Perioperative dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin in muscle-invasive bladder cancer (VESPER): survival endpoints at 5 years in an open-label, randomised, phase 3 study.

BACKGROUND: The optimal perioperative chemotherapy for patients with muscle-invasive bladder cancer is not defined. The VESPER (French Genito-Urinary Tumor Group and French Association of Urology V05) trial reported improved 3-year progression-free survival with dose-dense methotrexate, vinblastine, doxorubicin and cisplatin (dd-MVAC) versus gemcitabine and cisplatin (GC) in patients who received neoadjuvant therapy, but not in the overall perioperative setting. In this Article, we report on the secondary endpoints of overall survival and time to death due to bladder cancer at 5-year follow-up. METHODS: VESPER was an open-label, randomised, phase 3 trial done at 28 university hospitals or comprehensive cancer centres in France, in which adults (age ≤18 years and ≤80 years) with primary bladder cancer and histologically confirmed muscle-invasive urothelial carcinoma were randomly allocated (1:1; block size four) to treatment with dd-MVAC (every 2 weeks for a total of six cycles) or GC (every 3 weeks for a total of four cycles). Overall survival and time to death due to bladder cancer (presented as 5-year cumulative incidence of death due to bladder cancer) was analysed by intention to treat (ITT) in all randomly assigned patients. Overall survival was assessed by the Kaplan-Meier method with the treatment groups compared with log-rank test stratified for mode of administration of chemotherapy (neoadjuvant or adjuvant) and lymph node involvement. Time to death due to bladder cancer was analysed with an Aalen model for competing risks and a Fine and Gray regression model stratified for the same two covariates. Results were presented for the total perioperative population and for the neoadjuvant and adjuvant subgroups. The trial is registered with ClinicalTrials.gov, NCT01812369, and is complete. FINDINGS: From Feb 25, 2013, to March 1, 2018, 500 patients were randomly assigned, of whom 493 were included in the final ITT population (245 [50%] in the GC group and 248 [50%] in the dd-MVAC group; 408 [83%] male and 85 [17%] female). 437 (89%) patients received neoadjuvant chemotherapy. Median follow-up was 5·3 years (IQR 5·1-5·4); 190 deaths at the 5-year cutoff were reported. In the perioperative setting (total ITT population), we found no evidence of association of overall survival at 5 years with dd-MVAC treatment versus GC treatment (64% [95% CI 58-70] vs 56% [50-63], stratified hazard ratio [HRstrat] 0·79 [95% CI 0·59-1·05]). Time to death due to bladder cancer was increased in the dd-MVAC group compared with in the GC group (5-year cumulative incidence of death: 27% [95% CI 21-32] vs 40% [34-46], HRstrat 0·61 [95% CI 0·45-0·84]). In the neoadjuvant subgroup, overall survival at 5 years was improved in the dd-MVAC group versus the GC group (66% [95% CI 60-73] vs 57% [50-64], HR 0·71 [95% CI 0·52-0·97]), as was time to death due to bladder cancer (5-year cumulative incidence: 24% [18-30] vs 38% [32-45], HR 0·55 [0·39-0·78]). In the adjuvant subgroup, the results were not conclusive due to the small sample size. Bladder cancer progression was the cause of death for 157 (83%) of the 190 deaths; other causes of death included cardiovascular events (eight [4%] deaths), deaths related to chemotherapy toxicity (four [2%]), and secondary cancers (four [2%]). INTERPRETATION: Our results on overall survival at 5 years were in accordance with the primary endpoint analysis (3-year progression-free survival). We found no evidence of improved overall survival with dd-MVAC over GC in the perioperative setting, but the data support the use of six cycles of dd-MVAC over four cycles of GC in the neoadjuvant setting. These results should impact practice and future trials of immunotherapy in bladder cancer. FUNDING: French National Cancer Institute.

Complete Transurethral Resection before Radical Cystectomy May Improve Oncological Outcomes.

