):744-749    . Gilling PJ, Wilson LC, Westenberg AM, Fraundorfer MR. A ran-  domized trial comparing the long-term results of HOLEP and  TURP in urodynamically obstructed patients: results at 7 years.  J Urol. 2008;179:671; Abstract.   Kuntz R, Lehrich K, Ahyai S. Holmium laser enucleation of the  prostate versus open prostatectomy for prostates greater than 100  grams: 5-year follow-up results of a randomised clinical trial.  Eur Urol. 2008;53(1):160-166   El-Hakim A, Elhilali MM. Holmium laser enucleation of the pros-  tate can be taught: the first learning experience. BJU Imt.  2002;90(9):863-869   Elzayat EA, Elhilali MM, Holmium laser enucleation of the pros-  tate (HoLEP): long-term results, reoperation rate, and possible  impact of the learning curve. Eur Urol. 2007;52(5):1465-1471  Salonia A, Suardi N, Nasproi R, et al Holmium laser enucleation  versus open prostatectomy for benign prostatic hyperplasia: an  inpatient cost analysis. Urology. 2006;68(2):302—306   Fraundorfer MR, Dunton N, Das A, Gilling PJ. Holmium laser  resection of the prostate is more cost-effective than transurethral  resection of the prostate: actual values based on a randomised pro-  spective trial. ANZ J Surg. 1999;696:A115   Aho T, Gilling P, Kennett K, Westenburg AM, Fraundorfer MR,  Frampton CM. Holmium laser bladder neck incision versus hol-  mium laser enucleation of the prostate as outpatient procedures for  prostates less than 40 grams: a randomized trial. J Urol. 2005;174:  210-214   Cornford PA, Biyani CS, Powell CS. Transurethral incision of the  prostate using the holmium:YAG laser: a catheterless procedure.  J Urol. 1998;159(4):1229-1231   Tan A, Gilling PJG, Kennett K, Fletcher H, Fraundorfer M. Long  term results of holmium laser ablation of the prostate. BJUI. 2003;  92:707—709   Kumar SM. Photoselective vaporization of the prostate: a volume  reduction analysis in patients with lower urinary tract symptoms  secondary to benign prostatic hyperplasia and carcinoma of the  prostate. J Urol. 2005;173(2):5 11-513   Gilling PJ, Kennett KM, Fraundorfer MR. Holmium laser resection  of the prostate (HoLRP) versus transurethral resection of the pros-  tate (TURP): results of a randomised trial with 2 years follow-up.  J Endourol. 2000;14:757—760   Westenberg A, Gilling P, Kennett K, Frampton C, Fraundorfer M.  Holmium laser resection of the prostate (HoLRP) versus transure-  thral resection of the prostate (TURP): results of a randomised trial  with long-term follow-up (4 year minimum). J Urol. 2004;172:  16-619    The application of novel technology and innovative surgical  techniques has contributed greatly to the advance of endourol-  ogy over the past two decades. Key developments include  endoscopic access to the urinary tract and advances in intra-  and extra-corporeal stone fragmentation techniques. Of these  techniques, laser technology has also been applied to other  branches of urology including prostate surgery, ablation of  urothelial tumors, and treating urinary strictures. The safe  introduction of this potentially hazardous technology has  required defining stringent safety guidelines, which encom-  pass protection of both the patient and the user. In this chap-  ter, physics of laser is discussed, along with the review of its  application in treating stones.    The foundations for the development of this technology can  be traced to theories developed by Albert Einstein and  Satyendranath Bose whose work on photons were the basis  of the stimulated emission of radiation. In the early 1950s,  Charles Townes and colleagues developed a “maser,” based  on microwave amplification, which was applied to atomic  clocks, receivers in radio telescopes, and other uses. In fact,  Townes did publish a paper in 1958 describing the theoreti-  cal possibility of a laser, with light rather than microwaves  being amplified; he subsequently went on to share the Nobel  Prize for Physics in 1964.   The acronym LASER (light amplification by stimulated  emission of radiation) dates from the late 1950s when Gordon  Gould used the term in his doctoral thesis.!    The laser beam is generated by passing light through a “las-  ing medium,” which is a material with properties that allow  it to amplify light by stimulated emission of photons  (Fig. 9.1). The medium may be solid, liquid, gas, or plasma.  As the medium absorbs energy, electrons are raised into a    higher-energy state; upon dropping down to a lower-energy  level, photons are emitted. When the photons collide, further  photons are emitted. Photons are reflected along the optical  chamber with opposing mirrors at either end generating the  laser beam.   The characteristics of a laser beam are that it is coherent,  collimated, and monochromatic. This means that the energy  waves are in phase, do not diverge (1.e., are focused), and are  of a single wavelength (unlike white light). The wavelength  is determined by the lasing medium used, and this in turn  helps to determine the depth of penetration of the beam.   As the laser beam encounters tissue, it will be absorbed,  scattered, and reflected depending on the characteristics of  the tissue and laser, respectively. The most important of these  is absorption, with the intensity of the laser beam decreasing  exponentially as the beam enters the absorbing medium  (Lambert-Beer law). The laser energy is converted to heat,  which thereby causes tissue coagulation or vaporization.    Lasers are generally classified as to the type of laser medium  or by their effect on human tissue (principally their propen-  sity to damage skin and retina). Differences between medical  lasers and other applications are summarized in Table 9.1.    Common solid-state lasers include Nd:YAG (neodymium  yttrium aluminum garnet) which has a wavelength of 1,064  nm and Ho:YAG (holmium) with a wavelength of 2,100 nm.  Of these, the Holmium has generated the greater interest in  the past few years, possibly related to its application in a  range of surgeries including calculi as well as prostates and  strictures. The wavelength approaches that of water (1,910  nm), and both prostate and renal stones contain significant  amounts of water and therefore absorb holmium laser energy.  Mucosal effects are limited, even with direct contact, to a  depth of penetration of 0.4 mm, thereby limiting collateral  damage.   Another laser finding widespread application more  recently in urology is the KTP (potassium titanyl phosphate).  This is in fact a modification of Nd:YAG, the product of  which is passed through a KTP crystal, thus halving its wave-  length to 532 nm. As this wavelength is well absorbed by  hemoglobin, this laser is particularly suited to photoselective  vaporization of prostate (PVP) tissue. The depth of penetra-  tion is 1-2 mm. Another variation is the FREDDY laser (or  frequency doubled double pulse Nd:YAG laser), which  switches between the 1,064 and 532 nm wavelengths, allow-  ing the same laser to be used for both lithotripsy and prostate  ablation.   Like Holmium, Thulium is also a rare earth metal, and has  been developed as a laser in recent years. Factors including  cost have prevented its widespread use so far, but there are  now several studies supporting its use in the treatment of  bladder outflow obstruction.    Gas lasers include those using CO, (9.6, 10.6 um) and Argon  (350-500 nm). The CO, laser is an infrared laser, with a long  wavelength (10,640 nm) that produces a very short depth of  penetration (less than 0.2 mm), lending itself to treating  superficial lesions (e.g., penile lesions).    Pulsed dye lasers were used during the early development of  laser technology in urology, but advances in laser technology  have generally replaced these lasers, which were based on  organic dyes as the medium.    The four main modalities for endoscopic stone fragmenta-  tion are pneumatic (electrokinetic), ultrasonic, electrohy-  draulic, and laser. Laser lithotripsy is now generally  synonymous with holmium laser treatment. The basis for  stone fragmentation with the holmium laser depends on a  combination of photothermal, photomechanical, and cavita-  tion-bubble effects. Unlike the mechanical modalities of  ultrasound or pneumatic lithotripsy, the laser involves absorp-  tion of its particular wavelength by the water molecules of  the stone. Vaporization of these molecules then leads to bub-  ble formation within the stone, and their collapse leads to  fragmentation. A second effect is that of a thermochemical  reaction at the stone surface, such that the laser causes crater  formation by “stone meltdown" at the stone surface. Third,  the laser generates a spherical cavitation bubble, which then  produces a shock wave upon its collapse; this shock wave  produces the photoacoustic effect of stone fragmentation  upon hitting the stone. The longer the pulse width of the laser  (duration of each pulse of laser energy), the greater the  energy involved in generating the cavitation bubble — this  mechanism is similar to pneumatic lithotripsy, for example,  but is only one of the several mechanisms of action of the  laser as mentioned. Comparisons of laser with other modali-  ties are shown in Table 9.2.   A key advantage of the laser is that there is less retropul-  sion of the stone. There is some migration of the stone (due  to generation of internal shock waves and creation of vapor  bubbles, which push away the stone) but less so than the  pneumatic lithotrite, for example. Other modalities create a    Study Comparison Results  Bapat Laser vs. Fragmentation Secondary  et al^ pneumatic (97% laser procedures (2%  vs. 81% laser vs. 14%  pneumatic) pneumatic)  Manohar Laser vs. Stone-free rates Secondary  et al’ pneumatic (84% laser procedures  vs. 88% (12% laser vs.  pneumatic) 16%  pneumatic)  Ziaee URS vs. Stone-free rates  et al ESWL (72% URS  vs. 79%  ESWL)  Hautmann URS vs. Stone-free rate  et al’ ESWL (97% URS  vs. 78%  ESWL)    very strong shock wave with “scatter” of energy and poten-  tial injury to the adjacent urothelium. As this is less apparent  with laser fragmentation, its use is favored for ureteric stones.  Furthermore, the laser’s ability to break stones to dust parti-  cles gives the benefit of not needing to remove fragments  endoscopically (e.g., with graspers or baskets) and even pos-  sibly avoiding the need for a stent. The smaller diameter  fibers (200 or 365 um) used with a holmium laser enable  fragmentation of upper tract stones that are accessed using a  flexible ureterorenoscope; this is not achievable with mechan-  ical lithotrites as they do not permit deflection of their  probes.   Power settings vary, but typically holmium laser stone  fragmentation is performed with incremental increases in  power from 0.5 to 1.0 J at 6-10 Hz, with higher settings being  usually reserved for the kidney or ablative procedures.   Choice of laser machine depends on the likely uses — more  expensive high-energy machines offer the versatility of  application to ablative, e.g., prostate surgery, though the  energy for this is far higher (at 80—100 W); if solely used for  stone treatment, a lower energy holmium machine (20-30  W) can be used, with considerable cost savings albeit less  versatile.    Discussion of lasers in prostate surgery is beyond the scope  of this chapter, except for a broad outline. Since the intro-  duction of pulsed coumarin dye lasers in the 1980s,’ urol-  ogy has witnessed a reemergence of the popularity of this  therapy with the arrival of the ablation and enucleation  techniques. The KTP (or *"Greenlight") laser uses a    wavelength of 504 nm, and produces a vaporization of the  prostate by its side-firing ablative delivery — the PVP. The  holmium laser (wavelength 2,100 nm) has also been applied  in an ablative role, though its end-firing fiber can also be  used to enucleate the prostate, a similar principle to tran-  surethral resection of prostate (TURP) — the so-called hol-  mium enucleation of prostate (HoLEP). One of the  advantages of the enucleative technique is that it provides  tissue for histological analysis, though there have been  comments about the longer learning curve when compared  with the relatively easier method of vaporization, and also  removal of the enucleated prostate lobes requires a dedi-  cated morcellation device. Nevertheless, HoLEP provides  the advantages of reduced bleeding, avoidance of TUR  syndrome (by using saline instead of glycine), and option  of treating larger glands than the traditional TURP as  there are no safety time constraints (akin to Millin's  prostatectomy).    There is increasing familiarity with the use of the laser with  a flexible cystoscope in the treatment of small bladder tumor  recurrences, which have traditionally been diathermized.  The practical limitations of laser availability for these cases  are more restrictive than the actual technical aspects of this  treatment.   In the upper tract, there appears to be increasing accep-  tance of laser treatment of small, focal, low-grade low vol-  ume disease, which traditionally would have been dealt with  by radical nephroureterectomy. Although the latter is still  arguably the “gold standard" for the treatment of upper tract  transitional cell tumors, there is increasing long-term evi-  dence for the safe use of laser ablation of tumors.’    Although there may be a role for lasers in the management  of strictures in the ureter and pelvi-ureteric junction, this  field is more controversial. The primary management of an  idiopathic PUJ obstruction remains a pyeloplasty, though  some advocate the use of endopyelotomy following failed  pyeloplasty. The use of lasers to perform this incision has  been proposed in some centers,’ just as incision of ureteric  strictures has been performed using the holmium laser by  some.? The long-term success or failure of these proce-  dures may be a reflection of the actual operation itself  rather than the energy modality (e.g., laser) used to carry  it out.    The management of stones in different clinical settings will  often be determined by the availability of an energy source to  break the stone and the range of endoscopic equipment on  hand. While a distal ureteric stone can be successfully cleared  with electrokinetic force as well as laser, a higher ureteric  stone or a stone in the kidney may need greater versatility as  seen with a laser probe through a flexible ureterorenoscope.  Several studies have compared laser with other treatments  for ureteric stones, in particular for those in the proximal ure-  ter. These include recent comparisons with pneumatic litho-  tripsy®’ and also ESWL.*?    One of the concerns of holmium usage has been with uric  acid calculi owing to the release of cyanide as a by-product.  Incremental increases in cyanide production are seen with  higher energy settings with a recommendation to keep power  settings below 1.0 J,'°'' though systemic absorption of this  leading to death has not been reported. Other stones that may  be refractory to laser treatment include calcium oxalate  monohydrate.    The recently updated EAU guidelines on the management of  ureteric stones include recommendation for safe use of uret-  eroscopy. This mentions studies describing safe use of hol-  mium laser during ureteroscopy in pregnancy, and proposed  that this is a reasonable option in specialist centers after fail-  ure of conservative treatment. Watterson et al described eight  pregnant patients at two tertiary centers who were treated for  symptomatic urolithiasis or encrusted stents, and reported no  obstetric complications of ureteroscopy with holmium laser  treatment."    Safety training is mandatory for all staff involved in laser  treatments. These measures include those relating to the  treatment area (e.g., operating room), staff, and patient. The  operating room must have clear warning signs prohibiting  entry during laser use, be locked while the laser is in use,  have darkened or shielded windows to prevent errant laser    light; the laser machine should be stored in a safe location,  and the starting key/switch be the responsibility of a named  individual. Energy use should be documented in a book each  occasion the laser is used.   The patient should be given protective eyewear even if the  eyes are closed during a general anesthetic. Similarly, all  staff in the operating room require protective eyewear. Clear  instructions should be given for when the laser is to be acti-  vated and switched off.    Future improvements in laser technology are discussed in a  review paper by Pierre and Albala.'* Changes in the laser  machines (based on the lasing medium) as well as the optical  laser fibers for delivery of the laser energy are described.  Other factors such as patient demands and market costs will  also influence choice of lasers in the future.    1. Gould G, Gordon R. The LASER, light amplification by stimulated  emission of radiation. In Franken PA, Sands RH, eds. The Ann Arbor  Conference on Optical Pumping. University of Michigan;1959   2. Watson GM, Wickham JE. Initial experience with a pulsed dye laser  for ureteric calculi. Lancet. 1986;1:1357—1358   3. Lucas SM, Svatek RS, Olgin G, et al Conservative management in  selected patients with upper tract urothelial carcinoma compares  favourably with early radical surgery. BJUT. 2008;102(2):172-176   4. Biyani CS, Cornford PA, Powell CS. Retrograde endoureteropyelo-  tomy with the holmium:YAG laser. Initial experience. Eur Urol.  1997;:32(4):471-474   5. Bagley D, Erhard M. Use of the holmium laser in the upper urinary  tract. Tech Urol. 1995;1(1):25-30   6. Bapat SS, Pai KV, Purnapatre SS, et al Comparison of holmium  laser and pneumatic lithotripsy in managing upper-ureteral stones.  J Endourol. 2007;21(12):1425-1427   7. Manohar T, Ganpule A, Desai M. Comparative evaluation of Swiss  LithoClast 2 and holmium:YAG laser lithotripsy for impacted  upper-ureteral stones. J Endourol. 2008;22(3):443-446   8. Ziaee SA, Halimiasl P, Aminsharifi A, et al Management of 10-15-  mm proximal ureteral stones: ureteroscopy or extracorporeal shock-  wave lithotripsy? Urology. 2008;71(1):28-31   9. Hautmann S, Friedrich MG, Fernandez S, et al Extracorporeal  shockwave lithotripsy compared with ureteroscopy for the removal  of small distal ureteral stones. Urol Int. 2004;73(3):238—243   10. Teichman JM, Vassar GJ, Glickman RD, et al Holmium: YAG litho-  tripsy: photothermal mechanism converts uric acid calculi to cya-  nide. J Urol. 1998;160(2):320-324   11. Corbin NS, Teichman JM, Nguyen T, et al Laser lithotripsy and  cyanide. J Endourol. 2000;14(2):169-173   12. Watterson JD, Girvan AR, Beiko DT, et al Ureteroscopy and  holmium:YAG laser lithotripsy: an emerging definitive manage-  ment strategy for symptomatic ureteral calculi in pregnancy.  Urology. 2002;60(3):383-387   13. Pierre SA, Albala DM. The future of lasers in urology. WJU.  2007;25:275—283    Bladder cancer is the fourth most common cancer in men  with 8,373 new diagnoses of bladder cancer made in the  United Kingdom in 2006' (Incidence of 29.3 per 100,000 in  men; 9.3 in women). Initial diagnosis is usually made endo-  scopically using both macroscopic appearances and micro-  scopic features of the tumor. Tissue is commonly obtained  via transurethral resection of bladder tumor (TURBT) using  diathermy, but if the tumors are small and/or the bladder is  thin, cold cup biopsy forceps with diathermy coagulation  may be used.? The mainstay of surveillance currently is out-  patient local anesthetic flexible cystoscopy. Any recurrences  identified are then initially treated with TURBT or biopsy  and cystodiathermy with further treatments given depending  on the clinical indications.   With the advent of laser technology and its use in other  areas of urology, much interest has been generated in the use  of lasers to treat bladder tumors. Laser therapy for bladder  cancer was first reported in Germany in the 1970s and  approved for use in the USA in 1984 but is still not the stan-  dard of care. In particular, the perceived benefit of improved  hemostasis (allowing catheter-free treatment and facilitating  treatment of patients on anticoagulants) and the possibility  of performing procedures under local anesthetic make this an  attractive option. This chapter reviews the potential role of  different types of lasers in bladder cancer management, look-  ing at the evidence for both ablation and, more recently,  resection using this technology.    Lasers deliver energy as photons of light generated by excited  atoms returning to their resting energy state.? The wavelength  is determined by the properties of the lasing medium. Tissues    contain chromophores that selectively absorb light of differ-  ent wavelengths; effects are generated via thermal energy —  coagulating or vaporizing tissues depending on the amount  of heat involved. If coagulative necrosis is achieved, the tis-  sue maintains its structure and heals via deposition of  collagen.   Surgical lasers have differing properties depending on the  substance used to produce the laser (the lasing material,  which determines the wavelength) and chromophore that  absorbs the laser energy in tissues, e.g., blood or water. The  laser's penetration is measured by the extinction length, the  depth at which 9046 of the incident laser energy is absorbed  and converted into heat. Lasers with different extinction  length are suitable for different therapies.   Lasers are already widely used in urological surgery to  ablate and resect prostates, fragment stones, incise strictures,  treat genital warts, and ablate upper tract transition cell car-  cinoma. They are particularly suited to endourological sur-  gery because the fibers are small enough to fit down the  working channel of scopes, relatively flexible, and can be  targeted to produce a relatively small area of heating effect —  to treat the pathology and spare healthy tissue. Of crucial  importance, lasers have good hemostasis on soft tissues and  can maintain the endoscopic field of view.    Lasers can be used for bladder tumor ablation and/or tumor  resection depending on the type of laser used and its power  settings.^^ An advantage of using laser in bladder tumor  ablation is that it seems to be less painful than standard elec-  trocautery, which some authors have suggested is due tothe  rapid heating destroying neural tissue in contrast to electro-  cautery, which causes current to propagate backward along  nerve fibers (Table 10.1). This potentially allows ablative  treatment under local anesthetic in an out-patient setting.   It has also been reported that laser treatment does not  excite the obturator nerve, negating the need for paralysis of    Table 10.1 Advantages and disadvantages of lasers in the treatment of  bladder tumors    patients with tumor on the lateral wall of the bladder. In the-  ory, this should allow a more complete resection of tumor in  this notoriously difficult location. It is also useful for the  treatment of tumors in other difficult locations — bladder  diverticulum and near the ureteric orifice.   The bleeding is less when using a laser compared with  diathermy and therefore a decreased requirement for irriga-  tion.? This allows the treatment of patients with coagulopa-  thies or on anticoagulants with less morbidity. Also, the  decreased requirement for irrigation facilitates catheter-free  surgery and, therefore, day case treatment." Intra-  operatively, saline is used for irrigation rather than glycine,  thus avoiding the rare complication of TUR syndrome.    The main disadvantage of using a laser for the treatment of  bladder tumors is the loss of tissue for histological analysis,  which has often limited its use to low-grade, superficial, recur-  rent tumors.?? There are specific changes that are induced in  the urothelium in response to the laser — coagulation necrosis,  ulceration, granulation, and healing by fibrosis — which make  histological interpretation difficult particularly with respect  to accurate staging.”   The potential for perforation of the bladder or nearby  pelvic organs (especially bowel) is a complication of the  Nd:YAG laser but with the newer lasers the depth of penetra-  tion is so much lower that this is largely a historical compli-  cation. ^'^ However, the lack of depth of penetration can lead  to inadequate treatment of tumor.   Regardless of the type of laser used, the theater staff and  surgeon must be formally trained in its use and be available  when required. There are strict legal requirements for laser  safety: staff and patient wearing goggles, room to have lim-  ited access, all windows are covered, signs outside the the-  ater, etc.    The expense of the treatment (laser machine and fibers)  can be either a disadvantage or an advantage depending on  whether it is being bought specifically for this purpose or if  procedures previously requiring admission and general anes-  thesia are now day cases.    The neodymium: YAG laser was the most commonly used at  the outset of laser treatment of bladder cancer and many of  the published studies are, therefore, based on this laser.^?  Recently, however, it has been superseded by the holmium:  YAG laser, perhaps not only due to its use in other areas of  urology — causing it to be more readily available in depart-  ments — but also due to its safer tissue penetration.” In the  last year, reports of thulium: YAG laser offer a new and poten-  tially exciting development in the use of lasers for bladder  cancer treatment?!    The Nd:YAG laser was the first laser to achieve widespread  use in urology. This laser uses a Neodymium:YAG crystal  (Yttrium Aluminum Garnet) and produces an invisible light  of continuous 1,064 nm wavelength. The long extinction  length and penetration of 5-10 mm are due to its poor absorp-  tion by both water and tissue. The Nd:YAG laser causes  damage by coagulative necrosis. Macroscopically, the tissue  appears ulcerated and covered with eschar in the acute phase.  Microscopically, areas of necrotic tissue are seen, which are  sharply delineated from adjacent tissue. At about 8 weeks,  these lesions show healing and marked granulation tissues  and chronically dense fibrosis occurs."?   The deep penetration gives effective coagulation and can  achieve transmural coagulation of the bladder wall without  perforation; however, the long extinction length can also  result in tissue damage to pelvic organs beyond the bladder,  e.g., bowel in the absence of bladder perforation.'*'* This is  particularly pertinent in thinned areas, e.g., the dome of the  bladder and, in these cases, it is important to keep the bladder  relatively empty to reduce this risk. In a series of over 2,000  cases, the rate of intestinal perforation was 0.0196. The  authors advised a lower power of 30 W with the Nd:YAG  laser in patients who have had previous laser therapy to the  bladder or tumors on the posterior bladder wall."   The standard noncontact Nd:YAG technique uses 30—40  W of energy, with the fiber held 3-4 mm from the lesion  surface; energy is then applied in a continuous fashion to  coat the surface. The tumor undergoes whitish discoloration    as it is coagulated, and these areas may then be displaced to  treat deeper layers. Hemostasis is such that continuous irri-  gation and routine postoperative catheterization are rarely  needed. The dangers of bladder injury and occult bowel per-  foration have led to the Nd:YAG largely losing favor for  treatment of bladder tumors.    When an Nd:YAG laser is used in combination with potas-  sium titanyl phosphate crystal, a visible green light laser is  produced with a wavelength of 532 nm. This laser therefore  has short extinction length with tissue penetrance of 1—2  mm. In well vascularized tissues, penetrance can be as little  as 1-2um creating high temperatures, which vaporize tissue.  The absorption in water is low leading to concerns about the  effect of scattered photons or the misfired laser beam. This  laser could be used for treating superficial lesions and poten-  tially has a greater margin for safety, but would be very slow.  There are no reports of its use in the literature for the treat-  ment of bladder cancer probably due to the better efficacy of  holmium: YAG.    A greater understanding of the behavior of light and tissue  interactions led to the development of the 2,100 nm  Holmium: YAG laser? There are also thulium ions present,  which provide cross-relaxation preventing the laser from  generating an excessive amount of heat and allowing it to fire  at a repetitive pulsed rate at room temperature. The holmium  laser experiences a short extinction length both in tissue and  in irrigation fluid, as it is absorbed by water. The laser can  produce both coagulation and tissue vaporization depending  on power properties and because it is absorbed well by water,  penetrance is limited to 0.5-1 mm. This makes it safer in the  bladder than Nd YAG, but it can be more time-consuming  and care must be taken to ensure adequate penetration of the  tumor base.    The most recent development is the Thullium:YAG laser, a  continuous laser on a similar wavelength to the holmium: YAG  laser (2,000 nm), but the thulmium ions are excited directly  by high-power laser diodes.? This increased power efficiency  avoids excessive heat generation and so negates the require-    ment for elaborate cooling and insulation mechanisms. The  pulsed holmium laser creates a tearing action on tissues,  whereas the continuous output from the thullium laser gives  smoother incisions and better vaporization and coagulation.  Early results using this laser for prostate vaporization and  more recently for ablation of bladder tumors are emerging in  the literature."    Transurethral resection although still the standard treatment  for bladder cancer has a number of limitations, one of which  is that cutting into the tumor and shedding viable tumor cells  into the bladder may be one of the factors responsible for  tumor recurrence.” Laser ablation allows noncontact  tumor necrosis, which may explain the decrease in local  recurrence reported with laser ablation." ?   Several techniques for ablating bladder tumors have been  described over the years. Initially, the Nd: YAG laser was  used with energy applied circumferentially to the tumor  including a margin of 0.5—1 cm to ensure treatment of sur-  rounding precancerous areas, coagulation of vessels, and in  particular, lymphatics around the tumor." However, subse-  quent studies have not confirmed the "sealing" of lymphatics  and no dynamic scintography trials have confirmed this  hypothesis. Depending on the clinical factors, the tumor was  then sampled using biopsy forceps and the remaining tissue  was ablated with the laser. More recently, Holmium and then  Thulium lasers have been used to ablate tumors and this has  usually been achieved by noncontact "painting" of the laser  onto the tumor until white discoloration is seen indicating  coagulation. If this could not be achieved, then the contact  technique was used to vaporize the tissue.”    Beer et al report their experience of using an Nd:YAG laser  to treat 400 patients with superficial bladder cancer over an  8-year period." A 0.6 mm quartz fiber with a continuous  wave output and power of 40—50 W was applied to each area  for 3-4 s to coagulate bladder tumors under spinal or local  anesthetic. In tumors 20.5 cm diameter and in patients with  evidence of infiltration, a preoperative staging transurethral  resection was also performed. In smaller tumors, tissue for    histological examination was first removed using biopsy for-  ceps. They found that the general recurrence rate (33-54%)  was not significantly different to the recurrence rate amongst  similar patients undergoing electrocautery but the local  recurrence rate was significantly reduced in those treated  with laser (7 vs. 25%).   A similar finding was seen in an earlier prospective ran-  domized trial of standard TURBT with laser ablation for T1  and T2 tumor recurrences of bladder cancer.'* Local recur-  rence was reduced in the laser treatment group but overall  tumor recurrence rate was similar. This has been confirmed  in other studies."   To assess the effect of laser ablation on invasive bladder  tumors, Tarantino and colleagues used an Nd:YAG laser to  ablate tumors in 18 patients with clinical T1 to T3 disease  prior to radical cystectomy but after an initial transurethral  resection of tumor.” Eleven of the 18 patients had pathology  at cystectomy, which was unchanged or had progressed since  the patients' original transurethral resection. Seven of the  patients had a lower pathological stage (three had no residual  tumor). Results were more favorable in the group of patients  who had a shorter time between laser ablation and cystec-  tomy, suggesting that progression may have been due to  recurrence rather than incomplete original resection.   There are more limited studies published using laser to  treat invasive bladder cancer. The depth of penetration of the  Nd:YAG laser is an advantage here allowing treatment  through to the tumor base to be applied endoscopically. A  management strategy combining transurethral resection by  electrocautery and laser ablation was used in 15 patients with  T2 disease. Ten patients were followed for a mean of 57  months without evidence or recurrence, one patient died of  an unrelated disease and was found to have no evidence of  disease at autopsy, and the remaining four patients failed  treatment and went on to either cystectomy or external beam  radiotherapy.”   The depth of penetration of Nd:YAG although useful in  treating invasive cancer increases the potential for bowel  injury. Combination of laser ablation and transperitoneal lap-  aroscopy with mobilization of bowel away from the bladder  wall and continuous visual monitoring has been described.  This allows treatment of more invasive tumors and treatment  of tumor on the serosal surface of the bladder. The laparo-  scopic technique also permits bladder biopsy and assessment  of pelvic lymph nodes but does not seem to offer an advantage  over standard TURBT. This technique is reported in a small  series of 5 patients with T2-T3a bladder cancer who were  unfit for cystectomy.” The treatment was trialed as palliation  in these patients, who had frequent recurrences of problem-  atic bleeding. A power of 50 W was used endoscopically and  20 W laparoscopically in two patients. Four of the 5 patients  developed local recurrences within 1—4 months postopera-  tively and 3 required transurethral resection for symptom    control. The advanced stage of disease is demonstrated in the  fact that 3 patients had distant metastases within 9 months.    The properties of laser ablation with respect to improved  coagulation and lower anesthetic requirements have led to an  interest in its use in those with superficial bladder tumors  and/or significant comorbidities.” 6   The relatively low intensity of pain when compared with  electrocautery techniques combined with the fact that laser  fibers can be used in combination with flexible cystoscopes  enable this treatment to be delivered in the out-patient setting  and under local anesthetic (Fig. 10.1). Clearly, this is particu-  larly advantageous in patients with multiple comorbidities in    whom resection under general anesthetic carries a significant  risk. Laser ablation is reported to achieve better hemostasis  than standard electocautery and diathermy, and many series  describe treatment of anticoagulated patients without inci-  dent. However, this has not always been the experience of the  authors. Decreased blood loss is important in those with  comorbidities and the patient can be catheter-free immedi-  ately post procedure, which also allows the procedure to be  performed without requiring an overnight stay.   The largest series reported as yet is that of Jonler et al from  Denmark. This series of 88 procedures in 52 patients  describes the treatment of superficial (TaG1) bladder tumor  recurrences with holmium:YAG laser under lignocaine gel  anesthesia. They used a 40 W holmium:YAG laser delivered  through a 0.2—0.4 mm fiber held a few millimeters from the  tumor. The tumor was then coagulated or vaporized depend-  ing on the energy delivered. An average of two tumors was  treated in each patient ranging in size from 2 to 30 mm (mean  5 mm). The procedure took approximately 15 min. Eighty-six  percent of procedures were completed with no complaint of  pain from the patient and no procedures were terminated  owing to pain. On questioning, all of the patients would chose  this method of treatment over a standard general anesthetic  TURBT should they develop further suitable tumors. In 88  procedures, three complications arose: one patient required  urethral catheterization post procedure, one required interven-  tion for bleeding, and a third developed epididimo-orchitis.   Of note, the authors reported the technique to have a short  learning curve. The five surgeons performing the local anes-  thetic procedures were questioned as the difficulty of each  procedure. Seventy-eight percent were described as easy.  The surgeons halved their operating time between the first  and last cases of their own series, and reported confidence in  tackling larger or more numerous tumors.   The local anesthetic laser ablation was 350€ cheaper than  a comparable day case TURBT and 1,350€ cheaper than a  TURBT requiring overnight stay. Since the procedure could  be carried out in clinic, the further advantages were freeing  up of the department's operating theater for other procedures  and the requirement of a substantially smaller team to oper-  ate (two compared with five for a TURBT).   Soler-Martinez and colleagues used a 10 W holmium  laser (less expensive than the higher-power lasers) through a  flexible cystosope to ablate early recurrences of superficial  bladder tumors (pTaG1).™ Thirty-six patients were treated  under local anesthetic and intravenous sedation. All patients  had a cold cup biopsy taken at the beginning of the procedure  and at the end of the procedure 40 mg of mitomycin was  instilled intravesically. Patients tolerated this well and were  discharged the same day catheter-free. This technique had an  overall recurrence rate of 2596 at 12 months.   A study carried out by German et al has shown that  5-1096 of patients with superficial bladder cancer will    develop recurrences that are small in size and number.” If  laser ablation under local anesthetic proves to be comparable  with cystodiathermy in the longer term as current research  suggests, these patients could be treated in the out-patient  setting without the risks and resources associated with a gen-  eral anesthetic procedure.   In summary, from the literature and our own experience,  holmium laser ablation of superficial bladder tumors under  local anesthetic seems safe, effective, and well tolerated by  patients. The technique appears easy to learn and presents  several resource advantages in that it can save money and  theater operating time. It is a particularly attractive technique  for use in the elderly and those with multiple comorbidities.    Though evidence is mounting to suggest laser ablation of  tumors may be comparable with TURBT in terms of tumor  recurrence rate and favorable with respect to complications,  there remains a significant limitation to the technique. The  coagulation and vaporization of bladder tumors affects the  volume and quality of tissue available for histological analy-  sis. Tumor histology is clearly important for prognosis and  also for differentiating superficial from muscle invasive can-  cers (Fig. 10.2). Radiological imaging has proven unreliable  at demonstrating muscle invasion, leaving biopsy as the only  method. These problems have largely prevented the use of  lasers to treat primary tumors. Research on lasers and bladder  tumors has mainly been in cancer recurrences where the ini-  tial tumor was superficial on histology and where the recur-  rences were also judged by the surgeon to be superficial.  Exciting new developments have been reported in the litera-  ture using holmium and thullium lasers for en bloc resection  of bladder tumors.?*? (Fig. 10.3). The anticipated oncologi-  cal benefits of such a technique are: ability to resect tumors  en bloc for histological analysis, coagulation of the tumor  margins at resection by the laser potentially decreasing tumor  cell scatter, and use of the laser to treat the tumor base.   Das et al published their work in 1998 reporting the use of  holmium laser to resect bladder tumors (HoLRBT).”’ Using  a modified resectoscope and an end firing fiber, they per-  formed resections on 23 patients with newly diagnosed blad-  der transitional cell carcinoma (TCC). Cold cup biopsies  were then taken of the tumor base and compared with the  resection specimens. These biopsy specimens did not alter  the stage of the bladder tumor in any case implying that the  laser resection gave an accurate way of staging the tumor.   In 2008, Zhu and colleagues working in Beijing published  work with holmium laser resection of bladder tumor  (HoLRBT) as a primary treatment for clinically nonmuscle  invasive bladder tumors.’ One-hundred and one patients    Fig. 10.2 Examples of bladder tumor specimens: (a) superficial (b) invasive   laser fiber. (a) Laser fiber fi "d  circumscribing base. (b) b    were treated with an en bloc resection (allowing histological  analysis) and coagulation of the base of the tumor followed  by a postoperative intravesical mitomycin C regimen. For the  HoLRBT group, a 100 W Holmium:YAG laser was used  with a 550 um fiber through a 5F open-ended ureteric cath-  eter. These patients were compared with 111 similar patients  who underwent conventional transurethral electroresection  of bladder tumor (TURBT). Both groups had a similar dis-  ease-free survival. The patients undergoing HoLRBT had a  significantly longer operative time but significantly shorter  length of catheterization. There were no obturator kicks in  the HoLRBT group but 7/111 in the TURBT group with  three perforations. Histology was adequate with minimal  effect from thermal artefact. The authors conclude that  HoLRBT may represent a promising alternative to TURBT.    Itis not yet clear how treatment with the newly developed  thulium laser can be compared with holmium laser for the  resection of bladder tumors.**** A recently published case  series reports its use in the treatment of recurrent superficial  bladder cancer (ThuRBT).*! Thirty-two patients were treated  via flexible cystoscopy under general anesthetic. A 200 um  fiber was used at power levels of 5-15 W in a continuous and  pulsed mode. After coagulating the tumor, it was removed  with biopsy forceps and random biopsies were taken off the  tumor base, margin, and bladder. Mean tumor size was 1.5  cm and mean operation time was 25 min. Two patients  required irrigation postoperatively and all had a urinary cath-  eter, which was removed the following day. Recurrence rates  were 28% at 12 months. In the discussion, the authors com-  mented that while vaporization with the holmium laser  results in little or no tissue left for histological examination,  in contrast, tissue was obtained in all cases with ThuRBT.  Unfortunately, however, the architectural detail was dis-  torted, so that while tumor grade was available for every  case, the pathologist was not always able to stage the tumor.    A novel approach to the treatment of bladder tumors is to use  gene therapy to influence the disease at genetic level.  Although some advances have been made in this area, the  major difficulty has been delivering the gene and transport-  ing it into the cell. Transfection rates of naked DNA into a  cell are poor. Work published in 2002 by Knoll and col-  leagues from Mannheim, Germany, looked at the effect of  laser energy on DNA transfection rate in vitro.** A suspen-  sion of transitional carcinoma cells was mixed with DNA  plasmids and subjected to laser energy from neodymium: YAG  or holmium:YAG lasers. FACS analysis looking for the  reporter gene in cancer cells showed that Nd: YAG was not  effective but holmium: YAG laser was found to increase the  transfection rates to satisfactory levels. Transfection rate fur-  ther increased with increasing frequency and energy levels  (optimum 10 Hz, 2,000 mJ) (rates rose from 18.3 to 58.3%).  With further analysis, gene therapy could offer an alternative  intravesical therapy to decrease implantation of tumor cells  at the time of transurethral resection.    Laser technology has been used to resect and ablate bladder  tumors over the past 30 years. A variety of lasers have been  tried but neodyium: YAG, holmium:YAG, and more recently    thulium: YAG are the only ones with clinical application for  the bladder. Initial studies used a neodyium: YAG laser with  a penetration depth of 4-6 mm but holmium:YAG laser is  now in common use for prostate and stone surgery and there-  fore available in many departments. It has a wavelength of  2,140 nm and depth of penetration of only 0.3-0.4 mm mak-  ing it an attractive option for resection in the bladder. Several  studies have shown laser TURBT using a 550 um fiber to be  feasible, but there are still questions regarding the adequacy  of the specimen for histology. The main advantages of laser  resection are improved hemostasis potentially facilitating  catheter-free day case treatment, resection in saline, and en  bloc resection. An exciting potential for laser treatment in  bladder tumor is the ablation of recurrent papillary tumors  under local anesthetic using a holmium or thulium laser fiber  through a flexible cystoscope. The advantage offered over  electrocautery is less discomfort and bleeding allowing out-  patient treatment of higher volume tumors and patients on  anticoagulation. Given the high incidence of TCC of the  bladder, the co-morbidity of the patients, cost of inpatient  admission, risks of general anesthesia, frequent recurrence  and the indolent nature of many tumors, and treatment under  local anesthetic in the “office” setting are attractive for both  the patient and the surgeon.    1. Office for National Statistics. Cancer Statistics Registrations:  Registrations of Cancer Diagnosed in 2006, England. Series MB1  no.37. London: National Statistics; 2008   2. Thomas K, O’Brien TS. Improving transurethral resection of blad-  der tumour: the gold standard for diagnosis and treatment of blad-  der tumours. Eur Urol. 2008;(suppl 7):524—528   3. Teichmann HO, Herrmann TR, Bach T. Technical aspects of lasers  in urology. World J Urol. 2007;25(3):221-225   4. Pietrow PK, Smith JA Jr. Laser treatment for invasive and noninva-  sive carcinoma of the bladder. J Endourol. 2001;15:415—418   5. Eschenbach A. The neodymium-yittrium aluminium garnet (Nd:  YAG) laser in urology. Urol Clin North Am. 1986;13(3):381-392   6. Smith JA. Endoscopic applications of laser energy. Urol Clin North  Am. 1986;13(3):405-420   7. Holzbierelein JM, Smith JA. Surgical management of noninvasive  bladder cancer (stages Ta/T1/CIS). Urol Clin North Am. 2000;27(1):  15-24   8. Smith JA. Laser surgery for transitional cell carcinoma. Urol Clin  North Am. 1992;19(3):473—483   9. Hossain MZ, Khan SA, Salam MA, Hossain S, Islam R. Holmium  laser treatment of superficial bladder carcinoma. Mymensingh Med  J. 2005;14(1):13-15   10. Muraro GB, Grifoni R, Spazzafumo L. Endoscopic therapy of super-  ficial bladder cancer in high-risk patients: holmium laser versus  transurethral resection. Surg Technol Int. 2005;14:222-226   11. Johnson DE. Use of the holmium: YAG laser for treatment of super-  ficial bladder carcinoma. Lasers Surg Med. 1994;14(3):213-218   12. Lopez-Beltran A, Luque RJ, Mazzucchelli R, et al. Changes pro-  duced in the urothelium by traditional and newer therapeutic proce-  dures for bladder cancer. J Clin Pathol. 2002;55:641—647    Ruiz-Tovar J, González R, Conde S, Morales V, Martinez-Molina  E. Jejunal and bladder perforation: complication of intravesical  Nd-YAG laser irradiation of bladder tumour. Acta Chir Belg. 2008;  108(5):595—596   Greskovich FJ II, von Eschenbach AC. Bladder perforation result-  ing from the use of the neodymium:YAG laser. Lasers Surg Med.  1991;:11(1):5-7   Hofstetter AG. Application of lasers in bladder cancer. Semin Surg  Oncol. 1992;8(4):214—216   Gross AJ, Herrmann TR. History of lasers. World J Urol. 2007;25(3):  217-220   Beer M, Jocham D, Beer A, et al. Adjuvant laser treatment of blad-  der cancer: 8 years! experience with the Nd: YAG laser 1064 nm. Br  J Urol. 1989;63:479-478   Beisland HO, Seland O. A prospective randomized study on  neodymium: YAG laser irradiation versus TUR in the treatment of  urinary bladder cancer. Scand J Urol Nephrol. 1986;20:209-212  Kardos R, Magasi P, Karsza A. Nd-Yag laser treatment of bladder  tumours. Int Urol Nephrol. 1994;26(3):3 17-322   Tarantino AE, Aretz HT, Libertino JA, et al. Is the neodymium:  YAG laser effective therapy for invasive bladder cancer? Urology.  1991;38:514   Beisland HO, Sander S. Neodymium: YAG laser irradiation of stage  T2 muscle-invasive bladder cancer: Long-term results. Br J Urol.  1990;65:24   Gerber GS, Chodak GW, Rukstalis DB. Combined laparoscopic  and transurethral neodymium: yttrium-aluminum-garnet laser treat-  ment of invasive bladder cancer Urology. 1995;45:230—233   Jgnler M, Lund L, Bisballe S. Holmium: YAG laser vaporization of  recurrent papillary tumours of the bladder under local anaesthesia.  BJU Int. 2004;94:322   Soler-Martinez J, Vozmediano-Chicharro R, Morales-Jiménez P,  et al. Holmium laser treatment for low grade, low stage, noninvasive  bladder cancer with local anesthesia and early instillation of mito-  mycin C. J Urol. 2007;178(6):2337-2339   Syed H, Biyani C, Bryan N, Brough S, Powell C. Holmium: YAG  laser treatment of recurrent superficial bladder carcinoma: initial  clinical experience. J Endourol. 2001;15:625—627    Morten J, Lund L, Bisballe S. Holmium: YAG laser vaporisation of  recurrent papillary tumours if the bladder under local anaesthesia.  BJU Int. 2004;94:322—325   Das A, Gilling P, Fraundorfer M. Holmium laser resection of blad-  der tumors (HoLRBT). Tech Urol. 1998;4:12   Zhu Y, Jiang X, Zhang J, Chen W, Shi B, Xu Z. Safety and efficacy  of holmium laser resection for primary nonmuscle-invasive bladder  cancer versus transurethral electroresection: single-center experi-  ence. Urology. 2008;72(3):608-612   Saito S. Transurethral en bloc resection of bladder tumours. J Urol.  2001;166:2148-2150   Fraundoerfer M, Cresswell M, Gilling P, Kabalin J. Bladder  tumour resection with the holmium laser. BJU Int. 1997;80(suppl  2):39   Gao X, Ren S, Xu C, Sun Y. Thulium laser resection via a  flexible cystoscope for recurrent non-muscle-invasive blad-  der cancer: initial clinical experience. BJU Int. 2008;102(9):  1115-1118   Fried NM, Murray KE. High-power thulium fiber laser ablation of  urinary tissues at 1.94 mm. J Endourol. 2005;19:25—31   Bach T, Herrmann TR, Cellarius C, Gross AJ. Bladder neck inci-  sion using a 70 W 2 micron continuous wave laser (RevoLix). World  J Urol. 2007;25:263—267   Boyd P, Burnand K. Site of bladder tumour recurrence. Lancet.  1974;2:1290-1292   Hafner C, Knuechel R, Zanardo L, et al. Evidence for oligoclonality  and tumour spread by intraluminal seeding in multifocal urothelial  carcinomas of the upper and lower urinary tract. Oncogene. 2001;  20:4910-4915   Ray E, O’Brien TS. Should urologists be spending more time on the  golf course? BJU Int. 2007;100:728-729   German K, Hasan ST, Derry C. Cystodiathermy under local  anaesthesia using the flexible cystoscope. Br J Urol. 1992;69:  518-520   Knoll T, Trojan L, Langbein S, Sagi S, Alken P, Michel MS. Impact  of holmium:YAG and neodymium:YAG lasers on the efficacy of  DNA delivery in transitional cell carcinoma. Lasers Med Sci. 2004;  19(1):33-36    Laser energy has been increasingly used in recent times in  urology, most notably in the treatment of stone disease and  benign prostatic hyperplasia. In the laparoscopic realm, laser  energy has remained experimental. This chapter will review  the current status of laser applications in laparoscopic  urology.    The principles of laser physics and laser-tissue interactions  are well described in a number of excellent reviews.'* In  essence, the well-known laser acronym stands for light  amplification through the stimulated emission of radiation.  Laser light is (1) coherent, whereby the light wave trains  travel in phase in both time and space, (2) collimated,  whereby the radiation beams travel in parallel, (3) mono-  chromatic, whereby the photon waves are of the same wave-  length, and (4) of high energy.   The production of laser light requires a laser generator, an  excitation source, a lasing medium, and a resonator to pro-  duce amplification via optical feedback (see Fig. 11.12)  Atoms within the lasing medium are energized by the excita-  tion source so that the electrons in the resting ground state,  E°, are stimulated to higher and progressively higher energy  levels (E'-E"). Typically, only a small proportion of the  atoms exist in these higher energy states. When most of the  atoms of the lasing medium are energized, population inver-  sion occurs, which is critical to the laser process. Spontaneous  emission then occurs whereby energized atoms spontane-  ously decay after a given time E? and thereby emit photons at  a given wavelength as monochromatic light (see Fig. 11.1b).  This spontaneous emission then precipitates stimulated emis-  sion, in which the emitted photons interact with other high-  energy-state electrons and stimulate their subsequent decay  and associated photon emission. Hence, amplification occurs  whereby one photon is able to stimulate the emission of  additional photons and so on (see Fig. 11.1c). As long as    population inversion continues, the laser light continues to  be amplified. The photons are reflected back and forth by  mirrors within the resonator, and continued photonic interac-  tion with high-energy-state electrons results in further ampli-  fication (see Fig. 11.1a). Additionally, this reflection process  aligns the photon wave trains in space and time producing  coherence and collimation of the laser light. Typically, one  of the mirrors of the resonator, the optical coupler, is semi-  transparent and allows the collimated, coherent monochro-  matic photon waves to be released from the lasing medium  as a laser beam, which is subsequently directed toward the  target tissue.   The interaction of laser light with tissues is governed by  photomechanical, photochemical, and photothermal mecha-  nisms.” Photomechanical effects occur when short pulses of  high wattage laser energy are applied and disrupt the cellular  architecture via photoacoustic shocks, whereas photochemi-  cal interactions occur when low-energy laser light induces a  chemical reaction within the cell. Photothermal interactions  are the most characteristic in laser surgery and are governed  by the tissue-specific absorption characteristics. At tempera-  tures of 45—50?C, enzymatic changes occur, at 60°C, protein  denaturation occurs and results in coagulation, and cellular  vaporization occurs at 90—100?C. Continued heating to sev-  eral hundred degrees results in tissue carbonization and burn-  ing.” These photothermal effects are governed by the applied  power density, also known as the irradiance, which is  expressed as a function of energy per unit area or watts/cm’.    Irradiance = intensity/area = watts/cm?.  The energy density expressed as a function of time is known  as the fluence and is the product of irradiance, and the  exposed time is expressed as Joules (J)/cm?.   Fluence = (intensity x time)/area = watts.s/em? = J/cm’.  Increasing irradiance increases the tissue temperature and  favors vaporization and tissue cutting. This effect is favored  by small diameter fibers, which produce a small spot size,    Fig. 11.1 (a) Laser generator. (b) a  Spontaneous emission. Resting state  electrons are energized via the  excitation source (A) to a higher energy  level (B). The electrons then decay  back to the resting state (C) and in the  process emit a given wavelength of  ionizing radiation (D). (c) Stimulated  emission. Emitted ionizing radiation  (A) interacts with high-energy state  electrons of energized atoms (B) to  precipitate their decay to the resting  state (C) thus producing further  ionizing radiation of the same  wavelength (D)    to the tissue to minimize beam divergence, and the applica-  tion of the beam at right angles to the tissue to focus the laser  spot. Conversely, the reciprocal of these factors decreases the  irradiance and favors coagulation and hemostasis.   When laser light is applied to a tissue, it can be transmit-  ted, absorbed, scattered, or reflected? The absorption of laser  light by the tissue produces the resultant effects of the laser  beam. The presence of chromophores such as melanin and  hemoglobin and the water content of the tissues govern the  laser absorption profile. In the ultraviolet and visible range of  the spectrum from approximately 100 nm to 800 nm, there is  very little water absorption. Water absorption begins at  approximately 1,000 nm and has a large peak at 3,000 nm. In  the visible light spectrum, hemoglobin and melanin domi-  nate absorption. The Hemoglobin curve has three main  absorption peaks at 418, 542, and 577 nm and decreases by  approximately 600 nm. Melanin has a broad overlapping    absorption band ranging across the ultraviolet, visible, and  near infrared spectrum.    The principal laser types, which may be suitable for laparo-  scopic use, are the carbon dioxide (CO,), neodymium-doped  yttrium-aluminum-garnate (Nd:YAG), the holmium-doped  yttrium-aluminum-garnate (Ho:YAG), the potassium-titanyl-  phosphate (KTP), or lithium triborite (LBO) crystals, which  generate the 532 nm wavelength, and most recently the thu-  lium laser.   The CO, laser has a wavelength in the far infrared spec-  trum with a wavelength of 10,600 nm and thus has shallow  penetration because of the high water content of body tissues.    It is not as hemostatic as other laser types and typically seals  vessels up to 0.5 mm in diameter? In addition, this laser type  has traditionally required rigid delivery systems that limit its  laparoscopic use. Its main mechanism is via a photothermal  effect. Omniguide? flexible photonic band-gap fibers have  recently been developed (Omniguide Inc., Cambridge, MA)  to allow flexible delivery of CO, laser light. Nonetheless it is  unlikely that this laser would be suitable to achieve hemosta-  sis in laparoscopic urological procedures because of the  larger sizes of the vessels involved such as in laparoscopic  partial nephrectomy (LPN).   The 1,064 nm Nd:YAG laser is not preferentially absorbed  by water or by tissue chromophores, but it penetrates deeply  into the tissue. It is hemostatic and coagulates vessels up to  3-5 mm in diameter and has predominantly photothermal  effects.^" In contrast, the 2100 nm Ho:YAG laser is a high-  energy pulsed laser, which produces its effect by predomi-  nant photomechanical mechanisms. The depth of penetration  is typically 0.5 mm.* The photomechanical effects on tissues  tend to produce irregular cut margins and also theoretically  may disseminate malignant cells during oncological proce-  dures through tissue splattering.? Additionally, these photo-  mechanical properties have been noted to splatter tissue  fragments onto the laparoscope lens and interfere with the  laparoscopic view.'?   The 532 nm KTP laser is produced by passing an Nd: YAG  laser beam through a frequency doubling KTP crystal. This  wavelength is in the green light spectrum and is absorbed pre-  dominantly by hemoglobin. It vaporizes tissues through pho-  tothermal effects and has excellent hemostatic properties.  These properties have led to its widespread use and develop-  ment in the treatment of benign prostatic hyperplasia with the  development of the high-powered 80 W Greenlight? PV and  120 W Greenlight? HPS systems developed by Laserscope  (San Jose, CA), now recently acquired by American Medical  Systems (Minnetonka, MN). The HPS system now utilizes the  more stable LBO crystal to generate the 532 nm wavelength.  These laser generators produce very rapid pulses of high-  powered 532 nm laser energy in a quasicontinuous mode.   The most recent laser type to be examined is the 2,013 nm  thulium laser. This laser penetrates to a depth of approxi-  mately 0.5 mm and has properties similar to that of the hol-  mium laser, but is delivered in a continuous wave form, and  therefore avoids the photomechanical splattering effects  associated with the holmium laser."    Most work in laser laparoscopic applications has centered on  the upper tract, principally with laser LPN. Initially, however,  the work focused on laser welding of the pyeloureteral    anastomosis in laparoscopic pyeloplasty. This was based on  the initial difficulties associated with intracorporeal suturing  when laparoscopic urology was in its infancy. Laser welding  utilizes the photothermal properties of laser light whereby  laser energy is applied to a solder, typically 50% human albu-  min, in conjunction with laser wavelength specific chro-  mophores such as indocyanine green or flourescein to facilitate  laser light absorption. The dyed solder thus absorbs most of  the light energy and increases the temperature at the repair  site, which denatures the solder and results in a coagulum,  which initially increases the initial strength at the repair site.  Eden and Copcoat in 1996 described the use of laser weld-  ing as a means of facilitating the pyeloureteral anastomosis in  laparoscopic pyeloplasty.'* In this study using the acute and  survival porcine model, KTP human albumin laser welding  was compared with gelatine resorcin formaldehyde (GRF)  glue and fibrin glue. GRF glue produced anastomotic adhe-  sion, which was insufficiently flexible to withstand rotation of  the anastomosis and was thus abandoned. Both laser welding  and fibrin glue produced supraphysiological leak pressures,  but the fibrin glue was significantly faster to perform and eas-  ier to apply in comparison with laser welding. Laser welding  was found to be demanding and required dry tissue edges that  needed to be precisely aligned without any shear force. Also  the end point of laser welding was felt to be subjective and  easily exceeded, resulting in significant tissue thermal injury.  The authors thus opted to proceed with fibrin glue as their  anastomotic method of choice in an initial clinical series."  In a similar study, Wolf and coworkers in 1997 laparo-  scopically repaired 22 proximal ureterotomies in 14 pigs  using either fibrin glue, laser welding, Endo-Stitch? suturing,  or free suturing. Urine leak was assessed immediately via  the retrograde instillation of methylene blue, while long-term  survival analysis was performed at 12 weeks using retro-  grade pyelography, pressure-flow assessment, bursting pres-  sures, and histological analysis. Fibrin glue produced more  favorable radiographic findings and flow characteristics  when compared with KTP human albumin laser welding and  suturing. Though laser welding was faster then free suturing,  it was not superior to free suturing in other aspects. The  authors concluded that given the expense of laser systems,  laser welding would need to be significantly superior to free  suturing to justify its routine clinical use. Barrieras et al in  2000 assessed 53 pyelpplasties in 50 pigs and found that nei-  ther laser welding using an 804 nm diode laser nor fibrin glue  was superior to standard suturing in the long term and was  associated with a higher incidence of urinoma formation.’  Recently, Shumalinsky et al in 2004 demonstrated successful  laser welding of the pyeloureteral anastomosis in ten farm  pigs using a fiber-optic CO, laser soldering system.'^ In this  assessment, the authors developed a unique, flexible, fiber-  optic CO, laser delivery system, which included a real-time  infrared thermal sensor that regulated the laser output within    a 2-3?C temperature range. Successful tissue welding of the  pyeloureteral anastomosis was demonstrated at up to 1 month  following the procedure as assessed with postoperative intra-  venous urography, ultrasound, and histology.   Ultimately, however, laser welding of the pyeloureteral  anastomosis has not demonstrated an advantage over stan-  dard suturing techniques. As laparoscopy has evolved, intra-  corporeal suturing is readily learned by residents in training  and forms an integral part of the laparoscopic urologist's  armamentarium and is not considered the technically  demanding highly advanced skill that it once was.  Accordingly, laser welding of the pyeloureteral anastomosis  is not performed in routine clinical practice.    Most investigation of laser applications in laparoscopic urol-  ogy has centered on LPN. Approximately, 35,000 renal  tumors are diagnosed annually in the US." The incidence of  renal cell carcinoma (RCC) has been increasing in recent  years largely due to an increasing use of imaging modalities  detecting incidental, small, asymptomatic renal masses.'*'?  Many of these tumors are small, «4 cm, and as such may be  candidates for partial nephrectomy (PN).   Recently, LPN has been developed and offers equivalent  oncological and renal function outcomes but with improved  convalescence when compared with open partial nephrec-  tomy (OPN).? However, LPN is a technically demanding  procedure that is practiced only in selected centers of exper-  tise and is difficult to master. The most accepted technique  replicates the open procedure and involves hilar clamping,  cold scissor excision, collecting system closure, and sutured  hemostasis with the application of a Surgicel Nu-Knit?  (Ethicon Inc., NJ) bolster and Floseal? (Baxter, IL) for addi-  tional hemostasis.*! Hilar clamping is limited to 30 min to  minimize the impact of warm ischemia. Such time con-  straints add to the technical demands of the operation. Renal  parenchymal reconstruction is complex and requires rapid,  free-hand suturing that is technically challenging, which in  conjunction with the time constraints of hilar clamping, has  limited the widespread dissemination of the technique.   The ideal LPN scenario would be to excise the renal mass  with minimal blood loss, without hilar clamping, and in a  technically straightforward manner while maximizing onco-  logical control and minimizing any impact on renal function  in a safe manner. A number of modalities and energy sources  have been explored in an attempt to meet these aims such as  microwave tissue coagulation," radiofrequency dissec-  tion,” bipolar energy,” argon beam coagulation,” ultra-  sonic shears,” and water-jet dissection; however, none has  been proved universally successful.    Lasers of various types have been investigated as poten-  tial hemostatic energy sources in PN for many years; how-  ever, none gained widespread acceptance as laser OPN  offered no advantage when compared with the standard open  surgical technique. However, the complexity of LPN has led  to resurgence in the investigation of laser PN to simplify  LPN and to eliminate warm ischemia.   The CO, laser was the first laser type to be investigated in  OPN by Hughes and Scott in 1972, who initially described  CO, laser PN in dogs.? Further animal and clinical investiga-  tions were performed; ^' however, the CO, laser alone was  not sufficient for hemostasis in these reports and additional  ligatures were required to control the larger vessels. As the  CO, laser coagulates small vessels of up to 0.5 mm, it is  unlikely that this laser will play a significant role in PN.   The Nd:YAG laser was the next to be investigated.°°*  Techniques included cold scalpel excision with spot lasing of  transected vessels and straight laser transection with and  without hilar clamping in cooled and uncooled kidneys. The  Nd:YAG laser was also combined with the CO," and KTP^  lasers in an attempt to limit the degree of thermal injury.  Overall collecting system closure was inadequate and hemo-  stasis was variable; however, Malloy et al in 1986 success-  fully used the Nd:YAG laser without hilar clamping in a  clinical series of 6 patients with solitary kidneys,” while  Korhonen et al 1993 used the Nd: YAG laser under cold isch-  emia in 6 patients with VHL.”   Johnson et al in 1992 then examined the Ho: YAG laser in  clamped PN in the canine model and demonstrated a two-  fold reduction in the depth of necrosis using the Ho: YAG  laser when compared with the Nd:YAG.“ They also noted  that collecting system closure was inadequate.   Thus ended the open era in which the CO,, Nd:YAG, KTP,  and Ho:YAG lasers were assessed. The overall conclusions  were that laser dissection, though achievable, offered no  advantage to standard open surgical techniques. In contrast  to the open era where open laser PN offered no advantage to  open surgery, laser PN offers the potential of allowing the  wide spread dissemination of an otherwise difficult tech-  nique that is performed only in selected centers of expertise.   The Nd:YAG laser was the first to be examined in the lap-  aroscopic context by Janetscheck et al in 1998, who in a  series of seven LPNs for small renal masses described its use  in combination with the argon beam coagulator in the  unclamped kidney in 1 patient.*°   The Ho:YAG laser has been investigated more exten-  sively. Though it appears effective, tissue splattering limits  its usefulness. Lotan et al 2001 initially presented a video of  Ho:YAG laser LPN in an unclamped porcine model at the  19th World Congress of Endourology and SWL." Estimated  blood loss was «50 mL. Blood splattering onto the laparo-  scope and smoke generation were particular problems. In  2002, the authors described the clinical use of the Ho: YAG    laser in three cases of a complex cyst, a nonfunctioning  lower-pole moiety in a duplex system in an 8-year boy, and a  case of RCC." The hilum was not clamped in 2 of 3 cases. In  case 1, fibrin glue was applied to the cut surface to prevent  secondary hemorrhage. Estimated blood loss was «50 mL.  The second case involved the excision of a nonfunctioning  lower pole moiety in a duplex system. The lower pole vessels  were clipped and divided. Blood loss was « 100 mL and oxi-  dized cellulose was applied to the cut renal surface. The third  case, a 2.5 cm exophytic RCC, was resected without hilar  clamping. The estimated blood loss was 500 mL. The argon  beam coagulator and fibrin glue were also applied. In these  cases, splattering was particularly troublesome when larger  vessels were transected. Then in 2004 this same group per-  formed five acute and five survival lower pole laser transperi-  toneal LPNs in five pigs using the Ho:YAG laser.'? Fibrin  glue was applied to the cut surface to seal the collecting sys-  tem. Blood loss was <50 mL for each procedure. Extravasation  was noted in two of the survival kidneys. Again blood splat-  tering and smoke generation were problematic.   Diode lasers have also been trailed. Ogan et al in 2002  performed ten laparoscopic transperitoneal partial nephrec-  tomies in five 45-50 kg female farm pigs without hilar clamp-  ing using a 980 nm diode laser." After transection fibrin glue  was applied to seal the collecting system. The laser was  insufficient for hemostasis in three of the ten partial nephrec-  tomies and adjunctive hemostatic clips were necessary to  stop bleeding from larger vessels toward the center of the  parenchyma. The mean laser time was 84 min and the mean  blood loss was 150 mL. There was minimal extravasation in  three kidneys on ex vivo retrograde pyelography. The depth  of necrosis was up to 2 mm. In 2003, this group examined the  810 nm pulsed diode laser combined with 50% liquid-  albumin-indocyanine green solder to weld the parenchyma  to achieve hemostasis and seal the collecting system.? Five  survival and five acute heminephrectomies were assessed in  five farm pigs. The renal pedicle was clamped and the hemi-  nephrectomy was performed with scissors. The solder and  the laser were then applied to the cut renal surface. The mean  blood loss was 43.5 mL and the warm ischemia time 11.7 min.  Two of the acute kidneys demonstrated minimal urine  extravasation on ex vivo retrograde pyelography, although  none of the survival kidneys demonstrated any clinically rel-  evant urine leak.   Recently, high-power 532 nm wavelength laser systems  have been developed. The 80 and 120 W Greenlight? PV and  HPS systems (Laserscope®) have become established as  effective treatment options in the management of bladder  outflow obstruction from benign prostatic hyperplasia.  Moinzadeh et al in 2005 examined KTP laser LPN in the  unclamped calf model using the Greenlight? PV system.”  This study is unique in that it was the first to use the robust  calf model, which the authors theorize as more closely    representing the human scenario, because of its large kidney  size. In this study, six Jersey calves weighing 76-94 kg  underwent 12 staged bilateral transperitoneal LPNs in the  unclamped kidney including left kidney chronic LPN with 1  month follow-up in 6 and right kidney acute LPN with imme-  diate sacrifice in 6. Two techniques were investigated, which  included ablative vaporization of renal tissue in five subjects  and wedge resection in seven. Eleven of the 12 procedures  were performed without hilar clamping. The mean total oper-  ating time was 2.9 h and the mean blood loss was 119 mL.  The mean lasing time was 56 min. At 1 month follow-up  there was no evidence of urine-leak on pyelography or AV  fistula on arteriography. The procedures were performed  using the 80 W quasi-continuous KTP Greenlight? PV sys-  tem with a 600 um bare-tip end-firing fiber delivered through  a 5 mm suction irrigation hand-piece. Smoke generation was  noted and necessitated the use of a smoke evacuator system  and two insufflators to counteract the loss of the pneumoperi-  toneum. Collecting system entries were repaired with run-  ning suture. Acute necrosis was minimal at 0.8 mm.   Hindley et al in 2006 performed transperitoneal KTP laser  LPN in four pigs. In this study, the Greenlight? PV system  delivering high power 80 W KTP laser energy via a 600 um  fiber without renal cooling or hilar clamping?! The mean  blood loss was «30 mL. In one procedure, a 7 mm vein was  transected that required a single laparoscopic clip to secure  hemostasis. The mean operating time was 42 min. The zone  of necrosis was 1 mm. The authors report that the hemostatic  properties of the KTP laser were excellent, but also noted  that smoke production was a particular problem.   In an attempt to overcome the problem of smoke produc-  tion, Liu et al in 2006 examined saline irrigation during KTP  laser LPN in the porcine model.” The authors initially theo-  rized that different insufflation gasses may affect smoke for-  mation. An initial ex vivo study was performed where resected  kidneys were placed in a sealed container filled with either  argon, helium, or CO,, and the kidney was cauterized by elec-  trocautery passed through laparoscopic ports. There was no  difference in smoke production with the various gasses and  the authors concluded that the smoke was generated from the  laser-tissue interaction. Similar findings were noted in vivo.  Fourteen LPNs were performed without hilar occlusion in  four pigs with continuous saline irrigation to suppress smoke  production. Thirteen of the fourteen partial nephrectomies  were performed without hilar clamping and with successful  suppression of smoke. The laser fiber fractured in the suction  cannula through which the fiber was passed in one proce-  dure, which could then not be completed. The mean PN time  was 13.14 min and the mean blood loss was 28.57 mL.   Anderson et al in 2007 examined the KTP laser LPN in  six pigs.” The technique was developed in the first two pigs  after which the remaining four pigs underwent a right-sided  laser LPN followed by a left-sided laser LPN 2 weeks later,    in which a mean of 30 g of renal tissue approximating a size-  able 2596 of the kidney mass was resected. The hilum was  clamped in all cases. The 80 W KTP laser was used at a set-  ting of 80 W for tissue cutting and 30 W for coagulation  delivered via a 365 um fiber. Hemostasis was successful in  all cases and no perioperative complications occurred. Mean  blood loss was 80 mL, mean laser time was 35 min and the  mean warm ischemia time was 34 min. Urinary extravasa-  tion was noted in 7 out of 8 kidneys on retrograde pyelogra-  phy. Saline irrigation eliminated smoke formation but slowed  the time of resection. Hilar clamping decreased smoke for-  mation and charring and greatly facilitated dissection. Smoke  production although less was still a factor and a smoke evac-  uator was required at a suction rate of 5 L/min. Fibrin glue  was used to seal the collecting system. The zone of necrosis  was up to 5 mm in the acute specimens, which the authors  hypothesize to be due to hilar clamping; however, this is at  odds with the results found by Benderev et al in 1987, who  found that hilar clamping decreased the necrotic zone with  the Nd:YAG laser. It may be that the larger amount of  excised tissue in this study may have accounted for this dif-  ference as more energy would have been likely to be required,  although the energy use was not reported.   We recently examined the clinical applicability of laser  Robotic-assisted LPN at the Cleveland Clinic in a pilot series  of 5 patients (manuscript in preparation). In this series, the  Greenlight® HPS 120 W system was used in conjunction  with the da Vinci? robotic unit to facilitate laser delivery (see  Fig. 11.2). Specific purpose-built, prototype robotic instru-  mentation was engineered for this study. As the green laser  light saturates the robotic camera system, KTP filters were    Fig. 11.2 Greenlight? laser robotic partial nephrectomy without hilar  clamping. An upper pole Greenlight? laser robotic partial nephrectomy  is performed in the perfused kidney using a custom-made da Vinci?  5 mm delivery instrument through which a 600 um laser fiber was  delivered    incorporated into the camera adapter to prevent laser flare  from obscuring the operative view. A prototype laser deliv-  ery device was also developed whereby a 5 mm da Vinci?  instrument (Intuitive Surgical, Sunnyvale, CA) was assem-  bled to allow the passage of the laser fiber through the center  of the instrument. This instrument allowed precise multidi-  rectional delivery of the laser beam. The laser beam was  delivered via a purpose-built, end-firing 600 um fiber using  the Greenlight? HPS (AMS/Laserscope) laser system to a  maximum setting of 80 W.   Following transperitoneal laparoscopic renal mobiliza-  tion, the tumor mass was defined using intraoperative laparo-  scopic ultrasound and the proposed line of parenchymal  incision was circumferentially scored with an electrocautery  robotic J-hook. The laser fiber was passed via the custom-  built laser instrument and activated using the Greenlight?  HPS laser system to a maximum setting of 80 W and was  used to incise the renal parenchyma and excise the mass  without hilar clamping. A CT-1 needle with 3-zero polygla-  ctin suture was used to perform meticulous running repair of  any collecting system defects.   The results of this pilot series are given in Table 11.1.  Hemostasis was problematic throughout the series. We found  that the Greenlight? laser did not coagulate vessels larger  than 4—5 mm such as the more centrally placed interlobar  arteries. All cases required additional hemostatic maneuvers  such as clips, suture, Floseal?, or surgical bolster. The mean  blood loss for the series was 400 mL. In the last three cases,    Age (years) Sil 46-65  BMI (kg/m?) 29 28-48  Preoperative creatinine (g/dL) 1.0 0.7-1.3  Tumor size (cm) 1.8 1.6-4.0  Hb pre (g/dL) 14.2 13.9-15.4  Hb post (g/dL) 10.8 10.2-12.8  Het pre (76) 43 41.7-47.2  Het post (76) 322,5) 31.5-38.4  OT time (min) 310 180-360  Mass excision time (min) 54 36-96  Warm ischemia time (min) 0 0-14  Total energy (J) 20,931 9,949-29,158  Lasing time (min) 8.5 3.2-17.1  Specimen weight (g) ON 4.5-61.5  Blood loss (mL) 400 200-1,300  Length of stay (days) 3 3-7    continuous suturing of the renal parenchyma was done, as  dissection proceeded to assist with hemostasis. Despite this,  hemostasis was difficult to achieve and the dissection pro-  ceeded slowly and mass excision times were in the order of  36-96 min. The high affinity of the 532 nm wavelength laser  light for hemoglobin resulted in absorption of the laser light  by free blood, which in turn decreased the cutting efficiency  of the laser beam. Therefore, continuous suction and irriga-  tion of the operative field was essential. One case required  hilar clamping with 14 min of warm ischemia time. This case  was complicated by postoperative hemorrhage requiring  embolization and a subsequent four unit blood transfusion.  The intraoperative blood loss in the final patient was 1,300  mL and a two unit intraoperative blood transfusion was  required. Final histology revealed two oncocytomas, two  clear cell RCCs and one papillary tumor. One margin was  focally positive. We found that laser transection resulted in  significant charring of the renal parenchyma which obscured  the intrarenal dissection planes and it is likely that this was a  major contributing factor to the focally positive margin.   Smoke generation during the procedures was problematic  and high flow insufflation at 40 L/min in conjunction with  active smoke evacuation by smoke suction units was required.  In addition, continuous irrigation by saline helped to decrease  smoke plume. In summary, Greenlight? laser robotic LPN did  not achieve adequate hemostasis, was slow with significant  smoke generation, and resulted in significant charring of the  renal parenchyma, which made intraoperative margin assess-  ment difficult.   Since this initial clinical robotic experience, Honeck et al  2008 compared the hemostatic potential of the Habib? 4x  bipolar resection device, the Greenlight? KTP laser, the  Ligasure? and Sonosurg? devices in an ex vivo porcine model  both with and without clamping, in which scalpel resection  was used as a control.” While KTP laser excision was rapid  and simple to handle, the blood loss without hilar occlusion  as assessed by measured sponge weights, was significant and  was similar to scalpel excision. The authors concluded that  none of the evaluated devices were sufficiently hemostatic  for LPN. Certainly, the comment by these authors and others  that facilitation and acceleration of the standard laparoscopic  technique to reduce warm ischemia while operating in a  nearly bloodless field as the more promising approach is well  worth noting.?^*   Finally, the 2,013 nm Thulium laser has been evaluated in  both animal and clinical series. Bui et al 2007 assessed the  30 W thulium laser delivered via a 365 um fiber passed  through a flexible cystoscope in conjunction with continuous  saline irrigation in a survival porcine model without hilar  clamping." Laser LPN was completed successfully in all  cases with an estimated blood loss of «50mL with minimal  smoke and minimal tissue charring. Fibrin glue was also  however applied to the exposed parenchyma. A limitation of    this study is that only the renal cortex was treated, and in the  authors' initial nonsurvival pilot assessment, they state that  the laser was unable to control the more centrally placed  larger medullary vessels near the hilum.   In an open series, Gruschwitz et al in 2008 reported suc-  cess with the thulium laser in 5 patients with tumor sizes  ranging from 1.2 to 3.8 cm at 30 W without hilar clamping  via an open loin approach.'' Operative time was reported in  one patient and was stated to be less than 20 min. The authors  state that the thulium laser can coagulate vessels up to 1.5  mm and that because of the short operative time, minimal  blood loss, and absence of clamping, the thulium laser may  be useful in high-risk patients. Whether these results will be  reproducible, particularly in a laparoscopic environment,  remains to be determined.   The collective data to date is insufficient to support the  routine use of laser energy during LPN. It is unlikely that  laser LPN will have the capacity to treat all renal masses.  Laser energy does not appear capable of sealing the larger,  more centrally placed vessels, and additionally is not likely  to effect the collecting system closure of its own accord.  Therefore larger, centrally placed tumors are unlikely to be  suitable for laser resection. Additionally, smoke production  is problematic and dissection times are slow. Tissue charring  also appears to interfere with intraoperative margin assess-  ment. At this juncture, laser LPN is unlikely to replace stan-  dard LPN with sutured parenchymal reconstruction.    Much less work has been done with regard to lower tract  laser laparoscopic applications. However, laser laparoscopic  radical prostatectomy (LRP) has recently been investigated.  The ultimate aim of radical prostatectomy is to maximize  outcomes in the triad of cancer control, continence, and  potency. The description of the cavernous nerves and their  relationship to the prostate as initially described by Walsh  and Donker represents one of the most significant advances  in urological practice in recent times.” Classically, the neuro-  vascular bundles (NVBs) containing the cavernous nerves  are described to pass distally within the leaves of the lateral  endopelvic fascia on the postero-lateral aspect of the pros-  tate.” However, more recent data indicates that the pelvic  autonomic neural pathways are more extensive than had been  initially appreciated and are prone to injury at multiple sites.  Significant numbers of nerve fibers exist on the ventral and  lateral aspects of the prostate, although their functional sig-  nificance is undetermined.^^^' Takenaka et al? demonstrated  that the pelvic splanchnic nerves continue to join the NVB  distal to the vesico-prostatic junction. Tewari et al? described  the trizonal neural architecture around the prostate gland that    comprises the proximal neurovascular plate (PNP), the pre-  dominant neurovascular bundles (PNB), and the presence of  accessory neural pathways (ANP). The PNP ranged from 3 to  10 mm lateral to the seminal vesicles, 0—7 mm from the prox-  imal prostate and lateral pedicles, 4—15 mm from the bladder  neck and 2-7 mm from the endopelvic fascia.“ The PNB  coursed along the posterolateral aspect of the prostate in the  groove between the prostate and the rectum but also extended  medially behind the prostate, while ANPs were noted in the  layers of levator fascia and the lateral pelvic fascia on the  antero-lateral and posterior aspects of the prostate.   It is thus apparent, that the pelvic autonomic neural anat-  omy is more complex and more extensive than has been pre-  viously appreciated. Therefore, collateral tissue injury must  be minimized to effectively preserve these structures.  Methods currently used to achieve hemostasis during laparo-  scopic and robotic radical prostatectomy include ultrasonic  shears,“ bipolar diathermy,” laparoscopic clips,” and lateral  vascular pedicle control with laparoscopic bulldog clamps.