Background Active surveillance (AS)/watchful waiting (WW) strategy for localized prostate cancer (PCa) is increasingly and broadly endorsed as a preferred option for initial treatment of men with very low- and low-risk PCa, but outcomes can be difficult to analyze in traditional, population-based registries. The recently released Surveillance, Epidemiology, and End Results (SEER) Prostate with WW dataset provides an opportunity to understand national patterns and trends in AS/WW, but the data source itself has not been well described. Objective To provide a comprehensive description of this dataset and investigate possible biases due to missing data. Design, setting, and participants The SEER is a population-based epidemiologic registry in the USA. Newly diagnosed PCa patient data were collected from 18 SEER registries between 2010 and 2015, with inclusion of a new treatment variable for AS/WW. We identified 316 724 patients in the entire cohort and 257 060 men with clinically localized PCa (T1-2N0M0). Intervention Various primary treatments for PCa. Outcome measurements and statistical analysis The degree of missing data for each variable was measured. In order to investigate possible bias due to missing data for cancer characterization, we compared two versions of the data: one that excluded cases with missing data and one dataset generated applying multiple imputations. Results and limitations Only 46% of cases had complete data on basic cancer characteristics for risk stratification. The excluded dataset (N = 118 821) differed significantly from the multiple imputation dataset (N = 257 060) in the distribution of every reported variable (all p < 0.001). The dataset does not distinguish WW from AS, which is a limitation. Conclusions While the SEER Prostate with WW dataset offers a new method to describe treatment trends for men with PCa, including the use of AS/WW, the amount of missing data should not be ignored. Patient summary While the Surveillance, Epidemiology, and End Results Prostate with Watchful Waiting dataset offers a new method to describe treatment trends for men with prostate cancer, including the use of active surveillance, it has a significant amount of missing data, which can be a source of potential bias if not addressed properly.

Background In patients with rare histologies of bladder cancer, including adenocarcinoma of the bladder (ACB) and squamous-cell carcinoma (SCC), there are limited standard therapy options, defining an unmet medical need. Objective In this comparative comprehensive genomic profiling (CGP) study, genomic alterations (GAs), and immuno-oncology (IO) biomarkers have been analyzed. Design, setting, and participants Within the Foundation Medicine database, 143 cases with centrally reviewed pure ACB, 2142 with pure urothelial carcinoma (UC), and 83 with pure SCC were subjected to CGP. All patients developed advanced disease following a primary diagnosis of bladder cancer. Intervention CGP using a hybrid capture–based assay and immunohistochemistry (IHC). Outcome measurements and statistical analysis Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA, and microsatellite instability (MSI) was determined on 114 loci. Programmed cell-death ligand-1 (PD-L1) expression was determined by IHC (Ventana SP-142 assay), with >1% tumor cells (TCs) or tumor-infiltrating lymphocytes (TILs) scoring positive. Results and limitations Pure ACB patients were younger and more often female than pure UC and pure SCC patients. UC and SCC had a significantly higher median TMB than ACB (p < 0.001). Rare CD274 (PD-L1) amplification cases were more frequently seen in SCC than in UC (5% vs 1%), and were not seen in ACB. MSI high status was very uncommon in all tumor types (0–1%). The frequencies of PD-L1 expression in both TCs and TILs was higher in UC and SCC (both 30%) than in ACB (18%). The results are limited by their retrospective nature and lack of clinical data annotation. Conclusions Deep sequencing revealed significant differences in IO biomarkers among the three major subtypes of bladder carcinomas. UC and SCC revealed higher frequencies of PD-L1 expression and higher TMB than ACB, and SCC has the highest frequency of CD274 amplification. The presence of pure SCC features should not disqualify patients for inclusion in IO trials. Patient summary Tumor samples from patients diagnosed with advanced pure adenocarcinoma of the bladder (ACB) or pure squamous-cell carcinoma (SCC) have been analyzed in terms of frequency of putative immunotherapy biomarkers. The results indicated that pure SCC of the bladder was characterized by genomic features that portend similar response possibilities to immunotherapy compared with the classical pure urothelial carcinoma. Conversely, for pure ACB there might be different therapeutic opportunities, such as targeted therapies against peculiar genomic alterations in selected patients.

Background Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic condition characterized by chronic pelvic pain related to the bladder with no effective treatment options. Objective To evaluate the efficacy and safety of transurethral resection (TUR) and transurethral coagulation (TUC) as treatments for Hunner lesion (HL) in IC/BPS. Design, setting, and participants A single-center, prospective, randomized controlled trial involving 126 patients with HL in IC/BPS. Intervention TUR or TUC. Outcome measurements and statistical analysis Primary outcome was recurrence-free time after surgery. Secondary outcomes included change of the number of frequency, nocturia, urgency episodes in voiding diaries, O’Leary-Sant Interstitial Cystitis Symptom Index (ICSI) and Interstitial Cystitis Problem Index (ICPI), pelvic pain and urgency/frequency (PUF) symptom scale, and visual analog scale (VAS) for pain and risk factors for recurrence. Results and limitations There were no differences in the recurrence-free time between treatment groups, a difference of 12.2 mo (95% confidence interval [CI], 11.1–17.6) for TUR, and a difference of 11.5 mo (95% CI, 9.03–16.1; p = 0.735) for TUC. No difference was found in decreased mean daytime frequency, nocturia, urgency episodes, ICSI, ICPI, PUF symptom scale, and VAS for pain between both groups over 12 mo. Regardless of treatment types, there were significant improvements in all symptom questionnaires and pain compared with baseline (all, p < 0.05). Treatment type (TUR or TUC), age, sex, previous history of hydrodistension, and number of HLs did not affect recurrence. Incidence of bladder injury was higher in the TUR group (7.9%) than in the TUC group (3.4%). Conclusions There was no difference in the recurrence-free time and effect on urinary symptoms, including pain between TUC and TUR, for HL. Taking into account procedure-related complications, the surgeon can choose the method with which he/she is most familiar and comfortable. Patient summary In patients with bladder pain syndrome with Hunner lesions, both endoscopic resection and coagulation of the lesions are effective treatments.

Background Since the implementation of robotic surgery, the platforms have been updating constantly in terms of arm configuration, tool design, scope settings, and the number of trocars placed. The introduction of new robotic technology is challenging and requires studies followed by technique adaptions. Objective This study aims to report a logical and technologically safe approach to the learning curve using the da Vinci single-port (SP) console and describes our robotic-assisted radical prostatectomy (RARP) technique step by step. Design, setting, and participants A prospective study from 26 consecutive patients who underwent RARP with the da Vinci SP console from June to August 2019. Surgical procedure All surgeries were performed with a transperitoneal technique; one robotic trocar was placed above the umbilicus and one additional 12 mm trocar was placed in the right lower quadrant. Measurements We described the step-by-step technique and reported the perioperative and pathological data. In addition, we considered the hospital length of stay and pain scale following surgery. Continuous variables were reported as median and interquartile ranges. Categorical variables were reported as frequencies and proportions. Result and limitations The total median operative time was 121 min, console time was 85 min, and blood loss was 50 ml. No complications were reported. In the final pathology, four patients had Gleason 6, 20 had Gleason 7, one had Gleason 8, and one had Gleason 9.Of the patients, 70% were ≤pT2 and 30% were ≥pT3a. Only 11% had positive surgical margins. This study is limited by the small number of patients and a short period of follow-up to evaluate functional and oncological outcomes of this new technology. Conclusions RARP with the da Vinci SP is feasible and safe. Therefore, the step-by-step technique described in this study could be considered an option to perform radical prostatectomies. However, we still need better-designed studies to compare the outcomes with those of the multiport platform. Patient summary We reported our step-by-step technique describing a safe approach to robotic-assisted radical prostatectomy during the transition from the Xi to the da Vinci single-port robot.

Background Androgen deprivation therapy improves the survival of castration-resistant prostate cancer (CRPC) patients, yet ultimately fails with debilitating side effects. Supraphysiological testosterone (SPT)-based therapy produces clinical responses with improved quality of life in a subset of patients. Currently, no information defines a durable response to SPT. Objective To identify key molecular phenotypes underlying SPT response to improve patient selection and guide combination treatment to achieve a durable response. Design, setting, and participants A patient-derived xenograft (PDX) preclinical trial was performed with 13 CRPC PDXs to identify molecular features associated with SPT response. Comprehensive intratumoral androgen, tumor growth, and integrated transcriptomic and protein analyses were performed in three PDXs resistant to the newer androgen receptor (AR) pathway inhibitor enzalutamide (ENZ) to define SPT response and resistance. Intervention Testosterone cypionate. Outcome measurements and statistical analysis SPT efficacy was evaluated by PDX growth, prostate-specific antigen (PSA) change, and survival. Intratumoral androgens were analyzed using mass spectrometry. Global transcriptome analysis was performed using RNA sequencing, and confirmed by quantitative real-time polymerase chain reaction and immunohistochemistry. Log-rank and Mann-Whitney tests were used for survival and molecular analyses, respectively. Results and limitations A durable SPT responder was identified, presenting robust repressions of ARv7 and E2F transcriptional outputs, and a DNA damage response (DDR) transcriptomic program that were altogether restored upon SPT resistance in the transient responder. ENZ rechallenge of SPT-relapsed PDXs resulted in PSA decreases but tumor progression. Conclusions SPT produces a durable response in AR-pathway inhibitor ENZ CRPC that is associated with sustained suppression of ARv7 and E2F transcriptional outputs, and the DDR transcriptome, highlighting the potential of combination treatments that maintain suppression of these programs to drive a durable response to SPT. Patient summary Patients with ENZ-resistant prostate cancer have very limited treatment options. Supraphysiological testosterone presents a prominent option for improved quality of life and a potential durable response in patients with sustained suppression on ARv7/E2F transcriptional outputs and DNA repair program.

Background Recently, robot-assisted kidney transplantation (RAKT) was recently introduced as renal replacement mini-invasive surgery. Objective To report surgical technique, including tips and tricks, and the learning curve for RAKT. Design, setting, and participants All consecutive RAKTs performed in the five highest-volume centers of the European Robotic Urological Society RAKT group were reviewed, and a step-by-step description of the technique was compiled. Surgical procedure Surgeries were performed with Da Vinci Si/Xi. The patient was placed in the lithotomy position. The Trendelenburg position was set at 20–30° and the robot was docked between the legs. Measurements Shewhart control charts and cumulative summation (CUSUM) graphs and trifecta were generated to assess the learning curve according to rewarming time (RWT), intra/postoperative complications, and renal graft function (glomerular filtration rate) on days 7 and 30, and at 1 yr. Linear regressions were performed to compare the learning curves of each surgeon. Results and limitations Arterial anastomosis time was below the alarm/alert line in 93.3%/88.9% of RAKTs, while venous anastomosis time was below the alarm/alert line in 88.9%/73.9%. The nonanastomotic RWT exceeded +3 standard deviation (SD) in 24.7% of procedures and +2SD in 37.1%. In only 46% cases, the RWT was below the alert line. The ureteroneocystostomy time was below +2SD and +3SD in 87.9% and 90.2% of cases, respectively. CUSUM showed that the learning curve for arterial anastomosis required up to 35 (mean = 16) cases. Complications and delayed graft function rates decreased significantly and reached a plateau after the first 20 cases. Trifecta was achieved in 75% (24/32) of the cases after the first 34 RAKTs in each center. Conclusions A minimum of 35 cases are necessary to reach reproducibility in terms of RWT, complications, and functional results. Patient summary Robot-assisted kidney transplantation requires a learning curve of 35 cases to achieve reproducibility in terms of timing, complications, and functional results. Synergy between the surgeon and the assistant is crucial to reduce rewarming time. High-grade complications and delayed graft function are rare after ten surgeries. Hands-on training and proctorship are highly recommended.