OBJECTIVES: The objective of this study was to assess the impact of complete transurethral resection of bladder tumors (TURBTs) before radical cystectomy on pathological and oncological outcomes of patients with muscle-invasive bladder cancer (MIBC) and high-risk non-MIBC. MATERIALS AND METHODS: The charts of all patients who underwent radical cystectomy for bladder cancer in 2 academic departments of urology between 1996 and 2016 were retrospectively reviewed. Patients were divided into 2 groups according to the completeness of the last endoscopic resection before radical cystectomy: macroscopically complete transurethral resection (complete) or macroscopically incomplete transurethral resection (incomplete). The primary end point was the recurrence-free survival (RFS). Secondary end points included cancer-specific survival (CSS) and rates of pT0 and downstaging. RESULTS: Out of 486 patients included for analysis, the TURBT immediately preceding radical cystectomy was considered macroscopically complete in 253 patients (52.1%) and incomplete in 233 patients (47.9%). In multivariate analysis, macroscopically complete TURBT was the strongest predictor of both pT0 disease (OR = 3.1; p = 0.02) and downstaging (OR = 7.1; p < 0.0001). After a median follow-up of 41 months, macroscopically complete TURBT was associated with better RFS (5-year RFS: 57 vs. 37%; p < 0.0001) and CSS (5-year CSS: 70.8 vs. 54.5%; p = 0.002). In multivariate analysis adjusting for multifocality, weight of endoscopic resection specimen, cT4 stage on preoperative imaging, interval between endoscopic resection and radical cystectomy, neoadjuvant chemotherapy, pT stage, and associated carcinoma in situ, macroscopically complete endoscopic resection remained the main predictor of better RFS (HR = 0.4; p = 0.0003) and the only preoperative factor associated with CSS (HR = 0.5; p = 0.01). CONCLUSION: A macroscopically complete TURBT immediately preceding radical cystectomy may improve pathological and oncological outcomes in patients with MIBC and high-risk MIBC.

[Pedagogical impact of a MOOC on surgical technique of kidney transplantation]. / Impact pédagogique d'un MOOC de technique chirurgicale de transplantation rénale.

OBJECTIVE: To evaluate the educational impact of a pilot MOOC (Massive Open Online Course), validated by the French College of Urology Teachers (FCUT), on the surgical technique of kidney transplantation. MATERIALS AND METHODS: We developed a MOOC on the surgical technique of kidney transplantation, based on a video of a surgical procedure, performed by an expert surgeon. The MOOC has been validated by the FCUT. We have created 2 student groups: 1) MOOC-pre-QCM group: visualization of the MOOC then answer to the MCQs and satisfaction questions; 2) MOOC-post-QCM group: answer to the MCQs then visualization of the MOOC then answers to the satisfaction questions. In total, 20 MCQs on the kidney transplantation technique were completed by the 2 groups. The answers were anonymous. RESULTS: A total of 142 people answered the MCQs (MOOC-pre-QCM group (n=66) and MOOC-post-QCM group (n=76)). Twenty-nine percent (41/142) of the participants were fellows and 71 % (101/142) were residents. The proportion of fellows and residents was identical between the 2 groups. The rate of correct answers to the 20 MCQs was statistically higher in the MOOC-pre-QCM group, compared to the MOOC-post-QCM group (88.6 % versus 73.3 %, P<0.0001). Ninety-one percent of students found the MOOC "Very Useful" or "Useful". The median MOOC rating, given by students, was 8/10. CONCLUSION: This study showed a positive impact of the MOOC on theoretical knowledge of kidney transplantation surgical technique. This MOOC could serve as a pilot project for the development of other MOOCs on urological surgery. LEVEL: 3.

The prognostic value of high-grade prostate cancer pattern on MRI-targeted biopsies: predictors for downgrading and importance of concomitant systematic biopsies.

PURPOSE: To assess the proportion and risk factors for downgrading and reclassification to favorable disease in patients having high-grade (HG) prostate cancer (PCa) pattern on magnetic resonance imaging (MRI)-targeted-biopsy (TB). METHODS: From a radical prostatectomy (RP) cohort, we included patients with pre-biopsy positive MRI and HG [defined by Grade Group (GG) ≥ 3] PCa on MRI-TB. All patients also underwent concomitant systematic biopsy (SB). The main endpoints were the rates of downgrading to GG2, overall downgrading, favorable disease (pT2 and GG2) on RP specimens, and biochemical recurrence-free-survival (RFS). We studied the correlations between HG on concomitant SB, final pathological outcomes and biochemical RFS curves. RESULTS: Overall downgrading, downgrading to GG2 disease and favorable disease were noted in 36.2%, 24.1%, and 15.4% respectively. HG on concomitant SB was correlated with pT3-4 disease (p < 0.001), pN1 disease (p < 0.001), positive surgical margins (p = 0.043), PSA recurrence (p = 0.003). In multivariable analysis, the presence of GG4-5 on TB (p = 0.013; OR 0.263) and the presence of HG on concomitant SB (p = 0.010; OR 0.269) were negatively and independently correlated with the risk of downgrading to GG2. The presence of HG on concomitant SB independently predicted RFS with a hazard ratio of 2.173 (p = 0.049; 95% CI 1.005-4.697). CONCLUSIONS: Our data shows that a limited HG restricted to TB can often be associated with a favorable grade in almost a quarter of the cases and downgraded in almost half of the cases. Detailed SB features, mainly the presence of HG on concomitant SB, was associated with a more accurate pathology and oncologic outcomes prediction, pleading for the maintenance of SB in MRI-positive patients.