^  Ultrasonic shears, bipolar diathermy, and monopolar dia-  thermy have all been shown to adversely affect cavernous  nerve function® and injure tissues across distances of 0.9,  1.3 and 2.1 cm, respectively, depending on the tissue type  and duration of activation.?^ Monopolar diathermy may also  injure tissues several centimeters from the site of instrument  activation.” Given the close proximity of the proximal neu-  ral plate to the bladder neck, lateral pedicle, and prostate  base, diathermy used at sites distant to the actual cavernous  nerves such as at the bladder neck may theoretically damage  these proximal neural structures.   Athermal techniques (ATs) have been developed to mini-  mize thermal injury to the cavernous nerves. However, theo-  retical concerns have been raised regarding the application of  bulldog clamps, mass suturing, bulk clipping, or stapling of  the pedicle, which may physically traumatize the adjacent  cavernous nerves and pelvic plexus.57?"! As a result, clipless  techniques have been advocated; however, these rely on the  use of bipolar energy.” In addition, despite recommendations  for the avoidance of thermal energy near the NVBs, thermal  energy is still used by many for bladder neck division? and  also for lateral pedicle control,? while many practitioners  continue to use ultrasonic shears extensively for the dissec-  tion of NVBs and posterolateral prostatic dissection simply  because of the speed of dissection and general ease of use.   As a result of these challenges, laser energy has been tri-  alled. Laser energy potentially allows for precise dissection  with good hemostasis and minimal adjacent tissue injury.  Current laser fibers typically have diameters of 100—1,000 um  and are much finer than the working surfaces of either bipo-  lar forceps or of ultrasonic shears. They are also finer than  bulldog clamps and the 5-10 mm clips used laparoscopi-  cally. Laser energy is a direct photonic beam which, in con-  trast to diathermy does not have an associated electrical field,    the diffusion of which may result in widespread thermal  injury. These theoretical benefits in concert with the advan-  tages of robotic-assisted radical prostatectomy (RARP) by  way of the highly magnified 3D view, wristed instrumenta-  tion, complete absence of tremor, and fine movement scaling  could theoretically allow for extremely fine and accurate dis-  section with a minimum of collateral neural damage and  improved operative outcomes, particularly with respect to  potency.   An initial pilot series of Nd: YAG laser nerve-sparing LRP  in 5 patients observed an acute mean depth of injury of 615 um  to the NVBs, a reduction in total operative blood loss of  213 mL with laser dissection when compared with 292 mL  with standard dissection and no laser-related complications.”  Following this, a series of studies has investigated the poten-  tial application of laser energy facilitating LRP in the canine  model." Initially, the canine model was assessed for its  suitability as a nerve-sparing radical prostatectomy model."  Then, the effects of the KTP laser on NVB function was  assessed and compared with cold scissor dissection.” In this  assessment, laparoscopic KTP laser dissection of the NVBs  was shown to be equivalent to cold scissor dissection and  superior to ultrasonic shears in preservation of cavernous  nerve function.” In this study, 36 adult male dogs underwent  laparoscopic mobilization of a unilateral NVB using KTP  laser (n = 12), ultrasonic shears (US) (n = 12), or AT using  cold scissors and titanium clips (n = 12). Half the dogs in  each group were sacrificed acutely while the remaining half  survived for 1 month. Peak penile intracavernosal pressure  normalized against simultaneously recorded mean arterial  pressure measurements (ICP%MAP) in response to cavern-  ous nerve stimulation were recorded from each bundle ini-  tially prior to mobilization and again immediately following  NVB mobilization. Peak ICP%MAP was again recorded at 1  month in the survival dogs immediately prior to sacrifice.  KTP laser mobilization was performed using a 15 W Aura  XP™ laser unit (Laserscope), in which a 200 um Endostat™  end-firing fiber was passed through a custom-made 5 mm  laser-delivery instrument.   The ICP%MAP following KTP laser dissection was com-  parable with that of cold scissor dissection both immediately  postoperatively and at 1 month. US dissection resulted in a  significant decrease in the mean ICP%MAP response when  compared with both the KTP and AT groups (acute  ICP%MAP: KTP 92%, AT 96%, US 49%. KTP vs. AT p =  0.54, US vs. KTP p < 0.001, US vs. AT p < 0.001; chronic  ICP%MAP: KTP 95%, AT 98%, US 58%. KTP vs. AT p =  0.71, US vs. KTP p = 0.02, US vs. AT p = 0.02). Histological  assessment of the prostate specimens from the laser group  demonstrated a zone of laser-induced necrosis of 600 um  (range: 500—2,000) when compared with a median of 1,200  um (range: 500—1,300) in the US group and 450 um (range:  300—1,200) of crush injury in the AT group. Thermographic    mapping of the ex vivo prostate specimens demonstrated sig-  nificant spread of heat onto the region of the NVBs with the  US, while there was less heat diffusion with the KTP laser.  Serial sectioning of the strips of harvested peritoneum dem-  onstrated a significantly greater area of thermal spread with  US shears than with KTP laser (median thermal spread  >60°C KTP 1.07 mm vs. US 6.42 mm, p « 0.01). The tem-  peratures at the tip of the US shears exceeded 150?C and  required 40 s to return to below 60?C. In comparison, heat  was not retained at the tip of the laser fiber.   On the basis of these findings, laser RARP was then  assessed. Laser RARP was performed in ten male dogs.  The study was divided into two phases. The first five dogs  constituted the acute, nonsurvival phase of the study, in  which the utility of laser prostatectomy using the robotic  approach was assessed and the technique was standardized.  An additional five dogs constituted the survival phase in  which the dogs were sacrificed 72 h postoperatively. Pre and  post dissection ICP%MAP were again recorded. Laser RARP  was performed completely using the KTP and Nd:YAG  lasers delivered from an 800 Series KTP/YAG™ Surgical  Laser System (Laserscope). The majority of the dissection  was performed using the KTP laser while the Nd: YAG laser  was used selectively for hemostasis of larger vessels as  required. In the acute study, the optimal power settings for  each laser type were determined and these settings were used  for the final five survival dogs.   All ten procedures were entirely completed with the use  of laser energy. Laser dissection was easy to perform and  proceeded efficiently. The median laser prostatectomy exci-  sion time (not including the urethrovesical anastomosis) was  65 min (range: 57-100). No additional hemostatic maneu-  vers such as clips, ultrasonic shears, or electrocautery were  required in any case. The median operative blood loss was 50  mL (range: 20-200), which included 200 mL blood loss  from a trocar-related splenic injury in one case. The median  postoperative hemoglobin and hematocrit were not signifi-  cantly decreased when compared with the preoperative val-  ues in the five survival animals (preoperative Hb 14.4 mg/dL  and postoperative Hb 12.6 mg/dL, p = 0.06; preoperative Hct  45.1% and postoperative Hct 40.2%, p = 0.06).   The median postdissection ICP%MAP was slightly  reduced; however, this was not statistically significant (pre-  operative ICP%MAP 99.3%, postoperative 77.096, p = 0.12).  Histological assessment of the excised acute specimens dem-  onstrated a zone of necrosis typically extending 0.5-1.0 mm  from the cut edge of the prostatic fascia, extending focally to  a maximum of 1.5 mm in some sections with areas of injured  but non-necrotic tissue of up to 2 mm beyond the cut edge.  There were no laser-related complications.   Finally, KTP laser robotic-assisted LRP was performed in  10 patients as a phase 1 clinical assessment (see Fig. 11.3)." In  this initial series, complete laser robotic radical prostatectomy    Fig. 11.3 Laser robotic-assisted laparoscopic radical prostatectomy  (LRP). Laser robotic-assisted LRP is performed using the 15 W Aura  XP™ laser unit delivered via a custom-made 5 mm da Vinci? robotic  instrument    was performed successfully using a low power 15 W  AuraXPTM KTP (Laserscope/AMS) laser unit. Additional  hemostatic maneuvers using clips, sutures, or diathermy  were required on an average of eight occasions per case. The  mean perioperative values were operative time 217 min,  blood loss 290 mL, hospital stay 39.9 h, mean laser time 65.9  min, and laser energy 20,862 J. Eight patients had pT2 dis-  ease and two had pT3. All surgical margins were negative.  There were no laser-related complications. There was one  urine leak and one drain site infection." The mean preopera-  tive SHIM score was 20.4 (range: 9-25) and at 6 months was  7.3 (range: 5-16) (unpublished data).   From this series of studies, it appears that laser RARP is  feasible; however, it is unclear as to whether this offers any  benefit over standard laparoscopic and robotic techniques.  Certainly, thermal energy should be avoided wherever pos-  sible in the region of the NVBs in accordance with standard  athermal dissection techniques. Whether laser energy offers  any benefit during laparoscopic or robotic radical prostatec-  tomy over current athermal practices remains to be seen and  the application of this technology to LRP and RARP is  unproven at this time.    In summary, lasers have been investigated in laparoscopic  urological applications ranging from laser tissue welding in  laparoscopic pyeloplasty through to laser laparoscopic and    laser robotic radical prostatectomy, while most development  has centered on LPN. Despite extensive investigation, laser  usage during laparoscopic urological procedures has not  gained widespread acceptance and remains experimental at  this time.    . Knappe V, Frank F, Rohde E. Principles of lasers and biophotonic    effects. Photomed Laser Surg. 2004;22(5):411—417  Reinisch L. Laser physics and tissue interactions. Otolaryngol Clin  North Am. 1996;29(6):893-914    . Stein BS. Laser physics and tissue interaction. Urol Clin North Am.    . Hughes BE, Scott WW. 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Anatomy of auto-  nomic nerve component in the male pelvis: the new concept from a  perspective for robotic nerve sparing radical prostatectomy. World J  Urol. 2006;24(2):136-143    Tewari A, Takenaka A, Mtui E, et al The proximal neurovascular  plate and the tri-zonal neural architecture around the prostate gland:  importance in the athermal robotic technique of nerve-sparing pros-  tatectomy. BJU Int. 2006;98(2):314—323   Dahl DM, L’Esperance J O, Trainer AF, et al Laparoscopic radical  prostatectomy: initial 70 cases at a U.S. university medical center.  Urology. 2002;60(5):859-863   Guillonneau B, Vallancien G. Laparoscopic radical prostatectomy:  the Montsouris technique. J Urol. 2000;163(6):1643—1649   Eden CG, King D, Kooiman GG, Adams TH, Sullivan ME, Vass  JA. Transperitoneal or extraperitoneal laparoscopic radical pros-  tatectomy: does the approach matter? J Urol. 2004;172(6 Pt 1):  2218-2223   Gill IS, Ukimura O, Rubinstein M, et al Lateral pedicle control dur-  ing laparoscopic radical prostatectomy: refined technique. Urology.  2005;65(1):23-27   Ong AM, Su LM, Varkarakis I, et al Nerve sparing radical prostate-  ctomy: effects of hemostatic energy sources on the recovery of cav-  ernous nerve function in a canine model. J Urol. 2004;172(4 Pt 1):  1318-1322   Tulikangas PK, Smith T, Falcone T, Boparai N, Walters MD. Gross  and histologic characteristics of laparoscopic injuries with four dif-  ferent energy sources. Fertil Steril. 2001;75(4):806-810   Walz J, Graefen M, Huland H. Basic principles of anatomy for opti-  mal surgical treatment of prostate cancer. World J Urol. 2007;  25(1):31-38   Chien GW, Mikhail AA, Orvieto MA, et al Modified clipless ante-  grade nerve preservation in robotic-assisted laparoscopic radical  prostatectomy with validated sexual function evaluation. Urology.  2005;66(2):419—423   Stolzenburg JU, Rabenalt R, Do M, Tannapfel A, Truss MC,  Liatsikos EN. Nerve-sparing endoscopic extraperitoneal radical  prostatectomy: University of Leipzig technique. J Endourol. 2006;  20(11):925-929   Gianduzzo TR, Chang CM, El-Shazly M, Mustajab A, Moon DA,  Eden CG. Laser nerve-sparing laparoscopic radical prostatectomy:  a feasibility study. BJU Int. 2007;99(4):875-879   Gianduzzo TR, Colombo JR, El-Gabry E, Haber GP, Gill IS.  Anatomical and electrophysiological assessment of the canine  periprostatic neurovascular anatomy: perspectives as a nerve spar-  ing radical prostatectomy model. J Urol. 2008;179(5):2025—2029  Gianduzzo T, Colombo JR Jr, Haber G-P, et al Laser nerve-sparing  laparoscopic radical prostatectomy: effects of potassium-titanyl-  phosphate laser on cavernous nerve function in a survival canine  model. J Urol. 2007;177(4):804   Gianduzzo T, Colombo JR Jr, Haber GP, et al Laser robotically  assisted nerve-sparing radical prostatectomy: a pilot study of tech-  nical feasibility in the canine model. BJU Int. 2008;102(5):  598—602   Gianduzzo T, Kaouk J, Colombo JR, et al KTP laser robotic nerve-  sparing radical prostatectomy: development and initial clinical  experience. In: Engineering and Urology Society 22nd Annual  Meeting; 2007:Abstract 212    Prostate cancer is the most commonly diagnosed malignancy  in the UK representing 2446 of male cancers; the death rate  from prostate cancer is significant at 3% of all male deaths.’  In many cases, the disease has a long period of asymptomatic  growth before developing into locally advanced or metastatic  disease with symptoms.   There are several existing options for the control of early  prostate cancer including radical prostatectomy (RP), utiliz-  ing open surgical, laparoscopic, or robotic techniques, exter-  nal beam radiotherapy (EBRT), and brachytherapy (BXT)  using either low dose or high dose rate techniques. More  recently, prostate cryotherapy has become available and new  technologies including high intensity focused ultrasound  (HIFU), interstitial treatment with photosensitizers and laser  radiation are evolving into clinically relevant entities.   Despite the range of technologies employed to target early  prostate cancer, none has become the definitive treatment for  the most common of male malignancies. This is due to the  fact that all have significant drawbacks, as well as advan-  tages, over each other and compared with conservative ther-  apy for early prostate cancer. The literature on radical  treatment for early prostate cancer has few randomized trials.  In this difficult intellectual terrain, we describe the current  and future place of prostate cryotherapy.    The aims of treatment for organ confined prostate cancer are  to prevent progression from early disease to metastatic,  locally advanced disease or symptomatic disease within the  patient's lifetime or as a cause of a shortened lifespan via the  mechanisms described in Fig. 12.1. Its additional aim should  be to achieve this without causing new symptoms or disease  in the patient.   The late Dr Whitmore as director of urology at the  Memorial Sloane Kettering Cancer Centre noted, of existing  treatments for prostate cancer, “When cure is possible is it    necessary and when it is necessary, is it possible?" This ques-  tion is equally valid today and the value of cryotherapy may  lie mainly in the group of men with significant primary or  recurrent disease in whom the possibility of cure remains a  challenge.   Cryotherapy has been applied to all the stages of nonmet-  astatic prostate cancer described in the gray-shaded area of  Fig. 12.1. This chapter will describe current results of cryo-  therapy treatment as well as the theory underpinning the  technique and possible areas for future development.    The history of prostate cryotherapy was recently reviewed by  Ahmed et al’. Though modern cryotherapy is a relatively  recent and constantly evolving technique, the recognition  that cold could be used to treat tumors is not novel. Therapeutic  cryotherapy started with the work of Dr James Arnott from  Brighton, UK. In the 1840s, he described the use of ice slush  for topical anesthesia and to treat tumors including cervical  cancer using a wide speculum to achieve freezing. He made  an important conclusion following his observation on the  use of cryotherapy in the treatment of cancer “Congelation    arresting the accompanying inflammation, and destroying the  vitality of the cancer cell, is not only calculated to prolong  life for a great period, but may not improbably, in the early  stage of the disease, exert a curative action.” He published his  work in the Lancet in 1850 and his cryotherapy apparatus  was shown in the Great Exhibition in London in 1851.   Topical applications of ice slush were not suitable for reli-  ably achieving adequately reduced temperatures in the —20  to —40°C range, and although gas liquefaction by adiabatic  expansion systems for cooling were invented in the 1870s,  delivery systems were not developed until the late 1890s.  The early 1900s saw an increase in the availability of liquid  nitrogen, which led to the possibility of topical treatment of  superficial lesions either by direct application of liquid nitro-  gen or application of a cooled metal probe.   It was not until 1961 that the neurosurgeon, Irving Cooper  and engineer, Arnold Lee developed a vacuum-insulated  needle delivery system for liquid nitrogen. This allowed an  iceball to be formed at the needle tip and variants of this  system were used to treat benign and malignant conditions at  a variety of sites including malignant brain tumors. Gonder?  used a transurethral probe with digital rectal monitoring to  freeze the prostate using liquid nitrogen. This process was  complicated by a high incidence of urethral sloughing and  recto-urethral fistulae.’   The modern renaissance of prostate cryosurgery was her-  alded by several developments. The description by Onik et al  of transrectal ultrasound guided cryotherapy in 1993^ using  dual liquid nitrogen cryoprobes heralded the era of modern  cryotherapy. The availability of more accurate thermocou-  ples! and the urethral warming catheter? led to reductions in  the significant complications of urethral sloughing and rectal  fistulae, which had been encountered in early cryotherapy.   Lastly, the progression from single- or dual-probe, liquid  nitrogen—based systems to the current multi-probe argon-  helium systems has led to better control of the cooling phase,  ability to actively warm the probe, and reduced trauma as an  effect of reduced probe size.   Currently available systems utilize the Joule-Thompson  effect. This is characterized by a change in temperature, pro-  duced in this scenario at the probe tip, when high pressure gas  is released to a lower pressure, and exits via the outer lumen  of the probe. The temperature at the probe tip may be reduced  or increased depending on the physical properties of the gas  chosen. Rapid cooling to temperatures as low as —186°C  may be achieved using argon; helium produces warming to  temperatures of up to 40?C. Figure 12.2 illustrates the iceball  generated during probe testing on a modern device.   Two systems are currently in widespread use. Galil  Medical introduced their third-generation cryotherapy sys-  tem (Seednet™) in the late 1990s. They developed ultra thin  17-gauge needle probes, which allowed more uniform cover-  age of the prostate. In 2003, Endocare introduced their    fourth-generation cryotherapy system (Cryocare™) CS),  which superseded their previous argon-helium system, intro-  duced in the mid-1990s.   The latest developments of the technique resulted from  the constant improvement in the quality of transrectal ultra-  sound images due to the evolution of high-definition multi-  planar ultrasound arrays over the last 20 years. This has led  to an ability to more accurately monitor the iceball (which  can be seen as a hyperechoic rim with acoustic shadowing^)  and more accurately place the thermocouples used for tem-  perature monitoring.   This evolution in the technique, with evidence of a signifi-  cant reduction in complications as advances in technology  occured? does mean that care is necessary in interpreting the  published results of prostate cryotherapy.    The aim of prostate cryotherapy is to destroy neoplastic tis-  sue and preserve vital structures around the prostate includ-  ing the bladder, rectum, and ideally the neurovascular  bundles. This requires precise freezing process to achieve the  maximum tissue ablation within the prostate without damage  to the critical structures.   In modern prostate cryotherapy, several cryoprobes are  used and cells are exposed to variable thermal parameters  depending on their location from the freezing probe. Larson  et al’ reported two areas of tissue damage surrounding the  cryotherapy probe. Areas near the probe undergo coagulative  necrosis; while at a greater distance from the probe, tissues  undergo squamous metaplasia and hemorrhage, which is  replaced by polymorphonuclear leukocytes infiltrate.!° It is    well known that two mechanisms are responsible for cell  death: direct injury caused by ice formation and indirect isch-  emic effect caused by microvascular changes. During freez-  ing, extracellular ice forms at a temperature range between —7  and —20°C. A hyperosmolar extracellular environment draws  water from the cells and lead to cell dehydration and shrinkage  (the solute effect injury). At even lower temperatures («—15?C),  ice will extend to the intracellular space." Homogenous  intracellular ice crystals are noticed at temperature lower  than —40?C, which is almost always lethal to the cells.!!   During thawing, the extracellular space is hypotonic and  water enters the cells to augment the solute effect and results  in cell rupture. Microvascular effects start with vasoconstric-  tion and tissue anoxia during the freezing phase, which results  in tissue necrosis. This is followed by vasodilatation, increased  vascular permeability, and tissue edema during the thawing  phase which contributes to the solute effect cell injury.  Following freezing, blood vessels show endothelial cell dam-  age and microthrombus formation and complete cessation of  circulation follows in few hours." Apoptotic cell death can  be identified in the peripheral zone of the cryolesion, where  cells are exposed to sublethal freezing temperature."    Several physical parameters appear to influence the biologi-  cal tissue changes described earlier. These include the freez-  ing rate, temperature nadir, thawing rate, duration of freeze,  and number of freeze cycles.    Rapid freezing is essential for intracellular ice formation and  is associated with higher rate of cell death." However, there  was no agreed definition of rapid freezing. In vitro studies  demonstrated that intracellular ice formation can be achieved  with freezing rate between 3 and 50?C/min,^/5 while  Tatsutani et al" demonstrated that a freezing rate of 25°C/  min is essential for intracellular ice formation and complete  cell death. Factors affecting the freezing rate include the dis-  tance of the tissue from the center of the ice ball, vascularity,  and water content of the treated organ."    The critical temperature that results in complete ablation  of the prostate tissue is not well defined. Early reports    demonstrated a temperature of —20?C or less is essential to  kill the cells.'*!° More recently, studies have shown that  —40°C is required for complete destruction of prostate tis-  sue.” Larson et al? reported on six prostate cancer patients  who underwent prostate cryotherapy using single cryother-  apy probe followed by RP, as a definitive treatment. They  identified that the critical temperature required to achieve  uniform coagulative necrosis was —41.4°C in the double  freeze cycle compared with —61.7?C in the single freeze  cycle, though clearly, further tissue changes might have  occurred if a greater time had been allowed to elapse between  cryotherapy and prostatectomy.    Thawing phase is an important mechanism that results in cell  destruction during the freeze-thaw cycle. During thawing  phase, cells are exposed to different damaging mechanisms  including solute effect, ice crystal recrystallization, and rep-  erfusion injury.?! It was demonstrated that slow thawing rates  are associated with a significant increase in cell death when  compared with active thawing.” Slow thawing exposes tis-  sues to prolonged time of osmotic imbalance, oxidative  stress, and growth of ice crystals and hence is associated  with increased cell death.”    Although the optimum duration of freezing is not yet well  defined, it is known that the length of exposure to freezing  temperatures affects cell viability post cryotherapy.” Early  reports suggested that duration of freezing is less important  when the tissue is treated to a temperature less than —40?C as  a smaller amount of water remain unfrozen.*' Klossner et al?  demonstrated that prostate cancer cells held at the critical  temperature of —40?C for 2 min showed the maximum abla-  tive level (~93%) when compared with cells, which just  reached the critical temperature (2496).    The importance of double freeze-thaw cycle for complete  ablation of prostate tissue has been identified in an in vivo  study.? The volume of necrotic tissue significantly increased  from 4 to 13% following double freeze-thaw cycle. A recent  report demonstrated enhanced lethal effect of cryotherapy  following the second freeze-thaw cycle." The mechanism    behind increased cell death following the second freeze-  thaw cycle is not well understood. Cellular disruption and  loss of cell membrane integrity following the first freeze  causes an increase in thermal conductivity during the second  freeze, which results in faster and more extensive tissue  freezing during the second freeze-thaw cycle.” In addition,  extended exposure to cold injury may sensitize cancer cells  following the first freeze.”    Organ confined prostate cancer remains amenable to cryo-  therapy today, although increasing competition from other  treatment options means that this is infrequently used for pri-  mary treatment in the UK when compared with radiotherapy  and RP. Guidance was issued from the UK National Institute  of Clinical Excellence (NICE), based on their literature  review which was prepared in 2004.” This stated that in view  of the current scarcity of evidence on the efficacy and safety  of primary cryotherapy, it was not recommended for men  with localized prostate cancer other than in the context of  controlled clinical trials comparing their outcomes with  those of more established interventions.   The Cochrane review group considered cryotherapy for  localized prostate cancer in 2007? and their findings sup-  ported these conclusions. The American Urological  Association (AUA) has stated that there are insufficient pub-  lished data to perform a meta-analysis of the results of cryo-  surgery for early prostate cancer and include this modality in  the 2007 guidelines on the management of clinically local-  ized prostate cancer."   Best practice guidelines from the AUA on prostate cryo-  therapy suggest that although there is a scarcity of evidence,  short-term outcomes for intermediate and high risk organ  confined disease may be similar to those from radiotherapy  at follow-up durations «8 years." The latest publications  detailed in the results section include patients with 10-year  follow-up.    Cryotherapy has also been used to treat locally advanced  prostate cancer. However, a recent randomized controlled  trial in T2c-T3b (bilateral organ confined, capsular penetra-  tion, or seminal vesical invasion) by Chin et al? has sug-  gested that biochemical disease-free survival was poorer in  men who underwent cryotherapy as their primary treatment    modality than in those who underwent primary EBRT.  Clearly, the subgroup of patients with capsular penetration  and a contraindication to EBRT may wish to consider cryo-  therapy as primary therapy.    The failure rates for contemporary EBRT in biochemical  control of organ-confined prostate cancer range from 24 to  85% depending on the risk profile of the assessed group and  the planning and delivery of radiotherapy.??' Owing to the  widespread use of EBRT often at lower radiation doses than  are used currently, this is potentially the largest group of  patients who are suitable for prostate cryotherapy. The work-  load of such patients who may require cryotherapy is also  higher, in part due to the relative lack of other established  modalities, which are recognized as effective in the treat-  ment of locally recurrent disease after radiotherapy.    Guidelines by the AUA and the NICE, UK, detail appropri-  ate investigations to confirm staging prior to local ablative  therapy in patients with pathologically confirmed prostate  cancer." Use of established staging nomograms (Roach?  or Partin^) should be encouraged and the possibility of  lymph node (LN) sampling considered if the chance of LN  involvement is 21596." As in patients undergoing primary  treatment, a prostate volume of more than 40 cm? requires 3  months cytoreductive hormone therapy to facilitate the pro-  cedure and reduce the risk to the surrounding structures.?    Rising serum prostate specific antigen (PSA) level is usually  the first sign of treatment failure in prostate cancer. The PSA  may fluctuate in the first 18 months following radiotherapy."  If there is a persistent rise in PSA, which fulfils the Phoenix  definition of biochemical failure (nadir PSA + 2.0 mmol/dL)  then staging investigations for salvage therapy may be  instigated.*’   The possibility of lower urinary tract infection should be  excluded. Restaging pelvic MRI scan and bone scan is man-  datory to exclude patients with metastatic disease prior to  prostate biopsy. Prostate biopsy is mandatory to confirm local  recurrence. Saturation prostate biopsy (20-40 cores) is more    sensitive than transrectal biopsy (10 cores) in detection of  recurrent cancer in irradiated patients.** Cytoreductive andro-  gen deprivation should be employed when prostate volume is  >40 cm’. The role of pelvic LN dissection should be consid-  ered in men at higher risk of having locally advanced disease  based on the characteristics of their initial presentation (using  the Roach or Partin nomograms identified earlier).    Our protocol requires a phosphate enema on the morning of  surgery, after which the patient is anesthetized, usually with  general or regional anesthetic. In the lithotomy position, the  patient is draped and the perineum prepared with aqueous  iodine solution. A flexible cystoscopy is performed to check  for possible urethral problems, which might prevent the  placement of the warming system, and the patient then has a  catheter placed. A volume measurement is then performed  and the number of probes necessary is calculated. A stepping  unit mounted either on the floor or attached directly to the  operating table may be used. Commercial software is avail-  able to optimize placement of the cooling probes based on  the gland volume and the location of the critical structures  (rectum and urethra); however, this is not widely used and  most operators place the cryoprobes freehand via a perineal  template. For typical salvage cases, this would result in the  placement of 6-12 of the Galil Seednet probes in 2-3 rows,  at approximately 10 mm intervals. Thermocouples are then  placed in four locations; anterior to Denonviliers fascia, in  the anterior prostate, at the prostatic apex, and in the sphinc-  ter, all under ultrasound control. The catheter is then removed  and a flexible cystoscopy performed to allow placement of a  guidewire in the bladder and the urethral warmer is placed  over the guidewire. A typical setup for cryotherapy is repro-  duced in Fig. 12.3. The two freeze cycles are then com-  menced with careful monitoring of the freeze using the  temperature probes and the ultrasound images. This tech-  nique was used to produce the results in the series of patients  treated at our institution.”    Biochemical recurrence free survival (BRFS) rates after  primary cryotherapy are variable ranging from 60 to 90% at  the last follow-up. This depends on the criteria used in  defining the cutoff PSA recurrence rate. The outcome also  varies depending on the risk groups with better outcome in  the low-risk patients (those with a PSA level <10 ng/mL, a    Fig. 12.3 Setup for prostate cryotherapy with urethral warmer in situ,  black cryoprobes and white thermocouples inserted via a perineal  template    Gleason score <6 and a clinical stage <T2b) when com-  pared with the high-risk patients (those with two or more  unfavorable risk factors from a PSA level >10 ng/mL, a  Gleason score 27, and clinical stage >2b).® The use of  preoperative hormone ablation therapy impacts on the  long-term results of the procedure. Tables 12.1 and 12.2  summarize the results and complications of the recent stud-  ies of primary prostate cryosurgery. Cohen et al"' assessed  370 patients who had undergone prostate cryotherapy as  primary treatment for locally advanced prostate cancer. The  10-year actuarial biochemical recurrence-free survival  (BRFS) for low risk, medium risk, and high risk was  80.56, 74.16, and 45.54%, respectively. The 10-year posi-  tive biopsy rate was 2396. Hubosky et al? retrospectively  reviewed 89 patients for 11 months who had undergone pri-  mary cryotherapy of the prostate. Their results were compa-  rable with those of Cohen et al*' series with regard to the  local cancer control. Long et al? presented a multi-  institutional report following primary prostate cryotherapy.  A total of 975 patients were treated over 5 years. Two PSA  thresholds were used (0.5 and 1 ng/mL) to define biochemi-  cal disease recurrence. Seventy-five percent of the patients  were in the intermediate and high-risk group. The 5-year  actuarial BRFS rates were 60% in the low-risk patients    Series Impotence (96) Incontinence (96) Recto-urethral Urethral slough (96) Pain  Stricture/  fistula  retention     when compared with 36% in the high-risk group (PSA cut- rate was defined as PSA level «0.5 ng/mL. The 7-year actu-  off 0.5 ng/mL). The positive biopsy rates ranged from 18to arial BRFS rate were 61, 68, and 61% for the low-risk,  24%. Bhan et al“ reported on 590 patients who underwent — intermediated-risk, and high-risk groups, respectively, with  cryoablation of the prostate and followed for 7 years; BRFS a positive biopsy rate of 13%.    Complication rates are low following primary prostate cryo-  therapy apart from erectile dysfunction, which remains a  serious problem.“ Table 12.2 summarizes the complication  rate following primary cryotherapy of the prostate. Recto-  urethral fistulae are very uncommon in modern primary cry-  otherapy series («0.596 in reports from the last decade).*°  The impotence rate in the primary cryotherapy ranges from  53 to 96%. Donnelly et al^ reported that the nerves have the  potential to recover 12 months following cryotherapy and  half of their patients had recovered potency by 36 months.  Incontinence rates varied considerably but were <10% in  most series.    There has been controversy in evaluating the clinical response  following cryotherapy of the prostate. PSA level cutoffs of  0.1, 0.2 (above nadir), 0.3, 0.4, and 0.5 ng/mL have been  used to define biochemical failure.” Connolley et al  demonstrated that PSA cutoff value of 20.5 ng/mL is a strong  predictor of positive biopsy at 12 months post cryotherapy.  Table 12.3 summarizes the outcome of the recent salvage  cryotherapy case series.   In our center the first 100 salvage cryotherapy patients  were followed with 3 monthly serum PSA level over mean  follow-up period of 33 months. We used the American Society  for Therapeutic Radiology and Oncology (ASTRO) defini-  tion and cutoff value 20.5 ng/mL to define the biochemical    failure. Using the ASTRO definition, 6096 of men remained  disease free at 3 years follow-up. Unsurprisingly, high-risk  patients showed the least favorable outcome. This may reflect  undetected subclinical systemic disease, persistent local can-  cer progression, or involvement of the seminal vesicle”.  Seventy-three percent of low-risk patients with no risk factor  remained free from biochemical recurrence at 5 years  follow-up.   A recent retrospective case series reported on 279 patients  who had undergone salvage cryotherapy for recurrent pros-  tate cancer? At 5 years, 59% were free from biochemical  failure and 67.4% had a negative biopsy following the proce-  dure. Bahn et al^ presented the longest follow-up series of  salvage cryotherapy. At 7 years follow-up, the combined  BRFS using PSA cutoff of 0.5 ng/mL was 59%. At the  London Health Sciences Centre in Ontario, 187 patients with  locally recurrent prostate cancer have been treated with sal-  vage cryotherapy.^ They reported BRFS of 5696 with a mean  follow-up of 39 months. Preoperative PSA level was an inde-  pendent predictor for BRFS and patients with preoperative  PSA less than 4 ng/mL had better outcome.    Almost all patients following salvage cryotherapy will have  some degree of lower urinary tract symptoms (LUTS) sec-  ondary to urethral slough, most of which will resolve in the  first 6 months (Table 12.4). Urethral slough rates have been  reduced from 40*! to 5%**°° in many series since the intro-  duction of urethral warming catheter, which protects urethral  mucosa during cryotherapy. In contemporary salvage cryo-  therapy series, the urinary incontinence rate has dropped      Pisters et al? 69.2 4.4 12  Ng et al? N/A 3 (severe) p  Ismail et al^ 86 6 (severe) 1  Robinson et al^ 56 29 (moderate to severe)  Lam et al“ 83.3 175 0  Bahn et al? N/A 8 3.4  Ghafar et al? N/A 7.9 0  Chin et al™* 6.7 33  de la Taille et al^ N/A 9 0  Pisters et a? 12 pe 1  Bales et al“' 100 95.5 N/A    Urethral slough Pain  X Stricture/retention    32 N/A 6.8  14 DI  16 4 2)    N/A 5) 9  N/A N/A N/A  0 SIS 0  doll 8.5  N/A 26 S    dramatically with recent studies reporting incontinence rates  of 3-6%.**° Although urethral warming has been successful  in reducing urinary morbidity, it may compromise cancer  control by protecting a rim of prostatic tissue around the ure-  thra from freezing.™   Erectile dysfunction is the most frequently occurring  complication following prostate cryotherapy," ^ primarily  due to the ice ball extending into the neurovascular bundles  when attempting to completely eradicate the tumor. The  impotence rate in salvage cases range from 56 to 100%. In  salvage cryotherapy most patients suffer from a degree of  erectile dysfunction owing to previous hormone therapy and  pelvic irradiation.   The most serious complication of salvage cryotherapy is  the development of recto-urethral fistula. New treatment  advances and better control of the procedure have signifi-  cantly reduced this complication to <4% in salvage cases.^*6    Areas for Potential Advances  in the Management of Organ Confined  Prostate Cancer Using Cryotherapy    In prostate cryotherapy, the whole prostate gland is frozen  including the periprostatic tissue with neurovascular bundles  to eradicate all tumor cells. As a result, the incidence of erec-  tile dysfunction is high. In an attempt to preserve potency,  Onik et al^ described focal nerve sparing prostate cryotherapy  where they treated part of the prostate which contained the  tumor. After a mean follow-up of 50 months, 95% of the    treated patients had stable PSA and 80% maintained their  potency. In a different approach, the neurovascular bundle  was successfully preserved by active warming, but this  resulted in an incomplete ablation of prostate tissue. Lambert  et al? presented 28 months (range 9-72 months) follow-up of  25 patients treated with primary focal cryotherapy. Eighty-  four percent of patients had not experienced biochemical  failure and only 14% showed positive biopsy on the treated  site. Potency was maintained in 71% and no patient reported  any worsening LUTS or incontinence. Focal nerve sparing  cryotherapy has not been applied in salvage treatment.    LAC is a new technique that attempts to protect healthy tis-  sue around the prostate without limiting the cryoablation of  unwanted tissue. Laser radiation administered from the ure-  thra into the prostate during freezing process maintains the  temperature in the urethral wall and surrounding region  above the damaging level, and at the same time lethal tem-  perature is achieved in the surrounding prostate tissue. The  margin of laser protected area increases with injecting light  absorbing dye into the periurethral tissue.”    The rate of recto-urethral fistula following prostate cryother-  apy is low; however, this remains a potentially catastrophic  complication. Avoiding excessive freezing at the posterior  margin of the prostate protects the rectum from freezing    injury. Therefore, whole gland ablation which is necessary  for complete eradication of prostate cancer will always be  associated with the risk of fistula. Modifying the cryotherapy  technique to achieve lethal temperature (<—40°C) posteriorly  while avoiding potential rectal injury was attempted using  different techniques. Cytron et al? inserted two cryotherapy  needles into the Denonvellier's fascia for active warming  using the thawing phase when the temperature drops below  0°C in the posterior prostate. This approach successfully  maintained a PSA level of «0.5 ng/mL in 80.696 of the  patients treated and no rectal injury was reported. Other stud-  ies have addressed this issue by manipulating the transrectal  ultrasound probe to increase the distance between the rectal  wall and the prostate. The mean distance was increased by  7.1 mm without impairing the ultrasound quality image.”    There are limitations to the maximum improvement techni-  cal innovations in the delivery of cold to the prostate can  achieve, given the close relationship between the critical  structures that surround the prostate. Other options for  improving outcomes include the application of treatments  adjuvant to the application of cold.    Freezing results in necrotic cell death; 3mechanisms are  responsible for this:'^    (a) Extracellular ice crystal formation, which leads to cell  hyperosmolarity and post hypertonic lysis    The use of anticancer drugs as sensitizing agents to enhance  apoptotic cell death at the peripheral zone of the cryogenic  lesion may improve the efficacy of cryotherapy. Clarke et al’*  demonstrated that the combination of cryotherapy and Tumor  necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL)  resulted in enhanced prostate cancer cell death owing to  apoptosis at —10°C. The same group demonstrated enhanced  efficacy of cryotherapy when combined with sublethal con-  centration of 5-fluorouracil in vitro.”   Goel et al investigated the ability of tumor necrosis fac-  tor alpha (TNF-a) to enhance cryoinjury in vivo. Temperature  threshold for necrosis was increased with the addition of  TNF-a prior to cryotherapy and the combined treatment  resulted in growth delay of the tumor in the experimental  animals which require further investigation.    Systemic antitumor immune response has been postulated  following prostate cryotherapy. Clinical case reports observed  regression of metastatic disease and symptoms relief follow-  ing prostate cryotherapy, which implies that a protective  immune response may be induced." The mechanism of  such clinical observation was not clear. Local tumor destruc-  tion by cryotherapy results in the release of a large amount of  cryonecrotic tissue and tumor antigens. This may enhance the  uptake of these antigens by local dendritic cells and priming  of naive T cells in regional LNs resulting in tumor-specific  immune response and tumor eradication.” The cryoimmune  response has been studied in several animal models. Both  immunostimulatory and immunoinhibitory effects have been  reported.   The precise mechanism of the immunostimulatory effect is  not clear. Early cytokine-mediated response,***' the involve-  ment of T-cell immunity and enhanced natural killer (NK)  cells cytotoxicity," ^^ and the development of antitumor anti-  bodies? have all been suggested as possible immune stimula-  tions. Suppressed immunity and enhanced tumor growth and    Prostate cryotherapy may be used to treat a variety of presen-  tations including localized primary prostate cancer, locally  advanced disease, and for salvage after failed radiotherapy.  The most established of the three roles is currently in salvage  treatment. The relative merits of primary treatment with cry-  otherapy for localized and locally advanced disease com-  pared with other existing modalities have yet to be fully  explored with comparative studies. Contemporary random-  ized trials would be useful in each of the disease subgroups.  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Focal cryosurgery:  encouraging health outcomes for unifocal prostate cancer. Urology.  2007;69(6):1117—1120   Romero-Mendez R, Franco W, Aguilar G. Laser-assisted cryosurgery  of prostate: numerical study. Phys Med Biol. 2007;52(2):463-478  Cytron S, Paz A, Kravchick S, Shumalinski D, Moore J. Active  rectal wall protection using direct transperineal cryo-needles for  histologically proven prostate adenocarcinomas. Eur Urol. 2003;  44(3):315—320; discussion 320-321   Jones JS. Ultrasound probe positioning to minimize the risk of  recto-urethral fistula during cryosurgical ablation of prostate can-  cer. BJU Int. 2007;100(1):58—62; discussion 62   Clarke DM, Robilotto AT, VanBuskirk RG, Baust JG, Gage AA,  Baust JM. Targeted induction of apoptosis via TRAIL and cryoab-  lation: a novel strategy for the treatment of prostate cancer. Prostate  Cancer Prostatic Dis. 2007;10(2):175-184   Clarke DM, Baust JM, Van Buskirk RG, Baust JG. Addition of anti-  cancer agents enhances freezing-induced prostate cancer cell death:  implications of mitochondrial involvement. Cryobiology. 2004;  49(1):45-61   Goel R, Swanlund D, Coad J, Paciotti GF, Bischof JC. TNF-alpha-  based accentuation in cryoinjury-dose, delivery, and response. Mol  Cancer Ther. 2007;6(7):2039-2047   Gursel E, Roberts M, Veenema RJ. Regression of prostatic cancer  following sequential cryotherapy to the prostate. J Urol. 1972;108(6):  928—932   Soanes WA, Ablin RJ, Gonder MJ. Remission of metastatic lesions  following cryosurgery in prostatic cancer: immunologic consider-  ations. J Urol. 1970;104(1):154—159   den Brok MH, Sutmuller RP, van der Voort R, et al In situ tumor  ablation creates an antigen source for the generation of antitumor  immunity. Cancer Res. 2004;64(1 1):4024-4029   Joosten JJ, Muijen GN, Wobbes T, Ruers TJ. In vivo destruction of  tumor tissue by cryoablation can induce inhibition of secondary tumor  growth: an experimental study. Cryobiology. 2001;42(1):49-58  Sabel MS, Nehs MA, Su G, Lowler KP, Ferrara JL, Chang AE.  Immunologic response to cryoablation of breast cancer. Breast  Cancer Res Treat. 2005;90(1):97—104   Friedman EJ, Orth CR, Brewton KA, Ponniah S, Alexander RB.  Cryosurgical ablation of the normal ventral prostate plus adjuvant  does not protect Copenhagen rats from Dunning prostatic adenocar-  cinoma challenge. J Urol. 1997;158(4):1585-1588   Hoffmann NE, Coad JE, Huot CS, Swanlund DJ, Bischof JC.  Investigation of the mechanism and the effect of cryoimmunology  in the Copenhagen rat. Cryobiology. 2001;42(1):59—68   Hayakawa K, Yamashita T, Suzuki K, et al Comparative immuno-  logical studies in rats following cryosurgery and surgical excision  of 3-methylcholanthrene-induced primary autochthonous tumors.  Gann. 1982;73(3):462-469   Moore FT, Blackwood J, Sazenbacher L, Pace WG. Cryotherapy for  malignant tumors. Immunologic response. Arch Surg. 1968;96(4):  527-529    Treatment decisions regarding prostate cancer (PCa) are dif-  ficult because of the protracted course of the disease and the  morbidity associated with treatment. With the increased inci-  dence of localized prostate cancers at diagnosis, new treatment  modalities have been developed to decrease morbidity without  affecting oncologic results. Though cancers are multifocal in  the majority of cases, approximately 2046 are unifocal. This  affords the opportunity for the application of treatment tar-  geted to a solitary focus of cancer, which would potentially  decrease morbidity associated with whole gland treatment.    The importance of treating localized prostate cancer has been  demonstrated by the prospective, randomized Scandinavian  study that compared active surveillance to radical prostatec-  tomy (RP). This study has shown that RP increases both pros-  tate cancer-specific and overall survival after a median  follow-up of 10.8 years. Evolution of the disease was slow  for the first 10 years of follow-up, after which they observed  a difference in overall survival between the two groups.!  Interestingly, a difference in overall survival was seen only in  patients less than 65 years old, a category of patients for  which erectile function is often of prime importance. In  another study, Johansson et al showed that 16% (35/233) of  patients diagnosed with cTO-T2 prostate cancers and fol-  lowed by watchful waiting died of prostate cancer after a  mean follow-up of 21 years.? Of the patients who died, 45 and  40% had localized and low-grade lesions, respectively.  Finally, results from the Connecticut Tumor Registry,’ which  included 1,618 patients 75 years or younger who underwent  surgery, external beam radiation therapy or initial observation  for clinically localized prostate cancer demonstrated that at    an average follow-up of 13.3 years, 13% of patients had died  of PCa. Patients who elected observation had significantly  worse cancer-specific survival than those who underwent  elected surgery. Taken together, these three studies show that  treatment can increase cancer-specific and overall survival  and that localized disease can lead to death after more than 15  years. It also suggests that patients undergoing active surveil-  lance may need effective definitive treatment if life expec-  tancy is more than 15 years.    The reports from the Consensus Conference on Focal  Treatment of Prostatic Carcinoma defined focal therapy as an  individualized treatment that selectively ablates known dis-  ease and preserves existing functions, with the overall objec-  tive of minimizing lifetime morbidity without compromising  life expectancy.* Focal therapy can involve the local applica-  tion of treatment to a specific focus, and the term “image-  guided focal therapy" is used when it is done under real-time  imaging.^" Focal therapy have been further subdivided into  hemiablation when treatment involves a complete lobe and  subtotal ablation when both lobes are targeted with the excep-  tion of a rim of parenchyma close to the neurovascular  bundle(s).*-? Others have used the term “conformal cryoab-  lation" to define bilateral ablation with preservation ablation  of one neurovascular bundle on the unaffected side.*    There are currently no widely accepted indications for focal  therapy for prostate cancer. Selection of patients should be  based on their preoperative risk for extraprostatic and bilat-  eral disease. Recently, a group termed the International Task  Force on Prostate Cancer and the Focal Lesion Paradigm  has published its recommendations for clinical use of focal  ablation therapies. These are summarized in Table 13.1.*    Table 13.1 Proposed clinical, biopsy, and imaging criteria for focal  therapy patient selection?   PSA velocity less than 2 ng/mL yearly in the year prior to diagnosis   Maximum percentage of cancer in each core (e.g., 2096)  Maximum length of cancer in each core (e.g., 7 mm)  Maximum percentage of total cores with cancer (e.g., 3396).    These recommendations are guidelines, but data are cur-  rently lacking to encourage widespread use of these thera-  pies. Assuming that the targeted focus of prostate cancer is  completely ablated by focal therapy, the main challenge in  the establishment of indications for focal therapies is to accu-  rately select patients with localized, unifocal prostate cancer  and for which the treatment would improve the overall sur-  vival. Therefore, the success of focal therapy does not rely  solely on the ability of the therapy to eradicate cancerous  prostate tissue but also on the accuracy of the clinical predic-  tive models, biopsy, and imaging techniques to identify a  unilateral and localized prostate cancer.    When considering focal ablative therapy for prostate cancer,  some questions exist regarding prostate cancer biology and  the ability to characterize it accurately. These questions are  summarized in Table 13.2, with the applicable studies  described in the subsequent text.    Many studies have looked at the prevalence of unifocal pros-  tate cancer on RP specimens. Mouraviev et al analyzed par-  affin-embedded RP specimens from patients with clinically  localized PCa with low-risk features." Pathologic assess-  ment of 1,184 specimen paid particular attention to laterality.  Completely unilateral cancers were identified in 227 (19.2%)  patients. Similar results were obtained by Iczkowski et al    Questions Answers   What is the prevalence of PAE ne  unilateral prostate cancer in  low-risk disease?  What is the prevalence of 2015s    prostate cancers with adverse  features^ on the controlateral  side when TRUS-biopsy  show unilateral prostate  cancer?    What is the PPV of TRUS  biopsies to detect unilateral  prostate cancer?    6-core biopsy: 27!  10-12 core biopsy: 46-6795 *°  3D-template biopsy: 80°   TRUS biopsies?  Relative to pathology on radical prostatectomy specimens  "Adverse features are defined as tumor volume >0.5 cm’, positive mar-  gins, extraprostatic extension, and Gleason score >6  *Relative to pathology on 3D template biopsies  "Seventy-six percent sensitivity for unilateral cancer, based on ex vivo  simulation." PPV is a personal communication from Werahera based  on the data from his paper    when they analyzed a series of 393 perineal RP specimens  and observed that prostate cancers were unifocal in 23%,  unilateral in 23%, and organ-confined in 89%." Ohori et al  analyzed 1,000 RP specimens from early stage PCa patients  finding a similar frequency of unilateral lesions in 18%.”  The index lesion represented an average of 80% of the total  cancer volume. In those with extracapsular extension (ECE),  the largest focus of cancer was responsible in 90%. This  raises the question as to whether therapy should be extended  beyond the prostatic capsule to eradicate potentially extrapro-  static disease.   Rukstalis et al presented a retrospective analysis of 112  nonselected consecutive RP specimens.!! They observed that  21% of patients had unifocal prostate cancer, with a median  number of two foci for multifocal prostate cancers. They  hypothesized the effect of focal targeted therapy assuming  that the largest tumor would be the one targeted. By limiting  treatment to 3, 6, or 9 out of 12 prostate zones (thereby spar-  ing the contralateral neurovascular bundle), cancer control  could be accomplished with a 37, 34, and 21% risk of signifi-  cant (1.e., 20.5 mL) residual disease, respectively. Importantly,  they did not consider other parameters such as PSA, clinical  staging, and extent of biopsy to select their patients. Since  some cancers had a Gleason score of 8 or a PSA above 100,  the postulated efficacy of focal therapy might have been  increased if more stringent preoperative criteria had been  chosen. However, despite these limitations, this concept    serves as a basis for the clinical implementation of subtotal  glandular therapy.    Adverse Contralateral Pathological Features  in Low-Risk Patients with Unilateral  Disease at Biopsy    In a study from John Hopkins, Yoon et al reviewed the pros-  tatectomy specimens for which the preoperative biopsy pre-  dicted limited disease (Gleason score 6 or less, less than  three positive core, less than 50% of cancer in any core).'^  Sixty-five percent had cancers present on the contralateral  side with an average volume of 0.2 cm? per nodule. Thirteen  percent had a significant tumor (20.5 cm?) contralateral to  the index tumor, half of them located in the transition zone.  At RP, 20% of the patients had an adverse pathological fea-  ture on the contralateral side of the biopsy, described as  tumor volume >0.5 cm’, positive margins, extraprostatic  extension, or Gleason score >6. However, one limitation of  that study is that there was no detail about the number of  biopsy cores obtained preoperatively.    Determination of Unilateral Disease by Image-Guided  Biopsy of Early Stage PCa    Owing to the present inability to reliably image PCa, clini-  cians rely mainly on information obtained by extended pros-  tate biopsy. Iczkowski et al reviewed a series of 393 RPs and  compared the results to preoperative biopsies." Patients had  a mean of 11 core biopsies preoperatively. Unilateral pros-  tate cancer at biopsy and at RP were 62 and 23%, respec-  tively, for a correlation of 0.7. Unilateral prostate cancers at  prostatectomy were predicted preoperatively by unilaterality  and unifocality at biopsy with odd ratios of 2.6 and 4.3,  respectively. Unilaterality at biopsy could better predict uni-  laterality at prostatectomy when 9-core or more biopsies  were obtained. This is in agreement with the results of Mayes  et al who reported that 7396 of unilateral prostate cancers  after six core transrectal ultrasonography (TRUS) biopsies  were bilateral at prostatectomy, demonstrating the impor-  tance of adequate prostate sampling before treatment deci-  sion.'’ In another study, Bulbul et al showed that when  12-core biopsies showed unilateral PCa, pathology after RP  showed unilateral disease in 67% of cases.'*    Barzell et al used template-guided transperineal, 3D mapping  to identify clinically significant PCa prior to recommending    treatment.° These authors performed an average of 1.88 biop-  sies per cm? of prostate in patients who had unilateral PCa on  TRUS-guided biopsy. The average and median numbers of  cores obtained on initial biopsy were 11 and 12, respectively.  After template-guided transperineal biopsies, 46% redemon-  strated unilateral disease.^    Crawford et al simulated a template saturation biopsy (TSB)  protocol on 86 prostates with carcinoma after autopsy.” They  applied a protocol where biopsies were taken at each 5 or  10 mm. The 5 mm protocol was more precise that the 10 mm  protocol, but necessitated a mean of 54 biopsies per prostate.  Using the 5 mm protocol, they could detect unilateral can-  cers with a sensitivity of 7696. The positive predictive value  of TSB for unilateral prostate cancer was 8096 (Werahera,  personal communication). Moreover, the sensitivity of TSB  for clinically significant cancers was 9596 (defined as 20.5  cm, or Gleason >6) and Gleason patterns 4 or 5 were detected  in all ten tumors where they were present. These results sug-  gest that TSB might have a role in the evaluation of patients  before focal therapy of the prostate.   Taken together, these data show that before considering  focal ablation therapy:    1. At least 12 or more cores should be obtained at TRUS  biopsy and should include some additional biopsies in the  transition zone.   2. The positive predictive value of standard repeat TRUS  biopsy for unilateral disease may be, at the best, 46%.   3. Twenty percent of prostate cancers on TRUS have  adverse pathologic features on the contralateral side at  prostatectomy.   4. Better sampling using template-guided transperineal, 3D  pathologic mapping to identify clinically significant PCa  might be useful after initial biopsy to recommend treatment.    At this time, there is no imaging modality that can determine  the exact localization of small volume PCa.?' Some investi-  gators have conducted correlation studies between radio-  graphic images and whole-mount RP pathology slides.”  Villers et al evaluated suspicious areas within the prostate by  pelvic phased array dynamic contrast-enhanced magnetic  resonance imaging (MRI) for predicting the intraprostatic  location and volume of clinically localized PCa in 24    patients.” Sensitivity, specificity, and positive and negative  predictive values for small PCa lesions in the transition or  peripheral zones were 90, 88, 77, and 95%, respectively, for  foci greater than 0.5 cc. However, in another study by  Nakashima et al, endorectal MRI correlated with histological  examination for tumors only larger than 1.0 cm in diameter  in 95 patients.” The ability of endorectal MRI for detecting  tumors less than 1.0 cm regarding accuracy, sensitivity, and  positive predictive value were 24, 26, and 76%, respectively.    Prostate cancer is more vascularized than normal prostate tis-  sue.” This characteristic served as a basis to study contrast-  enhanced Doppler ultrasound (CEDUS) to detect prostate  cancer. Ultrasound contrast agents consist of small encapsu-  lated gas bubbles that are administered intravenously and  remain intravascular. These microbubbles are detected in the  bloodstream and increasethe sensitivity of color (CD) and  power Doppler (PD) imaging. The role of CEDUS has been  recently reviewed by Wink et al”. Using, CEDUS, Goossen  et al were able to lateralize the tumor in 78% of cases.*° A  large patient group was evaluated with CEDUS before RP  and 68-79% of all tumor foci larger than 5 mm were detected.  Unal et al showed that sensitivity and specificity of the  CEDUS were 87% (26/30) and 79% (23/29), respectively,  for the expert observer.” When combined with PSA, the sen-  sitivity was still 87% but the specificity increased to 100%.  Mitterberger et al showed that CEDUS-targeted biopsy  detected more cancers than random biopsies with a reduced  number of biopsy cores, and it detected cancers with higher  Gleason scores and more cancers than random biopsy.”  Therefore, CEDUS could be a useful tool to use in the con-  text of focal therapy to localize the tumor side, increase sen-  sitivity of TRUS biopsies, and image the tumor during  treatment.    As stated previously, focal therapy for prostate cancer  implies any treatment that can target a focus of cancer  within the prostate gland. Treatment may freeze (cryother-  apy), heat (thermoablation), or irradiate (radiosurgery) the  focus of cancer. Focal therapy for prostate cancer can be  divided into clinically tested and experimental technolo-  gies. The first category implies that the efficacy of the tech-  nology has been tested by posttherapy biopsies and evaluated  clinically for side effects on continence and erectile func-  tions. The experimental technologies are those for which    the physical principles have shown efficacy in ablating  tumors in patients, but for which follow-up with posttreat-  ment biopsies and assessment of side effects are missing.  Only cryotherapy falls in the first category of technologies  while experimental technologies include high intensity  focal ultrasound (HIFU), vascular targeted photodynamic  therapy (VTP), radiosurgery, focal brachytherapy, and  Interstitial Laser Thermoablation.    The main mechanism of cytotoxicity of cryotherapy is coag-  ulative necrosis. Cryotherapy induces cell injury by four  main mechanisms: osmotic shock, mechanical injury, cell  hypoxia, and induction of immune response. Molecular  mechanisms of action include protein denaturation, cell  membrane rupture, accumulation of a toxic concentration of  cellular elements, vascular thrombosis, and apoptosis,*°  which can be divided into direct and indirect mechanisms.  Direct mechanisms occur in successive steps that occur when  tissue is cooling or thawing.” First, when interstitial fluid  reach 0°C, crystallization begins and osmotic pressure in the  nonfrozen interstitial fluid increases. This causes a shift of  fluid from intracellular to extracellular compartments and  subsequently cell constituent changes. When temperature  reaches —15?C, all extracellular fluid 1s frozen, which leads  to mechanical shearing forces on the cellular membranes. At  these steps, many cells are threatened but most cell death  occurs when intracellular ice is formed. Intracellular crystal  formation is most likely to occur when rapid cooling tem-  perature is used since it does not allow water to exit cells  before freezing. A temperature of less than —40?C is required  for homogenous intracellular ice crystal formation.?' During  thawing, when tissue is around —20 to 25°C, a process called  recrystallization occurs, which further damages the cells by  creating large crystals. This process results from the fusion  of crystals during warming of ice. Other direct injuries to  cells are caused by the movement of hypotonic extracellular  fluid created by thawing that reenters the cells, causing cell  swelling, membrane disruption, and death.   Indirect injuries to tissue by cryotherapy mainly involve  vascular changes. Vascular changes are thought to be the  main mechanism of cell death in cryotherapy. It occurs  around —20°C and involves vasoconstriction, platelet occlu-  sion, and microthrombi formation, which lead to cellular  hypoxia and death. Technical aspects, such as the number of  freeze-thaw cycles, temperatures reached, velocity of freez-  ing and thawing, duration of freezing, and the presence of  heat sinks affect the cytoxicity of cryotherapy.    Cryosurgical ablation of prostatic tissue is performed using a  system of cryoprobes that are inserted into the prostate under  TRUS guidance. Measurements of the prostate, particularly  length, are taken to ensure that the entire length of the pros-  tate is treated. Wider prostates can be treated with the use of  additional probes. Longer prostates, at least until recently,  were treated by moving the probes apically after treating the  base and mid-gland. However, newer probes are able to pro-  duce longer zones of freezing that eliminate the need for a  “pull-back.”   Probes are placed into the prostate with or without the use  of a template grid. Position is checked in both the transverse  and longitudinal planes. The tips of the cryoprobes should  extend to the capsule at the base of the bladder. Temperature  probes are placed at the prostatic apex, external sphincter,  Denonvillier’s fascia, rectal wall, and adjacent to the neuro-  vascular bundles. A recent breakthrough in cryotherapy has  come with the development of third-generation cryotechnol-  ogy, such as the IceRod™ (Oncura, Amersham) 17-gauge  cryoneedle with an advanced heat exchanger and the  Multitemp™ 1601 temperature monitoring system (TMS,  InvivoSense, Trondheim, Norway). It facilitates a potentially  more safe and targeted treatment technique.’ Probes can be  selected based on the size of the iceball desired, and the tem-  perature probes have an ability to give multiple temperature  readings at various positions along their length.   Once an adequate number of probes have been placed, the  bladder and urethra are inspected by performing a flexible    cystoscopy to ensure no probes traverse them, which is a  function of the width of the iceball that is produced by the  probes being used. A urethral warming catheter is placed,  and the freezing cycle is started. Progression of the iceball is  monitored visually by TRUS and by the temperature read-  ings. Frozen tissue does not transmit US, so it appears entirely  anechoic. For this reason, freezing is initiated anteriorly.  Starting posteriorly would prevent visual monitoring of ante-  rior ice formation. Once —40°C is reached in the desired tis-  sue and it is entirely encompassed by ice for a brief period,  thawing is initiated. A second freezing cycle is performed  once the tissue has thawed. It is important to make sure that  the ice extends slightly beyond the tissue being ablated, as  the lethal zone lies just inside the edge of the iceball. Great  care is also taken to not freeze the wall of the rectum or exter-  nal sphincter. Visualizing the progression of the ice and  watching the temperatures make avoiding any injury to these  structures straightforward.    Table 13.3 summarizes the first pilot clinical trials of focal  hemiablation for unilateral lesions and targeted cryoablation  of a presumed unifocal lesion. Lambert et al reported data on  patients treated with hemiablation." The authors defined  their biochemical failure as a PSA nadir greater than 50% of  the pretreatment PSA level. Of the 25 patients, 21    84 <50% nadir, 12% 71%  nadir +2 8%untreated lobe,  4% treated lobe  93 ASTRO?! 4% untreated lobe 88.9% total,  48.1% fully  recovered;  40.8% medically  assisted  95 ASTRO 0 (in 1 case caner 8096  was found on  MRIS in  untreated lobe)  80.5 ASTRO 23%! 710.6%    Bx biopsy; DDFS biochemical disease-free survival; PSA prostate specific survival; MRIS MRI spectroscopy    *SeedNet, Galil Medical, Plymouth, PA  ’Results from a two center trial  *Cryocare Endocare, Irvine, CA    "Twenty-three percent for the whole series of 60 patients but only 35 patients were biopsied. Forty percent (14/35) of those biopsied had positive    (84%) demonstrated PSA failure-free survival over a median  follow-up of 28 months. Repeat prostate biopsy revealed PCa  in the contralateral lobe in 896 of patients and in the treated  lobe in 4% (2 and 1 patients, respectively). Seventeen (71%)  of 24 patients who were potent preoperatively remained so  postoperatively. All patients preserved complete urinary  continence.   Bahn et al reported the results of 31 patients from two insti-  tutions with clinically organ-confined, unilateral PCa con-  firmed by targeted and systematic biopsy using color Doppler  TRUS-guidance.? Tumor control data at a mean follow-up of  70 months were excellent. Using the ASTRO definition of  PSA recurrence (three consecutive rises in PSA), they reported  biochemical disease-free survival (DDFS) in 92.896 of patients  with a 9696 negative-biopsy rate. The one patient with a posi-  tive biopsy in the apex of the contralateral untreated lobe was  disease-free after retreatment with full-gland cryotherapy.  The total potency-preservation rate was 88.9%. There were  no cases of incontinence or other complications.    Onik recently published an updated series of 21 patients  treated with targeted focal cryoablation of a unifocal tumor.  Preoperatively, all patients had two series of prostate biop-  sies using color Doppler TRUS examination to identify and  target any suspicious areas of abnormally increased flow or  altered echogenicity All patients were potent preopera-  tively. Five patients had intermediate risk and five had high  risk based on D'Amico criteria. At an average follow-up of  50 months, biochemical disease-free survival was obtained  in 9596 of patients by ASTRO definition. Nineteen patients  had a prostate biopsy after 1 year, and no cancer was found  in the treated or contralateral side. Potency was maintained  in 8096 with no complications reported. This series suggests  the effectiveness of focal therapy when patients are accu-  rately staged preoperatively using repeating TRUS biopsies  and color doppler ultrasound.    Ultrasound is a high-frequency vibration produced by a trans-  ducer at a range higher than the ear can detect.*° If the fre-  quency of ultrasound is increased and focused on a precise  point, it can lead to tissue destruction. HIFU destroys tissue  by two mechanisms that lead to coagulation necrosis: thermal  injury and cavitation. Thermal injuries occurs after the tissue  absorbs the ultrasounds and converts it to heat. Temperature    in the tissue on which HIFU is targeted can reach up to 100°C  in a few seconds. The energy generated during HIFU therapy  results in destruction of lipid-based membranes and protein  degradation, which constitutes the main disruptive action on  the tumor. The cavitation mechanism involves the formation  of microbubbles in the targeted tissue. Collapse of these bub-  bles further destroys the tissue. This latter effect, which could  be considered undesirable depending on whether one wants  to achieve collateral damage to surrounding structures, may  need to be minimized depending on the clinical situation.    Two types of devices are currently on the market: Ablatherm  (EDAP TMS S.A., Vaulx-en- Velin, France) and the Sonablate  (Focus Surgery, Inc, Indianapolis, IN). The Ablatherm device  uses two different therapeutic (3 MHz) and imaging (7.5  MHZ) transducers, while the Sonablate uses a single trans-  ducer (4 MHz) for both imaging and treatment.” Treatment  is performed under gray-scale ultrasonography under a rectal  cooling device, which prevents thermal rectal injuries.    Given its ability to focally direct energy, HIFU can be poten-  tially applied as focal therapy. Muto et al recently published  a series of 29 patients with prostate cancer treated by focal  HIFU using the Sonoblate 500 device." Patient selection  was based on TRUS biopsy showing unilateral disease.  Posttreatment biopsies were positive in 23.596 (4/17) of  patients in 1 year. Urethral stricture was reported in one case,  and no change on IPSS was observed after therapy. No data  were reported relative to erectile function. Further studies  with better-defined preoperative criteria must be done to  ascertain the efficacy of HIFU as a focal therapy.    VTP is based on the activation of a photosensitive drug that  is toxic to cells when excited at a specific wavelength.??  Neither light nor the photosensitive drug are toxic alone but,  when combined, produce oxygen metabolites that cause  apoptosis by targeting the mitochondria, lysosomes, and cell  membranes. Vascular damage and immunologic stimulation  are also secondary mechanisms.    V'TP may be suitable for minimally invasive outpatient pro-  cedure with reproducible cancer control and minimal side  effects.” This novel therapy uses a new generation of an  intravenously administered bacteriochlorophyl-derived photo  sensitizer Tookad (WSTO09) that absorbs light in the visible-  near-infra-red (VIS-NIR) wavelength with maximum light  energy absorption at 763 nm.   A phase I/II non-randomized study at University College  Hospital of London is enrolling men with previously  untreated PCa in a focal therapy clinical trial. To date, a total  of 27 men have been treated, 14 with a two-fiber VTP and 13  with a multifiber VTP. The interim results from this trial  demonstrate a dose response that appears to correspond to an  increase in the volume of hypoperfusion observed on post-  treatment MRI with increasing total light energy delivered to  the prostate.” Further development of this type of therapy  also includes a search for other photosensitizing agents.    Traditionally, radiotherapy has been administrated as a  whole gland therapy, and it is associated with side effects on  surrounding organs. Its biology is well known and beyond  the scope of this chapter. Development of new techniques  such as conformal- and intensity modulated-radiotherapy  allows radio-oncologists to target specific regions in the  prostate. These techniques decrease irradiation of surround-  ing organs. Furthermore, development of real-time localiza-  tion of the prostate during therapy has allowed better  accuracy in prostate irradiation. The advances in conformal  radiotherapy and imaging have led to the development of  focal radiosurgery.    Radiosurgery is the application of high dose of radiation  therapy directly to a tumor under precise imaging.“ It has  been studied mainly in the treatment of lung and brain tumors  with successes over 8046 for lung cancer. A study has recently  started for localized prostate cancer using the Cyberknife  (Accuray, Inc. Sunyvale, CA). The Cyberknife technology  uses a robotic arm that is automatically repositioned to track  the targeted tissue with a high level of accuracy. This tech-  nology could potentially be used to treat focal lesions."    Brachytherapy has been used as a whole gland therapy for  more than 15 years. It is recognized as an effective therapy    for low to low-intermediate risk prostate cancer. With accu-  rate localization of a focal lesion, radioactive seeds could be  placed in and around the area of interest. A pilot study has  been performed by D' Amico et al on nine patients with local-  ized prostate cancer. No data have yet been reported regard-  ing the oncological outcomes of this treatment.“    Interstitial laser thermotherapy use photothermal energy cre-  ated by one or two sources placed in the vicinity of the tumor.  This causes coagulation of the tissue in an ellipsoid form of  1.5 cm in length and 1cm in diameter.? This procedure takes  20—30 min and heats the tissue to 90°C.    A pilot study by Trachenberg has been done in five patients  using focal interstitial laser thermotherapy. Follow-up biopsy  was done at 6 months in two patients, and it showed absence  of residual tumor in the treated area. However, one tumor  was found on the contralateral side in one patient. After lap-  aroscopic prostatectomy in this patient, no residual tumor  was found in the treated region, demonstrating efficacy of  the technique to eradicate tumor.”    There is no established manner to follow a patient after focal  therapy. Biopsy is probably the most accurate method to  evaluate the efficacy of focal therapy in eliminating the can-  cer in the treated zone. Some studies have used systematized  posttreatment biopsies to determine the success of therapy."  A problem with follow-up biopsy is the possible detection of  nonsignificant cancers on the contralateral side, which might  create anxiety for the patient. After such a diagnosis, should  patients be placed on active surveillance? Should patients  receive whole gland treatment? Obviously, there is no answer  to this question, but when considering focal therapy we  believe that this possibility should be discussed before inter-  vention. On the basis of data from Yoon et al, the patient can  be counseled that the risk of significant contralateral prostate  cancer is about 20%.'° The accuracy of the preoperative eval-  uation is important to decrease the chance of postoperative  detection of contralateral lesions.   Some urologists have used PSA and the ASTRO criteria  to evaluate recurrence." ^^^? Lambert also used a nadir of less    than 50% as a criterion of failure.” Others have used MRI to  follow their patients and evaluate treatment efficacy." The  significance of these techniques regarding oncologic success  is unknown.    Oncological outcomes with RP and radiotherapy for low-  risk prostate cancer are excellent, but these oncologic out-  comes might be due in part to the prolonged natural history  of screening-detected prostate cancer." Since currently the  main indication for focal therapy is in localized low-risk  prostate cancer, quality of life outcomes after RP, radiother-  apy, and brachytherapy are very important aspects to be con-  sidered. For a focal therapy to be justified, it would have to  demonstrate at least equivalent quality of life outcomes when  compared with standard therapies, without compromising  oncologic outcomes. Erectile dysfunction in previously  potent men has been estimated to be around 36-83% after  brachytherapy,“ 39-53% after external beam radiother-  apy,"^* and approximately 35% after bilateral nerve-sparing  RP.?* Incontinence after RP is approximately 5% at 1 year.”  While 3796 of patients have voiding symptoms during the  first 60 days after brachytherapy, persistent urinary symptoms  occur in 1-5% of patients.^' Moderate to severe urinary symp-  toms are observed in 3—23% of patients after radiotherapy.  Rectal complications are rare after RP but occur in 3-32% of  patients after external radiotherapy. Rectal bleeding occurs  in 1—4% after brachytherapy.“ The term “trifecta” has been  proposed as the perfect combination of three main outcomes:  absence of PSA-recurrence, preservation of erectile function,  and continence.” The “trifecta” is obtained in 62% of patients  after RP. Before widespread adoption, focal therapy in pros-  tate cancer should demonstrate the same or better “trifecta”  rates than classic therapy for prostate cancer.    Focal ablation of the prostate is a new minimally invasive  approach that is still experimental. Our conclusions based on  the available published data are:    1. Low-risk patients should be those to whom this therapy  should be offered.   2. Since success of this approach is based on adequate pre-  operative staging, diagnosis of unilateral prostate cancer  should be based on 12-core biopsies with additional 6-12  core biopsies on the negative side. Since repeat negative  biopsy does not guarantee absence of cancer on the    contralateral side on follow-up biopsy, patients should be  informed of the possibility of subsequent active surveil-  lance or whole-gland treatment. The role of 3D-template  saturation biopsies may significantly improve staging of  patients prior to therapy.   3. Short-term outcomes should be assessed by posttreatment  biopsy since the significance of outcomes based on PSA-  values (Nadir, ASTRO criteria) or imaging are unknown.    included in studies since preservation of these functions is  the main goal of focal ablation of the prostate.    1. Bill-Axelson A, Holmberg L, Filen F, et al Radical prostatectomy  versus watchful waiting in localized prostate cancer: the Scandinavian  prostate cancer group-4 randomized trial. J Natl Cancer Inst.  2008; 100(16):1144—-1154   2. Johansson JE, Andren O, Andersson SO, et al Natural history of  early, localized prostate cancer. JAMA. 2004;291(22):2713-2719   3. Albertsen PC, Hanley JA, Penson DF, Barrows G, Fine J. 13-year  outcomes following treatment for clinically localized prostate can-  cer in a population based cohort. J Urol. 2007;177(3):932-936   4. 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Front Radiat Ther Oncol. 2007:40:395—406  D'Amico AV, Cormack R, Tempany CM, et al Real-time magnetic  resonance image-guided interstitial brachytherapy in the treatment  of select patients with clinically localized prostate cancer. /nf  J Radiat Oncol Biol Phys. 1998;42(3):507-515   Trachtenberg J HM, Weersink R, et al Image guided laser thermo-  therapy for focal ablation of prostate cancer. In: Abstracts of the  Eighth Annual Meeting of the Society of Urologic Oncology; 29  November-1 December 2007; Bethesda, Maryland: USA Urology  Oncology: Extraordinary Opportunities for Discovery; 2007:96—97  D'Amico AV, Moul J, Carroll PR, Sun L, Lubeck D, Chen MH.  Cancer-specific mortality after surgery or radiation for patients with  clinically localized prostate cancer managed during the prostate-  specific antigen era. J Clin Oncol. 2003;21(11):2163—2172  Cesaretti JA, Kao J, Stone NN, Stock RG. Effect of low dose-rate  prostate brachytherapy on the sexual health of men with optimal  sexual function before treatment: analysis at > or = 7 years of  follow-up. BJU Int. 2007;100(2):362—367   Merrick GS, Butler WM, Wallner KE, et al Erectile function after  prostate brachytherapy. Int J Radiat Oncol Biol Phys. 2005;62(2):  437—447   Zelefsky MJ, Wallner KE, Ling CC, et al Comparison of the 5-year  outcome and morbidity of three-dimensional conformal radiother-  apy versus transperineal permanent iodine-125 implantation for  early-stage prostatic cancer. J Clin Oncol. 1999:17(2):517—522  Mantz CA, Nautiyal J, Awan A, et al Potency preservation follow-  ing conformal radiotherapy for localized prostate cancer: impact of  neoadjuvant androgen blockade, treatment technique, and patient-  related factors. Cancer J Sci Am. 1999;5(4):230-236   Eastham JA, Scardino PT, Kattan MW. Predicting an optimal out-  come after radical prostatectomy: the trifecta nomogram. J Urol.  2008; 179(6):2207—2210; discussion 2210-2211   Carini M, Masieri L, Minervini A, Lapini A, Serni S. Oncological  and functional results of antegrade radical retropubic prostatectomy  for the treatment of clinically localised prostate cancer. Eur Urol.  2008;53(3):554—561   Gelblum DY, Potters L, Ashley R, Waldbaum R, Wang XH,  Leibel S. Urinary morbidity following ultrasound-guided trans-  perineal prostate seed implantation. /nt J Radiat Oncol Biol Phys.  1999:45(1): 59-67    Increasing use of sonography, computed tomography (CT),  and magnetic resonance imaging (MRI) has led to a rapid  rise in the discovery of small renal tumors and an increase in  the detection of renal cell cancer (RCC). Although these inci-  dentally discovered masses tend to be smaller and of lower  grade than symptomatic lesions,'? the majority (65-80%) of  these tumors are renal cell carcinomas (RCC) when patho-  logically analyzed.? In addition, nearly 60% of these lesions  will exhibit growth during active surveillance (mean 0.26  cm/year), such that given a long life expectancy, lesions in  younger patients may grow sufficiently to become symptom-  atic or to metastasize."   Radical nephrectomy has traditionally been considered  the “gold standard" for the treatment of renal masses.  Nephron-sparing surgery, such as partial nephrectomy, was  developed to preserve renal function in patients with bilateral  renal masses, hereditary cancer syndromes, or renal insuffi-  ciency. With intermediate term and long-term cancer control  rates similar to radical nephrectomy,^^ indications for partial  nephrectomy have expanded to patients without imperative  indications, and successful surgery is now only limited by  technical factors such as proximity to the renal hilum or col-  lecting system."*   Morbidity and prolonged convalescence of open surgery  led to the development of laparoscopic partial nephrectomy.  Though laparoscopic partial nephrectomy improves postoper-  ative pain and is a viable option in some patients with small  renal masses, the surgery is technically demanding and associ-  ated with complication rates similar to open partial nephrec-  tomy.?'? Owing to these limitations and the increased detection  of tumors in younger patients, there has been a recent push  toward the development of minimally invasive therapies for  renal tumors, including tissue ablative techniques.   In situ ablation methods such as radiofrequency ablation  (RFA) and cryotherapy offer potential benefits when com-  pared with the extirpative approach, including a decreased  complication rate, shorter convalescence, absence of an isch-  emic period, and the possibility of using intravenous sedation  over general anesthesia.*'! All of these potential benefits are    clearly desirable in the increasingly older, sicker patients who  represent an increasing proportion of patients with incidental  renal masses. While these potential benefits make renal  tumor ablation attractive for both patient and surgeon, suc-  cessful cancer control and long-term outcomes of the therapy  are required prior to broad adoption of these technologies.   