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Purpose: Cigarette smoking is a risk factor for developing nonmuscle invasive bladder cancer, and continued smoking exposure after diagnosis may increase the likelihood of adverse clinical outcomes. We compare self-reported vs biochemically verified nicotine exposure to determine the accuracy of self-report among recently diagnosed nonmuscle invasive bladder cancer patients., Materials and Methods: This cross-sectional analysis consisted of 517 nonmuscle invasive bladder cancer patients who contributed a urine or saliva specimen the same day as self-reporting their smoking, use of e-cigarettes, nicotine replacement therapy and whether they lived with a smoker. Cotinine, the primary metabolite of nicotine, was used as an objective biomarker of recent nicotine exposure., Results: The prevalence of high, low and no cotinine exposure was 13%, 54% and 33%, respectively. Overall, 7.3% of patients (38/517) reported being a current cigarette smoker, while 13% (65/517) had cotinine levels consistent with active smoking exposure. Of these 65 patients 27 denied current smoking, resulting in a sensitivity of self-reported current smoking of 58%. After considering other sources of nicotine exposure such as e-cigarettes, cigars, nicotine replacement therapy and living with a smoker, the sensitivity was higher, at 82%. Nearly all patients with low cotinine denied any smoking-related exposure., Conclusions: Our findings suggest either biochemical verification with cotinine or additional questions about other sources of nicotine are needed to accurately identify nonmuscle invasive bladder cancer patients who have smoking-related exposures. Accurate classification of active and passive smoking exposure is essential to allow clinicians to advise cessation and help researchers estimate the association between post-diagnosis smoking-related exposure and nonmuscle invasive bladder cancer recurrence risk.

Background: Plasmacytoid urothelial carcinoma (PUC) is a rare, aggressive histologic variant of urothelial cancer characterised by a diffuse growth pattern and CDH1 mutation. We studied the efficacy of preoperative platinum-based chemotherapy in nonmetastatic PUC and immune checkpoint inhibitors (ICIs) in advanced PUC., Methods: Cases of nonmetastatic PUC and advanced PUC treated with ICIs at our institution were identified. Outcomes were compared to those of a published cohort of patients with urothelial carcinoma not otherwise specified., Results: We identified 81 patients with nonmetastatic PUC. Of the patients with localised disease who underwent neoadjuvant chemotherapy, pathologic complete response and downstaging rates were 12 and 21%, respectively. Pathologic downstaging was not associated with significant improvement in clinical outcomes. Up to 18% of localised disease and 28% of locally advanced cases had unresectable disease at the time of surgery. ICI-treated advanced PUC (N = 21) had progression-free and overall survival of 4.5 and 10.5 months, respectively, and a 38% response rate. FGFR3 and DNA damage response gene alterations were observed in 3 and 15% of cases, respectively., Conclusions: PUC is associated with high disease burden and poor chemosensitivity. Increased awareness and recognition of this disease variant will allow for new treatment strategies.

Background: Immune checkpoint inhibitors are an important therapeutic option for urothelial carcinoma, but durable responses are achieved in a minority of patients. Identifying pre-treatment biomarkers that may predict response to these therapies or who exhibit intrinsic resistance, is of paramount importance., Objective: To explore the prevalence of PD-L1 copy number alteration in urothelial carcinoma and correlate with response to immune checkpoint inhibitors., Methods: We analyzed a cohort of 1050 carcinomas of the bladder and upper urinary tract that underwent targeted next generation sequencing, prospectively. We assessed PD-L1 protein expression, copy number status (next generation sequencing/FISH), and detailed treatment response., Results: We identified 9 tumors with PD-L1 amplification and 9 tumors with PD-L1 deletion. PD-L1 protein expression was the highest in PD-L1 amplified tumors. Of the 9 patients whose tumors harbored PD-L1 amplification, 6 received immunotherapy with 4 deriving clinical benefit, and two achieving durable response. Of the 9 patients whose tumors had PD-L1 copy number losses, 4 received immunotherapy with 3 experiencing disease progression., Conclusions: PD-L1 copy number alterations may serve as potential biomarkers of response to immunotherapy in urothelial carcinoma patients, if validated in larger cohorts.

Background: Alterations in fibroblast growth factor receptor 3 (FGFR3) occur in ∼15% of muscle-invasive bladder cancers (MIBCs) and metastatic urothelial carcinomas (mUCs)., Objective: To determine the association between FGFR3 status and response to platinum-based chemotherapy in patients with MIBC or mUC., Design, Setting, and Participants: The authors conducted a retrospective review and comparison of patients having (1) MIBC treated with neoadjuvant chemotherapy (NAC), (2) mUC treated with first-line platinum-based chemotherapy (M1 cohort), and (3) MIBC who were from The Cancer Genome Atlas (TCGA)., Intervention: Platinum-based chemotherapy., Outcome Measurements and Statistical Analysis: Pathologic response, recurrence-free (RFS) or progression-free (PFS) survival, and overall survival (OS) were compared between patients with FGFR3 alteration (FGFR3alt) and those without it (FGFR3wild type [FGFR3wt]) in the three cohorts., Results and Limitations: Nine of 72 NAC patients (13%) had FGFR3alt, of whom none had pathologic complete response and three had residual non-MIBC (carcinoma in situ, n = 1; pT1, n = 2). FGFR3alt was associated with shorter RFS (hazard ratio, 2.74; p = 0.044) but not OS. Among TCGA patients who underwent adjuvant chemotherapy (n = 74), FGFR3alt patients had shorter RFS as well. Conversely, among chemotherapy-naive TCGA patients, FGFR3alt was associated with longer RFS and OS. In the M1 cohort (FGFR3alt, n = 27; FGFR3wt, n = 81), FGFR3alt was associated with higher rates of pulmonary metastases and nonregional lymphadenopathy. Despite lower response rates among FGFR3alt patients (37% vs 49%; p = 0.056), PFS and OS were not significantly different from FGFR3wt patients., Conclusions: FGFR3 status is associated with lower responses to platinum-based chemotherapy, which may prompt exploration of nonchemotherapeutic approaches for perioperative management of FGFR3alt urothelial cancers., Patient Summary: Approximately 15% of bladder cancers harbor mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Our findings suggest that FGFR3 mutations might be associated with lower responses and shorter time to recurrence among patients with muscle-invasive bladder cancer who received perioperative platinum-based chemotherapy. FGFR3 status does not significantly impact response to chemotherapy among those with metastatic urothelial cancers., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: The aim of this study was to determine drug delivery/toxicity, and pathologic/surgical outcomes of patients with muscle-invasive bladder cancer (MIBC) receiving neoadjuvant gemcitabine-cisplatin (GC) plus radical cystectomy-pelvic lymph node dissection (RC-PLND)., Patients and Methods: Chemotherapy and surgical/pathologic outcomes were retrospectively analyzed with 5-year survival follow-up at a referral center. Post-neoadjuvant chemotherapy (NAC) pathologic endpoints included complete response (pT0N0), residual non-MIBC (pTa/Tis/T1N0), and ≥ MIBC (≥ pT2 and/or N+). Associations of pathologic/surgical findings with overall survival (OS), disease-free survival (DFS), and surgical management with RC-PLND were analyzed (Cox regression)., Results: Clinical T2a-T4aN0M0 MIBC patients (n = 154) from January 2000-October 2012 received GC plus RC-PLND. Patients (n = 117; 76%) received GC × 4 and 136 (88%) GC × 3. Five-year OS was 61% (95% confidence interval [CI], 53-71). Median number of resected lymph nodes (LNs) was 19. Down-staging was observed as follows: pT0N0: 21%; pTa/Tis/T1N0: 25%, with similar 5-year OS (85% and 89%, respectively). Five-year OS for < pT2 versus ≥ pT2 residual disease was 87% (95% CI, 78%-98%) versus 38% (95% CI, 27%-53%); P < .001. Post-NAC stage ≥ pT2 (HR, 6.79; 95% CI, 2.63-17.53; P < .001), positive LN (HR, 3.64; 95% CI, 1.84-7.19; P < .001), and positive margins (HR, 4.15; 95% CI, 1.68-10.25; P = .002) were associated with increased risk of all-cause death (multivariable analysis). An HR of 0.97 (95% CI, 0.94-1.00) was observed for each additional node removed, but this effect was not statistically significant (P = .056)., Conclusions: Neoadjuvant GC achieves meaningful pathologic responses. Patients with ≥ pT2 residual disease, positive margins, or positive LN post-chemotherapy have inferior survival., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: We evaluated trends in oncologic characteristics and outcomes as well as perioperative management among patients undergoing radical cystectomy at Memorial Sloan Kettering from 1995 to 2015., Materials and Methods: We retrospectively reviewed our institutional database to analyze changes in disease recurrence probability, cancer specific and all cause mortality, incidence of muscle invasive bladder cancer, use of perioperative chemotherapy, rate of positive soft tissue surgical margins and lymph node yield., Results: In 2,740 patients with nonmetastatic urothelial carcinoma undergoing radical cystectomy from 1995 to 2015 the 5-year probability of disease recurrence decreased from a peak of 42% in 1997 to 34% in 2013 (p=0.045), while the 5-year probability of cancer specific mortality likewise declined from 36% in 1997 to 24% in 2013 (p=0.009). The incidence of nonmuscle invasive disease before radical cystectomy did not change, comprising 30% to 35% of patients across the study period. Use of neoadjuvant chemotherapy rose significantly as 57% of patients with muscle invasive bladder cancer from 2010 to 2015 received it. We observed a corresponding rise in complete pathological response (pT0) at radical cystectomy, as well as decreasing positive soft tissue surgical margins (10% to 2.5%) and rising lymph node yield (7 to 24) from 1995 to 2015., Conclusions: During a 21-year period outcomes after radical cystectomy at our institution improved significantly, as the probability of recurrence and cancer specific mortality decreased. Increasing use of neoadjuvant chemotherapy, rising pT0 rates, decreased positive soft tissue surgical margins and increasing lymph node yields likely contributed, suggesting that optimized surgical and perioperative care led to improved cancer outcomes in patients undergoing radical cystectomy.

