PRDM10 directs FLCN expression in a novel disorder overlapping with Birt-Hogg-Dubé syndrome and familial lipomatosis.

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder characterized by fibrofolliculomas, pulmonary cysts, pneumothoraces and renal cell carcinomas. Here, we reveal a novel hereditary disorder in a family with skin and mucosal lesions, extensive lipomatosis and renal cell carcinomas. The proband was initially diagnosed with BHD based on the presence of fibrofolliculomas, but no pathogenic germline variant was detected in FLCN, the gene associated with BHD. By whole exome sequencing we identified a heterozygous missense variant (p.(Cys677Tyr)) in a zinc-finger encoding domain of the PRDM10 gene which co-segregated with the phenotype in the family. We show that PRDM10Cys677Tyr loses affinity for a regulatory binding motif in the FLCN promoter, abrogating cellular FLCN mRNA and protein levels. Overexpressing inducible PRDM10Cys677Tyr in renal epithelial cells altered the transcription of multiple genes, showing overlap but also differences with the effects of knocking out FLCN. We propose that PRDM10 controls an extensive gene program and acts as a critical regulator of FLCN gene transcription in human cells. The germline variant PRDM10Cys677Tyr curtails cellular folliculin expression and underlies a distinguishable syndrome characterized by extensive lipomatosis, fibrofolliculomas and renal cell carcinomas.

The impact of the COVID-19 pandemic on renal cancer care.

PURPOSE: To evaluate the impact of the COVID-19 pandemic on renal cell carcinoma (RCC) care in the Netherlands. METHODS: Newly diagnosed RCCs between 2018 and 2021 were selected from the Netherlands Cancer Registry; 2020-2021 was defined as COVID period and 2018-2019 as reference period. Numbers of RCCs were evaluated using 3-week-moving averages, overall and by disease stage and age. Changes in treatment were evaluated with logistic regression analyses. To evaluate possible delays in care, time to start of treatment was assessed. The cumulative number of metastatic RCC (mRCC) over time was assessed to evaluate stage shift. RESULTS: During the 1st COVID wave (weeks 9-22, 2020), the number of new RCC diagnoses decreased with 15%. Numbers restored partially in 2020, but remained 10% lower compared to 2018/2019. The decline was mostly due to a drop in T1a/T1b RCCs and in age > 70 years. 2021 showed similar numbers of new RCC diagnoses compared to 2018/2019 without an increase due to previously missed RCCs. Treatment-related changes during the 1st COVID wave were limited and temporarily; less surgery in T1a RCCs in favor of more active surveillance, and in mRCC targeted therapy was preferred over immunotherapy. Time to start of firstline treatment was not prolonged during the 1st COVID wave. No increase in mRCC was found until the end of 2021. CONCLUSIONS: The COVID-19 pandemic resulted in fewer RCC diagnoses, especially T1a/T1b tumors. Treatment-related changes appeared to be limited, temporarily and in accordance with the adapted guidelines. The diagnostic delay could lead to more advanced RCCs in later years but there are no indications for this yet.

Positioning the role of urine cytology within the diagnostic pathway for UTUC: supportive but inconclusive.

PURPOSE: With the introduction of kidney-sparing surgery (KSS) for low-risk Upper Tract Urothelial Carcinoma (UTUC), correct risk-stratification has become crucial. High-grade cytology is one of the decisive variables to stratify a tumor as high-risk. To position the role of urine cytology in the diagnostic pathway of UTUC patients, we evaluated the accuracy of urine cytology by comparing the outcomes with histopathology. METHOD: Patients with UTUC evaluated between 2010 and 2020, and diagnosed by imaging, cytology and histopathology were selected. Descriptive statistics were used to compare cytology with histopathological outcomes using crosstabs. Clinical performance characteristics of cytology were determined for the presence of a malignancy. RESULTS: This study included 176 patients with confirmed histopathological UTUC. Concordance between cytology and biopsy results was found in 14.8% of low-grade tumors and 16.8% of high-grade tumors. Comparing cytology with radical nephroureterectomy (RNU) specimens revealed concordance rates of 1.6% for low-grade tumors and 22.9% for high-grade tumors. Notably, 51.1% of urine cytology results were false negative. Sensitivity for detecting high-grade and low-grade tumors with a positive urine cytology was 56.6% and 52.6%, respectively, with specificities of 54.8% and 37.2%. CONCLUSION: In the current study, cytology appears to exhibit limited reliability when used as a sole diagnostic tool for assessing tumor grade and consequently risk stratification. It is imperative to recognize these limitations, optimize urine sampling techniques, and leverage a combination of diverse diagnostic methods for the most effective and individualized treatment decision-making.