In this chapter, we review the current status of RFA for  treatment of the small renal mass including the mechanism  of tissue destruction, technical considerations, anatomic con-  siderations, surgical technique, postoperative follow-up,  cancer control outcomes, and complications. Other ablative  techniques are covered comprehensively by other authors  within this text.    RFA uses monopolar alternating electric current that is deliv-  ered directly into the target tissue at a frequency of 450-1,200  kHz. This high-frequency current leads to vibration of ions  within tissue as the current alternates polarity, resulting in  molecular friction and heat production. Increasing tempera-  ture within the target tissue leads to cellular protein denatur-  ation and cell membrane disintegration. Heat, therefore, is  not directly supplied by the probe itself, but rather by the  agitation of ions within the tissue." As RFA is a temperature-  based technology, heat distribution in the tissue surrounding  the probe is affected by tissue impedance, native tissue tem-  perature, thermal conductivity, and heat loss through blood  circulation, with the temperature decreasing as the distance  increases from the probe (temperature l/radius).'^*   The ability of RFA to ablate the target tissue relies on the  power delivered to the probe as well as the maximum tem-  perature obtained and the duration of the ablation. In in vitro  studies using human prostate tissue, Bhowmick et al achieved  irreversible cell injury when benign and malignant cell lines  were heated to 45?C for 60 min, 55?C for 5 min, and 70?C  for 1 min.'*'° Histological analysis in these studies dem-  onstrated coagulative necrosis, characterized by membrane  disruption, protein denaturation, and vascular thrombosis."    Subsequent work in both human and animal models demon-  strated that treated tissue is initially characterized by a well-  circumscribed necrotic area with extensive cellular edema  and localized tissue inflammation. After 3—7 days, the tissue  begins to demonstrate the effects of coagulative necrosis  with extensive nuclear degeneration and chronic inflamma-  tion. By day 30, there is a total loss of the cytoplasmic bor-  ders with no remaining normal renal architecture, and by day  90 there is a near total resorption of the necrotic focus with  ultimate autoamputation.'*'? Repeating these studies in renal  cancer cell lines in the mouse model confirmed the effective-  ness of ablation in both benign and malignant tissues.”°    RFA can be performed with either a temperature-based or  impedance-based system. Temperature-based systems work  by measuring tissue temperatures at the tip of the electrode  and are based on achieving a specific temperature for a given  period of time. Though these systems accurately measure the  temperature of the tissue at the electrode tip, they do not  measure the temperature of the surrounding parenchyma.  Alternatively, impedance-based systems measure the tissue  impedance (resistance to alternating current) at the electrode  tip and are based on achieving a predetermined impedance  level that indicates complete tissue ablation. While these sys-  tems are able to measure the actual tissue desiccation at the  electrode tip, they have been associated with incomplete  ablation in animal models.”!   Another major classification in RFA technology is the dif-  ferentiation between dry and wet RFA. As tissue desiccation  increases in the target lesion, the charring effect on tissue  leads to increased impedance and resistance to the alternat-  ing current of the electrode, limiting the size of the ablation  zone. Wet RFA probes deliver a constant saline infusion to  mitigate the charring effect and premature rise in impedance.  Although lesions tend to be larger using the wet electrode,  there is less control of the exact size of ablation, which may  lead to overtreatment of the target zone and disruption of  adjacent normal parenchyma.”   There are several products currently approved for perform-  ing RFA.? Two of the RFA systems use Christmas tree or  umbrella-shaped multitine electrodes. The RITA device  (Aniodynamics, Queensbury, NY) uses thermistors embedded  in five of the nine electrodes to modulate energy based on the  temperature of each electrode as well as the average tempera-  ture of the electrodes in aggregate. The LeVeen system  (Boston Scientific, Natick, MA) is an umbrella-shaped device  that is based on tissue impedance rather than temperature. The  Valleylab system (Mansfield, MA) uses an impedance-based  system composed of a single 17-gauge (“cool tip") electrode    that is cooled internally with chilled saline to prevent charring  of tissue adjacent to the probe. Although randomized human  trials of various systems do not exist, a direct comparison of  these systems in the porcine liver demonstrated larger zones  of ablation with the wet-RFA and “cool tip" systems, more  spherical ablation volumes with the 12-tinned electrodes,  and better reproducibility with the 9-tine electrodes.”    High blood flow volumes in the region of tissue ablation act  as a "heat sink" for radiofrequency energy, such that target  temperatures may not be obtained on a consistent basis when  lesions are close to large vessels. This is a particularly rele-  vant factor in renal malignancy as the kidney receives 2096  of cardiac output and RCC is notoriously vascular. On the  basis of this phenomenon, tumors that are closer to the renal  hilum and segmental renal arteries can be difficult to treat as  target temperatures may not be reached owing to countercur-  rent heat exchange. Temporary clamping of the renal hilum  during RFA increases the size of the initial treatment lesion  and shortens the time to reach the target temperature.”  However, over time the size of the lesions appear to equili-  brate, such that after 4 weeks there is no difference in the size  of the treated area in patients who undergo clamping vs.  those who do not. As such, hilar clamping is not currently  recommended owing to the risk of arterial thrombosis and  ischemia-reperfusion injury to normal parenchyma.   To prevent complications of hilar clamping, some authors  have advocated selective arterial embolization when per-  forming RFA. Hall et al reported an innovative combination  of embolization with polyvinyl alcohol and percutaneous  RFA in a 67-year-old patient with a 2.5 x 3.0 cm tumor in a  solitary kidney.” A CT scan performed at 8 weeks post abla-  tion showed a complete lack of contrast enhancement in the  treated area. At 3 months post ablation, a biopsy revealed  fibrous tissue and necrotic cellular debris with no evidence  of malignancy. We have successfully employed this same  technique in a few central or large (24 cm) tumors to reduce  the circulatory heat sink.   Tumor location is the most important determinant for the  choice of surgical approach. Injury to adjacent organs,  including bowel, liver, spleen, and the renal collecting sys-  tem, from high frequency energy, may lead to significant  morbidity. To avoid these injuries, anterior tumors within 1  cm of colon or small bowel and those in close proximity to  the liver, spleen, ureter, or renal pelvis should be managed  with a laparoscopic approach (lap-RFA). Posterior or  laterally-based tumors that are far removed from adjacent  structures may be ablated percutaneously (perc RFA) under  CT or MR guidance.”    Prospective clinical trials validating exact clinical indica-  tions for RFA of renal masses are lacking in the literature.  Early studies of RFA included mostly patients who were  determined to be poor surgical candidates owing to signifi-  cant co-morbidities, had multiple bilateral tumors, or those  with compromised renal function. As experience with RFA  has increased and results have continued to appear promis-  ing, more treatments are being carried out on healthier  patients with solitary small renal masses.   At our institution, candidates for RFA include patients  with small solid renal masses («4 cm) with contrast enhance-  ment (210-12 Houndsfield Units) on CT or MRI. In addi-  tion, tumors must be located 20.5 cm from the ureteropelvic  junction or renal pelvis and >1 cm from segmental renal ves-  sels. RFA is offered as an alternative to open partial nephre-  ctomy, laparoscopic partial nephrectomy, or laparoscopic  radical nephrectomy in these patients.   Patients participate in a thorough discussion of the risks,  benefits, and alternatives to RFA before consenting to this  procedure. Specifically, patients are informed that while can-  cer control data are extremely encouraging for renal RFA,  long-term follow-up to 5 years and beyond is just now  becoming available.” Patients are also counseled about the  risks of various complications and the expected convales-  cence period after ablation vs. laparoscopic or open partial  nephrectomy.” Patients must agree to a strict protocol of  radiographic follow-up, and understand that recurrence may  require repeat RFA or even radical nephrectomy.    After induction of anesthesia, the patient is positioned on the  CT table to perform the ablative procedure. Though most  patients will be placed in the prone position for treatment of  posteriorly located tumors, some patients may require vari-  able positioning to best expose their tumor for placement of  the percutaneous probe. For instance, a patient who has dif-  ficult access to the tumor due to the spleen lying within close  proximity may be placed in the right lateral decubitus posi-  tion over a small kidney cushion to role the spleen anteriorly  and allow for direct percutaneous access. Once the position-  ing is felt to be appropriate, an initial CT scan is performed  to observe whether there is a clear path to the kidney. If posi-  tioning appears appropriate and the patient's creatinine clear-  ance permits, intravenous contrast is administered and the  scan is repeated to further delineate the lesion.   Once the lesion location and a clear access path have been  confirmed, a 20-Guage Chiba needle is directed such that the  tip of the needle is located adjacent to the rim of the central    portion of the tumor. Placement of this "finder needle" is  important as it less traumatic than the ablative probe and lim-  its bleeding as well as the risk of damage to the surrounding  structures such as the bowel or pleura. The CT scan is  repeated at that time and if positioning is correct, the ablative  probe is advanced to the rim of the tumor and the tines are  deployed to create an ablation zone approximately 5-10 mm  beyond the tumor margin. After the tines have been deployed,  an 18-Guage true-cut biopsy needle is used to obtain 2-3  biopsy specimens. Biopsy should not be performed prior to  probe placement, as bleeding from the tumor may obscure  the radiographic appearance of the mass.   After CT scan confirms appropriate deployment of the  tines, ablation is carried out using temperature-based RFA  with the RITA Medical Systems model 1500 RF generator  coupled to a 14-Gauge Starburst XL probe. The generator  modulates power up to 150 W, to achieve an average tempera-  ture of 105?C, as measured by five of the nine tines in the  Starburst XL probe. Once the target temperature is reached,  tumors requiring tine deployment less than 2 cm are ablated  for 5 min, tine deployment between 2 and 3 cm ablated for 7  min, and tine deployment over 3 cm for 8 min. A 30 s cool-  down period is followed by a second ablation cycle of identi-  cal duration. If the was not adequately covered by the tines  during the first ablative procedure, the probe can be reposi-  tioned and the ablation repeated until the tumor has been ade-  quately treated. To prevent bleeding of the electrode site and  minimize the risk of tract seeding, the tract is ablated by with-  drawing the tines into the probe and then gradually removing  the probe from the renal fossa, keeping probe temperature  above 70°C. Once the probe has been removed, a contrast CT  scan can be performed to confirm complete tumor ablation.    General contraindications to laparoscopic surgery apply to  laparoscopic RFA, including multiple intra-abdominal adhe-  sions, history of peritonitis, bowel distention, and severe  chronic obstructive pulmonary disease (COPD). As previ-  ously mentioned, laparoscopy should be considered the pri-  mary approach for all patients with anterior lesions and for  those with lesions located within close proximity to other  intra-abdominal organs. After induction of general anesthe-  sia, the patient is positioned in the modified flank position at  30—45? and strapped to the table using 2-in. cloth tape. Three  trocars are placed with a 12-mm trocar in the umbilicus, a  5-mm trocar one-third of the way down between the xyphoid  and umbilicus, and a 12-mm trocar in the mid-clavicular line  2—4 cm below the umbilicus.   After reflecting the bowel and exposing Gerota's fascia,  the perinephric fat is dissected away from the kidney to    fully expose the lesion. A laparoscopic ultrasound probe is  brought through the inferior laparoscopic port to confirm  the lesion characteristics including the size and depth of  penetration. Once the lesion has been exposed, the RFA  probe is introduced through a separate stab incision along a  perpendicular orientation to the tumor surface. The elec-  trode is brought to the surface of the lesion and the tines are  deployed to the base of the tumor using ultrasound guid-  ance. Tines are positioned to create a zone of ablation 0.5-1  cm beyond the tumor margin and tine deployment is recon-  firmed with ultrasound prior to beginning the ablation in  an identical manner to that used with the percutaneous  approach.   There are two key differences to account for while per-  forming laparoscopic ablation when compared with the per-  cutaneous route. First, whereas biopsy during percutaneous  RFA can only be performed with needle core biopsies, lap-  aroscopic RFA allows for large tumor biopsies using a 5-mm  toothed biopsy forceps. To decrease bleeding from the rela-  tively large biopsy site, we routinely perform biopsy after  the ablation is complete, in contrast to percutaneous RFA  where biopsies are performed before the ablation procedure.  We have previously shown that postablation biopsies are  fully interpretable by pathologists and equivalent to pretreat-  ment biopsy specimens.??   The second major difference between laparoscopic and  percutaneous ablation is that real-time monitoring of the  ablation during laparoscopic ablation is not possible with  the use of ultrasound owing to radiofrequency interference  and formation of microbubbles at the periphery of the lesion  that limit ultrasound visualization. However, because the  temperatures at the margin of ablation are constantly moni-  tored by the Starburst probe, tissue ablation is predictable  and real-time monitoring is unnecessary. To date, there have  been no studies indicating that real-time monitoring of the  lesion increases cancer-free survival in RFA. In fact, there  are some indications that patients undergoing laparoscopic  RFA, where real-time monitoring is not possible, have bet-  ter ablation success than those undergoing percutaneous  procedures.”    Owing to the fact that RFA is still a relatively new technol-  ogy, close follow-up of patient outcomes is required. At our  institution, each patient undergoes biannual physical exami-  nation, chest radiography, liver function tests, alkaline phos-  phatase measurement, and contrast-enhanced CT at 6 weeks,  6 months, and annually thereafter. A radiologist and urolo-  gist review all CT or MRI images to evaluate for any remain-  ing tumor or recurrence of the lesion (Fig. 14.1). With further    experience at our institution and internationally, the follow-  up imaging protocols continue to be refined.   RFA leads to desiccation of tissue, localized inflamma-  tion, coagulative necrosis, and eventual replacement of the  lesion with fibrosis. Immediate imaging following RFA dem-  onstrates circumferential high attenuation corresponding to  the hyperemic inflammatory response demonstrated in sur-  rounding normal parenchyma on histological examination. It  is important to recognize this as a normal postRFA response,  as areas of hyperemia may be mistaken for persistent con-  trast enhancement of viable tumor.” The true extent of  ablation is not fully realized until 7 days after the procedure,  corresponding to the histological completion of coagulative  necrosis. As such, initial postoperative imaging should be  completed at 6 weeks, at which time the zone of treatment  can be adequately assessed.   Incomplete ablation is defined as any enhancement within  the tumor ablation zone on CT or MR seen at the initial  6 week study. As RFA is delivered in a spherical distribution,  any untreated tissue is typically found at the periphery of  the lesion in a crescent-shaped distribution (Fig. 14.2).  Recurrence is defined as any enhancement within the tumor  ablation zone after an initially normal 6-week CT or MRI.  Unlike incomplete ablation, recurrence may be seen any-  where in the ablation zone. Over time, tumors will involute  to a degree and may significantly decrease in volume.”  However, as previously described, shrinkage of the ablated  lesion, in contrast to cryotherapy, is not a requirement for  ablation success, as long as growth and contrast enhance-  ment are absent.”   Some investigators have questioned the validity of a  radiographic definition of ablative success.’ The majority  of these investigators, however, utilize traditional hematox-  ylin and eosin (H & E) staining in evaluating posttreatment  biopsies, which is inadequate for assessing cell viability  since cellular architecture is preserved after RFA and there-  fore not indicative of viability.” Problems with H & E  staining as a measurement of tissue viability are overcome  by utilizing nicotinamide adenine dinucleotide (NADH)  diaphorase staining, which indicates viability by the reduc-  tion of tetrazolium salts to a water-based blue dye called  formazan.“ Though the majority of studies using NADH  diaphorase staining have identified only nonviable cells  within biopsies of RF-treated lesions, some studies have  revealed persistent positive staining of tumor cells immedi-  ately after tissue ablation, raising the concern of viable cells  within the ablation zone. To clarify the extent of tissue via-  bility in RF-treated lesions, Anderson et al performed  NADH diaphorase staining on RFA ablated renal tissue in  the porcine model." Overall, 14% biopsies showed viable  tissue when analyzed less than 150 min after ablation, while  no lesion showed persistent NADH diaphorase activity 3 h  after ablation. Therefore, it is essential to take timing into    Fig. 14.1 (a) Pretreatment contrast enhanced CT scan demonstrates a  2.7 cm enhancing renal mass in the mid pole of the left kidney. (b)  Intraprocedural CT scan with patient placed in the prone position. The  multitined RITA electrode is deployed to achieve an ablation zone    account when evaluating for persistent cellular viability  following RFA and any study evaluating persistence of via-  bility immediately after ablation should be read with close  scrutiny.   Owing to the fact that routine postoperative biopsies are  often difficult to obtain in patients who have clear evidence  of response based on imaging, and the fact that comprehen-  sive studies assessing tissue viability and persistence of  malignancy have confirmed complete cell death, we do not  currently recommend postoperative biopsy to patients with  normal imaging.    0.5-1 cm beyond the margin of the tumor. (c) Postoperative contrast CT  scan demonstrating the ablated renal mass with absence of contrast  enhancement    A recent meta-analysis of RFA found an overall major com-  plication rate of 3.1% for percutaneous procedures and 7.4%  for laparoscopic procedures.*! Major complications in lap-  aroscopic cases included significant blood loss in 3%, con-  version to open surgery in 2%, and one case each of liver  laceration, congestive heart failure, hemorrhage leading to  nephrectomy, pulmonary embolism, myocardial infarction,  pancreatic injury, ureteropelvic junction obstruction, and  urine leak. Minor complications occurred in approximately    Fig. 14.2 Six week posttreatment contrast CT (prone) showing resid-  ual crescent-shaped peripheral enhancement of posterior mid pole renal  tumor consistent with incomplete ablation. This patient underwent a  successful repeat RFA with complete ablation of remaining tumor    10% of cases, with perirenal hematoma, transient hematuria,  increased serum creatinine, and probe site pain or parasthe-  sias being the most common. As with all invasive procedures,  the complication rate has diminished with more RFA experi-  ence, owing to an appreciation of the potential pitfalls.    Though short-term studies have been overwhelmingly posi-  tive in favor of RFA, the true utility must be measured with  long-term follow-up studies. The initial human studies dem-  onstrated the safety and feasibility of RFA by performing the  procedure in patients immediately prior to performing radical  or partial nephrectomy."^^* In 1999, McGovern et al reported    Table 14.1 Reported results for radiofrequency ablation of renal tumors with at least 36 months of follow-up  Mean tumor    the first use of RFA with the intent to treat renal carcinoma"!  in an elderly individual who refused surgery for a 3.5 cm  enhancing renal mass. Contrast enhanced CT scan performed  2 h following the ablation showed a nonenhancing region at  the site of the previous tumor, which was confirmed by 1 and  3 month follow-up CTs. These authors later reported their  experience treating nine tumors in 8 patients (including the  initial patient above) with tumor sizes ranging from 1.2 to 5  cm.” Two of the larger tumors (4.4 and 5.0 cm) demonstrated  persistent enhancement and were treated with additional RFA.  With a mean follow-up of 10.3 months (range 3-21) no patient  demonstrated recurrence of metastatic renal cell carcinoma.   Since the initial results with RFA of renal masses, several  authors have confirmed its effectiveness in regard to short-  term and intermediate-term cancer-specific survival. In  their review of published data on RFA of renal cancer in 337  patients, Park et al found an excellent disease-specific survival  (94.896) after RF ablation of small tumors (mean size 2.4 cm),  with a mean follow-up of 19 months. It is important to remem-  ber that in the majority of the ablation literature, cancer-spe-  cific survival rates often include patients who have undergone  a second or third ablation for an incompletely treated lesion.  In this review, Park found that 8.896 of patients required  reablation for incompletely treated lesions following RFA.   Though initial success is encouraging, intermediate-term  and long-term results are only now being reported. When  evaluating intermediate-term results of a new treatment  modality, it is important to report results with minimum fol-  low-up rather than the average follow-up of the group.  Accordingly, there are only three currently available long-  term studies on patients undergoing RFA for renal masses  (Table 14.1). In patients with biopsy-proven RCC and a min-  imum follow-up of 3 years, the recurrence-free survival  appears to be comparable with that of early studies, approach-  ing 9596. These results confirm that the majority of renal cell  recurrences occur within the first 3 years and are likely owing  to incomplete ablation rather than recurrent cancer.    of tumors with RCC size (range, follow-up recurrences treatmentto free survival  cm) (range, after 3 recurrence survival? (96)  months) years (range, (96)  months)   et al^ specified  Levinson Percutaneous (33) 34 18 (53) 2 (1-4) 61(41-80) 3 7-30 80 71   etal® ^ Laparoscopic (1)  Tracy Percutaneous (68) 102 66 (72%) 2.3 (0.9-5.4) 51 (36-84) 1 3-36? 94 90    “Recurrence-free survival of all patients in cohort with biopsy-confirmed RCC, including those who recurred prior to the minimum follow-up of 3    "Number of recurrences occurring after minimum follow-up of 3 years, which does not include early recurrences    As the incidence of small renal masses increases, so does the  desire to pursue minimally invasive therapies for their treat-  ment. RFA represents one of the unique therapies for this  purpose. When approached laparoscopically, ablation is  associated with minimal morbidity that appears favorable in  comparison with open or laparoscopic partial nephrectomy.  Percutaneous treatment allows for the outpatient manage-    ment of small renal masses with considerable improvement  in convalescence when compared with extirpative surgery.  With medium to long-term follow-up, cancer recurrence  rates remain low with nearly 95% of patients having no evi-  dence of recurrence after 3 years and up to 7 years. Further  long-term results are required to determine if cancer out-  comes are equivalent to traditional surgery.    . Pantuck AJ, Zisman A, Rauch MK, Belldegrun A. Incidental renal    . Luciani LG, Cestari R, Tallarigo C. Incidental renal cell carcinoma-    age and stage characterization and clinical implications: study of  1092 patients (1982-1997). Urology. 2000;56(1):58-62   [Small incidental renal tumors.  Evaluation and biological parameters]. Urologe A. 2007;46(5):478;  480-474    . Abouassaly R, Lane BR, Novick AC. Active surveillance of renal    . Lane BR, Novick AC, Babineau D, Fergany AF, Kaouk JH, Gill IS.    Comparison of laparoscopic and open partial nephrectomy for tumor  in a solitary kidney. J Urol. 2008;179(3):847—851; discussion 852    . Gill IS, Kavoussi LR, Lane BR, et al Comparison of 1,800 laparo-    scopic and open partial nephrectomies for single renal tumors.  J Urol. 2007;178(1):41—46    . Fergany AF, Hafez KS, Novick AC. Long-term results of nephron    sparing surgery for localized renal cell carcinoma: 10-year fol-  lowup. J Urol. 2000;163(2):442-445    . Matin SF, Gill IS, Worley S, Novick AC. Outcome of laparoscopic    radical and open partial nephrectomy for the sporadic 4 cm. or less  renal tumor with a normal contralateral kidney. J Urol. 2002;168(4  pt 1):1356-1359; discussion 1359-1360   Ramani AP, Desai MM, Steinberg AP, et al Complications of laparo-  scopic partial nephrectomy in 200 cases. 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In vitro thermal  therapy of AT-1 Dunning prostate tumours. Int J Hyperthermia.  2004;20(1):73-92   Rehman J, Landman J, Lee D, et al Needle-based ablation of renal  parenchyma using microwave, cryoablation, impedance- and tem-  perature-based monopolar and bipolar radiofrequency, and liquid  and gel chemoablation: laboratory studies and review of the litera-  ture. J Endourol. 2004;18(1):83-104   Hsu TH, Fidler ME, Gill IS. Radiofrequency ablation of the kidney:  acute and chronic histology in porcine model. Urology. 2000;56(5):  872-875   Crowley JD, Shelton J, Iverson AJ, Burton MP, Dalrymple NC,  Bishoff JT. Laparoscopic and computed tomography-guided percu-  taneous radiofrequency ablation of renal tissue: acute and chronic  effects in an animal model. Urology. 2001;57(5):976—980   Walsh LP, Anderson JK, Baker MR, et al In vitro assessment of the  efficacy of thermal therapy in human renal cell carcinoma. 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Combined  embolization and percutaneous radiofrequency ablation of a solid  renal tumor. AJR Am J Roentgenol. 2000;174(6):1592—1594   Ogan K, Jacomides L, Dolmatch BL, et al Percutaneous radiofre-  quency ablation of renal tumors: technique, limitations, and mor-  bidity. Urology. 2002;60(6):954—958   Matsumoto ED, Johnson DB, Ogan K, et al Short-term efficacy of  temperature-based radiofrequency ablation of small renal tumors.  Urology. 2005;65(5):877—881   Johnson DB, Saboorian MH, Duchene DA, Ogan K, Cadeddu JA.  Nephrectomy after radiofrequency ablation-induced ureteropelvic  junction obstruction: potential complication and long-term assess-  ment of ablation adequacy. Urology. 2003;62(2):351—352  Margulis V, Matsumoto ED, Lindberg G, et al Acute histologic  effects of temperature-based radiofrequency ablation on renal tumor  pathologic interpretation. Urology. 2004,64(4):660—663   Hui GC, Tuncali K, Tatli S, Morrison PR, Silverman SG. Comparison  of percutaneous and surgical approaches to renal tumor ablation:  metaanalysis of effectiveness and complication rates. J Vasc Interv  Radiol. 2008;19(9):13 11-1320   Zlotta AR, Wildschutz T, Raviv G, et al Radiofrequency interstitial  tumor ablation (RITA) is a possible new modality for treatment of  renal cancer: ex vivo and in vivo experience. J Endourol. 1997;11(4):  251-258   Goldberg SN, Gazelle GS, Compton CC, Mueller PR, Tanabe KK.  Treatment of intrahepatic malignancy with radiofrequency ablation:  radiologic-pathologic correlation. Cancer. 2000;88(11):2452—2463  Walther MC, Shawker TH, Libutti SK, et al A phase 2 study of  radio frequency interstitial tissue ablation of localized renal tumors.  J Urol. 2000;163(5):1424—1427    35. Rutherford EE, Cast JE, Breen DJ. Immediate and long-term CT  appearances following radiofrequency ablation of renal tumours.  Clin Radiol. 2008;63(2):220—230   36. 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Outcomes of radiofre-  quency ablation (RFA) for small renal tumors: experience in 102  tumors with more than 3 years of follow-up. In: Abstract presenta-  tion. 26th World Congress of Endourology, Shanghai, China; 2008    High-Intensity Focused Ultrasound  in the Management of the Small Renal Mass    High-intensity focused ultrasound (HIFU) is an attractive  new option in the management of the small renal mass, espe-  cially in view of its noninvasive or minimally invasive appli-  cations. Using well-established principles, this ablative  therapy can be used to treat a variety of solid tumors with  few side effects. As a result, there is a great deal of research  being carried out in this field, and a number of commercially  available devices already exist.    HIFU has been investigated as an ablative technique for  many years. Wood et al were the first to describe bio-effects  from a plane ultrasound transducer in 1920s.! Further, basic  scientific research resulted in the first clinical application of  the technology in the 1950s when Fry et al used HIFU for the  treatment of focal neurological conditions such as Parkinson's  disease.^? However, as the ability to create a predictable  lesion improved, it became clear that the rate-limiting step  was targeting. Without reliable imaging to accurately assess,  target, and monitor the ablated area or “lesion,” the early  investigators strived to create reversible damage to allow  them to site the definitive treatment lesions? and thus attempt  controlled and accurate ablation. This method was not good  enough, and it was only with the advent of vastly improved  imaging techniques, such as ultrasound, computerized  tomography (CT), and magnetic resonance imaging (MRI),  that HIFU research began to move forward again. With these  advances, clinicians and scientists once again became inter-  ested in applying HIFU as a noninvasive method of treating  tumors, especially urological malignancy.   Over the last 20 years, a great deal of experimental work  has been carried out, both laboratory based and in the form  of clinical trials, aimed at developing devices that can deliver  treatments with safe and effective outcomes. This has led to  the development of commercial devices that can now deliver    HIFU accurately and in a reproducible fashion, and the goal  of a noninvasive cancer treatment draws ever nearer.    Unlike diagnostic ultrasound, which usually employs fre-  quencies in the range of 1-20 MHz, frequencies of 0.84  MHz are generally used during the clinical applications of  HIFU, and the energy levels carried in the HIFU beam are  several orders of magnitude greater than those of a standard  diagnostic ultrasound beam. The intensity of the energy in  the ultrasound beam is increased by up to 10,000 times greater  than those of a standard diagnostic ultrasound beam, and  focused tightly, causing the temperature at the focus to rise  rapidly above 80°C.° Even for very short exposures, this level  of heating should lead to effective cell killing." This area of  coagulative necrosis or "lesion" occurs with little damage to  overlying or surrounding tissue and can be targeted from out-  side the body, thus providing noninvasive tissue damage. A  typical lesion is cigar shaped and approximately 12 x 3 mm;  the size does vary with the transducer design (Fig. 15.1).    Ultrasound causes tissue damage through two predominant  mechanisms. The first is by the conversion of mechanical  energy into heat and the second is through cavitation. As an  ultrasound beam propagates through a tissue, some of its  energy is converted to heat. The rate of ultrasound-mediated  heating dQ/dt within a unit volume of tissue depends on its  absorptive properties and can be predicted by the following  equation:    where œ is the absorption coefficient. Under normal circum-  stances, this heat will dissipate rapidly through both direct    thermal conduction and convection from the flowing blood  (convection). If the rate of heating exceeds the rate of cool-  ing, the result will be a local temperature rise. Arrest of cel-  lular reproduction will occur if the temperature is maintained  above 43?C for 60 min or longer. This is of particular rele-  vance for existing “hyperthermia” or “thermotherapy” treat-  ments, where the aim is to raise the temperature of the target  tissues to a precise temperature (usually just above 42.8°C)  for a defined period of time. In contrast, HIFU relies on the  fact that, above a threshold of 56°C for 1 s, rapid thermal  toxicity occurs, causing irreversible cell death through coag-  ulative necrosis. During HIFU treatments, the temperature at  the focus can rise rapidly above 80°C,° which, even for very  short exposures, should lead to effective cell killing,’ and  thus, precise monitoring of temperature is unnecessary.  There is a steep temperature gradient between the focus and  the neighboring tissue, which is demonstrated by the sharp  demarcation between the volume of necrotic tissue (lesion)  and normal surrounding cells seen on histology (Fig 15.1).*  The cooling effect of perfusion may limit the reliability of  other forms of hyperthermia treatment, for which there is  sufficient time during exposures for local thermal diffusion  and heat dissipation from the target region. This factor can be  practically eliminated during HIFU treatment by keeping  individual exposure times below 3 s.? The size of an indi-  vidual lesion will vary with drive frequency, and beam geom-  etry, and is also dependent on exposure parameters such as  intensity, time, target tissue, and the focal depth in the tissues.   Acoustic cavitation is complex, and unpredictable, but the  end result is also cell necrosis induced through a combination  of mechanical stresses and thermal injury. Ultrasound causes    the tissues to vibrate, and the molecular structure is subjected  to alternating compression and rarefaction. During rarefac-  tion, gas can be drawn out of solution to form bubbles, which  oscillate in size (stable or noninertial cavitation) or collapse  rapidly (unstable or inertial cavitation), causing mechanical  stresses and generating temperatures of 2,000—5,000 K in the  microenvironment. The maximum displacement amplitude  of tissue particles during a wave cycle is in the order of  micrometers and is proportional to the pressure amplitude  within the tissue. This is determined by the energy carried in  the wave at that site and is proportional to the square root of  the incident intensity at any given frequency. The maximum  displacement amplitude is also inversely proportional to the  drive frequency at any given intensity.!! Cavitation is there-  fore dependent on frequency, negative pressure amplitude,  and intensity, and the cavitation threshold also lowers as tem-  perature increases." Diagnostic ultrasound exposures gener-  ally operate at frequencies >2 MHz and have lower pressure  amplitudes than do therapeutic exposures, but during HIFU  exposures, it is not possible to eliminate the possibility of the  occurrence of cavitation entirely.   The effect of heating is both more repeatable and more  predictable than cavitation, which made it the preferred  mode of cell killing in early clinical applications of HIFU.  More recently, bubble appearance has been used as an indi-  cator of successful ablation, '^ and in fact, work is now under-  way to investigate whether ultrasound contrast agents can be  used safely to increase the volume of tissue ablation in a  given time.^ The mechanisms behind any such potential  effect remain unclear, but it may be that the contrast agents  act as seeds to promote cavitation.    15 High-Intensity Focused Ultrasound in the Management of the Small Renal Mass    The observed tissue changes following HIFU begin charac-  teristically with appearances of homogeneous coagulative  necrosis. As a result, following treatment a volume of  necrotic tissue is left, which should correspond to the tar-  geted tissue. However, histological evidence of coagulation  necrosis following thermal ablation requires at least 24—48 h"  to develop; thus, lesions that are examined immediately after  ablation do not show changes characteristic of necrosis.  Subtle changes including erythrocyte homogenization, varia-  tion of shape, size, and lysis of red cells within blood vessels,  endothelial damage and granular protein deposits on vessel  walls, homogenization of vascular smooth muscle, shrinkage  and loss of cell membrane detail of tumor cells, and pyknosis  of nuclei can be seen on H&E staining. However, none of  these features is entirely specific, especially given the mor-  phological heterogeneity seen in renal cell carcinoma (RCC).  Indeed, RCCs commonly have areas of necrosis, hemor-  rhage, and hyalinization of stroma in untreated tumors, and  these vary within each tumor.   A handful of published investigational studies of nephre-  ctomies following radiofrequency (RF) ablation have yielded  mixed results from pathological assessment of ablation.  Michaels et al'* reported that the vast majority of their 15  patient series revealed residual tumor viability immediately  after ablation, whereas Matlaga'? reported complete treat-  ment in eight out of ten patients after just a single 12-min RF  ablation treatment. In addition to the different methodologies  used to perform RF ablation, other factors, such as the pos-  sible uncertainties about the true area ablated, may play a  role in these discrepant results. For example, it has been  shown in the liver that specialized stains are required to iden-  tify ablated tumor, particularly in the acute post-ablation  period.” Hence, the precise role of pathological assessment  after RF ablation patients has been questioned"!   A method that may avoid the problems of routine histo-  logical examination of acutely ablated tissue is nicotinamide  adenine dinucleotide (NADH) diaphorase staining. NADH is  a coenzyme present in cytoplasm and mitochondria. It is  integral to oxidation and reduction reactions in glycolysis,  the Krebs cycle, and cellular respiration. NADH diaphorase  is a ubiquitous cellular enzyme that catalyzes substrate  reduction by the transfer of electrons from NADH, yielding  reduced substrate and NAD*. One such substrate is p-nitroblue  tetrazolium (Sigma-Aldrich). Diaphorase has been shown to  be active only in viable cells, and its activity ceases immedi-  ately after cellular death.”   In a porcine model, negative NADH staining has corre-  lated well with effective ablation.^ ^ ^ NADH staining has  been used as an adjunct to routine H&E staining to study the  effects of renal RF ablation. ?* However, there continues to  be some debate as to the best timing of specimen staining.    Stern et al” commented that although negative NADH stain-  ing is consistent with nonviability, their results suggested  that false-positive staining can occur immediately following  radiofrequency ablation (RFA), making the predictive value  of positive NADH diaphorase staining unclear. This was sup-  ported by Anderson et al? who observed that tissue that is  apparently viable on NADH staining within 2.5 h of RFA  may in fact have been ablated. From the literature, there is no  clear resolution to this problem, but H&E alone may not be  sufficient, and at this time, a combination of H&E and NADH  is probably optimal when assessing ablation in a specimen  that has been resected immediately after ablation (Fig. 15.2).   When the ablated tissue is left in situ, the subsequent  inflammatory response includes granulation tissue formation  at the periphery of the necrotic region after approximately 7  days, showing the presence of immature fibroblasts and new  capillary formation? and the migration of polymorphonuclear  leucocytes deep into the treated volume. Two weeks follow-  ing HIFU, the periphery of the treated region is replaced by  proliferative repair tissue. The repair process has not been  investigated in detail at the cellular level beyond this time  frame, but sequential anatomical imaging records a gradual  shrinkage of treated volumes over time, which indicates  replacement of the necrotic region with fibrous scar tissue.”    There are several ways to monitor an HIFU treatment, and  this has led to the development of a variety of devices, a few  of which are now commercially available. These devices,  although applying the same basic principles for ablation  using HIFU, use different imaging modalities to target organs  and monitor the effect of the treatment given. Accurate treat-  ment monitoring is essential. Today, HIFU is monitored and  guided by either ultrasound or MRI.   Diagnostic ultrasound is the most common imaging  modality used to direct therapeutic ultrasound. It is widely  available, relatively inexpensive, mobile, and easily applied.  Using the same modality for imaging and ablation is logical,  as the limitations of the imaging will correspond to the limi-  tations of the HIFU beam and as such enable the operator to  assess the suitability of a given approach. The diagnostic  imaging transducer is usually built into the treatment trans-  ducer and is directed in the same plane as the treatment head.  This means that real-time assessment is possible, and thus  adjustment to treatment parameters during treatment can be  made to optimize efficacy and safety. Real-time gray-scale  changes seen immediately following ablation are used to  judge the extent of treatment.” These gray-scale changes or  "bright-ups" are thought to represent boiling tissue and  therefore guarantee sufficient temperatures for cell death.    The clear disadvantage of ultrasound is the relatively poor  image quality, which can be difficult to interpret. The image  quality can degrade rapidly as a consequence of changes in  the acoustic properties of tissues'*; this may occur when  heating or when edema has occurred in the targeted tissue or  within the tissue in front of the target, e.g., perinephric fat.  MRI is increasingly being used to guide HIFU treatments.  MR is highly sensitive in localizing tumors and provides pre-  cise anatomical resolution for tumor targeting. MR has many  parameters that are temperature sensitive, and small tempera-  ture elevations (+1°C) can be detected.” As a result, the HIFU  focus can be located at relatively low powers, and the accu-  racy of targeting can be verified. In addition, by using tem-  perature-sensitive MR imaging sequences, focal temperature  elevations and effective thermal doses may be estimated.*!  The disadvantages of MR include its cost and size. Practically,  MR has lower spatial resolution than ultrasound and real-time    assessment of treatment relies on relatively slow, computer-  generated assumptions of temperature change; as a result,  treatment time is also prolonged.    The HIFU technique has been investigated extensively in  small and large animals and been shown to be successful for  the treatment of liver tumors in the former? and in the selec-  tive destruction of normal liver, bladder, muscle, and kidney  in the latter.** ^ Small animal studies have also shown that  HIFU does not increase the risk of tumor metastasis.?   The evidence from both animal-based research and human  clinical trials is that local pain, transient fever, and skin tox-  icity are the most frequently occurring adverse events. ?'    15 High-Intensity Focused Ultrasound in the Management of the Small Renal Mass    Pain is usually transient, mild, and short-lived, while fever is  thought to be caused by a combination of the release of intra-  cellular ions, nucleic acids, proteins, and their metabolites  into the extracellular space.” Skin toxicity is usually limited  to small superficial burns, but significant burns can occur as  Leon-Villapalos et al? describe in their case report on a  patient with full thickness burns following MR-guided HIFU  treatment of uterine fibroids. Skin burns occur because out-  side the focal region, energy deposition is maximal at inter-  faces between tissues of differing acoustic impedances, and  the most significant of these interfaces is the skin surface.  There are other potential complications of HIFU treatment  such as inadvertent injury to hollow viscera adjacent to the  target tumor, and abscess formation following bacterial colo-  nization of the necrotic volume following successful abla-  tion.” These are very rare and have been reported in less than  0.196 of cases.    With these factors in mind, there are three generic types of  HIFU device: extracorporeal, transrectal, and laparoscopic.   Extracorporeal devices are large devices and can be used  to treat a variety of conditions including liver, kidney, pancre-  atic, pelvic, and bone tumors. These extracorporeal devices  use transducers with a longer focal length (10-15 cm) and  use either ultrasound or MRI to target the organ. The first  commercially available extracorporeal device was designed  and developed in Chongqing, China. The Model JC HIFU  device (HAIFU™ Technology Company, China)? was the  first commercially available extracorporeal HIFU device, and  the majority of the published clinical data come from work  with this device. This is the only ultrasound-guided extracor-  poreal device that has a CE Mark (Conformité Européene),  the European kite mark that is awarded to a device once it has  been proven to be safe in humans. The second extracorporeal  device is the MR-guided focused ultrasound (MRgFUS) sys-  tem (ExAblate 2000, InSightec, Haifa, Israel)”; this device is  only licensed for use with uterine fibroids.   Transrectal probes were designed for the treatment of pro-  static disease. Transrectal devices are smaller, with short  focal lengths (4—5 cm), operating at higher frequencies than  extracorporeal devices, and they use ultrasound guidance.  There are two devices in use around the world: The Ablatherm  (Ablatherm, Technomed International; Lyon, France) and  the Sonablate?-500 (Focus Surgery, Indianapolis, IN, USA)."!  These devices rely on similar principles, and as such, their  results are comparable. This device cannot be used in the  management of renal tumors.   Laparoscopic HIFU is delivered using a transducer  mounted in a probe, which can be passed through an 18-mm    port. Thus, the transducer is small, with an even shorter focal  length (2.5—3.5 cm) and once again operates under ultra-  sound guidance. The Sonablate?-Laparoscopic HIFU system  (Focus Surgery, Indianapolis, IN, USA and Misonix Inc.,  Farmingdale, NJ, USA) is the first device of this kind to have  reached clinical trials.    Renal tumors comprise 3% of all solid neoplasms, and the  incidence of RCC has risen by 2.3-4.3% annually over the  last three decades, with 51,190 new cases and 12,890 deaths  expected in the USA in 2007.? With the advent of high-  quality and easily accessible imaging, the rate of detection of  small renal masses has greatly increased. Luciani et al? stud-  ied a series of more than 1,000 patients and found that the  incidental discovery of renal tumors increased from 13 to  59% in the period between 1982 and 1997. Almost half of  those with incidentally found masses were more than 65  years old. In the UK, there are around 6,000 new cases each  year, most commonly occurring in the seventh and eighth  decades.“   With this ever-growing group of newly diagnosed patients,  the management of the small renal mass has become an  important area of debate. Nephron-sparing surgery by partial  nephrectomy (where indicated) is still seen as the gold stan-  dard,“ and active surveillance remains a popular option for  these small renal masses; however, there is a growing place  for low morbidity, ablative techniques in the management of  this patient group, many of whom are elderly. Cryotherapy, "^  RFA,” and extracorporeal HIFU* have all been proposed as  treatment options for small RCC («4 cm).   The kidney has been used as an animal model for HIFU  ablation. Linke et al (1973)? were the first to report success-  ful kidney tissue ablation using HIFU on rabbits. The test  animals were kept for more than 1 year following HIFU  exposure. Long-term assessment showed the treated area of  healthy kidney was replaced with a thin fibrous scar on gross  histological analysis of the specimens.   Adams et al (1996)?? treated implanted VX-2 tumors in  rabbit kidneys as part of a two-phase trial. The first phase  involved the ablation of implanted tumors during an open  procedure, whereas in the second phase the implanted tumors  were ablated in an extracorporeal fashion. The kidneys were  excised shortly after exposure and assessed histologically for  ablation. The authors found areas of discrete renal damage in  all nine tumors treated in the first phase. In the second phase,  seven out of nine tumors showed evidence of ablation;  however,ablation was seen throughout the implanted tumors  in only two cases. Accurate targeting of the tumors remained  difficult at that time.    Watkin et al (1997) used a large animal model to assess  the feasibility of noninvasive renal tumor ablation?! An  extracorporeal HIFU transducer was used to evaluate the  time/exposure thresholds for kidney damage in ex vivo pig  kidney. Eighteen porcine kidneys were treated in vivo at a  depth of 40 mm from the skin surface, with acute damage  detected in 13 kidneys (67%). The lesions appeared well cir-  cumscribed with a pale central area surrounded by a hemor-  rhagic rim.    Clinical trials looking at the use of HIFU in the management  of small kidney tumors remain few. Vallancien et al (1993)?  reported the first clinical feasibility study. Eight patients  received extracorporeal HIFU exposures followed by neph-  rectomy. They reported evidence of ablation in the treated  areas following excision of the kidney, but encountered a  high rate of skin burns with 10% of patients suffering from  this complication.   Marberger et al (1993)? reported a series of 16 patients  who had renal tumors treated with HIFU. In 14 patients, a  10-mn? volume of renal tumor was treated with HIFU, and  this was followed by immediate surgical resection of the  kidney. In nine patients, areas of acute tissue necrosis were  seen, although the lesions only measured between 15 and  3596 of the original targeted volume. Two patients were  treated with curative intent; however, both had incomplete  ablation with residual disease visible on follow-up MRI.   Wu et al (2003)** have described a series of 13 patients  with renal tumors who have received HIFU treatment. They  only comment on the ten patients who were treated with pal-  liative intent, the three receiving HIFU with curative intent  were not analyzed. They showed that nine out of ten patients  described a reduction in tumor-related pain, while hematuria  resolved in seven out of eight cases.   Hacker et al (2006)? used an experimental hand-held  extracorporeal technology to ablate 43 porcine and human  kidneys. However, technical success was mixed, and the  authors concluded that further work was required in the dos-  age and application of this system.   The first prospective, nonrandomized clinical trial to eval-  uate the safety and effectiveness of HIFU in the treatment of  small kidney tumors has been carried out by our group at the  University of Oxford; the results are as yet unpublished,  although interim results were published by Iling et al  (2005).*° Twenty-one patients with kidney tumors were  treated, six receiving HIFU prior to nephrectomy, allowing  histological assessment, and 15 undergoing HIFU followed  by radiological follow-up. MRI changes suggestive of tumor    response to HIFU treatment have been seen in 12/21 cases  (5796). Fourteen patients within the radiology group were  eligible for assessment: complete ablation was seen in four  cases (2996) and complete or partial ablation in eight patients  (5796). Mild, transient discomfort was reported by 12/21  patients, and moderate discomfort in 4/21, but severe pain  needing prolonged opiate analgesia was not encountered.  Minor skin toxicity was seen in 5/21 patients. Recovery time  was short with none of the patients remaining in hospital for  more than 24 h, and the treatment has proven to be repeatable  in those patients with a partial response. We have shown that  it is feasible to ablate small renal tumors, and importantly,  neither renal function nor overall health were adversely  affected (Fig. 15.3).    Published preliminary results have shown some evidence of  ablation in all trials looking at HIFU for kidney tumors.  However, we have shown that less than a third of patients  with small renal tumors achieve complete ablation. Specific  reasons for these low-complete ablation rates have yet to be  fully elucidated, but are likely to include rib interaction and  body habitus. A laparoscopic probe may overcome the practi-  cal constraints of extracorporeal HIFU posed by the ribcage,  allowing direct ablation of the tumor under direct ultrasound  visualization. This approach may provide a nephron-sparing  procedure without the associated risks of bleeding or urinary  leakage.   The Sonablate®-Laparoscopic HIFU system (Focus  Surgery, Indianapolis, IN, USA and Misonix Inc., Farmingdale,  NJ, USA) has been tested in both ex vivo and in vivo in large  animal models. A team at the University of Chicago depart-  ment of surgery, led by Professor Shalhav,*” ?* used eight  female farm pigs weighing between 27 and 36 kg to assess the  equipment. A total of 16 kidneys were treated, with the ani-  mals divided into two groups for the evaluation of the tissue  effects of the laparoscopic HIFU equipment: an acute group  (n = 4, killed at 4 days post-HIFU treatment) and a sub-  acute group (n = 4, killed at 14 days post-HIFU treatment).  Following HIFU treatment and sacrifice according to group,  the kidneys were analyzed by a single, blinded pathologist.   The results from this in vivo study confirmed that kidney  ablation was feasible with a mean volume of necrosis of 4.5  + 2.94 cm? (range 0.8—-10.5). Only two intra-operative com-  plications were described. The first occurred in the first  lesion performed in the study. Only limited dissection had  been performed, and postmortem assessment revealed ther-  mal injury to the adjacent back muscle wall. The second  complication occurred on animal no. 4 where the ipsilateral  ureter was included in the treatment zone, and thermal    15 High-Intensity Focused Ultrasound in the Management of the Small Renal Mass    damage was noted to this structure as a result. They con-  cluded that the 18-mm probe could be inserted through a  standard port so that effective HIFU could be delivered to a  healthy porcine kidney, and that complications were  minimal.   Klingler et al? have used the laparoscopic HIFU device to  treat ten kidneys with solitary renal tumors. In the first two  patients with 9-cm tumors, a defined marker lesion was placed  prior to laparoscopic radical nephrectomy. In eight patients  with a mean tumor size of 22 mm (range, 11—40), the tumor  was completely ablated as in curative intent, followed by lap-  aroscopic partial nephrectomy in seven tumors. One patient  had post-HIFU biopsies and was followed radiologically.  Specimens were studied by detailed and whole-mount his-  tology, including NADH stains. At histological evaluation,    both marker lesions showed irreversible and homogeneous  thermal damage within the targeted site. Of the seven tumors  treated and removed after HIFU, four showed complete abla-  tion of the entire tumor. Two tumors had a 1-3-mm rim of  viable tissue immediately adjacent to where the HIFU probe  was approximated, and one tumor showed a central area with  about 20% vital tissue. There were no intra- or postoperative  complications related to HIFU.   In Oxford, the laparoscopic device has been used to treat  seven patients with small renal tumors prior to laparoscopic  radical nephrectomy. Our experience is similar to that of the  Vienna group. The treatment has proven to be safe and by the  end of the series effective. Phase II trials are now planned to  assess the use of this device in patients with small renal  tumors («3 cm) (Fig. 15.4).    HIFU is an exciting prospect for the noninvasive treatment of  kidney tumors. The position and size of small renal tumors  makes them an ideal target for this treatment. The data to  date have shown that it is not straightforward. Targeting and  successfully treating an entire tumor consistently has proven  to be difficult with rib interaction, perinephric fat, and body  habitus suggested as possible reasons for a 30% success rate  in the only prospective, curative trial to date. A laparoscopic  approach may overcome these problems, and early works  suggest that complete ablation is possible; however, this  approach is more invasive and will need to be proven to be  safer than and as effective as other minimally invasive proce-  dures such as cryoablation and RF.   However, despite mixed results to date, further work is  underway, and more clinical trials are proposed with new  technology to try and overcome some of the limiting factors.  Extracorporeal HIFU remains the only noninvasive option  for this growing group of patients and can be performed as a  day case. If the success rate can be improved, HIFU would  seem to be a reasonable option for many patients in the first  instance, with repeat treatments possible or salvage surgery  as an option if the treatment proves unsuccessful. If this were  the case, a large group of patients would have their kidney  cancer cured without ever having to see a knife or a hospital  ward, a prospect that continues to drive the research teams  forward in an effort to perfect the treatments.    1. Wood RW, Loomis AL. The physical and biological effects of high-  frequency sound waves of great intensity. London Edinburgh Dublin  Phil Mag J Sci. 1927;4:417-436   2. Fry WJ, Mosberg WH, Barnard JW, Fry FJ. Production of focal  destructive lesions in the central nervous system with ultrasound.  J Neurosurg. 1954;11:471-478    . Fry WJ, Barnard JW, Fry FJ, Krumins RF, BJ F. 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Nat Rev Cancer. 2005;5(4):321—327   Illing RO, Leslie TA, Kennedy JE, Calleary JG, Ogden CW,  Emberton M. Visually directed high-intensity focused ultrasound  for organ-confined prostate cancer: A proposed standard for the  conduct of therapy. BJU Int. 2006;98(6):1187—1192   Hynynen K, Pomeroy O, Smith DN, et al MR imaging-guided  focused ultrasound surgery of fibroadenomas in the breast: a feasi-  bility study. Radiology. 2001;219:176-185   Hynynen K, Darkazanli A, Unger E, Schenck JF. MRI-guided non-  invasive ultrasound. Med Phys. 1993;20(1):107-115   ter Harr G, Rivens I, Chen L, Riddler S. High intensity focused  ultrasound for the treatment of rat tumours. Phys Med Biol.  1991;36(11):1495-1501   Vaughan MG, ter Haar GR, Hill CR, Clarke RL, Hopewell JW.  Minimally invasive cancer surgery using focused ultrasound: a pre-  clinical, normal tissue study. 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Effect of high-intensity focused ultrasound on  patients with hepatocellular cancer — preliminary report. Chin J  Ultrasonog. 1999;8(4):213-216   Chaussy C, Thuroff S. High-intensity focused ultrasound in prostate  cancer: results after 3 years. Mol Urol. Fall 2000;4(3):179-182  Madersbacher S, Kratzik C, Szabo N, Susani M, Vingers L,  Marberger M. Tissue ablation in benign prostatic hyperplasia with  high-intensity focused ultrasound. Eur Urol. 1993;23(suppl 1):39-43  Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer sta-  tistics, 2007 CA Cancer J Clin. 2007;57(1):43-66   Luciani LG, Cestari R, Tallarigo C. Incidental renal cell carcinoma-  age and stage characterization and clinical implications: study of  1092 patients (1982-1997). Urology. 2000;56(1):58—62   Cancer Research UK. UK Kidney Cancer Statistics 2001; 2006  Fergany AF, Hafez KS, Novick AC. Long-term results of nephron  sparing surgery for localized renal cell carcinoma: 10-year fol-  lowup. 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Focused extracorporeal pyrotherapy: experimental study and feasi-  bility in man. Semin Urol. 1993;11(1):7-9   Marberger M, Schatzl G, Cranston D, Kennedy JE. Extracorporeal  ablation of renal tumours with high-intensity focused ultrasound.  BJU Int. 2005;95(suppl 2):52—55   Wu F, Wang ZB, Chen WZ, Bai J, Zhu H, Qiao TY. Preliminary  experience using high intensity focused ultrasound for the treatment  of patients with advanced stage renal malignancy. J Urol. 2003;  170(6 Pt 1):2237-2240   Hacker A, Michel MS, Marlinghaus E, Kohrmann KU, Alken P.  Extracorporeally induced ablation of renal tissue by high-intensity  focused ultrasound. BJU Int. 2006;97(4):779-785   Illing RO, Kennedy JE, Wu F, et al The safety and feasibility of  extracorporeal high-intensity focused ultrasound (HIFU) for the  treatment of liver and kidney tumours in a Western population. Br  J Cancer. Oct 17. 2005;93(8):890—895   Shalhav A. High intensity focused ultrasound renal tissue ablation:  a laparoscopic porcine model. Chicago: Department of Surgery,  University of Chicago; 2005   Paterson R, Barret E, Siqueira T, et al Laparoscopic partial kidney  ablation with high intensity focused ultrasound. J Urol. 2003;169(1):  347-351   Klingler HC, Susani M, Seip R, Mauermann J, Sanghvi N,  Marberger MJ. A novel approach to energy ablative therapy of  small renal tumours: laparoscopic high-intensity focused ultra-  sound. Eur Urol. 2008;53(4):810—816; discussion 817-818    The management of localized prostate cancer has centered on  surveillance or radical therapy such as prostatectomy or  radiotherapy. Furthermore, because of the reduction in dis-  ease severity as a result of early detection, it is quite likely  that the small absolute risk reduction — of approximately 596  over 10 years that has been demonstrated in a randomized  controlled trial comparing surgery with watchful waiting — in  men with low-to-moderate risk disease is likely to be reduced  even further. The advent of active surveillance with selective  delayed intervention is also very likely to make this differ-  ence in mortality between surveillance and radical therapy  less significant. As radical treatments carry significant mor-  bidity with operative complications (wound infection, hem-  orrhage, and hospital stay) and can cause significant long-term  toxicity (incontinence, impotence, and rectal problems),  there has been a demand to develop ablative therapies that  attempt to reduce treatment burden while retaining cancer  control and avoiding the psychological morbidity associated  with surveillance. Although a number of minimally invasive  therapies have been described, e.g., cryosurgery, high-  intensity-focused ultrasound (HIFU), radiofrequency abla-  tion, and photodynamic therapy, each one is at a different  stage in its evaluation and diffusion into clinical practice.    Ultrasound refers to mechanical vibrations above the thresh-  old of human hearing (16 kHz) and has the ability to interact  with tissue to produce biological changes. Ultrasound is gen-  erated by applying an alternating voltage across a piezoelec-  tric material such as lead zirconate titanate. These materials  oscillate at the same frequency as the alternating current  causing ultrasound wave that can propagate through tissues.  This in turn causes alternating cycles of increased and  reduced pressure (compression and rarefaction, respectively).  Diagnostic ultrasound usually uses frequencies in the range  of 1-20 MHz, but therapeutic HIFU uses frequencies of    0.8-3.5 MHz with delivery of energy within the ultrasound  beams that are several times greater than the energy levels  within diagnostic ultrasound (Fig. 16.1). Therapeutic ultra-  sound can be conveniently divided into two broad categories:    Fig. 16.1 Schelieren images of the ultrasound transducer during imag-  ing and HIFU therapy modes. During the HIFU mode, the entire trans-  ducer crystal surface is excited with RF high voltage to generate a sharp  and narrow beam for treatment of the tissue. During imaging, ultra-  sound transducer uses only the center segment of the crystal to generate  a long and uniform beam. From Sanghvi et al.? Copyright 2009, with  permission from Elsevier    “low” intensity (0.125-3 W/cm?) and “high” intensity (25  W/cm’). The former can stimulate normal physiological  responses to injury and accelerate other processes such as the  transport of drugs across the skin. The high-intensity ultra-  sound can selectively destroy tissue if delivered in a focused  manner.?   HIFU relies on the physical properties of ultrasound,  which allows it to be brought into a tight focus, using an  acoustic lens, a bowl-shaped transducer, or an electronic-  phased array. As ultrasound propagates through a tissue,  zones of high and low pressure are created. When the energy  density at the focus is sufficiently high (during the high-pres-  sure phase), tissue damage occurs. The volume of ablation  (or lesion) following a single HIFU pulse or exposure is  small and varies according to transducer characteristics. It is  typically cigar shaped with dimensions in the order of 1—3  mm (transverse) x 8-15 mm (along beam axis). To ablate  larger volumes of tissue for the treatment of solid cancers,  these lesions are placed adjacent to each other. The two pre-  dominant mechanisms of tissue damage are by the conver-  sion of mechanical energy into heat and “inertial cavitation.”  If tissue temperatures are raised above 56°C, then immediate  thermal toxicity can occur, provided the temperature is main-  tained for at least 1 s. This will lead to irreversible cell death  from coagulative necrosis. In fact, during HIFU, the temper-  atures achieved are much greater than this, typically above  80?C, so even short exposures can lead to effective cell death.  Inertial cavitation occurs at the same time, but is neither as  controllable nor predictable. It occurs because of the alter-  nating cycles of compression and rarefaction. At the time of  rarefaction, gas can be drawn out of solution to form bubbles,  which then collapse rapidly. The mechanical stress and a  degree of thermal injury induce cell necrosis! (Fig. 16.2).  Histologically, the tissue changes that occur are homoge-  neous coagulative necrosis, with an inflammatory response    Fig. 16.2 Inertial cavitation. An  ultrasound wave progresses  through tissue causing  alternating cycles of increase  and decreased pressure. Gas is  drawn out during rarefaction to  create bubbles that can collapse  and release energy to raise local  temperature at the microscopic  level. From Kennedy.’ With  permission from Nature  Publishing Group    that follows, leading to the formation of granulation tissue —  indicated by the presence of immature fibroblasts and new  capillary formation — at the periphery of the necrotic area at  about a week after treatment. Polymorphonuclear leukocytes  migrate deep into the treated tissue, and then at 2 weeks, the  boundary of the treated region is replaced by proliferative  repair tissue. The repair process has not been investigated in  detail at the cellular level beyond this time, but imaging tech-  niques using contrast-enhanced ultrasound or magnetic reso-  nance imaging show an eventual shrinkage of treated  volumes, indicating that the necrotic area has been replaced  by fibrous scar tissue.   The placement of the small HIFU lesions requires precise  planning for an entire tumor to be ablated reliably.  Furthermore, patient movement can lead to areas of viable  malignant tissue remaining after treatment, and even in ideal  situations, other factors can prevent a successful treatment.  The most important of these include the heat-sink effect and  calcification. The heat-sink effect relates to one area that  overheats in the HIFU pulses pathway and thus prevents ade-  quate ultrasound propagation to the targeted area; such a phe-  nomenon occurs ifthe time between HIFU pulses is inadequate  for tissue cooling or if an area is high in water content, such  as a cyst. In addition, highly vascularized tissues might be  more resistant to thermal ablation owing to the heat-sink  effect of their blood supply. Calcification simply leads to  reverberation and shielding of the targeted area from parts of  the HIFU pulse, leading to inadequate heating of the tissue.    Currently, there are two commercially available transrectal  devices that can treat the prostate gland — the Ablatherm?    device (Edap-Technomed, Lyon, France) and the Sonablate?  500 (Focus Surgery, Indianapolis, IN).    The Ablatherm? device until very recently had separate  imaging (7 MHz) and therapy transducers (3 MHz), which  had a fixed focal length of 4 cm. Prostate imaging during  treatment was not possible but performed between treatment  zones by inserting the imaging transducer through the thera-  peutic transducer. The latest modification to the Ablatherm®  combines treatment and planning probes so that visual feed-  back is possible during treatment. However, because the  Ablatherm® uses algorithm-driven treatment protocols with  preset energy levels, individual pulse-energy levels cannot  be modified by the operator. Other features include the incor-  poration of the probe into a table that holds the pump and  cooling mechanism and on which the patient is placed in the  right lateral position. Treatment is done to each lobe in turn  and performed anterior to posterior within a complete block  that incorporates the full anterior—posterior height of the  prostate. A number of safety features that monitor the rectal-  wall energy deposition are in place to prevent damage to this  area. Many centers that use the Ablatherm® combine tran-  surethral resection of the prostate (TURP) or bladder neck  incision to reduce gland size and stricture formation.    The Sonablate® system consists of a rectal probe (containing  the transducer) with an operating frequency of 4 MHz that  attempts to optimize the combined imaging and therapy roles  of the transducer (Figs. 16.3 and 16.4). This has the advan-  tage of allowing visualization of treatment effect, following  each pulse of the treatment cycle. Degassed water is pumped  through the system and is chilled to temperatures of 17—20  °C to prevent rectal-wall injury by heat buildup. Rectal-wall  monitoring features are also in place with this probe.  Treatment planning, execution, and monitoring are controlled  using a user interface that allows the surgeon to precisely tar-  get the area of treatment, adjust the focal length of the trans-  ducer (currently 3, 4, or 4.5 cm), and alter the power intensity  delivered to each focal zone individually (Fig. 16.5). Rather  than a protocol-driven treatment, the power intensity of each  pulse is guided by gray-scale changes within the targeted  area that represent steam, so that greater certainty about cell  kill is obtained.’ In other words, the power is raised to obtain  what we have deemed “Uchida” changes (or gray-scale “pop-  corning”), named after the Japanese urologist who pioneered  work using the Sonablate 500. The Sonablate 500 delivers    treatment to the prostate in three separate blocks. The ante-  rior portion of the prostate is treated initially, followed by  midzone, and then posterior gland (Fig. 16.6). The probe  requires adjustment between each of these blocks. The poste-  rior block is always treated using the 3-cm focal length and  with lower energy levels. Within each zone, multiple overlap-  ping lesions are created to enhance ablation (Fig. 16.7).    Fig. 16.5 Screen capture demonstrating what the operator sees during  a Sonablate 500 treatment. The lower two images demonstrate pretreat-  ment axial and sagittal images whereas the upper two images show the    Fig. 16.6 Diagrammatic representation of the Sonablate 500 within the  rectum and the treatment blocks, anterior, posterior, and middle as  depicted    treatment with continual updates in images. This live comparison to the  prostate prior to energy delivery allows adjustments to be made to  energy on a pulse by pulse basis    Fig. 16.7 Diagrammatic representation each HIFU pulse delivered to  the anterior block. Rows of pulses adjacent to each other are used to  ablate larger areas of prostate    Historically, when extremes of care (surgery vs. no treat-  ment) have been the only therapeutic options available in  treating a condition, a predictable result can be observed.  Within urology, there are several examples of this, but per-  haps the best relates to the trend in relation to the manage-  ment of benign prostatic hyperplasia (BPH). Until recently,  there were only two options for a man with lower urinary  tract symptoms, surgery or watchful waiting. Today, a man  with lower urinary tract symptoms is very likely to reject  both of these options and instead opt for either medical ther-  apy or one of the minimally invasive approaches to the dis-  ease.^ The trade-off that men make is acceptance of a slight  reduction in efficacy in exchange for greater convenience  and a better toxicity profile.’   BPH is a common condition in which the choice of treat-  ment has been between watchful waiting and surgery.  Surveillance carries the risk of progression of symptoms.  Over the last 50 years, TURP has become the “gold-standard”  for the surgical management of BPH. It can result in a signifi-  cant clinical improvement in just over 9096 of those who have  severe symptoms." However, there is need for general or  regional anesthesia, postoperative catheterization, and a hos-  pital stay of 2-3 days. Alongside a morbidity of one in five  that includes transfusion (2-5%), erectile dysfunction (5%),    urethral/bladder neck stricture, urinary incontinence (0.4—  1.3%), and retrograde ejaculation (60-70%), TURP is not an  easy alternative to surveillance or medication. Furthermore,  the results in terms of symptomatic improvement following  TURP for those men who have mild-to-moderate symptoms  are less significant, with just below 8096 showing improve-  ment. At present, medical management with five alpha  reductase inhibitors and alpha blockers have evolved to  achieve a central role in the management of BPH, so much so  that surgery is reserved in those that fail medical management  or those that present with acute urinary retention. For this  group of men, alternatives to the traditional TURP have been  sought. HIFU has been investigated for use in BPH. The most  recent studies that have used HIFU in treating BPH are sum-  marized in Table 16.1.??^? Although HIFU did show improve-  ments in urodynamic and symptomatic parameters, they were  slow to materialize and of short duration with other signifi-  cant complications. Importantly, a significant proportion of  men, 5—44%, required a secondary TURP because of treat-  ment failure within 1 or 2 years. Outcomes on impotence and  incontinence, and other morbidity outcome data were poorly  reported in these series. Consequently, using HIFU for BPH  has not been popular, especially since new improved energy  modalities, including the traditional TURP, have been shown  to be far better. Other heat-based modalities, such as micro-  wave therapy, and new laser energies to vaporize or resect  prostate tissue have also come to the fore.   Recurrent urinary  retention (n = 2)  and urethrorectal  fistula (n = 1)    24 Recatheterization  (16%); hema-  tospermia (13%);  hematuria (9%);  acute retention  (4%); perineal pain  (11%); epididymitis  (9%)    Retention (39%);  hematospermia  (796); epididymitis  (3%); hematuria  (8%); dysuria (2%);  UTI (1.596)    The use of HIFU for the treatment of localized prostate can-  cer has until recently been nested within a small number of  enthusiasts. They have refined the indications, developed the  technology, and disseminated their early experience. Fourteen  series have so far reported outcome data, with four using the  Sonablate 500 and the remainder using the Ablatherm  device.'*** There was double reporting of a number of series,  but this was not always made explicit in the papers (Table  16.2). The number of patients treated ranged from 30 to 402,  and mean follow-up ranged from 11 to 76.8 months.  Morbidity data were inconsistently reported (Table 16.3).  Incontinence rates were 0.5-15.496, and impotence rates  ranged from 13 to 53%. These did not always grade the  incontinence, and where grading was used, these differed  and were therefore not comparable across series. Definitions  of impotence and potency had similar problems. Fistulae  rates ranged from 0 to 2%, although most of the fistulae were  in the early experience with prototype machines. Other  symptoms were inconsistently and selectively reported in  most series. Neoadjuvant hormonal therapy was primarily  used for cytoreduction of gland size but represented a possi-  ble confounding factor for cancer-control rates. D'amico risk  stratification was reported in six series, while one series cat-  egorized all patients as high risk using another definition  (stage 2T3a, Gleason score 8-10, PSA > 20 ng/mL).  Biochemical outcome was reported using either mean PSA  values at longest follow-up, PSA nadir values («1, «0.5,  «0.2, «0.3, and 0.1 ng/mL), old American Society for  Therapeutic Radiology and Oncology (ASTRO) criteria, and  ASTRO Phoenix criteria (validated for radiotherapy only).  Biopsies were not carried out in all men in all series, but only  one did not report on biopsy data. Most series included HIFU  retreatments within the overall outcome data with the mean  HIFU sessions ranging from 1.17 to 1.4 (Table 16.2). Second  HIFU therapies were regarded as part of the treatment proto-  col rather than treatment failures per se, since one of the  advantages of HIFU has been purported to be its repeatabil-  ity, sometimes up to three times for men who have residual  prostate cancer.   The exact follow-up protocol to be used and criteria for  success or failure are yet to be ascertained in HIFU therapy  of prostate cancer. A number of groups have demonstrated  that gadolinium contrast-enhanced MRI may be of use in the  early determination of cancer control. Areas of necrosis are  obvious through lack of enhancement, and areas of residual  undertreated tissue can be shown as early as 2 weeks after  treatment with good correlation to biochemical outcome  (Figs. 16.8 and 16.9). The exact role for contrast-enhanced  MRI in follow-up of patients after HIFU is yet to be  determined.?^'?    The natural history of prostate cancer prevents the use of  mortality as an outcome measure in most short- to medium-  term reports. As a result, surrogates in the form of biochemi-  cal failure have emerged. However, the optimal definition of  biochemical failure is far from clear. Indeed, because of this  lack of certainty, the reporting of minimally invasive modali-  ties has shown little consistency. The variability in biochemi-  cal outcome is demonstrated by the differing PSA nadirs  used to define successful outcome with groups using any one  of PSA «1, «0.5, 0.4, «0.3, «0.2, and «0.1 ng/mL. A PSA of  «0.2 ng/mL has evidence within radical prostatectomy series  demonstrating its effectiveness to predict long-term out-  comes, but such evidence is insufficient for HIFU.? A num-  ber of series use three successive PSA rises to define treatment  failure according to the old ASTRO criteria to define bio-  chemical failure after radiotherapy.** This has its own draw-  backs since the old ASTRO criteria are not appropriate for  evaluating PSA elevations sooner than 3—5 years after treat-  ment and were only developed for use in radiotherapy.  Indeed, with the emergence of the ASTRO Phoenix criteria  (nadir + 2 ng/dL),* the old definition is in itself questionable,  although some HIFU series have attempted to use this new  definition. The Phoenix definition of failure is being used by  the Federal Drug Administration (FDA) as the key determi-  nant of success against which HIFU will be assessed in FDA  Phase II/II trials in the United States, so this may need to be  adopted as a reasonable standard for the foreseeable future.   Equally, morbidity data are reported poorly. Most series  do not define incontinence or impotence, while the majority  show inconsistent reporting of other perceived minor com-  plications. As the premise of minimally invasive ablative  therapies is to reduce the morbidity of therapy for men with  localized prostate cancer while retaining cancer control and  thus overcome the therapeutic dilemma that such men pres-  ently face, such lack of open reporting regarding morbidity  data is disappointing. Although such data are difficult within  the constraints of retrospective case series, it is important  that a minimum data set is agreed on for reporting  complications.   Assessing health technology outcomes is difficult because  of the hardware and software developments that occur, as  well as improved treatment delivery from overcoming the  initial learning curve. For this reason, comparison with other  series using transrectal HIFU and other modalities is prob-  lematic, since not all publications make such changes  explicit. The impact of these changes, as well as the intro-  duction of rectal cooling, is evident by a reduction in the  rectoprostatic fistula rate. It was not always clear, especially  from the HIFU series, whether software modifications  occurred and to what proportion of patients it was applied to.  Using the Sonablate? 500, our own group has demonstrated  that changing power levels in a real-time fashion so as to  visualize gray-scale changes (so-called “Visually directed   70% (sufficient for 0 Stricture (14.6% suprapubic catheter;  penetrative sex) 44% urethral catheter); UTI/dysuria   9, and 12 months: 33.8, mild-moderate debris/dysuria in all  18.1, 39.1, 23.9 and for 4-6 weeks  28.1  IIEF decreased from 16 0.6 Urethral stricture (1596)  to 12  1796 (of 34 "sexually 2 All had transitory (2 months) frequency,  active” prior to urgency, difficulty urination;  treatment) Stricture 24%  13% (“erectile 1 TURP 0.5%; stricture 22%;  dysfunction") epididymitis 6%  55.3% (erectile function 0 Bladder neck stricture/necrotic tissue  sufficient for (requiring surgery) 24.5%; UTI  intercourse) (7.8%); pelvic pain (3.7%)  Not reported Not reported Not reported  53% 0.6 Most had transient urgency and  frequency; UTI 4%; TURP/bladder  neck incision 11.7%; perineal  discomfort 1.4%   39% 0 Stricture 12%; UTI 2%;  hematuria 0.5%; perineal pain 3%;  urgency 5%   32% 0 Acute urinary retention 6%; urinary  infection 10%; Transient hematuria  66%; transient urgency 50%    HIFU”) within each focal-treatment zone leads to signifi-  cantly lower PSA levels postoperatively in the primary set-  ting.^ This was the first attempt at standardizing HIFU  treatment.   Another difficulty in comparing HIFU with other treat-  ments for localized prostate cancer is best illustrated by  examining the demographic features of published trials.    Most HIFU reports include patients in their late seventies  and mid-eighties, as the technology was initially used on  men who were not suitable for other radical therapies. Such  heterogeneity makes the interpretation of disease-free sur-  vival and overall survival between studies difficult. This  group may benefit least from treatment and suffer a greater  amount of morbidity from ablative techniques.    Fig. 16.8 (a) Pretreatment dynamic gadolinium contrast enhanced  axial MRI demonstrating a malignant lesion in left upper quadrant of  prostate at the midgland. (b) Post-HIFU (Sonablate 500) dynamic con-  trast enhanced axial MRI at the same level demonstrating entire pros-    Fig. 16.9 Post-HIFU (Sonablate 500) dynamic contrast enhanced MRI  in a different patient demonstrating viable tissue in the anterior region  of the prostate as demonstrated by enhancement. Residual prostate can-  cer and a PSA 30.5 ng/mL was demonstrated at 6 months    Men who have external beam radiation therapy (EBRT) or  interstitial brachytherapy for clinically localized PCa have a  20-30% chance of experiencing biochemical failure defined    tate lacking blood supply (dark area). The catheter is seen. No residual  cancer or prostate tissue was seen at 6 month biopsies, with an unre-  cordable PSA demonstrated at follow-up    by ASTRO criteria.” Salvage therapy using prostatectomy,  cryosurgery, brachytherapy, and HIFU have been applied in  the salvage setting for this group of men, provided that stag-  ing investigations demonstrate localized disease." The suc-  cess rates following salvage procedures are considerably  lower than those that have been reported following primary  treatments.*' Patients experiencing biochemical recurrence  following radical EBRT may have either a local recurrence  or a metastatic disease, or both. Patients thought to have a  localized recurrence after EBRT have historically been  offered radical prostatectomy, androgen ablation therapy, or  observation. These therapies are not without significant side  effects, so other modalities such as cryotherapy and bra-  cyhtherapy have recently been investigated in this setting.  Surgery, brachytherapy, and cryotherapy have a cancer-  control (estimated 5-years biochemical disease-free status  rate) of 31-83%, 20-89%, and 18-74% (one series at 5-years  and other series at 1—2 years), respectively. However, the  average fistula rates were 4.7, 3.4, and 2.5%, respectively.  Incontinence rates varied with modality and were 17-67%,  0-31%, and 4.3-96%, respectively.”   The use of salvage HIFU has been reported in a number  of series using both the Ablatherm® and Sonablate 500  devices. Gelet et al demonstrated good early results in 71  men, with negative biopsy rates as high as 80 and 61%,  achieving a PSA nadir of <0.5 ng/mL. Forty-four percent  were reported as free of biochemical relapse at last review  (mean, 14.8 months follow-up [range 6-86]).