Purpose: Disease recurrence after radical cystectomy generally occurs within 2 years and has a poor prognosis. Less well defined are the outcomes in patients who experience a late recurrence (more than 3 years after radical cystectomy). We report our institutional experience with late recurrences and describe the relationships between time to recurrence, management strategies and survival., Materials and Methods: The study cohort comprised 2,315 patients who underwent radical cystectomy for urothelial carcinoma at our center between 2000 and 2014, of whom 617 had a recurrence. Median followup for survivors was 2.6 years after recurrence (IQR 0.95-4.5). For the study we considered disease recurrence as recurrences outside the urinary tract. We compared baseline characteristics and post-recurrence management between those with recurrence 3 or less and more than 3 years after radical cystectomy., Results: A total of 58 patients with late recurrence had significantly lower consensus T stage and lower frequency of nodal involvement. The average 1-year bladder cancer death rate from the time of recurrence declined from 66% to 50% to 33% for patients with recurrence times of 6 months, 2 years, and 5 years after radical cystectomy, respectively. For patients who survived at least 1 year after recurrence, the estimated survival at 5 years after recurrence was 45% for those with late recurrence and 21% for patients who had an early recurrence. Local consolidative therapy (metastasectomy or radiation) was more common in patients with late recurrence (19% vs 3.6%, p <0.0001). Cancer specific survival in early recurring cases was significantly worse than in late recurring cases in the subset receiving local consolidation (p=0.02)., Conclusions: The prolonged lifespan of patients experiencing a late recurrence after radical cystectomy can be leveraged to individualize management. There is strong rationale for investigating the role of metastasectomy in the management of late recurrences.

Objectives: To evaluate treatment patterns and associated outcomes of patients with urethral cancer., Patients and Methods: After obtaining institutional review board approval we identified 165 patients treated for primary urethral cancer between 1956 and 2017. Treatment included monotherapy (surgery or radiation), dual therapy (surgery+radiation, surgery+chemotherapy, or chemotherapy+radiation) or triple therapy (surgery+radiation+chemotherapy). Rates of different treatments were described by treatment year. The association between treatment type and outcomes was evaluated with multivariable Cox regression models, adjusting for disease characteristics., Results: The study cohort included 74 men and 91 women, with a median age of 61 years. Common histologies were squamous cell (36%), urothelial (27%) and adenocarcinoma (25%). At presentation, 72% of patients had invasive disease, 24% had nodal involvement, and 5% had metastases. Treatment included monotherapy (57%), dual therapy (21%), and triple therapy (10%). The use of monotherapy decreased over time, while rates of dual therapy remained consistent, and rates of triple therapy increased. The median follow-up was 4.7 years. Estimated 5-year local recurrence-free, disease-specific and overall survival were 51%, 48% and 41%, respectively. Monotherapy was associated with decreased local recurrence-free survival after adjusting for stage, histology, sex and year of treatment (P = 0.017). There was no evidence that treatment type was associated with distant recurrence, cancer-specific or overall survival., Conclusions: We found preliminary evidence that multimodal therapy, more commonly used in recent years, was of benefit in patients with primary urethral cancer. This finding should be confirmed in further studies involving multiple centres because of the low incidence of the disease., (© 2020 The Authors BJU International © 2020 BJU International Published by John Wiley & Sons Ltd.)

Background: Postoperative ileus is a common complication of intraabdominal surgeries, including radical cystectomy with reported rates as high as 32%. Perioperative fluid administration has been associated with improvement in postoperative ileus rates, but it is difficult to generalize because earlier studies lacked standardized definitions of postoperative ileus and other relevant outcomes. The hypothesis was that targeted individualized perioperative fluid management would improve postoperative ileus in patients receiving radical cystectomy., Methods: This is a parallel-arm, double-blinded, single-center randomized trial of goal-directed fluid therapy versus standard fluid therapy for patients undergoing open radical cystectomy. The primary outcome was postoperative ileus, and the secondary outcome was complications within 30 days post-surgery. Participants were at least 21 yr old, had a maximum body mass index of 45 kg/m and no active atrial fibrillation. The intervention in the goal-directed therapy arm combined preoperative and postoperative stroke volume optimization and intraoperative stroke volume variation minimization to guide fluid administration, using advanced hemodynamic monitoring., Results: Between August 2014 and April 2018, 283 radical cystectomy patients (142 goal-directed fluid therapy and 141 standard fluid therapy) were included in the analysis. Postoperative ileus occurred in 25% (36 of 142) of patients in the goal-directed fluid therapy arm and 21% (30 of 141) of patients in the standard arm (difference in proportions, 4.1%; 95% CI, -5.8 to 13.9; P = 0.418). There was no difference in incidence of high-grade complications between the two arms (20 of 142 [14%] vs. 23 of 141 [16%]; difference in proportions, -2.2%; 95% CI, -10.6 to 6.1; P = 0.602), with the exception of acute kidney injury, which was more frequent in the goal-directed fluid therapy arm (56% [80 of 142] vs. 40% [56 of 141] in the standard arm; difference in proportions, 16.6%; 95% CI, 5.1 to 28.1; P = 0.005; P = 0.170 after adjustment for multiple testing)., Conclusions: Goal-directed fluid therapy may not be an effective strategy for lowering the risk of postoperative ileus in patients undergoing open radical cystectomy.