Background The Veterans Affairs Cooperative Studies Program study #553 was designed to evaluate the efficacy of adjuvant chemotherapy added to the standard of care (SOC) for patients who are at high risk for relapse after prostatectomy. Objective To test whether addition of chemotherapy to surgery for high-risk prostate cancer improves progression-free survival (PFS). Design, setting, and participants Eligible patients after prostatectomy were randomized to the SOC group with observation or to the chemotherapy group with docetaxel and prednisone administered every 3 wk for six cycles. Randomization was stratified for prostate-specific antigen, Gleason, tumor stage, and surgical margin status. Outcome measurements and statistical analysis The primary endpoint was PFS. Secondary endpoints included overall, prostate cancer–specific, and metastasis-free survival, and time to androgen deprivation therapy. Results and limitations A total of 298 of the planned 636 patients were randomized. The median follow-up was 59.1 mo (0.2–103.7 mo). For the primary endpoint, the two groups did not statistically differ in PFS (median 55.5 mo in the chemotherapy group and 42.2 mo in the SOC group; test adjusted for site via gamma frailty p = 0.21; adjusted hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.58–1.11; p = 0.18). Prespecified subgroup analyses showed benefit in PFS for patients with tumor stage ≥T3b (HR 0.54, 95% CI 0.32–0.92; p = 0.022) and patients with Gleason score ≤7 (HR 0.65, 95% CI 0.43–0.99; p = 0.046). Secondary endpoint analyses are hampered by low event rates. The most common adverse events (≥grade 3 related or possibly related to chemotherapy) included neutropenia (43%), hyperglycemia (20%), and fatigue (5%), with febrile neutropenia in 2%. Conclusions Adjuvant chemotherapy in high-risk prostate cancer using docetaxel and prednisone did not lead to statistically significant improvement in PFS for the intention-to-treat population as a whole. The analysis was challenged by lower power due to accrual limitation. Subgroup analyses suggest potential benefit for patients with Gleason grade ≤7 and stage ≥ pT3b (ClinicalTrials.gov number NCT00132301). Patient summary In this randomized trial, we tested whether addition of chemotherapy to surgery for high-risk prostate cancer decreased the risk of prostate-specific antigen rise after surgery. We found no benefit from docetaxel given after radical prostatectomy, although some subgroups of patients may benefit.

Background Active surveillance (AS) is the preferred management option for most men with grade group (GG) 1 prostate cancer (PCa). Questions persist regarding long-term outcomes and the optimal approach to AS. Objective To determine survival and metastatic outcomes in AS patients. Secondary objectives were to measure the cumulative incidence and association of patient-level factors on biopsy grade reclassification. Design, setting, and participants A prospective, active, open-enrollment cohort study was conducted from 1995 through July 2018 at a tertiary-care academic institution. Patients with very-low-risk or low-risk PCa were enrolled. Intervention AS with semiannual prostate-specific antigen (PSA) and digital rectal examination, serial prostate biopsy, and multiparametric magnetic resonance imaging (mpMRI). Outcome measurements and statistical analysis The 10- and 15-yr cumulative incidences of primary and secondary outcomes were determined. Results and limitations Overall, 1818 men were monitored on AS for a median of 5.0 yr (interquartile range 2.0–9.0). There were 88 non-PCa deaths, four PCa deaths, and one additional case of metastasis. The cumulative incidence of PCa-specific mortality or metastasis was 0.1% (95% confidence interval, 0.04–0.6%) at both 10 and 15 yr. The 5-, 10-, and 15-yr cumulative incidences of biopsy grade reclassification were 21%, 30%, and 32%, respectively. On multivariable analysis, biopsy grade reclassification was associated with older age, African-American race, PSA density, and increased cancer volume on biopsy, and men who underwent mpMRI prior to enrollment were less likely to undergo grade reclassification. Our selection and monitoring are more stringent than many other contemporary AS programs. Conclusions In a large, single-institution, prospective AS cohort, the risk of cancer death or metastasis was <1% over long-term follow-up. Consistent with clinical guidelines, these data support the use of AS for the management of most men diagnosed with GG1 PCa. Patient summary This study investigated long-term outcomes in patients with grade group 1 prostate cancer managed with active surveillance (AS). Ten years after enrolling in AS, the risk of metastasis or death from prostate cancer was <1%, while 48% of men switched to treatment. Patients who underwent multiparametric magnetic resonance imaging (mpMRI)/ultrasound-fusion targeted biopsy prior to enrollment were less likely to experience biopsy grade reclassification during follow-up, suggesting a role for mpMRI as part of a comprehensive risk assessment to confirm AS eligibility. These findings support the safety of AS in most men with grade group 1 prostate cancer, but specific outcomes may differ in programs with less intensive monitoring.

No data are available on the surgical safety of radical cystectomy (RC) and pelvic lymph node dissection (PLND) after the administration of checkpoint inhibitors. We aimed at reporting the first prospective rigorous assessment of perioperative outcomes after RC and extended PLND following neoadjuvant pembrolizumab in a contemporary cohort of patients with muscle-invasive bladder cancer (MIBC) enrolled in the PURE-01 trial. From February 2017 to June 2019, a total of 68 consecutive patients who received three courses of 200 mg pembrolizumab intravenously every 3 wk and were subsequently treated with either open or robot-assisted RC and PLND at a single high-volume tertiary referral center were identified. All men had prospectively collected data about intra- and postoperative outcomes. Postoperative complications were graded according to the Clavien-Dindo system. Perioperative data were prospectively and systematically collected during patient interviews at 90 d after surgery according to the European Association of Urology (EAU) Guidelines Panel recommendations on reporting and grading complications. Overall, 52 (77%) versus 16 (23%) patients underwent robot-assisted versus open RC, and 31 patients (46%) received an orthotopic neobladder. Median blood loss and length of stay were 150 ml and 12 d, respectively. Overall, 52 (77%), 47 (69%), and 22 (32%) patients experienced any-grade complications, grade ≥2 complications, and readmission at 90 d, respectively. High-grade complications (defined as Clavien-Dindo ≥3a) were observed in 23 patients (34%). The most frequent complications were fever (n = 35, 52%) and ileus (n = 21, 31%). None of the patients experienced perioperative mortality at 90 d. Our data represent the first prospective evidence supporting the surgical safety of RC and PLND in patients with N0M0 MIBC who received neoadjuvant immunotherapy with pembrolizumab. Patient summary The current study represents the first prospective evidence supporting the surgical safety of radical cystectomy and pelvic lymph node dissection in patients with nonmetastatic bladder cancer who received neoadjuvant immunotherapy with pembrolizumab.

Background Standard management in the UK for high-risk stage 1 nonseminoma germ cell tumours of the testis (NSGCTT) is two cycles of adjuvant bleomycin, etoposide (360 mg/m2), and cisplatin (BE360P) chemotherapy, or surveillance. Objective To test whether one cycle of BE500P achieves similar recurrence rates to two cycles of BE360P. Design, setting, and participants A total of 246 patients with vascular invasion–positive stage 1 NSGCTT or combined seminoma + NSGCTT were centrally registered in a single-arm prospective study. Intervention One cycle comprising bleomycin 30000 IU on days 1, 8, and 15, etoposide 165 mg/m2 on days 1–3, and cisplatin 50 mg/m2 on days 1–2, plus antibacterial and granulocyte colony stimulating factor prophylaxis. Outcome measurements and statistical analysis The primary endpoint was 2-yr malignant recurrence (MR); the aim was to exclude a rate of ≥5%. Participants had regular imaging and tumour marker (TM) assessment for 5 yr. Results and limitations The median follow-up was 49 mo (interquartile range 37–60). Ten patients with rising TMs at baseline were excluded. Four patients had MR at 6, 7, 13, and 27 mo; all received second-line chemotherapy and surgery and three remained recurrence-free at 5 yr. The 2-yr MR rate was 1.3% (95% confidence interval 0.3–3.7%). Three patients developed nonmalignant recurrences with localised teratoma differentiated, rendered disease-free after surgery. Grade 3–4 febrile neutropenia occurred in 6.8% of participants. Conclusions BE500P is safe and the 2-yr MR rate is consistent with that seen following two BE360P cycles. The 111 study is the largest prospective trial investigating one cycle of adjuvant BE500P in high-risk stage 1 NSGCTT. Adoption of one cycle of BE500P as standard would reduce overall exposure to chemotherapy in this young population. Patient summary Removing the testicle fails to cure many patients with high-risk primary testicular cancer since undetectable cancers are often present elsewhere. A standard additional treatment in Europe is two cycles of chemotherapy to eradicate these. This trial shows one cycle has few adverse effects and comparable outcomes to those seen with two cycles.

Background Despite technical improvements introduced with robotic surgery, management of complex tumours (PADUA score ≥10) is still a matter of debate within the field of transperitoneal robot-assisted partial nephrectomy (RAPN). Objective To evaluate the accuracy of our three-dimensional (3D) static and elastic augmented reality (AR) systems based on hyperaccuracy models (HA3D) in identifying tumours and intrarenal structures during transperitoneal RAPN (AR-RAPN), compared with standard ultrasound (US). Design, setting, and participants A retrospective study was conducted, including 91 patients who underwent RAPN for complex renal tumours, 48 with 3D AR guidance and 43 with 2D US guidance, from July 2017 to May 2019. Surgical procedure In patients who underwent 3D AR-RAPN, virtual image overlapping guided the surgeon during resection and suture phases. In the 2D US group, interventions were driven by US only. Measurements Patient characteristics were tested using the Fisher’s exact test for categorical variables and the Mann-Whitney test for continuous ones. Intraoperative, postoperative, and surgical outcomes were collected. All results for continuous variables were expressed as medians (range), and frequencies and proportions were reported as percentages. Results and limitations The use of 3D AR guidance makes it possible to correctly identify the lesion and intraparenchymal structures with a more accurate 3D perception of the location and the nature of the different structures relative to the standard 2D US guidance. This translates to a lower rate of global ischaemia (45.8% in the 3D group vs 69.7% in the US group; p = 0.03), higher rate of enucleation (62.5% vs 37.5% in the 3D and US groups, respectively; p = 0.02), and lower rate of collecting system violation (10.4% vs 45.5%; p = 0.003). Postoperatively, 3D AR guidance use correlates to a low risk of surgery-related complications in 3D AR groups and a lower drop in estimated renal plasma flow at renal scan at 3 mo of follow-up (–12.38 in the 3D group vs –18.14 in the US group; p = 0.01). The main limitations of this study are short follow-up time and small sample size. Conclusions HA3D models that overlap in vivo anatomy during AR-RAPN for complex tumours can be useful for identifying the lesion and intraparenchymal structures that are difficult to visualise with US only. This translates to a potential improvement in the quality of the resection phase and a reduction in postoperative complications, with better functional recovery. Patient summary Based on our findings, three-dimensional augmented reality robot-assisted partial nephrectomy seems to help surgeons in the management of complex renal tumours, with potential early postoperative benefits.