Surgical outcomes and proposal for a treatment algorithm for urethral strictures in transgender men.

OBJECTIVES: To assess our results of surgical treatment for urethral strictures in transgender men, and to provide a surgical treatment algorithm. PATIENTS AND METHODS: A single centre, retrospective cohort study was conducted of transgender men who underwent surgical correction of their urethral stricture(s) between January 2013 and March 2020. The medical charts of 72 transgender men with 147 urethral strictures were reviewed. The primary outcomes were the success and recurrence rates after surgical treatment for urethral strictures. RESULTS: The median (interquartile range [IQR]) follow-up was 61 (25-202) months. At last follow-up, 50/72 (69%) were able to void while standing (after one [60%], two [20%], three [6%], four [8%], five [4%], or seven [2%] procedures), 10/72 (14%) await further treatment, two of the 72 (3%) sat to void despite good urodynamic function, and 10/72 (14%) had a definitive urethrostomy. Of 104 surgical treatments included in separate success rate analysis, 65 (63%) were successful (43/75 [57%] after phalloplasty, 22/29 [76%] after metoidioplasty). The highest success rates in short urethral strictures were seen after a Heineke-Mikulicz procedure (six of seven cases), and in longer or more complicated urethral strictures after two-stage with graft (four of six), two-stage without graft (10/12), pedicled flap (11/15, 73%), and single-stage graft (seven of seven) urethroplasties. Grafts used were buccal mucosa or full-thickness skin grafts. Success rates improved over time, with success rates of 38% and 36% in 2013 and 2014, to 71% and 73% in 2018 and 2019, respectively. We concluded with a surgical treatment algorithm based on previous literature, stricture characteristics, and our surgical outcomes. CONCLUSION: The highest success rates were seen after a Heineke-Mikulicz procedure in short urethral strictures; and after graft, pedicled flap, or two-stage urethroplasties in longer or more complicated urethral strictures. Finally, most of the transgender men were able to void while standing, although in some multiple surgical procedures were necessary to accomplish this.

Standardised uptake values as determined on prostate-specific membrane antigen positron emission tomography/computed tomography is associated with oncological outcomes in patients with prostate cancer.

OBJECTIVES: To investigate the association between intraprostatic, intratumoral maximum standardised uptake values (SUVmax ) on prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) in patients with prostate cancer (PCa) prior to robot-assisted radical prostatectomy (RARP) and pathology outcomes, including pathological International Society of Urological Pathology score (pISUP) and lymph node (LN) status (pN0/pN1). PATIENTS AND METHODS: A bi-centric, secondary analysis of two previous, prospective cohort studies was performed in 318 patients with biopsy confirmed PCa and who were scheduled for RARP. Before surgery, patients received a PSMA PET/CT with either 68 Ga-PSMA-11 (59% of the patients) or 18 F-PSMA (DCFPyL; 41%) as radiotracer. PET/CT images were analysed both visually and semi-quantitatively by measuring the SUVmax of the most intense suspect lesion in the prostate. The association between the SUVmax of the primary tumour and pre- and postoperative variables was analysed. RESULTS: The SUVmax was associated with clinical and biopsy preoperative variables, as well as with pISUP score and pathological tumour stage. Patients with a pISUP of ≤2 showed significantly lower SUVmax compared to patients with a pISUP of >2 for both tracers (SUVmax18 F-PSMA: median 5.1 vs 9.6, P = 0.002; SUVmax68 Ga-PSMA-11: 6.6 vs 8.6, P = 0.003). Moreover, patients with pN1 had significantly higher median SUVmax than those with pN0/pNx for both tracers (SUVmax18 F-PSMA: 7.9 vs 12.3, P = 0.04; SUVmax68 Ga-PSMA-11: 7.6 vs 12.0, P < 0.001). On multivariable logistic regression analysis, the intraprostatic SUVmax was an independent predictor of pN1 for both 68 Ga-PSMA-11 (per doubling: odds ratio [OR] 1.96, 95% confidence interval [CI] 1.27-3.01)) and 18 F-PSMA (per doubling: OR 1.79, 95% CI 1.06-3.03). CONCLUSION: Intraprostatic, intratumoral PSMA intensity on PET/CT, as semi-quantitatively expressed by SUVmax , may be a valuable innovative biomarker in patients with localised PCa, as it is highly associated with known conventional prognostic factors, such as pISUP and LN status.