Purpose: We determined the diagnostic performance of 18 F-FDG (fluorodeoxyglucose) positron emission tomography/computerized tomography for detecting nodal metastases in patients with muscle invasive urothelial bladder cancer before radical cystectomy., Materials and Methods: Preoperative 18 F-FDG positron emission tomography/computerized tomography scans (208) were retrospectively reviewed. Scans were routinely performed in 185 patients with muscle invasive urothelial bladder cancer between August 2012 and February 2017, all of whom underwent radical cystectomy and pelvic lymph node dissection. Analyses were stratified by clinical node involvement and chemotherapy status. The diagnostic performance of 18 F-FDG positron emission tomography/computerized tomography was assessed according to sensitivity, specificity, positive predictive value and negative predictive value., Results: Lymph node metastases at time of pelvic lymph node dissection were present in 21.8% of those without suspicious nodes on computerized tomography (clinically node negative) and 52.6% of those with suspicious nodes on computerized tomography (clinically node positive). Median metastatic focus size was 5 mm. In clinically node negative cases 18 F-FDG positron emission tomography/computerized tomography rarely detected nodal metastases (sensitivity 7% to 23%). In clinically node positive cases negative 18 F-FDG positron emission tomography/computerized tomography was useful in ruling out lymph node metastases (sensitivity 92% to 100%). This study was limited by its mixed population and focus on pelvic nodal metastases only., Conclusions: 18 F-FDG positron emission tomography/computerized tomography appears to be most useful for better characterization of enlarged nodes identified by computerized tomography. Routine preoperative 18 F-FDG positron emission tomography/computerized tomography has limited utility in clinically node negative cases.

The role of a thorough pelvic lymph node dissection at radical cystectomy for high risk bladder cancer is an important component for quality surgical care. Selected patients with advanced disease involving the retroperitoneal lymph nodes (limited nodal disease, significant response to systemic therapy, and the ability to resect all sites of prior involvement) may benefit from surgical resection., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context: A noninvasive multiparametric magnetic resonance imaging (MRI)-based scoring system for predicting muscle-invasive bladder cancer (MIBC), the "Vesical Imaging Reporting and Data System" (VI-RADS), was recently developed by an international multidisciplinary panel. Since then, a few studies evaluating the value of VI-RADS for predicting MIBC have been published., Objective: To review the diagnostic performance of VI-RADS for the prediction of MIBC., Evidence Acquisition: PubMed and EMBASE databases were searched up to November 10, 2019. We included diagnostic accuracy studies using VI-RADS to predict MIBC using cystectomy or transurethral resection as the reference standard. Methodological quality was evaluated with Quality Assessment of Diagnostic Accuracy Studies-2. Sensitivity and specificity were pooled and plotted using hierarchical summary receiver operating characteristics (HSROC) modeling. Meta-regression analyses were done to explore heterogeneity., Evidence Synthesis: Six studies (1770 patients) were included. Pooled sensitivity and specificity were 0.83 (95% confidence interval [CI] 0.70-0.90) and 0.90 (95% CI 0.83-0.95), and the area under the HSROC curve was 0.94 (95% CI 0.91-0.95). Heterogeneity was present among the studies (Q = 29.442, p <  0.01; I 2  = 87.93%, and 90.99% for sensitivity and specificity). Meta-regression analyses showed that the number of patients (>205 vs ≤205), magnetic field strength (3 vs 1.5 T), T2-weighted image slice thickness (3 vs 4 mm), and VI-RADS cutoff score (≥3 vs ≥4) were significant factors affecting heterogeneity (p ≤  0.03)., Conclusions: VI-RADS shows good sensitivity and specificity for determining MIBC. Technical factors associated with MRI acquisition and cutoff scores need to be taken into consideration as they may affect performance., Patient Summary: A recently established noninvasive magnetic resonance imaging-based scoring system shows good diagnostic performance in detecting muscle-invasive bladder cancer., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose of Review: The orthotopic neobladder and ileal conduit are the two most commonly utilized urinary diversions among patients undergoing radical cystectomy. Although orthotopic diversion offers several advantages, only 20% of patients nationally receive this diversion, with decreasing utilization over time. The purpose of this article is to review advantages of each diversion type and considerations in patient selection, review trends in diversion utilization and perioperative and functional outcomes, and examine recent studies evaluating methods of optimizing diversion selection and patient satisfaction and outcomes., Recent Findings: Decreasing utilization of orthotopic diversion has coincided with the increasing utilization of minimally invasive surgical techniques. A multicentre robotic series demonstrated a higher incidence of high-grade complications with intracorporeal diversion, reflecting the learning-curve associated with this technique. Patient satisfaction with urinary diversion is associated with informed decision-making and goal alignment. Ongoing quality of life studies is aiming to identify predictors of patient satisfaction with the selected urinary diversion and may help guide patient counselling., Summary: Given the potential advantages of orthotopic diversion, its decreasing use is a concerning trend. Elucidating patient goals and informed decision-making are critical to patient satisfaction. A patient-centred approach should be used when selecting the type of urinary diversion for a given patient.

Purpose: Urothelial cancers (UCs) have a substantial hereditary component, but, other than their association with Lynch syndrome, the contribution of genetic risk factors to UC pathogenesis has not been systematically defined. We sought to determine the prevalence of pathogenic/likely pathogenic (P/LP) germline variants in patients with UC and identify associated clinical factors., Patients and Methods: Overall, 586 patients with UC underwent prospective, matched tumor-normal DNA sequencing. Seventy-seven genes associated with cancer predisposition were analyzed; allele frequencies were compared with publicly available database., Results: P/LP germline variants were identified in 80 (14%) of 586 individuals with UC. The most common P/LP variants in high- or moderate-penetrance genes were BRCA2 (n = 9; 1.5%), MSH2 (n = 8; 1.4%), BRCA1 (n = 8; 1.4%), CHEK2 (n = 6; 1.0%), ERCC3 (n = 4; 0.7%), and NBN and RAD50 (n = 3; 0.5% each). Sixty-six patients (83%) had germline P/LP variants in DNA-damage repair (DDR) genes, of which 28 (42%) had biallelic inactivation. Patients with P/LP variants were more commonly diagnosed at an early age (22% v 6% in those without variants; P = .01). BRCA2 and MSH2 were significantly associated with an increased risk for UC (odds ratio, 3.7 [ P = .004] and 4.6 [ P = .001], respectively). Current clinical guidelines for referral for genetic testing failed to identify 6 (26%) patients with high-penetrance variants., Conclusion: Clinically significant P/LP germline variants in DDR genes frequently are present in patients with advanced UC. The presence of DDR germline variants could guide cancer screening for patients and their families and serve as predictive biomarkers of response to targeted or immunotherapies. Family history-based criteria to identify patients with hereditary UC susceptibility are insensitive. Broader germline testing in UC, particularly in those of young ages, should be considered.