Intra-database validation of case-identifying algorithms using reconstituted electronic health records from healthcare claims data.

BACKGROUND: Diagnosis performances of case-identifying algorithms developed in healthcare database are usually assessed by comparing identified cases with an external data source. When this is not feasible, intra-database validation can present an appropriate alternative. OBJECTIVES: To illustrate through two practical examples how to perform intra-database validations of case-identifying algorithms using reconstituted Electronic Health Records (rEHRs). METHODS: Patients with 1) multiple sclerosis (MS) relapses and 2) metastatic castration-resistant prostate cancer (mCRPC) were identified in the French nationwide healthcare database (SNDS) using two case-identifying algorithms. A validation study was then conducted to estimate diagnostic performances of these algorithms through the calculation of their positive predictive value (PPV) and negative predictive value (NPV). To that end, anonymized rEHRs were generated based on the overall information captured in the SNDS over time (e.g. procedure, hospital stays, drug dispensing, medical visits) for a random selection of patients identified as cases or non-cases according to the predefined algorithms. For each disease, an independent validation committee reviewed the rEHRs of 100 cases and 100 non-cases in order to adjudicate on the status of the selected patients (true case/ true non-case), blinded with respect to the result of the corresponding algorithm. RESULTS: Algorithm for relapses identification in MS showed a 95% PPV and 100% NPV. Algorithm for mCRPC identification showed a 97% PPV and 99% NPV. CONCLUSION: The use of rEHRs to conduct an intra-database validation appears to be a valuable tool to estimate the performances of a case-identifying algorithm and assess its validity, in the absence of alternative.

Adjuvant radiotherapy versus early salvage radiotherapy plus short-term androgen deprivation therapy in men with localised prostate cancer after radical prostatectomy (GETUG-AFU 17): a randomised, phase 3 trial.

BACKGROUND: Adjuvant radiotherapy reduces the risk of biochemical progression in prostate cancer patients after radical prostatectomy. We aimed to compare adjuvant versus early salvage radiotherapy after radical prostatectomy, combined with short-term hormonal therapy, in terms of oncological outcomes and tolerance. METHODS: GETUG-AFU 17 was a randomised, open-label, multicentre, phase 3 trial done at 46 French hospitals. Men aged at least 18 years who had an Eastern Cooperative Oncology Group performance status of 1 or less, localised adenocarcinoma of the prostate treated with radical prostatectomy, who had pathologically-staged pT3a, pT3b, or pT4a (with bladder neck invasion), pNx (without pelvic lymph nodes dissection), or pN0 (with negative lymph nodes dissection) disease, and who had positive surgical margins were eligible for inclusion in the study. Eligible patients were randomly assigned (1:1) to either immediate adjuvant radiotherapy or delayed salvage radiotherapy at the time of biochemical relapse. Random assignment, by minimisation, was done using web-based software and stratified by Gleason score, pT stage, and centre. All patients received 6 months of triptorelin (intramuscular injection every 3 months). The primary endpoint was event-free survival. Efficacy and safety analyses were done on the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT00667069. FINDINGS: Between March 7, 2008, and June 23, 2016, 424 patients were enrolled. We planned to enrol 718 patients, with 359 in each study group. However, on May 20, 2016, the independent data monitoring committee recommended early termination of enrolment because of unexpectedly low event rates. At database lock on Dec 19, 2019, the overall median follow-up time from random assignment was 75 months (IQR 50-100), 74 months (47-100) in the adjuvant radiotherapy group and 78 months (52-101) in the salvage radiotherapy group. In the salvage radiotherapy group, 115 (54%) of 212 patients initiated study treatment after biochemical relapse. 205 (97%) of 212 patients started treatment in the adjuvant group. 5-year event-free survival was 92% (95% CI 86-95) in the adjuvant radiotherapy group and 90% (85-94) in the salvage radiotherapy group (HR 0·81, 95% CI 0·48-1·36; log-rank p=0·42). Acute grade 3 or worse toxic effects occurred in six (3%) of 212 patients in the adjuvant radiotherapy group and in four (2%) of 212 patients in the salvage radiotherapy group. Late grade 2 or worse genitourinary toxicities were reported in 125 (59%) of 212 patients in the adjuvant radiotherapy group and 46 (22%) of 212 patients in the salvage radiotherapy group. Late genitourinary adverse events of grade 2 or worse were reported in 58 (27%) of 212 patients in the adjuvant radiotherapy group versus 14 (7%) of 212 patients in the salvage radiotherapy group (p<0·0001). Late erectile dysfunction was grade 2 or worse in 60 (28%) of 212 in the adjuvant radiotherapy group and 17 (8%) of 212 in the salvage radiotherapy group (p<0·0001). INTERPRETATION: Although our analysis lacked statistical power, we found no benefit for event-free survival in patients assigned to adjuvant radiotherapy compared with patients assigned to salvage radiotherapy. Adjuvant radiotherapy increased the risk of genitourinary toxicity and erectile dysfunction. A policy of early salvage radiotherapy could spare men from overtreatment with radiotherapy and the associated adverse events. FUNDING: French Health Ministry and Ipsen.