Background In the PURE-01 study, pembrolizumab was given preoperatively before radical cystectomy in clinical T2-4aN0M0 patients. An accurate clinical response assessment may be useful for developing new perioperative strategies in these patients. Objective To evaluate the association between bladder multiparametric magnetic resonance imaging (mpMRI) findings after pembrolizumab and the pathological complete response (CR; pT0). Design, setting, and participants Patients were staged using bladder mpMRI whereby radiologists were asked to characterize the following parameters: residual disease at T1- and T2-weighted images (step 1: yes/no), presence of hyperintense spots within the bladder wall on diffusion-weighted imaging (step 2: yes/no), and presence of pathological contrast enhancement (step 3: yes/no), before and after three cycles of pembrolizumab. Examinations were internally assessed by two senior radiologists and externally evaluated by a third senior radiologist. Intervention To evaluate bladder tumor response after neoadjuvant pembrolizumab, mpMRI was used. Outcome measurements and statistical analysis The primary objective was to predict the pT0 after neoadjuvant pembrolizumab by relying on the mpMRI findings. Cohen’s kappa statistics was used to assess interobserver variability. Univariable analyses for pT0 were performed including internal and external post-therapy mpMRI steps. Results and limitations From February 2017 to October 2018, 82 patients (164 total mpMRI assessments) were analyzed. The agreement between the internal and external mpMRI assessments after therapy was acceptable (κ values ranging from 0.5 to 0.76). Each mpMRI step was significantly associated with pT0 in both internal and external assessments. In patients with CR/no evidence of residual disease (NED) in all internally evaluated mpMRI steps (N = 37), the pT0 was seen in 23 (62%), compared with 19 of 26 externally evaluated NED patients (73%). Conclusions In post-pembrolizumab muscle-invasive bladder cancer, mpMRI sequence assessment had acceptable interobserver variability and represented the basis for the proposal of a radiological CR/NED status definition predicting the pT0 response to pembrolizumab. After validation of these findings with external datasets, we propose this tool for developing bladder-sparing immunotherapy maintenance therapies. Patient summary Assessment of the extent of disease in patients with muscle-invasive bladder cancer using conventional imaging yields serious limitations. In the PURE-01 study, we evaluated the potential of bladder multiparametric magnetic resonance imaging (MRI) to predict the pathological complete response to neoadjuvant pembrolizumab. After validation with larger datasets, the proposed stepwise assessment incorporating multiparametric MRI sequences will be used at our center to develop bladder-sparing approaches in future studies.

Background Active surveillance (AS) protocols rely on rectal examination, prostate-specific antigen, imaging, and biopsy to identify disease progression. Objective To evaluate whether an AS regimen based on magnetic resonance imaging (MRI) or clinical stage changes can detect reclassification to grade group (GG) ≥2 disease compared with scheduled systematic biopsies. Design, setting, and participants We identified a cohort of men initiated on AS between January 2013 and April 2016 at a single tertiary-care center. Patients completed confirmatory testing and prostate MRI prior to enrollment, then underwent laboratory and physical evaluation every 6 mo, MRI every 18 mo, and biopsy every 3 yr. Outcome measurements and statistical analysis MRI results were evaluated using composite Likert/Prostate Imaging Reporting and Data System v2 scoring. MRI and clinical changes were assessed for association with disease progression. Univariable and multivariable regression models were used to predict upgrading on 3-yr biopsy. Results and limitations At 3 yr, of 207 men, 66 (32%) had ≥ GG2 at biopsy: 55 (83%) with GG2, 10 (15%) with GG3, and one (1.5%) with GG4. Among patients with a 3-yr MRI score of ≥3, 41% had ≥ GG2 disease, compared with 15% with an MRI score of <3 (p = 0.0002). The MRI score increased in 48 men (23%), decreased in 27 (13%), and was unchanged in 132 (64%) men. Increases in MRI score were not associated with reclassification after adjusting for the 3-yr MRI score (p = 0.9). Biopsying only for an increased MRI score or clinical stage would avoid 681 biopsies per 1000 men, at the cost of missing ≥GG2 disease in 169 patients. Conclusions An AS strategy that uses MRI or clinical changes to trigger prostate biopsy avoids many biopsies but misses an unacceptable amount of clinically significant disease. Prostate biopsy for men on AS should be performed at scheduled intervals, regardless of stable imaging or examination findings. Patient summary An active surveillance strategy for biopsy based only on increases in magnetic resonance imaging score or clinical stage will avoid many biopsies; however, it will miss many patients with clinically significant prostate cancer.

Background No standard therapy has been established for localised prostate cancer patients with prostate-specific antigen (PSA) failure after radical prostatectomy (RP). Objective To determine whether radiotherapy ± hormone therapy is superior to hormone therapy alone in such patients. Design, setting, and participants This study is a multicentre, randomised, open-label, phase 3 trial. Patients with localised prostate cancer whose PSA concentrations had decreased to <0.1 ng/ml after RP, and then increased to 0.4–1.0 ng/ml, were randomised to the salvage hormone therapy (SHT) group (80 mg bicalutamide [BCL] followed by luteinising hormone-releasing hormone agonist in case of BCL failure) or the salvage radiation therapy (SRT) ± SHT group (64.8 Gy of SRT followed by the same regimen as in the SHT group in case of SRT failure). From May 2004 to May 2011, 210 patients (105 in each arm) were registered, with the median follow-up being 5.5 yr. Outcome measurements and statistical analysis The primary endpoint was time to treatment failure (TTF) of BCL. Results and limitations TTF of BCL was significantly longer in the SRT ± SHT group (8.6 yr) than in the SHT group (5.6 yr; hazard ratio 0.56, 90% confidence interval [0.40–0.77]; one-sided p = 0.001). Thirty-two of 102 patients (31%) in the SRT ± SHT group did not have SRT treatment failure. However, clinical relapse-free survival and overall survival did not differ between the arms. The most frequent grade 3–4 adverse event was erectile dysfunction (83 patients [80%] in the SHT group vs. 76 [74%] in the SRT ± SHT group). Limitations include the short follow-up periods and surrogate endpoint setting to allow definitive conclusions. Conclusions Initial SRT prolongs TTF of BCL in patients with post-RP PSA failure, indicating that SRT ± SHT is more beneficial than SHT alone. Patient summary Patients who have prostate-specific antigen failure after radical prostatectomy benefit from salvage radiation therapy prior to salvage hormone therapy.

Background LATITUDE, a randomized, double-blind trial, compared abiraterone acetate and prednisone (AAP) + androgen deprivation therapy (ADT) versus placebo (PBO) + ADT in high-risk metastatic castration-sensitive prostate cancer (mCSPC). Objective To assess the correlation of prostate-specific antigen (PSA) kinetics with overall survival (OS) and radiological progression-free survival (rPFS). Design, setting, and participants A post hoc analysis of data from 597 men receiving AAP + ADT and 602 receiving PBO + ADT. Outcome measurements and statistical analysis The associations of PSA-related outcomes (rates of confirmed 50% [PSA50] and 90% [PSA90] decline from baseline PSA [Prostate Cancer Working Group 2 criteria], rates of PSA < 0.2 ng/ml, median nadir PSA, time to PSA nadir [TPN], and time to PSA progression [TPP] with long-term outcomes [OS and rPFS]) were evaluated. Hazard ratios (HRs) were estimated using Cox proportional hazard model. Correlations of TPP with coprimary endpoints rPFS and OS were evaluated using Kendall’s tau (KT). Results and limitations AAP + ADT significantly delayed median TPP versus PBO + ADT (33.2 vs 7.4 mo; HR: 0.3, p < 0.001). TPP correlated with rPFS (KT = 0.921) and OS (KT = 0.666). In the AAP + ADT group, 91% had PSA50 and 79% had PSA90 responses (relative risk [RR]: 1.36 and 2.30, respectively; p < 0.001 for both comparisons vs PBO + ADT). Compared with nonresponders, PSA50 and PSA90 responders had reduced risk of death (RR: 0.44 and 0.12, respectively). At 6 mo, 40% receiving AAP + ADT and 6.5% receiving PBO + ADT achieved PSA ≤0.1 ng/ml, which was significantly associated with longer rPFS and OS. Median nadir PSA was 0.09 ng/ml with AAP + ADT versus 2.36 ng/ml with PBO + ADT. Median TPN (AAP + ADT, 6.4 mo; PBO + ADT, 3.8 mo) positively correlated with rPFS and OS. Conclusions Superior PSA response dynamics with AAP + ADT versus ADT + PBO strongly correlated with long-term outcomes of rPFS and OS in high-risk mCSPC. Patient summary We found that low prostate-specific antigen levels (≤0.1 ng/ml) after 6 mo may indicate a good long-term response to treatment. Our results need confirmation.

Background BC2001, the largest randomised trial of bladder-sparing treatment for muscle-invasive bladder cancer, demonstrated improvement of local control and bladder cancer–specific survival from the addition of concomitant 5-fluorouracil and mitomycin C to radiotherapy. Objective To determine the impact of treatment on the health-related quality of life (HRQoL) of BC2001 participants. Design, setting, and participants 458 UK patients with T2-T4a N0 M0 transitional cell carcinoma of the bladder. Intervention Patients were randomised to the chemotherapy comparison (radiotherapy, 178, or chemoradiotherapy, 182); and/or to the radiotherapy comparison (standard, 108, or reduced high-dose volume radiotherapy, 111). Outcome measurements and statistical analysis Patients completed Functional Assessment of Cancer Therapy—Bladder (FACT-BL) questionnaires at baseline, end of treatment (EoT), and 6, 12, 24, 36, 48, and 60 months after radiotherapy. The primary endpoint was change from baseline in the bladder cancer subscale (BLCS) at 12 months. Results and limitations Data were available for 331 (92%) and 204 (93%) participants at baseline and for 192 (54%) and 114 (52%) at 12 months for the chemotherapy and radiotherapy comparisons, respectively. HRQoL declined at EoT (BLCS –5.06 [99% confidence interval: –6.12 to –4.00, p < 0.001]; overall FACT-B TOTAL score –8.22 [–10.76 to –5.68, p < 0.01]), recovering to baseline at 6 months and remaining similar to baseline subsequently. There was no significant difference between randomised groups at any time point. Conclusions Immediately following (chemo)radiotherapy, a significant proportion of patients report declines in HRQoL, which improve to baseline after 6 months. Two-thirds of patients report stable or improved HRQoL on long-term follow-up. There is no evidence of impairment in HRQoL resulting from the addition of chemotherapy. Patient summary Quality of life of bladder cancer patients treated with radiotherapy ± chemotherapy deteriorates during treatment, but improves to at least pretreatment levels within 6 months. Addition of chemotherapy to radiotherapy does not affect patient-reported quality of life.