*° In this same  series, the rate of rectourethral fistula was 6%, with 7% suf-  fering urinary incontinence requiring pads and 17%    developing a bladder neck stenosis. In the latest update to  their series, this group has now reported on 167 patients  treated with 194 HIFU sessions with a mean of 18.1 months  follow-up (range 3-121). Bladder outlet obstruction occurred  in 2096 with 7.896 overall going into urinary retention within  3 months due to stricture or necrotic tissue. Overall, 49.596  developed urinary incontinence with grade 1, 2, and 3 in 18,  22, and 9.5%, respectively. Worryingly, 11% required artifi-  cial urinary-sphincter implantation. Such an outcome may be  explained using a bladder neck incision in all men prior to  HIFU, although this is uncertain. Fecal incontinence occurred  in 1.2%, while 3% developed a fistula. The mean PSA nadir  was 2.38 (+6.22 ng/mL) (median PSA nadir 0.19 ng/mL).  Local cancer control was achieved in 73% as demonstrated  by negative biopsies. Thirty-one percent had biochemical  relapse but had negative biopsies. Seventeen patients devel-  oped metastatic disease; 11 of these patients died of prostate  cancer.” Challacombe et al report on a small series of 12  patients who underwent salvage HIFU using the Ablatherm  device. Incontinence requiring pad usage was reported by  two patients (16.7%) with one requiring an artificial urinary  sphincter. One patient (8.3%) developed a urethral stricture,  and worryingly, two men (16.7%) developed a rectourethral  fistula. Forty-two percent of patients failed treatment after a  mean of 22 (+SD 5.9) months using the ASTRO-Phoenix cri-  teria, but 67% achieved a PSA of «0.5 ng/mL. In our own  series, we have treated 31 men using the Sonablate 500 with  a mean follow-up of 7.4 months (range 3-24). Side effects  included stricture or intervention for necrotic tissue in 11  men (36%), urinary tract infection or dysuria syndrome in 8  (2696), and urinary incontinence in 2 (796). The high stric-  ture rate is probably explained by the avoidance of a bladder  neck incision or TURP prior to HIFU. Rectourethral fistula  occurred in two men, although one was due to patient move-  ment as a result of inadequate anesthesia, so the true rate is  probably closer to 3%. One half the patients had PSA levels  of «0.2 ng/mL at last follow-up. Three had metastatic dis-  ease, while another two had local, histologically confirmed  failure. A further four had evidence of biochemical failure  only. Overall, 71% had no evidence of disease following sal-  vage HIFU." These series demonstrate the problem with  accurate staging as current staging modalities cannot detect  micrometastatic disease at the time of recurrence.   In the setting of salvage therapy for failed high-dose rate  radiotherapy and where low-dose brachytherapy has been  used in addition to external beam radiotherapy, we have  shown that the risk of fistula formation is significant, affect-  ing three of five men treated with salvage HIFU.* It may be  that using transperineal biopsies to ascertain local histology  rather than transrectal biopsies may aid in reducing the rectal  damage that can occur. In addition, a focal salvage approach  in which just the areas of cancer are treated to reduce the  energy deposition within the compromised rectal mucosa    may also help to reduce the morbidity with any salvage  procedure.   Although salvage HIFU is able to significantly lower the  PSA in men who have previously undergone radiotherapy  for organ-confined prostate cancer, it carries significant side  effects. Clearly, longer-term follow-up and prospective mul-  ticenter randomized controlled trials are required to assess  whether these encouraging results are truly equivalent to  other salvage treatments such as surgery, brachytherapy, and  cryosurgery. The difficulty in accurately staging recurrent  disease to exclude metastatic disease is still problematic, and  such large trials will require strict inclusion criteria to mini-  mize this difficulty.    Efforts to reduce such morbidity from treatment of localized  prostate cancer have mainly centered on the refinement of  surgery (laparoscopic and robotic prostatectomy) or radio-  therapy (intensity modulation and conformal) so as to restrict  damage to surrounding structures. However, as the premise  of radical therapy has not changed, the success of such modi-  fications in reducing genitourinary toxicity has been  limited.^^^   Focal therapy involves treatment directed only at the can-  cer focus and a margin of tissue surrounding the cancer. ^^?  Most treatment-related side effects are due to injury to the  immediate surroundings of the prostate and not due to treat-  ment of the prostate per se. The surrounding structures can  be described as capsule, pelvic nerves/ganglia, bladder neck,  bladder, seminal vesicles, rhabdo-sphincter, Denonvilliers  fascia, and rectum. Although the profile of treatment-related  toxicities depends on the type of treatment given, they share  a remarkable similarity and can be summarized as follows:  erectile dysfunction, ejaculatory dysfunction, stress-related  urinary incontinence, urge-related urinary incontinence,  reduced functional bladder capacity, urethral or bladder neck  strictures, and bowel dysfunction. In summary, radical radio-  therapy on average causes moderate-to-severe rectoanal tox-  icity and urinary problems in almost one half of patients,  with nearly all suffering minor symptoms. Surgery causes  less damage rectally, but a third suffers chronic urinary  symptoms. On average, both modalities give rise to impo-  tence in about one half of men.*°*!   Since unifocal or unilateral disease is present in up to  30-40% of men who are diagnosed in the PSA-screened era,  it is feasible to attempt focal ablation of just the cancer areas  or hemiablation or one side of the prostate in which unilat-  eral disease is present. The modalities of cryosurgery, HIFU,  photodynamic therapy, and radiofrequency ablation, as well  as brachytherapy, are capable of creating localized focal   To date, only case series carried out in single institutions  have reported on their early results with focal therapy. Onik  et al” first reported their results on hemiablation using cryo-  therapy. These results have recently been updated in 55 men  completing at least 1-year follow-up. Ninety-five percent  (52/55) had stable PSA (as defined by ASTRO criteria) and  of the 51 who were potent prior to the procedure, 44 (86%)  remained potent afterwards. One had a previous TURP and  was incontinent. However, four patients (7%) had to be  retreated due to cancer left in the untreated area. This equates  to the error rate quoted for transperineal template biopsies,  which were used to verify unilateral cancer in this group of  men. Transrectal biopsies by virtue of sampling error are  inherently flawed in detecting all cancer foci. To reinforce  this, data using transperineal template biopsies with sampling  of the prostate at 5 mm intervals shows that just under half of  patients deemed to have unilateral disease by TRUS biopsy  were actually shown to have cancer in both sides.?^* This  cryosurgery series has obvious limitations with the lack of  clear recruitment data, lack of true trial conditions with insti-  tutional review board approval, and poor reporting. Bahn  et al” have recently reported another series in which hemiab-  lation was carried out using cryosurgery. At a mean follow-  up of 70 months, biochemical disease-free status, according  to the ASTRO definition, was maintained by 92.896 of  patients (26/28) and a 96.096 negative-biopsy rate (24/25)  was observed. The one biopsy-positive patient was subse-  quently treated with full-gland cryosurgery and remains dis-  ease free. Potency was maintained by 48.196 of patients  (13/27), and another 40.796 (11/27) were potent with oral  pharmaceutical assistance, yielding a total potency-  preservation rate of 88.996. These results are also encourag-  ing, although in addition to the limitations described for the  study by Onik et al, there is an additional problem. The inves-  tigators used color Doppler-guided TRUS biopsies to verify  unilateral disease as well as posttreatment success. Since this  technique does not carry the necessary accuracy for cancer  detection, significant under-treatment and lack of verification  by using the same diagnostic tool for follow-up biopsies was  a major problem.***’ Another group demonstrated in 60 men,  who underwent focal cryosurgery followed by penile reha-  bilitation with a vacuum device, that 73% of those potent  prior to treatment maintained potency alongside a low incon-  tinence rate of 3.6%. After therapy, 35 patients underwent  biopsy, with 14 showing positive findings (40.0%) at a mean  of 12.0 months posttreatment. Thirteen out of fourteen  patients were actually from the untreated side. This was not  surprising since this group did not report on using any further  evaluation beyond TRUS biopsy to establish the location of  cancer. Lambert et al reported on a small series of 25 who  underwent hemiablation cryosurgery for presumed unilateral    disease, although again this was based on TRUS biopsy at  diagnosis only.^' Of the 24 patients potent prior to hemiabla-  tion cryosurgery, 17 (7196) were potent postoperatively.  There was no rectal toxicity or incontinence. Recognizing  that biochemical failure was difficult to define, this group  used a PSA nadir greater than 5096 of pretreatment levels as  indicative of biochemical disease-free survival, giving rise to  a value of 84%. Only seven patients were eligible for repeat  biopsy using either a PSA nadir of more than 5096 or a PSA  nadir plus 2 ng/mL as determined by the investigators.  Recurrent cancer was detected in three patients, with two  recurrences on the contralateral side and one recurrence on  the ipsilateral side of the cryosurgery. All were retreated suc-  cessfully. Finally, Muto et al report on hemiablation using the  Sonablate® 500 HIFU device.” Twenty-nine patients who  were found to have unilateral disease on the basis of TRUS  biopsy were treated to ablation of both peripheral zones and  one half of the transition zone. Ten percent (3/28) had posi-  tive biopsies at 6 months, whereas 23.596 (4/17) had further  positive biopsies at 12 months. There was no significant  change in the IPSS, but there was one urethral stricture and  one urinary tract infection. Although demonstrating feasibil-  ity of focal therapy using a transrectal HIFU device, the tox-  icity reporting in this series was very poor and the group tried  to make comparison to a nonrandomized group that were  treated with whole-gland HIFU.   This very limited data from uncontrolled case series sug-  gests that treatment-related toxicity could be reduced by  treating malignant areas while preserving a significant  amount of prostate tissue. Equally, the data suggest that it  might be possible to obtain clinically important periods of  remissions from disease progression. Nonetheless, what is  now required is a standardized assessment of a focal therapy  intervention in a well-characterized group of men with a  follow-up regimen under prospective trial conditions. Two  prospective National Cancer Research Network (UK) HIFU  trials using the Sonablate? 500 device, evaluating the role of  hemiablation of unilateral disease and focal ablation of bilat-  eral, low-volume disease verified by template transperineal  prostate biopsies, are being undertaken at our center. At the  time of writing this chapter, interim results have demon-  strated the preservation of genitourinary function in 9596 of  men with residual cancer in the treated areas of approxi-  mately 10%.” A prospective ethically approved trial evaluat-  ing hemiablation cryosurgery using template biopsies to  verify location of disease is also underway in Colorado,  USA, and Duke Cancer Centre, USA.^   Focal therapy in treating organ-confined prostate cancer  proposes a radical paradigm shift in our current thinking.  Questions about whether such a treatment is ethical have  now given way to questions about how best to localize dis-  ease, which modality is most efficacious in ablating discrete  areas of tissue, and how best to define failure and monitor    untreated areas. More exciting is the proposition that if small,  low-grade foci of cancer exist in association with large, high-  grade "index" lesions, do we need to ablate all foci or can we  ablate just the index lesion and obtain cancer control rates  near equivalent to whole-gland treatment in the first 5-10  years of follow-up. If so, it may be possible to “postpone”  the morbidity of whole-gland therapy until later in life to  such a time as when there is progression of disease warrant-  ing further treatment. If there were no recurrence or disease  progression, then this postponement could be indefinite.    Until controlled comparative trials are carried out, it will be  difficult to determine whether HIFU or any of the compet-  ing devices delivering these energies is the optimal treat-  ment. It is therefore an opportune time to begin a debate on  standardizing the reporting of such series to allow compari-  son, and think about long-term prospective data collection,  since randomized controlled trials are difficult to recruit in  such settings. HIFU for the treatment of prostate cancer  has the desired short- to medium-term biochemical and his-  tological outcomes combined with a reduction in health-  care and toxicity burden that would justify its further  evaluation as a treatment for localized prostate cancer. The  recent National Institute for Clinical Excellence (NICE)  prostate cancer guidelines in the UK? have recommended  that HIFU as well as cryotherapy be limited to clinical tri-  als, although their latest recommendation for implementing  the guidelines has accepted that registry data should be  viewed as having equivalence to long-term prospective tri-  als. This clearly must have the added proviso that all patients  treated at a center are entered into the registry and data  recorded in a prospective fashion at each follow-up to pre-  vent selection bias.“The role of focal therapy as a future  management strategy for men with early prostate cancer  could represent a tremendous change that will ultimately  benefit patients by delivering cancer treatment with a very  low risk of sideeffects.    Hashim Uddin Ahmed and Mark Emberton receive funding  from the Medical Research Council, Pelican Cancer  Foundation, The Prostate Research Campaign, UK, and  Prostate Cancer Research Centre, UK, for work in focal ther-  apy of prostate cancer. In addition, Mark Emberton receives  funding and is a consultant for Negma Lerads, France (man-  ufacturers of TOOKAD, a photodynamic agent used in    prostate cancer therapy), and Misonix/Focus Surgery/  UKHIFU (manufacturers and distributors of the Sonablate?  500 HIFU device). Mark Emberton and Hashim Ahmed are  approved proctors for training other surgeons in the use of  the Sonablate 500 machine and have received fees for this  activity.    1. Bill-Axelsen A, Holmberg L, Mirrja Ruuth, et al. Watchful waiting  and prostate cancer. NEJM. 2005;352:1977-1984  2. Sanghvi NT, Foster RS, Bihrle R, et al Noninvasive surgery of pros-  tate tissue by high intensity focused ultrasound: an updated report.  Eur J Ultrasound. 1999;9(1):19-29  3. Hill CR, ter Haar GR. Review article: high intensity focused ultra-  sound-potential for cancer treatment. Br J Radiol. 1995;68(816):  1296-1303  4. Kennedy JE. High-intensity focused ultrasound in the treatment of  solid tumours. Nat Rev Cancer. 2005;5(4):321—327  5. Haar GT, Coussios C. High intensity focused ultrasound: physical  principles and devices. Int J Hyperthermia. 2007;23(2):89—104  6. O’Leary MP. 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In: European Association of Urology,  Annual Meeting; 2009:Abstract 863   Gelet A, Chapelon JY, Poissonnier L, et al Local recurrence of pros-  tate cancer after external beam radiotherapy: early experience of  salvage therapy using high-intensity focused ultrasonography.  Urology. 2004,63(4):625—629   Kirkham AP, Emberton M, Hoh IM, Illing RO, Freeman AA, Allen  C. MR imaging of prostate after treatment with high-intensity  focused ultrasound. Radiology. 2008;246(3):833-844   Rouviére O, Lyonnet D, Raudrant A, et al MRI appearance of pros-  tate following transrectal HIFU ablation of localized cancer. Eur  Urol. 2001;40(3):265-274   Ganzer R, Rogenhofer S, Walter B, et al PSA nadir is a significant  predictor of treatment failure after high-intensity focussed ultra-  sound (HIFU) treatment of localised prostate cancer. Eur Urol.  2008;53(3):547—553   American Society for Therapeutic Radiology and Oncology  Consensus Panel. Consensus statement: guidelines for PSA follow-  ing radiation therapy. In J Radiat. 1997;37:1035—1041   Roach M III, Hanks G, Thames H Jr, et al Defining biochemical  failure following radiotherapy with or without hormonal therapy in  men with clinically localized prostate cancer: recommendations of  the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat  Oncol Biol Phys. 2006;65(4):965-974   Illing RO, Leslie TA, Kennedy JE, Calleary JG, Ogden CW,  Emberton M. Visually directed HIFU for organ confined prostate  cancer — a proposed standard for the conduct of therapy. BJU Int.  2006;98(6):1187—1192    Shipley WU, Thames HD, Sandler HM, et al Radiation therapy for  clinically localized prostate cancer: a multiinstitutional pooled  analysis. JAMA. 1999;281:1598-1604   Zelefsky MJ, Kuban DA, Levy LB, et al Multi-institutional analysis  of long-term outcome for stages T1-T2 prostate cancer treated with  permanent seed implantation. Int J Radiat Oncol Biol Phys.  2007;67:327-333   Pollack A, Hanlon AL, Horwitz EM, et al Prostate cancer radio-  therapy dose response: an update of the fox chase experience.  J Urol. 2004;171:1132-1136   Touma NJ, Izawa JI, Chin JL. Current status of local salvage thera-  pies following radiation failure for prostate cancer. J Urol. 2005;  173(2):373-379   Nguyen PL, D’Amico AV, Lee AK, Warren Suh W. Patient selec-  tion, cancer control, and complications after salvage local therapy  for postradiation prostate-specific antigen failure: a systematic  review of the literature. Cancer. 2007;110:1417—1423   Nguyen PL, D’Amico AV, Lee AK, Suh WW. Patient selection,  cancer control, and complications after salvage local therapy for  postradiation prostate-specific antigen failure: a systematic review  of the literature. Cancer. 2007;110(7):1417—1428   Murat FJ, Poissonnier L, Rabilloud M, et al Mid-term results dem-  onstrate salvage high-intensity focused ultrasound (HIFU) as an  effective and acceptably morbid salvage treatment option for locally  radiorecurrent prostate cancer. Eur Urol. 2009;55:640-647  Zacharakis E, Ahmed HU, Ishaq A, et al The feasibility and safety  of high-intensity focused ultrasound as salvage therapy for recur-  rent prostate cancer following external beam radiotherapy. BJU Int.  2008; 102(7):786-792   Ahmed HU, Ishaq A, Zacharakis E, et al Rectal fistulae after sal-  vage high-intensity focused ultrasound for recurrent prostate cancer  after combined brachytherapy and external beam radiotherapy. BJU  Int. 2009;103:32 1-323   Hegarty NJ, Kaouk JH. Radical prostatectomy: a comparison of  open, laparoscopic and robot-assisted laparoscopic techniques. Can  J Urol. 2006;13(suppl 1):56-61   Khoo VS. Radiotherapeutic techniques for prostate cancer, dose  escalation and brachytherapy. Clin Oncol (R Coll Radiol).  2005;17(7):560-571   Ahmed HU, Pendse D, Illing R, Allen C, van der Meulen JH,  Emberton M. Will focal therapy become a standard of care for men  with localized prostate cancer? Nat Clin Pract Oncol.  2007;4(1 1):632-642   Eggener SE, Scardino PT, Carroll PR, et al International Task  Force on Prostate Cancer and the Focal Lesion Paradigm. Focal  therapy for localized prostate cancer: a critical appraisal of ratio-  nale and modalities. J Urol. 2007;178(6):2260—2267   Nilsson S, Norlen BJ, Widmark A. A systematic overview of radia-  tion therapy effects in prostate cancer. Acta Oncol. 2004;43(4):  316-381   Meraney AM, Haese A, Palisaar J, et al Surgical management of  prostate cancer: advances based on a rational approach to the data.  Eur J Cancer. 2005;41(6):888—907   Barqawi A, Crawford ED. Focal therapy in prostate cancer: future  trends. BJU Int. 2005;95:273-280   Onik G, Narayan P, Vaughan D, Dineen M, Brunelle R. Focal  “nerve-sparing” cryosurgery for treatment of primary prostate can-  cer: a new approach to preserving potency. Urology. 2002;60:  109-114   Onik G, Vaughan D, Lotenfoe R, Dineen M, Brady J. “Male  lumpectomy”: focal therapy for prostate cancer using cryoablation.  Urology. 2007;70(6 suppl): 16-21   Ahmed HU, Stevens D, Barbouti O, et al Prostate cancer risk strati-  fication and cancer mapping — template transperineal prostate map-  ping biopsies. In: European Association of Urology Annual Meeting;  2008    Barqawi A, Lugg J, Wilson S, Kim F, Crawford ED. The role of  3dimensional systematic mapping biopsy of the prostate in men  presenting with apparent low risk disease based on extended tran-  srectal biopsy. In: AUA Annual Meeting, Orlando; 2008   Bahn DK, Silverman P, Lee F Sr, Badalament R, Bahn ED,  Rewcastle JC. Focal prostate cryoablation: initial results show can-  cer control and potency preservation. J Endourol. 2006;20(9):  688—692   Barqawi AB, Lugg JE, Crawford ED. Target focal therapy in early  prostate cancer: initial single institution results. In: ASCO Annual  Meeting; 2007   Donnelly BJ, Saliken JC, Brasher P, Ernst S, Lau H, Trypkov K. A  Randomised controlled trial comparing external beam radiation and  cryoablation in localized prostate cancer. In: American Urological  Association Annual Meeting; 2006:Abstract 1141    Ellis DS, Manny TB Jr, Rewcastle JC. Focal cryosurgery followed  by penile rehabilitation as primary treatment for localized prostate  cancer: initial results. Urology. 2007;70(6 suppl):9-15   Lambert EH, Bolte K, Masson P, Katz AE. Focal cryosurgery:  encouraging health outcomes for unifocal prostate cancer. Urology.  2007;69(6):1117—1120   Muto S, Yoshii T, Saito K, Kamiyama Y, Ide H, Horie S. Focal  therapy with high-intensity-focused ultrasound in the treatment of  localized prostate cancer. Jpn J Clin Oncol. 2008;38(3):192-199  Graham J, Baker M, Macbeth F, Titshall V; Guideline Development  Group. Diagnosis and treatment of prostate cancer: summary of  NICE guidance. BMJ. 2008;336(7644):610-612   National Institute of Clinical Excellence (UK). NICE Prostate  Cancer Management Guidelines, Implementation Advice. http://  www.nice.org.uk/nicemedia/pdf/CG58ImplementationAdvice.doc    The growing field of regenerative medicine seeks to counter-  act injuries in which the body's healing responses fail to  respond with new functional tissue. To date, growth factors  and cytokines have shown some clinical impact, by stimulat-  ing the production of new cells by the body or enhancing  function of the existing cells in the body. Newer modalities,  however, focus on the formation of new functional tissue  substitutes for those lost. Regenerative technology, thus, has  wide applications across multiple-organ systems and indeed  the entire spectrum of disease processes. The restoration of  functional tissue to heart and bone can theoretically provide  treatment of congestive heart failure and osteoporosis. The  formation of functional skin lessens the reliance on local and  free plastic surgical flaps used in reconstruction and skin  grafting. Generating neural tissue can treat disease states  such as spina bifida. The regeneration of pancreatic tissue  can be used to treat diabetes.   Tissue bioengineering represents a radically new field of  study, with significant possibilities for implementation that  could revolutionize the field of urology, most specifically in the  area of reconstructive surgery. Reconstructive surgery is per-  formed by urologists in both pediatric and adult patients for a  variety of conditions. Pediatric urologists perform complex  plastic surgical reconstructions for cases of ambiguous genita-  lia, as well as for cloacal and exstrophy malformations.  Reconstructive urologists conduct a large variety of posttrau-  matic procedures for injuries to the genitourinary tract, both  cosmetic and functional. Neurourologists and uro-oncologists  use bowel segments extensively in bladder augmentation and  neobladder formation, respectively. These procedures are tech-  nically demanding and can be hindered by a limited availability  of local epithelial tissue available for reconstruction. Tissue can  be harvested from other sites in the body, but this is also fraught  with the potential for new complications in distant body sites.   The goal of tissue engineering is the development and  successful implantation of functional biologic substitutes  that can supplement or augment the existing function of an    organ. It usually involves a matrix of some kind, used as a  scaffold on which cells may or be introduced. The cells may  be autologous cells or pluripotent precursor cells.   Human embryonic stem cells have been shown to have  the capability of differentiating into cells from all three  embryonic germ layers, proving them to have true pluripo-  tency. Ectodermal structures, such as skin and neurons 5;  mesodermal structures, such as blood, cardiac cells, and car-  tilage*’*° and endodermal structures, such as pancreatic cells?  have all been formed in vitro. The use of human embryonic  stem cells, however, requires fetal demise and is a hotly con-  tested ethical and political dilemma." Because of this,  researchers are searching for other more ethically neutral  sources of stem cells for use in the study of regenerative  medicine.   Fetal cells have been in clinical use for the last decade.  Umbilical cord blood has stem-cell potential and has been  used both in the treatment of hematological disorders? and  as a source of mesenchymal stem cells. The fetal kidney, spe-  cifically the metanephric mesenchyme, is a potential source  of these stem cells as well? Although hematopoietic cells  have been used clinically, there are still ethical consider-  ations regarding the actual transplantation of fetal tissue.’  Progress in these fields is limited by the extensive debate  between various political groups. Autologous amniotic fluid  stem cells are also under investigation as another source of  ethically neutral pluripotent progenitor cells.“   Efforts are currently underway to engineer tissue from  every cell type of the genitourinary system that a biological  substitute for use in reconstructive surgical procedures may  be developed. Artificial kidney, ureter, bladder, urethra, and  skin, once successfully engineered, could be used in the  maintenance, restoration, and improvement of tissue func-  tion, all without utilizing tissue from a distant site or separate  organ system. Tissue bioengineering may provide a novel  source of autologous biocompatible tissues for use in recon-  structive urologic procedures. In this chapter, we will inves-  tigate current advances in tissue bioengineering on an  organ-by-organ basis.    Historically, renal failure was invariably fatal. With the  advent of hemodialysis and transplantation, mortality has  been seen to decrease substantially in these populations.  These methods have proved indispensable to the manage-  ment of patients with end-stage renal disease. Renal trans-  plantation is the gold standard of therapy, with dialysis as a  bridge to donor kidney availability. Even so, these are not  flawless treatments.   Both dialysis and transplantation carry their own unique  morbidities, ranging from effect on lifestyle and problem-  atic vascular access to donor shortage and graft rejection.  Both interventions are costly, with dialysis patients costing  more than $50,000 per year and posttransplantation patients  costing $17,000 per year. Research is continually directed  at the restoration of renal function by alternative  approaches.   More advanced forms of hemodialysis show promise in  decreasing mortality of patients with renal failure, even those  on dialysis. A renal assist device is an extracorporeal circuit  that seeks to recreate the actual anatomy of the nephron,  using human renal proximal tubule cells. Although shown to  potentially limit mortality, the renal assist device is still  subject to the morbidity of being and externalized dialysis  unit with vascular access required. Bioartificial kidneys,  which in theory could be implanted and perform continuous  dialysis, would be advantageous in limiting the impact on  patient lifestyle accorded by hemodialysis. Such a device is  largely dependent on technological advancement, and though  nanoengineered filtration membranes have been produced, ?  feasible application into a portable transplantable unit is still  distant.   Tissue engineering provides a cutting edge alternative to  artificial approximation of renal function. The isolation,  expansion, and implantation of cells have potential in the  development of functional kidney units grown extracorpore-  ally. Renal bioengineering is especially challenging given  the multiple functions of the kidney and the intricacy of its  structure. Cell transplantation and kidney-cell expansion has  been proposed as a method of augmenting or supplementing  renal-cell function in impaired kidneys. A possible strategy  involves the extraction (via biopsy) of renal cells from an  affected kidney, growth of these cells in culture, seeding of  the cells onto a scaffold, and subsequent implantation of the  scaffold back into the original patient.   In ^5, Atala et al showed in vivo renal-cell growth and  nephron organization after extracorporeal attachment to such  a biodegradable polymer scaffold. It was later shown that  even single cells could redevelop into tubular structures once  seeded.” Subsequently, functional kidney structures were  seen to actually secrete a urine-like fluid, indicating that    tissue-engineered units, once implanted, actually have the  ability to excrete solutes in a similar fashion to normal kid-  ney tissue.” Histologically, vascular structures, glomeruli,  and tubules are seen. More recently, three-dimensional cul-  ture systems that promote adhesion of expanded cells to one  another as opposed to the culture dish have been utilized.  This allows for generation of more three-dimensional tissue  units.) Expanded primary renal cells, when placed in such a  system, began to develop into structures that looked like  tubules and glomeruli and stained positively for Tamm-  Horsfall protein, which is normally expressed in the thick  ascending limb of the loop of Henle, as well as the distal  convoluted tubules.”   Extensive research has gone into the nature of the scaf-  fold. An acellular collagen-based kidney matrix has proven  to be a good frame to which renal cells can adhere and  develop into tubules.’ This is a naturally derived lattice that  has potential in being the basis for renal augments in the  future. Modifications have been made to the scaffold to fur-  ther enhance survival of engineered tissue, such as incorpo-  ration of  calcium-peroxide-based oxygen-generating  particles.“ This proved protective to cells when incubated  under hypoxic conditions and may have import in the gen-  eration of larger implants, which are hindered in their growth  by oxygen diffusion limits.   Cell-based approaches have shown promise, both in vitro  and in vivo, but the clinical application of this technology is  still relatively far away. Current questions address the devel-  opment of a sizeable enough mass of tissue to functionally  augment the kidney, as well as the successful integration of  said mass into the patient, establishing circulatory and excre-  tory continuity. Ultimately, perhaps, tissue-engineered kid-  neys will be transplanted routinely into patients, obviating  both the need to await availability of a donor kidney and the  need for lifelong immunosuppression, as well as limiting the  phenomenon of graft rejection.    The bladder can be affected by many disorders that occur  across a wide age range. Pediatric patients born with menin-  gomyelocele can be affected with neurogenic bladder of  varying degrees of severity. The typical low-volume, low-  compliance bladder seen in patients with spina bifida carries  with it the risk of transmission of higher storage pressures to  the upper tracts. It was for good reason that this population  served as the index population in describing the role of blad-  der augmentation.*’ At the other end of the age spectrum are  patients with bladder cancer, whose bladders are removed  secondary to a disease process. Whatever the etiology, the  end result is the same. Patients with bladder deficiency, with   The bladder differs from the kidney in that its functions  are more limited and defined. It is not nearly as complex, as  vital to life, or as intricate in its composition as the kidney.  The bladder is primarily a storage organ. If its contractile  function is absent or diminished, urine can still be cleared  from the body by intermittent catheterization. If catheteriza-  tion is viewed as an acceptable adjunct to urinary storage  from a lifestyle perspective, then defunctionalized bladder  needs to be able to accommodate an appropriate volume of  urine as well as maintain that urine at a low enough pressure  to prevent deleterious transmission of pressure to the upper  tracts.   Currently, bladder augmentation and substitution is per-  formed using intestinal segments, most commonly ileum and  colon. Many different types of reconstructions have been  described. On one end of the operative spectrum are basic  bladder augmentations, whereas at the other extreme lie  complex continent nonrefluxing orthotopic urinary diver-  sions, such as the T-pouch.*’ Although highly effective and  technically impressive, such diversions are accompanied by  their own specific constellation of complications, including  but not limited to metabolic disturbances, ^ diminished bone  health,? and stone formation.? Because of this, research  continues to discover new ways to augment or replace blad-  der that avoid the manipulation of bowel.   The concept of seeding a scaffold with cells, as mentioned  previously, can be found at the center of bladder engineering.  The basic idea is that the matrix serves as the lattice on which  the cells can grow and differentiate; as this occurs, the scaf-  fold itself degrades until all that remains is engineered blad-  der tissue. The important criteria for such a matrix are that it  is acellular, so that the bladder cells are the only true cells in  the graft; that it will degrade to leave only graft behind; and  that it is immunologically inert and will not provoke a host  response against it.   Cell-seeded bladder matrices were first used in dogs.  Autologous cells were grown and applied to matrices, then  implanted into dogs. It was seen that tissue-engineered blad-  der specimens showed a normal capacity to retain urine, nor-  mal compliance, and normal histologic organization.” This  discovery showed for the first time that tissue bioengineering  could conceivably reconstitute a transplantable, immune-  neutral organ that functioned appropriately and stored urine  effectively. This discovery opened the door to clinical trials  of tissue-engineered bladder implantation.   In 2006, Atala et al’ published a report of seven patients  with meningomyelocele between the ages of 4 and 19 years  who were candidates for augmentation cystoplasty. These  patients underwent a bladder biopsy. The specimens were  expanded in tissue culture and seeded onto a dome-shaped,  collagen-based scaffold. Seven weeks after the biopsy, the    scaffolds were implanted onto the existing bladder as an aug-  mentation. Serial urodynamics during follow-up showed  decreased bladder pressures and increased compliance, satis-  fying the requirements of the bladder as a storage organ.  Ongoing clinical trials further investigate the utilization of  tissue-engineered bladders in human subjects. These studies  suggest that tissue-engineered bladders may be a viable  option not only for patients of the future but also for patients  of the present day.    Nonseeded acellular matrix grafts have been implanted in  rats, with regeneration of ureteral wall components, but sub-  sequent efforts to use such grafts in tubularized ureteral  replacement were unsuccessful. Cell-seeded synthetic scaf-  folds, however, have shown promise. Cells were expanded  in vitro and applied to lattices of tubular polyglycolic acid.  After subcutaneous implantation, in vivo layering was noted,  with luminal and muscle layers. Continued research seeks to  establish successful interposition of tubularized tissue-engi-  neered ureteral structures in continuity with the urinary  tract.    The urethra can be compromised by congenital abnormali-  ties, but it is most often the acquired maladies that necessi-  tate urethral surgery. Posttraumatic defects, such as urethral  disruption or urethral stricture formation, can often not be  repaired primarily and may require harvesting of tissue from  distant body sites for successful reconstruction. The use of  local skin flaps has been described, as have graft harvests of  bladder or buccal mucosa”’, but these are still subject to com-  plications. Unwanted intraurethral hair growth can be seen  in the use of epidermal grafts, and all areas can potentially  contract or scar. Additionally, anastomotic sites are at risk  for stone formation, stricture, or conversely, diverticulum  development.   Animal studies replacing urethral tissue with segments of  acellular collagen-based matrix graft in an onlay fashion  have been described,!! in which the animals were able to  void through their newly constructed urethras. No signs of  voiding dysfunction were readily apparent, and histologic  examination showed wide caliber urethras with normal  appearing tissue with a confluent transitional cell layer con-  firmed by immunohistochemistry. This approach was subse-  quently applied in human subjects with hypospadias or  urethra stricture disease as the impetus for reconstructive    surgery. In addition, anastomosing the acellular matrix in an  onlay fashion, good results were seen in 34 of 40 patients,  with increased flow rate and good caliber urethras. Six of the  40 patients redeveloped urethral stricture. The advantage of  the use of such a matrix is that it does not have to be  implanted with host cells and can be packaged and distrib-  uted for immediate “off-the-shelf” use, obviating the need  for graft harvest and excess morbidity. Acellular matrix  grafts are effective for shorter length strictures less than 0.5  cm long."   Acellular matrices are only able to successfully replace  urethra if anastomosed in an onlay fashion. Attempts at tubu-  larized repair using acellular matrices proved unsuccessful,  with development of recurrent strictures and contracture of  the grafts.? If tubularized segments of urethra are needed,  cell-seeded matrices tend toward more promising results.'*  As shown in animal studies, the tubularized matrices, when  seeded with autologous bladder epithelial and smooth mus-  cle cells, develop into strictureless urethras of normal cali-  ber, whereas acellular matrices uniformly result in collapsed  urethral sections with stricture development. The implication  of this study is that by using autologous cell-seeded tubular-  ized collage scaffolds, the potential for replacement of part  or all of the penile urethra exists, without the added morbid-  ity of graft harvest at the time of surgery. Clearly, the poten-  tial impact on the urethral or reconstructive urologist is  tremendous, as patients requiring urethroplasty represent a  population that can become frustrated by continuing urinary  difficulties and a relatively high incidence of complications.  Human studies are required to assess the practical feasibility  of tissue engineering of the male urethra.    The application of reconstructive surgery in the case of the  penis is largely related to erectile dysfunction. The corporal  tissue has lost its erectile function, and the main conceptual  goals remain the same: either augment existing corporal  function or introduce a substitute for it. Currently, these two  arms of therapy are approximated by both medical and surgi-  cal management. Early medical management with intracav-  ernosal papaverine and intraurethral alprostadil showed  reasonably good results, but it was the FDA approval of  sildenafil in 1998 that established a new therapy to reestab-  lish function in corporal tissue.”   In cases refractive to medical therapy, implantable devices  are used as substitutes for languishing corpora. Penile pros-  theses have been in use for decades since being described?  and have been composed of various materials. Semirigid  devices maintain the penis at a constant level of tumescence,  while inflatable implants can be filled to order by siphoning    fluid from an implanted reservoir using a pump placed in the  scrotum.” Although highly effective, complications can arise  by virtue of the alien nature of the implant itself, which is  continually subject to infection, with early or delayed pre-  sentation. Tissue engineering attempts to sidestep these  potential complications by utilizing and implant that is either  immunologically inert or of autologous origin.   Similar cell-seeding techniques to those described previ-  ously have been attempted using culture-expanded corporal  smooth muscle cells applied to biodegradable polyglycolic  acid polymers. After in vivo implantation, corporal cells  could be visible grossly and histologically, indicating the  potential for cultivation of tissue-engineered corpora."  Acellular nerve grafts have been implanted in rodents with  transected cavernous nerves with more rapid return of erec-  tile function." This represents a potential “off-the-shelf”  product that could theoretically be used at the time of deep  pelvic surgeries with higher risk of disruption of the neural  input to the corpora, most notably radical prostatectomy. By  approaching the corpora as defunctionalized units in need of  augmentation of function, tissue-engineered erectile tissue  may provide a means of recovery of function.   If a substitutive effect analogous to a semirigid prosthesis  is desired, studies have described the novel formation of car-  tilaginous rods by seeding chondrocytes on cylindrical scaf-  folds. The seeded cylinders were implanted in vivo. On  retrieval, it was seen that the scaffold had biodegraded to  leave behind a milky white rod of cartilaginous tissue. The  maintenance of the approximate size and shape of the cylin-  der was an indication that the development of a possible  prosthesis was to some extent customizable, and the rigid  elasticity and strength of the rod itself suggested that it may  have utility, at least theoretically, as an implantable semirigid  prosthesis. Human trials are pending, but given these  advancements, it seems that tissue engineering with doubt-  less play some part in the surgical management of erectile  dysfunction.    The main function of the testis is the production of andro-  gens, in particular testosterone, which in turn have many  effects on male development, muscle, bone, and sexual func-  tion. Testicular dysfunction can arise in various congenital or  acquired conditions ranging from Klinefelter’s disease to  bilateral mump orchitis. In patients thus rendered function-  ally anorchic, lifelong androgen requirement therapy may be  required to maintain physiological levels of testosterone and  avoid adverse impacts on growth and sexuality.   Androgen replacement can be performed in various ways,  all with benefits and hindrances. Oral testosterone must be    taken in large amounts to overcome a "first pass" effect  whereby a large percent of the dose is rendered metaboli-  cally inactive in the liver. Such large doses can actually be  hepatotoxic.” When administered in a parenteral depot prep-  aration, usually every 3 weeks, testosterone levels are usu-  ally initially very high for the first few days only to bottom  out by 21 days, a fluctuation that shies away from the typical  diurnal pattern of testosterone release. This fluctuation can  result in disturbances in mood and libido. Transdermal  therapy via testosterone patches can deliver measured doses  but are associated with adverse cutaneous side effects at the  area of application, such as pruritis, induration, rash, and  necrosis of the skin.”   One basic approach toward restoration of testicular func-  tion in males is the transplantation of Leydig cells (intersti-  tial cells) from a donor into the anorchic male. Leydig cells  are the source of 9596 of testosterone in men; the rationale is  to introduce functional Leydig cells into an affected male to  reestablish the integrity of his hypothalamic-pituitary-  gonadal axis. Cell transplantation is limited by rejection of  the foreign cells by the host's immune system. Currently,  studies are focusing on immunoprotection of the transplanted  cells via encapsulation in a protective semipermeable mem-  brane that is biologically compatible with the recipient."  Encapsulation and subsequent implantation of Leydig cells  could conceivably create a transplantable unit that mirrors  the hormonal function of the testis and thus mirrors its diur-  nal secretory pattern in response to signals from the pituitary.  In theory, this is a more natural release of testosterone, with-  out dose adjustments or potential for injury to internal organs  or skin.   In a study by Machluf et al in 2003, approximately 1096  of normal adult rat Leydig cell population was encapsulated  in alginate microspheres and injected both subcutaneously  and intraperitoneally in castrated rats. They produced serum  testosterone levels of up to 4096 of normal, with the subcuta-  neous implants producing testosterone for a longer time  period.” This study shows the potential that exists in creat-  ing an encapsulated Leydig cell implant for in vivo testoster-  one replacement that approximates normal physiologic  release.   Another approach involves the creation of a testicular  prosthesis that is capable of eluting testosterone. Testicular-  shaped prostheses with a hollow center, made of tissue-  engineered chondrocytes, were created in a bioreactor and  then filled with 100 ug of testosterone enanthate and both  maintained in culture and implanted into athymic mice.  Eluted testosterone levels were physiologic for 40 weeks and  were calculated as being 60% of the injected volume.* Such  a prosthesis could have a role in patients who require both  prostheses and chronic hormone supplementation; though  such a prosthesis would require periodic reinjections of a  new testosterone load into the hollow center of the prosthe-    sis, it could provide a more cosmetic option to injectable tes-  tosterone that decreased the frequency of injection needed.    Vaginal disorders usually stem from congenital malforma-  tions and may be grouped into three broad categories, each  of which dictates appropriate operative intervention. These  three groups comprise the spectrum of vaginal agenesis,  ambiguous genitalia, and imperforate anus and urogenital  sinus variants. The need for vaginal reconstruction is rare  and is a challenging undertaking approached in different  manner by different specialties. Plastic surgeon and gyne-  cologists usually embark on dilatation in conjunction with  skin grafting, whereas pediatric urologists conduct recon-  struction with bowel segments in vaginoplasty.“   The discrepancy in preferred tissue source is not so lim-  ited; the use of many different tissues from multiple discrete  organ systems has been described in animals, including  omentum,” pericardium,” and lyophilized human dura.*! The  use of nonvaginal tissue is to repair the structure, but function  remains an issue that is largely not addressed. Additionally,  unwanted complications dependent on the type of tissue used  can be seen. The primary goal of vaginal reconstruction is the  approximation of anatomic normalcy, with functional nor-  malcy a secondary and largely unaddressed goal. In theory,  the ability to tissue engineer vaginal tissue would provide a  substrate for reconstruction that would not be subject to the  compromise in function as associated with other methods.   There are encouraging initial results with regards to the  use of tissue engineering of vaginal mucosa. Vaginal epithe-  lium and smooth muscle cells, when expanded in tissue cul-  ture and then seeded as mentioned earlier onto synthetic  matrices and implanted into athymic mice, can lead to the  formation of vaginal tissue, with cells replicating and surviv-  ing. By the 6th week following implantation, organization  into distinct epithelial and muscular layers was noted."   Recently, using a rabbit model, cells from a vaginal biopsy  were expanded in vitro and applied to a scaffold, and subse-  quently implanted in vivo as an autologous tissue-engineered  implant. Six months after vaginal replacement, radiographic  studies showed patent vaginas of good caliber with no evi-  dence of stricture. Histologic analysis showed organized epi-  thelial and muscle layers. Physiologic studies showed normal  responses of the neovaginas to electrical stimulation and to  adrenergic agonism.'* This exciting new data suggests that a  tissue-engineered vagina for vaginal reconstruction is a real  possibility in the near future.   It should be noted that this has significant impact in the  management of transgendered patients, specifically male-to-  female transsexuals. This type of surgery in this patient    population is not routinely performed in the general urologic  practice, with such procedures usually limited to specialty  centers. This patient population represents not only a shift in  the indications for vaginal reconstruction but also an increase  in the number of reconstructive procedures that are being  performed today. Currently, ileal segments are often used  in vaginoplasty, and laparoscopic approaches have been  described with good functional results." Bioengineered vag-  inal tissue could represent a significant advancement in the  practice of vaginal reconstruction in this growing popula-  tion, in that it can result in a neovagina composed of normal  epithelium, while obviating the morbidity associate with  graft harvest.    The application of tissue engineering with regard to the  uterus is readily apparent in patients with congenital disor-  ders resulting in a lack of sufficient uterine tissue to repro-  duce, that is, to maintain a growing fetus and then expel it  during labor. Research into the generation of uterine tissue  grown in vitro is still in its infancy. Seeded human myome-  trial cells have been grown on scaffolds that allow them to  adhere to each other rather than only to a culture dish, in  hopes that thicker tissue samples could be grown.^ These  bridging myocytes were tested for tensile strength and con-  tractile activity. Addition of oxytocin produced irregular  contractile activity, which, though not close to the contrac-  tions noted with the pattern of human labor, was significant  for the demonstration of myocytes grown and bridged in tis-  sue culture contracting in a coordinated manner.    Ovarian compromise can be the result of anything that lim-  its the ability of the ovary to produce oocytes capable of  differentiation into viable offspring, be it polycystic ovarian  syndrome, ovarian failure, or sterility. The role of tissue  engineering in these situations is less focused on the genera-  tion of de novo oocytes; instead, methods to apply tissue-  engineering technology to the preservation of existing  immature oocytes have been described. Granulosa cell-  oocyte complexes incorporated into an alginate hydrogel  culture system showed no degeneration and an intact zona  pellucida after 10 days. Approximately 40% of the oocytes  retrieved from in vitro growth were capable of progressing  to meiosis II. These studies could provide breakthroughs in  the preservation of oocytes of women who are at risk for  losing ovarian function, be it through progressive cystic    disease or impending chemotherapy. Further studies have  focused on the incorporation of ligands to the alginate lat-  tice that can affect the behavior and structure of the oocytes  themselves.    The urinary system is one governed by flow dynamics.  Appropriate one-way flow of urine is essential for proper  functioning of the system. Vesicoureteral reflux or backflow  of urine from bladder to ureter represents a malfunction in  the valve-like nature of the ureter as it tunnels through the  bladder wall. Urinary incontinence involves a deficiency in  the resistance to outflow of urine from the bladder. Although  fundamentally different disorders, both can be treated with  injection of bulking agents to limit flow of urine in an unde-  sirable fashion.   Ideal injectable agents are biocompatible and biodegrad-  able. Recently, injection of dextranomer microspheres in a  sodium hyaluronan solution (Deflux) has shown good results  at treating vesicoureteral reflux.“ For cases of urinary incon-  tinence, collagen remains a commonly used bulking agent.**   Autologous chondrocytes have been expanded in tissue  culture, and the resulting solution injected cystoscopically to  correct vesicoureteral reflux in children.'^ Similarly, autolo-  gous chondrocytes have been used in the treatment of stress  incontinence due to intrinsic sphincter deficiency in adults.?  More recently, attempts to inject the rhabdosphincter itself  with myoblasts caused significant strengthening one year  later, with attainment of continence.   Tissue engineering of injectable agents for bulking pur-  poses shows promising practical application, largely because  such usage is not dependent on scaffolding and structuring  the development of a complex organ. Such agents are by  definition nonantigenic and thus avoid the potential for aller-  gic or inflammatory reaction in humans. They additionally  have the potential to maintain their volumes, avoiding the  need for repeat injection as the agent degrades and inconti-  nence returns.    Tissue bioengineering remains on the cutting edge of medi-  cal technology. These processes are of significant impact to  the urologic surgeon, as every organ in the genitourinary  and reproductive system is under investigation. Research is  focused on improving methods of cell culture and in vitro  expansion of cell lines; improvement of polymers for use as  nonantigenic, biodegradable scaffolds for growth and    organization of these cells; and implantation of these seeded  scaffolds to assess tissue differentiation in vivo. Tissue bio-  engineering may provide a means of restoration of lost  function without the need for grafts and with much lower  morbidity. Despite promising data with regard to virtually  all types of urogenital engineering, much remains to be  done before tissue engineering is considered a viable corol-  lary to traditional reconstructive urological surgery. Most  of the advancements in this field have occurred rapidly and  in a relatively short period of time. Continued research is  essential to reach the true possibilities in this area of  study.    . Al-Awqati Q, Oliver JA. Stem cells in the kidney. Kidney Int.    . Amiel GE, Yoo JJ, Atala A. Renal therapy using tissue-engineered    . Annas GJ, Elias S. The politics of transplantation of human fetal    . Assady S, Maor G, Amit M, et al Insulin production by human    . Atala A, Bauer SB, Soker S, Yoo JJ, Retik AB. Tissue-engineered    . Atala A, Retik AB, Schlussel RN. Renal cell growth in vivo after    . Bent AE, Tutrone RT, McLennan MT, Lloyd LK, Kennelly MJ,    Badlani G. 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Surgical excision is widely accepted as the  gold standard for the treatment of a localized renal-cell car-  cinoma. Historically, renal tumors were treated by open-rad-  ical nephrectomy. Since the 1990s, however, laparoscopic  radical nephrectomy has provided equal efficacy in cancer  control with decreased morbidity and a more rapid convales-  cence.^" Although providing excellent cancer control, radi-  cal extirpation also sacrifices many normal nephrons, which  may prove problematic over time. Currently, because of the  widespread use of abdominal imaging, many renal tumors  are small, asymptomatic, and discovered incidentally. Thus,  there is a strong motivation to spare as much renal paren-  chyma as possible while treating these tumors. Surgical exci-  sion via partial nephrectomy spares much of the normal  tissue, yet it still provides excellent rates of cancer control  and long-term survival.? Whether done via an open or, more  recently, laparoscopic approach, partial nephrectomy is still  associated with a hospital stay and several weeks to conva-  lescence. Furthermore, there are risks such as bleeding,  infection, and urine leak, which may lead to considerable  morbidity. Also, renal hilum clamping and ischemia inherent  to the procedure results in nephron injury, although this is  usually temporary and recoverable. Finally, surgical difficul-  ties that may be encountered intraoperatively may lead to  conversion to radical nephrectomy, though infrequent. This  shows that this gold-standard nephron-sparing approach is  not exempt from disadvantages.   Just as open surgical approaches have yielded to less-  invasive laparoscopic approaches, there is a push toward  minimally invasive nephron-sparing treatment modalities as  well. The goals of any such modality include definitive  destruction of the lesion, preservation of normal surrounding  renal parenchyma, and consistent safety with low morbidity.  Thermal therapy, using either radio-frequency ablation  (RFA) or cryoablation, has been widely available in the past    decade. Whether performed laparoscopically or percutane-  ously, these thermal ablative techniques are certainly associ-  ated with little morbidity. However, there have been concerns  regarding cancer control. In 2005, Weld and Landman  reviewed the available literature on RFA and cryotherapy  and compared the results with those from laparoscopic par-  tial nephrectomy.? Their efforts confirmed the lower morbid-  ity of these thermal ablative techniques; however, the  recurrence rates were 7.9 and 4.696 for RFA and cryotherapy,  respectively, compared to only 2.7% for laparoscopic partial  nephrectomy. In a single-institution study by Nguyen et al,  they demonstrated 25 and 7.4% recurrence rates following  RFA and cryotherapy. Furthermore, it has been demon-  strated that biopsies of even nonenhancing lesions following  thermal ablation can still harbor viable cancer cells, thus  challenging our ability to reliably follow patients with imag-  ing after treatment. Lastly, when recurrences do happen, sur-  gical excision is often exceptionally difficult because of  extensive perinephric scarring." Certainly, though each  modality of therapy has its benefits, there is not a consensus  regarding optimal minimally invasive treatment as of yet.  Although still in its relative infancy with regard to its appli-  cation to renal tumors, noninvasive radiosurgical technology  is the latest advancement offered for the treatment of local-  ized renal cancer.    Radiation, when delivered at lower doses, changes tissue at  the cellular level through the induction of breaks in the DNA  and, thus, cellular apoptosis. At high doses, though, radiation  can result in complete ablation of tissue. Traditional external  beam radiation therapy (XRT) focuses high-energy radiation  at a tumor; however, it traditionally subjects the surrounding  normal tissue to its effects, and the margins of treatment are  indistinct. Because of the unacceptable collateral tissue dam-  age, XRT has been unable to safely deliver ablative doses.  Furthermore, XRT must often be delivered in many fraction-  ated doses to protect the skin and surrounding organs in the    path of the radiation beams. In contrast, radiosurgical ther-  apy may deliver a high dose of radiation in very few sessions  (fractions) or potentially only a single fraction.   XRT has been studied in the treatment of locally advanced  renal tumors, and its role was debated. An early report of a  surgeon's experience demonstrated that neoadjuvant XRT  may offer improved survival." Other trials, however, have  failed to demonstrate any increase in survival associated with  XRT in either the neoadjuvant or adjuvant settings. ^ '*   Regardless, complications such as bleeding, radiation  nephritis, duodenal stenosis, liver fibrosis, and even death  resultant from radiation-induced complications have all but  eliminated the use of renal XRT from modern practice. ^"  Still, in a recent study by Beitler et al, patients who had  refused surgical extirpation for localized renal tumors were  offered conformal XRT using a stereotactic body frame.'*  They received a dose of 40 Gy delivered in five fractions  over 15 days with a 1-cm margin around the tumor. With a  median follow-up of 26.7 months, 4 of the 9 patients were  still alive; all survivors had a minimum follow-up of 48  months and tumors less than 3.5 cm in diameter. Two patients  developed nausea and vomiting during the treatment, and  one of these experienced a 30-Ib weight loss over 30 days;  endoscopic biopsy 6 weeks after radiation revealed glandular  atypia in the stomach. The pathologist commented that this  was most likely caused by inflammation and radiation injury,  even though the stomach received no direct irradiation. The  authors concluded that conformal XRT may play a role in the  treatment of small, localized renal tumors. However, many  potential complications of XRT are due to respiratory excur-  sion (the inherent back-and-forth movement of the kidney  associated with the respiratory cycle) that makes precise  delivery of traditional XRT to a lesion a near impossibility.    Stereotactic radiosurgery was first introduced by Lars Leksell  in 1951.” The gamma-knife, a radiosurgical delivery system  created by Leksell, is now used as the standard of care in the  treatment of unresectable or multifocal brain tumors. The  gamma knife system employs an immobilization device to  keep the patient perfectly still while receiving radiation with  pinpoint accuracy. A brain lesion represents a perfect target  for radiosurgery because it is unaffected by respiratory  motion. If untreated, renal-cell carcinoma metastatic to the  brain results in death in only 1-2 months.” Radiosurgical  therapy has been shown to provide excellent local control of  these lesions and may significantly extend survival.*'~* The  study by Brown et al produced a median overall survival of  nearly 18 months after stereotactic radiosurgery for meta-  static brain tumors due to renal-cell carcinoma." These    outcomes support that even the most aggressive and advanced  renal-cell carcinomas respond to radiation therapy.    Application of new radiosurgical technologies such as  Cyberknife (Accuray Inc; Sunnyvale CA), Novalis System  (BrainLab AG; Heimstetten, Germany), and Tomotherapy  (Tomotherapy Inc; Madison, WI) allow frameless stereotac-  tic radiosurgery to now be delivered to “moving” organ tar-  gets, such as the kidney. The Cyberknife (Fig. 18.1), favored  by the authors, contains a lightweight 6-MV linear accelera-  tor mounted to a highly maneuverable robotic manipulator.  The manipulator can position and point the accelerator with  0.3 mm precision. Moreover, highly advanced image guid-  ance allows the radiation beam to follow and “correct” for a  moving target in real time using Synchrony, a tracking and  compensation system. Synchrony uses external markers in  conjunction with diagnostic X-ray images to guide the  robotic arm so that the beam always remains aligned with the  target. With the aid of Synchrony, the tumor motion can be  tracked in three-dimensional space, allowing for precise  treatment. The Cyberknife is also unique in its ability to  deliver ablative-dose radiation with exceptional precision  and little effect on surrounding tissue. This is accomplished  because the high-dose radiation is divided into hundreds of    beams, with each beam yielding a greatly reduced dose that  is essentially benign along its path.” However, at the focal  point, the dose of the beams are additive and eventually  equate to an ablative dose. Finally, because it is mounted on  a robotic arm, the Cyberknife directs its beams from numer-  ous positions nearly circumferentially around the focal point  with near exact precision.   Before any treatment using the Cyberknife, significant  planning must occur. Currently, under an active protocol at  our institution, patients undergo a CT scan followed by  placement of gold image-guidance markers (fIducials) in or  near the tumor using an 18-gauge spinal needle under local  anesthesia. Then, the patients are fitted for custom-made  plastic immobilization devices that fit snugly over the abdo-  men and chest and they undergo another CT scan or MRI.  During this pretreatment period, the scans are transferred to  a computer, and the renal tumor and normal structures (con-  tralateral kidney, spleen, stomach, liver, bowel, and spinal  cord) are each carefully outlined (Fig. 18.2). Finally, the  team of physicists uses the intricate treatment planning soft-  ware to calculate the beam arrangement based on the target  dose assignment and the anatomy of its relationship to dose-  limiting normal structures.    Radiosurgical technology is still in its relative infancy, and  thus, long-term studies are not available. However, short-  term analysis has been promising. Our initial evaluation of  the Cyberknife was published in 2003.” In this study, eight  pigs had each of their kidneys treated at predetermined  sites — each approximately 2 cm in diameter — throughout the  kidneys using a single dose of 24—40 Gy, followed by organ  harvest and histological examination 4-8 weeks later  (Fig. 18.3). The targeted sites were treated with 40 Gy and  evaluated 8 weeks after treatment demonstrated complete  tissue ablation surrounded by a small zone of partial fibrosis;  the remainder of the kidney was unharmed. Furthermore, on  gross inspection at the time of kidney procurement, there  was neither any evidence of perinephric scar nor any gross  radiation injury to the body wall or surrounding organs. This  animal study demonstrated the safety and efficacy of  achieving renal ablation using radiosurgical Cyberknife  technology.   Initial clinical studies using the Cyberknife to treat renal  neoplasms have been promising as well. Following our initial  animal study, a clinical protocol was designed to verify the  safety of renal radiosurgery. Ponsky et al treated three patients  who were good surgical candidates with a mean tumor size of  2.03 cm using a total of 16 Gy divided in four fractions over  2 days. Each patient underwent a CT scan 8 weeks    Fig. 18.2 Preprocedural planning CT. (a) Using the treatment planning  software, the normal organs are outlined so as to direct the beams for  dose-limiting purposes; the left renal tumor and treatment zones are  mapped. (b) The planned beams are directed from multiple angles so as  to limit the dose received by the normal organs in their paths    following treatment and then subsequently underwent either  open or laparoscopic partial nephrectomy. With follow up  ranging from 52 to 62 weeks, no adverse events or acute tox-  icities were noted. After surgical excision, histological exami-  nation in one patient showed a cavity without microscopic  evidence of viable tumor. The other two tumors demonstrated  pathological evidence of renal-cell carcinoma. This trial con-  firmed the safety of renal radiosurgery at a low dose. Based  on the results of the previous animal study, it was suspected  that the low doses used at the initiation of this clinical study  would not likely produce complete ablation of the renal tumor.  The authors, though, will continue to escalate the dose and  monitor patients with regards to safety and tumor ablative    Fig. 18.3 Porcine kidney procured 8 weeks following treatment. The  green arrows point to the cavity where the ablated tissue resided with a  zone of fibrosis beneath. The yellow arrow points to the gold fiducial  next to the zone of fibrosis    effects. Furthermore, this study will look to correlate the post-  treatment CT scan results with the postoperative histology.   Promising work with the Cyberknife is also being done  by Hong et al. Their initial evaluation included fourteen  patients with a mean tumor diameter of 4.1 cm who were  treated with 21 Gy divided in three fractions (7 Gy each)?  Patients were then imaged with CT scans every 3 months  following treatment. Tumor volume decreased by a mean of  9% at 3 months and by 44% at 12 months; and there was not  any progression of tumor in the 12-month follow-up period.  This study illustrates one of the effects of radiation therapy:  as the tumor is replaced by fibrotic scar, it contracts and the  lesion appears smaller. At this point, more investigation is  necessary not only to determine the optimal dose and frac-  tionation of radiation but also to correlate these CT findings  with the probability of complete tumor ablation. Certainly,  pathologic correlation would be ideal.    In the past 15 years, the practice of urology has largely  shifted from open surgery to laparoscopic approaches to sur-  gery. In recent years, minimally invasive ablative therapies  have emerged, and perhaps, they will shift to noninvasive  therapies such as radiosurgery. Certainly, renal radiosurgery  is an early stage of development, but the early results are  exciting. Although renal tumors historically were thought to  have been radiation-resistant, radiosurgery offers the poten-  tial to treat renal tumors more safely and at a higher dose  than traditional XRT. Complete tissue ablation has been  achieved in animals, and the safety of lower dose treatments  is established in humans. In the coming years, research will    focus to determine the optimal dose required for complete  tumor ablation, yet still achieve low morbidity. It will also be  important to determine whether any tumor characteristics  such as size, location, or pathologic subtype will present any  limitations or advantages to treatment. Moreover, ideal fol-  low-up protocols will also require development. In the mean-  time, we will watch with keen interest as tumors in other  abdominal and extra-abdominal organs are treated using  radiosurgical technology. We will study their successes and  failures and apply new technologies in the hope of achieving  the best outcomes possible.    1. American Cancer Society. Cancer Facts and Figures 2008. Atlanta:  American Cancer Society; 2008  2. Chan DY, Cadeddu JA, Jarrett TW, et al Laparoscopic radical neph-  rectomy: cancer control for renal cell carcinoma. J Urol.  2001;166(6):2095—2100  3. Ono Y, Kinukawa T, Hattori R, et al The long-term outcome of lap-  aroscopic radical nephrectomy for small renal cell carcinoma.  J Urol. 2001;165(6):1867—1870  4. Gill IS, Meraney AM, Schweizer DK, et al Laparoscopic radical  nephrectomy in 100 patients: a single center experience from the  United States. Cancer. 2001;92(7):1843-1855  5. Abbou CC, Cicco A, Gasman D, et al Retroperitoneal laparoscopic  versus open radical nephrectomy. J Urol. 1999;161(6):1776-1780  6. Permpongkosol S, Chan DY, Link RE, et al Long-term survival  analysis after laparoscopic radical nephrectomy. J Urol. 2005;  174(4):1222-1225  7. Portis AJ, Yan Y, Landman J, et al Long-term follow-up after lap-  aroscopic radical nephrectomy. J Urol. 2002;168(3):1257-1262  8. Weight CJ, Fergany AF, Gunn PW, et al The impact of minimally  invasive techniques on open partial nephrectomy: a 10-year single  institutional experience. J Urol. 2008;180(1):84—88  9. Weld KJ, Landman J. Comparison of cryoablation, radio-frequency  ablation, and high-intensity focused ultrasound for treating small  renal tomours. BJU Int. 2005;96:1224—1229  10. Ngyen CT, Lane BS, Kaouk JH, et al Surgical salvage of renal cell  carcinoma recurrence after thermal ablative therapy. J Urol. 2008;  180:104—109  11. Richie EW. The place of radiotherapy in the management of paren-  chymal carcinoma. J Urol. 1966;95:313-317  12. Juusela H, Malmio K, Alfthan O, et al Preoperative irradiation in  the treatment of renal adenocarcinoma. Scand J Urol Nephrol.  1977;11(3):277-281  13. Kjaer M, Iversen P, Hvidt V, et al A randomized trial of postopera-  tive radiotherapy versus observation in stage II and III renal adeno-  carcinoma. A study by the Copenhagen Renal Cancer Study Group.  Scand J Urol Nephrol. 1987;21(4):285-289  14. Kjaer M, Frederiksen PL, Engelholm SA. Postoperative radiother-  apy in stage II and III renal adenocarcinoma. A randomized trial by  the Copenhagen Renal Cancer Study Group. Int J Radiat Oncol  Biol Phys. 1987;13(5):665-672  15. Cox CE, Lacy SS, Montgomery WG, et al Renal adenocarcinoma:  a 28 year review with emphasis on rationale and feasibility of pre-  operative radiotherapy. J Urol. 1970;104(1):53-61  16. Kortmann RD, Becker G, Classen J, et al Future strategies in exter-  nal radiation therapy of renal cell carcinoma. Anticancer Res.  1999:19(2C):1601—1603    Cassaday JR. Clinical radiation nephropathy. Int J Radiat Oncol  Biol Phys. 1995;31(5):1249-1256   Beitler JJ, Makara D, Silverman P, et al Definitive, high-dose-per-  fraction, conformal, sterotactic external radiation for renal cell car-  cinoma. Am J Clin Oncol. 2004;27(6):646-648   Leksell L. The stereotaxic method and radiosurgery of the brain.  Acta Chir Scand. 1951;102(4):316-319   Posner JB. Diagnosis and treatment of metastases to the brain. Clin  Bull. 1974;4(2):47-57   Manon R, O’Neill A, Knisely J, et al Phase II trial of radiosurgery  for one to three newly diagnosed brain metastases from renal cell  carcinoma, melanoma, and sarcoma: an eastern Cooperative  Oncology Group Study (E6397). J Clin Oncol. 2005;23:  8870-8876   Chang EL, Selek US, Hassenbusch III SJ, et al Outcome variation  among "radioresistant" brain metastases treated with stereotactic  radiosurgery. Neurosurgery. 2005;56:936—945    Noel G, Valery CA, Boisserie G, et al LINAC radiosurgery for brain  metastasis of renal cell carcinoma. Urol Oncol. 2004;22(1):25-31  Brown PD, Brown CA, Pollock BE, et al Stereotactic radiosurgery  for patients with radioresistant brain metastases. Neurosurgery.  2002;51:656—667   Lunsford LD, Coffey RJ, Cojocaru T, et al Image-guided stereotac-  tic surgery: a 10-year evolutionary experience. Stereotact Funct  Neurosurg. 1990;54—55:375-387   Ponsky LE, Crownover RL, Rosen MJ, et al Initial evaluation of  cyberknife technology for extracorporeal renal tissue ablation.  Urology. 2003;61(3):498—501   Ponsky LE, Mahadevan A, Gill IS, Djemil T, Novick AC. Renal  radiosurgery: initial clinical experience with histological evalua-  tion. Surg Innov. 2007;14(4):265—269   Hong YM, Shanmugham L, La Rosa S, et al Cyberknife radiosurgi-  cal ablation of primary renal tumors [Personal Correspondence —  Presented at World Congress of Endourology]; 2008    The use of a stream of water or saline to dissect between tis-  sue planes during surgery has been applied for a number of  different applications." The technology has evolved, and  hydro-jet generators and delivery probes that provide more  range of pressure control and delivery accuracy have been  developed (ERBE Jet 2, ERBE, Inc., Figs. 19.1 and 19.2).   Previous studies have shown that different effects are seen  at varying pressure levels of hydrodissection. ^"? For fine  vascular preservation during dissection in porcine brain tis-  sue, a pressure setting of ten bar [146 psi (pounds per square  inch)] is optimal." In the canine parotid gland model, nerve  preservation is maintained at a pressure below 40 bar (580  psi).^ Previous human studies have illustrated that pressure  settings in the 225—305 psi (16-21 bar) range can be safely  utilized with nerve and microvascular preservation.^^?   In the field of urology, Shekarriz et al performed pioneer-  ing work using the hydrodissection technique for retroperito-  neal lymph-node dissection, laparoscopic nephrectomy, and  laparoscopic partial nephrectomy (with vascular clamp-  ing).^" Moinzadeh et al performed leading work using  hydrodissection in a calf model for laparoscopic partial  nephrectomy without the need for renal hilar clamping.*   This chapter presents the clinical human application of  the new ERBE™ Jet 2 generator (ERBE, Inc.) with a flexible  tip applicator device for use during robotic-assisted laparo-  scopic procedures. The new flexible applicator tip (Fig. 19.2)  allows the surgeon to insert the probe through the abdominal  wall (via a 14-gauge angiocatheter sheath), to hold the probe  in the fourth robotic arm, that can be molded into angles to  allow for more accurate delivery of the water jet in areas with  limited access (such as the lower pelvis).    The concept behind hydrodissection is that the hydro-jet may  be refined to a pressure setting at which saline dissects around  critical structures such as blood vessels and nerves allowing    potential tissue planes between different structures. This  would then allow these structures to be separated easily with  minimal sharp tissue dissection. Figure 19.3 illustrates this  concept. This provides a tool that can be used in a number of  operative situations as previously mentioned.    Robotic-Assisted Laparoscopic Radical  Prostatectomy with Hemostatic  Hydrodissection of the Neurovascular Bundles    Preservation of continence and potency after robotic-assisted  laparoscopic radical prostatectomy (RALP) are two key out-  comes that patients consider when comparing treatment  options for localized prostate cancer. Ensuring that positive  surgical margins are as low as possible provides oncologic  control. Various techniques to optimize these outcomes have  been employed. The following study presents the early out-  comes for hemostatic hydrodissection of the neurovascular  bundles (HYNEB) during RALP.    A review of 100 consecutive RALP HYNEB cases from  March 2007 to July 2008 (follow up from 1 to 16 months)  was performed. Bilateral HYNEB was performed (in high-  risk patients, wide margins were taken) using the ERBE?  hydrodissector. Outcomes were measured using validated  quality of life measurement tools including the Sexual Health  Inventory for Men preoperatively and postoperatively at  3-month intervals.    The flexible tip hydrodissector was used to lift the lateral  fascia off the prostate, thus separating the neurovascular bun-  dle. A pressure setting of 140 psi (9.7 bar) was used to mini-  mize injury to fine nerves and vessels.*” Direct dissection  within the lateral fascia was not performed to prevent poten-  tial trauma to the fine nerves in this area. The entire lateral  fascia and neurovascular bundle complex was lifted as one  entity. Figures 19.4 and 19.5 illustrate the use of the hydro-  dissector to release the neurovascular bundles.    Overall positive surgical margin rate was 14% (for patho-  logical stage T2 — 11% and stage T3 — 33%). Continence    (defined as using no pads or one pad for safety daily) was  51% at 1 month, 80% at 3 months, and 95% at 6 months.   For the last 50 patients, the positive surgical margin rate  was 8% (for pathological stage T2 — 4.9% and stage T3 —  22%). Continence at | month was 65, 83% at 3 months, and  100% at 6 months. In patients with a preoperative SHIM of  25 (19 patients), 7496 (14 patients) had return of erections  sufficient for intercourse (with or without the use of oral  phosphodiesterase inhibitors) by 6 months postoperatively.  Two of these patients were able to have intercourse 2 weeks  after surgery.    HYNEB may promote the early return of continence and  erectile function without significantly compromising posi-  tive margin rates.    Robotic and laparoscopic partial nephrectomy is a treatment  option for small renal masses («4 cm). During these cases,  clamping of the renal vessels is usually required to minimize  bleeding. This study illustrates the use of hemostatic hydro-  dissection in combination with bipolar and radiofrequency  coagulation during partial nephrectomy to avoid renal vascu-  lar clamping and renal ischemia.    Review of 25 cases from January 2006 to July 2008. Nineteen  patients underwent the procedure without vascular clamping  using hemostatic hydrodissection (Helix HydroJet™) with  bipolar vessel coagulation and radiofrequency coagulation  of the margin (RITA Habib probe™). Postoperative follow-  up ranged from 1 to 30 months (mean of 14 months).    The angled tip hydrodissection probe (Fig. 19.6) or the suc-  tion hydrodissector tip were used for this procedure. The  pressure was set at 300 psi (21 bar) to allow for renal paren-  chymal dissection with preservation of vessels.°'” Initially,  the tumor margins were evaluated using real-time intraoper-  ative ultrasound. These margins were then marked on the  renal capsule using monopolar cautery. The RFA ablator was    then used to coagulate a rim of renal parenchyma 1 cm  beyond the tumor margin. This ablated any large blood ves-  sels traversing this region (Fig. 19.7). The hydrodissector  was then used to dissect through the parenchyma at the edge  of the coagulated rim (Figs. 19.7 and 19.8). Once any remain-  ing small vessels were encountered, these were cauterized  using bipolar cautery and then incised. Using careful dissec-  tion with this technique, the entire tumor with a 1-cm margin  was safely removed without any vascular clamping of the  renal vessels. This allowed the rest of the kidney to be per-  fused during the entire procedure, and there was no renal  warm ischemia. This delicate dissection technique added  approximately 15-20 min to the procedure.    patient age was 58 (range 17—73), mean renal mass size was  2.4 cm (1.1—3.7 cm), mean estimated blood loss was 162 cc    (20—500 cc), and mean operative time was 197 min (105—300  min). All surgical resection margins were negative (tumor  and margins sent for frozen pathology exam intraopera-  tively). One patient had a horseshoe kidney. Ten patients had  a transperitoneal approach, and nine patients had a retroperi-  toneal approach. One patient with a delayed urine leak was  treated conservatively. Postoperatively, all patients’ serum  creatinine remained at baseline. Final surgical pathology was  as follows: nine renal-cell carcinomas, three angiomylipo-  mas, one oncocytoma, fige complex hemorrhagic cysts, and  one nonfunctioning upper pole. No tumor recurrences or  delayed bleeds have occurred thus far. Mean hospital dura-  tion of stay was 3 days (range of 1—6 days).    nephrectomy appears to be a safe technique that avoids renal  vascular clamping and renal ischemia.    The cost of the new hydrodissector device has reduced sig-  nificantly over the last few years. Comparative effectiveness  studies of using the hydrodissector techniques vs. existing    standards would be necessary to assess the cost-benefit ratio.  Further long-term follow-up and assessment would deter-  mine the merit of these techniques.    Hydrodissection technology continues to evolve and new  applications will emerge. We should aim to responsibly  assess and evaluate these techniques in a structured evidence-  based manner.    . Kaduk WM, Stengel B, Pohl A, Nizze H, Gundlach KK. Hydro-jet  cutting: a method for selective surgical dissection of nerve tissue.  Anexperimental study on the sciatic nerve ofrats. J Craniomaxillofac  Surg. 1999;27(5):327-330  2. Kaehler GF, Sold MG, Fischer K, Post S, Enderle M. Selective fluid  cushion in the submucosal layer by water jet: advantage for endo-  scopic mucosal resection. Eur Surg Res. 2007;39(2):93-97  3. Kockerling F, Yildirim C, Rose J, Scheidbach H, Geers P. Total  mesorectal excision with the water-jet-dissection. Technique and  results. Tech Coloproctol. 2004;8(suppl 1):5217-s225  4. Magritz R, Jurk V, Reusche E, Siegert R. Water-jet dissection in  parotid surgery: an experimental study in dogs. Laryngoscope.  2001;111(9):1579-1584  5. Meyer L, Uberruck T, Koch A, Gastinger I. Resection of the spleen  using the Water Jet dissection technique. J Laparoendosc Adv Surg  Tech A. 2004;14(5):321—324  6. Moinzadeh A, Hasan W, Spaliviero M, et al Water jet assisted lap-  aroscopic partial nephrectomy without hilar clamping in the calf  model. J Urol. 2005;174(1):317-321  7. Oertel J, Gaab MR, Knapp A, Essig H, Warzok R, Piek J. Water jet  dissection in neurosurgery: experimental results in the porcine  cadaveric brain. Neurosurgery. 2003;52(1):153-159; discussion  159  8. Shekarriz B. Hydro-Jet technology in urologic surgery. Expert Rev  Med Devices. 2005;2(3):287—291  9. Shekarriz B, Upadhyay J, Jewett MA. Nerve-sparing retroperito-  neal lymphadenectomy using hydro-jet dissection: initial experi-  ence. J Endourol. 2004;18(3):273-276  10. Shekarriz H, Shekarriz B, Burk CG, Kujath P, Bruch HP. Hydro-jet-  assisted pneumonectomy: a new technique in a porcine model.  J Laparoendosc Adv Surg Tech A. 2002;12(5):371-376   11. Shekarriz H, Shekarriz B, Kujath P, et al Hydro-Jet-assisted laparo-  scopic cholecystectomy: a prospective randomized clinical study.  Surgery. 2003;133(6):635—640   12. Shekarriz H, Shekarriz B, Upadhyay J, Burk C, Wood DP Jr, Bruch    Tissue substitutes for reconstructive procedures of the uri-  nary tract are required in a variety of acquired and congenital  pediatric and adult urological diseases. In the era of rapid  growth of tissue engineering and stem cell research and clin-  ical use, the tissue expansion field has fallen behind in the  search for viable substitutes in the urologic field. This chap-  ter shows the research and clinical work on tissue expansion  in the search of urinary tissue employed in urine conduction  and storage.   Among the various self-tissue substitutes such as oral  mucosa, pericardium, or allograft tissues that can be used,  only vascularized intestinal segments have been successful  with regard to the reconstructive surgery of the urinary blad-  der.'? Nevertheless, the use of bowel segments in the urinary  tract reconstruction is associated with significant disadvan-  tages, including metabolic complications, infections, stone  and tumor formation, and a variety of surgical risks associ-  ated with bowel surgery.' These disturbances are exagger-  ated in patients with compromised renal function and  children.   Although it is difficult to assess the total number of surgi-  cal cases performed in the United States, where such tissue  substitute is needed, a study from a single pediatric hospital  reported their experience with almost 500 cases of bladder  augmentation in a 25-year timeframe.^ The potential disad-  vantages of using intestinal segments in urinary tract recon-  struction include metabolic changes, mucus production, high  incidence of early and late surgical complications, and stone/  tumor formation.' In a search for more suitable tissue for  bladder reconstruction, a variety of sources have been already  explored.'?" The majority of these sources are still consid-  ered experimental, lacking any significant long-term clinical  or experimental results.   Chronic tissue expansion is an established concept for  creating new tissue in plastic surgery. The growth of native  skin has been successfully employed in procedures such as  breast reconstruction, craniofacial surgery, and reconstruc-  tive surgery in patients with extensive burns.