Performance of systematic, MRI-targeted biopsies alone or in combination for the prediction of unfavourable disease in MRI-positive low-risk prostate cancer patients eligible for active surveillance.

PURPOSE: To assess the upstaging/upgrading rates of low-risk prostate cancer (PCa) according to the biopsy scheme used (systematic (SB), targeted biopsies (TB), or both) in the setting of positive pre-biopsy MRI. PATIENTS AND METHODS: We included 143 consecutive men fulfilling the Toronto University active surveillance (AS) criteria who underwent a pre-biopsy positive MRI, a combination of SB and software-based fusion TB, and a radical prostatectomy, in two expert centres. The primary endpoints were the pathological upgrading and upstaging rates. Overall unfavourable disease (OUD) was defined by any pT3-4 and/or pN1 and/or ≥ GG 3. RESULTS: Using TB alone would have missed 21.7% of cancers including 16.7% of ≥ GG 3. The use of TB was significantly associated with a lower risk of ≥ Grade Group (GG) 3 disease (p < 0.006) in RP specimens. Combination of SB and TB lowered this risk by 39%, compared with TB alone. The biopsy scheme did not affect the upstaging rates which were substantial even in case of combination scheme (from 37 to 46%). OUD was detected in approximately 50% of cases. The presence of high grade on TB was the only independent predictive factor for both ≥ GG 2 (p = 0.015) and ≥ GG 3 (p = 0.023) in RP specimens. CONCLUSIONS: High grade on TB biopsies represented the major predictor of upgrading. Combination of SB and TB better defined the sub-group of patients having the lowest risk of reclassification, compared with TB or SB alone. The risk of non-organ-confined disease remained high, and could not be accurately predicted by MRI or systematic/targeted biopsy features.

Decreased accuracy of the prostate cancer EAU risk group classification in the era of imaging-guided diagnostic pathway: proposal for a new classification based on MRI-targeted biopsies and early oncologic outcomes after surgery.

PURPOSE: To assess the performance of EAU risk classification in PCa patients according to the biopsy pathway (standard versus MRI guided) and to develop a new, more accurate, targeted biopsy (TB)-based classification. MATERIALS AND METHODS: We included 1345 patients consecutively operated by radical prostatectomy (RP) since 2014, when MRI and TB were introduced in the diagnostic pathway. Patients underwent systematic biopsy (SB) only (n = 819) or SB and TB (n = 526) prior to RP during the same time period. Pathological and biochemical outcomes were compared between PCa men undergoing SB (SB cohort) and a combination of TB and SB (TB cohort). Kaplan-Meier and Cox regression models were used to assess biochemical recurrence-free survival (RFS). RESULTS: Both cohorts were comparable regarding final pathology and RFS (p = 0.538). The EAU risk classification accurately predicted outcomes in SB cohort, but did not significantly separate low from intermediate risk in TB cohort (p = 0.791). In TB cohort, the new proposed three-group risk classification significantly improved the recurrence risk prediction compared with the EAU risk classification: HR 4 (versus HR 1.2, p = 0.009) for intermediate, and HR 15 (versus HR 6.5, p < 0.001) in high-risk groups, respectively. A fourth group defining very high-risk cases (≥ T2c clinical stage or grade group 5) was also proposed. CONCLUSIONS: The new classification integrating TB findings we propose meaningfully improves the recurrence prediction after surgery in patients undergoing a TB-based diagnostic pathway, compared with standard EAU risk classification which is still relevant for patients undergoing only SB. External validation is needed.