Incidence of testicular cancer in trans women using gender-affirming hormonal treatment: a nationwide cohort study.

OBJECTIVE: To assess the incidence of testicular cancer in trans women (male sex assigned at birth, female gender identity) using gender-affirming hormonal treatment. PATIENTS AND METHODS: Data of trans women starting hormonal treatment at our gender identity clinic between 1972 and 2017 were linked to the national pathology database to obtain testicular cancer diagnoses. The standardised incidence ratio (SIR) was calculated using the number of observed testicular cancer cases in our cohort and the number of expected cases based on age-specific Dutch incidence rates. Subgroup analyses were performed in testicular tissues sent for histopathological analysis at the time of bilateral orchidectomy, and when follow-up exceeded 5 years. RESULTS: The cohort consisted of 3026 trans women with a median follow-up time of 2.3 interquartile range (IQR) (1.6-3.7) years. Two testicular cancer cases were identified whilst 2.4 cases were expected (SIR 0.8, 95% confidence interval 0.1-2.8). In addition, one testicular cancer case was encountered in an orchidectomy specimen (0.1%). In the 523 trans women with a follow-up time of >5 years (median [IQR] 8.9 [6.4-13.9] years), no testicular cancer was observed. CONCLUSION: Testicular cancer risk in trans women is similar to the risk in cis men. The testicular cancer cases occurred within the first 5 years after commencing hormonal treatment, and the percentage of cases encountered at the time of bilateral orchidectomy was low. As no testicular cancer was observed in trans women with a long follow-up period, long-term hormonal treatment does not seem to increase testicular cancer risk.

The Predictive Value of Preoperative Negative Prostate Specific Membrane Antigen Positron Emission Tomography Imaging for Lymph Node Metastatic Prostate Cancer.

PURPOSE: We sought to identify a subset of patients in whom an extended pelvic lymph node dissection during robot-assisted laparoscopic radical prostatectomy for localized prostate cancer could be omitted when preoperative prostate specific membrane antigen positron emission tomography showed no lymph node metastatic prostate cancer. MATERIALS AND METHODS: A total of 434 patients who underwent prostate specific membrane antigen positron emission tomography prior to robot-assisted laparoscopic radical prostatectomy and extended pelvic lymph node dissection were retrospectively analyzed. Patients were excluded from analysis when the prostate specific membrane antigen positron emission tomography showed evidence of distant metastases. The primary outcome was whether a negative for metastases prostate specific membrane antigen positron emission tomography was able to correctly rule out pelvic lymp node metastases after extended pelvic lymph node dissection, ie its negative predictive value. RESULTS: Overall sensitivity, specificity, positive predictive value and negative predictive value of prostate specific membrane antigen positron emission tomography for the detection of pelvic lymp node metastases were 37.9%, 94.1%, 64.3% and 84.4%, respectively. The negative predictive value of prostate specific membrane antigen positron emission tomography in patients with intermediate risk prostate cancer was 91.6% (95% CI 86-97), compared to 81.4% (95% CI 77-86) in patients with high risk prostate cancer. When only assessing patients with

Prostate Specific Membrane Antigen Positron Emission Tomography/Computerized Tomography in the Evaluation of Initial Response in Candidates Who Underwent Salvage Radiation Therapy after Radical Prostatectomy for Prostate Cancer.