* The expanded,  new tissue, created by chronic stretch, duplicates the mor-  phologic and functional characteristics of the native tissue.  The literature has been accumulated to explore the involved    mechanisms in response to tissue chronic stretch, and it dem-  onstrates that the mechanisms behind the principle of stretch-  induced cellular growth involve a network of several  integrated cascades that include growth factors;? '* extracel-  lular, cytoskeletal, and transmembrane structures;^ ion  channels;?^" protein kinases;? ^ second messenger sys-  tems; and transcriptional factors.” This network is ini-  tiated by a mechanical stimulus that sets into play a series of  precise reactions through what has been referred to as the    Chronic stretch-induced tissue is accompanied by increased  expression of several growth factors and receptors that may  contribute to cell proliferation and tissue remodeling required  for expansion. In smooth muscle cells, these proteins include  members of the transforming growth factor (TGF), epider-  mal growth factor (EGF), basic fibroblast growth factor  (bFGF), platelet-derived growth factor (PDGF), and nerve  growth factor (NGF) families.?'^ In the bladder smooth mus-  cle cells, mechanical stretch increased the expression of  heparin-binding EGF-like growth factor (HB-EGF) and one  of its receptors, ErbB1, resulting in inhibition of apoptosis."  Tissue expansion also induced production of NGF by urinary  tract smooth muscle cells;'' and lower urinary tract obstruc-  tion induced hypertrophy of bladder afferent and efferent  neurons that appeared to require increased NGF expression."  The latter finding supports the hypothesis that obstruction-  induced tissue expansion induces remodeling of the neural  networks.   Stretch-induced tissue expansion also involves extracel-  lular matrix production, which is required for stretch-induced  cell proliferation.? In vascular smooth muscle cells, mechan-  ical strain-induced fibroblast growth and extracellular matrix  production were accompanied by increased expression of  TGF-B1 and inhibited by a TGF-D1 neutralizing antibody."  Rapid tissue expansion may also injure ureteral tissue more  seriously than slow expansion, with associated ischemia and    inflammation. TGF-B1 may be the main regulating factor for  both the repair process and inflammatory response. We  observed 2—3-fold increases in TGF-D2 expression in por-  cine chronic expanded vs. native ureteral tissues.*!   Chronic tissue expansion has also been shown to induce  angiogenesis, with associated ischemia, which in turn can  stimulate the production of vascular endothelial growth fac-  tor (VEGF)." Ischemia induced by tissue expansion may  also determine the degree of any ensuing fibrosis. In our pre-  liminary study, no change in VEGF expression was observed  in the expanded ureteral tissue.*! It should be noted that all of  the above-cited literature regarding the mechanisms of  stretch-induced tissue remodeling pertains to skin tissue  expansion on cultured cells.    Tissue expansion techniques have also successfully been  used in genitourinary tract tissues in the experimental set-  ting. In 1996, Lailas and colleagues initially reported  chronic ureteral expansion for subsequent open ureterocys-  toplasty in a rabbit model.” Ten rabbits underwent unilateral  ligation at the ureterovesical junction and ipsilateral nephre-  ctomy. A silicone catheter was placed into the proximal ure-  ter and connected to a titanium injection port, which was  placed subcutaneously at the level of costal margin. Two  weeks later, a saline-antibiotic was injected in the port daily,  limited by the pressure in the system. Within 6 weeks, the  ureter was opened longitudinally on the anterior aspect,  reconfigured into a U-shaped patch, anastomosed to the blad-  der, and covered with an omental flap. A suprapubic tube was  placed for 10 days after the procedure. After 6 months, the  animals were euthanized. The cystogram showed a mean  increase of 260% in the bladder capacity. Urodynamic stud-  ies were compatible with a low pressure, high-capacity  bladder.   Ikeguchi and associates? performed chronic segmental  ureteral expansion in pigs. A latex balloon was located in the  distal ureter inserted through the renal parenchyma opened  surgically. A nephrostomy tube was also placed. Daily ure-  teral dilation (150—1,000 mL) was performed with 1—50 cm?  daily over a period of 2-4 weeks, with no anesthesia required.  Subsequently, an open ureterocystoplasty and reconstruction  of the ipsilateral ureter were carried out. A transurethral  catheter was maintained for 1 week. Cystograms revealed an  increased bladder capacity. The animals were sacrificed after  4 weeks, and the histological sections showed preservation  of ureteral architecture with epithelial regeneration.   In 2003, Desai and Gill from the Cleveland Clinic reported  their initial experience with a completely minimally invasive  approach for chronic ureteral balloon expansion followed by   This study was performed in female farm pigs, and five  animals were initially used to develop the prototype design  and insertion technique of the ureteral expansion balloon, its  inflation schedule, and the technique of laparoscopic uretero-  cystoplasty. Subsequently, the five animals entered the sur-  vival study.   All the five chronic animals underwent unilateral percuta-  neous insertion of the ureteral expansion balloon  (Microvasive, Natick, MA), a dual-channel balloon catheter:  one for inflation and the other for proximal nephrostomy  drainage (Fig. 20.1). The balloon, flanked by radiopaque  markers, was positioned in the juxtavesical ureter and dis-  tended with 2.5-3 mL of contrast medium to secure it in  position (Fig. 20.2b). The excess proximal length of the cath-  eter exiting the animal’s back was tunneled subcutaneously,  so that only the inflation and drainage ports were visible out-  side the skin.   Starting from the day after placement of the ureteral  expansion balloon, the ureter was gradually dilated by daily  incremental instillation of a dilute (1:4) contrast solution.  The inflation was carried out without anesthesia or analgesia.  Ureteral expansion was monitored radiologically every 7-10  days (Fig. 20.3).    Fig. 20.1 Ureteral expansion was performed using a novel silicone bal-  loon TUEC catheter having two channels: a smaller channel to inflate  balloon (c/) and a larger fenestrated channel to drain kidney (c2). The  14F shaft has multiple holes to facilitate proximal urinary drainage. The  balloon (b) has one radiopaque marker (m/ and m2) at its either end to  facilitate fluoroscopic confirmation during placement. Additional  radiopaque marker (m3) on shaft immediately proximal to the last  drainage hole should lie within the kidney. Terminal end of the catheter  is fashioned into a pigtail to facilitate retention in bladder. Single-step  dilator (d) is used to position 20F peel-away sheath (s) within renal col-  lecting system    Fig. 20.2 Procedures of  percutaneous insertion of TUEC,  and inflation of balloon. Balloon  position: deflated balloon is  positioned in juxtavesical ureter.  Left: incremental progressive  inflation of balloon causes  chronic expansion of juxtavesical  ureter. (c) Expanded juxtavesical  ureter. Note: the laterally-based  vascular supply to expanded  ureteral segment from the  internal iliac vessels. Reprinted  with the permission from The  Cleveland Clinic Center for  Medical Art & Photography ©  2009. All Rights Reserved    Laparoscopic ureterocystoplasty was performed in all  five animals after 3—4 weeks of ureteral expansion. All pro-  cedures were performed using a four-port transperitoneal  approach with the pig under general anesthesia. Initially, the  ureteral balloon was completely deflated, and the amount of  fluid aspirated was measured. The balloon was subsequently  refilled with the same amount of dilute antibiotic solution to  facilitate intraoperative identification, and to prevent intra-  operative spillage of potentially infected fluid if inadvertent  puncture of the balloon occur intraoperatively. The expanded  ureter was identified as a readily visible bulge adjacent to the  urinary bladder. The medial peritoneum overlying the  expanded ureter was incised to expose the ureteral wall. The    fallopian tube and ovary on the ipsilateral side were mobi-  lized away from the ureter. The bladder was mobilized by  dividing the medial umbilical ligament and the superior ves-  ical pedicle, and incised laterally in a longitudinal fashion  from just above the ureteral orifice up to the dome. The ure-  teral orifice and intramural ureter were preserved. On the  other hand, in the initial two animals, the bladder dome was  not excised, and in the latter three, approximately 80% of the  bladder was removed. The medial wall of the expanded ure-  teral segment was then incised using a J-hook monopolar  cautery electrode, thus, opening the expanded ureteral seg-  ment medially. Care was taken to minimize any mobilization  of the ureter, thus, maintaining intact the laterally based    Fig. 20.3 Light microscopic examination of: (a) normal ureter, (b)  tissue-expanded ureter, which reveals muscle hypertrophy and hyper-  plasia, and variable inflammatory infiltrate, and (c) native bladder.    Note: the expanded ureter (b) more closely resembles the thickness of  the bladder wall (c) than the normal ureter (a)    Fig. 20.4 Plain radiographs of the abdomen document progressive ureteral expansion (a) At 1 week with 12 mL volume. (b) At 2 week, volume  in balloon has increased to 46 mL. (c) At 25 days just prior to augmentation ureterocystoplasty with 140 mL in the balloon    vascularity of the expanded ureter (Fig. 20.4). The length,  site, and orientation of the ureteral incision were tailored to  the bladder defect (Fig. 20.5). After the ureteral incision was  completed, the balloon was deflated and the catheter  removed. The in-line tissue-expanded ureteral patch was  then anastomosed to the bladder in a running fashion using  2—0 Vicryl sutures on a CT-1 needle with freehand intracor-  poreal laparoscopic suturing and knot-tying techniques  (Fig. 20.6). After the posterior wall was sutured, an 18F ure-  thral catheter was inserted into the urethra through the blad-  der neck. The anterior wall was then sutured to complete the    augmentation ureterocystoplasty. A 22F suprapubic catheter  was left indwelling and brought out through the suture line  in the initial two animals only. A drain was positioned in the  prevesical space in all five animals and brought out through  a port site.   The suprapubic catheter was removed after 7 days, and  the urethral catheter was removed after 14 days if not spon-  taneously expelled earlier. The drain, if not spontaneously  expelled, was removed a day after the urethral catheter was  removed. All the animals underwent laboratory, radiologic,  urodynamic, and histologic investigations (Table 20.1).    Fig. 20.5 (a-c) Steps during the laparoscopic ureterocystoplasty.  Reprinted with the permission from The Cleveland Clinic Center for  Medical Art & Photography O 2009. AII Rights Reserved    Fig. 20.6 Cystogram performed immediately prior to autopsy at 3  months. Augmented bladder reveals capacity of 600 mL. There is grade  II reflux in the right ureter    Radiologic  Plain film Weekly during balloon inflation  Prior to augmentation  ureterocystoplasty  Cystogram At 1-month follow-up    Urodynamics Prior to euthanasia  Cystoscopy At 1-month follow-up (N 5 2)  Prior to euthanasia  Histology  Light microscopy During augmentation cystoplasty    *Seven tissue biopsies were obtained from the five animals at the time  of augmentation ureterocystoplasty for cytokine assay    Additionally, electronic microscopy exam of the expanded  ureter and measurement of VEGF and TGF-B2 in the  expanded ureteral tissue were performed in selected animals.  The animals were euthanized at 15 days (N = 1), 1 month  (N = 1), 2 months (N = 1), and 3 months (N = 2).   AII the five animals underwent successful ureteral expan-  sion over a mean of 25 days. The mean final volume of the  ureter was 180 mL. AII the animals readily tolerated the daily  incremental instillation of dilute contrast solution without  apparent pain or discomfort. The ureteral expansion balloon  did not malfunction in any case, as judged by leakage of  fluid, blockage of the channel, balloon migration, or  rupture.   Radiologic volumetric assessment of the ureteral balloon  during the phase of ureteral expansion was commensurate  with the amount of fluid instilled. We did not note any com-  plications during ureteral expansion. Proximal urinary drain-  age through the fenestrated channel of the ureteral expansion  catheter was adequate in all five animals.   Laparoscopic ureterocystoplasty was feasible in all five  animals without the need for open conversion. Periureteral  adhesions were encountered close to the expanded ureter,  which were lysed laparoscopically. The expanded ureter  appeared thick and highly vascular, with areas of urothelial  denudation. Intraoperative instillation of saline through the  urethral catheter at the end of the ureterocystoplasty revealed  a watertight anastomosis in all five cases. Postoperative com-  plications, namely, lower ureteral obstruction and pyelone-  phritis with sepsis, were seen in two animals (Table 20.2).   Over a follow-up ranging from 15 days to 3 months, the  mean bladder capacity was 575 mL (380-940 mL). The Pves  at maximum capacity was 14 cm H,O,°*'®*! and bladder  compliance was 71 mL/cm H,O (35.3-188 mL/cm H,O).  Uninhibited detrusor contractions were not evident on the  urodynamic evaluation in any of the five animals (Table  20.3). Cystography revealed ipsilateral reflux in four renal    Mean time for balloon insertion (min)  Mean time for bladder augmentation (min)    Subtotal cystectomy performed (N) 3  Ureteral stenting (N) 2  Urethral catheter (N) 5    units: grade II in one animal, grade IV in two animals, and  grade V in one animal (Fig. 20.7). At autopsy, one renal unit  demonstrated lower-ureteral obstruction and therefore,  showed no reflux on cystography. There was no contralateral  reflux in any renal unit. In all four refluxing units, the refluxed  contrast drained from the kidney immediately after the blad-  der was emptied, thereby ruling out any ureteral obstruction.  Additionally, the cystogram did not reveal contrast extrava-  sation in any case.   Cystoscopy and bladder biopsy was performed in all ani-  mals after 1 month and the bladder revealed a fully regener-  ated mucosa in four animals; one animal euthanized at 15  days still had patchy areas of denuded mucosa. Laboratory  examination revealed minimal metabolic alterations in four  animals. One animal that developed pyelonephritis and  urosepsis had evidence of azotemia, hyponatremia, hyper-  kalemia, and acidosis. The mean serum creatinine concentra-  tion was 1.3 mg/dL at baseline, 0.9 mg/dL at bladder  augmentation, and 2 mg/dL at euthanasia.   At autopsy, the ureteral patch appeared well vascularized,  and the ureterocystoplasty suture line was healed in all five  animals. The ipsilateral renal parenchyma appeared grossly    (weeks) (80%) Ipsilateral Anastomotic Bladder Resting Full capacity Compliance Involuntary  cystectomy reflux leak capacity (mL) (mL/cm) H,O bladder   (grade)c contractions  1 2 No 2 No 600 3.0 20 92519 Absent  2 4 No 4 No 380 2.0 12 38.0 Absent  3 8 Yes - No 940 3.0 8 188 Absent  4 12 Yes 4 No 430 4.0 12 53.8 Absent  5 12 Yes 5 No 520 6.0 18 43.3 Absent    *Cystographic examination was performed at 1 month (N 5 3) and at autopsy by injecting contrast through a urethral catheter. In all refluxing renal    units, obstruction was ruled out by documentation of prompt drainage of contrast from the collecting system    Fig. 20.7 Autopsy photographs. (a) Augmented bladder and both renal  units. Healed suture line between expanded ureteral patch (u) and native  bladder (b) is seen (arrows). (b) Interior of the augmented bladder  shows demarcation (arrows) between expanded ureter (u) and native  bladder (b). Notice the complete epithelialization of the expanded ure-  teral patch    normal in three cases, with pre-euthanasia intravenous urog-  raphy (IVU) revealing prompt opacification with mild hydro-  nephrosis. One animal with a lower ureteral obstruction  revealed thinning of parenchyma and poor function on IVU.  At autopsy, the obstruction was found to be the result of  flimsy synechia formation at the junction where the upper,  normalcaliber, ureter entered the expanded ureteral segment.  The animal with pyelonephritis and urosepsis had a grossly  scarred kidney that was nonfunctioning on IVU.   Light microscopic examination of biopsies of the  expanded ureter obtained at the time of augmentation cysto-  plasty revealed muscle hypertrophy and hyperplasia, mucosal  atrophy, and variable inflammatory infiltrate. The histologi-  cal examination of the expanded ureter revealed persistent    muscle hypertrophy and hyperplasia, a fully regenerated  transitional epithelium, and variable amount of fibrosis.   Transmission electron microscopy performed on the ure-  teral tissue obtained at the time of laparoscopic augmenta-  tion revealed cellular evidence consistent with muscular  hypertrophy and hyperplasia.   Preliminary data on growth factor expression in expanded  ureteral tissue obtained and snap frozen at the time of aug-  mentation ureterocystoplasty revealed a 2—3-fold increase in  TGF-B2 (median 44 pg/mL; range 27-49 pg/mL) over con-  trols (normal ureter 16 pg/mL). There was no increase in  VEGF expression in the expanded ureteral tissue when com-  pared with control samples.   Although the potential for ureteral tissue expansion in the  context of urinary tract reconstruction has been preliminarily  explored, none of the investigators have taken the issue far  enough to explore the cellular and molecular mechanism  involved in visceral tissue expansion and remodeling. The  tissue expansion in the GU system is yet to be advanced to a  place where it can have a real practical use by urologists, to  the extent that skin expansion has become an accepted part  of plastic reconstructive surgery.   Encouraged by the principles mentioned earlier and  potential value of expanded ureteral tissue, we pursued  development and proof of concept of a methodology that  would enable us to obtain excess ureteral tissue with mini-  mally invasive surgical techniques. The expanded ureteral  tissue can be used in open or laparoscopic surgical tech-  niques in a variety of reconstruction applications for the  lower urinary tract. Further, our preliminary studies have  provided motivation for the pursuit of biological markers  possibly responsible for visceral tissue remodeling.    Following the laboratory experiments and upon availability of  the opportunity in two outside medical centers, the same  authors performed this procedure in three patients (outside the  United States), with the approval from the ethical committee  at each local institution. Clinical data from these patients have  been encouraging, supporting our laboratory data. Specifically,  we treated two women and one man, aged 14, 65, and 54  years, respectively. Each patient suffered from a noncompli-  ant bladder with reduced capacity (range 15-150 mL).   After percutaneous placement of the balloon, in-line  expansion of the distal ureter was achieved on an out-patient  basis over 23-38 days to a volume of upto 218 mL. Notably,  all the three patients did not require any analgesia during this  entire expansion process.   Operative time for the laparoscopic augmentation ure-  terocystoplasty ranged from 2 to 3 h, and blood loss was    25-50 mL. Each patient commenced oral intake on the same  day and ambulated within 24 h. There were no complications  at any stage of this study. Postoperatively bladder capacity  increased significantly to 250—280 mL at 2-month follow-up.  The first patient has now completed 2-year follow-up with  durable success. All the three patients have experienced sig-  nificant improvement in the voiding symptoms, and the renal  function is well preserved.    The availability of an urothelium-lined, muscle-backed, vas-  cularized, autogenous, in-line tissue material for the purposes  of augmentation, and possibly even replacement of the uri-  nary bladder would indeed be a major advance.   This could eliminate the use of bowel (and its attendant  morbidity) in urinary tract reconstruction. Potentially, such a  bladder substitute could have mucosal, myogenic, and neu-  rogenic attributes that approximate those of a functionally  intact urinary bladder. The study described earlier represents  a concerted effort at establishing and developing this novel  field of visceral tissue expansion.   The search for the ideal substitute tissue for bladder aug-  mentation is still ongoing. Currently, intestinal segments  remain most commonly used for bladder augmentation.  Although the results of augmentation cystoplasty using vari-  ous bowel segments have generally been acceptable, these  tissues are associated with absorptive metabolic changes,  mucus production, and stone formation, the magnitude of  which is dependent on the length and segment of the bowel  used.? Significant research in the past few decades has  focused on alternative tissue substitutes for urinary tract  reconstruction. These have included tissue-engineered mate-  rials, xenografts such as small-intestinal submucosa (SIS),  and techniques such as autoaugmentation and deepithelial-  ized bowel.” Some of these techniques, although promising,  have either been insufficiently durable or require consider-  able refinement. The ureter, with its transitional epithelium,  is potentially an optimal tissue for bladder augmentation.”   Augmentation ureterocystoplasty has been reported, with  encouraging long-term urodynamic results, and limited, if  any, metabolic changes. However, the amount of ureteral tis-  sue needed to provide an urodynamically acceptable bladder  augmentation can be obtained only in a patient with a large  megaureter. Therefore, currently, augmentation ureterocys-  toplasty is limited to the occasional patient with a megau-  reter and a nonfunctioning kidney, who requires bladder  augmentation.   Thus, although the potential for ureteral tissue expansion  for urinary tract reconstruction has been demonstrated, fur-  ther characterization of the biology of ureteral expansion and    refinement of the technique are necessary prior to its clinical  application. The experimental study published by Desai and  Gill was designed specifically to address the following cru-  cial issues: (1) the feasibility of percutaneous insertion of the  ureteral expansion device; (2) the efficacy of this novel bal-  loon in expanding the ureter to the desired volume while  simultaneously providing adequate drainage of the renal  unit; (3) a safe and reliable time-line schedule and regimen  for ureteral balloon expansion; (4) the technical feasibility of  performing laparoscopic augmentation ureterocystoplasty  using the tissue-expanded ureter; and (5) the biologic nature  of the expanded ureteral tissue and its efficacy in providing a  urodynamically adequate bladder augmentation in a survival  porcine model.   Postoperative complications occurred in two animals.  One animal developed lower-ureteral stenosis, hydrouretero-  nephrosis, and poor ipsilateral renal function, and the other  animal had pyelonephritis with sepsis. At autopsy, the animal  with lower-ureteral obstruction revealed flimsy adhesion for-  mation at the junction of the expanded ureter with the proxi-  mal normal-caliber ureter. There was no transmural fibrosis  on histological examination of the stenotic area. This obstruc-  tion probably represents cross-healing of the opposite ure-  teral walls following mucosal denudation during the  expansion process, and can potentially be avoided by stent-  ing at the time of augmentation ureterocystoplasty until reep-  ithelialization is complete.   Moreover, the survival porcine study demonstrated that  progressive, incremental ureteral tissue overexpansion can  be carried out safely and reliably with a percutaneously  placed expansion balloon. This ureteral expansion is well  tolerated and can be performed over a 3-4-week period to  create a sizeable reservoir for bladder augmentation. The  expanded ureter is thick and vascular, and reveals histologi-  cal and electron microscopic features of durable ureteral  smooth-muscle hypertrophy and hyperplasia. This expanded  tissue can be used laparoscopically to augment the bladder.  Such augmented bladders possess good urodynamic prop-  erties over a 3-month follow-up period. This approach has  the potential to provide native, urothelium-lined tissue for  augmentation or, possibly, replacement of the urinary  bladder.   Concerted research on this subject will lead to further  development of this novel field of tissue expansion.    1. McDougal WS. Metabolic complications of urinary intestinal diver-  sion. J Urol. 1992;147:1199-1208   2. Oberpenning F, Meng J, Yoo JJ, Atala A. De novo reconstitution of a  functional mammalian urinary bladder by tissue engineering. Nat  Biotechnol. 1999;17:149-155    . Elbahnasy AM, Shalhav A, Hoenig DM, Figenshau R, Clayman  RV. Bladder wall substitution with synthetic and non-intestinal  organic materials. J Urol. 1998;159:628—637   . Snow BW, Cartwright PC. Bladder autoaugmentation. Urol Clin  North Am. 1996;23:323-331   . Dewan PA, Close CE, Byard RW, Ashwood PJ, Mitchell ME.  Enteric mucosal regrowth after bladder augmentation using demu-  cosalized gut segments. J Urol. 1997;158:1141-1146   . Soergel TM, Cain MP, Misseri R, et al Transitional cell carcinoma  of the bladder following augmentation cystoplasty for the neuro-  pathic bladder. J Urol. 2004;172:1649—1651   . Churchill BM, Aliabadi H, Landau EH, et al Ureteral bladder aug-  mentation. J Urol. 1993;150:716-720   . Neumann CG. The expansion of an area of skin by progressive dis-  tention of a subcutaneous balloon; use of the method for securing  skin for subtotal reconstruction of the ear. Plast Reconstr Surg.  1957;19:124—130   . De Filippo RE, Atala A. 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J Urol 1992;147:1199   Oberpenning F, Meng J, Yoo JJ, Atala A. De novo reconstitution of  a functional mammalian urinary bladder by tissue engineering. Nat  Biotechnol. 1999;17:149   Elbahnasy AM, Shahlav A, Hoenig D, et al Bladder wall substitu-  tion with synthetic and nonintestinal organic materials. J Urol.  1998;159:628   Dewan PA, Close CE, Byard RW, et al Enteric mucosal regrowth  after bladder augmentation using demucolized gut segments.  J Urol. 1997;158:1141   Churchill BM, Aliabadi H, Landau EH, et al Ureteral bladder aug-  mentation. J Urol. 1993;150:716    In 1904, Hugh Hampton Young was credited for having per-  formed the first radical prostatectomy in the United States by  the perineal approach.' However, because of the limited vis-  ibility afforded by the small incision, identification of critical  structures was restricted, making incontinence common and  impotence almost universal after surgery. An Irish surgeon  by the name of Terence Millin then developed the retropubic  approach to prostatectomy in 1947, which allowed for  greater visualization of crucial structures; however, morbid-  ity was increased owing to significant blood loss, rectal  injury, and urethral strictures, while incontinence remained  common, and most men were still impotent.   With the advent of the linear accelerator in the 1960s,  external beam radiation became the treatment of choice for  most men because of the significant side effects associated  with surgery. However, this modality introduced its own set  of morbidities in terms of rectal and bladder side effects, in  addition to suboptimal treatment of some cancers leading to  recurrence of disease. It was not until the early 1970s that  urologists began to develop a better understanding of the  periprostatic anatomy and vasculature leading to decreased  morbidity. In 1977, Walsh performed a prostatectomy on a  patient who was fully potent within a year from surgery,  leading him to believe that the cavernous nerves did not  course through the prostate as most urologists had originally  believed.? This discovery led Walsh to embark on a journey  to further elucidate the anatomy of the pelvic plexus and cav-  ernous nerves.   When Walsh traveled to Leiden, The Netherlands, in 1981  to attend a meeting, he inquired about the work of an acquain-  tance by the name of Pieter Donker, Chairman of Urology at  the University of Leiden, whom he had serendipitously met  a few years earlier while attending a meeting of the American  Association of Genitourinary Surgeons in Miami.’ Donker  had performed innovative dissections on the nerves innervat-  ing the bladder using fetal cadavers, because the tissues  proved to be optimal for anatomic dissections and the nerves    larger in relation to the surrounding structures.^ After spend-  ing several hours performing dissections, Walsh and Donker  had discovered that there were nerves located and traveling  outside the prostatic capsule and lateral to the urethra that  appeared to innervate the corpora cavernosa? (Fig. 21.1).  Walsh took this discovery back with him to the operating  room where he discovered that the vessels along the capsule  of the prostate coincided with the location of the cavernous  nerves they had identified in the fetal cadavers. Lepor further  confirmed through histologic studies that the cavernous  nerves were located on the dorsolateral aspect of the prostate  along the pelvic sidewall? Using this information, Walsh  determined that the neurovascular bundle (NVB) could be  used as a macroscopic landmark for intraoperative identifica-  tion of the cavernous nerves.° This discovery, along with pre-  cise understanding of the dorsal venous complex and  development of techniques for its ligation and a better under-  standing of the external striated urethral sphincter anatomy,  led to improvements in postoperative potency and urinary  continence, and ultimately, the resurgence of radical pros-  tatectomy for the treatment of localized prostate cancer by  the mid 1990s?    Fig. 21.1 Drawing by Walsh demonstrating autonomic pelvic nerves in  a male stillborn infant. (Reprinted from Walsh?, O 2009, with permis-  sion from Elsevier)    Despite having a better understanding of the anatomy of the  prostate, reported potency rates have varied widely (i.e.,  21-86%) following prostatectomy even with the use of bilat-  eral nerve preservation techniques."? Sural nerve grafting  has been employed in an attempt to enhance cavernosal nerve  regeneration in patients who required wide resection of the  NVB due to high-risk disease; however, the results have been  mixed. ?!! Several studies have been recently been performed  revisiting the periprostatic neuroanatomy to further delineate  the anatomic course of the cavernosal nerves.   Costello et al. performed detailed dissections of the NVB  and its relationship to the surrounding pelvic structures in  male adult cadavers. They discovered that the NVB appears  to arise from the most inferior limb of the pelvic plexus and  contains divisions that innervate the corpora cavernosa, rec-  tum, prostate, and levator ani musculature (Fig. 21.2). They  also demonstrated that the NVB splays laterally between the  lateral pelvic fascia and the prostatic fascia, and also posteri-  orly between the rectum and prostate." They concluded that  the cavernosal nerve could not be distinguished from the  other divisions of the NVB, thus limiting the success rate of  the anastamosis of a single sural nerve graft to distal severed  nerve endings.   Takenaka et al. demonstrated that the branches of the  hypogastric nerve and pelvic splanchnic nerve splay and  interdigitate at multiple levels instead of forming a distinct  nerve bundle. They concluded that the cavernous nerves are  located beyond the NVB and a surgically reconstructed NVB  by graft interposition cannot include the nerve in its entire    Fig. 21.2 Drawing demonstrating that the NVB contains divisions that  innervate the corpora cavernosa (CN), rectum (RNV), prostate (PNV),  and levator ani musculature (LANV). (From Costello et al.)    course.” Successful nerve grafting is further complicated by  their discovery that there can be significant anatomic vari-  ability between patients in the course of the cavernous  nerves.   Lunacek et al. performed dissections of the cavernous  nerves in fetal and adult cadavers and compared the location  of the nerves. They discovered that the cavernous nerves that  are initially found running along the lateral lobes of the pros-  tate, as observed in the fetal cadavers (and as Walsh and  Donker had discovered), eventually spread anteriorly and  form a concave "curtain" when the prostate enlarges as the  patient ages (Fig. 21.3). They also demonstrated that the cav-  ernous nerves course lateral and dorsal to the membranous  urethra.'* These findings were also confirmed by Sievert  et al., who demonstrated that approximately 25% of the auto-  nomic nerves were located anteriorly at the mid portion of  the prostate.'^ Kaul et al. were also able to demonstrate his-  tologically that the prostatic fascia on the anterolateral por-  tion of the prostate contained 25-50% of the total neural  tissue (Fig. 21.4).'° Zvara et al. performed a study in the rat  and human model showing that these nerve fibers on the  anterolateral aspect of the prostate stained positive for nico-  tinamide adenine dinucleotide phosphate  diaphorase  (NADPH-d), which is a cofactor for nitric oxide synthase,  the enzyme responsible for the synthesis of nitric oxide  (NO)." This provided evidence that some of the accessory  nerves in the periprostatic fascia produce NO, a principle  neurotransmitter responsible for erectile function. All of  these anatomic studies, taken together, suggest that acces-  sory neural pathways appear to exist in addition to the main  NVB, to provide innervation to the cavernosal bodies.  Furthermore, these studies highlight the inherent anatomic    Fig. 21.3 Lateral view of adult cadaver demonstrating splaying of the  CN (green asterisks) along the lateral aspect of the enlarged prostate (P)  after BPH has developed. The pelvic plexus (red asterisks) encase the  seminal vesicles (SV). B, bladder; U, right ureter. (From Lunacek et al.'^)    Fig. 21.4 S-100 nerve stain demonstrating accessory nerve fibers  within the prostatic fascia. (Reprinted from Kaul et al.'^, O 2005, with  permission from Elsevier)    complexity that underlies the cavernous nerves, thus explain-  ing in part the finding that many patients do not recover  their full erectile function following bilateral nerve sparing  prostatectomy.    The improved knowledge of the anatomic course of the cav-  ernous nerves has allowed for the development of techniques  to attempt more precise quantitative and qualitative nerve  sparing during radical prostatectomy. With the advent of min-  imally invasive surgical techniques, including laparoscopic  radical prostatectomy (LRP) and robotic assisted laparoscopic  radical prostatectomy (RALP), these techniques have allowed  for unprecedented intraoperative magnification of the prostate  and periprostatic structures including the NVB. These tech-    niques provide a 10x magnification, and in the case of RALP,  a high-definition image of the prostatic tissues, thus providing  a better opportunity to identify and preserve the putative  branches of the cavernous nerves that lie in between layers of  the levator, Denonvilliers', and the prostatic fascia.   Because of the anatomic variation in the course of the  cavernosal nerves that extend from the posterolateral to the  anterolateral surface of the prostate, several surgeons have  modified their approach at nerve preservation in patients  with low-stage, low Gleason prostate cancer. In 2005,  Lunacek et al. reported using a “curtain dissection" tech-  nique for nerve preservation during open radical retropubic  prostatectomy (RRP) that involved dissection of the NVBs  starting anteriorly, while using magnifying lenses to preserve  the nerve fibers that are spread in a concave fashion on the  anterolateral surface of the prostate."   Menon et al. reported about their RALP nerve-sparing  technique termed as the “veil of Aphrodite" that similarly  involves incising the prostatic fascia anterioromedially and  developing a plane between the prostatic fascia and prostatic  capsule in an antegrade fashion using the magnification  afforded by the daVinci robotic system, which effectively  peels the splayed cavernous nerves off the prostate.'*~° They  believe that the remaining curtains of the periprostatic tissue  contain the cavernous nerves and hang from the pubourethral  ligament, which creates the image of the so-called “veil”.   Nielsen et al. also reported on what Walsh has termed the  “high anterior release” nerve preservation technique used  during open RRP.” His technique is similar to the aforemen-  tioned techniques in that the levator fascia is released up high  on the anterioromedial aspect of the prostate using the  periprostatic fascia as a handle to minimize direct manipula-  tion and traction injury to the true cavernous nerve bundles  lying more posterolaterally.   The benefit of intraoperative magnification and the  changes in the techniques used to preserve the NVB have  resulted in improved potency rates while maintaining accept-  able positive margin rates. However, as the cavernous nerves  are microscopic and the macroscopic landmarks only serve  as a surrogate for the actual cavernous nerves, there is a need  for improved mapping of the true cavernous nerve fibers  responsible for penile erections. New imaging techniques  may assist with localization of the nerves to help target intra-  operative nerve dissection and also allow for a successful  nerve graft interposition.    The goal of intraoperative visual identification of the NVB is  mainly twofold: (1) to localize and anatomically map the true  nerve fibers responsible for controlling erections and possibly    continence during nerve sparing radical prostatectomy and  (2) to locate the cavernous nerve endings during non-nerve  sparing radical prostatectomy to facilitate graft anastamosis  to the actual ends of the severed nerve. The functional identi-  fication of the NVB by electrical stimulation also allows for  the evaluation of the continuity of a preserved NVB to aid in  determining whether or not a nerve graft should be inter-  posed. A combination of visual and functional identification  may allow surgeons to perform a better nerve-sparing pros-  tatectomy and help improve the potency and continence rates,  and also improve the success rate of nerve grafting when uti-  lized. Several technologies have been developed to achieve  these goals that will be reviewed in the following sections.    The CaverMap Surgical Aid (Blue Torch Corporation,  Norwood, MA) was developed to assist in intraoperative  localization of the cavernosal nerves by provoking an erec-  tile response through electrical stimulation of the nerve. It  has been shown that electrical stimulation of the cavernous  nerve may cause very small changes in tumescence or detu-  mescence of the penis, which may not be visible, but yet  physiologically detectable. The CaverMap device was  designed to measure changes in penile girth as little as 0.5%.  The system is composed of a control unit, a handheld nerve  stimulator, and a tumescence sensor placed around the penis  to measure changes in the circumference. Mapping of the  cavernous nerve is performed by placing the nerve stimula-  tion probe on the tissues suspected to contain the cavernous  nerve and using detected changes in penile tumescence dur-  ing stimulation to, in theory, affirm correct identification of  its location (Fig. 21.5). The CaverMap can then be used,  after removal of the prostate, to assess the continuity and  b Modified Dissection    Fig. 21.5 The CaverMap Surgical Aid can be used to map the course of  the cavernous nerve along the prostate. (a) Dissection resulting the resec-  tion of the cavernosal nerve due to incorrect intraoperative identification  of the nerves. (b) By noting where the probe tip is located when it elicits  a tumescence response, the course of the neurovascular bundles becomes  apparent and provides an anatomic “map” for the surgeon interested in  their preservation. (http://www.bluetorchmed.com/surgeons/index.html)    integrity of the cavernous nerves by proximal stimulation of  the nerves and assessing penile tumescence again. It can also  be used to localize the distal end of a severed nerve to facili-  tate nerve graft anastamosis.   In concept, the CaverMap Surgical Aid appears to provide  a sound solution to precise intraoperative cavernous nerve  localization in efforts to achieve optimal cavernous nerve  preservation during nerve-sparing radical prostatectomy.  Practically, however, results using the CaverMap have been  fraught with inconsistency. Klotz et al. reported a 94% potency  rate (16 of 17 patients) after the use of CaverMap for intraop-  erative nerve identification.” They also reported a 19% over-  all positive margin rate (five patients) in that study that  included patients with clinical stage T1c and T2a-c disease.  However, only three (12%) of the patients had positive mar-  gins confined to the apex and/or lateral margin, and it is con-  ceivable that the nerve-sparing approach may have altered the  margin status. For the other two patients with positive mar-  gins, one had positive margins with seminal vesicle invasion,  and the other had extensive positive margins with positive  lymph nodes. It is possible that the nerve-sparing approach  did not alter the final outcome in those two patients.   Klotz et al. then performed a prospective, randomized,  multicenter study using the CaverMap-assisted nerve-spar-  ing prostatectomy technique and compared it with conven-  tional nerve-sparing techniques. They found that, at 1 year,  the CaverMap group had a significant improvement in noc-  turnal tumescence when compared with the conventional  nerve-spare group (greater than 6096 tumescence for a mean  of 15.9 vs. 2.1 min, respectively) as measured by RigiScan,  an instrument used to measure penile tumescence and rigid-  ity.” However, the improved nocturnal tumescence did not  translate into a significant difference in the ability to have an  erection sufficient for intercourse (71 vs. 6296, P = 0.17).  Kim et al. reported that although they had a 7796 positive  CaverMap response rate, their overall potency rate was only  18% at 1 year.” Furthermore, Walsh et al. indicated that the  CaverMap device should not be used to determine if a struc-  ture should be excised or not, as they found the device to  have a low specificity of 54%.” This variability and lack of  precision was also supported by Holzbeierlein et al. who  showed that stimulation of an area on the anterior bladder  wall far away from the NVB resulted in tumescence almost  half the time.” While the CaverMap device had promising  early results, efforts to duplicate this have been met with  inconsistency and lack of specificity.    Ukimura et al. described a technique to provide real-time  intraoperative transrectal ultrasound (TRUS) imaging of the  prostate and periprostatic tissues and vessels to assist with    dissection to compensate for the muted tactile feedback pres-  ent when performing LRP.” As opposed to screening TRUS,  intraoperative TRUS combines prostate needle biopsy results  with real-time imaging, allowing the ultrasonographer to  direct the surgeon to a wider plane of dissection in areas of  suspicion such as near hypoechoic lesions or regions where  the biopsies were positive near the capsule. They reported the  potential advantages of real-time TRUS imaging as follows:  (1) it identifies the anatomical course of the NVB, (2) it mea-  sures the adequacy of NVB preservation, (3) it identifies the  apical margin of the prostate, (4) it aids in the dissection of  the posterior bladder neck, vas deferens, seminal vesicle, and  release of the rectal wall, and (5) it identifies any hypoechoic  bulging nodule to help in avoiding positive surgical mar-  gins.” They found that their positive surgical margin rates  decreased from 29 to 9% (P = 0.0002) with the use of intra-  operative TRUS during LRP, and were able to map the course  of the NVB using TRUS by tracing the arterial flow within  the NVB.” Based on the previous findings by Lepor et al.  documenting the lateral location of the cavernous nerve  within the NVB with relation to the vascular supply? it was  theorized that if the vascular supply in the NVB is preserved  after the nerve-sparing dissection, as demonstrated by  Doppler waveform analysis using TRUS, then the cavernous  nerves should be spared. They were also able to report on the  diameter of the NVB and the number of visible vessels within  the NVB before and after the dissection to evaluate the qual-  ity of the nerve-sparing dissection, and found a decrease in  the number of visible vessels from 2.6 to 1.1 and a decrease  in the cross-sectional area of the NVB by 11%. However,  these findings are yet to be correlated with any improvement  in the potency rates after nerve-sparing LRP.   Another serious limitation to the utilization of TRUS dur-  ing LRP is that it is operator-dependent and requires an expe-  rienced and dedicated ultrasonographer. This person is  positioned between the patient's legs for a majority of the  operation and is constantly involved with the interpretation of  the ultrasound and laparoscopic pictures simultaneously. The  additional, highly trained, personnel required may also trans-  late into a significant increase in the cost of the operation. In  addition, the use of TRUS during RALP poses an additional  challenge, as the daVinci robot is situated between the patient's  legs where the TRUS operator would normally sit. This may  limit the utility and widespread adoption of intraoperative  TRUS, as most prostatectomies in the United States are being  performed with robot assistance at the time of this writing.    Optical coherence tomography (OCT) is an imaging tech-  nique that allows for the real-time, high-resolution, atrau-  matic, cross-sectional imaging of the tissues, which has been    utilized in ophthalmology for retinal and corneal imaging as  well as in urology for bladder cancer staging.” The Niris  OCT system (Imalux, Cleveland, OH) has been utilized in  urologic applications and is comprised of an 8 F fiberoptic  probe and a computer console and screen. The fiberoptic  nature of the probe may allow for it to be integrated into the  laparoscopic instruments or other flexible devices in the  future. OCT is similar to B-mode ultrasonography, but  instead of measuring the backscattering of acoustic waves, it  measures the backscattering of near-infrared light. However,  unlike ultrasound, OCT does not require direct probe contact  with the tissue or a transducing medium, decreasing interfer-  ence with the operative instruments in the surgical field.  Image resolution as fine as 1-15 um can be achieved with a  maximal penetration depth of 1.6 mm, which allows for the  imaging of the microscopic structures such as the cavernous  nerves, lymphatics, blood vessels, and fascial planes.   Rais-Bahrami and Fried et al. demonstrated the use of  OCT in imaging of the cavernous nerve and periprostatic tis-  sue in the rat model.” The rat model proved to be an ideal  model for imaging because the cavernous nerve exists as a  large, visible structure with minimal intervening vasculature  or fat. To confirm the course of the cavernous nerve in the rat,  the nerve was identified and stimulated with simultaneous  intracorporeal pressure measurements, with penile length  and girth measurements recorded. Hematoxylin-eosin  stained histologic specimens of the cavernous nerve and  periprostatic tissues were then compared with the OCT  images obtained from the same location on the prostate and  were found to correlate well (Fig. 21.6).°*°   Rais-Bahrami and Aron et al. both reported on the use of  OCT to image human ex vivo prostatectomy specimens  immediately after removal.*°*’ Rais-Bahrami et al. found the  OCT images of human cavernous nerve and prostatic tissue  to be similar to that of the rat in that there was identical his-  tological correlation with the OCT images. However, identi-  fication of the NVB proved to be difficult when compared  with the rat prostate owing to the higher density of the pros-  tatic capsule and stroma, as well as the presence of more  blood vessels and fat resulting in a degradation of the signal.  Aron et al. also found that identification of the NVBs required  an experienced operator to distinguish them from adipose  tissue, small vessels, and lymphatics.   OCT, like real-time TRUS, also has the limitation of  requiring an experienced operator to interpret the images  obtained. While OCT has been used to aid in the intraopera-  tive identification and preservation of the NVB,” its success  has yet to be validated by potency results. Future improve-  ments in the technology resulting in greater depth of penetra-  tion and resolution may make OCT more feasible for  intraoperative identification of the cavernous nerve during  nerve-sparing prostatectomies or for the localization of cav-  ernous nerve endings to allow for a precise nerve-graft  anastamosis.    Fig. 21.6 OCT imaging and histologic (hematoxylin—eosin) correlation of rat CN (a, b) in cross-section and (c, d) in oblique section overlying    Takenaka et al. reported on the first attempt at the intraopera-  tive measurement of intracavernosal and intraurethral pres-  sure using an intracavernosal needle and intraurethral balloon  catheter after electrical stimulation of the NVB and the  accessory neural pathways in the region of the surgically  identified NVB using a Neuropack nerve stimulator device  and a bipolar electrode.” An increase in intracavernosal pres-  sure signified the presence of cavernous nerve fibers, while  an increase in pressure in the intraurethral balloon catheter  signified the presence of nerve fibers contributing to urinary  continence. By stimulating regions of the nerves away from  the identified NVB (i.e., posterolateral rectal wall) and the  actual NVB during open radical prostatectomy, the research-  ers were able to demonstrate that the course of the cavernous  nerves did not always correspond to the surgically identified  NVB and also showed that the NVB contains nerve fibers  contributing to urinary continence. This correlated with their    earlier findings that the nerves are actually splayed and  located beyond the NVB." These findings support the rela-  tive complexity of the cavernous nerve branches and their  anatomic course, but also confirm the involvement of some  of these fibers with urinary continence.    Confocal fluorescent microscopy (CFM) is a new technol-  ogy that has been described for use in gastroenterology, der-  matology, pulmonology, and urology, and provides such  incredibly detailed resolution that it allows for in vivo dif-  ferentiation of cancerous and normal tissue.’ CFM can    also provide adequate resolution to allow distinction between  some differentiated and undifferentiated cancers. CFM has  also been used to provide real-time in vivo images of periph-  eral nerves and deep-brain structures in rats genetically engi-  neered to express a fluorescent protein in all sensory and  motor neurons.?^ CFM allows for sufficient spatial resolu-  tion to produce images down to the axonal level. The  Cell-Vizio (Mauna Kea Technologies, Paris, France) is a  commercially available unit that utilizes CFM technology,  and is composed of a laser scanning unit, a small fiberoptic  probe, and an image processing unit. Real-time images can  be produced up to 12 frames per second, while the probe  allows for a lateral resolution of 3.5 um with a depth of pen-  etration of 15 um.   Boyette et al. used the CFM technology along with the  injection of a fluorescent retrograde nerve tracer to provide  in vivo real-time images of the cavernous nerve in rats." A  recombinant B-subunit of cholera toxin conjugated to a fluo-  rescent compound (AlexaFluor) served as the fluorescent  nerve tracer, and was injected into the corpus cavernosum of    male rats to allow for retrograde transport along the cavern-  ous nerves. They found that the optimal imaging of the cav-  ernous nerve was obtained after allowing for 9 days of  retrograde transport along the nerve. The cavernous nerves  were then exposed and imaged using CFM, which produced  exceptional images, even allowing for visualization of the  branching of the cavernous nerve (Fig. 21.7). Confirmation  that the nerves being imaged were actually the cavernous  nerve was obtained by electrical stimulation of the fluores-  cent nerve with simultaneous intracavernosal pressure  monitoring.   While CFM technology produces striking images in the  rat model, there are limitations to the technology that need to  be overcome before successful application in humans. The  depth of penetration of the probe is only 15 jum, which works  well for the rat model. However, as was encountered in trans-  lating OCT technology from the rat to human model, the  greater amount of periprostatic fat, vessels, and lymphatics  present in the human model may hinder the view of the nerve.  Another major limitation to the technology is the need for    Fig. 21.7 Figures a, b, and c are CFM images of rat CN obtained 9 days after injection of fluorescent nerve tracer into corpus cavernosum. Figure d  demonstrates accessory nerve branching into larger and smaller bundles. (Reprinted from Boyette et al.*°, © 2007, with permission from Elsevier)    injection of a fluorescent nerve tracer and waiting for retro-  grade transport to the cavernous nerve. While transport in the  rat model took 9 days, it has been estimated that it may take  up to 45 days for optimal imaging to be obtained in the  human owing to the four to five times greater distance from  the penis to the cavernous nerve the tracer has to travel.*°  Finally, while the short-term safety of the injected tracer  composed of the B-subunit of cholera toxin was demon-  strated in the rat model, long-term studies need to be per-  formed in humans before the technology can become main  stream.    The concept of using an injectable fluorescent nerve tracer to  localize the cavernous nerve was also described by Golijanin  et al." After the injection of a fluorescent dye called indocya-  nin green (ICG) into the rat penis and allowing time for ret-  rograde transport to the cavernous nerves, they used a  near-infrared fluorescence (NIRF) intraoperative imaging  system (SPY, Novadaq Technologies Inc., Mississauga,  Ontario, Canada) composed of a laser used to illuminate  fluorescent tissue and a camera sensitive to infrared fluores-  cence to capture images. Nerves were positively identified at  6, 8, 12, 18, 24, and 36 h after ICG injection. The maximal  nerve fluorescence was noted at 18 and 24 h postinjection.   The main advantage of NIRF using ICG as a fluorescing  agent over CFM with the injection of AlexaFluor is the sig-  nificantly shorter time required for retrograde transport of  the fluorescing agent. Nevertheless, further studies would be  required to determine the length of the time needed for ade-  quate transport of ICG from the penis to the cavernous nerves  in the human model. However, the downside to using ICG as  a fluorescing agent is that the agent contains iodine that  would limit its utility to patients without an allergy to  iodine.    While technologies such as CaverMap, intraoperative TRUS,  OCT, nerve stimulation, and intraoperative fluorescence  imaging demonstrate the feasibility of visualizing or approx-  imating the location of the cavernous nerve, precision is hin-  dered in the human model by the lack of resolution and depth  of penetration of the imaging modalities. In CFM, a minia-  turized confocal microscope can be attached to the end of a  conventional endoscope, allowing for point-by-point optical  sections to be obtained of the tissue in question and then ren-  dered into a 3D image by a computer, thus providing a real-    time virtual histologic image. The downside to this technology  is the need for injection of a fluorescing agent such as fluo-  rescein prior to obtaining images. Theoretically, this technol-  ogy can be applied to RALP for intraoperative identification  of the cavernous nerves, while simultaneously scanning for  cancerous tissue. Nerve tissue that is seen to be too close to  prostate glands with cancerous architecture could then be  sacrificed, while nerve tissue well away from the cancerous  glands could be spared.   Diffusion tensor imaging (DTI) is an MRI imaging modal-  ity that was developed to image white matter tracts in the  brain. It has been used to localize brain tumors in relation to  white matter tracts for neurosurgical planning, to provide  imaging of the cranial nerve pathways, as well as allow for  imaging of peripheral nerves such as the sciatic nerve. ^^!  DTI has also been shown to be able provide detailed prostate  anatomy as well as allow for delineation of neoplastic lesions  and areas of extraprostatic extension.^^* Perhaps, in the  future, it may be possible that DTI can be used alone or in  combination with functional MRI, which has been used for  localizing and staging tumor foci in the prostate, to provide a  preoperative map of the cavernous nerves and tumor foci, to  allow for augmented reality and intraoperative surgical  navigation.    Several technologies have been developed and studied in an  attempt to provide intraoperative NVB identification during  radical prostatectomy; however, unfortunately, none have  been reliable or specific enough. In addition, none of the  modalities described have been validated with long-term  potency outcomes to attest their efficacy at guiding intraop-  erative cavernous nerve preservation. 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Rigorous evaluation and reasoned adoption of new tech-  nology is a trademark of the field of urology.^ This ethos has  been central to the ascent of LPN. The evaluation and the  adoption of new technologies has impacted all the aspects of  the procedure, from preoperative planning, which is crucial  to identify appropriate candidates for LPN, to the perfor-  mance of the procedure itself, and finally postoperative care.   The procedural challenges of LPN are numerous and  interrelated. Hilar dissection and identification of renal vas-  culature can be daunting. Adequate mobilization of the kid-  ney is necessary to achieve a favorable environment for LPN.  Resection of the mass with negative margins while minimiz-  ing injury to adjacent vasculature, parenchyma, and collect-  ing system is difficult and paramount to the success of the  operation. The provision of a bloodless field by clamping,  whether en bloc or of the renal artery alone, leads to renal  ischemia and consequent deleterious effect on renal func-  tion. Renorrhaphy, including hemostasis and collecting sys-  tem closure if required, can be a challenge to accomplish  without damage to the remaining remnant.   From diagnosis in the clinic to treatment in the operating  theater, new technologies have great potential to favorably  alter the landscape of nephron-sparing approaches to renal  masses, in particular LPN.    The elucidation of the molecular pathways involved in the  pathogenesis of renal cell carcinoma (RCC) is revolutioniz-  ing the management of metastatic disease. In particular, sur-  vival in patients with advanced RCC is improved by novel    therapeutics that target the vascular endothelial growth  factor-mediated pathways promoting angiogenesis and  metastasis. In a similar fashion, translational research has  the potential to transform the diagnosis of renal masses.   At present, the evaluation of cystic and solid renal masses  focuses primarily on radiographic assessment, with preop-  erative biopsy rarely performed.* With imaging as the prin-  ciple diagnostic modality, modern nephron-sparing surgery  (NSS) series report 15-30% rates of benign final pathol-  ogy.” '! Nonetheless, the role of biopsy has been limited due  to an unacceptably high false negative rate due to difficulty  differentiating between benign and malignant neoplasms  (e.g., chromophobe RCC vs. oncocytoma)."   Recent advances in molecular biology are renewing focus  on renal biopsy for the diagnosis of renal masses and treat-  ment selection. If biomarkers offer greater sensitivity and  specificity than histopathology or cytology, biopsy in the  future could potentially obviate the need for surgery in  15-30% of patients.   Despite ample evidence in favor of the safety and onco-  logic efficacy of NSS, a large percentage of tumors amenable  to partial nephrectomy are removed with radical surgery."  Moreover, even NSS has an adverse impact on glomerular  filtration rate.'^'? Avoiding unnecessary insults to renal func-  tion through improved molecular diagnostics will be a sig-  nificant technical advance.   Molecular markers of the different subtypes of RCC have  been elucidated (Table 22.1). Similar to the development  of therapeutic alternatives to radical surgery, high-through  put techniques to identify DNA, RNA, miRNA, and pro-  teomic signatures associated with benign and malignant  renal masses may help spare nephrons.'57?    Preoperative planning for LPN is so essential to the ultimate  success of surgery that it can be considered as the first surgi-  cal step. Based on preoperative imaging, the surgeon should  have a clear vision as to the maneuvers that will be required    Loss of 3p, 9p; trisomy 7,17; + p53  Absent VHL gene mutation, gamma-enolase + MN/CAIX   Neopterin, TPS, Bcl-2, gamma-enolase, TS, MN/CA9 + STAT protein  NMP-22, extracellular matrix proteins, laminin, collagen IV + fibronectin    Bcl-2, p53, Ki67, CAIX, p21, TPS, PTEN, gamma-enolase, pyruvate kinase, TS, CD10, CD154,    Reprinted from Hari et al." Copyright 2008, with permission from Elsevier.    intraoperatively to successfully accomplish partial nephrec-  tomy in a minimally invasive environment. Helical computed  tomography (CT) scanning with 3D reformatting has become  an essential tool in the preoperative evaluation of renal  masses.   Obviating the need for more invasive angiographic imag-  ing, 3D reconstructions provide important information about  normal renal anatomy, the relationships of a renal mass to  main, segmental, and accessory renal vasculature, as well as  the proximity to the collecting system. An example is shown  in Fig. 22.1. The detail provided by 3D reconstructions can  be crucial to surgical planning, not just influencing the global  approach (open vs. laparoscopic), but also the technical  details (clamped vs. unclamped, wedge resection vs. polar  nephrectomy). In an analysis of almost 350 helical CT scans  in patients undergoing NSS, Derweesh et al. reported that  CT findings were predictive of calyceal entry at the time of  surgery. Such detailed preoperative information allows the  surgeon to plan and anticipate the need for collecting system  closure intraoperatively.?!   Preoperative virtual reality surgical rehearsal may be fea-  sible in the future, and would represent a significant advance.  One might want to determine prior to surgery, for example, if  NSS were technically feasible or if radical nephrectomy was  the only option. This is yet to materialize for renal surgery,  but small steps toward this end have been accomplished.  Preliminary proof-of-concept studies have shown that data  from 3D CT renderings can be transferred to the virtual real-  ity environment, but this has not yet entered the mainstream  clinical practice.” Virtual reality surgical simulation will  undoubtedly continue to be a focus of future investigation.    Despite continued refinement of technique and mounting  experience, LPN remains an advanced procedure, with most  surgeons facing three common challenges: adequate    parenchymal cutting, hemostasis, and reconstruction. This  has motivated investigation of new excision devices that  address all three technically demanding elements. Lasers are  at the forefront of the investigation because of their dual abil-  ity to vaporize (1.e., cut) tissue and coagulate.   Lasers are characterized by their wavelength-specific  medium, mode of emission (continuous, pulsed, or  Q-switched), and power output. The wavelength is propor-  tional to depth of tissue penetration, while emission mode  influences the degree of lateral heat conduction. The inter-  play of these factors with tissue composition, molecular  absorption, and perfusion determines the laser end-effect.^   The ideal laser for minimally invasive NSS should cut  precisely to limit collateral thermal damage, coagulate the  tumor bed without destroying tissue architecture to allow  margin assessment, and preserve visibility. No laser perfectly  satisfies these criteria. For instance, initial clinical studies  with the Ho:YAG laser revealed that it cuts and coagulates  effectively without the need for hilar clamping, but is handi-  capped by excessive smoke production and blood splatter.”  The CO, laser has been shown to be ineffective for hemosta-  sis, while the Nd:YAG and diode lasers both cause severe  tissue carbonization, obscuring margin analysis.”   In an attempt to improve the early experience, two new  lasers have been studied for use in LPN: the potassium titanyl  phosphate (KTP) laser and the thulium laser. The KTP laser  emits a visible green light beam with a wavelength of 532 nm.  This wavelength is in the range of hemoglobin absorption,  which may explain the KTP laser’s superb hemostatic effect,  particularly in vascular tissue. In a nonclamping survival calf  model, the KTP laser not only demonstrated excellent control  of bleeding, but also did so with submillimeter histologic dis-  ruption in the adjacent parenchyma.” These findings were  supported by a subsequent investigation in a porcine model  by Hindley et al.” The experiments were carried out success-  fully without hilar clamping. The system delivered very rapid  energy pulses, generating nearly continuous power output of  80 W, and hence, minimizing energy scatter. This translated  into a superficial 1 mm zone of coagulation necrosis at the    Fig. 22.1 3D CT scan image demonstrating a 4x4.3cm hypervascular interpolar left renal mass. There are two left renal arteries, including a lower  polar artery. (Image courtesy of Christoph Wald, Lahey Clinic)    excision margin and a deeper 1 mm zone of tubular lumen  collapse, nuclear pyknosis, and erythrocyte loss. Smoke pro-  duction remained a hindrance with the KTP laser, and modi-  fications are underway to correct this problem before  introducing the KTP laser into the clinical arena.   These two studies champion the precision and hemostatic  effect of the KTP laser. However, its true efficacy is still  uncertain. A recent ex vivo experiment with blood-perfused  porcine kidneys deemed the KTP laser inadequate for both  tissue coagulation and creation of clean, sharp resection    margins.” While this study differs significantly in design, it  underscores the need for additional research.   The thulium laser is another potential excision device that  has been evaluated in a survival animal model. Bui et al. per-  formed successful nonclamping LPN in five pigs using a  continuous-wave thulium laser with wavelength of 2 uum and  total power of 30 W.? The energy was delivered through a  365 um silica fiber. For improved intracorporeal laser manip-  ulation, the fiber was advanced through the working port of a  flexible cystoscope, and the entire unit was then introduced    through a 10 mm laparoscopic port. This system also allowed  continuous saline irrigation along the path of laser fiber,  thereby reducing smoke production and tissue carbonization.  On immediate histological analysis of the cut surface, there  was no evidence of charring or necrosis. Furthermore, the  continuous emission mode imparted superior cutting preci-  sion and eliminated blood splatter. The thulium laser also  achieved adequate coagulation of cortical vessels up to 1.6 mm.  However, the authors cautioned that the laser incompletely  sealed larger vessels near the hilum. Still, these preliminary  findings represent a step toward developing an ideal laparo-  scopic excision device. Additional testing of both the thu-  lium and KTP lasers will probably enable the surgeons to  attain that ideal device in the future.    Multiple imaging modalities may be employed preopera-  tively to characterize and localize a renal neoplasm. While  preoperative radiographic information provides a guide for  tumor excision, intraoperative delineation of tumor from  normal parenchyma remains essential for assessing the mar-  gin status and achieving complete tumor removal, which is  the goal of renal oncologic surgery.? Surgeons have long  relied on intraoperative frozen section to evaluate tumor  margins. However, the technical challenges of LPN along  with the time limit on warm ischemia have spurred the devel-  opment of real-time technologies with the same histologic  precision but shorter turn-around time.   Intraoperative laparoscopic ultrasound (ILUS) has been  the mainstay of dynamic tumor evaluation in LPN. Studies  have demonstrated that ultrasound aids in demarcating  tumor-free margins and identifying occult satellite lesions. ??  The discriminatory power of ILUS depends on the echotex-  tural differences between neoplastic and normal parenchyma.  Thus, if the tumor and the surrounding normal tissue share a  similar echo pattern, ILUS will be inadequate. To overcome  this limitation, several new technologies have emerged.  These include optical reflectance spectroscopy (ORS), opti-  cal coherence tomography (OCT), and Smart Needle mea-  surement of bioimpedance.   Optical diagnosis relies on the interaction of light energy  with tissue and analysis of the resultant change in the nature of  light. In ORS, light energy is applied to tissues, and the light  reflected back is detected and recorded as spectral data. Diffuse  reflectance, which is characterized in ORS, detects scatter  from intracellular components such as nuclei, which are typi-  cally altered in neoplastic disease. Thus, ORS can provide  real-time structural information about the tissues in question.   Several groups have investigated ORS as a tool for discrim-  inating between normal and neoplastic renal tissue. In a    preliminary ex vivo study, Parekh et al. interrogated multiple  pathologically confirmed radical nephrectomy specimens  using a portable fiber optic-based spectroscopic system.” They  were able to differentiate cancerous from normal specimens  based on fluorescence and diffuse reflectance spectra.  Moreover, ORS could distinguish between papillary and clear-  cell subtypes. The authors proposed a discriminatory algorithm  with high sensitivity and specificity, and concluded that ORS  might have a future role in intraoperative margin evaluation.   By applying optical analysis, investigators from UT  Southwestern were able to detect a positive margin in their  partial nephrectomy specimens.** While absorption of light  by hemoglobin is cited as a potential limitation of ORS  in vivo, one could argue that the promising results from non-  perfused ex vivo models are relevant to LPN, which is typi-  cally performed under ischemic conditions.   Similarly, OCT analyzes light-tissue interactions, specifi-  cally infrared light. OCT is conceptually similar to ultrasound  in that it detects a signal reflected back from the tissue, and  composes a dynamic, high spatial resolution image of the tis-  sue microstructure to a depth of 11 um. This yields an "opti-  cal biopsy"? The technology is suited for minimally invasive  surgery, as the fiber-optic device is easily advanced through a  laparoscopic port. Although it has found intraoperative appli-  cations in bladder and prostate disease, OCT has only recently  been employed for renal tumors. Chung et al. conducted a  preliminary investigation of OCT in LPN of 11 patients.”  OCT of parenchyma and capsule, both on and adjacent to the  renal mass, detected structural abnormalities in nine RCCs,  suggesting possible utility in assessing tumor margins.   Bioimpendance measurement via the percutaneous Smart  Needle system is another potential modality for discriminat-  ing between normal and neoplastic renal tissue. This technol-  ogy takes advantage of the distinct electrical properties of  malignant versus benign tissue, as previously demonstrated  in prostate cancer specimens.” With regard to renal disease,  the Smart Needle has been used for the confirmation of col-  lecting system entry during percutaneous procedures in a por-  cine model.” Investigators speculate that there may be a role  for bioimpedance measurement in renal oncology as well.   Optical technologies such as ORS and OCT, and mea-  surements of bioimpedance hold promise for tumor detec-  tion and margin assessment during laparoscopic NSS. These  new technologies are investigational but hold promise and  merit further study.    Achieving adequate hemostasis along the partial nephrec-  tomy defect is crucial to avoid either immediate or delayed  hemorrhage. Sutured renorrhaphy is currently the corner-  stone of this effort except for the most superficial resection,    but laparoscopic suturing is perceived to be technically  demanding, especially when done under ischemic condi-  tions. The ultimate hemostatic agent obviates suturing, can  be easily applied laparoscopically, has a fast onset, and is  able to seal large blood vessels and collecting system open-  ings in the deepest portion of the nephrectomy defect. To  date, no such agent exists and this goal remains elusive.  Several hemostatic agents are predominantly used as hemo-  static adjuncts, and these are reviewed as follows.   No single agent or suturing technique has proven supe-  rior, and typically depends on surgeon preference.” Msezane  et al. described four classes of tissue sealants.*° They include  collagen-based adhesives, hydrogel, fibrin sealants, and glu-  taraldehyde-based adhesives. These agents vary in their  mechanism of action, surface type for application, and cost.   Johnson et al. compared seven agents in a hypertensive  porcine model.*! They found that Floseal? and Tisseel? per-  formed well for small resections, but these results were  dependent on the systolic blood pressure. They concluded  that sutured repair is required for larger resections to ade-  quately control bleeding. Recently, Nogueira et al. performed  a prospective study comparing bovine and porcine-derived  gelatine matrix-thrombin sealants. Both the agents pro-  vided acceptable hemostasis without adverse events, both in  the early and late postoperative period. A novel hemostatic  agent using a chitosan hemostatic dressing has shown some  promise in initial studies.? Xie et al. conducted a feasibility  study in a porcine model and demonstrated complete hemo-  stasis after deployment of the chitosan dressing in 17 out of  a total of 18 procedures."   As mentioned, glues and sealants usually serve as an  adjunct to a bolster in the partial nephrectomy defect. The  bolster is composed of methylcellulose sheets manufactured  by Johnson & Johnson (Surgicel and Surgifoam®) and Pfizer  (Gelfoam®). Along with its inherent hemostatic properties, it  provides direct mechanical compression on the defect to pre-  vent further bleeding.*' Porpiglia et al. reported no signifi-  cant difference between two groups of patients who both  received parenchymal sutures, with one group also receiving  fibrin glue and collagen fleece.“ Although suturing has been  demonstrated to be the mainstay of hemostasis, facility with  intracorporeal suturing requires dedicated training, and  minor modifications to the bolster concept have moved away  from knot-tying. One innovation using knotless hemostatic  parenchymal sutures described by Canales et al. reported a  decreased ischemia time using polymer self-locking clips as  opposed to traditional free-hand suturing."   A recent technical modification aimed at decreasing isch-  emia time is an early unclamping technique reported by  Nguyen and Gill." A deep running suture is placed under  ischemic conditions and then the clamp is released. Bleeding  vessels are then sutured in the perfused kidney until all visi-  ble bleeding ceases. Adjunctive FloSeal and Tisseel are  applied, and a bolster may be omitted in select cases.^*    Another area where preoperative imaging information is  poised to re-shape the intraoperative environment is augmented  reality — the superimposition of anatomical data from imaging  studies onto the real-time operative images seen through the  video endoscope. Particularly for renal masses where the tar-  get organ is enveloped within retroperitoneal fat, augmented  reality has tremendous appeal. In the field of neurosurgery,  where the skull serves as a rigid reference point, augmented  reality is already well-integrated into clinical practice.”   Marescaux et al. from Strasbourg, France, recently des-  cribed the use of augmented reality for adrenalectomy, an  important advance with implications for all retroperitoneal  surgery.” In the reported case, superimposed images allowed  the surgeon to “see through" the retroperitoneal fat, with  cues as to the ultimate location of the right adrenal vein. For  renal surgery, similar applications may hasten hilar identifi-  cation and preclude inadvertent vascular injury.   Surgical navigation and image overlay for the kidney and  surrounding structures is more challenging than for the cen-  tral nervous system. Since the kidney must be mobilized to  achieve surgical exposure, anatomical relationships are dis-  turbed. Respiratory motion further complicates image fusion.  Nevertheless, Ukimura and Gill described fusing and 3D CT  reconstruction of a renal mass with the live intraoperative  laparoscopic view.?' The key to their success was the use of  optical sensors on the laparoscopic instruments, as well as  the strategically placed fiducials at various fixed points in the  surgical field and on the kidney itself. Real-time superim-  posed color-coded image displayed concentric "zones"  around the tumor at increasing distance from the tumor, pro-  viding an additional cue as to the dissection plane that would  achieve a negative margin (Fig. 22.2).    Fig. 22.2 Augmented reality image during laparoscopic partial nephrec-  tomy (Courtesy of Dr. Inderbir Gill, Cleveland Clinic). A red color marks  the tumor itself, with concentric colored zones at increasing distances from  the tumor. The green stripe indicates a safe margin for surgical resection    The drive to decrease incisional morbidity for patients under-  going partial nephrectomy is understandable, considering  that the pathologic findings will be benign in up to a third of  the patients." The latest advance in minimally invasive sur-  gery attempts to further reduce patient morbidity by consoli-  dating laparoscopic instrumentation through a single port,  usually placed in the umbilicus. Numerous abbreviations  have been put forth for this approach, including single-port  access and laparo-endoscopic single site surgery. Operating  through a single port has a rich history in the gynecologic  literature, where tubal ligations have been done as outpatient  procedures, as far back as in 1969.” Recently, surgeons have  made strides exploring single-port access for various uro-  logic applications.?*^*   Aron et al. at Cleveland Clinic reported results of a pilot  study of single-port LPN, successfully completed in four  patients.” These were performed using a single intraumbili-  cal multichannel port that incorporates two 5 mm and one  12 mm gel valve inlet (R-port, Advanced Surgical Concepts,  Dublin, Ireland). Tumor sizes ranged from 1 to 5.9 cm, oper-  ative time was between 4 and 5.8 h, and warm ischemia was  between 11 and 29 min. No intraoperative complications  were noted, surgical margins were negative, and one patient  experienced postoperative bleeding requiring angioembo-  lization. The authors were able to duplicate steps of the  standard laparoscopic procedure. However, with current  instrumentation, single-port partial nephrectomy is techni-  cally challenging and requires careful case selection. The  authors cautioned that single port laparoscopy for partial  nephrectomy currently should be limited to small, exophytic  lesions at high volume centers where technical expertise  exists.    Regardless of the surgical approach (open, laparoscopic, and  robotic), the goals of partial nephrectomy are as follows: (1)  remove the entire tumor surrounded by a margin of normal  parenchyma, (ii) reliably close the vascular channels and col-  lecting system at the resection bed, and (iii) avoid acute or  chronic compromise to normal remaining Kidney tissue.  These goals are often at odds with each other, contributing to  the technical difficulty of the procedure. Hilar clamping per-  mits a bloodless field that allows the surgeon to resect with  cold scissors, preserving the natural tissue characteristics so  that one can differentiate normal from cancerous tissue. The  price of clamping, particularly in patients with compromised   An attractive solution would be to interrupt blood flow  only to the tumor itself, such that partial nephrectomy could  proceed while normal parenchyma remains perfused. Nohara  et al. described selective clamping of the feeding vessel, and  they accomplished partial nephrectomy using this tech-  nique. However, this relies on the specific extrarenal anat-  omy and a dedicated vascular dissection of subsegmental  vessels with the attendant risk for vascular injury.   To circumvent these issues, Libertino et al. used biocom-  patible reverse thermosensitive polymers applied intravascu-  larly through a preoperatively positioned angiographic  catheter in a porcine model (Libertino, personal communica-  tion). The commercially available thermosensitive polymer,  LeGoo™ (Pluromed), is approved in Europe for temporary  vascular occlusion and is used in cardiovascular surgery  including coronary artery bypass. It has also been used at  Lahey Clinic in a porcine autotransplantation model.   LeGoo is part of a family of rapid transition polymers that  are liquid at cold temperatures, and become viscous gel as  they warm to body temperature. The viscosity and transition  temperature can be altered by varying the individual mixture  composition. For partial nephrectomy, the concept would  proceed as follows: (i) on-table angiography to define tumor  feeding vessel, (ii) positioning of catheter tip in segmental  vessel feeding the tumor, (iii) kidney and tumor mobiliza-  tion, (iv) LeGoo injection, which would polymerize at body  temperature, (v) completion of partial nephrectomy under  segmental occlusion conditions, and (vi) injection of cold  saline to dissolve the LeGoo. While still in an experimental  phase, temporary superselective vascular occlusion has the  potential to allow rapid and safe partial nephrectomy without  warm ischemic injury to normal parenchyma (Fig. 22.3).    LPN has equivalent intermediate-term oncologic outcomes  to open partial nephrectomy, with both the approaches  decreasing the overall risk of end-stage renal disease when  compared with radical nephrectomy.^ Hilar control is often  required during these procedures to aid in tumor excision,  pelvicalyceal suture repair, and parenchymal hemostasis.  Renal hilar clamping causes warm ischemia that can result in  permanent renal dysfunction. Although there is no absolute  cut-off, 30 min of warm ischemia is usually cited as an  acceptable limit. Advancing age and medical renal disease  may shorten the acceptable warm ischemia window.  Serum creatinine is an imperfect marker of renal dysfunc-  tion in the perioperative period, especially in patients with a  normal contralateral kidney. In some cases, elevations in    Fig. 22.3 (a) Arteriograms demonstrating selective occlusion of the  lower segmental branch of the left renal artery. No part of the lower  kidney is perfused apart from a small “blush” in the right-hand image,  which represents flow from a tiny segmental branch not seen in the left-  hand image. 'This is the preparation needed to obtain bloodless resec-    serum creatinine are delayed until 48—72 h after initial insult  to the kidney.” Furthermore, levels can be influenced by  nonrenal factors such as body mass index, muscle metabo-  lism, volume status, and dietary changes. Serum creatinine  may not reflect significant damage if there is adequate renal  reserve or enhanced tubular secretion of creatinine.‘   A significant need exists for new biomarkers of acute  renal injury. Biomarkers may allow earlier detection of acute  renal dysfunction, and improve our ability both to assess the  degree of renal insult and to predict durable decrements in  renal function. Of particular relevance to partial nephrec-  tomy, advanced molecular diagnostics might help to reduce  the renal morbidity of partial nephrectomy by signaling the  need for intervention.   Trof et al. recently reviewed three main classes of biomark-  ers.^ These included tubular enzymes, low-molecular-weight  proteins, and markers of glomerular filtration. Tubular enzymes  originate from lysosomes, brush-border membranes, and cyto-  plasm. These include a- and m-glutathione, S-transferase,  N-actyl-glucosaminidase, alkaline phosphatase, y-glutamyl  transpeptidase, and fructose 1,6-biphosphatase. This family of  markers detects acute tubular damage at an early stage, typi-  cally 12 h to 4 days prior to an increase in creatinine.”  However, tubular enzymes are released in mild renal injury,  limiting its ability to predict irreversible damage.   Urinary low-molecular weight proteins can be used to  detect proximal tubule damage, because they are not reab-  sorbed when these cells are dysfunctional. Some of these    tion of the renal parenchyma. While the circulation to the lower pole is  completely interrupted, flow to the upper portion of the kidney is pre-  served. (b) Gross image of segmental occlusion corresponding to arte-  riogram above. (Courtesy of John Libertino and Peter Madras, Lahey  Clinic Medical Center)    markers include œ, and p, microglobulin, retinol-binding  protein, adenosine deaminase-binding protein, neutrophil  gelatinase-associated lipocalin (NGAL), and kidney injury  molecule 1 (KIM-1). These proteins are freely filtered by the  glomerulus and reabsorbed, but not secreted by proximal  tubular cells. Their predictive value for ultimately requiring  renal replacement therapy is superior to tubular enzymuria,  but demonstrates wide variability in both sensitivity and  specificity.   NGAL is a 25 kDa protein that is usually expressed at  very low concentrations in the kidney, but is upregulated in  several nephron segments after ischemic injury, predomi-  nately in the proximal tubules. ^ Clinically, NGAL is an  independent predictor of renal injury in children who under-  went cardiopulmonary bypass surgery.