Active surveillance eligibility of MRI-positive patients with grade group 2 prostate cancer: a pathological study.

PURPOSE: To assess the final pathology risk in MRI-positive grade group (GG) 2 prostate cancer (PCa) patients undergoing targeted (TB) and systematic (SB) biopsies, and thereby, the possibility of active surveillance (AS) in this population. PATIENTS AND METHODS: We included 242 consecutive men diagnosed with GG2 PCa by a combination of SB and software-based fusion TB undergoing a radical prostatectomy (RP). The primary endpoints were the pathological findings in RP specimens, including favourable disease which was defined by a pT2 and GG1-2 disease. RESULTS: The rate of upgrading was 33% including 3% of GG 4-5 disease. MRI lesion size (p = 0.038) and tumor length per core (p < 0.001) were significantly lower in case of favourable pathology. Only 34.2% of not organ-confined disease was reported when only SB were positive, compared with 45.7% and 57.1% when GG2 was detected on TB only and on TB plus SB, respectively (p = 0.035). The number of positive cores on SB was significantly higher in not organ-confined disease (4.3 versus 2.9; p = 0.005). The risk of not organ-confined disease was only 20.8% in men who had a PSAD ≤ 0.20 ng/ml/gr, 1-2 positive biopsies and a maximal tumor length ≤ 6 mm per core, compared with 52.3% in men who did not fulfil all these criteria (p = 0.003). CONCLUSIONS: This study identified clinical, imaging, and pathological factors that were significantly associated with the final pathology risk. In case of positive MRI followed by TB showing GG2, AS could be offered in patients having a PSAD ≤ 0.20, a tumor length ≤ 6 mm and 1-2 positive cores.

Added Value of Concomitant Systematic and Fusion Targeted Biopsies for Grade Group Prediction Based on Radical Prostatectomy Final Pathology on Positive Magnetic Resonance Imaging.

PURPOSE: We assessed the added value of concomitant systematic biopsy for final grade group prediction in patients with positive magnetic resonance imaging who were undergoing targeted biopsy. MATERIALS AND METHODS: Included in study were 478 consecutive patients with prebiopsy positive multiparametric magnetic resonance imaging and a greater than 10-core systematic biopsy combined with fusion targeted biopsy who underwent radical prostatectomy. The primary end point was the grade group concordance between biopsy and radical prostatectomy pathology according to the biopsy technique. Clinical and biological factors associated with the performance of systematic biopsy were analyzed. RESULTS: Adding systematic biopsy to targeted biopsy modified the d'Amico risk classification toward more intermediate and high risk in 7.8% of cases, mainly from low to intermediate risk with low risk prostate cancer on targeted biopsy in 44.3%. This reclassification was significantly higher in patients with lower prostate specific antigen and with prostate specific antigen density less than 0.20 ng/ml/gm (11.7% vs 2.4%, p <0.001). The concordance rate between biopsy pathology and radical prostatectomy pathology significantly differed between targeted biopsy and targeted biopsy plus systematic biopsy (45.2% and 51.7%, respectively). The upgrading rate in radical prostatectomy specimens decreased by 22% when systematic biopsy was added to targeted biopsy. Patients in whom systematic biopsy did not modify grading were more likely to have pT3-4 and/or pN1 disease on final pathology (56.9% vs 38.3%, p=0.007). CONCLUSIONS: Grading concordance between biopsy pathology and radical prostatectomy pathology was improved by adding systematic biopsy in all patient subgroups. Patients with prostate specific antigen density less than 0.20 ng/ml/gm benefited the most from this combined biopsy strategy. Systematic biopsy reclassified a nonnegligible number of cases toward a higher risk category, mainly the low risk cases. Thus, systematic biopsy could modify treatment decision making.

Laparoscopy for living donor left nephrectomy: Comparison of three-dimensional and two-dimensional vision.