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., (Copyright © 2019 European Society of Medical Oncology and European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate differences in the incidence of benign ureteroenteric stricture, we compared stricture rates of robot-assisted radical cystectomy (RARC) and open radical cystectomy (ORC) using Surveillance, Epidemiology, and End Results-Medicare data., Methods: We identified 332 RARC and 1449 ORC performed between 2009 and 2014 to determine stricture rates at 6, 12, and 24 months following surgery. We defined ureteroenteric stricture as the need for procedural intervention. Additionally, we compared the incidence of stricture diagnosis. Multivariable proportional hazards regression was performed to determine factors associated with stricture development., Results: The incidence of ureteroenteric stricture at 6 and 12 months was higher for RARC vs ORC at 12.1% vs 7.0% (P < .01) and 15.0% vs 9.5% (P = .01), respectively. RARC vs ORC stricture incidence at 2 years did not differ significantly at 14.6% vs 11.4% (P = .29). Similarly, the stricture diagnosis rates were significantly lower following ORC at 6, 12, and 24 months (P < .05). In adjusted analysis, RARC (HR 1.64, 95%CI 1.23-2.19) and preoperative hydronephrosis (HR 1.51, 95% CI 1.17-1.94) were associated with the development of stricture. Higher hospital volume was associated with a lower risk of stricture (HR 0.40, 95%CI 0.26-0.63)., Conclusion: RARC is associated with a higher rate of ureteroenteric stricture diagnosis and intervention on a population-based level that is mitigated by higher hospital volume. A significant study limitation is inability to differentiate extracorporeal vs intracorporeal diversion. However, a stricture complication compounds the financial burden of care and efforts must be pursued to improve this surgical outcome., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction and Objective: Robot-assisted radical cystectomy (RARC) with intracorporeal urinary diversion (ICUD) has become an increasingly utilized approach to treating various bladder pathologies requiring extirpation. As surgeons have become more experienced with ICUD, especially with lesser-used diversions such as continent cutaneous reservoirs, the technique has evolved., Methods: We describe our technique and recent advances in the practical creation of robotic ICUD with a continent catheterizable pouch (CCP) built upon the open principles of the previously described "Indiana Pouch, " which uses the distal ileum and right colon. Modifications in anatomic mobilization and exposure, bowel segmentation using novel robotic bowel staplers, catheterizable channel creation, and addition of ileal chimney for uretero-enteric anastomoses are highlighted. The addition of the ileal chimney allows for ease of reconstruction in a fashion familiar to surgeons accustomed to performing intracorporeal ileal conduit and, therefore, may result in lower ureteroenteric stricture rates. Table 1 demonstrates the supplies used intraoperatively. Use of indocyanine green to assess vascularity in bowel and ureter intraoperatively is demonstrated. The port configurations are demonstrated using the DaVinci ® Xi platform. Also described are short-term outcomes of our initial experience., Results: Eleven consecutive patients (5 female) who have undergone ICUD with CCP were included. Of the eleven seven had malignant indications (bladder or urethral cancer) while 4 were for benign causes (2 radiation cystitis 2 interstitial cystitis). Mean blood loss was 235cc (range 100-500cc) and mean operative time was 8.5 h (range 7-13). There were no conversions to an open procedure and no patient required a blood transfusion. Hospital stay was 7.2 days on average (range 4-18) with no 30-day post-discharge readmissions. One patient had a Clavien grade 3 or greater complication at 30 days (Table 2). No urine leaks or bowel leaks were observed and no patien experienced stomal stenosis or uretero-enteric stenosis. At three months follow up, all patients were continent and satisfied with their diversion., Conclusions: RARC with CCP ICUD is a safe and effective approach to bladder removal and reconstruction. As more surgeons utilize RARC, growing attention to techniques of intracorporeal reconstruction will allow further implementation of this technique to cystectomy patients. Patients with adequate renal function (glomerular filtration rate of 40 mL/min or greater) and hepatic function, who understand the requirement for regular clean intermittent-catheterization and who possess mental acuity and manual dexterity to empty their pouch 4-6 times daily should be offered CCP ICUD as a reconstructive option following RARC., Competing Interests: Declartion of Competing Interest None.

Competing Interests: Conflicts of Interest: EJ Pietzak: Scientific Advisory Board: Merck; Consultant: Chugai Pharma. H Al-Ahmadie: Consultant: Bristol-Myers-Squibb, AstraZeneca, EMD Ser-ono. DF Bajorin: Honoraria from the speaker’s bureau of Merck; Consultant/advisory board: Merck, Pfizer, Bristol-Myers Squibb, Urogen, Genentech,Eli Lilly. JE Rosenberg: Stock and Other Ownership Interests: Merck, Illumina; Honoraria: UpToDate, Bristol-Myers Squibb, AstraZeneca, Medscape, Vindico, Peerview, Chugai Pharma; Consulting or Advisory Role: Lilly, Merck, Agensys, Roche/Genentech, Sanofi, AstraZeneca/MedImmune, Bristol-Myers Squibb, EMD Serono, Seattle Genetic, Bayer, InovioPharmaceuticals, BioClin Therapeutics, QED Therapeutic, Adicet Bio,Sensei Biotherapeutics; Patents, Royalties, Other Intellectual Property: Predictor of platinum sensitivity; Research Funding: Genentech, Oncogenex, Agensys, Mirati Therapeutics, Novartis, Viralytics, Genen-tech/Roche, Incyte, Seattle Genetics, Bayer; Travel, Accommodations, Expenses: Genentech/Roche, Bristol-Myers Squibb. BH Bochner: Chair of data safety monitoring committee: Genentech; CourseInstructor: Olympus. DB Solit: Consultant for Pfizer, Loxo Oncology and Illumina. G Iyer: Consultant: Bayer.

Purpose: To evaluate patient-reported outcomes (PROs) for bladder cancer patients undergoing neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) using longitudinal data and propensity-matched scoring analyses., Methods: 155 patients with muscle-invasive bladder cancer scheduled for RC completed the European Organization for Research and Treatment of Cancer questionnaires, EORTC QLQ-C30, EORTC QLQ-BLM30, Fear of Recurrence Scale, Mental Health Inventory and Satisfaction with Life Scale within 4 weeks of surgery. A propensity-matched analysis was performed comparing pre-surgery PROs among 101 patients who completed NAC versus 54 patients who did not receive NAC. We also compared PROs pre- and post-chemotherapy for 16 patients who had data available for both time points., Results: In propensity-matched analysis, NAC-treated patients reported better emotional and sexual function, mental health, urinary function and fewer financial concerns compared to those that did not receive NAC. Longitudinal analysis showed increases in fatigue, nausea and appetite loss following chemotherapy., Conclusion: Propensity-matched analysis did not demonstrate a negative effect of NAC on PRO. Several positive associations of NAC were found in the propensity-matched analysis, possibly due to other confounding differences between the two groups or actual clinical benefit. Longitudinal analysis of a small number of patients found small to modest detrimental effects from NAC similar to toxicities previously reported. Our preliminary findings, along with known survival and toxicity data, should be considered in decision-making for NAC.