‘   KIM-1 is another promising biomarker that is a type-1  membrane protein that can be determined in urine by Western  blot analysis and quantified by ELISA. Patients with a 1-U  increase in the urinary KIM-1 levels are subject to a 12-fold  increased risk for the presence of acute renal failure (ARF).   Trof et al. also described a class of biomarkers that mea-  sure the diminished glomerular filtration.“ Examples include  ProANP and cystatin C. Proatrial natriuretic peptide (1—98)  is the prohormone of ANP that does not bind to specific  receptors in blood and therefore its clearance depends on  renal function.” ProANP was a better predictor for the devel-  opment of ARF in a group of 29 septic patients than standard  biochemical markers such as cystatin C.”!    Coca et al. recently conducted a systematic review of  publications that evaluated serum and urinary biomarkers.”  They reviewed 31 studies involving 21 biomarkers and con-  cluded that serum cystatin C, urine interleukin 18 (IL-18),  and urine KIM-1 performed best for the differential diagno-  sis of established acute kidney injury (AKI). Serum cystatin  C, NGAL, IL-18, glutathione-S-transferase-r, and y-gluta-  thione-S-transferase performed best for early diagnosis of  AKI. Urine N-acetyl-B-glucosaminidase, KIM-1, and IL-18  performed best for early mortality risk prediction after  AKI.   A new class of biomarkers termed urinary exosomes has  recently been discovered. Exosomes are membrane vesicles  that are secreted by various cells including the entire  nephron. Zhou et al. reported that urinary exosomes such as  activating transcription factor 3 (ATF 3) were isolated from  patients with AKI, but not from patients with chronic kidney  disease or controls.” ATF 3 also increases significantly after  ischemia-reperfusion injury, peaking between O and 2 h  after the initial insult. These preliminary results look prom-  ising, but more studies are needed to gauge their clinical  utility.   Another promising class of markers is the group of netrins,  which are laminin-like molecules that were initially described  as neuronal guidance cues, but are also abundant in the kid-  ney."*? Netrin-1 is induced in tubular epithelial cells as early  as 3 h after ischemia-reperfusion injury and peaks at 24 h.’°  In a recent study of 13 patients with ARF, netrin-1 levels  increased dramatically, with no detectable netrin in the urine  of six healthy controls."   A wide spectrum of urinary and serum biomarkers are  being studied to help identify patients prone to ischemic  injury. Owing to the diversity of patient backgrounds, intrin-  sic renal disease, and etiology of renal insult, it is likely that  more than one biomarker will be needed. Individual bio-  markers have unique limitations; a broad biomarker panel  will therefore be required. In the future, such a panel will  allow practitioners to not only avoid ischemic injury in high-  risk patients, but to appreciate injury earlier. Furthermore,  elucidation of pathways of renal injury may provide molecu-  lar targets for targeted intervention.    New technologies have great potential to improve nephron-  sparing approaches to renal masses, in particular, LPN.  Translational research has the potential to transform the  diagnosis of renal masses from a predominantly radiographic  diagnosis to one rooted in the DNA, RNA, miRNA, or pro-  teomic profiles associated with the pathologic process itself.  Serum, urine, or tissue biomarkers may offer greater    sensitivity and specificity than histopathology or cytology,  and have the potential of reducing the 15-30% rate of benign  operative pathology. Avoiding unnecessary insults to renal  function through improved molecular diagnostics will be a  significant technical advance.   CT scanning with 3D reformatting has become an essen-  tial tool in the preoperative evaluation of renal masses. The  detail provided by 3D reconstructions is crucial to surgical  planning and has been shown to be predictive of the surgical  experience, including calyceal entry. Advances in 3D imag-  ing foretell the possibility of surgical rehearsal in a virtual  reality environment, which has been investigated in provoca-  tive proof-of-concept studies.   In addition to diagnostic advances, new technology prom-  ises to transform the techniques of LPN. New excision  devices, such as the thulium and KTP lasers, bring us closer  to the ideal of limited collateral thermal damage, excellent  hemostasis without destruction of tissue architecture or mar-  gins, and preserved visibility. ILUS can be very useful in  delineating tumor from normal parenchyma. Similarly, novel  optical technologies and bioimpedance tools hold promise  for improved tumor detection and margin assessment during  LPN.   Moreover, superimposition of anatomical data from imag-  ing studies onto real-time operative images seen through the  endoscope may further enhance the intraoperative environ-  ment. Fusing of 3D CT imaging with the live laparoscopic  view has already been accomplished. Successful use of aug-  mented reality has been described for adrenalectomy, and  has the potential to hasten hilar identification and preclude  inadvertent vascular injury in LPN.   Single-port partial nephrectomy, the latest advance in  minimally invasive surgery, consolidates laparoscopic instru-  mentation through a single port, usually placed in the umbi-  licus. This technically challenging approach may decrease  incisional morbidity and improve convalescence, but should  be limited at present to treatment of small, exophytic lesions  at high volume centers.   While LPN is much more favorable than radical surgery  from a renal-function perspective, some of the most exciting  new technologies aim to further reduce the adverse impact  on glomerular filtration. For instance, temporary superselec-  tive vascular occlusion has the potential to allow rapid and  safe partial nephrectomy without warm ischemic injury to  normal parenchyma. Finally, urinary and serum biomarkers  are being studied to help identify patients prone to ischemic  injury. A biomarker panel may not only allow practitioners to  avoid ischemic injury in high-risk patients, but to diagnose  durable renal injury sooner and with greater specificity.   LPN is a procedure that was conceived, improved upon,  and broadly accepted through the evaluation and adoption of  new technologies. This spirit of innovation continues to pro-  pel the procedure forward.    McDougall EM, Clayman RV, Chandhoke PS, et al Laparoscopic  partial nephrectomy in the pig model. J Urol. 1993;149(6):  1633-1636    sparing surgery for small renal cell carcinoma. J Urol. 1998;159(4):  1152-1155    . Scardino PT. Urology: a long history of innovation. Nat Clin Pract    . De Mulder PHM, Patard J, Szczylik C, Otto T, Eisen T. Current    status of targeted therapy in metastatic renal cell carcinoma. Eur  Urol Suppl. 2007;6:665—67 |    . 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J Urol. 2008;178:  2096-2102    Brian H. Irwin, Pradeep P. Rao, Mihir J. Stein, and Robert M. Desai    The last 30 years has seen an explosion in the development  and adoption of laparoscopy as the standard of care for the  treatment of many benign and malignant conditions within  the majority of areas of surgical practice. Following the ini-  tial laparoscopic nephrectomy performed by Clayman, lap-  aroscopic and robotic-assisted surgery has been applied to  nearly the entire gamut of the urologic surgical repertoire.  While urologic surgeons continue to strive for improvements  in morbidity and the cosmetic sequelae of laparoscopic sur-  gery, an effort has been extended toward minimization of  size and number of ports required for the performance of  these procedures. Laparoendoscopic single site (LESS) sur-  gery is a recently coined term that refers to a group of tech-  niques, which allow for laparoscopic interventions to be  performed through a single abdominal incision often hidden  within the umbilicus. While the term LESS has been recently  developed, the concept of LESS surgery is not singular.  Single incision surgery has been performed for decades dur-  ing percutaneous procedures on the kidney as well as in  gynecology' and general surgery.” The current acceleration  in the interest for these techniques has been promoted by the  recent introduction of new instrumentation and access  devices, incorporation of novel approaches, and new and  existing robotic platforms into the repertoire combined with  the familiarity of current practitioners with advanced laparo-  scopic techniques. As such, within the past year, nearly the  entire spectrum of extirpative and reconstructive urologic  procedures has been performed using LESS surgery.    The concept of LESS surgery has been around for many years  and has been used across many surgical specialties. Tens of  thousands of tubal ligations have been performed through  the years? in gynecologic practice, with an offset laparoscope  via a single puncture technique. In more contemporary    series, the pediatric and general surgical literature has  reported on the use of single incision techniques for perito-  neal catheter insertions in children? and retroperitoneoscopic  adrenalectomies using large 4.5-cm trocars without insuffla-  tion.^ Historically, many attempts have been made to mini-  mize the invasiveness of procedures using techniques that  would now fall under the heading of LESS procedures."   An extension of LESS surgery called natural orifice trans-  luminal endoscopic surgery (NOTES) was first described in  2003. It was developed along the same philosophical basis as  LESS surgery, with the expressed goal of reducing morbidity  and maximizing the cosmetic appeal of the surgical incisional  scars associated with interventions." Animal studies, primar-  ily in the porcine model, have been used to explore various  NOTES techniques.? These procedures have typically been  performed with flexible endoscopes passed via the mouth,  vagina, or rectum using integral working channels for the  introduction and manipulation of surgical graspers, cutting  devices, and other instruments within the surgical field. While  these techniques have been developed and used relatively  extensively in the laboratory setting, they have yet to be  applied to any significant number of reported clinical cases.  This has been in large part owing to the technical challenge  involved in performing these procedures and the unfamiliar-  ity of the clinicians with the flexible instrumentation and  optics. As such, most of the reported NOTES animal cases by  urologists have been undertaken using a hybrid NOTES tech-  nique in which the more familiar laparoscopic approach is  used to aid in the surgery with the introduction of an addi-  tional 12-mm port in the umbilicus.'? In contrast to the less  familiar NOTES techniques, LESS procedures attempt to  offer similar reductions in morbidity and improved cosmesis,  while using the laparoscopic instrumentation which is more  familiar to current surgeons with equivalent results.   A relatively large number and variety of LESS procedures  have been reported in the urologic literature shortly follow-  ing the initial reports of LESS clinical successes. The moti-  vation for this swift expansion in the popularity of LESS  surgery is likely multi-factorial. Urologists have been com-  fortable approaching structures through the abdominal wall  and via the retroperitoneum for decades. As such, it is logical    that techniques that allow surgeons to approach organs of the  urinary tract in a similar manner will be adopted with relative  ease when compared with those requiring the surgeon to  view and manipulate structures through a hollow viscus.''  When the surgeon is employed, the opportunity to use more  familiar instruments and the learning curve with LESS may  be shorter, while maintaining the cosmetic benefits seen with  a single umbilical incision which can be easily hidden with  careful closure.   The approaches for LESS surgery generally fall into one of  the two categories. In the first, single-site surgery, multiple con-  ventional laparoscopic ports are placed via a single incision to  allow for the simultaneous introduction of the required instru-  ments and camera devices. The second general category of  LESS procedures involves the introduction of a purpose-  designed multi-channel port through the abdominal wall to  access the peritoneal cavity. Such single ports surgery can pro-  vide a lower profile point of access to the surgical field, mini-  mizing the potential interaction of ports within the small working  space afforded by these approaches. Whether carried out by  single-incision or single-port technique, the access point may be  placed within the umbilicus, an existing cicatrix on the abdo-  men, or at an extra-umbilical site on the abdomen or flank.    Because several techniques have been described for perform-  ing single-site surgeries over the course of the past few  decades across many specialties, various terminologies and  acronyms have been used to describe these laparoscopic pro-  cedures (Table 23.1). Owing to the variety of descriptions of  these techniques, researchers and potential collaborators  have had difficulties in the past identifying studies using  similar approaches. LESS was proposed as a common nomen-  clature by a consortium comprised of experts from fields  across several surgical specialties to address this problem.  Once coined, this term was also endorsed by the Urologic  NOTES Working Group in a recent communication."   With the adoption of this common taxonomy, scientific  communications, performance of clinical trials, and consistent  research practices have been coordinated and standardized.  This universal language has allowed for more efficient use of  search engines as they are applied to the developing literature  to promote the fast dissemination of ideas and results.    Perhaps, the forces that have provided the largest impetus for  the quick dissemination of these techniques have been recent  improvements in access devices, optics, and instrumentation.    MISPORT Minimally invasive single port surgery  SILS Single incision laparoscopic surgery   SPELS Single port endoscopic and laparoscopic surgery  SPEARS Single port endoscopic and robotic surgery  SPE Single port endoscopic surgery    In spite of the new developments in instrumentation, the  interaction of the necessary elements to perform the case  (i.e., instruments, cameras, and access devices) continues to  occur at the common point where they are introduced into  the abdomen as well as both intra- and extra-corporeally. At  times, it is necessary for the surgeon's hands to be crossed to  maximize triangulation within the abdomen. This leads to a  situation in which the left-handed instrument appears on the  right side of the screen and vice versa.   These limitations can largely be overcome with practice,  but there remains a very distinct learning curve involved with  attempting LESS procedures. To facilitate the surgeon along  this learning curve, research has focused on developing new  technologies to help minimize these limitations, and formal  teaching and certifying protocols have been proposed. A  brief description of the currently available devices used in  LESS surgery is presented in Table 23.2.    LESS surgery can be carried out through a variety of access  devices. The initial LESS surgical procedures were carried  out using conventional laparoscopic trocars within a single  skin incision through separate fascial sites. Ports of varying  lengths and with small external components are favored to  help reduce the interaction of instruments and ports limiting  the movement of instruments intra-abdominally. Reports on  the use of shortened ports with reduced intra-abdominal    profiles have also been published, again with the goal of  minimizing instrument interaction intracorporeally.'*   More recently, specific access devices have been devel-  oped which allow for the performance of single-port surgery  while allowing multiple instruments to be passed into the  abdominal cavity at the same time while maintaining pneu-  moperitoneum. Currently, the most familiar and widely used  access system remains the TriPort (Advanced Surgical  Concepts, Co. Wicklow, Ire land) (Fig. 23.1).? This device  has received FDA approval for use in humans. It consists of    12—25-mm incision  Two 5-mm, one 12-mm port and one insufflation port  Port introducer available    Low-profile — in-line design  Digital chip-on-the-tip technology, available in 0, 30°,  and flexible versions    two components, a retracting ring made up of two semi-rigid  rings connected by a double barreled plastic sleeve and a  multi-channel valve, which uses a unique elastomeric mate-  rial similar to that of the more familiar GelPort (Applied  Medical, Rancho Santa Margarita, CA) to prevent the loss of  pneumoperitoneum alongside the instruments. The currently  available TriPorts have one 12-mm and two 5-mm ports to  accommodate instruments within the same working space.  The size of the incision used with the TriPort can be tailored  to the specific application. The device can be placed through    Fig. 23.1 The TriPort (Advanced Surgical Concepts, Co. Wicklow,  Ireland) (a) applied to a model abdominal wall and (b) as viewed from  above. Note the presence of three working channels and an insufflation  port. Reprinted from Irwin et al", Copyright 2009, with permission  from Elsevier    a fascial incision measuring between 10 and 30 mm via an  open technique but is also supplied with an introducer that  allows for the placement of the port into a previously insuf-  flated abdominal cavity. While the larger variation of the  device, the QuadPort, does not currently come with such an  introducer and must be placed via an open technique, it can  be used in even larger incisions of up to 50 mm in length  allowing for more working room. Each of the two available  configurations for the QuadPort (one 15-mm, one 12-mm,  and two 5-mm ports; or four 12-mm ports) can be particu-  larly useful for extirpative procedures in which a larger inci-  sion is needed for specimen removal. Both the TriPort and  the QuadPort have housings that support the instrument  valves, contain a separate insufflation port, and can be   The Uni-X Single Port Access Laparoscopic system  (PNavel systems, Cleveland, OH) has been used during the  successful completion of a number of LESS procedures.  While the device is capable of allowing the introduction of  up to three 5-mm instruments simultaneously, it requires  placement via an open techniques and suture fixation to the  fascia to remain in place.   As a novel use of the familiar GelPort, used more com-  monly during hand-assisted procedures, radical nephrectomy  has been performed using three conventional laparoscopic  ports placed through the elastomeric gel.'° This system has  the advantages of allowing for the use of different port con-  figurations within the gel, as well as the placement of differ-  ent sizes and shapes of ports and instruments directly though  the gel without the loss of pneumoperitoneum. The gel can  be introduced into an even larger incision during extirpative  procedures, allowing the surgeon to take advantage of the  entire incisional length from the outset of the procedure. This  has been particularly helpful during radical and donor neph-  rectomy in which the intact specimen must be removed  through a sizable incision. One drawback of the GelPort used  with LESS procedures is the ballooning effect seen during  insufflation. This causes the instruments to be pushed further  from the operative field, further limiting the already reduced  ability to triangulate within the abdomen, and provides a less  stable fulcrum for the instruments than some of the other  purpose-designed LESS access devices.   Other single-port devices which remain in various stages  of commercialization include the SILS Access (Covidien/  Autosuture, Hamilton HM FX, Bermuda) and AirSeal  (Surgiquest, Orange, CT). As of the date of this publication,  to our knowledge, no published reports using these latter two  devices yet exist.    The primary hindrances encountered during LESS are (1) the  loss of the triangulation familiar to the surgeon from conven-  tional laparoscopy and (2) the “chopsticks” effect leading to  the interaction of instruments both intra- and extra-corpore-  ally (Fig. 23.2). The use of special instrumentation has  allowed these obstacles to be overcome or minimized in clin-  ical practice. The use of prototype fixed-shaft bent instru-  ments during the performance of single-port LESS procedures  was described by Rane et al and Desai et al using the  TriPort;'? the use of similar prototype instruments devel-  oped by PNavel Systems was reported by Kaouk et al, using  the Uni-X device platform."   To further compensate for the loss of triangulation during  LESS procedures, various newer articulating instrument    23 New Advances in Urologic Laparoendoscopic Single Site (LESS) Surgery 201    Fig. 23.2 LESS Instrumentation. (a) Note that instrument clashing,  which is common during LESS surgery, has been somewhat reduced  with the use of a fixed-bent instrument. (b) The surgeon's left hand  holds an articulating dissector while the right holds a flexible camera  device. Reprinted from Irwin et al", Copyright 2009, with permission  from Elsevier    systems have been developed including the RealHand HD  series (Novare Surgical Systems, CA), the Roticulator series  (Covidien/Autosuture), and those made by Cambridge Endo  (Framingham, MA). These companies have attempted to  duplicate the full spectrum of available laparoscopic instru-  ments including endo-shears, needle drivers, graspers, and  hook electrocauteries in these lines of articulating instrue-  ments.” The currently available articulating instruments are  primarily limited by the technical difficulty involved with  training for their use as well as a lack of sufficient strength to  provide robust retraction and dissection.    The clashing of instruments with the camera device as they  pass through a common fulcrum continues to be a recurring    difficulty seen during LESS surgery. The large profile of the  perpendicular light source on most conventional laparoscopes  exacerbates this problem. By using a video laparoscope, in  which the camera is integrated with a coaxial light cable in  line with the shaft of the telescope with a low profile handle,  such as the EndoEye (Olympus, Orangeburg, NY), this prob-  lem can be minimized.” This system is available in 5 and  10 mm sizes in 0 and 30? configurations as well as with a flex-  ible actively deflectable tip of 10 mm size. A 45? telescope  with a co-axial light guide attachment has also been devel-  oped for use in LESS (Karl Storz, Tuttlingen, Germany).   In an elegant way, Park et al have developed a new camera  system, which can be introduced completely into the body and  manipulated through the abdominal wall with the use of a  magnetic anchoring and guidance system, which they have  termed “MAGS.”! This system has already been used suc-  cessfully in an initial porcine model literature? and, more  recently, in the first human clinical cases (Cadeddu, personal  communication). Currently, this system has been used primar-  ily to control the camera device, but other instruments may be  adapted for use in the same manner allowing the surgeon to  control them without the use of a port that needs to physically  go through the abdominal wall. Another benefit of this type of  system is that it allows the surgeon to change the vantage  points several times during a given procedure if desired, with-  out the need for the placement of additional ports.    Experience in clinical trials with LESS surgery has increased  exponentially since the initial reports in the literature of its  successful use in human subjects (Table 23.3). Raman et al  reported the first human single umbilical incision nephrecto-  mies in three humans (two nonfunctioning kidneys and one  renal mass) with the use of three conventional 5-mm laparo-  scopic ports adjacent to each other as previously described. ''  A 12-mm trocar was placed following dissection for the  introduction of a laparoscopic vascular stapling device for  the control of the renal hilum. No complications were  reported following the surgeries performed with an average  operative time of 133 min and patients were discharged on  the second postoperative day. A 3-mm subxiphoid port was  used in the only right-sided nephrectomy for liver retraction.  The authors used an articulating grasper (RealHand HD) for  the surgeon's left-hand instrument and a straight instrument  in the right hand. Rane et al performed the first LESS proce-  dures — two simple nephrectomies for nonfunctioning renal  units resulting from long-standing calculus disease, one  orchiopexy, one orchiectomy, and one ureterolithotomy.'? In  this series of five cases carried out with the use of the TriPort,  all were completed successfully without complications with  a mean operative time of 83 min.    References Number Procedures OR time Hospital Complications Analgesic use  of patients (min) stay (days) (morphine  equivalents)  Raman et al!! 3 Nephrectomy 133 2) None -  Kaouk 2007 4 Renal cryotherapy 150 2.8 and 2 1 -=  1 Kidney biopsy  1 Radical nephrectomy  4 Radical prostatectomy  Rane et al'* 1 Simple nephrectomy - = None -  1 Right orchidectomy - - None m  il Left ureterolithotomy - - None -  1 Left orchidopexy, - - None -  appendectomy  1 Right simple nephrectomy — = None =  Kaouk et al!” 5 Sacrocolpopexy 150 p, None -  Ponsky et al'® 1 Radical nephrectomy 96 2 None 34.3  Gill et al” 4 Donor nephrectomy 242 - - 34.8  Goel and Kaouk™ 6 Renal cryotherapy 170 23 1 -  Aron et al” 5 Partial nephrectomy 270 (Median) 3 (Median) 1 -  Cadeddu 2008 11 Nephrectomy 122 (Median) 2 (Median) None 8  Kaouk and Goel% 7 Partial nephrectomy (two 163 33 One focally positive margin -  performed robotically)  Desai et al 13 Simple nephrectomy 145 2 64  4 Radical nephrectomy 208 35 Bleeding from gonadal -  vein — clipped  17 Donor nephrectomy 230 DID Corneal abrasion, dyskinesia 23  from anti-emetics  6 Partial nephrectomy 2l 71:2 One postoperative bleed 28  required angio-  embolization  1 Renal cyst excision 60 1 None =  2 Nephroureterectomy 90 3 None m  16 Pyeloplasty (2 performed — 236 2 None 28  robotically)  Ureteroneocystostomy 210 2 None -  3 Ileal interposition 330 4 One anastomotic leak required —  nephrostomy tube  32 Simple prostatectomy (1 113 3 One mortality in Jehovah’s DO  performed robotically) Witness from hemorrhage  Two postoperative bleeds  required surgical interven-  tion Four postoperative  bleeds required transfusion  alone 1 bowel injury  required exploration 1 UTI  il Transvesical mesh sling 100 1 None =  removal  1 Adrenalectomy 150 3 One renal vein injury repaired —  leading to renal vein  thrombosis requiring long  term anticoagulation  (patent at 3-month  follow-up)  1 Hysterectomy 120 p None =    Fig. 23.3 (a) Postoperative appearance of surgical incision following  LESS simple nephrectomy with morsellation of the specimen. Note that  the incision is hidden completely within the umbilicus. (b) Postoperative  appearance of surgical incision and specimen following LESS radical  nephrectomy with intact extraction of the specimen. Notice that the  incision extends slightly outside of the borders of the incision. Reprinted  from Irwin et al", Copyright 2009, with permission from Elsevier    Two early reports followed, which detailed the use of  purpose-designed multi-channel single-port surgical plat-  forms. In the first, Desai et al described a simple nephrec-  tomy and a pyeloplasty performed via a transumbilical  approach (Fig. 23.3)" with mean operative times of 220 and  160 min, respectively. A supplemental 2-mm needlescopic  port was placed to aid in reconstruction during pyeloplasty.  Patients were discharged on postoperative days 1 and 2,  respectively, without complications.   In the second of such reports, Kaouk et al detailed their use  of LESS techniques in 10 patients undergoing LESS nephrec-  tomy (n= 1), sacrocolpopexy (n = 4), renal cryotherapy (n = 4),  and renal biopsy (n = 1).? Using a combination of bent and  articulating instruments via the Uni-X port without additional  ports, all cases were completed in a mean operating time of  2.5 h. One patient in the cryotherapy group required prolonged  oxygen supplementation and transfusion postoperatively.    The indications for LESS within the clinical human expe-  rience have expanded to include more complex cases since  the initial reports of its safe application in benign diseases of  the upper and lower urinary tracts. Desai et al described their  use of the umbilical LESS approach during six reconstruc-  tive procedures in four patients.” Two bilateral pyeloplasties,  ileal ureteral interposition (Fig. 23.4), and a ureteroneocys-  tostomy were carried out with the aid of a 2-mm needle-  scopic grasper for dissection and suturing. The ileal ureteral  interposition required slight extension of the umbilical inci-  sion to perform an extracorporeal bowel reconstruction. All  procedures were completed without reported complications.   Donor nephrectomy requires the very judicious use of the  newly developed techniques in the process of being estab-  lished to protect these otherwise healthy altruistic patients.  Realizing the potential for significant consequences, Gill and  his team attempted this high-profile procedure in four LESS  donor nephrectomies only after substantial experience with  LESS techniques.” The TriPort was used in all cases again  with aid of a 2-mm needlescopic grasper for retraction dur-  ing hilar dissection and graft extraction within an endoscopic  specimen bag. With a mean warm ischemia time of 6.2 min,  a median length of 3.3 cm of renal artery, 4 cm of renal vein,  and 15 cm of ureter were harvested. Upon transplantation, no  delayed graft function or graft loss were seen in this small  series; and no intra- or postoperative complications were  reported. Donor patients had minimal pain, with all reporting  0/10 visual analog pain scale scores at 2 weeks of  follow-up.   The pediatric surgical population has been traditionally  treated only with well-established treatments. In their initial  report of the application of LESS surgery in the pediatric uro-  logic population, Kaouk and Palmer performed unilateral  LESS varicocelectomy in three adolescents using the Uni-X  port and fixed-bent instruments.? All procedures were per-  formed as outpatient surgery with operative times of less  than 1 h.   Only after the techniques were well established in benign  disease and the surgeons felt comfortable with their experi-  ence and skill were these techniques applied to the urological  oncological arena. The first single-access radical nephrec-  tomy with intact specimen retrieval was reported by Ponsky  et al'^ A GelPort was used with three standard laparoscopic  ports via a 7-cm paramedian incision using standard laparo-  scopic instruments. Minimal blood loss was encountered  during the 96 min procedure, and the patient was discharged  on postoperative day 2 without complication.   Single-port access renal cryoablation (SPARC) was per-  formed in six patients for the treatment of renal masses with  a mean tumor size of 2.6 cm by Goel and Kaouk.™ This  group again favored the use of the Uni-X system with bent  and articulating instruments. Two transperitoneal procedures  were performed transumbilically, and the remaining four    Fig. 23.4 (a) Postoperative  cosmetic appearance and (b)  radiographic appearance of  cystogram following LESS ileal  ureter creation. Note that the  umbilical incision has been  extended slightly to allow for  extracorporeal harvest of the  ileal segment and performance  of bowel anastomosis.  (Reproduced from Irwin et al")    were carried out retroperitoneally with the placement of the  device at the tip of the 12th rib. Ultrasonic guidance was used  for real-time monitoring of the resultant ice ball provided by  a laparoscopic ultrasound probe introduced next to the single  port through the same incision. A single cryoprobe was intro-  duced through the single port for smaller tumors, while addi-  tional probes were placed percutaneously for larger tumors.  A mean operative time of 170 min was reported and the  resultant hospital stay had a mean of 2.3 days. One patient  required a 1-week hospital stay and blood transfusion for the  treatment of respiratory difficulty.   By any measure, laparoscopic partial nephrectomy  remains a technically demanding procedure. Two series  detailing the use of LESS surgery in partial nephrectomy  have been reported to date. Aron et al described the use of  the TriPort in LESS partial nephrectomy in four patients for  tumors ranging in size from 1 to 5.9 cm (median tumor size  3 cm).? A 2-mm grasper was again used to assist in the  reconstruction of the renal defect via a needlescopic port.  One patient underwent conversion to conventional laparos-  copy with the addition of a single 5-mm port. Median warm  ischemia time was 20 min (range 11—29) during a total  median operating time of 270 min. The median estimated  blood loss and hospital stay were 150 mL and 3 days,  respectively. Postoperative complications were seen in only  one patient who developed postoperative hemorrhage and  pulmonary embolism. In a subsequent series, Kaouk et al    performed seven LESS partial nephrectomies, including  two in which robotic assistance was used. ^ Again, one  patient required conversion to conventional laparoscopy to  control bleeding within the tumor resection bed. A single  focally positive margin on final pathology, which was ini-  tially read as negative on intra-operative frozen section,  was reported.   LESS radical prostatectomy including nerve sparing for  the treatment of prostate cancer has been performed success-  fully in carefully selected patients. These cases are techni-  cally challenging as they require the surgeon to be familiar  with both precise dissection as well as reconstructive tech-  niques. By selecting patients who were at clinical stage Tl1c,  had had no prior pelvic surgery, and had a BMI x35, Kaouk  et al carried out LESS radical prostatectomy in four patients.”  They reported a mean total operative time of 285 min con-  sisting primarily of 200 min for prostate excision and an  additional 66 min for vesicourethral anastomosis. Within this  small series, two (50%) had positive margins and one (25%)  developed a recto-urethral fistula 2 months out from surgery.  Reporting on their experience in both cadaveric models as  well as in the living humans, Barret et al were similarly able  to successfully complete LESS radical prostatectomies."' In  the cadaveric model, a combination of both straight rigid and  flexible articulating instruments were used. They noted that  while the articulating instruments were helpful at times dur-  ing the case for dissection, the standard instrumentation was    equally necessary. This group also performed a robotic-  assisted LESS radical prostatectomy in a live patient with an  estimated blood loss of 500 mL. Bilateral nerve preservation  was achieved with negative surgical margins.   The first comparative study between laparoscopic and  LESS applications was reported by Raman et al, in which  they compared 11 LESS nephrectomies to 22 standard lap-  aroscopic nephrectomies.'* A matching protocol was applied  in which patients’ age, surgical indication, and tumor size  were used to identify the groups in a 2:1 ratio for compari-  son. Similar outcomes were reported with regard to operative  time (122 vs. 125 min), percent decrease from preoperative  hemoglobin, analgesic use, length of stay, and complication  rate between the two groups. Indeed, to further delineate the  benefits of LESS procedures, prospective randomized com-  parative analyses incorporating quality of life investigations  are needed.   To date, the largest series compiled in the LESS experi-  ence was reported by Desai et al, encompassing their experi-  ence with 100 LESS procedures. The series includes relatively  heterogeneous group of procedures, such as nephrectomies  (n = 40) (simple, partial, radical, and donor), nephroureterec-  tomy (n = 2), renal cyst excision (n = 1), pyeloplasty (n = 16),  ureteroneocystostomy (7 = 2), ileal ureter (n = 3), adrenalec-  tomy (n = 1) and hysterectomy (n = 1), as well as transvesical  simple prostatectomy (n = 32) and mesh sling removal (n = 1).  The breadth of possibilities for LESS surgery within the uro-  logical surgery repertoire is exemplified by this diverse  series.   Skepticism regarding the rapidity with which the technique  is adopted is expected and can breed a healthy respect for  these procedures in the minds of the pioneers, pushing the  limits of technology. In a multi-institutional review of three  high-volume centers, the authors have found that in our series  of over 1,250 upper tract laparoscopic cases, only 11.6% were  even attempted using LESS techniques despite the surgeons’  familiarity with the skill sets and instrumentation needed for  both conventional and LESS laparoscopy. Of those attempted  using LESS techniques, only 6.8% were converted to a stan-  dard laparoscopic technique requiring the placement of addi-  tional ports to safely complete the procedure. This low rate of  conversion to standard laparoscopy suggests that the early  pioneers in the field have been highly selective in choosing  and counseling patients appropriate for LESS approaches. In  addition, they have been able to identify their own limitations  during this early phase of development of the techniques.    As the minimally invasive surgical world is being redefined  through the use of surgical robotics, a natural extension of  this has been the hybridization of the technology with LESS    surgery. The first group to report on the use of the DaVinci-S  (Intuitive Surgical, Sunnyvale, CA) robotic system in con-  junction with a TriPort single-port access device was Kaouk  et al. They discussed their experience in three patients while  performing a radical prostatectomy, a pyeloplasty, as well as  a radical nephrectomy, for a 5.6-cm right-sided renal mass.?  The TriPort was used with a 12-mm 3D camera and 5-mm  grasping instrument placed through the device with an addi-  tional 8-mm robotic port placed alongside the TriPort in the  same incision for the other robotic instrument. All cases were  completed successfully using this platform without the need  for placement of additional ports. Similar results were  reported with regard to operative times (radical prostatec-  tomy = 5h, pyeloplasty = 4.5 h, radical nephrectomy = 2.5 h),  estimated blood loss (radical prostatectomy = 250 mL, pyelo-  plasty = 80 mL, radical nephrectomy = 200 mL), and hospi-  tal length of stay (radical prostatectomy = 1.5 days,  pyeloplasty = 2 days, radical nephrectomy = 2 days), as are  seen in the conventional robotic-assisted laparoscopic litera-  ture. Pain was minimal in all patients (visual analog scale  score of 0) at 1 week of follow-up. They described signifi-  cant “clashing” of the robotic arms, but concluded that this  platform might provide an opportunity to shorten the learn-  ing curve associated with conventional single-port laparos-  copy. While the DaVinci system has a significantly limited  range of motion while performing LESS surgery, purpose-  designed robotic platforms such as flexible robotics and min-  iature in vivo robotics may, in the future, simplify the  performance of LESS procedures.   Flexible robotics allows the operator to remotely manipu-  late a flexible endoscope along with flexible instruments  passed through the endoscope's working channel to perform  delicate tasks. Such tasks could be carried out via a single  skin incision or through a naturally occurring orifice. This  could allow the surgeon to overcome some of the limitations  encountered while working with rigid systems particularly in  LESS surgery. Both animal model studies and subsequent  patient trials have been reported using this technology while  performing ureterorenoscopic procedures for stone disease.”   The development of small completely in vivo mini robots,  termed “microrobots,” has begun to show promise. These  microrobots, like the flexible robotic platform or the MAGS  system, can be introduced into the abdomen via either a natu-  ral orifice or a small single incision. Here, they have been  used to perform small tasks such as biopsy* and cholecys-  tectomy,? and have the potential for use in a large number of  applications across many disciplines.   Purpose-built single port robots have yet to be developed.  Once available, they may well allow for the dissemination of  LESS technology beyond a few, highly skilled academic cen-  ters. They would allow for the use of articulating instruments  in a manner that would prevent inadvertent instrument colli-  sion and provide larger ranges of motion in the LESS setting  than is currently available.    LESS surgery has, so far, been primarily applied to standard  laparoscopic procedures within a carbon dioxide pneumo-  peritoneum. With the development of newer access devices  has come the proposal for the use of novel approaches. In the  conventional and robotic-assisted laparoscopic literature,  transvesical procedures including simple and radical pros-  tatectomy?? as well as ureteral reimplantation" have been  performed. These cases have typically been prohibitively  complex, in large part, owing to the need for several entry  points into the bladder. In hopes of simplifying the access to  the bladder for these cases, Desai et al described a single-  port transvesical enucleation of the prostate procedure using  LESS techniques. In this procedure, a pneumovesicum is cre-  ated to take advantage of the potential working space within  the bladder while avoiding entry into the peritoneal cavity.”  Such transluminal surgery has been made possible by the  development of new single-incision access devices.    The development of groups such as the Urologic NOTES  working groups and the LESSCAR consortium has secured  the future of LESS surgery as one that will be both well docu-  mented and promoted. The LESSCAR consortium has not  only helped to develop and disseminate a common nomen-  clature to assist in the coordination and monitoring of clini-  cal data as they become available, but has also proposed the  creation of a LESS registry to promote the same ends. With  such a registry, a central source would be equipped to design  and oversee the development and execution of prospective  randomized trials needed to determine the effectiveness and  potential benefits of such new techniques.   With the formation of such these organizations, leaders in  the field are in a position to formulate teaching platforms and  curricula to allow for the safe and efficacious propagation of  the techniques within the surgical community. By doing so,  they will provide a critical service to the success of LESS  surgery, which may be mimicked by other newly developing  techniques across medical disciplines.    1. Wheeless CR Jr. An inexpensive laparoscopy system for female  sterilization. Am J Obstet Gynecol. 1975;123(7):727-733   2. Buess G, Kipfmuller K, Hack D, Grussner R, Heintz A, Junginger  T. Technique of transanal endoscopic microsurgery. Surg Endosc.  1988;2(2):71-75    insertion of peritoneal dialysis catheters in children. J Pediatr Urol.  2006;2(4):308-311    adrenalectomy for adrenal tumors via a single large port. J Endourol.  2005;:19(7):788—792    . Canes D, Desai MM, Aron M, et al Transumbilical single-port sur-    . Gettman MT, Lotan Y, Napper CA, Cadeddu JA. Transvaginal lap-    aroscopic nephrectomy: development and feasibility in the porcine  model. Urology. 2002;59(3):446—450   Clayman RV, Box GN, Abraham JB, et al Rapid communication:  transvaginal single-port NOTES nephrectomy: initial laboratory  experience. J Endourol. 2007;21(6):640—644   Raman JD, Bensalah K, Bagrodia A, Stern JM, Cadeddu JA.  Laboratory and clinical development of single keyhole umbilical  nephrectomy. Urology. 2007;70(6):1039-1042   Irwin BH, Rao P, Stein RJ, et al Laparoendoscopic single site sur-  gery in urology. Urol Clin North Am. 2009;36:223-235   Box G, Averch T, Cadeddu J, et al Nomenclature of natural orifice  translumenal endoscopic surgery (NOTES) and laparoendoscopic  single-site surgery (LESS) procedures in urology. J Endourol. 2008;  22(11):2575—2581   Raman JD, Bagrodia A, Cadeddu JA. Single-incision, umbilical  laparoscopic versus conventional laparoscopic nephrectomy: a  comparison of perioperative outcomes and short-term measures of  convalescence. Eur Urol. 2008;55:1198-1204   Tracy CR, Raman JD, Cadeddu JA, Rane A. Laparoendoscopic  single-site surgery in urology: where have we been and where are  we heading? Nat Clin Pract Urol. 2008;5(10):561-568   Ponsky LE, Cherullo EE, Sawyer M, Hartke D. Single access site  laparoscopic radical nephrectomy: initial clinical experience. J  Endourol. 2008;22(4):663—666   Desai MM, Rao PP, Aron M, et al Scarless single port transumbili-  cal nephrectomy and pyeloplasty: first clinical report. BJU Int.  2008;101(1):83-88   Rane A, Rao P, Rao P. Single-port-access nephrectomy and other  laparoscopic urologic procedures using a novel laparoscopic port  (R-port). Urology. 2008;72(2):260—263   Kaouk JH, Haber GP, Goel RK, et al Single-port laparoscopic sur-  gery in urology: initial experience. Urology. 2008;71(1):3-6  Raman JD, Cadeddu JA, Rao P, Rane A. Single-incision laparo-  scopic surgery: initial urological experience and comparison with  natural-orifice transluminal endoscopic surgery. BJU Int. 2008;  101(12):1493-1496   Park S, Bergs RA, Eberhart R, Baker L, Fernandez R, Cadeddu JA.  Trocar-less instrumentation for laparoscopy: magnetic positioning of  intra-abdominal camera and retractor. Ann Surg. 2007;245(3):379-384  Zeltser IS, Bergs R, Fernandez R, Baker L, Eberhart R, Cadeddu  JA. Single trocar laparoscopic nephrectomy using magnetic anchor-  ing and guidance system in the porcine model. J Urol. 2007;178(1):  288—291   Gill IS, Canes D, Aron M, et al Single port transumbilical  (E-NOTES) donor nephrectomy. J Urol. 2008;180(2):637-641  Goel RK, Kaouk JH. Single port access renal cryoablation (SPARC):  a new approach. Eur Urol. 2008;53(6):1204—1209   Aron M, Canes D, Desai MM, Haber GP, Kaouk JH, Gill IS.  Transumbilical single-port laparoscopic partial nephrectomy. BJU  Int. 2008;103:516-521    Kaouk JH, Goel RK. Single-port laparoscopic and robotic partial  nephrectomy. Eur Urol. 2009;55(5):1163—9   Desai MM, Stein R, Rao P, et al Embryonic natural orifice tran-  sumbilical endoscopic surgery (E-NOTES) for advanced recon-  struction: initial experience. Urology. 2009;73(1):182-187   Desai MM, Aron M, Canes D, et al Single-port transvesical simple  prostatectomy: initial clinical report. Urology. 2008;72(5):960—965  Kaouk JH, Palmer JS. Single-port laparoscopic surgery: initial expe-  rience in children for varicocelectomy. BJU Int. 2008;102(1): 97-99  Kaouk JH, Goel RK, Haber GP, Crouzet S, Desai MM, Gill IS.  Single-port laparoscopic radical prostatectomy. Urology. 2008;  72(6):1190—1193   Barret E, Sanchez-Salas R, Kasraeian A, et al A transition to lap-  aroendoscopic single-site surgery (LESS) radical prostatectomy:  human cadaver experimental and initial clinical experience. J  Endourol. 2009;23:135-140    Kaouk JH, Goel RK, Haber GP, Crouzet S, Stein RJ. Robotic  single-port transumbilical surgery in humans: initial report. BJU  Int. 2008;103:366—369   Desai MM, Aron M, Gill IS, et al Flexible robotic retrograde renos-  copy: description of novel robotic device and preliminary labora-  tory experience. Urology. 2008;72(1):42-46   Rentschler ME, Dumpert J, Platt SR, Farritor SM, Oleynikov D.  Mobile in vivo biopsy and camera robot. Stud Health Technol  Inform. 2006;119:449-454   Lehman AC, Dumpert J, Wood NA, et al Natural orifice cholecys-  tectomy using a miniature robot. Surg Endosc. 2009;23(2):260-266  Desai MM, Aron M, Berger A, et al Transvesical robotic radical  prostatectomy. BJU Int. 2008;102(11):1666—1669    . Gill IS, Ponsky LE, Desai M, Kay R, Ross JH. Laparoscopic cross-    Surgery has been rapidly evolving in the past few decades as  new technologies are being adopted. Abdominal surgery has  traditionally been performed through large incisions into the  peritoneal cavity. In the past decade, traditional open surgery  has been increasingly replaced by minimally invasive laparo-  scopic and robotic techniques. As a result, patient outcomes  have improved, with faster recovery from smaller incisions. On  the other hand, the field of gastrointestinal endoscopy has also  been witnessing major advances. Developing from flexible  endoscopy to endoscopic retrograde cholangiopancreatography  (ERCP) in the 1950s and 1970s to endoscopic ultrasound in the  1980s, endoscopic technology has been transformed from serv-  ing purely diagnostic purposes to therapeutic applications.   Some investigators, amalgamating their experiences from  the fields of minimal access laparoscopic surgery and of flex-  ible gastrointestinal endoscopy, have proposed the concept  of operating in the peritoneal space through natural orifices,  such as the mouth, anus, vagina, and bladder. This translumi-  nal approach offers “scarless surgery.” There is no abdominal  wall incision, and the complications of wound infections,  hernias, adhesions, or dehiscence are eliminated. Natural ori-  fice transluminal endoscopic surgery (NOTES) is potentially  the next paradigm shift in minimally invasive surgery. It  offers the exciting potential to be safer, less invasive, and  possibly more cost-effective than the traditional open surgi-  cal or laparoscopic approach.    Kalloo et al are credited with the fist description of the  NOTES procedure in 2000, in which they demonstrated the  feasibility and safety of a per-oral transgastric endoscopic  approach to the peritoneal cavity with long-term survival in  a porcine model. Their published description came out in  2004.! Since then, several investigators have pursued NOTES  study in animal survival and nonsurvival models, and there  has been a surge in the number of different procedures    performed with NOTES being reported at national meetings  and published in the literature. Initial reports dealt with diag-  nostic procedures including endoscopic peritoneoscopy, liver  biopsy, lymphadenectomy, and abdominal exploration. This  was followed by a variety of successful transluminal proce-  dures including oophorectomy, partial hysterectomy, trans-  gastric jejunostomy, and gastrojejunostomy in both survival  and nonsurvival porcine models.’   To discuss this novel approach, 14 leaders from the  American Society of Gastrointestinal Endoscopy (ASGE)  and the Society of American Gastrointestinal and Endoscopic  Surgeons (SAGES) met in New York City in July 2005.? This  group published its deliberations as the NOTES Working  Group White Paper.* The White Paper delineated the antici-  pated technical barriers to further development of NOTES,  emphasized the need for development to be carried out by  interdisciplinary teams of surgeons and gastroenterologists  and emphasized that any human procedures be performed  only with institutional review board (IRB) approval.  Subsequently, the first international conference on NOTES  was held in Scottsdale, Arizona, in March 2006.   Research in the western part of the world was confined to  animal models. The first human experience was gained by  Drs. Rao and Reddy from India who presented their series of  seven transgastric human appendectomies with good results.'?  Today, human NOTES is already being reported from numer-  ous centers, and the results appear promising. The first clinical  series of transgastric peritoneoscopy has recently been pub-  lished;° multiple groups are accumulating patients in studies of  NOTES cholecystectomy, either via the transgastric or trans-  vaginal route.’ * Cadaveric studies showed the feasibility and  safety of performing advanced procedures through NOTES in  humans.’ As expected, there are teething issues, generating  vigorous debates from the skeptics and the cautious.    The peroral transgastric route was chosen to access the peri-  toneal cavity in initial trials because of a potentially lower  risk for surrounding organ injury using the anterior wall of    the stomach. Also, the gastric flora is less contaminating to  the peritoneal cavity when compared to the other available  natural orifices. It has been shown by a recent study that  transgastric instrumentation does contaminate the abdominal  cavity, but the pathogens do not mount a clinically signifi-  cant response in terms of either the species or the bacterial  load. Techniques commonly used to reduce the bacterial load  are: preoperative overnight fasting, antibiotic lavage of the  stomach, perioperative intravenous antibiotic cover, and  using sterile overtube through the gastrotomy. The least vas-  cular area, midway between the vascular arcades lying along  the greater and lesser curvatures of the stomach, is chosen.  The port is placed in the proximal body of the stomach for  lower abdominal procedures such as appendectomy. A simi-  lar site in the antrum, midway between the arcades, is chosen  for upper abdominal procedures such as cholecystectomy. A  standard wire-guided needle knife, using blended current, is  used to create a stab gastrotomy at the selected site. Adequate  pneumoperitoneum is created through this stab, which is fur-  ther enlarged using a balloon or a sphincterotome for pas-  sage of the double-channel endoscope. The most important  issue in NOTES that is hotly debated and is an area of active  research is the safe closure of the gastric access.! Devices  ranging from endoscopic clips to stapling devices have been  used with considerable success in both animal and human  studies.    The transvaginal route was used to obviate the disadvantages  of operating with a retroflexed scope when performing a  cholecystectomy.'! The transvaginal route provides a more  direct view of the organs of interest for liver biopsies and  cholecystectomies. A triangular area between the uterosacral  ligaments, which is avascular without innervations, is chosen  for the port placement. The difficulties of port closure are  also averted as the port can be hand-sewn under vision. The  transvaginal route has also been used to extract laparoscopi-  cally divided specimens, in a modification of the hybrid pro-  cedure (discussed later). Potential ill-effects of this route  from the gynecological point of view are formation of adhe-  sions, spread of preexisting endometriosis, infertility, and  dyspareunia."   The transanal route was introduced subsequently to over-  come the gender hurdle posed by the transvaginal route.  Experience with transanal endoscopic microsurgery instru-  mentation has been transferred to performance of NOTES  procedures." The rectal port of entry allows rigid laparo-  scopic instruments to be introduced into the peritoneal cavity  and enables performance of gastrointestinal procedures the  same as in standard laparoscopic surgery. However, extra-    long instruments are necessary for dissection from the pel-  vis. The potential disadvantages of the transanal route are  also significant and include issues of sterility, the risk of  inadvertent trauma to adjacent organs during transmural  puncture, and the risk of colonic wall shearing."    Thoracoscopy and mediastinoscopy have been performed in  animal models transesophageally.'^ The self-approximating  transluminal access technique (STAT) was used to enter the  mediastinum. The submucosal tunnel creates a flap-valve  that, alone, may be sufficient for preventing esophageal leak.  The technique provided excellent visualization of mediastinal  and intrathoracic structures. Pleural biopsy could be easily  obtained under direct visualization. Structures that are diffi-  cult to visualize via traditional cervical mediastinoscopy and  thoracoscopy were seen well with this approach. A complete  Heller's myotomy of the gastroesophageal junction has also  been performed with this approach without complication."    In this technique, a single port is introduced through the  umbilicus. Operating instruments, flexible or rigid, are passed  through the multiple channels available in this port. At the  end of the procedure, the scars are hidden inside the umbili-  cus, thus achieving the "scarless" status. This technique has  been termed “‘single-port NOTES.'* Since the umbilicus is  an embryonical (E) natural orifice, the term E-Notes has also  been used.” NOTUS (natural orifice transumbilical sur-  gery),? SILS (single-incision laparoscopic surgery)" and  TUES (transumbilical endoscopic surgery)" are its other  labels. Single-port sleeve gastrectomy,” donor nephrectomy,  right hemicolectomy, bilateral single-session Anderson-  Hynes pyeloplasty, ileal ureter, and ureteroneocystostomy  with a psoas hitch™ have all been shown to be feasible and  safe when performed by experienced laparoscopic surgeons.    Some of the major issues that need to be addressed in NOTES  are blindly performed primary incisions, and uncontrolled  pneumoperitoneal pressure, no support for the endoscope in  the abdominal cavity, inadequate vision, insufficient illumi-  nation, limited retraction and exposure, and the complexity  of suturing and performing a safe anastomosis. All these    could be overcome by using the hybrid technique.” It com-  bines laparoscopy and natural orifice surgery techniques.  Transgastric/transvaginal procedures are performed with  guidance from another instrument introduced through a lap-  aroscopic port. The hybrid technique offers a superior vision  source independent of the working endoscope. The initial  puncture and incision can be done safely under laparoscopic  observation, thereby avoiding injury to adjacent organs.   While some groups used only a needlescope via the per-  cutaneous route, "^ others have used instruments via the lap-  aroscopic port for retraction,” and sometimes even as another  working port.” Hybrid-NOTES could be an ideal first step  before the introduction of “pure” NOTES into clinical prac-  tice. Thus far, hybrid procedures have validated the safety of  many natural orifice procedures in humans. Human hybrid  transvaginal and transgastric peritoneoscopies,” cholecys-  tectomies," nephrectomy,” and sigmoidectomy? have  already been reported. Natural orifice (transvaginal or tran-  sanal) extraction of laparoscopically dissected specimen is  also described as a modification of hybrid notes.   Another variant of the hybrid technique is the “dual lumen"  technique.*' Simultaneous use of transgastric and transvaginal  routes provide the same advantages of the hybrid technique  while avoiding an external scar. It has also been described  as the “rendezvous” technique. Distal pancreatectomy* and  small bowel resection and anastomosis?" have been done  safely using this variant technique of Hybrid NOTES.    Entering the peritoneal cavity with the echoendoscope has  been avoided because this endoscope is rather rigid and dif-  ficult to handle and maneuver in a limited space. However,  EUS has been used to guide NOTES procedures. Blind  NOTES access through the antrum, posterior stomach wall,  and rectum could result in catastrophic complications. EUS-  guided access through these sites has been shown to substan-  tially reduce this risk.” EUS appears promising as an adjunct  to NOTES access, particularly as more experience is gained  in definitively excluding the presence of at-risk extraluminal  structures.?    Over the past decade, robots have been appearing in the  operating room and in the endoscopic suite. It will be no  wonder if they will soon have a defined role in NOTES.  Using the da Vinci surgical system and accessing the    peritoneal cavity through a single-port pyeloplasties, partial  nephrectomies and radical nephrectomies have been  performed with ease and safety in porcine models.  Intracorporeal suturing is significantly enhanced using the  robot, especially through the challenging transluminal natu-  ral orifice approach. A two-armed dexterous miniature  in vivo robot with stereoscopic vision capabilities has suc-  cessfully demonstrated various capabilities in a nonsurvival  natural orifice surgical procedure in a porcine model.” The  design and kinematic configuration of the robot allows for its  complete insertion into the peritoneal cavity and provides  intuitive visualization and sufficient force application for tis-  sue manipulation within the dexterous workspace. Further  development of robots adaptive to NOTES would boost  efforts toward clinical NOTES applications.    The fundamental skill set necessary to perform NOTES  includes both minimally invasive surgical skills and endo-  scopic skills. While the latter is required for appropriate  employment of the instrument, the former is required for rec-  ognition of anatomy and orientation inside the peritoneal  cavity. Hence, the ASGE/SAGES working group had recom-  mended the establishment of multidisciplinary team possess-  ing advanced therapeutic endoscopic and advanced  laparoscopic skills to study NOTES.? Animal laboratory  facilities to perform research and training should be avail-  able to the multidisciplinary team for exploration of NOTES  techniques and procedures. IRB approval must be obtained  before introduction of NOTES procedures in human patients.  Some institutions are developing training programs for  digestivists incorporating both surgical and gastroenterologic  training.” A steep learning curve has been reported from one  such training program, despite the presence of an investiga-  tor with experience in NOTES.    Urologists of the present era possessing both minimally inva-  sive surgical skills and endoscopic skills are ideal candidates  to take up the mantle of NOTES specialists. The first experi-  mental application of NOTES in urology was published in  2002 when transvaginal nephrectomy was performed in the  porcine model. Confirmatory experimental studies using the  gastrointestinal tract for NOTES were first published in  2004.” Gettman et al in 2006 described the initial clinical  case in which they evaluated the bladder as a portal for  NOTES.* Subsequently, NOTES has been used to perform    urological procedures in humans starting from transvesical  peritoneoscopy to transvaginal donor nephrectomy” safely  and effectively.    There are many potential advantages of NOTES over con-  ventional surgery. Much like laparoscopy has demonstrated  less physiologic impact than laparotomy, NOTES may cause  less physiologic insult than either laparoscopy or laparotomy.  Absence of scar has obvious advantages.? There is the lack of  common complications of conventional surgery such as  wound infections and incisional hernia. It may probably  reduce the formation of intraabdominal adhesions.^?   Given the portability of NOTES equipment, NOTES might  shift the surgeon from the operating theater to the patient's  bedside. Major interventional procedures might be carried out  in the future in an intensive care unit (ICU) setting. Moving the  equipment to the patient, rather than vice versa, might reduce  the resource requirements and potential complications of trans-  porting a patient to the operating room. Moreover, NOTES  could be performed under conscious sedation, rather than gen-  eral anesthesia, again favoring ICU-based procedures.   NOTES offers specific advantages to select population of  patients. Patients with no percutaneous access, as in the  patient with abdominal wall burns who underwent the first  NOTES appendectomy, will derive special benefits from  NOTES.’ Another group is the morbidly obese, who will  benefit greatly from NOTES, when done with minimal anes-  thesia and rapid postoperative convalescence.*! Studies have  already demonstrated the feasibility of obesity surgeries,  such as sleeve gastrectomy, by NOTES.”   The interest in NOTES has motivated lot of research  among the major makers of laparoscopic and endoscopic  instruments. Current and future endoscopists and lapraosco-  pists will reap the benefit of this research, because many  techniques and devices that are developed for NOTES will  be also put to use in conventional procedures.   Lastly are the cosmetic benefits of NOTES. It has been  shown that young people would prefer to undergo a scarless  experimental procedure than a well-established conventional  procedure even after being educated about the risks involved.?    NOTES being a new technique requires refinement before it  can be employed in daily clinical practice. It has its fair share  of skeptics, faces various technical and intellectual chal-  lenges, and several key issues need to be addressed.    Infection of the peritoneal cavity by organisms carried in  by the scope from the orifices has been an obvious area of  concern. Extensive surgical experience with bacteriologic  contamination of the peritoneum during bowel surgery shows  that if gross spillage is avoided and appropriate antibiotic  cover is provided, the contamination is well tolerated. A  recent study has shown that transgastric instrumentation does  contaminate the abdominal cavity, but the pathogens do not  mount a clinically significant response in terms of either the  species or the bacterial load." On the other hand, NOTES  transgastric ventral hernia repair was found to have a high  infection rate, despite adequate antibiotic precautions.?  Introduction of new organisms that are commensals of the  mouth, anus, or the vagina into the peritoneal cavity is  another important issue.   Reliable closure of the transgastric defect remains a  key component for advancement of NOTES into clinical  practice.^* Peritonitis in even a minor percentage is unac-  ceptable, considering the safety of laparoscopy in this  regard. Endoscopic sutures and clips have been used in the  earlier reports. T tags have been used for transluminal  colonic defects closure with considerable success in the  animal model. Today, various stapling devices, including  the NDO Plicator," originally designed for endoscopis  plication for GERD, the endoscopic tissue plicating  devices (TPD), and the automated flexible stapling device  (SurgASSIST)? among many others, have been evaluated  and safety proved in various studies. Fluid- and air-leak  tests are simple techniques that can be used to evaluate  in vivo the adequacy of the transluminal access site clo-  sure after NOTES procedures.^?   Triangulation, tissue retraction, and apposition are the  fundamental principles in any laparoscopic procedure. The  current endoscopes, however, have limited ability to manipu-  late the intraabdominal organs. There is a fixed parallel ori-  entation of the view and instrument axes, reducing the ability  for three-dimensional assessment. They have insufficient  angulation, tolerate very little push force, and have a very  narrow accessory channel. NOTES tools that are being devel-  oped are expected to address these issues soon?!   Working off the axis of the camera angle (i.e., off axis) as  is routine in laparoscopic surgery is a problem surmountable  with practice and a little mental exercise when rigid scopes  are used." However, when flexible scopes are used in  NOTES, the off-axis view results in spatial incongruity,  requiring severe mental strain. This will prevent complex  procedures from being performed with the speed and facility  that in-line visualization would allow. Potential solutions  include the use of multiple cameras to achieve the appropri-  ate inline view of the working area? and the use of computer  interface (live video manipulator)** between the video feed  and the actual image of the end organ, which automatically  adjusts the axis of the camera angle with every deviation.    To date, the advantages of NOTES have been only theo-  retical. No study has so far shown scientific evidence of the  proposed benefits of a scarless surgery. For wider acceptance  of this technique in the scientific community, trials compar-  ing NOTES to conventional surgery need to be undertaken.   Pursuit of NOTES in any institute requires animal lab  facilities and procurement of advanced tools and devices that  incur huge costs. However, when NOTES gains general  acceptance, the actual expenditures might be outweighed by  decreased consequential costs.”    New innovations come to the fore by breaking down older  borders in an intelligent fashion. When the flexible endo-  scope was taken beyond the gastrointestinal lumen into what  lies beyond the confines of the gastrointestinal tract, skeptics  called it blasphemous. However, continued collaboration  between the gastrointestinal endoscopists and minimally  invasive surgeons has resulted in the burgeoning growth of  NOTES that it now represents a paradigm shift in surgery.   While NOTES may represent a new era in surgery, it is  still largely an experimental field. Although clinical NOTES  is gaining momentum, the field should remain in check while  rigorous laboratory work is performed and cogent clinical  trials are undertaken. The zeal for NOTES should not take  precedence over the welfare of the patient. Well-managed  human studies need to be conducted to determine the safety  and efficacy of NOTES in a clinical setting. Although many  limitations need to be surmounted before NOTES can reach  the human clinical trial stage, the prospect of safe, minimally  invasive, and scarless surgery appears very promising. The  near future will tell whether current barriers will be broken  down and NOTES will acquire a fixed place in the diagnosis  and therapy of maladies in humans.    1. Giday SA, Kantsevoy SV, Kalloo AN. Principle and history of  Natural Orifice Translumenal Endoscopic Surgery (NOTES). Minim  Invasive Ther Allied Technol. 2006;15(6):373-377   2. dela Fuente SG, Demaria EJ, Reynolds JD, Portenier DD, Pryor AD.  New developments in surgery: Natural Orifice Transluminal  Endoscopic Surgery (NOTES). Arch Surg. 2007;142(3):295-297   3. Rattner D, Kalloo A. ASGE/SAGES Working Group. ASGE/SAGES  Working Group on Natural Orifice Translumenal Endoscopic  Surgery. October 2005. Surg Endosc. 2006;20(2): 329—333   4. Bowman D. 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Natural orifice transluminal endoscopic  surgery in future obesity treatment. Chirurg. 2008;79(9):837-842  Ramos AC, Zundel N, Neto MG, Maalouf M. Human hybrid  NOTES transvaginal sleeve gastrectomy: initial experience. Surg  Obes Relat Dis. 2008;4(5):660—663   Hagen ME, Wagner OJ, Christen D, Morel P. Cosmetic issues of  abdominal surgery: results of an enquiry into possible grounds for a  natural orifice transluminal endoscopic surgery (NOTES) approach.  Endoscopy. 2008;40(7):58 1-583   Narula VK, Happel LC, Volt K, et al Transgastric endoscopic peri-  toneoscopy does not require decontamination of the stomach in  humans. Surg Endosc. 2009;23(6):1331—1336   Buck L, Michalek J, Van Sickle K, Schwesinger W, Bingener J. Can  gastric irrigation prevent infection during NOTES mesh placement?  J Gastrointest Surg. 2008;12(11):2010-2014   Voermans RP, Worm AM, van Berge Henegouwen MI, Breedveld P,  Bemelman WA, Fockens P. In vitro comparison and evaluation of  seven gastric closure modalities for natural orifice transluminal  endoscopic surgery (NOTES). Endoscopy. 2008;40(7):595-601  McGee MF, Marks JM, Onders RP, et al Complete endoscopic clo-  sure of gastrotomy after natural orifice translumenal endoscopic  surgery using the NDO Plicator. Surg Endosc. 2008;22(1):  214-220   McGee MF, Marks JM, Jin J, et al Complete endoscopic closure  of gastric defects using a full-thickness tissue plicating device.  J Gastrointest Surg. 2008;12(1):38-45   Meireles OR, Kantsevoy SV, Assumpcao LR, et al Reliable gastric  closure after natural orifice translumenal endoscopic surgery  (NOTES) using a novel automated flexible stapling device. Surg  Endosc. 2008;22(7):1609-1613   Dray X, Gabrielson KL, Buscaglia JM, et al Air and fluid leak tests  after NOTES procedures: a pilot study in a live porcine model.  Gastrointest Endosc. 2008;68(3):5 13-519   Swanstrom LL, Whiteford M, Khajanchee Y. Developing essential  tools to enable transgastric surgery. Surg Endosc. 2008;22(3):600-604  Swanstrom L, Zheng B. Spatial orientation and off-axis challenges for  NOTES. Gastrointest Endosc Clin N Am. 2008;18(2):315-324; ix  Reavis KM, Melvin WS. Advanced endoscopic technologies. Surg  Endosc. 2008;22(6):1533-1546. Epub 2008 Apr 10   Tang SJ, Bergs R, Jazrawi SF, et al Live video manipulator for  endoscopy and natural orifice transluminal endoscopic surgery  (with videos). Gastrointest Endosc. 2008;68(3):559-564   Maffei M, Dumonceau JM. The future of “NOTES”. Rev Med  Suisse. 2008;4(169): 1879-1881    Osamu Ukimura, Masahiko Nakamoto, Yoshinobu Sato,  Makoto Hashizume, Tsuneharu Miki, Mihir Desai, Monish Aron,    In conventional open surgery, intraoperative surgical planning  was determined by unifying all the human senses, based on a  combination of the surgeon's experience and intraoperative  information, obtained, for example, from direct vision and tac-  tile feedback. In order to update surgical planning during sur-  gery, the surgeon has needed extensive imagination to combine  the intraoperative anatomical information with preoperative  2-D images or with knowledge based on surgical experience.  With the significant advantage of minimal invasiveness for the  patients, emerging surgical techniques, such as endoscopic sur-  gery, percutaneous intervention, or the extracorporeal approach,  have increasingly become alternative therapeutics to the con-  ventional open approach. However, these have distanced the  surgeon from the real surgical field, diminishing his understand-  ing through limited access. The emerging 3-D endoscope, the  flexible endoscope, and robot arms have successfully compen-  sated for some of the disadvantages during laparoscopic sur-  gery. However, in the modern era of minimally invasive urology,  the search for new technology has continued, to compensate for  the diminished human understanding, to decrease the learning  curve, or even to make the new approach superior to the conven-  tional approach. Emerging computer-aided digital imaging  technology provides a powerful new opportunity to obtain real-  time 3-D visualization of the surgical fields, even beyond the  surgical view, for the surgeon to have an idea of how to optimize  the surgical approach and how to decrease surgical morbidity.  Computer-aided imaging technology gives logical infor-  mation to improve presurgical planning, intraoperative guid-  ance, or predictive surgical navigation, to increase the  precision of the expert surgeon as well as to decrease the  learning curve of the novice. Intraoperative navigation can  lead the surgeon to reduce redundant surgical acts, thus  decreasing surgical errors and shortening operating times.    Augmented reality (AR) is a novel computer technology for  image-guided surgery to display 3-D computer graphics of    the surgical space. These are synchronized geometrically  and superimposed onto the real endoscopic surgical view,  presenting 3-D information of the surgical target beyond the  real surgical view. The advantage of this technology is to  allow real-time 3-D visualization of the surgical anatomy  beyond the endoscopic vision, which it has never been pos-  sible to obtain by the human senses alone. It can combine  any intraoperatively or preoperatively acquired imaging  (including US, CT, MRI, functional MRI, PET, or scintigra-  phy) and pathological data, and reconstruct them into 3-D  computer graphics for surgical navigation.'*   The AR technology system consists of a computer work-  station, a tracking system, an imaging modality, an endoscope,  and a display system. In this system, since the angle and direc-  tion of the endoscope is tracked in real time by a special sen-  sor (such as an optical or magnetic sensor), the 3-D space of  the reconstructed 3-D image can be accurately synchronized  with the 3-D space of the endoscopic surgical field.   AR and earlier computer-aided techniques have been  implemented most prominently in neurosurgery, facilitated  by the fact that the brain exists in a relatively fixed space sur-  rounded by a bony reference.^" Because AR images cannot  yet be projected in real time, using AR for other surgical spe-  cialties is difficult, since most human organs are not rigid,  but deform according to the rhythms of heartbeat and respi-  ration, the air pressure of laparoscopic instillation, the pro-  gression of the surgery, or when physically probed. Despite  these difficulties, AR methods are gaining increasing recog-  nition in multiple fields of surgery, especially in minimally  invasive surgery. We believe that the prostate is an attractive  target for AR-assisted surgery, because it is a relatively fixed  organ on the anterior surface of the rectal wall in the pelvis,  which is at the bottom of the abdominal cavity, and disloca-  tions by the rhythms of heartbeat and respiration are minimal  compared to other intraabdominal organs. While the kidney  may suffer dislocation due to the rhythms of heartbeat and/or  respiration, we believe it is also an attractive target for  AR-assisted surgery, because it is a relatively fixed organ, in  which the 3-D anatomical information of the tumor location  and the major vasculature in preoperative CT will provide  significant information to help the surgeon.    Recently, a case report of augmented-reality-assisted lap-  aroscopic adrenalectomy was described, using a preopera-  tive CT image." Although the feasibility of using AR was  reported, the absolute role and indications for AR in surgery  have not yet been established. The outcomes discussed in  most published reports to date have included user-friendly  features, the accuracy of targeting tissues, and favorable cost  as end points. The current limitations of AR systems are  related to concerns about feasibility, accuracy, and under-  appreciation of device sophistication. Existing opinions are  that experienced surgeons may benefit from such systems by  extending the limits of the safe area to allow for more com-  plete and radical operative therapy, while less experienced  surgeons may benefit by more rapidly getting oriented to  critical anatomic landmarks.    In a contemporary series of studies of localized prostate can-  cer (clinical T1-T2 disease) treated by radical prostatectomy  (RP), pathological extracapsular extension of the cancer  (pT3 disease), which has been associated with poor progno-  sis, was reported in 21% to 46% of patients. ^ Another  occurrence that is likely to increase the risk of cancer posi-  tive surgical margins is iatrogenic prostate capsulotomy by  the surgeon contending with the cancer in the intricate pelvic  anatomy. Since most prostate cancers arise in the peripheral  zone close to the capsular margin, generally only minimal  normal soft tissue surrounds the cancer nodule. Attempts to  achieve wide surgical margins during RP may risk damage to  the neurovascular bundle (NVB) or the urethral sphincter. In  nerve-sparing RP, the risk of capsulotomy is especially high  in the regions of the right and left NVBs, which lie close to  the posterolateral surface of the prostate capsule.   Given the difficulties in avoiding capsulotomy during RP  while sparing the NVB and urethral sphincter, and the asso-  ciations of positive surgical margins and the extracapsular  extension of prostate cancer with adverse prognosis, it would  be of considerable benefit to provide accurate real-time intra-  operative information about the location and extent of the  cancer in relation to the surrounding tissues. Such informa-  tion could also help the laparoscopic surgeon overcome the  muted tactile feedback during laparoscopic RP (LRP).   Traditionally, during open surgery, surgeons have relied  on surgical vision and the palpation of structures in the surgi-  cal field, together with surgical planning based on preopera-  tive imaging studies. During surgery, the required abstract  assembly of both pre and intraoperative information within  the surgeon's brain is suboptimal and can potentially be  improved upon. More importantly, the concerned anatomy of    the surgical fields continually changes during RP from the  preoperative anatomy, because of the progression of the sur-  gical procedures, underscoring the need for a real-time intra-  operative imaging modality to assist the surgery.   We recently developed a novel real-time intraoperative  TRUS-guided technique of LRP, with energy-free release of  the NVBs.'*'° Intraoperative TRUS is capable of imaging  the prostate contour anatomy and a substantial percentage  of nonpalpable prostate cancers, as well as periprostatic  anatomy such as the course, dimensions, and vascularity of  the NVBs. Currently, about 40% of patients undergoing  LRP for localized prostate cancer have hypoechoic cancer  nodules detectable by TRUS. Intraoperative TRUS monitor-  ing during LRP allows individualized, precise dissection  tailored to the specific prostate contour anatomy, thus com-  pensating for the muted tactile feedback of laparoscopy. In  our initial experience, real-time TRUS guidance signifi-  cantly decreased the incidence of positive surgical margins  during LRP.   As we described in those recent reports, real-time intraop-  erative TRUS guidance has been effective in overcoming the  disadvantage of muted tactile feedback during minimally  invasive LRP. However, the use of that technique with LRP  remains limited by the difficulty of mentally synchronizing  (registering) the TRUS image on a video screen other than  the live video monitor of the laparoscopic surgery. An ideal  situation would be to precisely determine the locations in  three dimensions of the prostate, prostate cancer, NVBs, and  other relevant pelvic tissues, and superimpose 3-D images of  those tissues onto the intraoperative laparoscopic view of the  surgery, which could then guide appropriate modification of  surgical resection. An adaptation of our AR technology has  made that possible, and the success of real-time intraopera-  tive TRUS guidance of LRP makes it ideal to provide the  images for that next important step of computer-aided image-  guided surgery."    The AR system includes a workstation (computer and soft-  ware), a tracking system (sensor and marker), an imaging  modality (such as a US probe), an endoscope, and a display  system (Fig. 25.1). Essential steps of AR technology include  the abilities (1) to calibrate the instruments, (2) to segment  the region of interest in imaging and to construct a 3-D vir-  tual model of it, (3) to track laparoscope and surgical instru-  ments in real time, to synchronize the 3-D virtual model  fused with the real surgical display, and (4) to register the  3-D space of the model onto the real patient's 3-D surgical  space, while minimizing organ movement during progress of  the surgery.    Figures 25.1 and 25.2 show how our AR system will be  arranged in the operating room for use during TRUS-guided  LRP. For a generation of AR images during LRP, we have  used a Passive Polaris? optical position sensor (Northern  Digital Inc., Waterloo, Ontario, Canada) (Fig. 25.1) with the  TRUS probe, a laparoscope, and one pair of dissecting scis-  sors each fitted with a triangular planar rigid body (passive  tracker probe, Northern Digital Inc.) containing spherical,  retroreflective optical markers (Northern Digital Inc.)  mounted at each corner. The rigid bodies with markers are  attached to parts of the devices that remain outside the  patient’s body. The dissecting scissors will be used to cali-  brate superimposition of the initial AR image of the prostate  onto the live laparoscopic view. The positions of the TRUS  probe, laparoscope, dissecting scissors, and optical position  sensor with respect to each other and the patient are shown in  the figure. The intraoperative TRUS images, normally viewed  only on the US screen, are shown on the workstation screen,  where the cancer nodule, prostate, NVB, and other structures  are traced on the TRUS images, and the 3-D image is con-  structed. The 3-D image is then superimposed on the laparo-  scopic video screen in a geometrically accurate manner.   We are using a US machine (Pro Focus, B-K medical,  Herlev, Denmark) with a biplane TRUS probe (type 8808,  B-K medical) for US image acquisition (Fig. 25.1). TRUS  images are digitized as a 320 x 240 matrix using a Sunvideo  Sbus card (Sun Microsystems, Mountain View, CA). Three  spherical, retroreflective optical markers for the Polaris sys-  tem (NDI-1201115, Northern Digital Inc.) have been fixed    Fig. 25.1 Augmented reality  (AR) system: polaris, infrared  optical camera (left upper) and  its role to track the position of  the instruments with optical  markers attached (left bottom),  optical marker attached  laparoscope (right upper),  optical marker attached TRUS  (left middle), and optical marker  attached scissors (right bottom)    on the proximal end of the TRUS probe with a triangular  planar passive tracker probe (TA-200, Northern Digital, Inc.)  and its attachment.    Fig. 25.2 AR system for laparoscopic radical prostatectomy (RP):  TRUS and laparoscopic systems in the operating room. The location of  the optical position sensor was moved from its actual unobstructed  position relative to the TRUS probe and laparoscope for ease of viewing  all of the connections in this figure    Intraoperatively acquired images such as real-time US or  fluoroscopy could be accurately superimposed onto the vid-  eoscopic view, if there was no movement in the surgical field  between the image acquisition time and the image projection  time. However, when preoperatively acquired high-resolu-  tion imaging modality scans such as CT or MRI are used for  image guidance, the space of the preoperative image needs to  be registered to the ongoing real surgical space in the patient  during the procedure. In our AR system, we have mainly  used reconstructed 3-D surgical models with TRUS and MRI  in prostate surgery and CT for kidney surgery.    A specially shaped acrylic phantom board has been designed  for the US calibration (Fig. 25.3). This board was placed  under water, and a TRUS probe was positioned over the cali-  bration board in such a way that the US section was com-  pletely coincident with the plane of the board. A 2-D US  image was then acquired. When a sequence of TRUS images  is acquired, the transformation defining the 3-D positions  and orientations of the TRUS probe with attached optical  trackers is simultaneously acquired along with each image.    This acquisition is performed at a rate of about 15 frames/s.  One sequence of acquired images usually consists of 240—  300 slices of 2-D TRUS images. A 3-D model of the phan-  tom is reconstructed from the US images. The 3-D positions  of the tips of the M-shaped part will be used as the control  points of the calibration procedure. Digitization of the tips of  the calibration board will be performed using the Polaris  system.   