human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: PURPOSE Up to 50 % of patients treated with intravesical agents for high grade nonmuscle invasive bladder cancer will have disease recurrence . Response rates to current second line intravesical therapies are low and for these high risk patients novel agents are necessary . Our previously completed phase I trial showed docetaxel was a safe agent for intravesical use . Nanoparticle albumin-bound paclitaxel ( Abraxane ® , ABI-007 ) has been shown to have increased solubility and lower toxicity compared to docetaxel in systemic therapy . Thus , we assessed the dose limiting toxicity and maximum deliverable dose of intravesical nanoparticle albumin-bound paclitaxel . MATERIAL S AND METHODS Inclusion criteria for this institutional review board approved phase I trial were recurrent high grade Ta , T1 and Tis transitional cell carcinoma of the bladder for which at least 1 prior st and ard intravesical regimen failed . Six weekly instillations of nanoparticle albumin-bound paclitaxel were administered with a modified Fibonacci dose escalation model used until the maximum deliverable dose was achieved . The primary end point was dose limiting toxicity and the secondary end point was response rate . RESULTS A total of 18 patients were enrolled in the study . One patient demonstrated measurable systemic absorption after 1 infusion . Grade 1 local toxicities were experienced by 10 ( 56 % ) patients with dysuria being the most common , and no grade 2 , 3 or 4 drug related local toxicities were encountered . Of the 18 patients 5 ( 28 % ) had no evidence of disease at posttreatment evaluation . CONCLUSIONS Intravesical nanoparticle albumin-bound paclitaxel exhibited minimal toxicity and systemic absorption in the first human intravesical phase I trial to our knowledge . A larger phase II study has begun to formally evaluate the activity of this regimen Introduction : Gemcitabine , a chemotherapeutic agent , has been shown to be active against transitional cell cancer of the bladder . The aim of the study was to determine the pharmacokinetic profile of gemcitabine , administered intravesically in patients with carcinoma in situ(CIS ) . Material and Methods : Nine patients with CIS refractory to intravesical bacillus Calmette-Guérin ( BCG ) therapy were enrolled .  Gemcitabine was given in 50 ml 0.9 % NaCl by catheterization and held in the bladder for 1 h , once weekly for 6 consecutive weeks . The pharmacokinetics for gemcitabine metabolites were performed in plasma and serum . Dose levels were : 1,000 , 1,250 , and 1,500 mg . Clinical evaluation was repeated 4 weeks after therapy and thereafter every 6 months . Results : Grade -1 neutropenia was observed only in 1 patient . Grade -1 urinary frequency and hematuria were observed in 1 and 3 patients , respectively . No grade 2–4 toxicity or clinical ly relevant myelosuppression were observed .  Gemcitabine  was detectable in serum , but with an irrelevant pharmacological effect , in only 1 patient treated with 1,500 mg of gemcitabine . With regard to activity , after 6 instillations of this drug , 4 complete responses were observed . Conclusion : Intravesical gemcitabine is well tolerated and safe . No systemic absorption with a clinical or pharmacological effect was detected and only slightly irritative bladder symptoms were observed . These results warrant further investigation in phase-II trials PURPOSE Carcinoma in situ represents high grade anaplasia of the bladder mucosa . Intravesical immunotherapy with bacillus Calmette-Guérin is the gold st and ard treatment for patients with carcinoma in situ . Patients with carcinoma in situ refractory to bacillus Calmette-Guérin are c and i date s for major surgery such as radical cystectomy . We identified the maximum tolerated dose and the recommended dose , and evaluated the safety profile of paclitaxel-hyaluronic acid bioconjugate given by intravesical instillation to patients with carcinoma in situ refractory to bacillus Calmette-Guérin . MATERIAL S AND METHODS A total of 16 patients with carcinoma in situ refractory to bacillus Calmette-Guérin were enrolled in a phase I , open label , single