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While there are no universally accepted standards for radical cystectomy and pelvic lymph node dissection in patients with locally advanced bladder cancer, accumulating data suggest that removing the bladder with a wide margin of perivesical fat and an increased number of lymph nodes reduces local recurrence and improves survival. [ABSTRACT FROM AUTHOR]

Bladder cancer, the sixth most common cancer in the United States, is most commonly of the urothelial carcinoma histologic subtype. The clinical spectrum of bladder cancer is divided into 3 categories that differ in prognosis, management, and therapeutic aims: (1) non-muscle-invasive bladder cancer (NMIBC); (2) muscle invasive, nonmetastatic disease; and (3) metastatic bladder cancer. These NCCN Guidelines Insights detail recent updates to the NCCN Guidelines for Bladder Cancer, including changes in the fifth edition of the WHO Classification of Tumours: Urinary and Male Genital Tumours and how the NCCN Guidelines aligned with these updates; new and emerging treatment options for bacillus Calmette-Guérin (BCG)-unresponsive NMIBC; and updates to systemic therapy recommendations for advanced or metastatic disease.

Importance: With the ongoing bacillus Calmette-Guèrin (BCG) shortage, alternate therapeutic options for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) are needed., Objective: To report the 5-year outcomes of a cohort from a prospective phase 2 trial of patients with high-risk NMIBC who underwent 12 instillations of induction BCG without maintenance., Design, Setting, and Participants: Between November 2015 and June 2018, patients at Memorial Sloan Kettering Cancer Center with primary or recurrent NMIBC (high-grade Ta, T1 tumors, with or without carcinoma in situ) were prospectively enrolled to receive 2 induction courses (12 intravesical instillations) of BCG without maintenance therapy. The analysis itself took place on July 28, 2023., Main Outcomes and Measures: Recurrence-free survival (RFS) and cancer-specific survival (CSS) was assessed by landmark analysis at 7.5 months. Recurrence was defined as pathologic high-grade disease., Results: Among 81 patients (65 men [84%] and 12 women [16%] with a median [IQR] age of 72 [64-77] years) who consented to participate in the study, 75 remained evaluable for long-term follow-up analysis. Twenty-one patients experienced high-grade recurrence, yielding a 5-year RFS rate of 69% (95% CI, 58%-81%), with a median (IQR) follow-up of 4.4 (3.8-5.3) years for patients without recurrence. Three patients died of bladder cancer, corresponding to a CSS rate of 97% (95% CI, 93%-100%) with a median (IQR) follow-up of 4.9 (4.2-5.7) years for survivors. Using 2 induction courses reduced the amount of BCG per patient from 27 vials to 12 vials., Conclusion and Relevance: Twelve induction instillations of BCG without maintenance for patients with high-risk NMIBC reduced the number of vials needed per patient while providing acceptable oncologic outcomes. Given the ongoing BCG shortage, this modified regimen may provide a suitable alternative in this setting.

Purpose: Patients with residual invasive bladder cancer after neoadjuvant chemotherapy (NAC) and radical cystectomy have a poor prognosis. Data on adjuvant therapy for these patients are conflicting. We sought to evaluate the natural history and genomic landscape of chemotherapy-resistant bladder cancer to inform patient management and clinical trials., Methods: Data were collected on patients with clinically localized muscle-invasive urothelial bladder cancer treated with NAC and cystectomy at our institution between May 15, 2001, and August 15, 2019, and completed four cycles of gemcitabine and cisplatin NAC, excluding those treated with adjuvant therapies. Survival was estimated using the Kaplan-Meier method, and multivariable Cox proportional hazards models were used to identify predictors of recurrence-free survival (RFS). Genomic alterations were identified in targeted exome sequencing (Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets) data from post-NAC specimens from a subset of patients., Results: Lymphovascular invasion (LVI) was the strongest predictor of RFS (hazard ratio, 2.15 [95% CI, 1.37 to 3.39]) on multivariable analysis. Patients with ypT2N0 disease without LVI had a significantly prolonged RFS compared with those with LVI (70% RFS at 5 years). Lymph node yield did not affect RFS. Among patients with sequencing data (n = 101), chemotherapy-resistant tumors had fewer alterations in DNA damage response genes compared with tumors from a publicly available chemotherapy-naïve cohort (15% v 29%; P = .021). Alterations in CDKN2A/B were associated with shorter RFS. PIK3CA alterations were associated with LVI. Potentially actionable alterations were identified in more than 75% of tumors., Conclusion: Although chemotherapy-resistant bladder cancer generally portends a poor prognosis, patients with organ-confined disease without LVI may be candidates for close observation without adjuvant therapy. The genomic landscape of chemotherapy-resistant tumors is similar to chemotherapy-naïve tumors. Therapeutic opportunities exist for targeted therapies as adjuvant treatment in chemotherapy-resistant disease.