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 before 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), 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, 33 (28%) statements achieved level 1 consensus and 49 (42%) statements 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 where further evidence is available to guide our approach., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Inverted urothelial papilloma (IUP) and urothelial papilloma (UP) are rare urothelial neoplasms that typically follow a benign clinical course. Oncogenic mutations in FGFR3, HRAS, and the TERT promoter have been reported in these entities but no comprehensive molecular analysis has been performed. We sought to characterize the genomic landscape of IUP and UP using whole-exome and targeted next-generation sequencing. In IUP, 10 of 11 tumors harbored oncogenic hotspot mutations in HRAS and the remaining tumor had an oncogenic KRAS mutation. None of the IUP tumors harbored TERT promoter or FGFR3 mutations. In UP, 8 of 11 tumors had oncogenic KRAS mutations and two had oncogenic HRAS mutations. One UP tumor had oncogenic mutations in FGFR3, PIK3CA, and the TERT promoter, and arose in a patient with recurrent non-invasive papillary urothelial carcinomas. In contrast to urothelial carcinoma, the APOBEC mutational signature was not present in any IUP and UP tumors, and oncogenic alterations in chromatin remodeling genes were uncommon in both IUP and UP. The current study suggests that IUP and UP are driven primarily by RAS pathway activation and lack the more common genomic features of urothelial cancers. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

The introduction of immune checkpoint blockade (ICB) therapy has transformed the management of advanced bladder cancer (BC). Despite its limitations, PD-L1 immunohistochemistry may serve as a predictive biomarker of anti-PD-L1/PD1 therapy. While urothelial carcinoma (UC) patients with predominant or pure variant histology (UCV) account for up to one-third of advanced cases, to date, most ICB BC studies have excluded patients with such histologies. To assess the potential utility of ICB in patients with UCV, we analyzed PD-L1 expression in UCV and compared 3 commonly used and commercially available PD-L1 antibodies. Full sections from 84 UCV cases were stained with clones SP263, 22C3, and SP142, all of which are considered predictive assays to identify UC patients who are more likely to respond to anti-PD-1/PD-L1 inhibitors durvalumab, pembrolizumab, and atezolizumab, respectively. Expression on tumor cells (TC) and tumor-infiltrating immune cells (IC) was assessed. Staining extent and characteristics were evaluated, and concordance among the 3 clones was determined at various cutoff points as used in previous studies in BC. We found that PD-L1 was expressed in a significant percentage of UCV cases at different cutoff points (cutoff 1% TC: 37% to 54%, cutoff 5% TC: 23% to 37%), with the highest expression in UC with squamous differentiation. These figures are equal to or higher than those for classic/pure UC (4% to 30%). The results suggest that patients with UCV may benefit from anti-PD-1/PD-L1 therapy and argue against the exclusion of UC with predominant or pure variant histology from clinical ICB studies. The highest expression in both TC and IC was observed with clone SP263, followed by 22C3 and SP142, and all clones showed strong agreement in a pairwise comparison, both in TC and IC (R-values: 0.780 to 0.901), which indicates that all 3 clones are potentially useful in the evaluation of PD-L1 expression in UCV.

Purpose: As we begin to leverage Big Data in health care settings and particularly in assessing patient-reported outcomes, there is a need for novel analytics to address unique challenges. One such challenge is in coding transcribed interview data, typically free-text entries of statements made during a face-to-face interview. Latent Dirichlet Allocation (LDA) offers statistical rigor and consistency in automating the interpretation of patients' expressed concerns and coping strategies., Methods: LDA was applied to interview data collected as part of a prospective, longitudinal study of QOL in N = 211 patients undergoing radical cystectomy and urinary diversion for bladder cancer. LDA analyzed personal goal statements to extract the latent topics and themes, stratified by time, and on things patients wanted to accomplish and prevent. Model comparison metrics determined the number of topics to extract., Results: LDA extracted seven latent topics. Prior to surgery, patients' priorities were primarily in cancer surgery and recovery. Six months after the surgery, they were replaced by goals on regaining a sense of normalcy, to resume work, to enjoy life more fully, and to appreciate friends and family more. LDA model parameters showed changing priorities, e.g., immediate concerns on surgery and resuming employment decreased post-surgery and were replaced by concerns over cancer recurrence and a desire to remain healthy and strong., Conclusions: Novel Big Data analytics such as LDA offer the possibility of summarizing personal goals without the need for conventional fixed-length measures and resource-intensive qualitative data coding.

Urothelial carcinoma of the upper tract (UTUC) presents specific challenges regarding accurate staging and tumor sampling. We aimed to assess the feasibility of applying next-generation sequencing to biopsy specimens and gauged the concordance of their genetic profiles with matched radical nephroureterectomy (RNU) specimens. Of the 39 biopsy specimens collected, 36 (92%) had adequate material for sequencing using a hybridization-based exon capture assay (MSK-IMPACT). The most frequently altered genes across the patient cohort were consistent with the urothelial carcinoma-associated alterations identified in a cohort of 130 RNU specimens previously sequenced at our center, including mutations in the TERT promoter (64%), hotspot activating mutations in FGFR3 (64%), and frequent mutations in chromatin remodeling genes. For 12 patients, a matching tumor sample from a subsequent RNU was sequenced. We found a high level of concordance between matched biopsy and RNU specimens, up to 92% for the likely pathogenic alterations. PATIENT SUMMARY: We evaluated the feasibility of genomic characterization of tumor tissue collected at the time of ureteroscopic biopsy and found high concordance with subsequent radical nephroureterectomy specimens. Molecular characterization of urothelial carcinoma of the upper tract biopsies could guide treatment decision-making and identify high-risk patients who could benefit from neoadjuvant chemotherapy and low-risk patients who could benefit from conservative or organ-sparing strategies., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed the clinical and genomic data of 1,662 advanced cancer patients treated with ICI, and 5,371 non-ICI-treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all patients, higher somatic TMB (highest 20% in each histology) was associated with better overall survival. For most cancer histologies, an association between higher TMB and improved survival was observed. The TMB cutpoints associated with improved survival varied markedly between cancer types. These data indicate that TMB is associated with improved survival in patients receiving ICI across a wide variety of cancer types, but that there may not be one universal definition of high TMB.