institution study . A minimum of 3 eligible patients were included per dose level . Paclitaxel-hyaluronic acid solution ( ONCOFID-P-B ™ ) was administered for 6 consecutive weeks . The primary objective was to identify the maximum tolerated dose and the recommended dose . As secondary objectives the safety profile of ONCOFID-P-B , the pharmacokinetic profile after each instillation and the tumor response were also evaluated . RESULTS No dose limiting toxicity occurred at any drug level evaluated . The plasma levels of the study drug were always below the lower limit of quantification at all tested doses after each instillation . A total of 11 adverse events were reported by 7 patients and 9 ( 60 % ) showed complete treatment response . CONCLUSIONS Intravesical instillation of ONCOFID-P-B for carcinoma in situ refractory to bacillus Calmette-Guérin showed minimal toxicity and no systemic absorption in the first human intravesical clinical trial to our knowledge . Finally , satisfactory response rates were observed PURPOSE Prior phase II studies of intravesical gemcitabine have shown it to be active and well tolerated , but durable responses in patients with nonmuscle invasive bladder cancer who have experienced recurrence after bacillus Calmette-Guérin treatment are uncommon . We performed a multi-institutional phase II study within the SWOG ( Southwest Oncology Group ) cooperative group to evaluate the potential role of gemcitabine induction plus maintenance therapy in this setting . MATERIAL S AND METHODS Eligible patients had recurrent nonmuscle invasive bladder cancer , stage Tis ( carcinoma in situ ) , T1 , Ta high grade or multifocal Ta low grade after at least 2 prior courses of bacillus Calmette-Guérin . Patients were treated with 2 gm gemcitabine in 100 cc normal saline intravesically weekly × 6 and then monthly to 12 months . Cystoscopy and cytology were performed every 3 months , with biopsy at 3 months and then as clinical ly indicated . Initial complete response was defined as negative cystoscopy , cytology and biopsy at 3 months . RESULTS A total of 58 patients were enrolled in the study and 47 were evaluable for response . Median patient age was 70 years ( range 50 to 88 ) . Of the evaluable patients 42 ( 89 % ) had high risk disease , including high grade Ta in 12 ( 26 % ) , high grade T1 in 2 ( 4 % ) and carcinoma in situ in 28 ( 60 % ) with or without papillary lesions . At the initial 3-month evaluation 47 % of patients were free of disease . At 1 year disease had not recurred in 28 % of the 47 patients , all except 2 from the high risk group , and at 2 years disease had not recurred in 21 % . CONCLUSIONS Intravesical gemcitabine has activity in high risk nonmuscle invasive bladder cancer and offers an option for patients with recurrence after bacillus Calmette-Guérin who are not suitable for cystectomy . However , less than 30 % of patients had a durable response at 12 months even with maintenance therapy Purpose : To assess the clinical and pharmacodynamic activity of dovitinib in a treatment-resistant , molecularly enriched non – muscle-invasive urothelial carcinoma of the bladder ( NMIUC ) population . Experimental Design : A multi-site pilot phase II trial was conducted . Key eligibility criteria included the following : Bacillus Calmette-Guerin (BCG)-unresponsive NMIUC ( > 2 prior intravesical regimens ) with increased phosphorylated FGFR3 ( pFGFR3 ) expression by central ly analyzed immunohistochemistry ( IHC+ ) or FGFR3 mutations ( Mut+ ) assessed in a CLIA-licensed laboratory . Patients received oral dovitinib 500 mg daily ( 5 days on/2 days off ) . The primary endpoint was 6-month TURBT-confirmed complete response ( CR ) rate . Results : Between 11/2013 and 10/2014 , 13 patients enrolled ( 10 IHC+ Mut− , 3 IHC+ Mut+ ) . Accrual ended prematurely due to cessation of dovitinib clinical development . Demographics included the following : median age 70 years ; 85 % male ; carcinoma in situ ( CIS ; 3 patients ) , Ta/T1 ( 8 patients ) , and Ta/T1 + CIS ( 2 patients ) ; median prior regimens 3 . Toxicity was frequent with all patients experiencing at least one grade 3–4 event . Six-month CR rate was 8 % ( 0 % in IHC+ Mut− ; 33 % in IHC+ Mut+ ) . The primary endpoint was not met . Pharmacodynamically active ( 94–5,812 nmol/L ) dovitinib concentrations in urothelial tissue were observed in all evaluable patients . Reductions in pFGFR3 IHC staining were observed post-dovitinib treatment . Conclusions : Dovitinib consistently achieved biologically active concentrations within the urothelium and demonstrated pharmacodynamic pFGFR3 inhibition . These results support systemic administration as a viable approach to clinical trials in patients with NMIUC . Long-term dovitinib administration was not feasible due to frequent toxicity . Absent clinical activity suggests that patient selection by pFGFR3 IHC alone does not enrich for response to FGFR3 kinase inhibitors in urothelial carcinoma . Clin Cancer Res ; 23(12 ) ; 3003–11 . © 2016 AACR Purpose : We compared blue light flexible cystoscopy with white light flexible cystoscopy for the detection of  bladder cancer during surveillance . Material s and Methods : Patients at high risk for recurrence received hexaminolevulinate intravesically before white light flexible cystoscopy and r and omization to blue light flexible cystoscopy . All suspicious lesions were documented . Patients with suspicious lesions were referred to the operating room for repeat white and blue light cystoscopy . All suspected lesions were biopsied or resected and specimens were examined by an independent pathology consensus panel . The primary study end point was the proportion of patients with histologically confirmed malignancy detected only with blue light flexible cystoscopy . Additional end points were the false‐positive rate , carcinoma in situ detection and additional tumors detected only with blue light cystoscopy . Results : Following surveillance 103 of the 304 patients were referred , including 63 with confirmed malignancy , of whom 26 had carcinoma in situ . In 13 of the 63 patients ( 20.6 % , 95 % CI 11.5–32.7 ) recurrence was seen only with blue light flexible cystoscopy ( p < 0.0001 ) . Five of these cases were confirmed as carcinoma in situ . Operating room examination confirmed carcinoma in situ in 26 of 63 patients ( 41 % ) , which was detected only with blue light cystoscopy in 9 of the 26 ( 34.6 % , 95 % CI 17.2–55.7 , p < 0.0001 ) . Blue light cystoscopy identified additional malignant lesions in 29 of the 63 patients ( 46 % ) . The false‐positive rate was 9.1 % for white and blue light cystoscopy . None of the 12 adverse events during surveillance were serious . Conclusions : Office based blue light flexible cystoscopy significantly improves the detection of patients with recurrent bladder cancer  and it is safe when used for surveillance . Blue light cystoscopy in the operating room significantly improves the detection of carcinoma in situ and detects lesions that are missed with white light cystoscopy PURPOSE A phase II study was performed to assess the efficacy and tolerability of intravesical oportuzumab monatox in patients with urothelial carcinoma in situ of the bladder . Bacillus Calmette-Guérin treatment had previously failed in all patients . MATERIAL S AND METHODS A total of 46 patients received 1 induction cycle of 6 ( cohort 1 ) or 12 ( cohort 2 ) weekly intravesical oportuzumab monatox ( VB4 - 845 ) instillations of 30 mg , followed by up to 3 maintenance cycles of 3 weekly administrations every 3 months . RESULTS A complete response to oportuzumab monatox was seen in 9 of 22 patients ( 41 % ) in cohort 1 and 9 of 23 ( 39 % ) in cohort 2 at the 3-month evaluation . A total of 20 patients ( 44 % ) achieved a complete response . Two other patients without carcinoma in situ who achieved a complete response were not included in the study due to the development of noninvasive papillary ( Ta ) disease . Median time to recurrence in patients who achieved a complete response was 274 and 408 days in cohorts 1 and 2 , respectively . Overall 7 patients ( 16 % ) remained disease-free . Post- study assessment demonstrated that these patients were still disease-free at last followup ( 18 to 25 months ) . The most common adverse events were mild to moderate reversible bladder symptoms . CONCLUSIONS 
    Output:
    