Background The role of elective whole-pelvis radiotherapy (WPRT) remains controversial. Few studies have investigated it in Gleason grade group (GG) 5 prostate cancer (PCa), known to have a high risk of nodal metastases. Objective To assess the impact of WPRT on patients with GG 5 PCa treated with external-beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT + BT). Design, setting, and participants We identified 1170 patients with biopsy-proven GG 5 PCa from 11 centers in the United States and one in Norway treated between 2000 and 2013 (734 with EBRT and 436 with EBRT + BT). Outcome measurements and statistical analysis Biochemical recurrence-free survival (bRFS), distant metastasis-free survival (DMFS), and prostate cancer-specific survival (PCSS) were compared using Cox proportional hazards models with propensity score adjustment. Results and limitations A total of 299 EBRT patients (41%) and 320 EBRT + BT patients (73%) received WPRT. The adjusted 5-yr bRFS rates with WPRT in the EBRT and EBRT + BT groups were 66% and 88%, respectively. Without WPRT, these rates for the EBRT and EBRT + BT groups were 58% and 78%, respectively. The median follow-up was 5.6 yr. WPRT was associated with improved bRFS among patients treated with EBRT + BT (hazard ratio [HR] 0.5, 95% confidence interval [CI] 0.2–0.9, p = 0.02), but no evidence for improvement was found in those treated with EBRT (HR 0.8, 95% CI 0.6–1.2, p = 0.4). WPRT was not significantly associated with improved DMFS or PCSS in the EBRT group (HR 1.1, 95% CI 0.7–1.7, p = 0.8 for DMFS and HR 0.7, 95% CI 0.4–1.1, p = 0.1 for PCSS), or in the EBRT + BT group (HR 0.6, 95% CI 0.3–1.4, p = 0.2 for DMFS and HR 0.5 95% CI 0.2–1.2, p = 0.1 for PCSS). Conclusions WPRT was not associated with improved PCSS or DMFS in patients with GG 5 PCa who received either EBRT or EBRT + BT. However, WPRT was associated with a significant improvement in bRFS among patients receiving EBRT + BT. Strategies to optimize WPRT, potentially with the use of advanced imaging techniques to identify occult nodal disease, are warranted. Patient summary When men with a high Gleason grade prostate cancer receive radiation with external radiation and brachytherapy, the addition of radiation to the pelvis results in a longer duration of prostate-specific antigen control. However, we did not find a difference in their survival from prostate cancer or in their survival without metastatic disease. We also did not find a benefit for radiation to the pelvis in men who received radiation without brachytherapy.

Background Wnt signaling is a cellular pathway involved in embryogenesis, development, and neoplasia. Wnt-pathway activation may accelerate prostate cancer androgen-independent growth and mediate antiandrogen resistance. Since 10–20% of advanced prostate cancers harbor Wnt-activating mutations, we aimed to characterize the clinical features and response to novel antiandrogens in such patients. Objective To determine whether men with metastatic castration-resistant prostate cancer (mCRPC) who harbor Wnt-pathway mutations have poorer responses to first-line novel hormonal therapies: abiraterone/enzalutamide. Design, setting, and participants Patients with mCRPC who received first-line abiraterone or enzalutamide were retrospectively evaluated. Using tumor DNA analyses, we queried for activating mutations in CTNNB1 or inactivating mutations in APC or RNF43, all of which are predicted to stimulate Wnt signaling. Presence or absence of at least one Wnt-activating alteration was correlated with clinical-pathologic characteristics and treatment outcomes. Outcome measurements and statistical analysis Time to prostate-specific antigen (PSA) progression, overall survival (OS), and PSA response were measured. Cox regression models were used to test associations between Wnt status and clinical-pathologic outcomes; Kaplan-Meier and log-rank analyses were used to compare time-to-event endpoints. Results and limitations Of 137 patients evaluated, 11% (n = 15) had tumor DNA analysis showing at least one Wnt-stimulating alteration. Patients with Wnt-activating mutations had numerically fewer T3/T4 tumors than Wnt wild-type patients (31% vs 51%), but were otherwise generally balanced. Median time to PSA progression on first-line abiraterone/enzalutamide was shorter in Wnt-activated patients (6.5 vs 9.6 mo, hazard ratio [HR] 2.34, p = 0.003), as was OS (23.6 vs 27.7 mo, HR 2.28, p = 0.01). PSA responses were numerically worse in Wnt-activated patients (53% vs 75%, p = 0.12). Presence of Wnt-activating alterations (adjusted HR [aHR] 2.33, p = 0.007) and use of previous chemotherapy (aHR 1.83, p = 0.004) were both independently associated with increased hazard of progression. Conclusions Patients with somatic Wnt-pathway activating mutations have worse outcomes to first-line abiraterone/enzalutamide than Wnt wild-type patients. Our data suggest that additional genomically informed therapies are needed for this relevant subset of mCRPC patients. Patient summary In this report, we retrospectively examined outcomes of metastatic prostate cancer patients with or without Wnt-pathway mutations who received abiraterone or enzalutamide for the first time, in order to examine whether these mutations affect the prognosis. Our study suggested that patients who have Wnt-pathway activating mutations derived less benefit from abiraterone and enzalutamide when compared to patients without these mutations. We conclude that Wnt-pathway mutations might decrease the effectiveness of abiraterone and enzalutamide, and we propose that the Wnt pathway might be a good therapeutic target for these patients, in order to potentially reverse or prolong resistance to abiraterone and enzalutamide in men with Wnt mutations.

Context Magnetic resonance imaging (MRI), with or without MRI-targeted biopsy (MRI pathway), is an alternative test to systematic transrectal ultrasonography-guided biopsy in men suspected of having prostate cancer. At present, evidence on which test to use is insufficient to inform detailed evidence-based decision making. Objective To determine the diagnostic accuracy of the index tests MRI only, MRI-targeted biopsy, MRI pathway, and systematic biopsy, as compared with template-guided biopsy (reference standard), in detecting clinically significant prostate cancer, defined as International Society of Urological Pathology grade 2 or higher, in biopsy-naive men or those with a prior-negative biopsy (or mix of both). Evidence acquisition We systematically searched the literature and considered for inclusion any cross-sectional study if it investigated (1) one or more index tests verified by the reference standard, and (2) paired testing of the MRI pathway with systematic biopsy. Quality and certainty of evidence were assessed by the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) and Grading of Recommendations Assessment, Development and Evaluation, respectively. Evidence synthesis Accuracy analyses: Using a baseline cancer prevalence of 30%, MRI pathway (sensitivity 0.72 [95% confidence interval {CI}: 0.60–0.82]; specificity 0.96 [0.94–0.98]; eight studies) may result in 216 (180–246) true positives, 28 (14–42) false positives, 672 (658–686) true negatives, and 84 (54–120) false negatives per 1000 men. Systematic biopsy (sensitivity 0.63 [0.19–0.93]; specificity 1.00 [0.91–1.00]; four studies) may result in 189 (57–279) true positives, 0 (0–63) false positives, 700 (637–700) true negatives, and 111 (21–243) false negatives per 1000 men. Agreement analyses: With a direct comparison of the MRI pathway with systematic biopsy concerning significant disease, we found pooled detection ratios of 1.05 (95% CI: 0.95–1.16; 20 studies) in biopsy-naive men and 1.44 (1.19–1.75; 10 studies) in men with a prior-negative biopsy. Concerning insignificant disease, we found detection ratios of 0.63 (95% CI: 0.54–0.74), and 0.62 (95% CI: 0.44–0.88), respectively. Conclusions MRI pathway had the most favourable outcome in significant and insignificant prostate cancer detection compared with systematic biopsy. The certainty in our findings was reduced by study limitations. Patient summary We reviewed recent advances in prostate biopsy by magnetic resonance imaging (MRI) guidance and targeting for prostate cancer detection in comparison with standard diagnosis by systematic biopsies. The findings of this Cochrane review suggest that MRI pathway is better than systematic biopsies in making a correct diagnosis of clinically important prostate cancer and reducing redundant biopsies and the detection of unimportant cancers substantially. However, MRI pathway still misses some men with important prostate cancer. Therefore, further research in this area is important.

Background Robot-assisted partial nephrectomy (RAPN) represents a widely accepted minimally invasive alternative to open and laparoscopic surgery for the treatment of clinically localized renal tumors. Objective To assess the feasibility of RAPN in a contemporary series of patients with highly complex tumors (PADUA score ≥10) treated at four high-volume robotic surgery institutions. Design, setting, and participants Data from a prospectively maintained multi-institutional database on patients subjected to RAPN between 2010 and 2017 were reviewed. For the scope of this analysis, only patients with highly complex renal tumors, defined as a PADUA score between 10 and 14, were included. Surgical procedure RAPN was performed with the da Vinci Si or Xi surgical system (Intuitive Surgical, Sunnyvale, CA, USA) using novel technologies such as TilePro and near-infrared fluorescence imaging. Measurements Intraoperative, postoperative, surgical, and oncological outcomes were collected. Predictors of optimal surgical outcomes defined according to the Margin Ischemia and Complications binary system (absence of Clavien-Dindo >2 complications, warm ischemia time [WIT] <20 min, and absence of positive surgical margins) were determined using logistic regression models (LRMs). Results and limitations Overall, 255 patients with complex renal tumors were included. The mean operative time was 165 min and mean WIT was 18.6 min. Overall, WIT was longer than 20 min in 86 (33.7%) individuals, while a Clavien-Dindo >2 complication and positive surgical margins were observed in 13 (5.1%) and four (out of 211 patients with malignant histotypes; 1.9%) individuals, respectively. Optimal surgical outcomes were achieved in 158 (62.0%) patients. At a median follow-up of 28 mo, one (0.4%) local and two (0.8%) distant recurrences of the disease were observed. In multivariable LRMs, extremely complex tumors (PADUA score 12–13) were associated with an increased likelihood of not achieving optimal outcomes (odds ratio: 2.31; p = 0.024). Besides tumor complexity, male gender was also associated with a two-fold higher risk of not achieving optimal surgical outcomes (p = 0.029). Conclusions In experienced hands, RAPN can be considered as an effective treatment option even in cases of complex renal lesions. However, increasing tumor complexity may affect the surgical outcomes in this highly selected patient population. Patient summary We reported our multicentric experience with robot-assisted partial nephrectomy (RAPN) in patients with complex renal tumors. We demonstrated that, in experienced hands, RAPN is a feasible and safe treatment option even in such patients. Novel technologies applied to RAPN may further extend the indications without compromising the outcomes.