Background: There is limited ability to accurately diagnose and clinically stage patients with upper tract urothelial carcinoma (UTUC). The most easily available and widely used urinary biomarker is urine cytology, which evaluates cellular material yet lacks sensitivity. We sought to assess the feasibility of performing next-generation sequencing (NGS) on urine cytology specimens from patients with UTUC and evaluate the genomic concordance with tissue from primary tumor., Methods: In this retrospective study, we identified 48 patients with a diagnosis of UTUC treated at Memorial Sloan Kettering Cancer Center (MSK) between 2019 and 2022 who had banked or fresh urine samples. A convenience cohort of matching, previously sequenced tumor tissue was used when available. Urine specimens were processed and the residual material, including precipitated cell-free DNA, was sequenced using our tumor-naïve, targeted exome sequencing platform that evaluates 505 cancer-related genes (MSK-IMPACT). The primary outcome was at least 1 detectable mutation in urinary cytology specimens. The secondary outcome was concordance to matched tissue (using ANOVA or Chi-Square, as indicated)., Results: Genomic sequencing was successful for 45 (94%) of the 48 urinary cytology patient samples. The most common mutations identified were TERT (62.2%), KMT2D (46.7%), and FGFR3 (35.6%). All patients with negative urine cytology and low-grade tissue had successful cytology sequencing. Thirty-six of the 45 patients had matching tumor tissue available; concordance to matched tissue was 55% overall (131 of the total 238 oncogenic or likely oncogenic somatic mutations identified). However, in 94.4% (n = 34/36) of patients, the cytology had at least 1 shared mutation with tissue. Eleven (30.6%) patients had 100% concordance between cytology and tissue., Conclusions: Sequencing urinary specimens from selective UTUC cytology is feasible in nearly all patients with UTUC. Prospective studies are underway to investigate a clinical role for this promising technology., Competing Interests: Declaration of Competing Interest Andrew B. Katims certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matters or materials discussed in the manuscripts (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Wesley Yip serves as a consultant/advisor to Gilead. Eugene J. Pietzak serves as a consultant/advisor to Merck, Chugai Pharma, QED Therapeutics, Janssen, and Urogen Pharma. Bernard H. Bochner serves as a consultant/advisor to Olympus. Hikmat Al-Ahmadie serves as a consultant/advisor to AstraZeneca/MedImmune, Janssen, and PAIGE.AI. David B. Solit serves as a consultant/advisor to Pfizer, Loxo/Lilly Oncology, Vividon Therapeutics, Scorpion Therapeutics, Fore Therapeutics, FOG Pharma, Rain Therapeutics, and BridgeBio. Jonathan A. Coleman has uncompensated cooperative research agreements with AngioDynamics and Metabolon. None of these companies contributed to or directed any of the research reported in this article. The other authors (Andrew B. Katims, Christopher Gaffney, Sanaz Firouzi, Andreas Aulitzky, S. Machele Donat, Timothy F. Donahue, Harry W. Herr, Guido Dalbagni, Kwanghee Kim, and Oscar Lin) declare that they have no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: Neoadjuvant chemotherapy (NAC) has proven survival benefits for patients with invasive urothelial carcinoma of the bladder, yet its role for upper tract urothelial carcinoma (UTUC) remains undefined. We conducted a multicenter, single-arm, phase II trial of NAC with gemcitabine and split-dose cisplatin (GC) for patients with high-risk UTUC before extirpative surgery to evaluate response, survival, and tolerability., Methods: Eligible patients with defined criteria for high-risk localized UTUC received four cycles of split-dose GC before surgical resection and lymph node dissection. The primary study end point was rate of pathologic response (defined as < ypT2N0). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety and tolerability., Results: Among 57 patients evaluated, 36 (63%) demonstrated pathologic response (95% CI, 49 to 76). A complete pathologic response (ypT0N0) was noted in 11 patients (19%). Fifty-one patients (89%) tolerated at least three complete cycles of split-dose GC, 27 patients (47%) tolerated four complete cycles, and all patients proceeded to surgery. With a median follow up of 3.1 years, 2- and 5-year PFS rates were 89% (95% CI, 81 to 98) and 72% (95% CI, 59 to 87), while 2- and 5-year OS rates were 93% (95% CI, 86 to 100) and 79% (95% CI, 67 to 94), respectively. Pathologic complete and partial responses were associated with improved PFS and OS compared with nonresponders (≥ ypT2N any; 2-year PFS 100% and 95% v 76%, P < .001; 2-year OS 100% and 100% v 80%, P < .001)., Conclusion: NAC with split-dose GC for high-risk UTUC is a well-tolerated, effective therapy demonstrating evidence of pathologic response that is associated with favorable survival outcomes. Given that these survival outcomes are superior to historical series, these data support the use of NAC as a standard of care for high-risk UTUC, and split-dose GC is a viable option for NAC.