agent
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: PURPOSE Up to 50 % of patients treated with intravesical agents for high grade nonmuscle invasive bladder cancer will have disease recurrence . Response rates to current second line intravesical therapies are low and for these high risk patients novel agents are necessary . Our previously completed phase I trial showed docetaxel was a safe agent for intravesical use . Nanoparticle albumin-bound paclitaxel ( Abraxane ® , ABI-007 ) has been shown to have increased solubility and lower toxicity compared to docetaxel in systemic therapy . Thus , we assessed the dose limiting toxicity and maximum deliverable dose of intravesical nanoparticle albumin-bound paclitaxel . MATERIAL S AND METHODS Inclusion criteria for this institutional review board approved phase I trial were recurrent high grade Ta , T1 and Tis transitional cell carcinoma of the bladder for which at least 1 prior st and ard intravesical regimen failed . Six weekly instillations of nanoparticle albumin-bound paclitaxel were administered with a modified Fibonacci dose escalation model used until the maximum deliverable dose was achieved . The primary end point was dose limiting toxicity and the secondary end point was response rate . RESULTS A total of 18 patients were enrolled in the study . One patient demonstrated measurable systemic absorption after 1 infusion . Grade 1 local toxicities were experienced by 10 ( 56 % ) patients with dysuria being the most common , and no grade 2 , 3 or 4 drug related local toxicities were encountered . Of the 18 patients 5 ( 28 % ) had no evidence of disease at posttreatment evaluation . CONCLUSIONS Intravesical nanoparticle albumin-bound paclitaxel exhibited minimal toxicity and systemic absorption in the first human intravesical phase I trial to our knowledge . A larger phase II study has begun to formally evaluate the activity of this regimen Introduction : Gemcitabine , a chemotherapeutic agent , has been shown to be active against transitional cell cancer of the bladder . The aim of the study was to determine the pharmacokinetic profile of gemcitabine , administered intravesically in patients with carcinoma in situ(CIS ) . Material and Methods : Nine patients with CIS refractory to intravesical bacillus Calmette-Guérin ( BCG ) therapy were enrolled .  Gemcitabine was given in 50 ml 0.9 % NaCl by catheterization and held in the bladder for 1 h , once weekly for 6 consecutive weeks . The pharmacokinetics for gemcitabine metabolites were performed in plasma and serum . Dose levels were : 1,000 , 1,250 , and 1,500 mg . Clinical evaluation was repeated 4 weeks after therapy and thereafter every 6 months . Results : Grade -1 neutropenia was observed only in 1 patient . Grade -1 urinary frequency and hematuria were observed in 1 and 3 patients , respectively . No grade 2–4 toxicity or clinical ly relevant myelosuppression were observed .  Gemcitabine  was detectable in serum , but with an irrelevant pharmacological effect , in only 1 patient treated with 1,500 mg of gemcitabine . With regard to activity , after 6 instillations of this drug , 4 complete responses were observed . Conclusion : Intravesical gemcitabine is well tolerated and safe . No systemic absorption with a clinical or pharmacological effect was detected and only slightly irritative bladder symptoms were observed . These results warrant further investigation in phase-II trials PURPOSE Carcinoma in situ represents high grade anaplasia of the bladder mucosa . Intravesical immunotherapy with bacillus Calmette-Guérin is the gold st and ard treatment for patients with carcinoma in situ . Patients with carcinoma in situ refractory to bacillus Calmette-Guérin are c and i date s for major surgery such as radical cystectomy . We identified the maximum tolerated dose and the recommended dose , and evaluated the safety profile of paclitaxel-hyaluronic acid bioconjugate given by intravesical instillation to patients with carcinoma in situ refractory to bacillus Calmette-Guérin . MATERIAL S AND METHODS A total of 16 patients with carcinoma in situ refractory to bacillus Calmette-Guérin were enrolled in a phase I , open label , single