Background Prostatic artery embolisation (PAE) has been associated with an improvement of lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH), but conclusive evidence of efficacy from randomised controlled clinical trials has been lacking. Objective To assess the safety and efficacy of PAE compared with a sham procedure in the treatment of LUTS/BPH. Design, setting, and participants A randomised, single-blind, sham-controlled superiority clinical trial was conducted in 80 males ≥45 yr with severe LUTS/BPH refractory to medical treatment from 2014 to 2019 in a private clinic, with efficacy assessments at 6 and 12 mo after randomisation. One patient in the PAE group and three in the sham group did not complete the study. Intervention Patients were randomised 1:1 upon successful catheterisation of a prostatic artery to either PAE or a sham PAE procedure without embolisation. After 6 mo, all 38 patients randomised to the sham group who completed the single-blind period underwent PAE, and both groups completed a 6-mo open period. Outcome measurements and statistical analysis An intention-to-treat analysis of all randomised patients was performed. The coprimary outcomes were the change from baseline to 6 mo in the International Prostate Symptom Score (IPSS) and the quality of life (QoL) score at 6 mo, analysed with analysis of covariance and t test, respectively. Results and limitations Mean age was 63.8 ± 6.0 yr, baseline IPSS 26.4 ± 3.87, and QoL score 4.43 ± 0.52. At 6 mo, patients in the PAE arm had a greater improvement in IPSS, with a difference in the change from baseline of 13.2 (95% confidence interval [CI] 10.2–16.2, p < 0.0001), and a better QoL score at 6 mo (difference: 2.13; 95% CI 1.57–2.68, p < 0.0001) than the patients in the sham arm. The improvements in IPSS and QoL in the sham group 6 mo after they performed PAE were, respectively, 13.6 ± 9.19 (p < 0.0001) and 2.05 ± 1.71 (p < 0.0001). Adverse events occurred in 14 (35.0%) patients after PAE and in 13 (32.5%) after sham, with one serious adverse event in the sham group during the open period. No treatment failures occurred. Limitations include a single-centre trial, only severe LUTS/BPH, and follow-up limited to 12 mo. Conclusions The improvements in subjective and objective variables after PAE are far superior from those due to the placebo effect. Patient summary Clearly superior efficacy of prostatic artery embolisation (PAE) compared with a sham procedure was found in this study, which supports the use of PAE in patients with typical symptoms associated with benign prostatic hyperplasia.

Background After a lesion has been assessed adequately on multiparametric magnetic resonance imaging (mpMRI), magnetic resonance (MR)-guided biopsy (MRGB) is the logical next step. The choice of the MRGB technique, however, is difficult. Objective To show the advantages and disadvantages of the three commonly used MRGB techniques—MRI-ultrasound fusion MRGB (fus-MRGB), direct in-bore MRGB (inbore-MRGB), and cognitive MRGB (cog-MRGB), and to determine when each of the techniques can be used. Design, setting, and participants Based on expert opinion and literature overview, the advantages, disadvantages, and challenges of fus-MRGB, inbore-MRGB, and cog-MRGB are evaluated. Further, the clinical setting of each biopsy strategy is assessed. Surgical procedure Based on expert opinion and literature data, the three biopsy procedures are evaluated, and the important pros and cons are determined. Measurements The basic concept of each biopsy technique is reviewed, which would result in a clinical recommendation. This will be shown in individual patients. Results and limitations The accompanying video shows how fus-MRGB and inbore-MRGB are performed in our hospital. An important advantage of fus-MRGB is its generally availability; however, it has fusion-error limitations. Although not supported by evidence, inbore-MRGB seems to be better suited for smaller lesions, but is rather expensive. Cog-MRGB is easy to use and inexpensive, but is more operator dependent as it requires knowledge about both ultrasound and MR images. Readers should be aware that our MRGB approach is largely based on expert opinion and, where possible, supported by evidence. Conclusions This article and the accompanying video show different MRGB techniques. The advantages and disadvantages of the three biopsy techniques, as well as the clinical setting in which each biopsy strategy is being used in our hospital, are discussed. Fus-MRGB is our first choice for prostate biopsy. Direct inbore-MRGB is used in difficult lesions but is mainly used as a “problem solver” (eg, a negative biopsy with a high suspicion for clinically significant prostate cancer). In our opinion, cog-MRGB is best for sampling larger and diffuse lesions. Patient summary This third surgery in motion contribution shows our approach in magnetic resonance (MR)-guided biopsy (MRGB). Fusion MRGB is our first choice for prostate biopsy. In-bore MRGB is used in selected, difficult cases, mainly as a problem solver. In our point of view, cognitive MRGB seems to be best for sampling larger lesions and diffuse processes.

Context Non-visible haematuria (NVH) is a common finding and may indicate undiagnosed urological cancer. The optimal investigation of NVH is unclear, given the incidence of cancer and the public health implications of testing all individuals with this finding. Objective We review contemporary literature to determine the association of NVH with the diagnosis of bladder cancer (BC), upper tract urothelial carcinoma (UTUC), and kidney cancer (KC). Evidence acquisition A systematic review of original articles in English was completed in May 2019. Meta-analyses for the diagnostic accuracy of NVH and urine cytology were performed. Evidence synthesis We screened 1529 articles and selected 78 manuscripts that fulfilled our inclusion criteria for narrative synthesis. Forty manuscripts were eligible for a meta-analysis (reporting 19 193 persons). The likelihood of a urological cancer in patients with NVH increased with age (<1% in those aged <40 yr), male sex, and cigarette smoking. Less than 1% of patients are found to have a urological cancer after a negative NVH evaluation. Cancer detection rates in individuals evaluated for NVH ranged from 0% to 16% for BC in 37 studies, 0% to 3.5% for UTUC in 30 studies, and 0% to 9.7% for KC in 29 studies. Substantial statistical heterogeneity was present for the meta-analysis of detection rates. Conclusions We present an up-to-date review of the association of NVH with the diagnosis of BC, UTUC, and KC. Individuals with dipstick positive haematuria aged ≥40 yr, who have had potential precipitating causes excluded, should undergo an evaluation. Re-evaluation of patients with unremarkable initial investigations should be performed in high-risk patients or if new symptoms occur. Patient summary One in five people have microscopic traces of blood in their urine. This is an important indicator of urological cancer. Investigating all patients is uncomfortable and expensive. We evaluate the risk of cancer and estimate risks to groups of individuals.

Background A surgical adverse incident (AI) is defined as any deviation from the normal operative course. Current complication-grading systems mostly focus on postoperative events. Objective To propose an intraoperative AI classification (EAUiaiC) to facilitate reporting. Design, setting, and participants The classification was developed using a modified Delphi process in which experts answered two rounds of survey questionnaires organised by the European Association of Urology ad hoc Complications Guidelines Panel. Experts evaluated AI terminology using a 5-point Likert scale for clarity, exhaustiveness, hierarchical order, mutual exclusivity, clinical utility, and quality improvement. Outcome measures and statistical analysis We considered ≥70% agreement for inclusion or exclusion. The resultant EAUiaiC was evaluated using ten sample clinical scenarios. Numerical and graphical statistical techniques were used to report the results. Results and limitations In total, 343 respondents participated. The proposed EAUiaiC system comprises eight AI grades ranging from grade 0 (no deviation and no consequence to the patient) to grade 5B (wrong surgery site or intraoperative death). In the validation stage, EAUiaiC was rated highly favourably in terms of relevance and reliability (consistency) by 126 experts. Ratings for self-reported ease of use were at acceptable levels. Conclusions We propose a novel intraoperative AI classification (EAUiaiC) for use for urological procedures. Both the initial assessment of feasibility and the subsequent assessment of reliability suggest that it is a simple and effective tool for classifying intraoperative complications. Patient summary Complications in surgery are common. It is helpful to classify complications in a uniform and objective manner so that surgeons can easily compare outcomes and learn from complications. Here we propose a new classification system for complications that occur during urological surgical procedures. An abstract of this work was presented at the 2018 congress of the European Association of Urology.

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common.

Background There is large variability among radiologists in their detection of clinically significant (cs) prostate cancer (PCa) on multiparametric magnetic resonance imaging (mpMRI). Objective To reduce the interpretation variability and achieve optimal accuracy in assessing prostate mpMRI. Design, setting, and participants How the interpretation of mpMRI can be optimized is demonstrated here. Whereas part 1 of the “surgery-in-motion” paper focused on acquisition, this paper shows the correlation between (ab)normal prostate anatomical structures and image characteristics on mpMRI, and how standardized interpretation according to Prostate Imaging Reporting and Data System version 2 (PI-RADS v2) should be performed. This will be shown in individual patients. Surgical procedure To detect csPCa, three mpMRI “components” are used: “anatomic” T2-weighted imaging, “cellular-density” diffusion-weighted imaging, and “vascularity” dynamic contrast-enhanced MRI. Measurements Based on PI-RADS v2, the accompanying video shows how mpMRI interpretation is performed. Finally, the role of mpMRI in detecting csPCa is briefly discussed and the main features of the recently introduced PI-RADS v2.1 are evaluated. Results and limitations With PI-RADS v2, it is possible to quantify normal and abnormal anatomical structures within the prostate based on its imaging features of the three mpMRI “components.” With this knowledge, a more objective evaluation of the presence of a csPCa can be performed. However, there still remains quite some space to reduce interobserver variability. Conclusions For understanding the interpretation of mpMRI according to PI-RADS v2, knowledge of the correlation between imaging and (ab)normal anatomical structures on the three mpMRI components is needed. Patient summary This second surgery-in-motion contribution shows what structures can be recognized on prostate magnetic resonance imaging (MRI). How a radiologist performs his reading according to the so-called Prostate Imaging Reporting and Data System criteria is shown here. The main features of these criteria are summarized, and the role of prostate MRI in detecting clinically significant prostate cancer is discussed briefly.

Background Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. Objective To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management. Design A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts prior to voting during a consensus conference. Setting Online Delphi survey and consensus conference. Participants The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management. Outcome measurements and statistical analysis Statements were ranked by experts according to their level of agreement: 1–3 (disagree), 4–6 (equivocal), and 7–9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus). Results and limitations Overall, 116 statements were included in the Delphi survey. Of these statements, 33 (28%) achieved level 1 consensus and 49 (42%) achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease, and the evolving role of checkpoint inhibitor therapy in metastatic disease. Conclusions These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time when further evidence is available to guide our approach. Patient summary This report summarises findings from an international, multistakeholder project organised by the EAU and ESMO. In this project, a steering committee identified areas of bladder cancer management where there is currently no good-quality evidence to guide treatment decisions. From this, they developed a series of proposed statements, 71 of which achieved consensus by a large group of experts in the field of bladder cancer. It is anticipated that these statements will provide further guidance to health care professionals and could help improve patient outcomes until a time when good-quality evidence is available.