Objectives: To analyse the risk of uretero-enteric anastomotic stricture in patients randomised to open (ORC) or robot-assisted radical cystectomy (RARC) with extracorporeal urinary diversion., Patients and Methods: We included 118 patients randomised to RARC (n = 60) or ORC (n = 58) at a single, high-volume institution from March 2010 to April 2013. Urinary diversion was performed by experienced open surgeons. Stricture was defined as non-malignant obstruction on imaging, corroborated by clinical status, and requiring procedural intervention. The risk of stricture within 1 year was compared between groups using Fisher's exact test., Results: In all, 58 and 60 patients were randomised to RARC and ORC, respectively. We identified five strictures, all in the ORC group. In patients with ≥1 year of follow-up, the increase in risk of stricture from open surgery was 9.3% (95% confidence interval 1.5%, 17%). Of the five strictures, three were managed endoscopically while two required open revision. There was no evidence that perioperative Grade 3-5 complications were associated with development of a stricture (P = 1) and no evidence of a difference in 24-month estimated glomerular filtration rate between arms (P = 0.15)., Conclusions: In this study at a high-volume centre, RARC with extracorporeal urinary diversion achieved excellent ureteric anastomotic outcomes. Purported increased risk of stricture is not a reason to avoid RARC. Future research should examine the impact of different surgical techniques and operator experience on the risk of stricture, especially as more intracorporeal diversions are performed., (© 2022 BJU International.)

Introduction: Small cell carcinoma of the bladder (SCCB) is a rare variant of bladder cancer with poor outcomes. We evaluated long-term outcomes of nonmetastatic (M0) and metastatic (M1) SCCB and correlated pathologic response with genomic alterations of patients treated with neoadjuvant chemotherapy (NAC)., Patients and Methods: Clinical history and pathology samples from SCCB patients diagnosed at our institution were reviewed., Results: One hundred and ninety-nine SCCB patients were identified. (M0: 147 [74%]; M1: 52 [26%]). Among M0 patients, 108 underwent radical cystectomy (RC) (NAC: 71; RC only: 23; adjuvant chemotherapy: 14); 14 received chemoradiotherapy; the rest received chemotherapy alone or no cancer-directed therapy. RC-only patients had a median follow-up of 9.1 years, and median disease-free survival (DFS) and overall survival (OS) were 1.1 and 1.2 years, respectively. NAC patients had pathologic response (