institution study . A minimum of 3 eligible patients were included per dose level . Paclitaxel-hyaluronic acid solution ( ONCOFID-P-B ™ ) was administered for 6 consecutive weeks . The primary objective was to identify the maximum tolerated dose and the recommended dose . As secondary objectives the safety profile of ONCOFID-P-B , the pharmacokinetic profile after each instillation and the tumor response were also evaluated . RESULTS No dose limiting toxicity occurred at any drug level evaluated . The plasma levels of the study drug were always below the lower limit of quantification at all tested doses after each instillation . A total of 11 adverse events were reported by 7 patients and 9 ( 60 % ) showed complete treatment response . CONCLUSIONS Intravesical instillation of ONCOFID-P-B for carcinoma in situ refractory to bacillus Calmette-Guérin showed minimal toxicity and no systemic absorption in the first human intravesical clinical trial to our knowledge . Finally , satisfactory response rates were observed PURPOSE Prior phase II studies of intravesical gemcitabine have shown it to be active and well tolerated , but durable responses in patients with nonmuscle invasive bladder cancer who have experienced recurrence after bacillus Calmette-Guérin treatment are uncommon . We performed a multi-institutional phase II study within the SWOG ( Southwest Oncology Group ) cooperative group to evaluate the potential role of gemcitabine induction plus maintenance therapy in this setting . MATERIAL S AND METHODS Eligible patients had recurrent nonmuscle invasive bladder cancer , stage Tis ( carcinoma in situ ) , T1 , Ta high grade or multifocal Ta low grade after at least 2 prior courses of bacillus Calmette-Guérin . Patients were treated with 2 gm gemcitabine in 100 cc normal saline intravesically weekly × 6 and then monthly to 12 months . Cystoscopy and cytology were performed every 3 months , with biopsy at 3 months and then as clinical ly indicated . Initial complete response was defined as negative cystoscopy , cytology and biopsy at 3 months . RESULTS A total of 58 patients were enrolled in the study and 47 were evaluable for response . Median patient age was 70 years ( range 50 to 88 ) . Of the evaluable patients 42 ( 89 % ) had high risk disease , including high grade Ta in 12 ( 26 % ) , high grade T1 in 2 ( 4 % ) and carcinoma in situ in 28 ( 60 % ) with or without papillary lesions . At the initial 3-month evaluation 47 % of patients were free of disease . At 1 year disease had not recurred in 28 % of the 47 patients , all except 2 from the high risk group , and at 2 years disease had not recurred in 21 % . CONCLUSIONS Intravesical gemcitabine has activity in high risk nonmuscle invasive bladder cancer and offers an option for patients with recurrence after bacillus Calmette-Guérin who are not suitable for cystectomy . However , less than 30 % of patients had a durable response at 12 months even with maintenance therapy Purpose : To assess the clinical and pharmacodynamic activity of dovitinib in a treatment-resistant , molecularly enriched non – muscle-invasive urothelial carcinoma of the bladder ( NMIUC ) population . Experimental Design : A multi-site pilot phase II trial was conducted . Key eligibility criteria included the following : Bacillus Calmette-Guerin (BCG)-unresponsive NMIUC ( > 2 prior intravesical regimens ) with increased phosphorylated FGFR3 ( pFGFR3 ) expression by central ly analyzed immunohistochemistry ( IHC+ ) or FGFR3 mutations ( Mut+ ) assessed in a CLIA-licensed laboratory . Patients received oral dovitinib 500 mg daily ( 5 days on/2 days off ) . The primary endpoint was 6-month TURBT-confirmed complete response ( CR ) rate . Results : Between 11/2013 and 10/2014 , 13 patients enrolled ( 10 IHC+ Mut− , 3 IHC+ Mut+ ) . Accrual ended prematurely due to cessation of dovitinib clinical development . Demographics included the following : median age 70 years ; 85 % male ; carcinoma in situ ( CIS ; 3 patients ) , Ta/T1 ( 8 patients ) , and Ta/T1 + CIS ( 2 patients ) ; median prior regimens 3 . Toxicity was frequent with all patients experiencing at least one grade 3–4 event . Six-month CR rate was 8 % ( 0 % in