PURPOSE: We assessed predictors of short-term oncologic outcomes of patients who underwent salvage radiation therapy for biochemical recurrence after robot-assisted laparoscopic radical prostatectomy without evidence of metastases on prostate specific membrane antigen positron emission tomography/computerized tomography. MATERIALS AND METHODS: We retrospectively analyzed 194 patients with biochemical recurrence after robot-assisted laparoscopic radical prostatectomy who underwent prostate specific membrane antigen positron emission tomography/computerized tomography prior to salvage radiation therapy. Patients with lymph node or distant metastases on restaging imaging or at the time of extended pelvic lymph node dissection during robot-assisted laparoscopic radical prostatectomy were excluded, as were patients who received androgen deprivation therapy during or prior to salvage radiation therapy. A multivariable logistic regression analysis was performed to assess predictors of treatment response, defined as prostate specific antigen value ≤0.1 ng/ml after salvage radiation therapy. RESULTS: Overall treatment response after salvage radiation therapy was 75% (146/194 patients). On multivariable analysis, prostate specific antigen value at initiation of salvage radiation therapy (OR 0.42, 95% CI 0.27-0.62, p <0.001), pathological T stage (pT3a vs pT2 OR 0.28, 95% CI 0.11-0.69, p=0.006; pT3b vs pT2 OR 0.26, 95% CI 0.09-0.71, p=0.009) and local recurrent disease on imaging (OR 5.53, 95% CI 1.96-18.52, p=0.003) were predictors of treatment response. CONCLUSIONS: Salvage radiation therapy in patients without evidence of metastases on prostate specific membrane antigen positron emission tomography/computerized tomography showed a good overall treatment response of 75%. Higher treatment response rates were observed in patients with lower prostate specific antigen values at initiation of salvage radiation therapy, those with local recurrent disease on imaging and those with lower pathological T stage (pT2 vs pT3a/b).

Management impact of 18F-DCFPyL PET/CT in hormone-sensitive prostate cancer patients with biochemical recurrence after definitive treatment: a multicenter retrospective study.

PURPOSE: The aim of this study was to investigate whether an early, accurate identification of disease using 18F-DCFPyL PET/CT imaging resulted in a change of decision on treatment management, for individual patients with biochemically recurrent (BCR), hormone-sensitive prostate cancer. METHODS: In this retrospective study, a total of 253 patients with BCR who underwent restaging 18F-DCFPyL PET/CT were assessed. Two urologists specialized in uro-oncology were asked to formulate a preferred treatment for each patient before and after knowing the results of the 18F-DCFPyL PET/CT. RESULTS: Out of 253 patients, 191 (75%) underwent robot-assisted radical prostatectomy (RARP) as primary therapy, and 62 (25%) external beam radiation therapy (EBRT). In 103/253 cases (40.7%), a preferred treatment change based on the 18F-DCFPyL PET/CT findings was reported. In patients post-RARP, a positive 18F-DCFPyL PET/CT (OR 6.21; 95%CI 2.78-13.8; p < 0.001) and positive pathological lymph node status (pN1) (OR 2.96; 95%CI 1.15-7.60; p = 0.024) were significant predictors for an intended change of management, whereas a positive surgical margin (OR 0.42; 95%CI 0.20-0.88; p = 0.022) was inversely associated with an intended change of management. CONCLUSION: In this study, we found a significant impact of 18F-DCFPyL PET/CT on the intended management of patients with biochemically recurrent hormone-sensitive prostate cancer. A positive 18F-DCFPyL PET/CT scan, positive pathological lymph node status, and a negative surgical margin status were significantly associated with increased odds of having a change of management based on 18F-DCFPyL PET/CT findings.