Background: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is the standard of care for patients with muscle-invasive bladder cancer (MIBC). It is unknown whether this treatment strategy is appropriate for patients who progress to MIBC after treatment for prior noninvasive disease (secondary MIBC)., Objective: To determine whether clinical and genomic differences exist between primary and secondary MIBC treated with NAC and RC., Design, Setting, and Participants: Clinicopathologic outcomes were compared between 245 patients with clinical T2-4aN0M0-stage primary MIBC and 43 with secondary MIBC treated with NAC and RC at Memorial Sloan Kettering Cancer Center (MSKCC) from 2001 to 2015. Genomic differences were assessed in a retrospective cohort of 385 prechemotherapy specimens sequenced by whole-exome or targeted exon capture by the Cancer Genome Atlas or at MSKCC. Findings were confirmed in an independent validation cohort of 94 MIBC patients undergoing prospective targeted exon sequencing at MSKCC., Outcome Measurements and Statistical Analysis: Pathologic response rates, recurrence-free survival (RFS), bladder cancer-specific survival (CSS), and overall survival (OS) were measured. Differences in somatic genomic alteration rates were compared using Fisher's exact test and the Benjamini-Hochberg false discovery rate method., Results and Limitations: Patients with secondary MIBC had lower pathologic response rates following NAC than those with primary MIBC (univariable: 26% vs 45%, multivariable: odds ratio=0.4 [95% confidence interval=0.18-0.84] p=0.02) and significantly worse RFS, CSS, and OS. Patients with secondary MIBC treated with NAC had worse CSS compared with cystectomy alone (p=0.002). In a separate genomic analysis, we detected significantly more likely deleterious somatic ERCC2 missense mutations in primary MIBC tumors in both the discovery (10.9% [36/330] vs 1.8% [1/55], p=0.04) and the validation (15.7% [12/70] vs 0% [0/24], p=0.03) cohort., Conclusions: Patients with secondary MIBC treated with NAC had worse clinical outcomes than similarly treated patients with primary MIBC. ERCC2 mutations predicted to result in increased cisplatin sensitivity were enriched in primary versus secondary MIBC. Prospective validation is still needed, but given the lack of clinical benefit with cisplatin-based NAC in patients with secondary MIBC, upfront RC or enrollment in clinical trials should be considered., Patient Summary: A retrospective cohort study of patients with "primary" and "secondary" muscle-invasive bladder cancer (MIBC) treated with chemotherapy before surgical removal of the bladder identified lower response rates and shorter survival in patients with secondary MIBC. Tumor genetic sequencing of separate discovery and validation cohorts revealed that chemotherapy-sensitizing DNA damage repair gene mutations occur predominantly in primary MIBC tumors and may underlie the greater sensitivity of primary MIBC to chemotherapy. Prospective validation is still needed, but patients with secondary MIBC may derive greater benefit from upfront surgery or enrollment in clinical trials rather than from standard chemotherapy., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: To investigate genomic differences between urothelial carcinomas of the upper tract (UTUC) and bladder (UCB), with a focus on defining the clonal relatedness of temporally distinct tumors., Experimental Design: We prospectively sequenced tumors and matched germline DNA using targeted next-generation sequencing methods. The cohort included 195 UTUC patients and 454 UCB patients. For a subgroup of 29 patients with UTUC and a history of a subsequent UCB, both tumors were analyzed to assess their clonal relatedness., Results: With the progression to higher UTUC clinical state, there were fewer alterations in the RTK/RAS pathway but more alterations in TP53/MDM2. Compared with UCB, TP53, RB1, and ERBB2 were less frequently altered in UTUC (26% vs. 46%, 3% vs. 20%, 8% vs. 19%, respectively; Q < 0.001), whereas FGFR3 and HRAS were more frequently altered (40% vs. 26%, 12% vs. 4%, respectively; Q < 0.001). On the basis of an integrated analysis of tumor mutational burden, MSIsensor score and mutational signature, 7.2% of UTUC tumors were classified as MSI-high/MMR-deficient (MSI-H/dMMR). The risk of bladder recurrence after UTUC was significantly associated with mutations in FGFR3, KDM6A, CCND1, and TP53 . Comparison of UCB with corresponding UTUC tumors from the same patient supports their clonal relatedness., Conclusions: UTUC and UCB exhibit significant differences in the prevalence of common genomic alterations. In individual patients with a history of both tumors, UCB and UTUC were always clonally related. Genomic characterization of UTUC provides information regarding the risk of bladder recurrence and can identify tumors associated with Lynch syndrome., (©2018 American Association for Cancer Research.)

Background: Patient response burden is often raised as a human subject concern in consideration of the length or complexity of patient-reported outcome (PRO) instruments used in oncology., Objectives: To quantify patient response burden and identify its predictive factors., Methods: Data were collected presurgically during a prospective trial that used a comprehensive symptom and health-related quality-of-life (HRQOL) PRO assessment. A subset of patients also completed HRQOL interviews. Response burden was captured using an internally developed six-item instrument. Demographic and clinical characteristics as well as HRQOL scores were examined as potential predictors using hierarchical regression. Response burden was used to predict participant dropout at the first follow-up interval., Results: A total of 275 patients (mean age 67.5 years; 23.6% female) completed surveys (n = 126) or surveys in addition to interviews (n = 149). Patients experienced low response burden (mean 12.19 ± 11.65). Repetitive questions were identified by 60 patients (21.8%), whereas 31.6% indicated that additional information should be gathered; 35 patients (12.7%) identified repetitive questions and expressed a desire for additional items. Low self-reported cognitive function was a significant predictor of higher response burden (β = -0.20; t(270) = -3.38; P = 0.01; model-adjusted R 2 = 0.04). Response burden was not a significant predictor of study dropout., Conclusions: Despite completing a large battery of PRO measures and interviews, patients reported minimal response burden, with nearly one-third expressing that more questions should have been asked. Patients with lower cognitive function are more likely to report higher response burden when completing PRO measures. Further examination of patient characteristics related to response burden may reveal useful pathways for tailoring patient-centered interventions., (Copyright © 2019 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Purpose: While a definitive cure can be achieved by radical cystectomy and pelvic lymph node dissection in select patients with regional lymphadenopathy, the benefit remains uncertain in patients who present with non-regional metastases. We analyzed the survival outcomes of post-chemotherapy retroperitoneal lymph node dissection., Materials and Methods: We reviewed our institutional database and identified 13 patients with radiographically evident or biopsy proven retroperitoneal nodal metastases with a significant response to chemotherapy. These patients underwent consolidative surgery with concomitant or delayed retroperitoneal lymph node dissection. The primary endpoints were progression-free survival and disease-specific survival from the time of retroperitoneal lymph node dissection., Results: All patients had primary urothelial cell carcinoma. Twelve patients underwent concomitant radical cystectomy, pelvic and retroperitoneal lymph node dissection. Seven patients (54%) had residual disease in the retroperitoneum and the median number of retroperitoneal nodes containing metastases was 4 (IQR 2-6). Six (86%) developed disease recurrences within 2 years of surgery and 5 (71%) died of cancer. Of the 6 patients without residual disease in the retroperitoneum, 2 (33%) developed recurrences and died of disease progression. The 2-year disease-specific survival was worse for patients with residual disease in the retroperitoneum than those without residual retroperitoneal disease (34%, 95% CI 5-68 vs 50%, 95% CI 6-85)., Conclusions: The presence of retroperitoneal nodal metastases at post-chemotherapy retroperitoneal lymph node dissection is a poor prognosticator. Consolidative surgery with retroperitoneal lymph node dissection provides important prognostic information and may be therapeutic in a very small subset of these patients., Competing Interests: None of the authors have any conflict of interests.