Background Stereotactic body radiotherapy (SBRT) and elective nodal radiotherapy (ENRT) are being investigated as metastasis-directed treatments in oligorecurrent prostate cancer (PC); however, comparative data are still lacking. Objective To compare outcome and toxicity between both treatments. Primary endpoint was metastasis-free survival, adjusted for selected variables (aMFS). Design, setting, and participants This was a multi-institutional, retrospective analysis of 506 (SBRT: 309, ENRT: 197) patients with hormone-sensitive nodal oligorecurrent PC (five or fewer lymph nodes (LNs; N1/M1a), treated between 2004 and 2017. Median follow-up was 36 mo (interquartile range 23–56). Intervention SBRT was defined as a minimum of 5 Gy per fraction to each lesion with a maximum of 10 fractions. ENRT was defined as a minimum dose of 45 Gy in up to 25 fractions to the elective nodes, with or without a simultaneous boost to the suspicious node(s). The choice of radiotherapy (RT) was at the discretion of the treating physician, with treatments being unbalanced over the centers. Outcome measurements and statistical analysis In total, 506 patients from 15 different treatment centers were included. Primary treatment was radical prostatectomy, RT, or their combination. Nodal recurrences were detected by positron emission tomography/computer tomography (97%) or conventional imaging (3%). Descriptive statistics was used to summarize patient characteristics. Results and limitations ENRT was associated with fewer nodal recurrences compared with SBRT (p < 0.001). In a multivariable analysis, patients with one LN at recurrence had longer aMFS after ENRT (hazard ratio: 0.50, 95% confidence interval 0.30–0.85, p = 0.009). Late toxicity was higher after ENRT compared with that after SBRT (16% vs. 5%, p < 0.01). Limitations include higher use of hormone therapy in the ENRT cohort and nonstandardized follow-up. Conclusions ENRT reduces the number of nodal recurrences as compared with SBRT, however at higher toxicity. Our findings hypothesize that ENRT should be preferred to SBRT in the treatment of nodal oligorecurrences. This hypothesis needs to be evaluated in a randomized trial. Patient summary This study investigated the difference between stereotactic and elective nodal radiotherapy in treating limited nodal metastatic prostate cancer. Nodal relapse was less frequent following elective nodal radiotherapy than following stereotactic body radiotherapy, and thus elective nodal radiotherapy might be the preferred treatment.

Background Valid health utility values are essential for comparative effectiveness analyses. However, subjective utilities in long-term survivors of prostate cancer (PCa) with various oncological and functional outcomes have not been well described. Objective To quantify utilities in long-term survivors of PCa using the standard gamble method, generally regarded as the approach best grounded in economic theory. Design, setting, and participants We performed a cross-sectional study nested within a prospective cohort—Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE). Overall, 1884 (59.7%) of 3155 active participants across all disease states returned the questionnaire. Intervention Various primary treatments for PCa. Outcome measurements and statistical analysis Utility values for PCa health, sexual function, urinary function, bowel function, and overall health were measured, based on patients’ conditions at the time of the survey. Bias correction methods were employed. Results and limitations After exclusion of incomplete or disqualified data, 1740 (92.3% of responding) patients were included in the final analysis. The mean age was 73.1 ± 8.2 yr at a median of 9 yr (interquartile range: 6–11) since diagnosis. Mean utilities for PCa health and overall health were 0.934 ± 0.120 and 0.960 ± 0.100, respectively. After bias correction by probability weighting function, utilities were 0.866 ± 0.154 and 0.897 ± 0.142, and by mixed model correction, 0.845 ± 0.186 and 0.884 ± 0.176, respectively. Measured utilities were similarly high for specific functional outcomes, even with bias corrections. Survivorship bias and skewed proportion of disease status due to natural history of PCa were potential limitations. Conclusions Standard gamble-based utilities in long-term survivors of PCa were much higher than those determined previously. The results indicate substantial human resilience: most PCa patients adapt to their health status over time even if they experience incomplete functional recovery and would not take risk in pursuit of better quality of life. Patient summary We elicited health utilities (measures of quality of life) among long-term survivors of prostate cancer using the most robust method. These were much higher than previously reported values that were based on theoretical scenarios or indirect methods. Long-term survivors of prostate cancer may adapt well to their health conditions over time even if they experience disease-specific or functional problems.

Context Hereditary cases account for about 5% of all cases of renal cell carcinoma (RCC). With advances in next-generation sequencing, several new hereditary syndromes have been described in the last few years. Objective To review and summarise the recent preclinical and clinical literature in hereditary renal cancer. Evidence acquisition A systematic review of the literature was performed in November 2018 using PubMed and OMIM databases, with an emphasis on kidney cancer, genetics and genomics, clinical criteria, and management. Evidence synthesis Several autosomal dominant hereditary RCC syndromes have been described, including those related to germline pathogenic variants in VHL, MET, FH, TSC1/TSC2, FLCN, SDHA/B/C/D, BAP1, CDC73, and MITF. Clinical spectrum of SDH, BAP1, and MITF is still being defined, although these appear to be associated with a lower incidence of RCC. FH and likely BAP1 RCC are associated with more aggressive disease. Preclinical and clinical studies show that using systemic therapy that exploits specific genetic pathways is a promising strategy. Conclusions There are several well-described hereditary RCC syndromes, as well as recently identified ones, for which the full clinical spectrum is yet to be defined. In the new era of precision medicine, identification of these syndromes may play an important role in management and systemic treatment selection. Patient summary This review covers updates in the diagnosis and management of familial kidney cancer syndromes. We describe updates in testing and management of the most common syndromes such as von Hippel-Lindau, and hereditary leiomyomatosis and renal cell carcinoma. We also provide insights into recently described familial kidney cancer syndromes.

Context Several anti-programmed death-1 (anti-PD-1) and anti-programmed death ligand-1 (anti-PD-L1) antibodies have been approved by regulatory authorities for treatment of platinum-resistant metastatic urothelial cancer (mUC). The impact of these therapies on survival, and comparability of PD-1 versus PD-L1 blockade are unknown. Objective To determine the restricted mean survival time (RMST) of patients with platinum-resistant mUC treated with PD-1/PD-L1 inhibitors and to compare RMSTs in patients treated with PD-1 versus PD-L1 inhibitors. Evidence acquisition We searched for phase 1, 2, and 3 clinical trials that assessed PD-1 or PD-L1 inhibition for patients with platinum-resistant mUC. Literature review and study selection, data abstraction, and risk of bias assessment were performed by two reviewers. Survival data were reconstructed using an algorithm that derives individual time-to-event data from published Kaplan-Meier curves. The RMST with 95% confidence interval (CIs) was calculated. Evidence synthesis From 836 references, six clinical trials were included. Survival data were reconstructed for 1315 and 736 patients treated with PD-1/PD-L1 inhibitors and chemotherapy, respectively. The RMSTs with PD-1/PD-L1 blockade up to 12 and 18 mo of follow-up were 7.8 mo (95% CI 7.6, 8.1) and 10 mo (95% CI 9.7, 10.5), respectively. A network meta-analysis of two randomized trials revealed no significant difference in the RMST up to 18 mo with PD-1 versus PD-L1 blockade (1.0 mo; 95% CI −0.5, 2.3 mo). Using reconstructed survival data from all six trials, the RMSTs with PD-1 versus PD-L1 blockade up to 12 and 18 mo follow-up were 7.8 mo (95% CI 7.7, 8.2) versus 7.8 mo (95% CI 7.5, 8.2) and 10.1 mo (95% CI 9.6, 10.7) versus 10 mo (95% CI 9.5, 10.6), respectively. Conclusions Our RMST estimates may be used as benchmarks to contextualize survival outcomes and inform future trial design with PD-1/PD-L1 inhibitors. PD-1 versus PD-L1 blockade in patients with mUC yields comparable survival outcomes. Patient summary In this study, we found that outcomes for patients with metastatic bladder cancer treated with programmed death-1 and programmed death ligand-1 inhibitors, who received prior platinum-based chemotherapy, were similar.

Background The long-term oncological outcomes of laparoscopic (LRC) and robotic-assisted radical cystectomy (RARC) are still maturing compared with open radical cystectomy (ORC). Objective To evaluate the 5-yr oncological outcomes of patients recruited into the randomised trial of Open, Laparoscopic and Robot Assisted Cystectomy (CORAL) and extracorporeal urinary diversion. Design, setting, and participants A review of prospectively maintained database of 60 patients with muscle-invasive bladder cancer (MIBC) or high-risk nonmuscle-invasive bladder cancer (HRNMIBC) who were previously randomised in the CORAL trial to receive ORC, RARC, or LRC. This trial was designed to compare the perioperative and early oncological outcomes of these techniques. Outcome measurements and statistical analysis The outcomes of interest included 5-yr recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Kaplan–Meier curves were used to plot the recurrence and survival data. The curves between RFS, CSS, and OS were compared using the log-rank test. A two-sided p value <0.05 was considered significant. Results were analysed on the basis of intention to treat. Results and limitations A total of 60 patients with either MIBC (n = 38) or HRNMIBC (n = 21) were randomised in the CORAL trial to receive ORC, RARC, or LRC. The 5-yr RFS was 60%, 58%, and 71%; 5-yr CSS was 64%, 68%, and 69%; and 5-yr OS was 55%, 65%, and 61% for ORC, RARC, and LRC, respectively. There was no significant difference in RFS, CSS, and OS between the three surgical arms. The principal limitation is the small sample size. Conclusions There was no difference in 5-yr RFS, CSS, and OS rates of patients who underwent ORC, RARC, and LRC for management of bladder cancer. Minimally invasive techniques achieved equivalent oncological outcomes to the gold standard of ORC. However, the study was based at a single institution with a small sample size. Patient summary Patients who agreed to participate in the randomised trial of either open, laparoscopic, or robotic-assisted radical cystectomy for bladder cancer did not have different cancer outcomes at 5 yr.

In the randomized, open-label, phase 3 CheckMate 214 trial, nivolumab plus ipilimumab (nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 wk for four doses, then nivolumab 3 mg/kg every 2 wk) had superior efficacy over sunitinib (50 mg once daily, 4 wk on, 2 wk off) in patients with untreated International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate- or poor-risk advanced renal cell carcinoma; the benefits were sustained through extended follow-up. To better characterize the association between outcomes and IMDC risk in CheckMate 214, we completed a post hoc analysis (n = 1051) of efficacy by the number of IMDC risk factors. The investigator-assessed objective response rate (ORR), overall survival (OS), and investigator-assessed progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors v1.1 were evaluated. ORR with nivolumab plus ipilimumab was consistent across zero to six IMDC risk factors, whereas with sunitinib it decreased with increasing number of risk factors. Benefits of nivolumab plus ipilimumab over sunitinib in terms of ORR (40–44% vs 16–38%), OS (hazard ratio [HR] 0.50–0.72), and PFS (HR 0.44–0.86) were consistently observed in subgroups with one, two, three, or four to six IMDC risk factors (p < 0.05 for treatment × no. of risk factors interaction). These results demonstrate the benefit of first-line nivolumab plus ipilimumab over sunitinib across all intermediate-risk and poor-risk groups, regardless of the number of IMDC risk factors. Patient summary This report from the CheckMate 214 study describes a consistent efficacy benefit with first-line nivolumab plus ipilimumab over first-line sunitinib in all groups of patients with intermediate-risk or poor-risk advanced renal cell carcinoma, regardless of the number of risk factors they had before starting treatment. We conclude that there is a benefit of first-line treatment with nivolumab plus ipilimumab for all intermediate-risk patients, including those with one or two risk factors, and for all poor-risk patients, independent of the number of risk factors.