A systematic review on mutation markers for bladder cancer diagnosis in urine.

OBJECTIVES: To systematically summarise the available evidence on urinary bladder cancer (BC) mutation markers. Gene mutations are expected to provide novel biomarkers for urinary BC diagnosis. To date, evidence on urinary BC mutation markers has not proven sufficient to be adopted by clinical guidelines. In the present systematic review, diagnostic accuracy of urinary mutation analysis is separately assessed for primary BC diagnosis (BC detection) and for follow-up of BC patients (BC surveillance). METHODS: A literature search (PubMed, Embase.com and Wiley/Cochrane Library) and systematic review was performed up to 31 October 2019. As studies were too heterogeneous, no quantitative analysis could be performed. RESULTS: In total, 25 studies were summarised by qualitative analysis. For BC detection, diagnostic accuracy differed considerably for single mutation markers (sensitivity 1-85%, specificity 84-100%), and for marker panels (sensitivity 50-94%, specificity 43-97%). Similarly, for BC surveillance, diagnostic accuracy was highly variable for single mutation markers (sensitivity 0-85%, specificity 66-100%), and for marker panels (sensitivity 51-84%, specificity 66-96%). CONCLUSION: Urinary mutation analysis showed to be a promising diagnostic tool for non-invasive BC diagnosis. Nonetheless, we observed substantial differences in diagnostic accuracy of urinary BC mutation markers among publications. To translate the data summarised in the present review to future clinical practice, heterogeneity in research design, BC population, mutation analysis technique and urinary DNA should be considered. Eventual clinical implementation of urinary BC mutation markers can only be achieved by collecting more and stronger evidence. Combining different molecular assays might overcome current shortcomings of urinary mutation analysis.

Hospital volume is associated with postoperative mortality after radical cystectomy for treatment of bladder cancer.

OBJECTIVE: To contribute to the debate regarding the minimum volume of radical cystectomies (RCs) that a hospital should perform by evaluating the association between hospital volume (HV) and postoperative mortality. PATIENTS AND METHODS: Patients who underwent RC for bladder cancer between 1 January 2008 and 31 December 2018 were retrospectively identified from the Netherlands Cancer Registry. To create a calendar-year independent measure, the HV of RCs was calculated per patient by counting the RCs performed in the same hospital in the 12 months preceding surgery. The relationship of HV with 30- and 90-day mortality was assessed by logistic regression with a non-linear spline function for HV as a continuous variable, which was adjusted for age, tumour, node and metastasis (TNM) stage, and neoadjuvant treatment. RESULTS: The median (interquartile range; range) HV among the 9287 RC-treated patients was 19 (12-27; 1-75). Of all the included patients, 208 (2.2%) and 518 (5.6%) died within 30 and 90 days after RC, respectively. After adjustment for age, TNM stage and neoadjuvant therapy, postoperative mortality slightly increased between an HV of 0 and an HV of 25 RCs and steadily decreased from an HV of 30 onwards. The lowest risks of postoperative mortality were observed for the highest volumes. CONCLUSION: This paper, based on high-quality data from a large nationwide population-based cohort, suggests that increasing the RC volume criteria beyond 30 RCs annually could further decrease postoperative mortality. Based on these results, the volume criterion of 20 RCs annually, as recently recommended by the European Association of Urology Guideline Panel, might therefore be reconsidered.

The Surgical Techniques and Outcomes of Secondary Phalloplasty After Metoidioplasty in Transgender Men: An International, Multi-Center Case Series.