Purpose: To provide a summary of the Third International Consultation on Bladder Cancer recommendations for the management of non-muscle invasive bladder cancer (NMIBC)., Methods: A detailed review of the literature was performed focusing on original articles for the management of NMIBC. An international committee assessed and graded the articles based on the Oxford Centre for Evidence-based Medicine system. The entire spectrum of NMIBC was covered such as prognostic factors of recurrence and progression, risk stratification, staging, management of positive urine cytology with negative white light cystoscopy, indications of bladder and prostatic urethral biopsies, management of Ta low grade (LG) and high risk tumors (Ta high grade [HG], T1, carcinoma in situ [CIS]), impact of BCG strain and host on outcomes, management of complications of intravesical therapy, role of alternative therapies, indications for early cystectomy, surveillance strategies, and new treatments. The working group provides several recommendations on the management of NMIBC., Results: Recommendations were summarized with regard to staging; management of primary and recurrent LG Ta and high risk disease, positive urine cytology with negative white light cystoscopy and prostatic urethral involvement; indications for timely cystectomy; and surveillance strategies., Conclusion: NMIBC remains a common and challenging malignancy to manage. Accurate staging, grading, and risk stratification are critical determinants of the management and outcomes of these patients. Current tools for risk stratification are limited but informative, and should be used in clinical practice when determining diagnosis, surveillance, and treatment of NMIBC.

Background: The clinical significance of the plasmacytoid variant (PCV) in urothelial carcinoma (UC) is currently lacking., Objective: To compare clinical outcomes of patients with any PCV with that of patients with pure UC treated with radical cystectomy (RC)., Design, Setting, and Participants: We identified 98 patients who had pathologically confirmed PCV UC and 1312 patients with pure UC and no variant history who underwent RC at our institution between 1995 and 2014., Outcome Measurements and Statistical Analysis: Univariable and multivariable Cox regression and Cox proportional hazards regression to determine if PCV was associated with overall survival (OS)., Results and Limitations: Patients with PCV UC were more likely to have advanced tumor stage (p=0.001), positive lymph nodes (p=0.038), and receive neoadjuvant chemotherapy than those with pure UC (46% vs 22%, p<0.0001). The rate of positive soft tissue surgical margins was over five times greater in the PCV UC group compared with the pure UC group (21% vs 4.1%, respectively, p<0.0001). Median OS for the pure UC versus the PCV patients were 8 yr and 3.8 yr, respectively. On univariable analysis, PCV was associated with an increased risk of overall mortality (hazard ratio=1.34, 95% confidence interval: 1.02-1.78, p=0.039). However, on multivariable analysis adjusted for age, sex, neoadjuvant chemotherapy received, lymph node status, pathologic stage, and soft margin status, the association between PCV and OS was no longer significant (hazard ratio=1.06, 95% confidence interval: 0.78, 1.43, p=0.7). This retrospective study is limited by the lack of pathological reanalysis, and the impact of other concurrent mixed histology cannot be determined in this study., Conclusions: Patients with PCV features have a higher disease burden at RC compared with those with pure UC. However, PCV was not an independent predictor of survival after RC on multivariable analysis, suggesting that PCV histology should not be used as an independent prognostic factor., Patient Summary: Plasmacytoid urothelial carcinoma is a rare and aggressive form of bladder cancer. Patients with plasmacytoid urothelial carcinoma had worse adverse pathologic features, but this was not associated with worse overall mortality when compared with patients with pure urothelial carcinoma., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: To provide a comprehensive overview and update of the joint consultation of the International Consultation on Urological Diseases (ICUD) and Société Internationale d'Urologie on Bladder Cancer Urinary Diversion (UD)., Methods: A detailed analysis of the literature was conducted reporting on the different modalities of UD. For this updated publication, an exhaustive search was conducted in PubMed for recent relevant papers published between October 2013 and August 2018. Via this search, a total of 438 references were identified and 52 of them were finally eligible for analysis. An international, multidisciplinary expert committee evaluated and graded the data according to the Oxford System of Evidence-based Medicine., Results: The incidence of early complications has been reported retrospectively in the range of 20-57%. Unfortunately, only a few randomized controlled studies exist within the field of UD. Consequently, almost all studies used in this report are of level 3-4 evidence including expert opinion based on "first principles" research., Conclusions: Complications rates overall following RC and UD are significant, and when strict reporting criteria are incorporated, they are much higher than previously published. Complications can occur up to 20 years after surgery, emphasizing the need for lifelong follow-up. Progress has been made to prevent complications implementing robotic surgery and fast track protocols. Preoperative patient information, patient selection, surgical techniques, and careful postoperative follow-up are the cornerstones to achieve good results.

Objective: To assess the impact on recovery of bowel function using an 80 mm versus 60 mm gastrointestinal anastomosis (GIA) stapler following radical cystectomy and urinary diversion (RC/UD) for bladder cancer., Methods: We identified 696 patients using a prospectively maintained RC/UD database from January 2006 to November 2010. Two nonrandomized consecutive cohorts were compared. Patients between January 2006- and December 2007 (n = 180) were treated using a 60 mm GIA stapler, and 331 patients between January 2008 and December 2010 were subject to an 80 mm GIA stapler. All patients were treated on the same standardized postoperative recovery pathway. After accounting for baseline patient and perioperative characteristics, using a multivariable logistic regression model, we directly compared rates of postoperative ileus using a standardized definition., Results: Of 511 evaluable patients, ileus was observed in 32% (57/180) for 60 mm GIA versus 33% (110/331) for the 80 mm GIA. Preoperative renal function, age, gender, body mass index, and type of diversion were comparable between cohorts. On multivariate analysis, stapler size was not significantly associated with the development of ileus (GIA-60 vs GIA-80: OR 1.11; 95% CI 0.75, 1.66; P = .6). Positive fluid balance was associated with an increased risk (P = .019) and female sex a decreased risk (P = .008) of developing ileus compared to patients with negative fluid balance., Conclusion: The size of the intestinal bowel anastomosis (GIA 80 mm vs 60 mm) does not independently impact the time to bowel recovery following RC/UD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: We aimed to develop a structured scoring tool: cystectomy assessment and surgical evaluation (CASE) that objectively measures and quantifies performance during robot-assisted radical cystectomy (RARC) for men., Methods: A multinational 10-surgeon expert panel collaborated towards development and validation of CASE. The critical steps of RARC in men were deconstructed into nine key domains, each assessed by five anchors. Content validation was done utilizing the Delphi methodology. Each anchor was assessed in terms of context, score concordance, and clarity. The content validity index (CVI) was calculated for each aspect. A CVI ≥ 0.75 represented consensus, and this statement was removed from the next round. This process was repeated until consensus was achieved for all statements. CASE was used to assess de-identified videos of RARC to determine reliability and construct validity. Linearly weighted percent agreement was used to assess inter-rater reliability (IRR). A logit model for odds ratio (OR) was used to assess construct validation., Results: The expert panel reached consensus on CASE after four rounds. The final eight domains of the CASE included: pelvic lymph node dissection, development of the peri-ureteral space, lateral pelvic space, anterior rectal space, control of the vascular pedicle, anterior vesical space, control of the dorsal venous complex, and apical dissection. IRR > 0.6 was achieved for all eight domains. Experts outperformed trainees across all domains., Conclusion: We developed and validated a reliable structured, procedure-specific tool for objective evaluation of surgical performance during RARC. CASE may help differentiate novice from expert performances.

