***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 
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    ***EXAMPLES*** 
    Input: BACKGROUND  Photodynamic therapy is an effective treatment for actinic keratoses . Nevertheless , severe pain during the procedure is a serious adverse effect , which leads to interruption or even termination . Complete pain relief remains a difficult challenge . OBJECTIVE To evaluate the effect of a nitrous oxide/oxygen mixture on pain intensity during photodynamic therapy . METHODS This clinical trial has been design ed as a prospect i ve , single-centre , explorative , controlled , observational study . RESULTS We were able to detect a significant overall pain reduction of 55.2 % after application of a nitrous oxide/oxygen mixture by means of an intra-individual comparison . Furthermore , the total number of therapy interruption significantly decreased by 82 % after the inhalation analgesia . Additionally , treatment satisfaction ranged from ' extremely to very satisfied ' . CONCLUSIONS This study shows that analgesia by means of a nitrous oxide/oxygen mixture is a very effective and well-tolerated method for achieving significant pain reduction during photodynamic therapy Background Although photodynamic therapy ( PDT ) is becoming an important treatment method for skin lesions such as actinic keratosis ( AK ) and superficial basal cell carcinoma , there are still discussion s about which fluence rate and light dose are preferable . Recent studies in rodents have shown that a low fluence rate is preferable due to depletion of oxygen at high fluence rates . However , these results have not yet been verified in humans IMPORTANCE Daylight photodynamic therapy using topical methyl 5-aminolevulinic acid ( MAL ) for actinic keratoses ( AKs ) is as effective as conventional photodynamic therapy but has the advantage of being almost pain free . Daylight photodynamic therapy , however , requires dry and warm weather conditions . OBJECTIVE To establish if topical MAL photodynamic therapy using a white light light-emitting diode ( LED ) lamp is as effective and well-tolerated as daylight photodynamic therapy for the treatment of AKs . DESIGN , SETTING , AND PARTICIPANTS Overall , 22 men with significant photodamage and a high number of AKs were enrolled in this prospect i ve , r and omized , single-blind study , employing a split-scalp design , comparing the effectiveness and adverse effects of daylight photodynamic therapy and artificial white light ( AWL ) LED photodynamic therapy for the treatment of AKs on the forehead and scalp . Organ transplant recipients were excluded . Patients were treated and evaluated at an academic tertiary referral dermatology center . Treatment lasted from April 2014 to July 2014 and follow-up visits occurred for 9 months posttreatment . INTERVENTIONS Two symmetrical treatment fields were defined and AKs counted , mapped , and photographed at baseline , 1 , 3 , 6 , and 9 months . Patients had half of their scalp treated with daylight photodynamic therapy and the other half treated with AWL photodynamic therapy 1 week apart and r and omly allocated . MAL was applied , and treatment commenced 30 minutes later and lasted 2 hours . Irradiance , illuminance , and light spectra measurements were performed . The integrated dose in J/cm2 was measured . The effective light dose , weighted to the absorption spectrum for protoporphyrin IX , was calculated . MAIN OUTCOMES AND MEASURES The primary end point was the reduction in total AK count per treatment field . Secondary end points included adverse effects and patient satisfaction . RESULTS We enrolled 22 men with a median age of 72 years ( range , 47 - 85 years ) at baseline , the total ( median of AKs per field ) were 469 ( 20.5 ) for the DPDT group and 496 ( 20.5 ) for the AWLPDT group ( P = .34 ) . The median number and percentage of reduction in AKs per field were 12 and 62.3 % for DPDT and 14 and 67.7 % for AWLPDT at 1 month ( P = .21 and P = .13 , respectively ) . There was no significant difference in the reduction percentage of AKs for either treatment at 1 , 3 , and 6 months . At 9 months , the median number and percentage of reduction in AKs per field was 9.0 and 48.4 % for DPDT and 12.0 and 64.4 % for AWLPDT ( P = .13 