Background The majority of patients with overactive bladder (OAB) are aged >65 yr. There has been no prospectively designed study assessing treatment efficacy with the β3-adrenoreceptor agonist, mirabegron, specifically in this age group. Objective A phase IV study comparing flexibly dosed mirabegron versus placebo in elderly patients with OAB and urgency incontinence. Design, setting, and participants Community-dwelling patients aged ≥65 yr with OAB for ≥3 mo. Intervention Following a 2-wk placebo run in, patients with one or more incontinence episodes, three or more urgency episodes, and an average of eight or more micturitions/24 h were randomised 1:1 to double-blind 25 mg/d mirabegron or matched placebo, for 12 wk. After week 4 or 8, the dose could be increased to 50 mg/d mirabegron/matched placebo based on patient and investigator discretion. Outcome measurements and statistical analysis Coprimary endpoints: change from baseline to end of treatment (EOT) in the mean numbers of micturitions/24 h and incontinence episodes/24 h. Secondary endpoints: change from baseline to EOT in the mean volume voided/micturition, mean number of urgency episodes/24 h, and mean number of urgency incontinence episodes/24 h. Analysis of covariance (ANCOVA) was used for the mean number of micturitions/24 h, mean volume voided/micturition, and mean number of urgency episodes/24 h. Stratified rank ANCOVA was used for the mean numbers of incontinence episodes/24 h and urgency incontinence episodes/24 h. Results and limitations Statistically significant improvements were observed for mirabegron versus placebo in change from baseline to EOT in the mean number of micturitions/24 h, mean number of incontinence episodes/24 h, mean volume voided/micturition, mean number of urgency episodes/24 h, and mean number of urgency incontinence episodes/24 h. Safety and tolerability were consistent with the known mirabegron safety profile. Conclusions Mirabegron efficacy, safety, and tolerability over 12 wk were confirmed in patients aged ≥65 yr with OAB and incontinence. Patient summary We examined the effect of mirabegron compared with placebo in people aged 65 yr or older with overactive bladder and incontinence. Mirabegron improved the symptoms of overactive bladder compared with placebo. Side effects were similar to those already known for mirabegron.

Background Robot-assisted radical prostatectomy (RARP) is hampered by side effects that may have a serious impact on quality of life, particularly stress urinary incontinence. Continence rates may be improved by surgical reconstruction of the pelvic floor. Objective Video illustrations of different surgical techniques may be particularly worthwhile for practicing urologists in understanding the pelvic-floor anatomy and in the training of residents and fellows in urology. Design, setting, and participants We describe and video-illustrate commonly performed pelvic reconstructive techniques in RARP, as performed by experts in the field. Surgical procedure Surgical techniques have been described, such as posterior musculofascial reconstruction, anterior reconstruction and periurethral suspension, preservation of membranous urethral lengthening, bladder-neck reconstruction, and combinations. Measurements An overview of continence rates of the different techniques is given. Results and limitations All reconstructive surgical techniques result in similar short-term continence rates and good-to-excellent outcomes 1 yr after surgery. There are only a few randomized clinical trials comparing a reconstructive technique with “no reconstruction” or a different reconstructive technique, and outcomes are conflicting. Conclusions Although many of the procedures report a benefit with respect to early continence, benefits seem to diminish with longer follow-up. Whether any of the reconstructive techniques is superior to another is a matter of study. Patient summary Early continence rates might be improved by surgical reconstruction of the pelvic floor.

Background The importance of local failure (LF) after treatment of high-grade prostate cancer (PCa) with definitive radiotherapy (RT) remains unknown. Objective To evaluate the clinical implications of LF after definitive RT. Design, setting, and participants Individual patient data meta-analysis of 992 patients (593 Gleason grade group [GG] 4 and 399 GG 5) enrolled in six randomized clinical trials. Outcome measurements and statistical analysis Multivariable Cox proportional hazard models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), and distant metastasis (DM)-free survival (DMFS) and LF as a time-dependent covariate. Markov proportional hazard models were developed to evaluate the impact of specific transitions between disease states on these endpoints. Results and limitations Median follow-up was 6.4 yr overall and 7.2 yr for surviving patients. LF was significantly associated with OS (hazard ratio [HR] 1.70 [95% confidence interval {CI} 1.37–2.10]), PCSS (3.10 [95% CI 2.33–4.12]), and DMFS (HR 1.92 [95% CI 1.54–2.39]), p < 0.001 for all). Patients who had not transitioned to the LF state had a significantly lower hazard of transitioning to a PCa-specific death state than those who transitioned to the LF state (HR 0.13 [95% CI 0.04–0.41], p < 0.001). Additionally, patients who transitioned to the LF state had a greater hazard of DM or death (HR 2.46 [95% CI 1.22–4.93], p = 0.01) than those who did not. Conclusions LF is an independent prognosticator of OS, PCSS, and DMFS in high-grade localized PCa and a subset of DM events that are anteceded by LF events. LF events warrant consideration for intervention, potentially suggesting a rationale for upfront treatment intensification. However, whether these findings apply to all men or just those without significant comorbidity remains to be determined. Patient summary Men who experience a local recurrence of high-grade prostate cancer after receiving upfront radiation therapy are at significantly increased risks of developing metastases and dying of prostate cancer.

Background Patients with predominant variant histology (VH) of bladder tumors, defined as involving >50 % of the tumor specimens, are typically excluded from clinical trials, and for these patients, the efficacy of standard chemotherapy is limited. Objective To evaluate the activity of preoperative pembrolizumab in patients with muscle-invasive bladder carcinoma (MIBC) and VH, enrolled in PURE-01 study (NCT02736266). Design, setting, and participants In the open-label, single-arm, phase 2 PURE-01 study, three courses of 200 mg pembrolizumab preceding radical cystectomy (RC) were administered in T2-4aN0M0 MIBC patients. The amended study design included patients with predominant VH. Intervention Neoadjuvant pembrolizumab and RC. Outcome measurements and statistical analysis Pathological complete response (pT0) in intention-to-treat population was the primary endpoint. Biomarker analyses included programmed cell-death ligand-1 (PD-L1) expression using the combined positive score (CPS; Dako 22C3 antibody) and comprehensive genomic profiling (FoundationOne assay). Multivariable logistic regression analyses (MVAs) evaluated the histological category (predominant VH vs nonpredominant VH vs pure urothelial carcinoma), tumor mutational burden (TMB) and CPS in association with the pathological response. Results and limitations From February 2017 to June 2019, 114 patients were enrolled; 34 (30%) of them presented with VH, including 19 (17%) with predominant VH. In total, the pT0 rate was 37% (95% confidence interval [CI]: 28–46) and the pT ≤ 1 rate was 55% (95% CI: 46–65). The majority of predominant VH patients presented with squamous-cell carcinoma (SCC; N = 7), and six of seven (86%) had downstaging to pT ≤ 1, with one pT0; two of three lymphoepithelioma-like (LEL) variants had a pT0 response. None of the remaining nine predominant VHs had a response. On MVA, TMB and CPS were associated with both the pT0 and the pT ≤ 1 response, regardless of tumor histology. Conclusions The updated PURE-01 results confirm the activity of neoadjuvant pembrolizumab in MIBC. Patients with SCC and LEL features may be suitable for neoadjuvant immunotherapy trials. CPS and TMB are the key response predictors irrespective of the histological subtypes. Patient summary In the PURE-01 study, we have preliminarily evaluated the activity of neoadjuvant pembrolizumab in patients with predominant variant histology (VH). Of these patients, those harboring squamous-cell carcinoma or a lymphoepithelioma-like variant feature had major, although preliminary, pathological responses compared with those with other predominant VHs. Expression of programmed cell-death ligand-1 and tumor mutational burden may predict the pathological response to pembrolizumab, and provide a rationale for selecting patients according to these features instead of the histological bladder cancer subtypes.

Background The initial report from the ASIST trial showed little benefit from targeted biopsy for men on active surveillance (AS) for prostate cancer. Data after 2-yr follow-up are now available for analysis. Objective To determine if there was a difference in the AS failure rate in a 2-yr follow-up period among men undergoing magnetic resonance imaging (MRI) before initial confirmatory biopsy (CBx) compared to those who did not. Design, setting, and participants This is the 2-yr post-CBx follow-up for the ASIST trial, a prospective, randomized, multicenter, open-label study for men with Gleason grade group (GG) 1 cancer eligible for AS. Patients were randomized to CBx with 12-core systematic sampling or MRI with systematic and targeted sampling. Outcome measurements and statistical analysis Patients with GG ≤ 1 on CBx were followed for 2 yr and had MRI and biopsy at that time point. Patients failed AS if they were no longer under AS because of grade progression, clinical progression, subject choice, clinical judgment, treatment, or lost to follow-up. Clinically significant cancer (CSC) was defined as GG ≥ 2. Results and limitations In total, 259 men underwent CBx, 132 in the non-MRI and 127 in the MRI arm. After biopsy, 101 men in the non-MRI arm (76%) and 98 in the MRI arm (77%) continued AS. There were fewer men with AS failures in the MRI (19/98, 19%) compared to the non-MRI group (35/101, 35%; p = 0.017). At 2-yr biopsy there were fewer men with CSC in the MRI arm (9.9%, 8/81) than in the non-MRI arm (23%, 17/75; p = 0.048). Significant differences in AS failure rates were detected across the three centers in the MRI arm only (4.2% [2/48] vs 17% [4/24] vs 27% [7/26]; p = 0.019). Conclusions Baseline MRI before CBx during AS results in 50% fewer AS failures and less grade progression over 2 yr. The center where MRI and targeted biopsy is performed may influence AS failure rates. Patient summary The ASIST trial randomized 273 men on active surveillance with low-grade prostate cancer diagnosed within the last year to systematic biopsy or magnetic resonance imaging (MRI) with systematic and targeted biopsy. The initial report showed little benefit from targeted biopsy. However, after 2 yr of follow-up we found that baseline MRI before confirmatory biopsy resulted in 50% fewer failures of surveillance and less progression to higher-grade cancer. This confirms the value of MRI in men on surveillance. This study is registered at ClinicalTrials.gov (NCT01354171).