Objectives: To characterise the outcomes of neoadjuvant chemotherapy (NAC) pre-treated patients found to be lymph node (LN)-positive at the time of radical cystectomy and pelvic lymph node dissection (RC/PLND) for urothelial carcinoma of the bladder (UCB)., Patients and Methods: Of 1484 patients treated with RC/PLND for UCB from 2000 to 2010, we analysed 198 patients with clinically non-metastatic (cN0M0) muscle-invasive UCB who were found to be LN-positive at RC/PLND. As patients not receiving perioperative chemotherapy were significantly older and comorbid, we compared LN-positive patients previously treated with NAC (32 patients) to LN-positive patients treated with adjuvant chemotherapy (AC, 49 patients) using Cox proportional hazards models. A sensitivity analysis was designed to account for the additional time to RC in NAC patients., Results: The 3-year recurrence-free survival estimate for LN-positive NAC patients was 26%, compared with 60% for LN-positive AC patients. LN-positive patients treated with NAC had significantly higher risks of disease recurrence and cancer-specific mortality in univariate analyses (hazard ratio [HR] 2.86, 95% confidence interval [CI] 1.58-5.19, P = 0.001 and HR 2.50, 95% CI 1.34-4.65, P = 0.004, respectively) and multivariable analyses adjusting for pathological stage and LN density (HR 3.11, 95% CI 1.59-6.07, P = 0.001 and HR 3.05, 95% CI 1.46-6.35, P = 0.003, respectively). Sensitivity analyses similarly demonstrated worse outcomes for NAC pre-treated LN-positive patients., Conclusion: LN-positive patients previously treated with NAC have a poor prognosis, significantly worse than LN-positive patients subsequently treated with AC, and should be considered for protocols using sandwich chemotherapy approaches or novel agents. These results should be considered in the interpretation of and stratification for clinical trials., (© 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.)

Background: Open radical cystectomy (ORC) has proven to be an important component in the treatment of high-risk bladder cancer (BCa). ORC surgical morbidity remains high; therefore, minimally invasive surgical techniques have been introduced in an attempt to improve patient outcomes., Objective: To compare cancer outcomes in BCa patients managed with ORC or robotic-assisted radical cystectomy (RARC)., Design, Setting, and Participants: A prospective, randomized trial was completed between 2010 and 2013. Patients were randomized to ORC/pelvic lymphadenectomy (PLND) or RARC/PLND, with all undergoing open/extracorporeal urinary diversion. Median follow-up was 4.9 (IQR: 3.9-5.9) yr after surgery among surviving patients., Outcome Measurements and Statistical Analysis: Secondary outcomes to the trial included recurrence-free, cancer-specific, and overall survival., Results and Limitations: The trial randomized 118 patients who underwent RC/PLND and urinary diversion. Sixty were randomized to RARC and 58 to ORC. Four RARC-assigned patients refused randomization and received ORC; however, an intention to treat analysis was performed. No differences were observed in recurrence (hazard ratio [HR]: 1.27; 95% confidence interval [CI]: 0.69-2.36; p=0.4) or cancer-specific survival (p=0.4). No difference in overall survival was observed (p=0.8). However, the pattern of first recurrence demonstrated a nonstatistically significant increase in metastatic sites for those undergoing ORC (sub-HR [sHR]: 2.21; 95% CI: 0.96-5.12; p=0.064) and a greater number of local/abdominal sites in the RARC-treated patients (sHR: 0.34; 95% CI: 0.12-0.93; p=0.035). The major limitation to this study is that the trial was not powered to determine differences in cancer recurrences, survival outcomes, or patterns of recurrence., Conclusions: The secondary outcomes from our randomized trial did not definitively demonstrate differences in cancer outcomes in patients treated with ORC or RARC. However, differences in observed patterns of first recurrence highlight the need for future studies., Patient Summary: Of 118 patients randomly assigned to undergo radical cystectomy/pelvic lymphadenectomy and urinary diversion, half were assigned to open surgery and half to robot-assisted techniques. We found no difference in risk of recurring or dying of bladder cancer between the two groups., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context: Management of bladder cancer (BC) is primarily driven by stage, grade, and biological potential. Knowledge of each is derived using clinical, histopathological, and radiological investigations. This multimodal approach reduces the risk of error from one particular test, but may present a staging dilemma when results conflict. Multiparametric magnetic resonance imaging (mpMRI) may improve patient care through imaging of the bladder with better resolution of the tissue planes than computed tomography and without radiation exposure., Objective: To define a standardized approach to imaging and reporting mpMRI for BC, by developing a VI-RADS score., Evidence Acquisition: We created VI-RADS (Vesical Imaging-Reporting And Data System) through consensus using existing literature., Evidence Synthesis: We describe standard imaging protocols and reporting criteria (including size, location, multiplicity, and morphology) for bladder mpMRI. We propose a five-point VI-RADS score, derived using T2-weighted MRI, diffusion-weighted imaging, and dynamic contrast enhancement, which suggests the risks of muscle invasion. We include sample images used to understand VI-RADS., Conclusions: We hope that VI-RADS will standardize reporting, facilitate comparisons between patients, and in future years, will be tested and refined if necessary. While we do not advocate mpMRI for all patients with BC, this imaging may compliment pathology or reduce radiation-based imaging. Bladder mpMRI may be most useful in patients with non-muscle-invasive cancers, in expediting radical treatment or for determining response to bladder-sparing approaches., Patient Summary: Magnetic resonance imaging (MRI) scans for bladder cancer are becoming more common and may provide accurate information that helps improve patient care. Here, we describe a standardized reporting criterion for bladder MRI. This should improve communication between doctors and allow better comparisons between patients., (Copyright © 2018 European Association of Urology. All rights reserved.)

Purpose Neoadjuvant chemotherapy followed by radical cystectomy (RC) is a standard of care for the management of muscle-invasive bladder cancer (MIBC). Dose-dense cisplatin-based regimens have yielded favorable outcomes compared with standard-dose chemotherapy, yet the optimal neoadjuvant regimen remains undefined. We assessed the efficacy and tolerability of six cycles of neoadjuvant dose-dense gemcitabine and cisplatin (ddGC) in patients with MIBC. Patients and Methods In this prospective, multicenter phase II study, patients received ddGC (gemcitabine 2,500 mg/m 2 on day 1 and cisplatin 35 mg/m 2 on days 1 and 2) every 2 weeks for 6 cycles followed by RC. The primary end point was pathologic downstaging to non-muscle-invasive disease (< pT2N0). Patients who did not undergo RC were deemed nonresponders. Pretreatment tumors underwent next-generation sequencing to identify predictors of chemosensitivity. Results Forty-nine patients were enrolled from three institutions. The primary end point was met, with 57% of 46 evaluable patients downstaged to < pT2N0. Pathologic response correlated with improved recurrence-free survival and overall survival. Nineteen patients (39%) required toxicity-related dose modifications. Sixty-seven percent of patients completed all six planned cycles. No patient failed to undergo RC as a result of chemotherapy-associated toxicities. The most frequent treatment-related toxicity was anemia (12%; grade 3). The presence of a presumed deleterious DNA damage response (DDR) gene alteration was associated with chemosensitivity (positive predictive value for < pT2N0 [89%]). No patient with a deleterious DDR gene alteration has experienced recurrence at a median follow-up of 2 years. Conclusion Six cycles of ddGC is an active, well-tolerated neoadjuvant regimen for the treatment of patients with MIBC. The presence of a putative deleterious DDR gene alteration in pretreatment tumor tissue strongly predicted for chemosensitivity, durable response, and superior long-term survival.