and P = .05 , respectively ) . Pain was reported by 14 patients with DPDT and 16 patients with AWLPDT ( median maximum score [ out of 100 ] , 4 vs 6 ; P = .51 ) . Moderate erythema was reported by 9 patients after DPDT and 14 patients after AWLPDT . On a scale of 0 ( intolerable ) to 10 ( very tolerable ) patients rated DPDT as 9.5 and AWLPDT as 9 ( P = .37 ) . CONCLUSIONS AND RELEVANCE Photodynamic therapy using an AWL source was as effective and well-tolerated as daylight photodynamic therapy . TRIAL REGISTRATION clinical trials.gov Identifier : NCT02520700 INTRODUCTION Daylight photodynamic therapy ( DL-PDT ) with methyl aminolevulinate ( MAL ) is a simplified PDT procedure that was recently shown in a few trials to be effective for grade I actinic keratosis ( AK ) , with improved tolerability and reduced time of clinical attendance as compared to conventional PDT ( c-PDT ) . OBJECTIVE To evaluate the efficacy and tolerability of DL-PDT vs. c-PDT with MAL in the treatment of grade I AK on the face and scalp in Italy . METHODS Thirty-five patients with AKs on the face ( n = 17 ) or scalp ( n = 18 ) were prospect ively enrolled in an intra-patient , left-right , prospect i ve , comparison study between DL-PDT and c-PDT at a single centre between September and October 2013 . Weather conditions and outdoor temperature during daylight exposure were recorded for each DL-PDT session . Pain was assessed after the PDT session and local adverse events 2 days after treatment . Lesion response rate was evaluated on both sides at 3 months . AKs with complete regression were followed until 6 months . Patient 's preference for either treatment was recorded . RESULTS There was no difference in complete response ( CR ) rate of AK I at 3 months between DL-PDT and c-PDT ( 87 % vs. 91 % ; RR = 0.96 ; P = 0.16 ) . A lower CR rate was observed with DL-PDT than with c-PDT for AK II ( 36 % vs. 61 % ; RR = 0.58 , P = 0.06 ) and III ( 25 % vs. 46 % ; RR = 0.50 , P = 0.20 ) . Recurrence rate at 6 months was slightly higher for cleared AK I after DL-PDT than after c-PDT ( 17 % vs. 12 % , RR = 1.50 , P < 0.05 ) . DL-PDT was associated with lower pain ( ΔVAS = -2.2 , P < 0.01 ) and reduced severity of local adverse events ( ΔLSR = -1.4 , P < 0.01 ) than c-PDT . Increasing outdoor temperature was associated with the efficacy of DL-PDT and the severity of adverse events  . DL-PDT was preferred by 88 % of the patients . CONCLUSION MAL DL-PDT showed similar efficacy to c-PDT in the treatment of AK I of the face/scalp but was less effective than c-PDT for AKs II and III . DL-PDT was better tolerated being associated with lower pain and occurrence of fewer adverse events . Clinical response to DL-PDT was significantly moderated by outdoor temperature , increasing at higher temperatures BACKGROUND / PURPOSE Literature data suggest that lower fluence rates are preferable in terms of clinical response and tolerability for treating patients with actinic keratoses ( AKs ) . We aim ed to clarify the impact of different fluence rates on pain during photodynamic therapy ( PDT ) for AKs , as well as on treatment outcome . METHODS Individuals with at least three discrete AKs were recruited . Each lesion was r and omly allocated to 25 , 50 or 75 mW/cm2 of topical 5-aminolevulinic acid ( 5-ALA ) PDT , using non-coherent light source . Primary end point was pain during illumination , evaluated using a visual analogue scale ( VAS ) . Secondary end points were clinical outcome and adverse events . RESULTS Fifty adults , with 150 AKs lesions were recruited in the study .  Mean VAS score did not significantly differ between the groups of 25 and 50 mW/cm2 ( P=0.714 ) . However , mean VAS was significantly higher at the group of 75 mW/cm2 in comparison to the former ones ( P=0.000 ) . With respect to the clinical outcome and adverse events during the first year of follow-up , no differences were observed between the three groups . Comparison between the 25 and the 50 mW/cm2 ( P=0.749 ) , as well as between the former and the 75 mW/cm2 , did not show a dependence of complete response rate on fluence ( P=0.749 and P=1.000 , respectively ) . CONCLUSIONS According to our observations a fluence rate between 25 and 50 mW/cm2 is effective and better tolerated by patients treated with topical 