The main objective of this preliminary study was to evaluate the feasibility and safety of 3-D laparoscopic living donor left nephrectomy (LDLN). The secondary objective was to compare intraoperative and postoperative outcomes between 3-D and 2-D laparoscopic LDLN. All patients who underwent a laparoscopic LDLN from January 2015 to April 2018 in a university center were included. All surgeries were performed by three experienced surgeons. Seventy three patients were included the following: 16 underwent a 3-D laparoscopic LDLN (3-D group), and 57 underwent a 2-D laparoscopic LDLN (2-D group). Operative time and warm ischemia time (WIT) were significantly lower in the 3-D group (operative time: 80.9 ± 10.2 vs 114.1 ± 32.3 minutes in the 3-D and 2-D groups, P = .0002) (WIT: 1.7 ± 0.6 vs 2.3 ± 0.9 minutes in the 3-D and 2-D groups, P = .02). No conversion to open surgery occurred in both groups. Length of hospital stay was significantly shorter in the 3-D group. No major postoperative complications (Clavien ≥ III) occurred. One-year postoperative GFR was similar to 3-D and 2-D groups. Our preliminary study demonstrates that 3-D laparoscopic LDLN is a feasible and safe surgical procedure. Intraoperative and postoperative outcomes were similar in both 2-D and 3-D vision systems, but 3-D vision systems allow reduction in WIT and operative time.

Evaluation of the impact of a clinical pathway on the progression of acute urinary retention.

AIMS: The management of acute urinary retention (AUR) revolves around trial without catheter (TWOC) after prescription of an alpha-blocker. This study evaluates the implementation of a clinical pathway for AUR. METHODS: Specific clinical pathways for AUR was established between the Emergency Department and the Department of Urology in order to reduce the duration of bladder drainage that included standard prescriptions, an information sheet, and a note to be faxed to scheduling nurses to organize the trial without catheter (TWOC). The main endpoint was the reduction in the time between the AUR episode and TWOC, without decreasing urination. RESULTS: Between April 2015 and December 2016, 248 patients were treated in the Emergency Department, and externally, for AUR. One hundred and seventy patients were enrolled in the pathway group and 78 in the control group. The mean duration of urinary catheterization decreased by 5.5 days as did the number of patients lost to follow-up (32% vs 76%), without decreasing the successful voiding (46% vs 36%). The duration of the urinary catheterization was not related to the chance of successful voiding regardless of the urine volume and a drainage time of over 10 days significantly reduced the chance of success (68%, n = 26 versus 42%, n = 76; P = 0.0038). CONCLUSION: The implementation of a clinical pathway for AUR reduced the number of patients lost to follow-up and the catheterization duration, thus optimizing the management of these patients.

Management of urinary-tract fistulas using reversible balloon nephrostomy: a single-center retrospective analysis of 56 patients.

PURPOSE: To evaluate the effectiveness of balloon nephrostomy (BN) for treating urinary tract fistulas. MATERIALS AND METHODS: In a single-center retrospective analysis, 56 patients were treated using BN between 2003 and 2014. All causes of urinary tract fistula were included. We assessed the effectiveness of drainage, complications, and the types of reconstruction surgery used. Success was defined as fistula closure without surgery. RESULTS: The cohort consisted of 25 males (54%) and 31 females (55%) with a median age of 63 years who underwent BN for a urinary fistula secondary to surgery, i.e., urologic (40%; n = 22), gynecologic (34%; n = 19), or digestive (20%; n = 11). Of these patients, 48 (86%) had a history of cancer (49% had a tumor progression). Median drainage time was 90 days (10-583), with an average of three successive readjustments needed per patient. We obtained a 21% success rate (n = 12), morbidity was 6.5% (urinary sepsis, renal abscess, ureteral stricture), and 7% of patients developed ureteral stricture after balloon removal. There was no recurrence of any fistula within a median follow-up time of 15.2 months. CONCLUSION: This minimally invasive procedure can be used for selected urinary tract fistulas with few complications. It can also be used safely in populations that have several comorbidities.

Estetrol, a Fetal Selective Estrogen Receptor Modulator, Acts on the Vagina of Mice through Nuclear Estrogen Receptor α Activation.

The genitourinary syndrome of menopause has a negative impact on quality of life of postmenopausal women. The treatment of vulvovaginal atrophy includes administration of estrogens. However, oral estrogen treatment is controversial because of its potential risks on venous thrombosis and breast cancer. Estetrol (E4) is a natural estrogen synthesized exclusively during pregnancy by the human fetal liver and initially considered as a weak estrogen. However, E4 was recently evaluated in phase 1 to 2 clinical studies and found to act as an oral contraceptive in combination with a progestin, without increasing the level of coagulation factors. We recently showed that E4 stimulates uterine epithelial proliferation through nuclear estrogen receptor (ER) α, but failed to elicit endothelial responses. Herein, we first evaluated the morphological and functional impacts of E4 on the vagina of ovariectomized mice, and we determined the molecular mechanism mediating these effects. Vaginal epithelial proliferation and lubrication after stimulation were found to increase after E4 chronic treatment. Using a combination of pharmacological and genetic approaches, we demonstrated that these E4 effects on the vagina are mediated by nuclear ERα activation. Altogether, we demonstrate that the selective activation of nuclear ERα is both necessary and sufficient to elicit functional and structural effects on the vagina, and therefore E4 appears promising as a therapeutic option to improve vulvovaginal atrophy.