Background: Mucosal melanoma involving the urethra is a rare disease with distinct clinical and molecular characteristics and poor outcomes. Our current knowledge is limited by the small number of reports regarding this disease., Objective: To describe the clinical, pathological, and molecular characteristics of urethral melanoma., Methods: We summarized the clinicopathologic data for 31 patients treated for urethral melanoma from 1986-2017 at our institution. Genomic data from our institutional sequencing platform MSK-IMPACT ( n  = 5) and gene-specific PCR data on BRAF , KIT , and/or NRAS ( n  = 8) were compared to genomic data of cutaneous melanomas ( n  = 143), vulvar/vaginal melanomas ( n  = 24), and primary non-melanoma urethral tumors ( n  = 5) from our institutional database., Results: Twenty-three patients were diagnosed with localized disease, 7 had regional/nodal involvement and one had metastases. Initial treatment included surgery in 25 patients; seven had multimodal treatment. Median follow-up was 46 months (IQR 33-123). Estimated 5-year cancer-specific survival was 45%. No significant change in survival was observed based on a year of treatment.Primary urethral melanomas showed a higher frequency of TP53 mutations compared to cutaneous (80.0% vs. 18.2%, p  = 0.006) and vulvar/vaginal melanomas (80.0 vs. 25.0%, p  = 0.04). BRAF mutations were absent in urethral primaries (0% vs. 46% in cutaneous melanoma, p  = 0.02). Tumor mutation burden was higher in cutaneous than urethral melanomas ( p  = 0.04). Urethral melanomas had a higher number of somatic alterations compared to non-melanoma urethral tumors (median 11 vs. 5, p  = 0.03)., Conclusions: Our findings support a unique mutational landscape of urethral melanoma compared to cutaneous melanoma. Survival remains poor and is unchanged over the time studied., Competing Interests: B.H.B. is an Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. M.M.L. received research funds from KCI/Acelity, is an ad-hoc speaker for Intuitive Surgical, Inc. and serves in the advisory boards of JnJ/Ethicon and Takeda. A.G. is a consultant for Medtronic. R.M., B.H., R.G.D., A.S., N.E.B., E.R., A.N.S., S.M.D., H.W.H., G.D., T.F.D. declare no conflict of interests., (© 2022 – The authors. Published by IOS Press.)

The NCCN Guidelines for Bladder Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with bladder cancer and other urinary tract cancers (upper tract tumors, urothelial carcinoma of the prostate, primary carcinoma of the urethra). These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines regarding the treatment of non-muscle-invasive bladder cancer, including how to treat in the event of a bacillus Calmette-Guérin (BCG) shortage; new roles for immune checkpoint inhibitors in non-muscle invasive, muscle-invasive, and metastatic bladder cancer; and the addition of antibody-drug conjugates for metastatic bladder cancer.

Purpose: To compare oncologic outcomes and genomic alteration profiles in patients with bladder and urachal adenocarcinoma, urothelial carcinoma (UC) with glandular differentiation, and UC, not otherwise specified (NOS) undergoing surgical resection, with emphasis on response to systemic therapy., Methods: We identified patients with bladder cancer with glandular variants who underwent surgical resection at Memorial Sloan Kettering from 1995 to 2018 (surgical cohort) and/or patients who had tumor sequencing using a targeted next-generation sequencing platform (genomics cohort). Pathologic complete and partial response rates to neoadjuvant chemotherapy (NAC) and recurrence-free and cancer-specific survival were measured. Alteration frequencies between histologic subtypes were compared., Results: Thirty-seven patients with bladder adenocarcinoma, 46 with urachal adenocarcinoma, 84 with UC with glandular differentiation, and 1,049 with UC, NOS comprised the surgical cohort. Despite more advanced disease in patients with bladder and urachal adenocarcinoma, no significant differences in recurrence or cancer-specific survival by histology were observed after adjusting for stage. In patients with UC with glandular differentiation, NAC resulted in partial (≤ pT1N0) and complete (pT0N0) responses in 28% and 17%, respectively. Bladder and urachal adenocarcinoma genomic profiles resembled colorectal adenocarcinoma with frequent TP53 , KRAS , and PIK3CA alterations while the genomic profile of UC with glandular differentiation more closely resembled UC, NOS. Limitations include retrospective nature of analysis and small numbers of nonurothelial histology specimens., Conclusion: The genomic profile of bladder adenocarcinomas resembled colorectal adenocarcinomas, whereas UC with glandular differentiation more closely resembled UC, NOS. Differences in outcomes among patients with glandular bladder cancer variants undergoing surgical resection were largely driven by differences in stage. Cisplatin-based NAC demonstrated activity in UC with glandular differentiation, suggesting NAC should be considered for this histologic variant.