5-ALA PDT for AKs BACKGROUND Photodynamic therapy ( PDT ) of actinic keratosis ( AK ) using methylaminolaevulinate ( MAL ) is an effective and safe treatment option , but the procedure is painful . OBJECTIVES To evaluate the efficacy and pain associated with variable pulsed light ( VPL ) , a prospect i ve , r and omized , controlled split-face study was performed . METHODS Topical MAL-PDT was conducted in 25 patients with AK ( n = 238 ) who were suitable for two-sided comparison . After incubation with MAL , irradiation was performed with a light-emitting diode ( LED ) ( 50 mW cm(-2 ) ; 37 J cm(-2 ) ) vs. VPL ( 80 J cm(-2 ) , double pulsed at 40 J cm(-2 ) , pulse train of 15 impulses each with a duration of 5 ms , 610 - 950 nm filtered h and piece ) followed by re-evaluation up to 3 months . RESULTS The pain during and after therapy was significantly lower with VPL irradiation [ t ( d.f . = 24 ) = 4.42 , P < 0.001 ] . The overall mean + /- SD infiltration and keratosis score at 3 months after treatment was 0.86 + /- 0.71 ( LED system ) vs. 1.05 + /- 0.74 ( VPL device ) ( no statistically significant difference ; P = 0.292 ) . Patient satisfaction following both treatment modalities did not significantly differ at the 3-month follow up ( P = 0.425 ) . CONCLUSIONS VPL used for MAL-PDT is an efficient alternative for the treatment of AK that results in complete remission and cosmesis equivalent to LED irradiation but causes significantly less pain Background Photodynamic therapy ( PDT ) with 5‐aminolaevulinic acid ( ALA ) or its methylester [ methyl‐5‐aminolaevulinate ( MAL ) or 5‐amino‐4‐oxopentanoate ] was recently ranked as first‐line therapy for the treatment of actinic keratosis ( AK ) and is an accepted therapeutic option for the treatment of neoplastic skin diseases . BF‐200 ALA ( Biofrontera Bioscience GmbH , Leverkusen , Germany ) is a gel formulation of ALA with nanoemulsion for the treatment of AK which overcomes previous problems of ALA instability and improves skin penetration BACKGROUND The major drawback of the widely used photodynamic therapy ( PDT ) is treatment-related pain . OBJECTIVE Gain insight into the intensity of and predictive factors for painful burning sensation associated with PDT . METHODS A prospect i ve cohort study was performed at the department of Dermatology in the Maastricht University Medical Centre in Maastricht , a reference centre for dermatological oncology in The Netherl and s. A total of 141 lesions in 108 patients were included , treated from November 2008 until June 2009 with PDT for superficial basal cell carcinoma , Bowen 's disease ( BD ) or actinic keratosis ( AK ) .  Painful burning sensation was scored based on an 11-point pain intensity numeric rating scale ( PI-NRS ) ( 0=no pain ; 10=worst possible pain ) . RESULTS The percentage of patients with a PI-NRS score over six was 32.6 % and 37.9 % during the primary and follow-up PDT session respectively . A total of 76.6 % ( 95/124 ) of the patients was consistent in pain intensity score reporting . Factors associated with higher PI-NRS scores were treatment of AK or BD , tumour localization in the head/neck region , patient 's age over 70 , Fitzpatrick skintype I/II , photosensitizer 5-aminolevulinic acid and use of oral analgesics . After mutual adjustment of these factors , Fitzpatrick skintype remained the only independent predictor of PI-NRS scores during PDT . CONCLUSION It remains difficult to decide which patients should be considered for pain relieving measures . The solution remains to support all 
    Output:
    
Of these interventions : nerve block , subcutaneous infiltration anesthesia , cold analgesia , and transcutaneous electrical nerve stimulation , but not topical anesthetic gels , were associated with less PDT-related pain ; 5-aminolevulinic acid ( ALA ) tended to be more painful than methyl-5-aminolevulinate ( MAL ) ; daylight PDT was less painful than conventional PDT ; and lower irradiance delivery produced lower pain scores in general .
There is no single crystalized protocol for management of PDT-related pain .
Evidence suggests that continuous activation of low levels of PpIX with methods using lower irradiance and possibly shorter incubation times are associated with decreased pain without loss of PDT efficacy .