Impact of Patient- and Clinician-Reported Cumulative Toxicity on Quality of Life in Patients With Metastatic Castration-Naïve Prostate Cancer.

Background: Current toxicity evaluation is primarily focused on high-grade adverse events (AEs) reported by clinicians. However, the cumulative effect of multiple lower-grade AEs may also impact patients' quality of life (QoL). Further, patient-reported toxicity may be more representative of patients' treatment experiences. This study aimed to determine whether cumulative toxicity comprising all-grade AEs is more associated with QoL than cumulative toxicity comprising high-grade AEs only, and whether patient-reported cumulative toxicity is more associated with QoL than clinician-reported cumulative toxicity. Methods: Patients with metastatic castration-naïve prostate cancer participating in the phase III GETUG-AFU 15 trial completed questionnaires on AEs (at 3 and 6 months) and QoL (at baseline and 3 and 6 months). Clinicians reported AEs during clinical visits. Cumulative toxicity scores were calculated for clinicians and patients in 3 ways: total number of high-grade AEs, total number of all-grade AEs, and total number of all AEs multiplied by their grade (severity score). Relationships between cumulative toxicity scores and QoL were studied using longitudinal regression analyses; unstandardized (B) and standardized regression coefficients (ß) are reported. Results: Of 385 patients, 184 with complete QoL and toxicity data were included. Clinician-reported all-grade AEs (B, -2.2; 95% CI, -3.3 to -1.1; P<.01) and severity score (B, -1.4; 95% CI, -2.2 to -0.7; P<.01) were associated with deteriorated physical QoL, whereas the total number of high-grade AEs was not. All patient-reported scores were significantly (P<.01 for all) associated with deteriorated physical and global QoL. Standardized regression coefficients indicated that patient-reported toxicity scores were more associated with QoL outcomes than clinician-reported scores, with the strongest association found for the all-grade AEs and severity cumulative toxicity scores. Conclusions: Patient- and clinician-based cumulative toxicity scores comprising all-grade AEs better reflect impact on patient QoL than toxicity scores comprising high-grade AEs only. To assess the effect of toxicity on QoL, patient-reported cumulative toxicity scores are preferred.

Long-term oncological outcomes after robotic partial nephrectomy for renal cell carcinoma: a prospective multicentre study.

PURPOSE: This study aimed at reporting the long-term oncological outcomes of robotic partial nephrectomy (RPN) for renal cell carcinoma (RCC). METHODS: Data from all consecutive patients who underwent RAPN for RCC from July 2009 to January 2012 in three departments of urology were prospectively collected. Overall survival (OS), cancer-specific survival (CSS) and disease free-survival (DFS) were estimated using the Kaplan-Meier method. Prognostic factors associated with CSS were sought in univariate analysis. The log-rank test was used for categorical variables and the Cox model for continuous variables. RESULTS: 110 patients were included with a median follow-up of 64.4 months [95% CI = (61.0-66.7)]. Median age was 61 years (29-83) with 62.7% of men and 37.3% of women. Median RENAL score was 6 (4-10) with elective indications accounting for 95% of cases. Out of 27 patients (24.5%) who experienced peri-operative complication, 12 patients (10.9%) had a major complication (Clavien-Dindo grade ≥ 3). The TRIFECTA achievement rate was 52.7%. Three patients (2.7%) experienced local recurrence and seven patients (6.4%) progressed to a metastatic disease. 5-year OS, CSS, DFS were 94.9, 96.8, 86.4%, respectively. In univariate analysis, no pre/peri-operative characteristic was associated with DFS. No port-site metastasis was observed and there was one case of peritoneal carcinomatosis. CONCLUSION: In this multicenter series, long-term OS, DFS and CSS after RPN appeared comparable to large series of open partial nephrectomy, with no port-site metastasis and one case of peritoneal carcinomatosis.

External validation of a nomogram for identification of pathologically favorable disease in intermediate risk prostate cancer patients.