INTRODUCTION: Some transgender men express the wish to undergo genital gender-affirming surgery. Metoidioplasty and phalloplasty are procedures that are performed to construct a neophallus. Genital gender-affirming surgery contributes to physical well-being, but dissatisfaction with the surgical results may occur. Disadvantages of metoidioplasty are the relatively small neophallus, the inability to have penetrative sex, and often difficulty with voiding while standing. Therefore, some transgender men opt to undergo a secondary phalloplasty after metoidioplasty. Literature on secondary phalloplasty is scarce. AIM: Explore the reasons for secondary phalloplasty, describe the surgical techniques, and report on the clinical outcomes. METHODS: Transgender men who underwent secondary phalloplasty after metoidioplasty were retrospectively identified in 8 gender surgery clinics (Amsterdam, Belgrade, Bordeaux, Austin, Ghent, Helsinki, Miami, and Montreal). Preoperative consultation, patient motivation for secondary phalloplasty, surgical technique, perioperative characteristics, complications, and clinical outcomes were recorded. MAIN OUTCOME MEASURE: The main outcome measures were surgical techniques, patient motivation, and outcomes of secondary phalloplasty after metoidioplasty in transgender men. RESULTS: Eighty-three patients were identified. The median follow-up was 7.5 years (range 0.8-39). Indicated reasons to undergo secondary phalloplasty were to have a larger phallus (n = 32; 38.6%), to be able to have penetrative sexual intercourse (n = 25; 30.1%), have had metoidioplasty performed as a first step toward phalloplasty (n = 17; 20.5%), and to void while standing (n = 15; 18.1%). Each center had preferential techniques for phalloplasty. A wide variety of surgical techniques were used to perform secondary phalloplasty. Intraoperative complications (revision of microvascular anastomosis) occurred in 3 patients (5.5%) undergoing free flap phalloplasty. Total flap failure occurred in 1 patient (1.2%). Urethral fistulas occurred in 23 patients (30.3%) and strictures in 27 patients (35.6%). CLINICAL IMPLICATIONS: A secondary phalloplasty is a suitable option for patients who previously underwent metoidioplasty. STRENGTHS & LIMITATIONS: This is the first study to report on secondary phalloplasty in collaboration with 8 specialized gender clinics. The main limitation was the retrospective design. CONCLUSION: In high-volume centers specialized in gender affirming surgery, a secondary phalloplasty in transgender men can be performed after metoidioplasty with complication rates similar to primary phalloplasty. Al-Tamimi M, Pigot GL, van der Sluis WB, et al. The Surgical Techniques and Outcomes of Secondary Phalloplasty After Metoidioplasty in Transgender Men: An International, Multi-Center Case Series. J Sex Med 2019;16:1849-1859.

Value of a Marker Lesion in Non-Muscle-Invasive Bladder Cancer Patients Treated with Interleukin-2 Instillations: A Randomized Controlled Multicentre Trial.

PURPOSE: To compare the effect of intravesical interleukin-2 (IL-2) instillations with and without a marker lesion on time to recurrence (TTR) in non-muscle-invasive bladder cancer (NMIBC) patients. METHODS: A prospective randomized, controlled trial was conducted. Patients with multiple non-muscle-invasive tumours were randomized for a complete or incomplete transurethral resection (TURBT), followed by 3 IL-2 instillations. The primary end point was TTR. RESULTS: These are the results of an interim analysis, which was performed due to slow accrual after which the study was closed prematurely. Twenty-eight patients were randomized of which 17 were eligible on an intention-to-treat basis. Median TTR or last follow-up was 3 months (interquartile range [IQR] 3-10 months) for the complete and 4 months (IQR 3-8 months) for the incomplete TURBT group. The TTR between the 2 groups did not differ significantly (log-rank, p = 0.54). -Conclusions: These data do not support the hypothesis that a marker lesion enhances the therapeutic effect of IL-2 instillations in patients with NMIBC.

Consensus on molecular imaging and theranostics in prostate cancer.