A special projection-point-board was used to obtain the  camera calibration images, with each point on the board  being used as a control point (Fig. 25.4). The board was posi-  tioned so as to be nearly parallel to the image plane at four  different depths from the camera. In that way, the control  points were arranged as uniformly as possible within the 3-D  volume used in the clinical setting. The distance from the  camera to the center of this 3-D volume was adjusted so that  it lay approximately within the field of view of the camera,  which was focused on the volume center. The volume, which  should be sufficient to include the entire prostate and bilat-  eral NVB views, ranged typically from 12 x 12 x 12 cm! to  15x 15 x 15 cm?. The depth of field of the camera should be  adequate when the focus is fixed. The distance from the cam-  era to the volume center will be typically around 20 cm.    Fig. 25.3 Preoperative TRUS calibration: (a) acrylic phantom board;  (b) 2-D TRUS image of the phantom board; (c) 3-D model of the phan-  tom reconstructed from a series of TRUS images. In the process of cali-    bration, the location of the projected red-colored points (where the  radius is 1.0 mm) as control should be finally corrected to correspond to  the center of each point of the M-shaped image of the phantom board    The 3-D positions of the control points will be measured  using a Polaris pen probe. Fitting straight lines to the edge of  the board and extracting their intersection points will yield  the corresponding 2-D positions in the camera images. In a  typical focus setting, the estimated focal length will be about  410 pixels. During the calibration process, the location of the  small, red points should be finally corrected to correspond to  the center of each of the points on the projection-point-  board.    Preoperative Calibration of the Entire  System of 3-D Reconstruction and AR    The construction of a 3-D model from TRUS images and the  superimposition of the model on the camera images uses the  specially shaped acrylic phantom board. The following com-  parisons will be made for the evaluation and calibration of  preoperative errors within 1.0 mm:    * Comparison of the 3-D shape of the phantom recon-  structed from US images and the 3-D positions of the ver-  tices of the phantom measured by the Polaris system to  evaluate the accuracy of the 3-D US reconstruction.   * Comparison of the projection of the phantom to evaluate  the integration accuracy of the 3-D US reconstruction and  the superimposition.    For preoperative calibration, a total of six sequences of TRUS  images, three each in both transverse and longitudinal views,  each at three different depths (5.0 cm, 6.2 cm 7.4 cm, obtained  by transverse and longitudinal sweep directions using the  biplanar TRUS probe) will be prepared to reconstruct the    Fig. 25.5 AR visualization  (left) using the 3-D surgical  model with the biopsy  confirmed cancer blue area  (right), which was developed  from intraoperatively acquired  real-time 2-D TRUS image, to  be superimposed onto the  real-time laparoscopic view    3-D models for intraoperative acquisition. In every sequence,  the small, red points (red-colored points) (where the radius is  1.0 mm) denote the vertex positions of the phantom accu-  rately measured by the Polaris pen probe. The perceived ver-  tices of the reconstructed model should coincide well with  the accurately measured ones in all of the results with differ-  ent sequences. The preoperative errors will be corrected  within 1.0 mm at the five control points of the M-shaped part  of the phantom board.    Construct an intraoperative AR image of the prostate by trac-  ing the outline of the prostate in each 2-D TRUS image using  Virtual Place software (Medical Imaging Laboratory, Inc.,  Tokyo, Japan) and create a 3-D image from those 2-D images  by the volume-rendering method. Project the 3-D AR image  onto the laparoscopic screen according to the spatial coordi-  nates of the TRUS probe and laparoscope, as registered by  the Polaris Position Sensor.   Construct AR images of the cancer nodule, NVBs, lateral  pedicles, and the prostate in the region of the lateral pedicles  from successive TRUS images and superimpose those images  onto the laparoscopic view (Fig. 25.5). The NVBs will be  imaged with the US machine in Power Doppler mode,  because the blood flow in the NVBs and dorsal vein facili-  tates Power Doppler resolution of those structures in 3-D.  These 3-D images can be used directly by the AR system for  superimposition onto the laparoscopic view, requiring only  removal of the dorsal vein image, but eliminating the need to  make tracings of the 2-D images.    The key to image guidance is to know (1) where the surgical  targets are, (2) in which direction the surgical instruments  should advance, and (3) how close the tips of the instruments  are to the surgical target. The effectiveness of a surgical navi-  gation system is significantly related to the accurate registra-  tion of the 3-D surgical model in spatial relationship to the  surgical instruments and the surgical anatomy. Using the pre-  operatively acquired CT or MRI, the preoperative space of  the acquired image needs to be registered on the ongoing real  surgical space in a patient.   Optical tracking systems are the most prevalent track-  ing technology with a highly accurate and fast rate of sam-  pling data. There are two primary classes of optical tracker:  active and passive. An example of a passive system is the  Polaris system (Northern Digital, Inc., Waterloo, Ontario,  Canada), which we have used in our system. Three or more  reflective optical markers are attached to the instruments  in a specific triangulated figure. When an infrared stereo  camera unit emits light onto the markers, the reflected  light is received as digital data identifying the position and  angle data of the instruments with the optical markers  attached.   Magnetic tracking systems have the greatest potential in  accurate tracking technology. However, their use has been  limited because of an inherent feature, the distortion of the  magnetic field by the metallic instruments around the surgi-  cal space such as the surgical bed, endoscope, scissors, and  forceps. The magnetic tracking system consists of three com-  ponents, including (1) a magnetic field generator, which gen-  erates the magnetic fields around the surgical space, (2) a  magnetic sensor, which contains specific coils to produce  electrical signals within the generated magnetic fields, and  (3) a system workstation, which receives the sensor position  data and communicates the digital information with the host  computer and magnetic field generator.   In the interventional surgical procedure, a stereotactic  frame can be used by an interventional surgeon to avoid the  use of a highly technological tracking system. Such a frame  can be rigidly mounted to the operating room table or  patients' body, for example, mounted to the cranium in brain  surgery. Mounted needle guidance on it will direct accurate  needle placement into the target. These devices were the pre-  cursors to magnetic or optical trackers; however, they can  still be useful without requiring a continuous tracking sys-  tem. A robot arm can be also another promising tool for  localization of the surgical instruments. The digital coordi-  nates of the tips of scissors or forceps, which can be con-  trolled by the robot arm, can be accurately calibrated and  placed in a precise location.    In our initial experience, we employed the AR surgical naviga-  tion system in 25 laparoscopic surgeries, including 11 renal  surgeries and 14 pelvic surgeries. We were able to superimpose  the intraoperatively acquired 3-D US and preoperatively  acquired 3-D images of CT/MRI, which demonstrated the  anatomies of tumor and vital structures (such as the renal artery,  the collecting system, and the NVB), onto the real-time laparo-  scopic view (Figs. 25.5 and 25.6). The accuracy in superimpo-  sition was reasonably precise (theoretically, less than 3 mm  error in matched points) and sufficient to provide a 3-D percep-  tion beyond the surgical view, which has not been achieved by  any other imaging guidance system available today.   Among the 11 laparoscopic kidney surgeries, construc-  tion of 3-D images of surgical interest (renal tumor, collect-  ing system, and vasculatures) from preoperative CT data was  performed one day before the surgery, which required 1—2 h  (mean 1.3 h). Once the planned 3-D surgical models of the    Fig. 25.6 AR visualization (bottom) using the 3-D surgical model from  original preoperative CT image (upper), which is colored by four color-  coded-zonal navigation concept, to be superimposed onto the real-time  laparoscopic view    preoperative CT were constructed, the registration process  required 5-18 min (mean 12 min). Techniques of image reg-  istration included the use of the "iterative closest point  algorithm" and the "preoperative image to real-time-image  algorithm." During laparoscopic partial nephrectomy, the  3-D-constructed tumor image using AR was interpreted  directly by the surgeon. The accuracy of the superimposed  image was confirmed by the correspondence of the routine  electrocauterized surgical marking, which was suggested by  2-D-laparoscopic US in our routine laparoscopic partial  nephrectomy procedure.   In laparoscopic partial nephrectomy, we applied our original  concept of the four-color coded surgical navigation system. The  four sequential, color-coded zones were painted around the sur-  gical target such as a renal tumor: the tumor was colored red,  surrounded circumferentially by a 5-mm caution zone in yel-  low, a 10-mm planned dissection zone in green, and a >10-mm  healthy renal tissue zone in blue (Fig. 25.6). This newly devel-  oped concept aims to allow the surgeon to achieve a negative  surgical margin while maximizing preservation of the renal  function, by keeping the surgical dissection line within the green  zone (5-10 mm zone from the edge of the tumor). The interval  margin can be set at any required length (such as 5 mm), depend-  ing on the factors of (1) surgical planning, (2) possible errors of  the superimposed image in the surgical navigation system, and  (3) possible errors of the surgical procedure itself.   Real-time projection of the color-coded zonal surgical  navigation system helped the surgeon to determine intraop-  eratively where to cut (continuing to cut while staying in the  green zone) and what to preserve (preserving renal function  in the blue zone), contributing to the achievement of a nega-  tive surgical margin in all cases while maximizing preserva-  tion of the renal function. In renal surgery, AR facilitated  intraoperative identification of the renal artery and vein,  which were superimposed onto the renal hilar fat.   Among the 14 pelvic surgeries, including 13 laparoscopic  radical prostatectomies and a laparoscopic radical cystec-  tomy, construction of 3-D images of the prostate with a  biopsy-proven cancer area from intraoperative gray scale  10 MHz TRUS required 11-24 min (mean 17 min) during  surgery, after acquisition of intraoperative TRUS volume  data, which required less than 1 min. Another acquisition and  construction of 3-D-images of NVB from intraoperative  power Doppler TRUS required 3—7 min (mean 5 min) during  surgery. Since the 3-D-TRUS image was intraoperatively  acquired from the present surgical field, no registration pro-  cedure was needed. During LRP, the AR suggested cancer  area was interpreted directly by the surgeon, and then intra-  operative real-time TRUS guidance confirmed the corre-  spondence of the location in real time in our routine  TRUS-guided LRP procedure (Fig. 25.5).   Overall, less than 15 min per case were required for real  additional time on our surgical procedures using AR    technology. All surgical margins of 9 laparoscopic partial  nephrectomies and 14 laparoscopic radical prostatectomies  in the series were confirmed by pathology. In two cases, we  used preoperative MRI to superimpose the required data.  The technique of registration using MRI was the "preopera-  tive image to real-time image algorithm." AR-assisted nerve-  sparing LRP contributed to achieve a negative surgical mar-  gin for the cancer in all but one case (with a focal positive  margin at the site of seminal vesicle involvement in pT3b  prostate cancer) with a compatible recovery rate for erectile  dysfunction, as shown in our previous report.   Advantages of AR include, first, that it can provide a new  opportunity for the surgeon to allow direct interpretation of the  3-D image beyond the surgical view. The newly developed  concept of a “color-coded surgical navigation system" pro-  vided the surgeon with a 3-D “road map” beyond the surgical  view. This demonstrated the precise 3-D locations and extent  of the tumor in relation to the surrounding vital anatomies,  including vasculature or the collecting system, facilitating the  achievement of a negative surgical margin for the cancer while  maximizing preservation of the renal function. Second, using a  3-D TRUS model, which was acquired intraoperatively at vari-  ous time points during nerve-sparing LRP, the position and  orientation of the superimposed 3-D models of the prostate  cancer and NVB were sufficiently accurate to provide an  updated real-time perception of the 3-D anatomy according to  each advancing step in the nerve-sparing LRP. This suggests  the potential of achieving a negative surgical margin for the  cancer while maximizing the preservation of erectile function.    In conclusion, we developed this real-time surgical naviga-  tion system using AR technology, for various laparoscopic  urologic procedures, using reconstructed 3-D surgical plan-  ning models for the specific aims of the surgery, with preop-  erative CT, MRI, and/or intraoperative US. We developed  urological software for our AR navigation system, from  software originally developed for the guidance of breast-  conservative cancer surgery, and made it compatible with  laparoscopic procedures. As far as we know, we reported the  initial experience of using AR surgical navigation for a clini-  cal series of various laparoscopic surgeries in urology.    1. Sato Y, Nakamoto M, et al Image guidance of breast cancer surgery  using 3-D ultrasound images and augmented reality visualization.  IEEE Trans Med Imaging. 1998;17(5):68 1-693    . Nakamoto M, Nakada K, Sato Y, et al Intraoperative magnetic    tracker calibration using a magnetooptic hybrid tracker for 3-D  ultrasound-based navigation in laparoscopic surgery. IEEE Trans  Med Imaging. 2008;27:255—270    image-guided minimally invasive urology. Ukimura O, Gill S, ed.  Contemporary interventional ultrasonography in urology. Springer;  2009:179-184    . Iseki H, Masutani Y, Iwahara M, et al Volumegraph (overlaid three-    dimensional image-guided navigation). Clinical application of aug-  mented reality in neurosurgery. Stereotact Funct Neurosurg. 1997;  68:(1-4 Pt 1):18-24    . Kawamata T, Iseki H, Shibasaki T, Hori T. Endoscopic augmented    reality navigation system for endonasal transsphenoidal surgery to  treat pituitary tumors: technical note. Neurosurgery. 2002;50(6):  1393-1397    . Marescaux J, Rubino F, Arenas M, Mutter D, Soler L. Augmented-    . McNeal JE, Villers AA, Redwine EA, et al Capsular penetration in    prostate cancer. Significance for natural history and treatment. Am J  Surg Pathol. 1990;14:240    Wieder JA, Soloway MS. Incidence, etiology, location, prevention  and treatment of positive surgical margins after radical prostatec-  tomy for prostate cancer. J Urol. 1998;160:299   Guillonneau B, el-Fettouh H, Baumert H, et al Laparoscopic radical  prostatectomy: oncologicalevaluation after 1,000 cases a Montsouris  Institute. J Urol. 2003;169:1261   Rassweiller J, Seemann O, Schulze M, et al Laparoscopic versus  open radical prostatectomy: a comparative study at a single institu-  tion. J Urol. 2003;169:1689   Salomon L, Sebe P, De La Taille A, et al Open versus laparoscopic  radical prostatectomy: part II. BJU International. 2004;94:244  Ukimura O, Gill IS, Desai MM, et al Real-time transrectal ultra-  sonography during laparoscopic radical prostatectomy. J Urol.  2004;172:112-118   Gill IS, Ukimura O, Rubinstein M, et al Lateral pedicle control dur-  ing laparoscopic radical prostatectomy; refined technique. Urology.  2005;65:23-27   Ukimura O, Magi-Galluzzi C, Gill IS. Real-time transrectal ultra-  sound guidance during nerve-sparing laparoscopic radical prostate-  ctomy: impact on surgical margins. J Urol. 2006;175:1304-1310.  Ukimura O, Okihara K, Kamoi K, et al Intraoperative ultrasonogra-  phy in an era of minimally invasive urology. Int J Urol. 2008;15:  673-680    There has been an extensive investigation in recent times into  modalities used in the characterization of indeterminate renal  lesions. Unless the benign nature can be confidently diag-  nosed, suspicious lesions are still subjected to surgery or  biopsy.    This readily available modality allows quick and accurate  depiction of the renal mass. With different timing of contrast,  the lesions can be delineated from normal renal parenchyma  and relationships with intrarenal components such as vessels  and collecting system and extrarenal structures such as peri-  renal fascia, IVC, and spleen. Many protocols have been  described, but the principle of renal-mass imaging includes  the combination of an unenhanced scan with an early! and  late (nephrographic) scan? Enhancement within the mass or  its wall is readily assessed, and this is the single most reliable  factor in predicting renal malignancy.’ Furthermore, accurate  tissue characterization allows differentiation between benign  and malignant entities. This is particularly relevant in the set-  ting of renal angiomyolipoma where fat content is virtually  diagnostic of the condition. A notable, albeit rare, exception  is a small percentage of fat-containing RCC. However, in  these latter cases, there is often calcification present (which  is very rare in AML).*   There has been a recent interest in characterizing the his-  tological subtype of the renal tumor using imaging due to the  different prognoses and clinical implications. In terms of CT  enhancement, clear-cell carcinomas tend to enhance more  avidly than the other subtypes. Furthermore, a heterogeneous  mass with soft tissue and cystic components also favors a  diagnosis of clear-cell carcinoma.’ Papillary carcinoma has a  peripheral or uniform enhancement pattern due to reduced  vascularity in comparison to clear-cell subtype? The benign    oncocytoma may present as the typical well-defined lesion  with a central scar and spoke-wheel configuration of tumoral  vessels, but the enhancement pattern overlaps with that of a  clear-cell carcinoma.' For this reason, some urologists con-  sider oncocytoma as a surgical lesion since imaging, and  even biopsy, cannot reliably differentiate this entity from  renal-cell carcinoma. Chromophobe renal-cell carcinomas  tend to have a variable enhancement pattern? More work is  necessary, but it is possible that study of enhancement char-  acterization may aid the risk stratification for renal masses;  and that as surrogate for tissue vascularization help assess  the response to novel chemoimmunotherapeutic agents.    High-quality MR imaging is often used to further the inves-  tigation of the indeterminate renal mass. Other uses include  the assessment of lesions in patients with contraindication to  iodinated contrast and in young patients on regular follow up  (e.g., AML or hereditary renal tumors). With renal dysfunc-  tion, gadolinium-based contrast agents are contraindicated in  MR imaging due to the risk of nephrogenic systemic fibro-  sis,° however, unenhanced imaging still provides superior  tissue characterization than CT imaging. The assessment of  intralesional fat is very sensitive in MR imaging, and other  tissue components can be delineated and used to aid diagno-  sis, e.g., hemosiderin deposition in papillary carcinoma.  Chemical-shift imaging is an adaptation of a misregistration  artifact in MR imaging where the difference in resonant fre-  quencies between different soft tissue densities (e.g., water  and fat) leads to signal drop out, and this has traditionally  been used to differentiate the fat-containing adrenal adenoma  from metastasis. New adaptations of this technology have  been attempted to differentiate subtypes of renal masses.’  As with CT, magnetic resonance imaging (MRI) can be  used to assess the enhancement patterns of renal lesions, and  accurate MR angiograms and venograms can be performed  to assist in the planning of nephron-sparing surgery. This  topographic information is also invaluable in the imaging of  potential donor kidneys. MRI is useful in the interventional    setting, particularly for percutaneous biopsy and ablation  techniques. Newer technology even allows for intraproce-  dural monitoring of both cryoablation and radiofrequency  ablation (RFA), and this is predicted to become an important  area of research, as MRI is the most suited modality for  reproducible monitoring of real-time tissue changes with  focal ablative techniques.   Unlike in the assessment of the prostate (see the section  on "Prostate") diffusion-weighted MR imaging of the kidney  has no clear role in the investigation of renal-mass lesions,  although it has been shown to distinguish abnormal tissue  from normal parenchyma. It is not clear whether further dif-  ferentiation is possible, and further research is needed to  determine if any clinical applications are possible.    PET imaging using the glucose analog 18-fluoro-deoxy-p-  glucose (FDG) has played a limited role in the investigation  of the indeterminate renal mass thus far, though it may have  limited value in the investigation of the complex renal cyst  (to confirm benignity) and to characterize the indeterminate  lesion in patients with metastatic renal-cell carcinoma. In  terms of sensitivity, PET has similar diagnostic accuracy to  CT scanning (ramdave j urol, 2001) and higher documented  sensitivity rates of 100% with respect to lymph-node stag-  ing,*? but these data have not been confirmed.   Recent work has focused on differentiating clear-cell car-  cinoma from the other histological subtypes (as with CT, see  the section on CT) on the basis that the former is more  aggressive and likely to metastasize. Thus, if a nonclear-cell  carcinoma is diagnosed, then watchful waiting or minimal  access therapy (e.g., RFA) can be considered, especially in  elderly patients or those with significant comorbidity. This  technique uses a positron-emitting radionuclide, iodine-124,  labeled to an antibody (cG250) that recognizes the tumor  protein known as carbonic anhydrase IX. This protein is  expressed during the active phase of a clear-cell carcinoma.  A prospective clinical trial of 26 patients with known renal  masses involved PET scanning with I-cG250 antibody prior  to their surgery. The results show that the radioisotope is  94% sensitive and 100% specific in diagnosing clear-cell  carcinoma,” but again this promising data needs to be con-  firmed with larger studies.    Conventional B mode ultrasonography is a low cost, easily  performed, and safe imaging modality that remains pivotal in  the investigation of urinary tract abnormalities. In recent years,  however, contrast-enhanced ultrasonography has emerged as  a useful adjunct in the study of renal abnormalities. This    technique uses microbubbles as a contrast agent and has the  ability to study the enhancement pattern of an indeterminate  lesion. The gas-filled microbubbles have a lower density than  water — this results in acoustic impedance during ultrasound  imaging and increases the contrast between the intravascular  microbubbles and the surrounding tissues. The technique is  especially valuable in patients requiring enhanced imaging,  who have contraindications to both CT and MR contrast  agents. Other uses include the accurate assessment of the typi-  cal centripetal enhancement pattern of lesions such as renal  hemangioma.    Imaging for urinary stone disease previously included a  combination of X-ray, IVU, and ultrasound. However, as the  technology has improved, CT scanning has adopted a more  frequent role in the assessment of renal colic and the compli-  cations of urolithiasis. First, the low-dose unenhanced CT  KUB has replaced the IVU in most centers, and second, CT  pyelography is being used increasing in preoperative plan-  ning for endourological surgery. This technology allows  multiplanar reformatted images and 3D volume images  and movies to be constructed from the source data (Figs.  26.1 and 26.2). This allows accurate localization of urinary    Fig. 26.1 Horseshoe kidney with complex stone burden. Coronal  oblique MIP (a) and 3D volume rendered images (b) enable the  endourologist to assess the full distribution of urinary calculi and plan  optimal calyceal access for PCNL    Fig. 26.2 Virtual endoscopic view of a staghorn calculus (a). The cor-  responding axial image of the calculus is seen on the CT urogram (b)    calculi and, more importantly, guides the urologist in plan-  ning the optimal route of percutaneous access. This tech-  nique is particularly useful in planning for percutaneous  nephrolithotomy in malpositioned and distorted kidneys and  those patients with complex stone burden.'!'* Another prom-  ising area is the ability of CT to characterize the CT density  of a given stone, which roughly correlates with the hardness  of the stone and hence the likelihood of response to extracor-  poreal lithotripsy." Most recently, a new CT technique (dual-  energy CT) has further expanded the potential of CT for  characterization of stone content.'^   MR urography is not routinely advocated in the work up  of patients with urinary calculi, but it is recommended in  exceptional circumstances such as renal colic in children or  pregnant patients." Similar diagnostic accuracy to CT imag-  ing and IVU has been reported, ^? but the foremost limita-  tion of MR urography is that stones are seen as a signal void.  No MRI sequence as yet has been able to detect any intrinsic  or stone-specific signal.    CT urography has emerged as a very useful modality in the  investigation of urothelial malignancy. To a large extent, it  has replaced the IVU in assessment of the ureter and upper  tract, but its place in the modern management algorithm is  still under review. It is a tempting notion to consider this  modality a “one stop shop" for the complete evaluation of  the kidneys, ureters, and bladder (including accurate urothe-  lial assessment), but there are important considerations such  as radiation dose. A CTU working group of the European  Society of Urogenital Radiology recently recommended  CTU as a first-line investigation for macroscopic hematuria  in high-risk patients (age >50, smokers), and as a problem-  solving examination in complex cases.'? Furthermore, recent  studies have shown that CTU imaging of the upper tracts is  more sensitive in diagnosing urothelial abnormalities (nota-  bly, TCC) than do conventional retrograde pyelography.^?   Virtual endoscopy of the urinary tract is a promising  derivative of CT urography that promises accurate assess-  ment of the urothelium, and several studies have shown  increased sensitivity in detecting TCC than CT urography  alone.?'? This technique utilizes software to generate endo-  scopic views of the urinary tract from the source axial data  from the standard CT urogram procedure (Figs. 26.1 and  26.2). Multidetector scanners are required to acquire thin  enough cuts to produce an accurate representation. The limi-  tation of the technique is the added time required to construct  the images by the reading radiologist. Further work is  required but is possible that faithful 3D anatomical models  may be useful for both diagnosis and the teaching of endo-  scopic navigational skills.    As the frequency of detection of RCC has increased, there  has been an emergence in new therapies aimed at the abla-  tion of small tumors. Examples include RFA, cryotherapy,  and microwave ablation.   For RFA, thermal energy is delivered to a targeted lesion  (via US or CT) at temperatures designed to cause irreversible  cellular damage.   Because of increasing numbers of ablation procedures  being performed, there is a concordant increase in the num-  ber of posttreatment scans performed to assess treatment  response. Current practice usually involves early imaging  (within 2 weeks) to assess successful ablation then follow-up  scans at an appropriate interval (usually 6 months). Contrast-  enhanced CT is the most frequently used modality, and resid-  ual enhancement is taken as a surrogate indicator of residual  viable tumor tissue. For the immediate postoperative scan,    an unenhanced sequence is recommended to differentiate the  high attenuation "reactive hyperemia" in the normal paren-  chyma from untreated/enhancing tumor. In terms of follow-  up imaging, the principle sign of successful therapy is lack of  enhancement of a treated lesion. Many other signs have been  described, and these have been summarized in Table 26.1.   In terms of untreated or recurrence of the tumor, a cres-  cent of enhancing soft tissue is the cardinal sign detected on  contrast-enhanced CT scanning.    Advances in cross-sectional imaging, CT and MRI, has  allowed more accurate assessment of the relationship  between renal neoplasm and normal parenchyma. In particu-  lar, the proximity to renal vasculature and collecting system  and the presence of a pseudocapsule allows the urologist  to plan nephron-sparing surgery in appropriate cases.  Intraoperative ultrasound is an additional modality that pro-  vides real-time ultrasonic localization of renal lesions at the  time of operating. This technique has particular advantage in  the setting of hereditary renal neoplasia where multiple mass  lesions are often encountered in each kidney.    In terms of ureteric calculi, unenhanced CT KUB remains an  accurate first-line investigative tool. In pregnant women,  magnetic resonance urography (MRU) plays a distinct role  in distinguishing between physiologic hydronephrosis and  obstructive hydronephrosis secondary to calculi. While ure-  teric calculi may be difficult to identify on MR imaging  (being signal voids, as discussed earlier), the modality is  accurate in identifying the secondary signs of ureteric  obstruction such as perinephric and periureteral stranding,  hydronephrosis, and ureteric dilatation. Heavily T2-weighted  sequences are performed in both axial and coronal planes to  maximize diagnostic accuracy. Gadolinium-enhanced, or    excretory, MRU increases the sensitivity of diagnosing ure-  teric obstruction. As with CT urography, the contrast and  spatial resolution is improved with maximum urine volume  within the collecting system — this can be achieved with  diuretics, intravenous fluid, and ensuring a full bladder. With  the combination of static, excretory MRU, and conventional  MRI, a full assessment of the entire urinary tract can be  obtained in one procedure. The role of this modality contin-  ues to evolve as the quality of MR imaging improves. There  are still limitations to overcome such as the insensitivity of  detecting calcification, long acquisition time and imaging  artifacts, but it possible it may compete with the CT urogram  for diagnostic purposes.    For the most part CT or MR urography provides an accurate  assessment of the ureter and any pathology within. There are,  however, still occasional clinical scenarios where radiologi-  cal uncertainty exists, and further investigation is required.  Examples include differentiating the underlying cause of pel-  viureteric junction obstruction, tumor vs. postoperative scar-  ring, and distinguishing primary ureteric malignancy from  adjacent lymphadenopathy.” Additional abnormalities such  as submucosal calculi can also be detected even when this  was missed during ureteroscopy. Conventionally, these cases  can be closely monitored with interval imaging or more  aggressively with diagnostic laparoscopy, but endoscopic  ultrasound offers an alternative avenue of investigation. The  main advantage is accurate 360? assessment of the ureteric  wall and its layers. Technically, the procedure is performed  synchronously at the time of cystoscopy and retrograde pyel-  ography and involves collaboration between urologist and  radiologist. The ultrasound probe consists of a transducer  housed on a 7F catheter and is inserted into the ureter follow-  ing initial cannulation with wire and catheter. The exact loca-  tion of the probe can be monitored with fluoroscopy. The  disadvantages include the cost of the ultrasound equipment  and the necessity for general anesthetic.    Promising results have been shown in the MR assessment of  renal function. The main benefit lies in the combining of ana-  tomic detail with functional information in the assessment of  renal disease. This technique has value in the evaluation of  living donor Kidney, renal artery stenosis, and in patients    prior to nephrectomy. Renal artery perfusion and glomerular  filtration rates can be calculated using equations involving  the behavior of Gd-DTPA during contrast-enhanced MR  imaging.”    This technology allows fusion of two imaging modalities or  between imaging and real-time sensors that track position of  surgical instrumentation. This allows highly accurate localiza-  tion of abnormalities targeted for biopsy or therapy. Examples  include (i) the integration of cross-sectional imaging (CT or  MR) with real-time ultrasound imaging to pinpoint RFA and  (ii) robotic procedures linking the surgical technology with  CT or MR images. The principle of this innovation is the syn-  ergy of three-dimensional imaging detail with real-time surgi-  cal views, allowing the operator to perform more subtle and  delicate procedures in anatomically challenging locations.  There is also scope for the development of computer simula-  tion models to assist in the training of future surgeons.    Prostate cancer is one of the commonest cancers of the  elderly male population. Most prostate malignancies are  relatively slow-growing tumors, and gland-confined treat-  ment with curative intent is generally successful. However,  once the disease has spread beyond the gland, curative treat-  ment is not feasible. Therefore, it is essential that the initial  diagnosis and staging of prostate cancer is as accurate as  possible to ensure correct treatment stratification. In the same  way, follow-up imaging and the diagnosis of recurrent dis-  ease must also be accurate.   Transrectal ultrasound (TRUS), while readily available  and cost effective, lacks sensitivity and specificity. MRI is  used to stage disease once a diagnosis has been made, but  methods lack sensitivity and specificity for cancer detection  and localization. ^ More recently, morphologically based  prostate imaging is now being complemented by functional  and molecular imaging techniques.”    The introduction of TRUS revolutionized the ability to study  the prostate gland.” Not only did it enable excellent visual-  ization of the gland but also meant that targeted needle    biopsies could be performed simultaneously. A systematic  biopsy pattern is followed. The number of cores taken var-  ies from 6 to 12. However, multiple studies have shown that  systematic biopsy may miss a significant number of clini-  cally relevant cancers.? More recently, there has been a  trend to increase the number of biopsies taken to ensure a  higher positive yield. The saturation biopsy technique sam-  ples the whole gland either transrectally by taking 20 or  more core biopsies evenly distributed throughout the gland  or using a more systematic approach using a transperineal,  grid-based method using a brachytherapy template.”  Transperineal prostate mapping has been shown to improve  the accuracy of Gleason grading and, consequently, the dis-  ease burden in patients with localized prostate cancer and  therefore ensure more accurate disease stratification."' As a  result, these new techniques have been developed to aug-  ment conventional ultrasound and improve the detection of  cancer.    Neovascularity, as a result of tumor angiogenesis, is a well-  recognized phenomenon not just limited to prostate cancer.  Studies have shown that various different “abnormal” flow  patterns are associated with prostate cancer: diffuse increased  flow, focal increased flow, and asymmetric flow surrounding  the tumor focus. Early studies showed that up to 85% of  patients with prostate cancers more than 5 mm have visi-  bly increased flow in the area of tumor involvement.  Hypervascularity can also been seen in patients with isoechoic  tumors that are more difficult to identify. However, subse-  quent studies have shown that the use of color and power  Doppler will still miss some cancers and therefore does not  preclude routine prostate biopsy.”    Ultrasound-contrast agents are proving to be increasingly  useful in the detection and characterization of abnormal pro-  static tissue. Contrast agents work by increasing the signal-  to-noise ratio and therefore improving the detection of  low-volume blood flow. The newer agents developed have  many benefits, including being entirely restricted to the ves-  sel lumen resulting in increased detection of small vessels,  which are not obscured by surrounding tissue absorption of  the agent. They are also many times more reflective than  blood, therefore improving flow detection.” Used in combi-  nation with Doppler imaging, microbubble contrast agents  have shown to result in increased signal in areas of increased    vascularity, which (as previously stated) may correlate with  areas of malignant change. In a study by Pelzer et al,” tar-  geted biopsies, as determined by areas of hypervascularity  postintravenous contrast administration, were compared  with standard biopsies (ten cores). The results showed that  the detection rate of malignancy within the targeted cores  was significantly better than that of the standard cores  (p«0.01).    Elastography was first described by Ophir et al in 1991.” It  is a novel ultrasound technique for assessing tissue elasticity  in real time through the application of gentle pressure with a  conventional ultrasound probe. Originally, elastography  was only possible on organs that could be directly com-  pressed, for example, the thyroid, breast, and testicles. The  vast majority of the work on ultrasound elastography has  been done on the assessment of breast tissue. However, with  the development of intracavitary transducers, it has been  possible to apply the technique to deeper organs such as the  prostate.”   Elastography relies on the principle that abnormal (malig-  nant) tissue is usually stiffer than the surrounding normal  parenchyma. This difference in tissue compressibility or  elasticity results in an alteration of the ultrasound signal  received by the transducer when the tissues are compressed  by only a small amount (approximately 2%).” The pre- and  postcompression-received signals from various regions of  interest can then be analyzed and compared for differences.  Where tissues are found to be less compressible, a suspicion  of malignant change can be raised.   These findings can not only be used to directly assess for  possible sites of disease but can also be used to guide biopsy  under ultrasound guidance” and potentially reduce the num-  ber of total biopsies required.”   A similar principle is used in sonoelastography. This uses  an acoustic vibration in the audible range (30-200 Hz),  which is transmitted into the prostate gland. Color Doppler  imaging is then used to detect resultant tissue vibrations.  Abnormal areas of tissue (i.e., “stiffer” areas) will result in  decreased vibrations and therefore be reflected as a signal  void in the color Doppler image.” Several studies have sug-  gested that sonoelasticity imaging is more sensitive for tumor  detection and more accurate for the assessment of tumor  localization than conventional ultrasound."   Although there are undisputed problems with the tech-  nique such as failure to detect small tumors and a false-  positive detection of hyperplastic nodules and calcium,  overall, the recent work on prostate elastography and sono-  elastography is promising.    Conventionally, TRUS-guided prostate biopsies are per-  formed using standard two-dimensional (2D) images.  Because prostate carcinomas are nonuniformly distributed  throughout the gland, it would seem more logical to approach  biopsies using three-dimensional (3D) images, therefore,  obtaining a more realistic anatomical picture of the prostate  gland and increasing the accuracy of the biopsy.? New ultra-  sound machines are capable of delivering 3D images in real-  time, referred to as four-dimensional (4D) images.** These  4D images have been used in TRUS-guided prostate biopsies  and shown to improve diagnostic accuracy."?    MRI is already widely in use for the diagnosis and pretreat-  ment staging of patients with prostate cancer. Standard images  are usually obtained using a pelvic phase-array coil. Wide  field of view images are useful in determining local nodal  spread and the presence of any bony metastases. Multiplanar  T2 sequences are routinely obtained, providing good zonal  anatomical representation of the prostate gland, with areas of  malignant change typically showing as foci of decreased sig-  nal. However, low signal in the peripheral zone (where the  majority of cancers arise) can also be caused by hemorrhage,  prostatitis, hyperplastic nodules, or sequelae from radiation  or hormone therapy."' This reduces the sensitivity and speci-  ficity of conventional MRI. Endorectal coils improve detec-  tion of prostate cancer, as well as providing more accurate  information on local tumor staging, especially when results  are interpreted by experienced readers.“ Endorectal coils  work by increasing the signal-to-noise ratio by a factor of 10.  This results in higher spatial and spectral resolution.^   Faster MR sequences have also much improved imaging  of the prostate. The faster scanning times allows more planes  to be covered in the same amount of time and also decreases  the amount of motion artifact. The scanning parameters can  also be adjusted to increase the T2 weighting of the scan,  therefore, increasing the detectabilty of lesions.“   To further improve the diagnostic capability of prostate  MRI, various methods are being developed coupling conven-  tional MR with functional imaging. This shall not only improve  the accuracy of diagnosis but may also aid treatment planning.    The basis for contrast-enhanced MRI is the same as that for  contrast-enhanced ultrasound. Within malignant tissue,    angiogenic factors are released, resulting in new vessel for-  mation. Richer vessel density results in a more rapid and sus-  tained period of enhancement postcontrast administration.  The development of fast imaging techniques allows the entire  volume of the prostate to be covered in a few seconds"! and  therefore allows repeated imaging to be obtained at varying  time intervals postinjection of intravenous contrast. From the  data collected, various perfusion parameters can be deter-  mined, compared with similar data from normal areas of  prostate tissue, and analyzed to provide diagnostic informa-  tion on possible areas of malignant tissue. ^ Studies by  Engelbrecht et al? and Kim et al" have both shown that the  relative peak enhancement and contrast washout rates of  contrast can be used to confidently identify areas of abnor-  mal prostate tissue. Englebrecht et al^ concluded that, by  analyzing enhancement curves, the relative peak enhance-  ment was the most accurate perfusion parameter for detect-  ing cancer in the peripheral and central zones of the prostate  gland. Kim et al" demonstrated that the wash-in of the con-  trast (i.e., how fast an area enhanced) was more accurate for  detection of malignancy in the peripheral zone than when  using the standard MRI images. The sensitivity and specific-  ity for cancer detection based on the wash-out rate were 96  and 97%, compared with 75 and 53% on the T2 images alone  (p«0.05). Furthermore, early data suggests that peak enhance-  ment may also be particular to tumors of higher Gleason  grade. The promise of dynamic MRI is that it may allow the  identification of target or index lesions for focal ablative  therapies or directional biopsies for tumor risk stratification.    Conventional MRI detects the nuclear magnetic resonance  spectra of water in tissues and provides a combined signal-  intensity map of all hydrogen protons within one tissue type.  However, the signals from hydrogen protons in different  molecules actually have slightly different frequencies, a  property known as chemical shift. MRSI detects these differ-  ent frequencies and produces a map of signal intensity vs.  frequency and location." As such, MRSI can produce a  map of tissue metabolism. Much work had already been done  on the metabolic composition of normal prostate tissue,  which is known to contain high levels of citrate and low lev-  els of choline. In prostate cancer, there is a decrease in the  citrate level and a relative increase in the choline level due to  alterations in the tissue metabolism. Therefore, the MR  spectra obtained from areas of normal and malignant pros-  tate tissue will differ and may allow localization of tumor.  MR spectroscopy using endorectal coils has also been  shown to increase the sensitivity of targeted biopsies in   The disadvantages of MRSI are that it is time consuming,  results may vary due to postprocessing factors, and recent  biopsies may produce artifacts that degrade the images.  While it has been shown to be sensitive for detecting cancer  within the peripheral zone, detection of more central cancers  has not proved to be as successful, likely reflecting a differ-  ent metabolic composition of the transition zone tissue.’    Diffusion is the process of thermally induced random molec-  ular displacement or Brownian motion. All tissues have indi-  vidual diffusion characteristics based on their quantity of  free water and the permeability of the tissue itself. In prostate  cancer, the normal glandular architecture is disrupted and  replaced by aggregated cancer cells and fibrotic stroma.”  Consequently, there is less free motion of water in the malig-  nant tissue, i.e., restricted diffusion.   Diffusion-weighted images (DWI) can be obtained as part  of a routine MRI scan and additional apparent diffusion coef-  ficient (ADC) maps calculated. Areas of restricted diffusion  will show as areas of low signal on the ADC map and have  been shown to correlate with areas of biopsy proven prostate  cancer. The sensitivity of cancer detection is increased when  the findings are correlated with the standard T2 images.^!   DW imaging has the limitation of poor spatial resolution  and, as with all MR images, is susceptible to artifact from  recent biopsies.    Elastography is usually performed with ultrasound as the  imaging technique. However, research with MRI elastogra-  phy is underway.”    Most work into prostate MRI has been done using standard  1.5 Tesla (1.5 T) scanners routinely found in most depart-  ments. The introduction of new localized treatment options  such as high-intensity focused ultrasound (HIFU), image-  guided brachytherapy, and cryotherapy (see below) has  brought about a need for higher quality initial diagnostic and  staging imaging. Over the last few years, higher strength 3 T  scanners have been developed, and research has been carried   The increase in magnet strength results in a linear increase  in signal intensity with a relatively unchanged noise level.  This results in a higher signal-to-noise ratio and therefore  better spatial, temporal, and spectral resolution. However,  the increase in magnet strength does have its disadvantages,  namely, alteration in the inherent relaxation properties of tis-  sues, and therefore the acquired signal, as well as an increase  in artifact."   Recent studies have been carried out comparing the image  quality, tumor delineation and staging accuracy for prostate  cancer using 1.5 and 3 T scanners. The results show that  images obtained using pelvic phased-array coils at 3 T are  comparable with those obtained using an endorectal coil at  1.5 T.?** This is obviously beneficial to the patient as it obvi-  ates the need for an invasive procedure. While it is likely that  images obtained using an endorectal coil at 3 T will be supe-  rior, there is currently only limited data to support this.   At 3 T, imaging has also been shown to improve the sen-  sitivity and specificity of both dynamic contrast-enhanced  MR imaging and diffusion imaging.^^* Work on MRSI at  3 T is currently being undertaken with mixed results.    A few studies have addressed the feasibility of MRI-guided  prostate biopsies. Special biopsy equipment is necessary for  targeted MRI biopsy, in particular, the use of nonmagnetic  instruments. Data are currently limited but is anticipated that  the combination of functional with conventional MR imag-  ing may increase the yield of biopsies in patients with previ-  ous negative ultrasound-guided biopsies, but a high clinical  suspicion of prostate malignancy." A recent study by  Anastasiadis et al showed that MRI-guided biopsy detected  cancer in 55.596 of patients who had a previously negative  TRUS biopsy but had an elevated PSA, suspicious DRE, and  abnormal MRI findings.”    PET uses pharmaceuticals containing radionuclides that  decay by the release of protons to produce whole-body tomo-  graphic images, which can be combined with CT to produce  high-resolution images.” The most commonly used radionu-  clide is 2-18F-fluoro-2-deoxy-p-glucose (FDG). However,  the use of this in prostate cancer is challenging because of  the low-glucose utilization of the prostate gland (and there-  fore low uptake of the tracer) as well as its urinary excretion  meaning that tracer will collect in the bladder and may    obscure pathological uptake in the prostate gland and adja-  cent structures." Consequently, research has been done into  alternative PET tracers that are based on metabolic pathways  other than glucose. Current avenues of research include the  use of !!C- or '8F-choline and !!C-acetate, which are related  to membrane lipid metabolism, and ''C-methionine and  'SF_fluoro-L-thyosine, which are related to protein turnover.”  In 2007, Yamaguchi et al compared 11C-choline PET with  MRI and MRS in 20 patients with early prostate cancer. The  results showed a sensitivity of 10096 for the PET images for  detection of the primary lesion compared with 60% for MRI  and 65% for MRS.?    Cross-sectional images acquired by CT and MR can be for-  matted into 3D image sets and linked to sensors that track the  position of surgical instruments relative to the image set. These  images can be fused with other data sets to form compound  images that would aid surgeons in localizing disease sites and  to appreciate anatomical boundaries during surgery. These  applications can also be used to aid accurate biopsies."    With a large number of patients now undergoing localized  treatment for prostate cancer rather than radical prostatec-  tomy, it is important that imaging methods are tailored to  these patients, to allow regular, routine follow up and to  ensure that any recurrence is diagnosed.    Studies have been done into the use of contrast-enhanced  ultrasound and elastography to monitor patients after under-  going HIFU treatment. The initial results have been promis-  ing showing a reduction or absence of blood flow in treated  areas on both contrast-enhanced and Doppler imaging as  well as an alteration in the elastography of the treated tis-  $*? However, there has been some discrepancy with  reported MRI findings, ^ and further research is required into  these methods.    Specialized MR techniques, such as dynamic contrast-  enhanced (DCE) studies, DWI, and MRS, can also be used to    monitor localized treatment to the prostate gland. Essentially,  treatment aim is to induce cell death. Therefore, posttreat-  ment monitoring relies on the assessment of this, in terms of  lack of vascularity, lack of contrast enhancement, loss of nor-  mal tissue signal, and the transformation to signal character-  istics consistent with necrosis.   Studies looking at both HIFU and cryotherapy treatment  have concluded that while these changes can be identified  and in some cases do represent effective treatment, when  correlated with histological findings, MRI is not yet sensitive  enough to detect all areas of recurrence and therefore biopsy  is still required. 9    Ultrasound remains the imaging technique of choice in most  testicular pathologies. It can be used to differentiate between  various tumor types, but, as the vast majority of patients with  a suspected tumor will go on to have an orchidectomy, this is  not crucial.   More recently, intraoperative ultrasound has been used to  guide needle localization for nonpalpable tumors. In patients  with bilateral tumors or those with a solitary testicle, testis-  sparing surgery has been advocated to avoid the problems  associated with castration. Browne et al used intraoperative  ultrasound guidance in three such patients and avoided the  need for orchidectomy in one of them.” Organ-sparing sur-  gery for malignant testicular tumors is a controversial area,  as it does not follow the usual radical approaches of cancer  surgery. The limited data available is encouraging with respect  to disease-free survival, but the potential for local recurrence  and residual disease must not be forgotten.    CT is routinely used for staging and follow up of metastatic  disease. The disadvantages of this include the radiation dose  associated with it and the long-term effect that this may have  on the relatively young patient population involved. Possible  solutions have been to use low-dose CT or MRI. However,  both these techniques need to be validated in suitable surveil-  lance protocols in prospective trials.   FDG PET has been shown to be more sensitive than other  modalities for assessment of residual tumors in patients who  have previously undergone chemotherapy for seminomatous  tumors.” Nonseminomatous germ-cell tumors do not take up    FDG as readily and therefore use is limited in this patient  group. FDG PET has also been shown to be useful in the  detection of recurrence when patients have raised tumor  markers but no CT evidence of disease.”   2. Benjaminov O, et al Enhancing component on CT to predict malig-  nancy in cystic renal masses and interobserver agreement of differ-  ent CT features. AJR Am J Roentgenol. 2006;186(3):665-672   3. Kennelly MJ, Grossman HB, Cho KJ. Outcome analysis of 42 cases  of renal angiomyolipoma. J Urol. 1994;152(6 Pt 1):1988-1991   4. Zhang J, et al Solid renal cortical tumors: differentiation with CT.  Radiology. 2007;244(2):494—504   5. 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Q J Nucl Med Mol Imaging. 2007;51:260—271   Yamaguchi T, Lee J, Uemura H, et al Prostate cancer: a comparative  study of 11C-choline PET and MR imaging combined with proton  MR spectroscopy. Eur J Nucl Med Mol Imaging. 2005;32:742—748  Curiel L, Souchon R, Rouviere O, et al Elastography for the follow-  up o fhigh-intensity focused ultrasound prostate cancer treatment:  initial comparison with MRI. Ultrasound Med Biol. 2005;31:  1461-1468   Sedelaar JP, Aarnink RG, van Leenders GJ, et al The application of  three-dimensional contrast-enhanced ultrasound to measure volume  of affected tissue after HIFU treatment for localized prostate cancer.  Eur Urol. 2000;37:559-568   Souchon R, Rouviere O, Gelet A, et al Visualisation of HIFU  lesions using elastography of the human prostate in vivo: prelimi-  nary results. 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The role of imaging in the diagno-  sis, staging and management of testicular cancer. AJR. 2008;191:  387-395   De Santis M, Bechere A, Bokemeyer C, et al 2—18fluoro-deoxy-D-  glucose positron emission tomography is a reliable predictor for viable  tumour in post chemotherapy seminoma: an update of the prospective  multicentric SEMPET trial. J Clin Oncol. 2004;22:1034—1039    Charalampos Mamoulakis, Vassilios Tzortzis, Jorge Rioja Zuazu,  Maria P. Laguna Pes, Stavros Gravas, Hessel Wijkstra, and  Jean J. M. C. H. de la Rosette    Ultrasonograpy (US) has been employed to image the human  body for over half a century. It represents an established, ver-  satile, and one of the most popular medical imaging modali-  ties. The fact that it is rapid, effective, radiation free,  noninvasive, relatively inexpensive, portable, and posing no  known risks for human health allows it to be commonly used  as a primary diagnostic imaging modality. It is extensively  applicable as a reliable guidance tool in a variety of critical  interventional procedures and represents an emerging thera-  peutic tool as well, mainly in the form of high-intensity focused  US (HIFU). Modern US is primarily based on the application  of a pulse-echo approach with a brightness-mode (B-mode)  display, i.e., transmission of small ultrasound pulses, detection  of echo signals from structures lying along the pulse path  length, and final combination of the signals from many sequen-  tial, coplanar pulses into a tomographic “real-time” image.   US possesses a central role in the urologists’ armamen-  tarium. Since the first clinical applications in the 1940s, con-  tinued advances have expanded its role in the diagnosis,  management, and follow-up of urological patients. During  the last 15 years, it has undergone tremendous changes,  which are about to bring it well beyond its established role as  a noninvasive real-time imaging modality. Recent techno-  logical developments advanced its position in guiding uro-  logical procedures with higher precision and minimalization  of morbidity, implementation of innovative treatment options  (e.g., laparoscopic surgery or tumor ablation), and monitor-  ing therapy response. This chapter focuses first on the inno-  vations in ultrasound technology and second on their possible  application in the field of urology.    Latest technical improvements brought on profound altera-  tions in US imaging. Some of these, such as encoded pulses  and receive focusing, are nonadjustable and taking effect in    the background. Others such as harmonics and compounding  are operator-adjustable, representing real-time options. New  promising technologies for better characterization of lesions  include contrast-enhanced US (CE-US) and elasticity imag-  ing techniques. The recent innovations that improve the per-  formance of modern US equipment applicable in the field of  urology are described below and are schematically presented  in Table 27.1.!*    Most new technologies aim at improving spatial resolution.  These include digital beam formers, larger channel count,  coded pulse excitation, harmonic imaging, spatial compound  imaging, electronic focusing using array and matrix trans-  ducers, and endoscopic/intraoperative US.'*    Analog and digital beam formers provide pulse-delay  sequences for electronic beam steering, transmit, and receive  focusing. Single-element transducers have a sole fixed focal  zone and are limited to mechanical steering and focusing.  The number and location of focus points on the new systems  are operator-assigned for changing the transmit focus. The  receive focus is accomplished dynamically and is investiga-  tor independent.   Digital beam formers are preferable because they bear a  number of advantages, including programmability, accep-  tance of a wide range of signal frequencies, dynamic aper-  ture, and apodization capabilities. They expedite incorporation  of different transducers and novel technologies (programma-  bility function), offer the ability to accept new broad-band-  width transducers with short-pulse and harmonic technology  (wide frequency range), allow for keeping the beam width  narrow for best resolution by minimizing the beam-width  variation with depth (dynamic aperture), and finally permit    B) Technical innovations for improved lesion detection  and differentiation  Elasticity imaging  Contrast-enhanced ultrasonography    variation of vibration amplitude during transmission and  echo sensitivity during echo reception of adjacent structures  (apodization). In conclusion, digital beam formers are desir-  able because of their improved spatial resolution, upgrade  capabilities, use of broad-bandwidth technologies, and reduc-  tion of unwanted artifacts.   Channel count, i.e., number of beam formers (crystal ele-  ments per data line), determines the aperture size. The larger  the channel count, the greater the number of elements that  can be simultaneously activated to transmit a pulse/receive  echo signals per beam line and the larger the aperture, result-  ing in improved lateral resolution.    Imaging depth and spatial resolution constitute a fundamen-  tal trade-off in US. The effective imaging depth is determined  by the pulse amplitude and frequency. The amplitude relates  to the power setting on the system and is limited by safety  considerations. Higher frequencies improve axial resolution  at the cost of penetration depth. This can be overcome by  coded pulse-excitation technology, which provides good  penetration at the higher frequencies necessary for superior  spatial resolution."   This technology employs long high-energy pulses of  comparable safety to the short waveform ancestors, specifi-  cally shaped for targeted detection by the transducer and  submission of the returning echoes to special pulse-compres-  sion computer algorithms. The final result is an image with  increased signal-to-noise ratio and preserved spatial resolu-  tion at larger depths.” Coded pulse-excitation is applicable in  harmonic, compound, contrast, and Doppler technologies.  No inherent disadvantages are encountered apart from  increased cost, and therefore it represents a highly desirable  feature for diagnostic US imaging.    Ultrasound imaging is degraded by many factors related to  the different body wall layers, which constitute many sound  interfaces responsible for reverberations that produce echoes  leading to strong ring-down artifacts in the near field.  Harmonic US is the detection and display of echoes that are  integral multiples of the transmitted pulse frequency (funda-  mental or 1st harmonic; fj). For example, the 2nd harmonic  has twice the frequency of the fundamental (2 f,).   Tissue harmonic imaging uses B-mode technology.  Harmonic frequencies (2nd, 3rd, etc.) are generated by the  tissues, and the amplitude is increasing while the pulse is  traveling through the tissue. Therefore, harmonic imaging  represents a solution for eliminating the effects of skin sur-  faces (reverberations and ring-down). The intensity decreases  with increasing harmonic order. Furthermore, higher fre-  quency harmonic components are more attenuated. Therefore,  harmonic imaging is currently performed mainly with the  use of the 2nd harmonic component.   Briefly, the principle is the following‘: a narrowband f, is  transmitted, and harmonic frequencies are generated; echoes  (f, and harmonics) reach the transducer; and the machine  system filters out the f, and maximizes the harmonic signal.  Apart from filtering, additional methods to isolate the har-  monic component involve various subtractions and inversion  pulse technologies.   In addition to the decreased clutter in the near field caused  by ring-down from the body wall, resolution is improved  because a higher than the transmitted frequency (2x) is  received, lateral resolution is improved since harmonics are  generated by the more powerful central portion of the trans-  mitted f, beam, volume averaging is avoided since the beam  is effectively narrower, and side/grating lobes are too week  to generate harmonic signals.° As a result, harmonic imaging  improves the clinically useful artifacts (shadow and through  transmission) and reduces the “nasty” ones (lobe, ring-down  and volume averaging), especially in systems with concur-  rent coded pulse technology.    Electronic steering of parallel beams from an array trans-  ducer oriented along different directions is used to image  a specific tissue multiple times. Echoes acquired at differ-  ent angles are averaged together into a single composite  real-time image. A greater computational time compared  with conventional B-mode imaging is necessary since  multiple, rather than one, beams are used. Moreover, spa-  tial compounding is prone to sharpness reduction caused  by blurring artifact due to poor registration or misalign-  ment of individual frames as a result of distortions from   Similar to tissue harmonic imaging spatial compounding  is operator-adjustable and can be optimized. Blurring artifact  is related to the number of beams merged into each image.  Lower beam compounding rates are more suitable for areas  with higher motility, while higher numbers of beams are  typically reserved for areas with less motion. Speckle, noise,  clutter, and refractive shadows are often reduced, while con-  trast and marginal definition is improved."    Mechanical focusing in the Y axis is achieved by the place-  ment of a lens in front of the piezoelectric element or a  shaped element on the surface of the transducer. Array trans-  ducers carry a row of crystal elements, allowing for elec-  tronic focusing in the X direction. Matrix transducers have  multiple rows of elements, which allows for electronic focus-  ing in the X and Y direction. By steering the beam in the X  and Y planes, three- and four-dimensional (3D/4D) images  can be acquired.    Endoscopic or endoluminal US (EUS) is based on the use of  flexible endoscopes carrying high-frequency transducers at  their tips, and thereby have a high-axial resolution. Another  advantage is that the amount of interactions that affect an  ultrasound wave before it interacts with the tissue of interest  is decreased. EUS probe can consist of, e.g., 3.5-6.2 F, cath-  eters containing a rotating ultrasound transducer with a fre-  quency in the order of 9-30 MHz. In this case, the  catheter-based transducer attached to the ultrasound system  rotates continuously resulting in a 360° real-time cross-  sectional images.   Intraoperative US can be used in laparoscopic or open  surgical procedures, allowing for direct contact of the trans-  ducer on the organ of interest. Therefore, higher frequencies  can be used since the penetration requirement is reduced,  and finally, a better resolution is achieved. Recent advances  include the incorporation of new technology such as spe-  cially formed probes (endoluminal, laparoscopic, transrectal,  and transvaginal) and several functions (Doppler, harmonic,  3D/4D imaging, elastography CE-US, etc.) with the poten-  tial to enhance visualization of the surgical anatomy even  beyond the surgical view increasing operational precision.* It  can identify, for example, the location and depth of lesions to  guide the proper dissection plane within the kidney; it may  be used during partial nephrectomy to identify additional    occult tumors and can also be utilized transrectally to guide  the plane for neurovascular bundle dissection and reduce the  incidence of positive surgical margins during laparoscopic  radical prostatectomy.*    Elastography is a real-time, noninvasive method to image tis-  sue hardness. It represents an extension of the ancient art of  palpation and of earlier B-mode US-based methods to view  resultant tissue deformation/stiffness by palpation (“sono-  palpation”). The basic approach is to measure tissue motion  caused by force, to reconstruct the elastic parameters of the  tissue. In most cases, US is used to detect the motion or dis-  placement resulting from the applied stress. The excitation  stress can be either mechanical (static; slight compression  with the transducer or dynamic; mechanical vibrators) or  the radiation force of an ultrasound source; either static  or dynamic (transient methods, shear-wave methods, and  vibroacoustography).?   The basic principle is the following'?: two radiofrequency  signal sets are used; a precompression and a postcompres-  sion one. The first set of echoes returned to the transducer is  analyzed before being converted to the B-mode image and  the resultant frame is stored. The second set is produced and  stored during applying the excitation force to the tissue. The  two radiofrequency waveforms are windowed. The signal in  each precompression waveform window is cross-correlated  with a similar segment of the postcompression waveform  and the amount of shift occurred is found. The shift amount  of the signal equals the amount of tissue displacement at that  point in the image frame. The same process is followed for  each image frame point. The "strain" (rate-of-change) values  are displayed to form an “elastogram.” Hard tissues move as  a unit and are displaced about the same amount when com-  pressed. Therefore, the displacement rate-of-change versus  depth tends to zero. Softer tissues present much more dis-  placement closer to the compressing transducer than further  away, i.e., a larger displacement rate-of-change versus depth  (large strain values). Therefore, harder areas within soft tis-  sues show low strain values and are displayed dark, whereas  softer areas show higher strain values and are displayed  bright on the elastogram.   Classic parameters to describe tissue stiffness include the  Young elastic modulus (change in length of a material in rela-  tion to the stretching/compressive force applied) and the  shear modulus, which relates the deformability of a material  in response to force applied parallel to one of its surfaces.    The latter is computed directly by US estimation of the shear  wave velocity and can be used for the estimation of the  former.    The resolution of conventional Doppler US is limited to ves-  sels of approximately 1 mm in size, which is insufficient to  image the microvascular bed associated with, e.g., tumor  neovascularity (10-50 um). New functional imaging tech-  niques and the introduction of contrast agents together with  special perfusion software (e.g., vascular recognition imag-  ing software, Toshiba) has enabled the detection of even the  smallest vessels. Contrast agents consist of intravenously  injected microbubbles with a diameter, in the range of 1-10  um, i.e., small enough to penetrate into the smallest microvs-  sels after passing through the pulmonary circulation.” !' ?   Microbubbles are nowadays made by a central core of a  gas suspension in an aqueous carrier and an outer shell. The  gas is innocuous, fluorinated, with low solubility and spread-  ing capability (e.g., sulfur hexafluoride, octafluoropropane, or  decafluorobutane). The surrounding capsule is made of albu-  min or polymer, coated with a lipid or a surfactant for stabili-  zation (prevention of coalescence) and life-span prolongation.  The ideal agent should be deprived of significant side effects,  allergic potential, or nephrotoxicity and must survive during  the journey through the circulation toward the target.   Microbubbles have progressively evolved from the first  generation such as Levovist® (Schering, Berlin, Germany)  into the “modern” second-generation agents, which use an  immunologically inert lipoprotein shell, an inert gas and emit  more efficiently the ultrasound signal. Among the most  widely used agents today are SonoVue® (Bracco Imaging,  Milan, Italy), Optison& (Amersham Health AS, Oslo,  Norway), and Definity® (Bristol-Myers Squibb, Billerica,  Massachusetts). These agents differ in terms of their physical  properties. Modern bubbles are safe to use, and only minor  side effects have been reported (alteration of taste, general/  facial flush, local pain at the injection site).'*   Contrast agents contract and expand in response to pres-  sure oscillations of the ultrasound beam generating a scat-  tered field. They are very efficacious ultrasound scatters,  producing much stronger backscatter than blood or normal  tissue because of the extremely large differences between  the acoustic impedances of the gas inside the bubbles and the  surrounding liquid. Therefore, contrast agents provide the  ideal way for imaging a prostate or kidney tumor, by means  of microvessel imaging.   Contrast agents are imaged in general by two basic meth-  ods'!: Color/Power Doppler (CD/PD) US and gray-scale har-  monic imaging. Owing to the relative high-energy levels used,  conventional Doppler US disrupts most of the microbubbles    before their advent to the microvasculature. With PD-CE-US,  extra reflections of ultrasound signals in the blood flow after  the administration of microbubbles enhance the Doppler sig-  nal. When exposed to ultrasound energy, microbubbles dis-  play nonlinear behavior because they are able to expand more  than they can contract. Signal reflected from tissues is mainly  at the transmitted fundamental frequency. However, signal  reflected by microbubbles contains harmonics of the funda-  mental frequency, selectively visualized by ultrasound post-  processing techniques providing enhanced visualization.  Gray-scale harmonic imaging techniques use lower energies  resulting in less bubble destruction.   Continues harmonic imaging has been further improved  with the implementation of different techniques such as pulse  inversion, intermittent harmonic imaging, flash-replenishment,  and cadence contrast-pulse sequence (CPS), allowing for  detailed view of the microvasculature. Intermittent harmonic  imaging uses low energy to avoid bubble destruction and  limited number of frames of high energy to visualize the  bubbles." Flash-replenishment techniques involve high-  power flash pulses to destroy the microbubbles, followed by  low-power pulses to visualize contrast replenishment.'^ CPS  processes the reflections of a series of pulses with different  amplitudes and phases, which results in an optimized con-  trast-to-tissue ratio, and a microbubble contrast-only image  is constructed. ^   The interpretation of CE-US information is based on a  subjective estimation. It is considered highly operator-  dependent and a learning curve definitely applies.'? Various  methods have been described for introducing objectivity in  the assessment of images and bypass this inherent limita-  tion." Extra time and costs represent further disadvantages.  For example, it has been reported that the total investigation  time of a prostate CE-US study is increased by 5-10 min."    Some lesions is impossible to be imaged with a routine ultra-  sound scan plane, especially superficial lesions, longer than  the transducer footprint, or when imaging with array trans-  ducers. In these cases, extended field of view technology  allows for including the entire lesion in one image. The  transducer slowly moves across the large anatomic region of  interest, numerous images are acquired from many positions,  and the computer algorithm registers the images with respect  to each other, accounting for both translation and rotation of  the transducer. The relative positions of the images are deter-  mined by comparison of data features in the overlapping  regions and analyzed appropriately to form the complete    large extended field of view image. This mode is very useful,  for example, when the testis is markedly enlarged and cannot  fit in one view.”    The improved resolution achieved to date due to the recent  advances in ultrasound technology described earlier, together  with the sufficient computing power presently available, has  made possible 3D renderings of ultrasound images and their  real-time delivery (4D imaging), producing whole volume  view of solid structures.'?   This technology allows for the creation of a 3D image  from several 2D images. 4D-US incorporates a temporal  dimension to 3D technology, and it is useful for performing  volume assessments as a function of time in dynamic sys-  tems. It is achieved through rapid refresh rates of consecutive  3D image sets.”   Potential advantages of this technology include’: (a) elim-  ination of user-dependent scanning variation, (b) increased  measuring accuracy of volumes, (c) better appreciation of  the anatomic relationships, (d) greater confidence of inter-  pretation, (e) short image-acquisition time, (f) ability of  computer enhancement with image registration software that  permits postprocessing image manipulation in any plane to  derive further information, and (g) easier exam to exam com-  parison that facilitates follow-up.   Potential limitations are: (a) the need for highly trained  personnel to reduce the possibility of artifact introduction  during initial scan or data analysis and (b) higher investment  costs in a computational infrastructure to meet the hardware,  software, transfer/retrieval, and support requirements of this  technology. Although the results appear promising, the clini-  cal additional value still has to be determined.    The rationale behind the use of elasticity imaging for the  detection of prostate cancer (PCa) is that these tumors are  firmer than the surrounding normal parenchyma. Prostate  was the first organ to be considered for both elastography  and sonoelasticity imaging, i.e., the method using CD-US to  detect tissue vibrations resulting from acoustic vibrations in  the audible range transmitted to the organ. '?    The results based on a number of recent studies are prom-  ising.” These studies can be schematically divided into  two broad, conceptually overlapping categories: (a) Group A  (Table 27.2): studies that evaluate the technique as a diagnos-  tic tool for PCa detection based on images (no targeted biop-  sies obtained), 77 ? 3.5 (b) Group B: studies that evaluate  the method as a tool to support or replace transrectal ultra-  sound (TRUS)-guided systematic biopsy based on elastogra-  phy-targeted biopsy results.? 7 78-29. 32   Cochlin et al conducted the first clinical trial including 100  patients to investigate whether adding elastography imaging  with targeted biopsies of abnormal areas on gray-scale  ultrasound-guided systematic biopsy improves PCa detection  rate.”' Although the sensitivity of elastography was not high  enough to permit replacement of gray-scale imaging, its addi-  tion to the standard biopsy technique was justified because it  detected three extra patients at the expense of eight extra cores.   Kónig et al investigated 404 patients with a systematic  sextant biopsy protocol under conventional B-mode US in  conjunction with elastography imaging." A pathological  finding was seen on the elastograms in 84.146 of patients with  PCa. Only 64.296 of patients were detected after DRE and/or  TRUS. They concluded that PCa can be detected with a high  degree of sensitivity using this technique in conjunction with  conventional diagnostic methods for guided biopsies.   Elastography-guided prostate biopsy has been compared  directly with systematic biopsy in 230 screening volunteers.^*  One investigator performed up to five targeted biopsies in the  peripheral zone and subsequently, blindly to previous results,  another investigator performed 10 systematic biopsies guided  by conventional gray-scale TRUS. PCa was detected in 35%  of the population. Targeted biopsy protocol did not detect  significantly more patients with PCa compared with system-  atic biopsy protocol (30% vs. 25%, respectively). However,  the difference in detection rates per core was significant (tar-  geted vs. systematic: 12.7% vs. 5.6%). Targeted biopsy in a  patient with PCa has been found to be 2.9-fold more likely to  detect the tumor. Therefore, targeted biopsy protocol detected  more cases of PCa with fewer than half the number of cores.  No significant differences have been detected in the distribu-  tion of Gleason scores. The detection rate for targeted biopsy  has been slightly better in the apical areas.   To compare the detection of PCa and distribution of  Gleason scores, targeted biopsies based on conventional  TRUS, CD-US, and elastography were obtained along with  systematic sextant biopsies in 137 patients.” Targeted cores  were more likely than systematic cores to detect PCa. Positive  results on CD-US and elastography were strongly associated  with high-grade and moderate-to-high-grade cancers, respec-  tively. It was concluded that although CD-US and elastogra-  phy are encouraging adjuncts to improve PCa detection,  targeted biopsy alone is not sufficient to replace sextant  biopsy technique.    Table 27.2 Studies evaluating the role of elasticity imaging as a diagnostic tool for prostate cancer detection: Review of the literature    3D-SE performed considerably better in the depiction of  PCa for tumors with volumes 21 cm?    Detection rate was significantly higher for E (93%)  compared with TRUS (55%) and DRE (59%)   Detection rates similar for E (5596), TRUS (5596), and  DRE (64%) in previously treated patients    E can detect PCa foci with very good accuracy (92%)  Best sensitivity at the apex-mid gland    Detection rate for E (84%) superior to TRUS (31%)  Detection rate for combined modalities (100%)   Excellent detection for anterior tumors. Lower detection  rate for higher-grade tumors    Detection rate for E (74.1%) superior to TRUS (48.1%),  DRE (33.3%), CD (55.6%), and MRI (47.4%)    E can detect PCa foci with good accuracy (76%)  E findings correlate best in the apex   The detection rate increases with higher Gleason score  (up to 93% for scores >7)    Histopathological findings predicted by E in only 44.5%  of cases. E does not improve detection rate    PCa = Prostate cancer, RPS = radical prostatectomy specimens, 3D-SE = three-dimensional sonoelastography, US = gray-scale ultrasonography,  TRUS = Conventional transrectal ultrasonography, DRE = digital rectal examination, CD = color doppler, MRI = magnetic resonance imaging    *Patients treated previously with hormone therapy. Elastography detection rate dropped possibly due to lesion softer-rendered consistency by    *A randomized clinical trial, in which both arms have been submitted to conventional TRUS-guided 10-core biopsy. One arm has additionally been    Kamoi et al compared the performance of elastography  with conventional TRUS and PD-US in the detection of PCa  evaluating a clinical population 107 males. All of them  were submitted to transperineal systematic eight-core biop-  sies. Up to four biopsies were added based on suspicious  findings of each modality. Patient analysis showed that the  sensitivity of TRUS was significantly lower (5096) than that  of PD-US (70%) and elastography (68%), but specificity did  not differ significantly. All modalities showed comparable  accuracies ranging from 72% (TRUS) to 76% (elastogra-  phy), and the diagnostic performances did not differ signifi-  cantly. The diagnostic performances of pair-wise or all-three  modalities combinations also did not differ significantly.  However, analysis by core showed that the detection rate of  the PD-US and elastography combination was significantly  higher than that of systematic biopsy. It was concluded that    elastography may complement conventional US to minimize  the number of missing cancers.   Based on the current data described earlier, elastography  combined with TRUS, constitutes a simple, noninvasive,  relatively cheap technique, allowing for targeted biopsies  and may reduce the number of biopsy cores per patient.  Nevertheless, further clinical trials are still necessary and  already on the way to better define the advantages and the  exact role of this relatively novel technique in the diagnosis  of PCa.**   Apart from a possible role in the diagnosis of PCa, elas-  ticity imaging techniques may be useful for monitoring  HIFU ablation therapy in PCa because HIFU lesions are  stiffer than the surrounding normal untreated parenchyma.  Promising results have been recently published implying that  elastography might be able to replace MRI in these cases, but    further clinical trials are still needed before this application  is considered established. ?ó    The advent of microbubble-based contrast agents represents  a major revolutionary innovation in US. These agents in  combination with novel "contrast-specific" imaging modes  (e.g., pulse inversion harmonic imaging) pave the way for  several new indications for CE-US in urology. In prostate,  contrast agents may potentially facilitate the detection of  cancer, providing additional information on tumor size  (Fig. 27.1) and possibly aggressiveness, as well as the moni-  toring of antiangiogenic treatment results." This is because  prostate cancer shows an increase in both cell density and  vascularization. The increased cell density leads to change in  elasticity and may be visualized with elasticity imaging tech-  niques as already described earlier; the increased vascular-  ization can be visualized with CE-US.   To determine the value of CE-US in the detection, local-  ization, and treatment follow-up for PCa, a multicenter  research coordination project was carried out in four European  countries during the period 2002-2006 (CONTRAST, QLRT-  2001-2174). Recently, the project results based on 3,746  patients have been reported in comparison to published data  outside this research group. The individual studies of this  project published, employed various contrast agents imaged    Fig. 27.1 Contrast-enhanced  (1) and conventional  trans-rectal ultrasonography of  the prostate in the same patient  with prostate cancer (2) The  suspicious lesion is depicted as  a hypoechoic area (white  arrow) in conventional  trans-rectal ultrasonography. A  much larger lesion is depicted  by contrast enhancement (2:  white arrow). Contrast agents  may facilitate the detection of  cancer providing additional  information on tumor size    by a) CD-US,*** b) 3D-PD-US,* and c) novel nonlinear  imaging techniques (CPS).'^   The correlation of histological findings in radical pros-  tatectomy specimens with preoperative CE-US images  regarding tumor localization seems to be promising, show-  ing that technical improvements have led to an increased  sensitivity for the detection of perfusion patterns. Visualization  of lesions with increased microvascular density was feasible  both with the use of 3D-CE-PD-* and CE-CD-US.* 3D-CE-  PD-US has been found to be a better diagnostic tool than  digital rectal examination (DRE), prostate specific antigen  (PSA) level, gray-scale, or PD-US, and the most suitable  diagnostic predictor for PCa has been found to be the combi-  nation of 3D-CE-PD-US and PSA level." Based on wide-  band harmonic imaging, it has been shown that CE-US  improves the sensitivity for PCa detection but also demon-  strates focal enhancement in areas of benign hyperplasia.”  Nevertheless, accurate detection of localized tumors has  been reported in up to 78% of patients with 3D-CE-PD-US.