Purpose: Our goal was to determine the association between biochemically verified post-diagnosis smoking exposure and nonmuscle-invasive bladder cancer (NMIBC) recurrence risk., Materials and Methods: We conducted a prospective study of 354 NMIBC patients with a smoking history undergoing care between 2015 and 2018. Patients contributed at least 2 biospecimens during followup which were tested for cotinine to determine biochemically verified post-diagnosis smoking exposure (yes/no). Our primary endpoint was time to first recurrence after study start date. We examined whether post-diagnosis smoking exposure was associated with recurrence risk in multivariable Cox proportional hazards models that accounted for demographics, clinicopathological variables, time since diagnosis and pack-years., Results: Patients were predominantly White, male and had a median age of 68 years. Most patients had Ta disease (62%) and tumors of high grade (68%). Intravesical bacillus Calmette-Guérin was given to 63% of the cohort. Patients were followed for a median of 3.6 years since study start. Post-diagnosis smoking exposure was detected in 22% of patients, and 38.7% (137) of patients experienced a recurrence during followup. In multivariable models, only bacillus Calmette-Guérin treatment and prior recurrence rate were significantly associated with recurrence. There was no association between post-diagnosis smoking exposure and recurrence risk (HR: 0.73, 95% CI: 0.45-1.20)., Conclusions: In a cohort of patients with predominantly high risk NMIBC, post-diagnosis smoking exposure was not associated with NMIBC recurrence. However, smoking cessation support remains a critical component of cancer care given that the benefits of quitting extend far beyond NMIBC recurrence.