Rapid developments in imaging and treatment with radiopharmaceuticals targeting prostate cancer pose issues for the development of guidelines for their appropriate use. To tackle this problem, international experts representing medical oncologists, urologists, radiation oncologists, radiologists, and nuclear medicine specialists convened at the European Association of Nuclear Medicine Focus 1 meeting to deliver a balanced perspective on available data and clinical experience of imaging in prostate cancer, which had been supported by a systematic review of the literature and a modified Delphi process. Relevant conclusions included the following: diphosphonate bone scanning and contrast-enhanced CT are mentioned but rarely recommended for most patients in clinical guidelines; MRI (whole-body or multiparametric) and prostate cancer-targeted PET are frequently suggested, but the specific contexts in which these methods affect practice are not established; sodium fluoride-18 for PET-CT bone scanning is not widely advocated, whereas gallium-68 or fluorine-18 prostate-specific membrane antigen gain acceptance; and, palliative treatment with bone targeting radiopharmaceuticals (rhenium-186, samarium-153, or strontium-89) have largely been replaced by radium-223 on the basis of the survival benefit that was reported in prospective trials, and by other systemic therapies with proven survival benefits. Although the advances in MRI and PET-CT have improved the accuracy of imaging, the effects of these new methods on clinical outcomes remains to be established. Improved communication between imagers and clinicians and more multidisciplinary input in clinical trial design are essential to encourage imaging insights into clinical decision making.

The effect of timing of an immediate instillation of mitomycin C after transurethral resection in 941 patients with non-muscle-invasive bladder cancer.

OBJECTIVE: To investigate whether the timing of an immediate instillation of mitomycin C (on the day of transurethral resection of bladder tumour [TURBT] or 1 day later) has an impact on time to recurrence of non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: All patients with NMIBC who were enrolled in a prospective trial between 1998 and 2003, and treated with an early mitomycin C instillation (on the day of TURBT or 1 day later), were selected. Statistical analysis was performed with Kaplan-Meier curves and multivariable Cox regression. RESULTS: Administering an instillation of mitomycin C on the day of TURBT or 1 day later did not show a statistically significant difference in time to recurrence in a univariable model (log-rank P = 0.99). After correcting for the number of scheduled adjuvant instillations, no statistically significant difference could be detected either: hazard ratio 1.05 (95% confidence interval 0.81-1.35, P = 0.74). CONCLUSION: These data do not support the hypothesis that a very early instillation (on the day of TURBT) of mitomycin C decreases the risk of recurrence as compared with an early instillation (1 day after TURBT).

First-line non-cytotoxic therapy in chemotherapy-naive patients with metastatic castration-resistant prostate cancer: a systematic review of 10 randomised clinical trials.

The aim of this study is to systematically evaluate all available treatment options in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC). We systematically searched PubMed, EMBASE, and the Cochrane libraries up to 1 March 2016 for peer-reviewed publications on randomised clinical trials (RCTs). RCTs were included if progression-free survival (PFS), overall survival (OS), quality of life (QoL), or adverse events (AEs) were quantitatively evaluated. We assessed the risk of bias with the Cochrane Collaboration's tool and graded the evidence with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group's approach. We included 25 articles, reporting on 10 unique RCTs describing seven different comparisons. In one RCT, a prolonged OS and PFS (high quality) were found with abiraterone and prednisone compared to placebo plus prednisone. In one RCT, a prolonged OS and PFS (high quality) were found with enzalutamide compared to placebo. In two RCTs, a prolonged OS (high and moderate quality) was found with 223 radium compared to placebo, but its effect on PFS is unknown. In three RCTs, a prolonged OS (moderate quality) was found with sipuleucel-T compared to placebo, but no prolonged PFS (low quality). In one RCT a prolonged PFS (high quality) was found with orteronel compared to placebo, but no prolonged OS (moderate quality). In one RCT, a prolonged OS (moderate quality) was found with bicalutamide compared to placebo, but its effect on PFS is unknown. In one RCT, a prolonged PFS (high quality) was found with enzalutamide compared to bicalutamide, but its effect on OS is unknown. The best evidence was found for abiraterone and enzalutamide for effective prolongation of OS and PFS to treat chemotherapy-naive patients with mCRPC. However, taking both QoL and AEs into consideration, other treatment modalities could be considered for individual patients.