Currently, surveillance guidelines following surgical resection of clinically localized renal cell carcinoma (RCC) are clear within the first 5 yr; however, these lack the same degree of objectivity following this cutoff. We sought to investigate the long-term risk of recurrence in surgically treated RCC in order to determine the utility of long-term surveillance. A post hoc analysis of patients within the Eastern Cooperative Oncology Group—American College of Radiology Imaging Network (ECOG-ACRIN) E2805 trial cohort was performed. The 36-mo cumulative incidence of recurrence was assessed at set intervals following surgery, in order to dynamically assess recurrence through the use of a conditional survival model. Of the 1943 patients included in the original cohort, 730 developed recurrence. The 36-mo cumulative incidences of recurrence were found to be 31%, 26%, 19%, 16%, 19%, and 20% for patients at 0, 12, 24, 36, 48, and 60 mo from surgery, respectively. At 0 mo from surgery, age, pathological T3/4 stage (hazard ratio [HR] = 1.56), pathological N1/2 stage (HR = 2.38), and Fuhrman grades 3 and 4 (HR = 1.36 and HR = 2.41, respectively) were independent predictors of recurrence; however, this was not seen at 60 mo following surgery. These findings support that surveillance imaging should be performed beyond 5 yr following surgical resection of intermediate- to high-risk RCC. Patient summary : Follow-up for surgically resected localized renal cell carcinoma should be performed beyond 5 yr, for the rates of recurrence remain significant beyond this 5 yr endpoint.

Background Immune checkpoint inhibitors (ICIs) are approved for first-line (cisplatin unfit, PD-L1+) and platinum-refractory urothelial carcinoma (UC). Still, most patients experience progressive disease (PD) as the best response. Although higher response rates to subsequent systemic treatment (SST) have been described, post-PD outcome data are scarce. Objective To examine the outcome of UC patients who received SST and no SST after progressing to ICIs. Design, setting, and participants A retrospective analysis of UC patients progressing to frontline or later-line anti–PD-1/PD-L1 therapy in 10 European institutions was conducted between March 2013 and September 2017. Intervention Post-PD management as per standard practice. Outcome measurements and statistical analysis Overall survival (OS) was analyzed with a Kaplan-Meier model. Cox regression was used for multivariate analysis (MV). Impact of SST on OS was examined with a time-varying covariate model. Results and limitations A total of 270 UC patients with PD to ICIs (69 frontline, 201 later line) were analyzed. Of the patients, 57% of frontline-ICI-PD and 34% of later-line-ICI-PD patients received SST, and SST had an impact on OS in MV (frontline: hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.10–0.51, p < 0.001; later line: HR 0.22, 95% CI 0.13–0.36, p < 0.001). In the frontline-ICI-PD group, median OS with and without SST was 6.8 mo (95% CI 5.0–8.6) and 1.9 mo (95% CI 0.9–3.0), respectively. High disease burden (three or more metastatic sites: HR 2.49, p = 0.03; simultaneous liver/bone metastases: HR 3.93, p = 0.03) predicted worse survival. In later-line-ICI-PD group, response to ICIs (HR 0.37, p = 0.03), longer exposure to ICIs (HR 0.89, p = 0.002), and bone metastasis (HR 2.42, p < 0.001) predicted survival. The retrospective nature of this study and a lack of certain parameters limit the interpretation of our analysis. Conclusions Patients progressing to frontline ICIs are at risk of early death, excluding them from experiencing potential benefit from chemotherapy Patient summary Our analysis suggests that outcomes after failing immunotherapy are poor, particularly in UC patients who received no prior chemotherapy.

Background Vesical Imaging Reporting and Data System (VI-RADS) score is adopted to provide preoperative bladder cancer (BCa) staging. Repeated transurethral resection of bladder tumor (Re-TURBT) is recommended in most of high-risk non–muscle-invasive bladder cancers (HR-NMIBCs) due to possibility of persistent/understaged disease after initial TURBT. No diagnostic tools able to improve patient’s stratification for such recommendation exist. Objective To (1) prospectively validate VI-RADS for discriminating between NMIBC and muscle-invasive bladder cancer (MIBC) at TURBT, and (2) evaluate the accuracy of VI-RADS for identifying HR-NMIBC patients who could avoid Re-TURBT and detecting those at higher risk for understaging after TURBT. Design, setting, and participants Patients with BCa suspicion were offered multiparametric magnetic resonance imaging (mpMRI) before TURBT. According to VI-RADS, a cutoff of ≥3 to define MIBC was assumed. TURBT reports were compared with preoperative VI-RADS scores to assess accuracy of mpMRI for discriminating between NMIBC and MIBC. HR-NMIBC Re-TURBT reports were compared with preoperatively recorded VI-RADS scores to assess mpMRI accuracy in predicting Re-TURBT outcomes. Intervention Multiparametric MRI of the bladder before TURBT. Outcome measurements and statistical analysis Sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were calculated for mpMRI performance in patients undergoing TURBT and for HR-NMIBC patients candidate for Re-TURBT. Performance of mpMRI was assessed by receiver operating characteristic curve analysis. Ƙ statistics was used to estimate inter- and intrareader variability. Results and limitations A total of 231 patients were enrolled. Multiparametric MRI showed sensitivity, specificity, PPV, and NPV for discriminating NMIBC from MIBC at initial TURBT of 91.9% (95% confidence interval [CI]: 82.2–97.3), 91.1% (95% CI: 85.8–94.9), 77.5% (95% CI: 65.8–86.7), and 97.1% (95% CI: 93.3–99.1), respectively. The area under the curve (AUC) was 0.94 (95% CI: 0.91–0.97). Among HR-NMIBC patients (n = 114), mpMRI before TURBT showed sensitivity, specificity, PPV, and NPV of 85% (95% CI: 62.1–96.8), 93.6% (95% CI: 86.6–97.6), 74.5% (95% CI: 52.4–90.1), and 96.6% (95% CI: 90.5–99.3) respectively, to identify patients with MIBC at Re-TURBT. The AUC was 0.93 (95% CI: 0.87–0.97). Conclusions VI-RADS is accurate for discriminating between NMIBC and MIBC. Within HR-NMIBC cases, VI-RADS could, in future, improve the selection of patients who are candidate for Re-TURBT. Patient summary We investigated the accuracy of Vesical Imaging Reporting and Data System (VI-RADS) score to asses bladder cancer staging before transurethral resection of bladder tumors, and we explored the performance of VI-RADS score as a future preoperative predictive tool for the selection of high-risk non–muscle-invasive bladder cancer patients who are candidate for undergoing early repeated transurethral resection of the primary tumor site.

Context There have been substantial changes in the management of men with metastatic hormone-sensitive prostate cancer (mHSPC) over the past 5 yr, with upfront combination therapies replacing androgen-deprivation therapy (ADT) alone. A range of therapies have entered the space with no clear answer regarding their comparative efficacy. Objective To perform a systematic review and network meta-analysis to characterise the comparative efficacy of combination approaches in men with mHSPC. Evidence acquisition We searched multiple databases and abstracts of major meetings up to June 2019 for randomised trials of patients receiving first-line therapy for metastatic disease, a combination of ADT and one (or more) of taxane-based chemotherapy, and androgen receptor-targeted therapies. The primary endpoint was overall survival (OS) and we evaluated progression-free survival as a secondary outcome. We performed subgroup analysis based on the volume of disease. Evidence synthesis We found seven trials that met our eligibility criteria using either docetaxel, abiraterone acetate, enzalutamide, or apalutamide in combination with ADT. All agents in combination with ADT were shown to be superior to ADT alone; enzalutamide + ADT had the lowest absolute hazard ratio compared with ADT only (hazards ratio 0.53, 95% confidence interval 0.37–0.75), and an estimated 76.9% probability that it is the preferred treatment to prolong OS compared with other combination treatments, or with ADT alone. Enzalutamide appeared to have better OS compared with docetaxel in men with low-volume disease, but there was no difference in other comparisons. Conclusions Combination therapy with any of docetaxel, abiraterone acetate, enzalutamide, or apalutamide provides a significant OS benefit when compared with ADT alone. We did not identify significant differences in OS between different combination therapies. Subtle differences between these options provide clinicians considerable flexibility when selecting options for individual patients. Patient summary Many men with metastatic, hormone-sensitive prostate cancer should be managed with upfront combination therapy instead of androgen-deprivation therapy alone. Clinicians may consider many factors during the decision-making process, and thus management should be tailored for patients individually.

BACKGROUND Everolimus is a mammalian target of rapamycin (mTOR) inhibitor used in vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma (mRCC). It acts on only part of the mTOR complex (TORC1 alone). In vitro data support the use of mTOR inhibitors with broader activity (TORC1 and TORC2). OBJECTIVE The purpose of this study was to determine whether combined TORC1 and TORC2 inhibition with AZD2014 has superior activity to everolimus in VEGF-refractory clear cell mRCC. DESIGN, SETTING, AND PARTICIPANTS Patients with measurable mRCC and VEGF-refractory disease were eligible for this trial. INTERVENTION Starting in February 2013, patients were randomised (1:1) to AZD2014 (50 mg twice daily) or everolimus (10 mg once daily) until progression of disease at 10 centres across the United Kingdom. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Progression-free survival (PFS) was the primary end point and was compared using the stratified log-rank test. Secondary end points included tolerability, response rates, overall survival (OS), and pharmacokinetics (PK) analysis. The study was planned to recruit 120 patients. RESULTS AND LIMITATIONS Recruitment into the trial was stopped early (June 2014) due to lack of efficacy of AZD2014. At that point, 49 patients were randomised (26 to AZD2014 and 23 to everolimus). The PFS for AZD2014 and everolimus was 1.8 and 4.6 mo, respectively (hazard ratio: 2.8 [95% confidence interval (CI), 1.2-6.5]; p=0.01). Progression of disease as the best response to therapy was 69% for AZD2014 and 13% for everolimus (p<0.001). Grade 3-4 adverse events (AEs) occurred in 35% of AZD2014 and 48% of everolimus patients (p=0.3). Only 4% of patients stopped AZD2014 due to AEs. PK analysis suggested concentrations of AZD2014 were compatible with the therapeutic range. Final stratified OS hazard ratio at the time of trial closure (January 2015) was 3.1 (95% CI, 1.1-8.4; p<0.02). CONCLUSIONS The PFS and OS of AZD2014 were inferior to everolimus in this setting despite acceptable AE and PK profiles. PATIENT SUMMARY There is a strong rationale for testing mTOR inhibitors with a broader spectrum of activity than everolimus in metastatic clear cell renal cell carcinoma. AZD2014 is such an agent, but in this study, it was inferior to everolimus despite its attractive toxicity profile.

The use of [18F]- and [68Ga]-labeled inhibitors of prostate-specific membrane antigen (PSMA) for positron emission tomography (PET) imaging of prostate cancer is now widespread. We have proposed a reporting and data system called PSMA-RADS version 1.0, which is a framework for classifying PSMA-targeted PET scans and individual findings into categories that reflect the likelihood of the presence of prostate cancer.

We used the Template for Intervention Description and Replication (TIDieR) to find evidence that intervention reporting in urology randomized controlled trials is suboptimal. Action to improve intervention reporting is warranted and we advise extending TIDieR into Consolidated Standards for Reporting Trials guidelines.