*”°  In a larger group of 70 patients evaluated with the same tech-  nique, diagnosis by imaging alone has been improved from  61% (standard detection and staging investigations) to an  average of 86% of tumors with detection of loci 25 mm in  68—7996.?! In another small series, all T3 tumors could be  identified using microvascular imaging (Philips).?   The clinical value of these promising results should be  tested in a diagnostic setting. The effect of CE-US on the  prostate biopsy protocol and detection rate has been    extensively investigated. The combined research European  Community project concluded that a clear association  between prostate contrast enhancement and diagnosis of  clinically significant PCa exists. The sensitivity for diagnosis  is increased by CE-US targeted biopsies, fewer biopsies are  needed to achieve the same detection rate, and the tumors  detected by targeted biopsies present a higher Gleason score  than those detected by random biopsies."   These findings are in accordance with the promising  results from studies outside the European research project.  By employing various CE-US methods, including novel non-  linear imaging techniques (intermittent harmonic imaging,  flash-replenishment, CPS), these studies either directly  compared gray-scale ultrasound-guided systematic with  CE-targeted biopsy protocols ^ 9??? (Table 27.3) or investi-  gated the contribution of CE-US on systematic biopsy proto-  cols? and its value in predicting the nature of hypoechoic  lesions.'^ 18,58   Currently, CE-US enables visualization of PCa and tar-  geted biopsies applied upon a random protocol do increase  detection rate. However, sensitivity/specificity is still not  enough to avoid systematic random biopsies. Therefore,  CE-US does not yet have a role in routine clinical practice.  Many studies are on the way and a large prospective multi-  center study supported by Bracco Imaging, Milan, Italy, has  been initiated in an attempt to prove that currently available  CE-US techniques can be used in PCa diagnosis and that  targeted are superior to systematic biopsies.   The ability of CE-US to image prostate perfusion might  enable visualization of minimal invasive or medical treat-  ment effects that influence the perfusion of the organ (HIFU/  cryoablation, hormone therapy) in PCa and identify patients  with early relapse using the presence or absence of blood  signals as an indicator.”   In patients submitted to HIFU before radical prostatec-  tomy, it has been shown that the blood flow absence indi-  cated by 3D-PD-US following administration of contrast  agent (Levovist®) reflects affected tissue after ablation and  volume measurements of these areas can quantify the amount  of affected tissue.? Unfortunately, in a study investigating  the prediction of the HIFU-induced destruction uniformity, it  has been shown that pretreatment evaluation cannot identify  the nonresponders beforehand.” Thirty-five patients with  PCa underwent pre- and postcontrast (Levovist®) CD-US of  the prostate before HIFU treatment. Tissue destruction seen  in posttreatment random biopsies did not correlate with the  preoperative US findings.   Another application of CE-US is to monitor hormonal  treatment in patients with PCa. It has been reported that the  vascular enhancement of the carcinoma detected by CD- and  PD-US after the administration of Levovist® declines with  hormonal therapy similar to PSA and can be used to monitor  therapy.”    Apart from the potential “conventional” applications of  CE-US discussed earlier, in PCa, other more sophisticated  applications in the diagnosis and treatment at a cellular level  such as molecular imaging and sonoporation represent an  exciting field of urological research and will be the next fron-  tier to be reached."   Molecular imaging (visualization of biological processes  at the cellular/molecular level in living systems) aims at  viewing and quantifying early molecular changes associated  with disease, rather than the resulting morphological changes.  The superior sensitivity of contrast-specific imaging modes  may render US an ideal tool for noninvasive, real-time obser-  vation of in vivo biological events at the molecular level in  the vascular compartment. Efforts have been recently put on  the design/preparation of specific ligands bound on the phos-  pholipid-stabilized shell. This will result in specific localiza-  tion of the targeted bubbles on selected vascular receptor  sites upregulated in pathologies such as neoangiogenesis.  They will then potentially serve as molecular targets for  diagnosis and/or as therapeutic agents.   Sonoporation is a physical method that results in increased  cell permeability through acoustic cavitation caused by US  application in the presence of contrast agents. One of the  explanations is that cavitation causes the implosion of  microbubbles generating microjets, which open pores  through cell membranes, allowing for direct transfer of  drugs/genetic material into the cytoplasm. Pore opening is  reversible, allowing for preservation of cell viability and  transient with duration of a few seconds.^ Gas and shell  properties of the contrast agents have an important influence  on cell transfection,” and hard-shelled ones (gas microcap-  sules) are promising candidates for ultrasound-mediated  gene delivery.?   Recently, it has been shown that PCa cells could be trans-  fected both in vitro and in vivo, via microbubble-enhanced  US with short antisense oligodeoxynucleotides that down-  regulate the androgen receptor, decreasing its expression.^  In PCa, intratumoral delivery of DNA-Optison followed by  therapeutic ultrasound has been proposed as an effective,  nontoxic gene delivery method providing a safe clinical  alternative to current viral gene-delivery approaches where  short-term gene expression is needed.“ Delivery for example  of angiogenic inhibitors in PCa by this method seems to be  feasible.    Early work on prostate imaging identified several advantages  of 3D technology over 2D TRUS imaging with an improved  diagnostic capacity, accurate diagnosis of extraprostatic  tumor extension, and staging of localized PCa.^* ^ The 4D  technique has been used during TRUS-guided prostate    biopsies improving diagnostic accuracy. Further clinical  applications of 3D TRUS include assessing placement for  brachytherapy seeds-treatment mapping and guidance for  cryoablation of localized PCa in candidates unsuitable  for surgery."   Recently, a novel computer-aided US technology, based  on tissue characterization algorithms (HistoScanning™;  Advanced Medical Diagnostics, Waterloo, Belgium), has  been developed. This tissue differentiation, visualization,  and quantification tool identifies specific changes in solid-  organ morphology by extracting and quantifying statistical  features from 3D backscattered ultrasound radio frequency  data. The geometric accuracy of the system facilitates identi-  fication of minimal, localized tissue structures. The charac-  terization algorithms exploit the physical changes to sound  waves that result from the interaction of the ultrasound beam  and the cancer tissue (energy loss, erratic spatial energy dis-  tribution, and increased entropy). They can be applied in dis-  crete regions of interest in the prostate. Thus, the presence of  PCa can be ascertained within minute, discrete tissue vol-  umes. Prostate HistoScanning™ can spatially orientate can-  cer within the gland, enabling both determination of its  location and volume. It has been reported that this technol-  ogy can accurately detect foci of 20.50 mL” and has been  proposed as a potential triage test for men deemed to be at  risk of PCa who wish to avoid biopsy."    CE-US can play an important role in differentiating/charac-  terizing solid lesions and complex cystic masses of the kid-  ney. Tamai et al? assessed the value of CE-US in the diagnosis  of solid renal tumors in comparison to contrast CT. CE-US  has been found to be more sensitive in the detection of slight  tumor blood flow and a useful tool in the preoperative diag-  nosis mainly of hypovascular malignant renal tumors.   CE-CD-US has been shown to achieve better results in  the detection of tumor vascularity and the discrimination  between benign and malignant small renal masses than the  conventional CD-US.? The detection rate of intra-and/or  peritumoral vessels with the use of contrast agents was twice  that achieved without their use.   Ascenti et al" compared CE-US with triple-phase helical  CT in the classification of complex renal cysts using the  Bosniak system and found a complete concordance in the  differentiation of surgical and nonsurgical complex cysts  with a high interobserver agreement. In a similar study com-  paring CE-US with CT, Park et al? found that CE-US has a  better diagnostic accuracy, although the difference was not    significant. CE-US might better visualize septa number,  septa and/ or wall thickness, solid component, and the  enhancement of some renal cystic masses, resulting in  upgrading of the Bosniak classification and a change in the  treatment plan.   The characteristics of renal tumor perfusion detected by  CE-US based on CPS technology have been investigated and  have been compared with clinical diagnoses and histological  findings.” It has been reported that CPS may have a future  role in determining perfusion patterns in kidney tumors  (Fig. 27.2). CE-US based on CPS technology has also been  evaluated in the diagnosis of small renal masses («4 cm).  Similar diagnostic accuracy to multidetector CT has been  shown for renal masses of 2-4 cm, whereas CE-US has been  reported to be superior for lesions smaller than 2 cm.   The increasing use of ablation techniques for the manage-  ment of small renal masses poses the problem of optimal  monitoring of ablated tumors. Since success is defined as  absence of contrast enhancement on CT or MRI, CE-US may  also play a role in the follow-up of such cases (Fig. 27.3). It  has been shown that CE-US has the potential of monitoring  radiofrequency ablation (RFA) of renal tumors in animal  models.” In addition, it has been demonstrated that CE-US  based on CPS technology can be used to characterize perfu-  sions defects at different times, during the follow-up, after  renal cryoablation’*(Fig. 27.4). Nevertheless, additional clin-  ical studies are necessary to define precisely the potential of  this imaging technique for the characterization and follow-  up of indeterminate cystic masses, and further larger-scale  prospective studies comparing CE-US with CT are still  needed.   The new emerging field in CE-US is the generation of  targeted microbubbles to specific neoangiogenesis or tumoral  antigens to provide a tumor target therapy with antitumor  agent-labeled microbubbles in the future.    Elasticity imaging for visualization of renal masses has only  recently been investigated in vivo. Fahey et al® evaluated  acoustic radiation force impulse imaging for real-time visu-  alization of abdominal malignancies including two renal  masses. They provided the first images of renal tumors in the  human acquired in vivo using elasticity imaging and con-  cluded that acoustic radiation force impulse imaging  improves the visualization of kidney malignancies compared  with the sole use of conventional US.   Elasticity imaging has also been recently evaluated as a  possible aid in RFA in porcine kidneys by monitoring phase  changes in the echo signals caused by speed of sound varia-  tions and thermal expansion with temperature.*' A significant    Fig. 27.2 Contrast-enhanced  ultrasonography of the kidney.  The presence of a renal tumor 09:41:04  is imaged by cadence Pwrz-21dB    contrast-pulse sequence  technology (white arrow). The  presence of the tumor is better  visualized compared with  conventional B-mode imaging    Fig. 27.3 Contrast-enhanced  ultrasonography two weeks after  cryoablation of a kidney tumor  showing the perfusion defect  (white arrow). The three  respective perpendicular planes  are demonstrated (1, 2, 3) as well  as the volume rendering of the  three-dimensional data set (4)    Fig. 27.4 Contrast-enhanced  ultrasonography of the kidney  based on contrast-pulse  sequence technology (left) and  the respective conventional  B-mode imaging (right). The  perfusion defect (within circle)  after cryoablation of the renal  tumor is more clearly depicted  by contrast-enhanced  ultrasonography    correlation between elastographic estimations of the area  and volume of the thermal lesions and gross pathologic mea-  surements has been found. These results suggest that elas-  tography may prove to be a reliable method for monitoring  the RFA zone of renal lesions, overcoming the inaccuracy of  the current imaging modalities to provide real-time monitor-  ing, and thus it may result in an improvement of the RFA  efficacy.   The percutaneous ablative techniques for renal-cell carci-  noma treatment that have been developed require image  guiding for the precise placement of the needles. Recently,  the use of a novel technology named real-time virtual sonog-  raphy (RVS, Hitachi Medical Corporation, Japan) has been  described. RVS displays simultaneously the images of real-  time US with the corresponding CT or MR multiplanar views  from a stored volume data set. RVS seems to be a promising  alternative imaging tool to CT/MRI, providing excellent ana-  tomical orientation and navigation for percutaneous RFA of  solid renal tumors at a lower radiation exposure.   Imaging with 3D/4D-US may have several applications  such as, diagnosis and follow-up of hydronephrosis in chil-  dren, evaluation and follow-up of renal lesions, execution of  renal/adrenal biopsies and percutaneous procedures (neph-  rostomies, ablations).! 4D-US has been recently evaluated  for guiding percutaneous interventions. 4D-US has been  used to refer to both time-resolved and real-time 3D-US.  2D-US has been compared with the time resolved 4D-US for  percutaneous access in minimal calyceal dilatation using an    in vitro ultrasound phantom." It has been reported that  4D-US is at least as good as 2D-US in terms of quality of  punctures. Multiplanar reformatting longitudinal and trans-  verse images were found to be the most useful for needle  guidance.    EUS has been recognized as a complementary technique for  obtaining information regarding the ureteral and periureteral  anatomy. The ultrasound image is oriented and localized in  the upper urinary tract with the aid of real-time fluoroscopy.  Its principle indication is to image ureteropelvic junction  obstruction. Recently, it has been reported that EUS is more  sensitive than helical CT scan for detecting significant cross-  ing vessels, and its use can better prevent bleeding complica-  tions. In addition, the use of EUS to direct the choice of  treatment during endopyelotomy has been associated with a  success rate 29096.   EUS may contribute to the staging of upper urinary tract  transitional-cell carcinoma and the detection of submucosal  migration of ureteral stones. Moreover, it can be used in the  procedure guidance/assessment of other organs of the uro-  genital system. It can detect bladder cancer muscle invasion,    guide urethral instrumentations, assess sphincter function in  cases of urinary incontinence, guide collagen placement to  treat sphincter insufficiency, facilitate the diagnosis of closed  ostium urethral diverticulum, and contribute even in the  locoregional staging of prostate cancer.’   Crossing vessel detection in patients with ureteropelvic  junction obstruction is also possible with CE-CD-US. The  use of this imaging modality in comparison to CT and MRI  has been recently evaluated. Results have been correlated  with the laparoscopic pyeloplasty findings in 48 patients.  Forty-four patients demonstrated crossing vessels at laparos-  copy. CE-CD-US and MRI correctly detected all crossing  vessels, whereas CT missed four posterior veins. Based on  these results, CD-CE-US has been recommended as a first-  line imaging modality in these patients.   Results of tissue harmonic imaging combined with plain  abdominal radiography have been found to be comparable to  those obtained by CT in the diagnosis of ureteral stones in  patients with renal colic. It has been suggested that routine  use of CT in these patients could be reduced by this  strategy."    Although the advent of flexible instruments and digital chip  technology has significantly increased tolerability during  cystoscopy, it still remains an invasive procedure with main  drawbacks such as failure to evaluate adjacent structures, a  5-15% risk of urinary tract infection, patient's discomfort  and anxiety, and iatrogenic injury of the lower urinary tract.**  During last years, a lot of effort has been put on the develop-  ment of new noninvasive techniques for the evaluation of the  bladder. The value of 3D- versus 2D-US of the bladder has  been evaluated in 42 patients with hematuria.? 3D-US has  been reported to have a better diagnostic performance, pro-  viding an overall correct diagnosis in 8696 of the cases. The  sensitivity for malignant and benign bladder lesions was  100% and 71%, respectively.   In a similar study, the potential value of the virtual cystos-  copy based on 3D sonographic data has been evaluated for  the detection of bladder tumors.? The sensitivity and speci-  ficity of tumor detection has been 96.296 and 70.696, respec-  tively, with a positive and negative predictive value of 93.9%  and 8096, respectively. When combined with gray-scale,  multiplanar reconstruction sensitivity, specificity, and posi-  tive and negative predictive values have been increased to  96.4%, 88.8%, 97.6%, and 84.2%, respectively.   US estimation of the detrusor wall thickness has been  proposed to be a noninvasive predictor of bladder outlet  obstruction?! Akino et al” assessed the efficacy of  ultrasound-estimated bladder weight (UEBW) as an indica-  tor for surgery and its outcome in patients with benign pros-  tate hyperplasia. It was found that high UEB W is as important    as severe lower urinary tract symptoms in identifying male  patients at risk of surgery.   Traditionally, US has been used as diagnostic tool for the  evaluation of the urinary tract in children with vesicoureteral  reflux (VUR). Contrast-enhanced voiding urosonography  (VUS) was used only for the initial diagnosis in females and  in the follow-up of children already submitted to voiding  cystourethrography (VCUG).? Recently, the diagnostic  accuracy of VUS compared with that of VCUG in children  with VUR has been evaluated.” A 96% of diagnostic agree-  ment between the two techniques has been detected, suggest-  ing the use of VUS as a first step in the diagnosis of VUR in  children of both genders with a significant reduction in radia-  tion exposure.    The assessment of the testicular resistive index (RI) by  CD-US has been widely used to measure intratesticular  blood flow. Pinggera et al” investigated the value of the  intratesticular arteries RI using high-frequency CD-US in  the diagnosis of patients with sperm impairment. The greater  RI (20.6) found in patients with pathological sperm counts  seems to be a reliable indicator for routine clinical use to  identify subfertile men.   To date, no single reliable test has been able to provide  100% diagnostic accuracy of testicular torsion and the use of  CD-US of the testis can be misleading with false-negative  results. In a multicenter study, including more than 900  patients, the direct visualization of the twisted cord with high  resolution US has been proposed as a diagnostic method for  the testicular torsion. The finding of a twisted cord is a highly  sensitive and specific sign of testicular torsion, whereas the  direct and complete visualization of a linear cord strongly  indicates that surgery is unnecessary.”   HIFU was first described in 1998 as a minimally invasive  technique for the treatment of testicular tumors in a solitary  testis.” Recently, the long-term results of a phase II trial  have been presented.” It has been reported that transcutane-  ous HIFU followed by prophylactic irradiation permits an  organ-preserving, curative treatment for tumors in a solitary  testis.   Finally, the feasibility of delivering proteins to the testicu-  lar extracellular compartment has been recently evaluated.”  Ultrasound-targeted microbubble destruction is a feasible  method for delivering bioactive substances even in organs  with moderate to low blood perfusion, as long as they are  accessible by ultrasound.    Acknowledgements Dr Charalampos Mamoulakis thanks the  Alexander S. 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BJU Int.  2007:1001:47-50   Ascenti G, Mazzotti S, Zimbaro G, et al Complex cystic renal  masses: characterization with contrast-enhanced US. Radiology.  2007;2431:158-165   Park BK, Kim B, Kim SH, Ko K, Lee HM, Choi HY. Assessment of  cystic renal masses based on Bosniak classification: comparison of  CT and contrast-enhanced US. Eur J Radiol. 2007;612:310-314  Wink MH, de la Rosette JJ, Laguna P, Lagerveld BW, Wijstra H.  Ultrasonography of renal masses using contrast pulse sequence  imaging: a pilot study. J Endourol. 2007;21:466—472   Pallwein L, Mitterberger M, Gradl J, et al Diagnostic evaluation of  small renal masses: value of contrast-enhanced US in comparison  to multidetector CT. J Urol. 2008, 179 Suppl:331   Slabaugh TK, Machaidze Z, Hennigar R, Ogan K. Monitoring  radiofrequency renal lesions in real time using contrast-enhanced  ultrasonography: a porcine model. J Endourol 2005;19: 579-583  Wink MH, Laguna MP, Lagerveld BW, de la Rosette JJ, Wijkstra H.  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The use of endoluminal ultrasonography for preventing significant  bleeding during endopyelotomy: evaluation of helical computed  tomography vs endoluminal ultrasonography for detecting crossing  vessels. BJU Int. 2006;97:786-789   Keeley FX Jr, Tolley DA, Moussa SA. Patient selection before  endopyelotomy: can it improve the outcome? BJU Int. 2000;86:  773-716   Mitterberger M, Pinggera GM, Neururer R, et al Comparison of  contrast-enhanced color Doppler imaging (CDI), computed tomog-  raphy (CT), and magnetic resonance imaging (MRI) for the detec-  tion of crossing vessels in patients with ureteropelvic junction  obstruction (UPJO). Eur Urol. 2008;53:1254—1260   Mitterberger M, Pinggera GM, Neururer R, et al Plain abdominal  radiography with transabdominal native tissue harmonic imaging  ultrasonography vs unenhanced computed tomography in renal  colic. BJU Int. 2007;100:887—890   Newhouse JH, Amis ES Jr, Bigongiari LR, et al Radiologic investi-  gation of patients with hematuria. American College of Radiology.  ACR appropriateness criteria. Radiology. 2000;215 Suppl:687—691  Mitterberger M, Pinggera GM, Neuwirt H, et al Three-dimensional  ultrasonography of the urinary bladder: preliminary experience of  assessment in patients with haematuria. BJU Int. 2007;99:111—116  Kocakoc E, Kiris A, Orhan I, Poyraz AK, Artas H, Firdolas F.  Detection of bladder tumors with 3-dimensional sonography and  virtual sonographic cystoscopy. J Ultrasound Med. 2008;27:45—53    Oelke M, Hófner K, Jonas U, de la Rosette JJ, Ubbink DT, Wijkstra  H. Diagnostic accuracy of noninvasive tests to evaluate bladder out-  let obstruction in men: detrusor wall thickness, uroflowmetry, post-  void residual urine, and prostate volume. Eur Urol. 2007;52:  827-834   Akino H, Maekawa M, Nakai M, et al Ultrasound-estimated bladder  weight predicts risk of surgery for benign prostatic hyperplasia in  men using alpha-adrenoceptor blocker for LUTS. Urology. 2008 ;  72:817-820   Darge K. Voiding urosonography with US contrast agents for the  diagnosis of vesicoureteric reflux in children. II. Comparison with  radiological examinations. Pediatr Radiol. 2008;38:54—63  Giordano M, Marzolla R, Puteo F, Scianaro L, Caringella DA,  Depalo T. Voiding urosonography as first step in the diagnosis of  vesicoureteral reflux in children: a clinical experience. Pediatr  Radiol. 2007;37:674-677   Pinggera GM, Mitterberger M, Bartsch G, et al Assessment of the  intratesticular resistive index by colour Doppler ultrasonography  measurements as a predictor of spermatogenesis. BJU Int.  2008;101:722-726   Kalfa N, Veyrac C, Lopez M, et al Multicenter assessment of ultra-  sound of the spermatic cord in children with acute scrotum. J Urol.  2007;177:297-301   Madersbacher S, Kratzik C, Susani M, Pedevilla M, Marberger M.  Transcutaneous high-intensity focused ultrasound and irradiation:  an organ-preserving treatment of cancer in a solitary testis. Eur  Urol. 1998;33:195-201   Kratzik C, Schatzl G, Lackner J, Marberger M. Transcutaneous  high-intensity focused ultrasonography can cure testicular cancer in  solitary testis. Urology. 2006;67:1269—1273   Bekeredjian R, Kuecherer HF, Kroll RD, Katus HA, Hardt SE.  Ultrasound-targeted microbubble destruction augments protein  delivery into testes. Urology. 2007;69:386—389    As physicians embrace new technology and incorporate it  into practice, traditional approaches will metamorphose into  seemingly strange but incredibly useful paradigms. One  extraordinary transformation has been the incorporation of  telemedicine into daily practice. Defined as the real-time  transfer of information between health care providers across  various media, telemedicine can take several forms. In its  simplest form, telecommunication merely allows informa-  tion sharing between professionals to help facilitate medical  care delivery. In telemedicine's most ambitious application,  telesurgery, surgical care in its entirety is delivered over the  wire. With surgical fields evolving to incorporate electronic  and audio/visual adjuncts, telemedicine has found a new  channel for development. This development has been aided  by advancements in networking, audio/visual, computer, and  robotics technology.   Telementoring, a form of telemedicine, is the practice of  using communication technology to assist, guide, and edu-  cate other providers over an electronic medium during real-  time care delivery. It has been used in space-training missions,  naval vessels, and on land.' Applications have been most rel-  evant in surgical care, given the urgency and technical  demand of surgical care. In the field of urology, telementor-  ing has assumed a central role as communication technology  has boomed. As endoscopy and laparoscopy became more  widespread in their urologic applications, most urologic pro-  cedures have become inherently compatible with this form  of remote mentoring.   Minimally invasive urologic surgery benefits patients by  conferring improved postoperative cosmesis and expedited  convalescence. However, proficiency in laparoscopic surgery  is not easily attained. A steep learning curve is associated  with the successful acquisition of minimally invasive surgi-  cal skills? Additionally, surgeons performing laparoscopic  procedures are more than three times more likely to encoun-  ter complications if they do not receive additional training  after completing their requisites.* Although continued train-  ing is essential for laparoscopic surgeons, a limited number    of expert surgeons have a teaching background. Teaching  hospitals thus incur additional expenses and face logistic dif-  ficulties in recruiting mentors from outside institutions.   Telementoring eliminates some of these obstacles to  attaining laparoscopic surgical proficiency. With the excep-  tion of a one-time start-up cost of procuring the necessary  equipment, telementoring eliminates variable costs down the  road, rendering repeated training sessions economically fea-  sible. Telementoring also makes available the expertise of  trained laparoscopic surgeons to patients residing in remote  areas. Surgeons working at local hospitals in isolated regions  can be assisted directly by expert telementors during compli-  cated procedures. This assistance immediately benefits the  patients by bringing specialized care to their home region,  reducing the cost of travel, and lowering the risk of delayed  medical attention.   This chapter chronicles the history of telementoring and  reviews its current state and novel applications. In doing so,  it explores the benefits of telementoring and outlines current  and future limitations. This review helps the reader to  contextualize telementoring and its role in the future of  telemedicine.    Telementoring is by no means a recent development.  Following the invention of the telephone in 1876, an early  example of telementoring was recorded in 1906. Einthoven,  the renowned father of electrocardiology, transmitted an  electrocardiogram via telephone from his lab to a hospital  located a mile away.^ Early forms of telementoring relied pri-  marily on telephone lines or direct video/audio linkups. In  the late 1950s, the University of Nebraska established a tele-  medicine network that aimed to complement clinical training  and research in rural areas. Expanding the scope of this trial,  two-way audio/video connections were established in 1961  to provide television-based group therapy sessions in the  field of psychiatry.^ * Shortly thereafter, Debakey demon-  strated the didactic potential of telementoring by performing    transcontinental lectures between the United States and  Europe via a direct satellite uplink.°   A period of relative stagnancy followed the attempts at  telementoring in the 1960s, directly resulting from inadequa-  cies in telecommunication technologies. Cheap, effective  transfer of information was not a realizable goal until the  implementation of the Internet. Although Vinton Cerf and  Robert Kahn coined the term "Internet" in 1974, the physical  switch from the older NCP protocol to Transmission Control  Protocol/Internet Protocol (TCP/IP) did not occur until 1983.  It would be another 5 years before the Internet was open to  commercial interests. The commercialization of the Internet  served as the catalyst that transformed telemedicine, and  more specifically telementoring, to its present form.’    Laparoscopic procedures are inherently compatible with  telementoring. Many components of laparoscopic equipment  can be easily integrated with a telementoring setup. The most  basic arrangement consists of a laparoscopic camera that  outputs video footage to a computer equipped with a coder/  decoder (CODEC). The audio and visual data are digitized  and then transmitted via a local or wide area network. A mul-  titude of connections is available with varying speeds and  costs. Earlier trials used mostly modem (operating through  telephone lines) or ISDN connections. However, later trials  used broadband connections that reduced lag time signifi-    Remote site: Expert mentor observes  procedure using video feed and  guides mentee using telestration,  audio commentary, or even  manipulation of robotic equipment    cantly while improving reliability (Fig. 28.1). Under normal  circumstances, a connection speed of 128 Kbps is sufficient  to provide high-quality, two-way video transmission. As an  additional safeguard, most telementoring institutions use  redundant connections in case of connection interruption.   The setup at the mentor side is slightly different. Lacking  the operating table and surgical equipment, the mentor's  console includes, at a minimum, a computer equipped with a  web camera and microphone. More advanced telementoring  apparatuses include a telestrator program and interface,  which enable the mentor to annotate notable landmarks dur-  ing surgery (not unlike football commentaries) in an effort to  guide the local surgeon. Recent innovations in telerobotics  have made it possible for remote surgeons to manipulate  robotic assistive devices at the local site. This setup has pro-  found benefits for telementoring, but requires additional con-  nection resources and a specialized software protocol.  Overall, the necessary components of a basic telementoring  apparatus are not costly or sophisticated, which makes tele-  mentoring an ideal form of remote training.    In nearly all instances of telementoring, researchers have  strived for greater bandwidth in an effort to reduce time  delay. In addition to connection speed, the magnitude of time  delay is directly proportional to the distance between two  locations. Hardware functions, such as the time required to    Local site: audio/visual information  gathered from novice surgeon  performing the procedure.    encode and decode the signal, impose an additional intrinsic  lag to the overall signal transmission. Fabrizio et al con-  ducted a unique study to ascertain the effects of time delay  on telesurgical manipulations. His group used custom soft-  ware, Microsoft Plus (Microsoft Corp., Seattle, WA), to arti-  ficially impose a controlled time lag on a simulation of  operation. It was found that the participating surgeons exhib-  ited a high number of errors, per assigned task, when the  time delay was amplified to more than 700 ms. In a second  phase of the study, a learning curve was found for surgeons  operating with a 500-ms static time lag; the test subjects  completed their tasks with fewer errors and fewer  movements.   Time delay would most likely pose a lesser detriment to  telementoring, in contrast to telesurgery, because the local-  site surgeon ultimately is in command of the surgery. Slight  pauses in the audio/visual feed from the expert mentor can be  tolerated without immediate risks. However, despite tolera-  ble latency from limiting bandwidth, a reliable connection is  still essential. Out of the 17 laparoscopic cases recorded by  Bove et al, from 1998 to 2000, five could not be telemen-  tored because an adequate uplink could not be established.?    Present telementoring methods transcend basic audio/visual  exchange, as illustrated by the incorporation of robotics into  the modern repertoire of remote surgical training. The new  additions not only benefit the on-site surgeon by providing  robotic assistance but also give the expert mentor a greater  degree of manipulation. The following robotic devices have  been used in telementored laparoscopic trials.    The automated endoscopic system for optimal positioning  (AESOP) was originally designed for NASA space missions  by a team of engineers led by Yulun Wang. It has since been  adapted to function as a camera holder in laparoscopic sur-  geries. A robotic camera holder has the advantage of reduc-  ing inadvertent movements and decreasing the overall  crowding in the operating room. Later generations of the  AESOP are fully compatible with voice-activated commands  and can be integrated with the HERMES control center,  which acts as the central console to all peripheral devices.’  With the necessary software and connection, the AESOP can  be set up to give the mentoring surgeon direct control. The  expert surgeon is then able to manipulate the laparoscope,  directing a specific angle of approach for the novice.    The Socrates (Computer Motions, Inc., Goleta, CA) is an  FDA-approved device for teleeducation, designed for both  laparoscopic and open cases. Composed of multiple sub-  units, the suite has voice-activated controls for the robotic  camera arm (AESOP), an insufflator, and external lighting.  The Socrates also incorporates the HERMES unit for a cen-  tralized console of operation and is fully network compati-  ble, through IP linkup or ISDN connection. Direct connection  allows single-party telementoring sessions, whereas a paral-  lel connection enables multiple parties to view the operation.  This setup is highly beneficial to physician training. One  notable demonstration of its efficacy was a semester-long  course held at the Moscow State University, taught from a  remote operating room in the United States, some 6,000 mi  away.    Percutaneous access to the kidney (Urobotics Laboratory,  JHMI, Baltimore, MD) is a robotic arm designed to gain  renal access for procedures such as nephrostolithotomy  (Fig. 28.2). The PAKY can be controlled locally by the on-  site surgeon or by the remote mentor, via dedicated ISDN  lines. Although this device is undergoing further develop-  ment, its future implementation could very well minimize  radiation exposure for surgeons attempting percutaneous  renal access.”    The Zeus system (Computer Motions, Inc., Goleta, CA) is  divided into two constituent units: a surgeon-side console  and a patient-side subsystem. The surgeon-side console  receives input from the operator, which is then actuated by  the robotic arms attached to the operating table (patient side).  A myriad of surgical equipment can be interchanged from  the two robotic arms, and a third arm controls the endoscopic  camera. The primary objective of the Zeus is to minimize  tremors from the surgeon, thereby reducing complications.  Laparoscopic surgeries completed with the assistance of the  Zeus have outcomes comparable to unassisted attempts, but  the operative time is generally longer.'?   The Zeus system was a major contribution to the practice  of telementoring; it was the first system to enable the tele-  mentor to take over the operation, should complications  arise. Its feasibility is evidenced by the first transatlantic tele-  surgery performed by Marescaux in 2001." Marescaux,    Fig. 28.2 PAKY arm attached to AcuBot console. (Urobotics  Laboratory, JHMI, Baltimore, MD)    situated in New York, successfully performed a telerobotic  cholecystectomy in a 68-year-old female in Strasbourg,  France. Using a dedicated optic fiber network with asynchro-  nous transfer mode (ATM), physical inputs from the surgeon  were translated into robotic motion at the patient side. The  lag time was determined as approximately 80 ms, which had  minimal effect on the overall procedure. This landmark  accomplishment demonstrated the feasibility of remote tele-  robotic surgery, and had profound ramifications on the meth-  odology of telementoring.    The da Vinci surgical system was developed by Intuitive  Surgical, Inc. (Menlo Park, CA). The company merged with  Computer Motion, Inc. in 2003, resulting in the discontinued  production of the Zeus robot. Like the Zeus, the da Vinci  system comprises three subunits: the cart, the console, and  the endoscopic stack. A surgeon operator performs surgical    tasks with the high-definition, three-dimensional imagery  provided by the endoscopic stack. The operator's every  movement is translated into corresponding movements in the  two robotic arms, which can be fitted with an assortment of  surgical instruments. Position sensing effectively eliminates  tremors, and cable systems controlling the instrument joints  allow emulation of the finest movements.   Supplanting the ZEUS, the da Vinci system has assumed  a prominent role in telesurgery and telementoring. Four tele-  mentored, laparoscopic right nephrectomies were performed  in a porcine model using the da Vinci system. Duplicate con-  soles were set up so that the experienced surgeon, located in  Ohio or Colorado, guided the novice, situated in California.  The expert mentor, for three out of the four cases, manipu-  lated two out of the three robotic arms, illustrating the feasi-  bility of rapid switching of console operator. Broadband T1  connections were used, but sporadic packet loss was still  detected. If the image got pixelated, the remote surgeon  relinquished control and took on a mentoring role. Despite  the intermittent time delays, all four cases were completed  successfully. '?    Telementoring transports the expertise of trained surgeons to  rural or remote areas, making complicated surgeries feasible.  In one early instance of international telementoring, a surgi-  cal training system was established at Johns Hopkins  University in 1998.° An expert mentor provided remote  guidance during three laparoscopic surgeries: varicocelec-  tomy, nephrectomy, and adrenalectomy. The remote sites  were in Innsbruck, Austria, and Bangkok, Thailand. Three  ISDN lines, narrowband by current standards, formed the  dedicated connection. An average delay of less than 1 s was  recorded, but the overall outcome of the procedures was  unaffected. Even in this early trial of telementoring, the ben-  efits of telestration were discernible: landmarks were anno-  tated in the medium of video or still images.   In 2003, another telementored trial was attempted between  the United States and Brazil." The expert surgeon was again  located at Johns Hopkins University, but the remote site was  in Sao Paulo and Recife, Brazil. Improvements were made to  the overall setup, and a new CODEC was adopted. The new  Z360 video CODEC featured dual-channel control for  robotic arms of the AESOP, the telestrator, and the electro-  cautery. In this trial, two different connection types were  tested. The telementoring session achieved a frame rate of 15  with the dedicated ISDN lines and an enhanced 30 frames  per second with the T1 broadband. In addition to using the    AESOP robotic arm for the first case of varicocelectomy, the  second case of percutaneous nephrolithotomy was performed  with the aid of the PAKY. Urinary access was achieved with  the first needle pass. Both cases had good postoperative  results; the patients showed minimal blood loss and were  discharged 1 and 2 days after surgery, respectively.   In a randomized evaluation study conducted in 2005, it  was found that robotic-assisted percutaneous access had an  accuracy of 88%, compared with 79% by human operators  (p = 0.046). The results from this study confirm the benefits  of telerobotic assistance in modern urological procedures,  and the compatability of Percutaneous Access to the Kidney-  Remote Center of Motion (PAK Y-RCM) with telementored  procedures.    Medical care is often delayed on the battlefield, due to hos-  tile environments or sheer distance from hospitals. Even if  the patient is successfully transferred to field hospitals, it is  likely that available physicians may lack the experience to  provide specialty care. Telementoring proposes a solution by  making available the expertise of specialists. The formation  of the Battlegroup Telemedicine System (BGTM) is a prime  example of the use of telemedicine in a military setting.   The USS Abraham Lincoln is one of the first military ves-  sels to be fitted with laparoscopic equipment. While deployed  in the Pacific Ocean and Persian Gulf, five cases of inguinal  hernia were diagnosed among the fleet, facilitating the forma-  tion of the BGTM as a solution to treatment.'^ The BGTM  comprised three nodes, running on “off the shelf" equipment  such as laptops, modems, video cameras, and cellular phones.  The battle group is one node, and the two state-side nodes are  located at the Johns Hopkins University Applied Physics  Laboratory and San Diego Naval Medical Center. Five laparo-  scopic inguinal hernia repairs were completed successfully  under telementoring guidance despite the narrowband connec-  tion, which allowed only a choppy video feed of two to four  frames per second. The expert mentor nevertheless guided the  onboard surgeon through real-time telestration and an exchange  of image files, depending on connectivity. Audio exchange  was conducted by cellular phone, but the satellite voice com-  munication was frequently haphazard. These accumulated  experiences of the BGTM demonstrate the effectiveness of  telementoring, despite crude telecommunication equipment.    In extreme environments, modern telecommunication tech-  nologies have eliminated many of the shortcomings encoun-    tered in the BGTM experience. The Aquarius habitat is the  only underwater laboratory in the world. It is funded by the  U.S. National Oceanographic and Atmospheric Administration  (NOAA) and operated by the National Undersea Research  Center (NURC), based at the University of North Carolina at  Wilmington. As a premier training facility, NASA has used  the Aquarius to provide specialized training for future astro-  nauts. A series of Neemo undersea missions were carried out  at the Aquarius, with the Neemo 7 mission specifically  designed to evaluate the effectiveness of telementored surgi-  cal procedures in a space mission analog."   In 2004, the crew members participating in the Neemo 7  mission were given minimal training by physicians working  at McMaster University’s Center for Minimal Access  Surgery. The main objective of the training was to familiar-  ize the crew members with equipment operation and relevant  medical terminology. None of the participants, which  included aquanauts who were physicians, was fully versed in  the surgical procedures they would soon perform.   The aquanauts performed diagnostic ultrasonography on  fellow crew members and various surgical procedures on  simulated patients under telementoring guidance. The proce-  dures included ultrasound-guided abscess drainage, repair of  vascular injury, cystoscopy with basket stone extraction, and  laparascopic cholecystectomy. Through these simulated  exercises, it was concluded that interventional procedures  could be performed adequately if telementoring were pro-  vided in a similar setting. In the simulated laparoscopic  cholecystectomy, all three test subjects successfully com-  pleted the surgery. There was no discernible difference  between the nonphysician and the physician (nonsurgeon)  participants. Mean efficiency scores of 3.3 and 3.1 were  given, respectively, and the operative times of 28 and 27.5  min were similar. The laparoscopic cholecystectomies per-  formed with telerobotic assistance (operated by a CMAS  mentor) were significantly lengthier than the unassisted  cases. This discrepancy in length may suggest a degree of  coordination conflict between the mentor and mentee when  the mentor operates the robotic endoscope.   Despite this discrepancy, the Neemo 7 mission showcases  the capabilities of telementoring during medical emergen-  cies in extreme environments. Under extreme circumstances,  even individuals with minimal training can be guided through  relatively complex procedures.    The numerous opportunities afforded by telemedicine are  constrained by several limitations. The first consideration is  cost. Establishing a telementoring setup requires an immense  start-up cost; an estimate for a relatively advance system  runs as high as $20,000." This limitation is especially    detrimental for underdeveloped countries, which may have  the most to gain from telementoring. A solution may lie with  affiliations with larger, more financially stable hospitals in  developed nations. Larger institutions can distribute tele-  mentoring systems on lease, and smaller hospitals can use  the equipment until training is complete. Once the initial  setup cost has been overcome, each successive session of  telementoring saves the hosting hospital money. In this sce-  nario, costs associated with travel and lodging for visiting  faculty can be averted.   Second, limited resources can be problematic. Physicians  who are experts in their fields are highly coveted, and the  ones who are trained to use telemedical equipment are even  more in demand. Therefore, a relatively small number of  viable candidates are available for expert mentor positions.   Third, a basic level of surgical aptitude must be ascer-  tained in the novice surgeon, whether it is through a simula-  tion or by expert assessment. Procedural protocols must be  devised before the telementoring session, so that any confu-  sion or dissension can be avoided when the operation begins.  In the case of connection interruption or permanent discon-  nection, the on-site surgeon must know the appropriate  course of action. The on-site surgeon also must be capable of  converting laparoscopic surgeries to open or continuing  without the assistance of the telementor. One safeguard could  be the presence of an on-site expert, who can take over the  complex procedure, if necessary.   Fourth, telementoring, like telesurgery, is fraught with  medicolegal vulnerabilities. Issues corresponding to inter-  state or international telementored surgeries have to be  addressed. Although the on-site surgeon performs the bulk of  the surgery, the remote mentor in some instances controls  certain aspects of the operation. In fact, there is often the  possibility that the remote mentor may take over an opera-  tion if extenuating circumstances arise. These circumstances  require special consent to be obtained from patients.  Moreover, medical qualifications must be reconciled between  the two locations. Currently, medical qualifications from the  European Union are not recognized in the United States, and  the reverse is also true.'* An international medical authority  should be instated to provide oversight and legal protection  for the continued development of telemedicine, and its role  should facilitate the growth of international medical  cooperation.    In recent years, centers dedicated to telemedicine have been  established internationally. In Strasbourg, France, the Institut  de Recherche contre les Cancers de l'Appareil Digestif, in  conjunction with the European Institute for Telesurgery   In Canada, the Center for Minimal Access Surgery (CMAS)  was established at McMaster University in 1998. Its primary  objectives include the provision of clinical training and expert  consultations for physicians in rural areas of Canada. The  CMAS initiated its telementoring program in 1999 and its tel-  erobotic program in 2003. Between 2003 and 2005, CMAS  provided teleassistance for 21 laparoscopic surgeries, includ-  ing laparoscopic Nissen fundoplications, hemicolectomies,  low anterior resections, sigmoid resections, and hernia repairs.  Approximately 400 km separate the teaching hospital, St.  Joseph's Hospital in Hamilton, Ontario, from North Bay  General Hospital in rural Ontario. IP-VPN connections run-  ning at 15 Mbps were used, and telemedical transmissions  took precedence over other commercial traffic.!™ The sur-  geons recorded an average time delay of 135-140 ms, which  did not hinder overall performance. Zeus control consoles  were set up at both sites, enabling the mentor to take over the  operation, should the novice surgeon feel unable to proceed.   Canada is also an encouraging environment for cutting-  edge medical practices such as telementoring. The Canadian  Medical Protective Association (CMPA) covers physicians’  liability for all medical practices, and its authority extends  across the entire country. The CMPA eliminates many medi-  colegal and liability concerns that could make telemedicine  vulnerable to litigation.    The future bodes auspiciously for telementoring, and we can  expect to see its growth coinciding with the development of  minimally invasive surgeries. Many of the medicolegal con-  cerns will take center stage as interest increases from the  health sector, and those issues will need to be resolved to  permit international cooperation.   Developing technological trends also will invariably influ-  ence the future of telementoring. Researchers at the Royal Free  Hospital in London have used commercial-free software, such  as UltraVNC (http://ultravnc.sourceforge.net) and Windows  NetMeeting, to establish remote control connections between  computer workstations. No IT technicians were involved, and  specialized software costs were entirely circumvented.?' The  network-enhanced surgical training (NEST) trials foreshadow  the reduced costs of telementoring in the future.   In another innovative attempt of telementoring, urologists  at the Johns Hopkins Brady Institute conducted laparoscopic  surgeries under the guidance of the RoboConsultant  (RemotePresence-7; InTouch Health, Sunnyvale, CA).? The  telerounding robot not only provided the internal/external  camera view complete with telestration capabilities but also    Fig. 28.3 Telementoring in the operating room via RoboConsultant  (RemotePresence-7; InTouch Health, Sunnyvale, CA)    had a physical footprint that gave a remote presence to the  mentor (Fig. 28.3).   The future of telementoring may lie with remote presence  robotics that are fully integrated with surgical robots, so that  the mentor could survey external fields and integrate with the  endoscopic camera and/or manipulate surgical procedures as  necessary. Force feedback, or haptics, should be developed to  give the mentor an even greater “feel” of the surgical process,  allowing him or her to better direct the novice surgeon.   Plans exist to integrate imaging modalities directly with  intelligent robotics. These new designs will incorporate  advance sensor systems that use Raman spectroscopy to dis-  tinguish and selectively resect tumors automatically.” These  notions of high-tech medical treatment are no longer fiction  but rather attainable goals for the near future. However, until  those designs are actualized, telementoring will remain to  bridge the gap of disparity in skills among physicians and to  facilitate care for the patient.   Telementoring has a bright future; its applications may  grow to encompass medicine in remote areas, extreme envi-  ronments, and even the battlefield. The U.S. Department of  Defense has projects underway for rapid battlefield treatment  and evacuation. Future space exploration also is likely to  enlist more astronauts, particularly with the proliferation of  international space stations, and their well-being during such  missions is vital for success. Until true robotic surgeries sup-  plant conventional surgeries, telementoring will always have  a role in complicated procedures.    1. Sibert K, Ricci MA, Caputo M, et al The feasibility of using ultra-  sound and video laryngoscopy in a mobile telemedicine consult.  Telemed J E Health. Apr 2008;14(3):266—272    . See WA, Cooper CS, Fisher RJ. Predictors of laparoscopic compli-    . Barold SS. Willem Einthoven and the birth of clinical electrocardi-    Faust RA, ed. Robotics in Surgery. New York: Nova Science  Publisher, Inc.; 2007:35-47    . Rosser JC, Wood M, Payne JH, et al Telementoring. A practical    . Fabrizio MD, Lee BR, Chan DY, et al Effect of time delay on surgi-    . Bove P, Stoianovici D, Micali S, et al Is telesurgery a new reality?    Our experience with laparoscopic and percutaneous procedures.  J Endourol. Apr 2003;17(3):137-142   Guillonneau B, Cappele O, Martinez JB, Navarra S, Vallancien G.  Robotic assisted, laparoscopic pelvic lymph node dissection in  humans. J Urol. Apr 2001;165(4):1078-1081   Marescaux J, Leroy J, Gagner M, et al Transatlantic robot-assisted  telesurgery. Nature. Sep 27 2001;413(6854):379-380   Sterbis JR, Hanly EJ, Herman BC, et al Transcontinental telesurgi-  cal nephrectomy using the da Vinci robot in a porcine model.  Urology. May 2008;71(5):971—973   Lee BR, Bishoff JT, Janetschek G, et al A novel method of surgical  instruction: international telementoring. World J Urol. 1998;16(6):  367-370   Rodrigues Netto N, Jr., Mitre AI, Lima SV, et al Telementoring  between Brazil and the United States: initial experience. J Endourol.  May 2003;17(4):217-220   Patriciu A, Challacombe B, Dasgupta P, Kavoussi L, Stoianovici D.  Robotic telementoring/telesurgical system and randomized evalua-  tion study. Conf Proc IEEE Eng Med Biol Soc. 2005;2:2167—2170   Cubano M, Poulose BK, Talamini MA, et al Long distance telemen-  toring. A novel tool for laparoscopy aboard the USS Abraham  Lincoln. Surg Endosc. Jul 1999;13(7):673-678   Challacombe B, Kavoussi L, Patriciu A, Stoianovici D, Dasgupta P.  Technology insight: telementoring and telesurgery in urology. Nat  Clin Pract Urol. Nov 2006;3(11):611—617   Anvari M. Telesurgery: remote knowledge translation in clinical  surgery. World J Surg. Aug 2007;31(8):1545-1550   Anvari M, McKinley C, Stein H. Establishment of the world's first  telerobotic remote surgical service: for provision of advanced lap-  aroscopic surgery in a rural community. Ann Surg. Mar 2005;241(3):  460—464   Gambadauro P, Magos A. NEST (network enhanced surgical train-  ing): a PC-based system for telementoring in gynaecological sur-  gery. Eur J Obstet Gynecol Reprod Biol. Aug 2008;139(2):  222-225   Agarwal R, Levinson AW, Allaf M, Markov D, Nason A, Su LM.  The RoboConsultant: telementoring and remote presence in the  operating room during minimally invasive urologic surgeries using  a novel mobile robotic interface. Urology. Nov 2007;70(5):  970—974   Pandya A, Auner G. Robotics technology: a journey into the future.  Urol Clin North Am. Nov 2004;31(4):793-800    Throughout medicine and surgery, the use of simulation has  been increasing as a result of changing professional practice,  training, and improved technology. Surgical training has  shifted from an apprenticeship model to one of criterion-  based training.' The traditional Halstead apprenticeship  model of surgical training is widely used across Europe and  North America, but this concept of training has been chal-  lenged over the past few years. The paradigm "see one, do  one, teach one" is not applicable to modern surgery, and  those in favor of simulation have shifted to the paradigm of  “see several, simulate many, do one perfectly.” Simulation is  becoming an important area of research and is being increas-  ingly integrated into surgical training. Many hope that it may  be the answer to reduced working hours as scheduled by the  European Working Time Directive.   Urological surgery, particularly endourology, lends itself  well to simulation because cameras provide the interface  between instrument and user. Minimally invasive procedures  tend to allow only one surgeon to operate at a time (as opposed  to two or more standing over an open wound); thus, the tyro  must be competent before the chief can hand over control.    Simulation is defined as: “....an imitation of the conditions  of (a situation), e.g., for training.” Using an orange to prac-  tice suturing skills or practicing surgical knots on a table leg  are methods of simulation that have been used by surgeons  for many years to practice basic skills. Simulated clinical  problems have been used to teach resuscitation skills and  management of critically ill patients in the Advanced Life  Support™ and Advance Trauma and Life Support™ courses  for over 20 years; however, the integration of simulation as a  formal training tool to learn surgical skills or entire opera-  tions is still in its infancy.   Simulation is established as an important part of training  in several other fields such as the military and aviation    industries. Indeed, in commercial aviation simulation is a  compulsory part of training and assessment. Other industries  have set precedents for, and gathered evidence of, the impor-  tance of simulation for operator-dependent procedures.  Those involved in designing surgical education programs  and maintaining surgical standards should look to the airline  industry as an example of the power of simulation.  Simulation has the potential to reduce the learning curve  in a number of operations and thus may reduce the cost and  length of training required to reach competence. It may sim-  ulation may also make surgeons safer and more efficient pos-  sibly reducing costs and errors in surgery.’ As a consequence  of reduced training time and an increasing number of com-  plex endourological and laparoscopic procedures, medical  simulation has developed considerably over the past 10 years.    Training time is limited, and therefore, simulators must be  shown to be efficient training tools in terms of cost and time  if they are to be integrated into surgical training.‘ Rasmussen,  a Danish Cognitive Engineer, described three levels of human  behavior designed to reduce the potential for accidents in  man-machine interface systems; and this model can be  applied to the efficacy of surgical training. The three levels  of behavior are skill-based behavior (SBB), rule-based  behavior (RBB), and knowledge-based behavior (KBB).   SBB takes place without conscious control; tasks using  SBB movements are executed as smooth, automated, and  highly integrated patterns of behavior. Simple simulators  such as knot tying boards are able to teach SBB skills, how-  ever, to simulate complicated skills such as those required  for endourology and laparoscopy, a more advanced simula-  tor is required. Furthermore, the more realistic the simulator  the more likely the SBB learnt in a simulated environment  can be translated into the operating room.   RBB reflects the way in which tasks must be completed; in  the case of surgery, this reflects the operation protocol. To  teach this in a simulated environment, the simulator must be    able to simulate part of a procedure or the whole operation.  RBB should be extensively practiced to reduce procedural  mistakes; in the commercial world, pilots must practice take  off and landing procedures with simulators repeatedly, even  when in service, to reduce the risk of error.   KBB relates to unfamiliar situations in which no rules are  available and performance must be at higher conceptual level.  In the case of pilots, this may be the simulation of a hazard-  ous event requiring emergency action. Simulation of out of  the ordinary events increases the ability of an individual to  cope with them when they occur, such as the much triumphed  Janding of an airplane on the Hudson River following a bird  strike. For surgery, this relates to unexpected anatomical  variation or an inadvertent intraoperative complication.   Simulators may also have a role in assessment; however,  a good evidence base must be established to show that a  given simulator is an effective assessment tool. Provisional  studies support the use of simulators as assessment tools, but  before they can be used to select surgical trainees, further  research is needed using large cohorts of trainees.^ If a simu-  lator is able to provide real-time feedback, then it may help  trainees to achieve their performance aims and thus be a  more efficient training tool.’ In the short term, it is more  likely that performance on a simulator can be used to guide  training by identifying areas for development, rather than as  a formal selection tool.    Simulators may be divided into mechanical simulators, vir-  tual reality simulators, and hybrid simulators. Mechanical  simulators utilize real instruments in a simulated environ-  ment often using synthetic tissue substitutes to operate on; an  example of a mechanical simulator is a box trainer. The  instruments used are real, but the simulator needs realistic  tissues to work on, it has consumable costs, and it is difficult  to monitor errors and other indicators of performance.  Metrics are operator parameters that can be measured, and in  the case of surgical simulators, some metrics may become  reliable performance indicators. Computerized simulators  are able to easily produce many metrics for statistical  analysis.   The term virtual reality refers to “a computer-generated  representation of an environment that allows sensory interac-  tion, thus giving the impression of actually being present."*  Virtual reality simulators use real instrument handles, but all  movements are within an empty structure, the user visualizes  their actions on a computer monitor, which displays the vir-  tual world; thus, all tissues and instruments are simulated.  The simulator software and processing power must be  advanced enough to create a training tool that operates in real    time and represents surgery. They are often expensive to  purchase but are able to record metric data and do not have  the running costs of mechanical simulators.   Hybrid trainers are essentially mechanical simulators that  are augmented with computer-based instrument tracking that  allows the simulator to monitor performance and errors. One  of the principle advantages of hybrid simulation is that it uses  real instruments and (depending on the quality of the syn-  thetic tissues used) gives realistic tactile feedback. Hybrid  simulators also allow for the tracking of a wide variety of  instruments as long as the operating tip has been incorporated  into the augmented reality software. The surgeon can inspect  their work on the synthetic tissue and also get feedback form  the computer-based tracking mechanisms. Although assess-  ment of performance using hybrid simulators has been vali-  dated, it is important to note that the metrics generated are  often based on visual recognition systems rather than precise  tracking and this can lead to the generation of errors.   Simulators can be further divided into low-fidelity and  high-fidelity tools. Examples of low-fidelity simulators  include mechanical simulators such as box trainers and some  virtual reality simulators such as the MIST VR™ (Mentice)  during which the trainee has to move, transfer, or diathermy  objects. Low-fidelity simulators teach SBB and are generally  suited for junior trainees to learn basic skills. There is gener-  ally a better evidence for the use of low-fidelity simulators  compared with high-fidelity simulators, as they have been  available for longer.   High-fidelity simulators more accurately represent real  surgery; they require basic skills but also simulate complex  tasks or complete operations. Therefore, high-fidelity simula-  tors are able to teach RBB and KBB, in addition to the more  basic SBB. Animal models can be considered as high-fidelity  simulators of human surgery and are used in surgical training.  Several high-fidelity VR simulators, such as the LAP mentor,  have been developed for surgery. The operation protocol must  be followed; thus, teaching RBB and variations in anatomy  and pathology help develop KBB. However, to date, there are  no studies that prove that training on high-fidelity simulators  can improve operating-room performance.   Mechanical simulators and some virtual reality simulators  give the trainee force feedback through the instruments; this  is known as haptic feedback. The word haptic is derived from  the Greek word “haphe,” which means pertaining to the sense  of touch. Haptics or haptic technology refers to the incorpora-  tion of a mechanism, within a mechanical device, inferring  the sense of touch to the user by applying forces, vibrations,  and motions. In terms of VR, haptics describes the portrayal  of sensations from the virtual environment that are equivocal  to those felt in the real environment further submerging the  user in the virtual world. The science fiction writer Aldous  Huxley coined the use of the word haptics with regard to  technology in the novel “Brave New World"? in which he    described the "feelies;" cinemas in which the auditorium seats  had hand rests providing haptic stimulation.   Bholat demonstrated that laparoscopic surgery provided  haptic feedback (although altered from that felt in open sur-  gery) with a trial in which the tactile properties of objects  were compared in three situations during which the subjects  were blindfolded; direct palpation, conventional surgical  instruments, and laparoscopic instruments. The study dem-  onstrated that direct palpation had the highest accuracy for  shape identification, but that fine texture analysis was supe-  rior with instrumentation (be it laparoscopic or conventional),  and that all three situations were comparable for object  consistency.   Haptic devices for VR simulation can use motors, electro-  magnetic, hydraulics, or gyroscopes to impart tactile sensa-  tion to the user. Haptic devices do not usually measure the  specific force applied to an object, rather they measure the  direction, distance, and speed of movement to calculate  force.    As simulators are introduced into training and incorporated  into surgical curricula, an evidence base is gradually devel-  oping to support their usefulness as training tools. There is a  general consensus in the literature that simulators are impor-  tant for present-day surgical training, but there is only strong  evidence for a small number of surgical simulators. In order  for a simulator to be shown to act as a good training tool, it  must achieve specific operative and training objectives, and  it should be efficient in terms of cost and time.^ Furthermore,  the skills learnt should be transferable to the operating  room.   Ideally, a simulator should be able to monitor the perfor-  mance of a trainee to highlight areas that need to be improved  and to develop proficiency-based training programs. VR  simulators and hybrid simulators are able to measure numer-  ous metrics of performance, and these must be shown to be  valid and reliable indicators of performance before they are  used to guide training; there are numerous studies in the lit-  erature evaluating various metrics in a number of different  simulators.   Validity is a concept borrowed from the social sciences  and relates to the property of being true, correct, and realis-  tic.!! In the case of a simulator, validation looks at how real-  istically a surgical situation is reproduced and how accurately  the metrics relate to proficiency. A valid simulator is realistic  and measures true indicators of performance and may thus  be used as a training and assessment tool.   There is some variation in the definitions of validity, but  generally, it can be divided into face validity, content    validity, construct validity, discriminative validity, and most  importantly predictive validity. These all look to validate a  simulator from different perspectives and build up a picture  of the simulator. Face validity and content validity are sub-  jective assessments by experts; Face validity looks at how  well the simulator represents real surgery, and content valid-  ity analyses the individual components and tasks of the sim-  ulator. Construct validity looks at whetheratesting instrument  measures the attributes it was designed to measure; in the  case of surgical simulators, the metrics should reflect the  skill of the surgeon. Construct validity is generally evaluated  by comparing the performance of experts with novices.  Discriminative validity is similar to construct validity, but  the simulator must be able to distinguish smaller differences  in performance such as when testing surgeons with similar  experience. !!: ?   The ultimate way to validate a simulator is to establish  predictive validity by proving that scores achieved on a sim-  ulator accurately predict the future proficiency that will be  achieved in the operating room. The simulator should also  produce similar metrics when used repeatedly in the same  situation, and thus demonstrate reliability. Most VR simula-  tors are intrinsically reliable as the computer measures the  users movements exactly; however, hybrid simulators rely  on they accuracy of the visual-tracking system to produce  reliable results.''   Some simulators (such as the MIST VR™) have been  well validated, and it may be reasonable to use it as a forma-  tive assessment tool to guide training. However, to use a  simulator as a summative assessment tool for the selection or  revalidation of surgeons, there must be a very strong evi-  dence base to prove that the simulator is valid, reliable, and  effective. To date, no simulator has shown this.!*    As already discussed, many urological operations are per-  formed either via an endoscope or a laparoscope, and the  monitor, along with haptic feedback via the instruments, pro-  vides the interface between the surgeon and patient. The  images seen by the surgeon are two-dimensional images,  while the operation is performed in a three-dimensional  environment; this represents a transition from normal prac-  tice and must be learnt. Tactile sensation felt through an  instrument is of a very different nature to that felt with one’s  own hand" and exposure to the different sensory input is  required to allow proficiency in interpretation. Because of  the altered force feedback experienced during laparoscopic  surgery, altered force application must be learnt.   There is a large discrepancy between the movements pos-  sible with a hand compared with those available with an    instrument. Degrees of freedom (DF) are the set of indepen-  dent displacements that specify the displaced position of the  body or the system; the hand gives rise to at least 28 because  of its various joints, while the laparoscope and rigid endo-  Scope gives rise to 4; adjustment to this relatively constrained  environment must be learned. Furthermore, in laparoscopy,  the instruments work via a fulcrum effect in that an upward  movement of the hand produces a downward movement of  the instrument tip, another feature that extends the length of  the learning curve.'?   Because of these problems, many endourological and lap-  aroscopic operation are difficult to learn, but they are also  ideally suited for simulation. Consequently, numerous simu-  lators have been developed for urology and these are dis-  cussed below.    Early in the introduction of laparoscopic surgical techniques,  it became clear that the "learning curve" required to reach a  standard of competence compatible with operating indepen-  dently was steeper than that of open surgery. Moreover,  urology, unlike laparoscopic general surgery or gynecology,  lacks a relatively simple, high-volume procedure suitable for  training." Furthermore, many laparoscopic operations in  urology involve complicated reconstruction, and thus, a high  degree of skill is required. Simulation in laparoscopy is prob-  ably more developed than in the rest of urology as many  other specialties operate via a laparoscope, and thus, there is  a greater financial incentive to develop simulators for  laparoscopy.    A box trainer is a mechanical simulator in which the student  operates using real laparoscopic instruments and real sutures  on synthetic tissue substitutes or animal tissue. They are low-  fidelity simulators and can vary from the enterprising sur-  geon's home-made cardboard box equipped with a webcam  and instruments to specially designed dry simulators such as  the *3-Dmed Laparoscopic trainer™” (Limbs & Things GB)  (Fig. 29.1). Any force feedback is limited by the choice of  operative material; in the case of dead animal tissue, its prop-  erties may differ significantly from that of living tissue. Box  trainers have been shown to be effective devices for acquir-  ing basic laparoscopic skills; however, it is debatable how  complex the box trainers have to be to be effective. Chung  et al demonstrated how an inexpensive trainer made of a    webcam, cardboard box, desk lamp, and laptop computer  was comparable with more expensive commercially avail-  able trainers.'*   Numerous models have been developed to place inside a  box trainer to teach more complicated laparoscopic skills for  urology, and these include chicken-skin models to practice  the urethral anastamosis following laparoscopic radical pros-  tatectomy"? and a tumor mimic model for laparoscopic par-  tial nephrectomy.”    Among the best studied hybrid simulators is the ProMISTM  surgical simulator (Haptica Incorporated, USA), but there  are other systems on the market such as Surgical SIM LTSTM  (METI). Construct validity has been demonstrated by show-  ing that experienced surgeons performed better than novices,  but predictive validity has not been established.*! Several  small studies have compared the ProMIS™ with VR train-  ers; training outcomes were similar in the two groups, but the  users generally felt that the ProMISTM was more realistic  than the pure VR trainers.” Furthermore, one study has  shown that the measurements generated during training on  the ProMISTM compare well to validated observer scoring    systems, and thus, the ProMIS™ also has potential as an  assessment tool.”    Numerous low-fidelity and high-fidelity VR simulators are  available for laparoscopic training, and some of the high-  fidelity models also include basic low-fidelity training mod-  ules (e.g., LapSim™ and LapMentor™),   The best studied low-fidelity simulator is the MIST VR™  (Mentice). Two similar randomized controlled trials have  shown that training on the simulator improves real-life per-  formance during laparoscopic cholecystecomies.™*° In both  trials, residents performed the operation quicker, with fewer  errors and improved economy of movement. Furthermore, in  one trial, there were six incidents of “attending takeover”  where the attending surgeon felt it necessary to intervene to  ensure patient safety; all of these were within the non-VR  trained group.™   Other low-fidelity models such as the LapSim™ (Surgical  Science) and the Lap Mentor™ (Symbionix) have basic lap-  aroscopic modules, in addition to high-fidelity simulation.  Studies have established face, content, and construct validity  for these two simulators. Interestingly, the LapSIM™ has been    compared with box trainers in two trials; both trials showed  that the VR and box trainer groups improved more than the  control group, but there were only minor differences in perfor-  mance between the VR and the box trainer groups.” 7   The Procedicus MIST Nephrectomy™ (developed by  Guy’s Hospital, GSTT Charity and Mentice) is the only  high-fidelity simulator available for urology, and recently,  face, content, and construct validity have been demonstrated  (Figures 29.2—29.6). It has haptic feedback and simulates  retroperitoneal and transperitoneal nephrectomy. Other high-  fidelity simulators such as the LapSIM™ (surgical sciences)  and LapMentor™ (Symbionix) have cholecystectomy mod-  ules, but no modules specific to urology. However, some of  the skills learnt may be transferable to urology, and a recent  study by Lucas et al has shown that novices who train on the  VR cholecystectomy module (on the Lap Mentor™) perform  better than untrained novices when performing porcine neph-  rectomies.** Further studies are needed to see if procedure-  specific simulators have any advantage over low-fidelity  simulators.   To date, there have been seven trials to assess whether the  skills learned on laparoscopic VR simulators are transferable  to real surgery (either human or porcine), and all but one  have shown a positive transfer of skills." Importantly, three of  these used surgical residents rather than medical students  and all of these showed a positive transfer of skills. ^^ ??    Fig. 29.3 Three-dimensional modeling for virtual reality simulation: (a) posterior and (b) views of laparoscopic nephrectomy    Fig. 29.4 Three-dimensional modeling, comparing the operating posi-  tions for different procedures (in this case port positions for retroperito-  neal and transperitoneal laparoscopic nephrectomy)    TURP is one of the most commonly performed urological  operations and remains the gold standard for the surgical  management of BPH. TURP is also one of the most difficult  operations to learn as the surgeon has to coordinate the scope,  the loop, the diathermy current, and the flow of the irrigation  fluid. There are key surgical landmarks that must be avoided,  and vision can vary throughout the procedure because of  bleeding or debris. Reduced training time and the advent of  alternative minimally invasive techniques has resulted in  trainees performing fewer TURPs. In 1991, residents in the  United States performed on average 120 TURPs before grad-  uating; in 2002, the average was 62.*° Simulation offers a  potential tool to shorten the learning curve and achieve com-  petency, despite the reduced exposure to TURP surgery.    Mechanical simulators for TURP surgery have been devel-  oped such as the Bristol TURP Trainer™ (Limbs and Things)  that uses a sealed chamber, a real resectoscope, real electro-  cautery, and real irrigant. The prostate is a synthetic model that  does not bleed, but the chips need to be evacuated in the same  way as real surgery. As a mechanical simulator, it lacks the  ability to measure metrics of performance, but the user is able  to look at the synthetic prostate to evaluate their resection.   Several VR TURP simulators have been developed, but  the most advanced is the University of Washington VR TURP  trainer developed by Sweet and colleagues; it is licensed by  Medical Education Technologies Inc. as the SurgicalSIM  TURP™.” This simulator has haptic feedback and is able to  simulate all the components of a TURP, including bleeding  and irritant flow; it is also able to measure real-time metrics  of performance. Face and content validity have been estab-  lished by 72 board-certified urologists, and several perfor-  mance metrics are able to distinguish novices form experts.*!  The investigating group is currently assessing the effect of  simulation on operative performance.    Cystoscopy and ureteroscopy can be performed with both  rigid and flexible instruments, and therefore, simulators must  be able to replicate the additional movements possible with  flexible instruments. There are several high-fidelity mechani-  cal simulators available for upper and lower tract endourol-  ogy such as the Uro-Scopic trainer™ (Limbs and Things)  and the Scope Trainer'M (Medi Skills). They accurately  model the urinary tract, and the user can perform cystoscopy,  ureteroscopy, stent insertion, and lithotripsy. The trainee uses  the same instruments as in the operating room and, depend-  ing on the quality of the model, there is realistic haptic feed-  back. However, the models do not simulate bleeding and  cannot measure performance.   These high-fidelity mechanical models are relatively  expensive, and it is not known how realistic a model needs to  beto teach the basic skills required for endoscopy. Matsumoto  et al randomized medical students into three groups: one  trained on a low-fidelity model of the renal tract, one trained  on a high-fidelity model (Uro-Scopic Trainer™, Limbs, and  Things), and one received didactic teaching. The home-made  model of the renal tract used a Penrose drain as the urethra, a  cup for the bladder, and drinking straws as the ureters and  cost $20. There was no significant difference in performance  between the low-fidelity and high-fidelity training groups,  but the group that received only didactic training performed  significantly worse.”   VR endourology simulators are also available, and the  best studied is the URO Mentor™ (Symbionix), which is    able to simulate numerous cystoscopic and ureteroscopic  procedures and also has basic skills modules. It has been  shown that experienced surgeons perform significantly better  than medical students, but that, with training on the simula-  tor, medical students can reach the level of first-year resi-  dents.” It has also been shown that training on the URO  Mentor improves the performance of medical students when  performing ureteroscopy on cadavers.** The simulator is able  to measure performance, and this seems to correlate with the  skill of the surgeon.? The Uro-Trainer™ (Karl Storz) is a  new VR endourology trainer which incorporates haptic feed-  back; however, only initial validation studies have been  performed.    One of the most difficult parts of performing percutaneous  renal surgery is establishing a needle tract into the relevant  calyx. The surgeon (or radiologist) must integrate informa-  tion gained from imaging (fluoroscopy, ultrasound, or a com-  bination), knowledge of renal anatomy, and haptic feedback  from the needle. Botoca et al (2006) demonstrated a learning  curve of between 40 and 50 PCNL procedures to maximize  successful renal puncture and to minimize complications;  simulators have the potential to reduce this learning curve.*’   Several bench models for percutaneous tract simulation  have been developed and these can be divided into those that  use synthetic models and those that use animal tissues. The  Percutaneous Nephrolithotomy Trainer™ (Limbs and  Things) consists of synthetic tissues on a translucent slab  that can simulate fluoroscopy. It can be used to practice nee-  dle puncture, guide-wire insertion, tract dilatation, and stone  removal. The Perc Trainer™ (Medi Skills) is a similar syn-  thetic model but can be used with fluoroscopy and ultra-  sound. Two models using porcine kidneys have also been  described; in one model, the kidney is placed in a chicken  carcass and in the other it is embedded in silicone. These ex  vivo porcine kidney models may provide a more realistic  "feel" than the synthetic competitors.**   The PERC Mentor™ (Symbionix) is a VR simulator spe-  cifically designed to teach percutaneous renal access. A  metal needle with a spatial sensor is integrated into a virtual  environment in which the trainee has to gain renal access  under fluoroscopic guidance. Haptic feedback is provided by  a synthetic tissue plate, and there are modules to simulate  different clinical situations. User metrics are recorded by the  simulator, and construct validity has been established for  some of these in a study in which residents performed sig-  nificantly better than medical students. Studies have also  shown that training on the PERC mentor improved perfor-  mance during porcine percutaneous access, and thus, they    have shown some degree of skill transfer from the simulator  to real surgery.”    There are numerous simulators available for urology train-  ing, and there is a growing body of evidence supporting the  use of simulation in surgical training, including several ran-  domized controlled trials." A few simulators have been shown  to improve surgical performance in randomized trials, and  the evidence for the benefits of simulation is growing.   The use of simulators to improve team working and other  areas of "crisis resource management" in addition to clinical  skills has been used by anesthetics and other acute medical  specialties for a number of years. Urologists may be able to  use simulators as part of a simulated operating-room suite  and therefore educate the entire surgical team not just the  operating surgeon.”   Developments in simulation technology, particularly in VR  simulation, will result in increasingly realistic and complex  simulators. This combined with developments in surgery, such  as the use of robotics, will result in new simulators such as the  Surgical SIM - RSS™ robotic simulator (METI). Continuing  validation studies are needed to assess these new simulators  and further work is needed to evaluate how best to incorporate  currently available simulators into surgical training. With fur-  ther research and the continuing improvements in simulation,  it should become possible to integrate simulation into urology  in an evidence-based and cost-effective way.   The advent of revalidation in the United Kingdom may  also provide a role for urological simulation in the assess-  ment of surgical skills. With further developments in tech-  nology and a demand for increased patient safety, simulation  will have a key role in the training and assessment of tomor-  row's urologists.    . Satava RM. The future of surgical simulation and surgical robotics.  Bull Am Coll Surg. 2007;92(3):13-19   2. The Concise Oxford Dictionary of Current English. 9th ed. New  York: Oxford University Press; 1995   3. Nedas T, Challacombe B, Dasgupta P. Virtual reality in urology.  BJU Int. 2004;94(3):255-257   4. Cuschieri A, Francis N, Crosby J, Hanna GB. What do master sur-  geons think of surgical competence and revalidation? Am J Surg.  2001;182(2):110-116   5. Rasmussen J. Skills, rules and knowledge: signals, signs and sym-  bols and other distinctions in human performance models. IEEE  Transactions on Systems, Man | and Cybernetics. SCM.  1983;13(3):257-266 
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