OBJECTIVE: To establish an external validation of the new nomogram from Gandaglia et al which provides estimates of the probability of pathological favorable disease in pre-operatively defined intermediate-risk PCa. PATIENTS AND METHODS: Overall, 2928 intermediate-risk PCa patients according to the D'Amico classification undergoing RP and bilateral lymph node dissection in seven academic centres between 2000 and 2011. Pathologically favorable PCa was defined as low-grade organ-confined disease. The Receiver Operating Characteristic (ROC) curve was obtained to quantify the overall accuracy (Area Under the Curve, AUC) of the model to predict specimen-confined (SC) disease. Calibration curve was then constructed to illustrate the relationship between the risk-estimates obtained by the model and the observed proportion of SC disease. Kaplan-Meier method was used for PSA recurrence-free survival (PSA-RFS) assessment. RESULTS: Median age was 68 years. 10.6% patients finally presented pathologically favorable disease characteristics at RP. A higher PSAD (OR = 0.01; 95%CI = 0.00-0.04; P < 0.0001) and percentage of positive cores (OR = 0.97; 95%CI = 0.96-0.98; P < 0.0001) were associated with a reduced probability of favorable disease at RP in multivariate analysis. ROC curve analysis showed strongest accuracy of the model (AUC = 0.82; 95%CI = 0.79-0.84). Favorable PCa had a significantly better PSA recurrence-free survival rates as compared to unfavorable PCa after RP (94.2% vs 74.4% at 4 years, P < 0.0001). CONCLUSIONS: This external validation of the Gandaglia nomogram shows relevant accuracy with one out of ten patients in this intermediate risk PCa group with pathologically proven organ-confined disease. This validated risk calculator can help physician to distinguish favorable intermediate risk PCa that can be treated by conservative approach or safer nerve-sparing surgery.

Final results of the phase III URO-BCG 4 multicenter study: efficacy and tolerance of one-third dose BCG maintenance in nonmuscle invasive bladder cancer.

The objective of this study was to assess at 3 years bacillus Calmette-Guerin (BCG) maintenance treatment for NMIBC using one-third dose schedule and fewer instillations every 3 or 6 months. This was a phase III randomized study including patients with intermediate-risk or high-risk NMIBC, who received, after a full-dose induction schedule, three-weekly instillations of one-third dose BCG every 6 months (group I) and two-weekly instillations every 3 months (group II) during 3 years. We assessed oncological efficacy, BCG side effects, leukocyturia, and prostate-specific antigen. No tumor recurrence was reported at 36 months for 55 (82.09%) patients in group I versus 64 (90.14%) patients in group II (P=0.241). Muscle invasion was observed in six patients at 36 months (P=0.942). In terms of BCG toxicity, grade II and III local or systemic side effects were, respectively, reported in 8.7 and 23.9% of patients during the first year. Nevertheless, the adverse events (AEs) score at 36 months underlined a lower median value of 0.8 in group I versus 1.1 in group II (P=0.037). Furthermore, 9.9% major AEs occurred in group II versus 3% in group I (P=0.031). Leukocyturia and prostate-specific antigen level were not associated significantly with either tumor recurrence or muscle progression. We observed a significant difference in the AEs score at 36 months, suggesting less toxicity in patients who were treated with one-third dose of BCG for 3 consecutive weeks every 6 months.

Current impact of age and comorbidity assessment on prostate cancer treatment choice and over/undertreatment risk.

PURPOSE: We evaluated the influence of age and comorbidity (Charlson score assessment) on localized prostate cancer therapeutic management and the risk of prostate cancer over- and under-treatment. METHODS: Among the 2571 prostate cancer cases diagnosed in 2011, a subset of 633 patients was randomly selected from the prospectively accrued cohort of the Regional Cancer Registry, among the 17 participating institutions. Treatment distributions were examined for patients at each individual prostate cancer risk, age and comorbidity level and analyzed by multivariate logistic regression analysis. RESULTS: Treatments with curative intent were observed less often when age increased (p < 0.001). We found no impact of the Charlson score on the selection of a curative treatment [HR 0.89, 95 % CI (0.70-1.15)]. A 20 % overtreatment rate was reported in low-risk prostate cancer patients. For younger patients (65-75 years) with high comorbidity score, a 14 % overtreatment rate was observed. Conversely, a 16 % undertreatment rate was reported in older patients >75 years without any significant comorbidity. CONCLUSION: A better consideration of comorbidities could significantly reduce overtreatment in patients <75 year and promote curative treatment in aggressive prostate cancer for older patients without any significant comorbidity.