Purpose: Neoadjuvant gemcitabine and cisplatin (GC) followed by radical cystectomy (RC) is standard for patients with muscle-invasive bladder cancer (MIBC). On the basis of the activity of atezolizumab (A) in metastatic BC, we tested neoadjuvant GC plus A for MIBC., Methods: Eligible patients with MIBC (cT2-T4aN0M0) received a dose of A, followed 2 weeks later by GC plus A every 21 days for four cycles followed 3 weeks later by a dose of A before RC. The primary end point was non-muscle-invasive downstaging to < pT2N0., Results: Of 44 enrolled patients, 39 were evaluable. The primary end point was met, with 27 of 39 patients (69%) < pT2N0, including 16 (41%) pT0N0. No patient with < pT2N0 relapsed and four (11%) with ≥ pT2N0 relapsed with a median follow-up of 16.5 months (range: 7.0-33.7 months). One patient refused RC and two developed metastatic disease before RC; all were considered nonresponders. The most common grade 3-4 adverse event (AE) was neutropenia (n = 16; 36%). Grade 3 immune-related AEs occurred in five (11%) patients with two (5%) requiring systemic steroids. The median time from last dose of chemotherapy to surgery was 7.8 weeks (range: 5.1-17 weeks), and no patient failed to undergo RC because of AEs. Four of 39 (10%) patients had programmed death-ligand 1 (PD-L1)-positive tumors and were all < pT2N0. Of the patients with PD-L1 low or negative tumors, 23 of 34 (68%) achieved < pT2N0 and 11 of 34 (32%) were ≥ pT2N0 ( P = .3 for association between PD-L1 and < pT2N0)., Conclusion: Neoadjuvant GC plus A is a promising regimen for MIBC and warrants further study. Patients with < pT2N0 experienced improved relapse-free survival. The PD-L1 positivity rate was low compared with published data, which limits conclusions regarding PD-L1 as a predictive biomarker., Competing Interests: Samuel A. FuntEmployment: ByHeart (I)Stock and Other Ownership Interests: Kite, a Gilead company, Urogen pharma, Allogene Therapeutics, Neogene Therapeutics, Kronos Bio, Vida Ventures, IconOVir BioConsulting or Advisory Role: Merck, ImmunaiResearch Funding: Genentech/Roche (Inst), AstraZeneca (Inst), Decibel Therapeutics (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, AstraZeneca/MedImmune Hikmat Al-AhmadieConsulting or Advisory Role: Bristol Myers Squibb, EMD Serono, AstraZeneca/MedImmune, Janssen Biotech, PAIGE.AI Min Yuen TeoConsulting or Advisory Role: Janssen OncologyResearch Funding: Bristol Myers Squibb (Inst), Clovis Oncology (Inst), Pharmacyclics (Inst) Chung-Han LeeHonoraria: Intellisphere, Research to Practice, American Institute of Continuing Medical EducationConsulting or Advisory Role: Eisai, Bristol Myers Squibb, Merck, Pfizer/EMD Serono, ExelixisResearch Funding: Eisai (Inst), Bristol Myers Squibb (Inst), Calithera Biosciences (Inst), Exelixis (Inst), Merck (Inst) David AggenConsulting or Advisory Role: Boehringer Ingelheim, Seattle Genetics, Astellas PharmaPatents, Royalties, Other Intellectual Property: University of Illinois—Urbana Champaign(OPTIONAL) Open Payments Link: https://openpaymentsdata.cms.gov/physician/4226107 Deaglan McHughConsulting or Advisory Role: Progenics Arlyn ApolloEmployment: Covera Health (I)Leadership: Covera Health (I)Stock and Other Ownership Interests: Covera Health (I)Consulting or Advisory Role: Covera Health (I)Travel, Accommodations, Expenses: Covera Health (I) Kaitlyn FranceseConsulting or Advisory Role: Seattle Genetics, Astellas Pharma Yuanquan YangStock and Other Ownership Interests: Bristol Myers Squibb, Pfizer, AstraZenecaConsulting or Advisory Role: The Whiteoak Group Eugene PietzakHonoraria: UpToDateConsulting or Advisory Role: Merck, Chugai Pharma, QED Therapeutics, Janssen Alvin C. GohConsulting or Advisory Role: MedtronicTravel, Accommodations, Expenses: Medtronic William C. HuangHonoraria: Urogen pharmaConsulting or Advisory Role: Intuitive SurgicalResearch Funding: SonaCare Medical, photocure, Storz, Storz, Merck (Inst), Intuitive Surgical (Inst)Travel, Accommodations, Expenses: Photocure Dean F. BajorinConsulting or Advisory Role: Merck, Dragonfly Therapeutics, Fidia Farmaceutici S. p. A, Bristol Myers Squibb FoundationResearch Funding: Novartis (Inst), Merck (Inst), Bristol Myers Squibb (Inst), AstraZeneca (Inst), Astellas Pharma (Inst), Seattle Genetics/Astellas (Inst)Travel, Accommodations, Expenses: Merck Gopa IyerConsulting or Advisory Role: Bayer, Janssen, Mirati Therapeutics, Basilea, Flare Therapeutics, Loxo/LillySpeakers' Bureau: Gilead Sciences, The Lynx GroupResearch Funding: Mirati Therapeutics (Inst), Novartis (Inst), Debiopharm Group (Inst), Bayer (Inst), Janssen (Inst), Seattle Genetics (Inst) Bernard H. BochnerConsulting or Advisory Role: Olympus Arjun V. BalarLeadership: GT BiopharmaStock and Other Ownership Interests: GT BiopharmaHonoraria: Merck, Genentech/Roche, AstraZeneca/MedImmuneConsulting or Advisory Role: Genentech/Roche, Merck, Cerulean Pharma, AstraZeneca/MedImmune, Pfizer/EMD Serono, Incyte, Seattle Genetics/Astellas, Nektar, Dragonfly Therapeutics, GlaxoSmithKline, Bristol Myers Squibb/CelgeneResearch Funding: Merck (Inst), Genentech/Roche (Inst), AstraZeneca/MedImmune (Inst), Seattle Genetics, Gilead Sciences (Inst) Amir MortazaviHonoraria: Motive Medical IntelligenceConsulting or Advisory Role: Seattle Genetics, Debiopharm Group, PfizerResearch Funding: Acerta Pharma (Inst), Genentech/Roche (Inst), Merck (Inst), Novartis (Inst), Seattle Genetics (Inst), Mirati Therapeutics (Inst), Bristol Myers Squibb (Inst), Roche (Inst), Astellas Pharma (Inst), Debiopharm Group (Inst), Debiopharm Group (Inst) Jonathan E. RosenbergHonoraria: UpToDate, Medscape, Peerview, Research To Practice, Intellisphere, Clinical Care Options, Physicans' Education Resource, MJH Life Sciences, EMD SeronoConsulting or Advisory Role: Lilly, Merck, Roche/Genentech, AstraZeneca/MedImmune, Bristol Myers Squibb, Seattle Genetics, Bayer, BioClin Therapeutics, QED Therapeutics, Adicet Bio, Pharmacyclics, western oncolytics, GlaxoSmithKline, Janssen Oncology, Astellas Pharma, Boehringer Ingelheim, Pfizer/EMD Serono, Mirati Therapeutics, Immunomedics, Tyra Biosciences, Infinity PharmaceuticalsResearch Funding: Genentech/Roche (Inst), Seattle Genetics (Inst), Bayer (Inst), AstraZeneca (Inst), QED Therapeutics (Inst), Astellas Pharma (Inst)Patents, Royalties, Other Intellectual Property: Predictor of platinum sensitivity (Inst)No other potential conflicts of interest were reported.