IHC+ Mut− ; 33 % in IHC+ Mut+ ) . The primary endpoint was not met . Pharmacodynamically active ( 94–5,812 nmol/L ) dovitinib concentrations in urothelial tissue were observed in all evaluable patients . Reductions in pFGFR3 IHC staining were observed post-dovitinib treatment . Conclusions : Dovitinib consistently achieved biologically active concentrations within the urothelium and demonstrated pharmacodynamic pFGFR3 inhibition . These results support systemic administration as a viable approach to clinical trials in patients with NMIUC . Long-term dovitinib administration was not feasible due to frequent toxicity . Absent clinical activity suggests that patient selection by pFGFR3 IHC alone does not enrich for response to FGFR3 kinase inhibitors in urothelial carcinoma . Clin Cancer Res ; 23(12 ) ; 3003–11 . © 2016 AACR Purpose : We compared blue light flexible cystoscopy with white light flexible cystoscopy for the detection of  bladder cancer during surveillance . Material s and Methods : Patients at high risk for recurrence received hexaminolevulinate intravesically before white light flexible cystoscopy and r and omization to blue light flexible cystoscopy . All suspicious lesions were documented . Patients with suspicious lesions were referred to the operating room for repeat white and blue light cystoscopy . All suspected lesions were biopsied or resected and specimens were examined by an independent pathology consensus panel . The primary study end point was the proportion of patients with histologically confirmed malignancy detected only with blue light flexible cystoscopy . Additional end points were the false‐positive rate , carcinoma in situ detection and additional tumors detected only with blue light cystoscopy . Results : Following surveillance 103 of the 304 patients were referred , including 63 with confirmed malignancy , of whom 26 had carcinoma in situ . In 13 of the 63 patients ( 20.6 % , 95 % CI 11.5–32.7 ) recurrence was seen only with blue light flexible cystoscopy ( p < 0.0001 ) . Five of these cases were confirmed as carcinoma in situ . Operating room examination confirmed carcinoma in situ in 26 of 63 patients ( 41 % ) , which was detected only with blue light cystoscopy in 9 of the 26 ( 34.6 % , 95 % CI 17.2–55.7 , p < 0.0001 ) . Blue light cystoscopy identified additional malignant lesions in 29 of the 63 patients ( 46 % ) . The false‐positive rate was 9.1 % for white and blue light cystoscopy . None of the 12 adverse events during surveillance were serious . Conclusions : Office based blue light flexible cystoscopy significantly improves the detection of patients with recurrent bladder cancer  and it is safe when used for surveillance . Blue light cystoscopy in the operating room significantly improves the detection of carcinoma in situ and detects lesions that are missed with white light cystoscopy PURPOSE A phase II study was performed to assess the efficacy and tolerability of intravesical oportuzumab monatox in patients with urothelial carcinoma in situ of the bladder . Bacillus Calmette-Guérin treatment had previously failed in all patients . MATERIAL S AND METHODS A total of 46 patients received 1 induction cycle of 6 ( cohort 1 ) or 12 ( cohort 2 ) weekly intravesical oportuzumab monatox ( VB4 - 845 ) instillations of 30 mg , followed by up to 3 maintenance cycles of 3 weekly administrations every 3 months . RESULTS A complete response to oportuzumab monatox was seen in 9 of 22 patients ( 41 % ) in cohort 1 and 9 of 23 ( 39 % ) in cohort 2 at the 3-month evaluation . A total of 20 patients ( 44 % ) achieved a complete response . Two other patients without carcinoma in situ who achieved a complete response were not included in the study due to the development of noninvasive papillary ( Ta ) disease . Median time to recurrence in patients who achieved a complete response was 274 and 408 days in cohorts 1 and 2 , respectively . Overall 7 patients ( 16 % ) remained disease-free . Post- study assessment demonstrated that these patients were still disease-free at last followup ( 18 to 25 months ) . The most common adverse events were mild to moderate reversible bladder symptoms . CONCLUSIONS 
    Output:
    