Background: Radical cystectomy (RC) has the potential for profound changes to health-related quality of life (HRQOL)., Objective: To evaluate a broad range of HRQOL outcomes in a large RC cohort., Design, Setting, and Participants: A single-center prospective study enrolled RC patients from 2008 to 2014. We collected 14 separate patient-reported outcome measures at the presurgical visit and at 3, 6, 12, 18, and 24 mo after RC., Outcome Measurements and Statistical Analysis: To visualize the patterns of recovery over time across domains, we used generalized estimating equations (GEEs) with nonlinear terms. Given substantial differences in patient selection for the type of urinary diversion, we separately modeled longitudinal HRQOL within conduit and continent diversion groups. The mean pre-RC scores were compared to illustrate the baseline HRQOL differences between diversion groups., Results and Limitations: The analyzed cohort included 411 patients (n = 205 ileal conduit, n = 206 continent diversion). At baseline, patients receiving continent diversion reported better mean physical (p < 0.001), urinary (p = 0.006), and sexual function (p < 0.001), but lower social function (p = 0.015). After RC, GEE modeling showed physical function scores decreasing 5/100 points by 6 mo, and subsequently stabilizing or returning to baseline. By 12 mo, social function improved by 10/100 points among continent diversions, while remaining stable among ileal conduits. Global quality of life exceeded baseline scores by 6 mo. Sexual function scores were low before RC, with limited recovery. Psychosocial domains were stable or improved, except for 10/100-point worsening of body image among ileal conduits., Conclusions: RC patients reported favorable HRQOL recovery within 24 mo in most areas other than body image (ileal conduits) and sexual function (both). Importantly, large measurable decreases in scores were not reported by 3 mo after RC. These contemporary outcomes and the excellent locoregional control provided by RC further support it as the gold standard therapy for high-risk bladder cancer., Patient Summary: We review quality of life in the 24 mo following radical cystectomy. Large decreases in health-related quality of life were not reported, with most areas returning to, or exceeding, baseline, except for sexual function and body image., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

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.

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.

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.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on the clinical presentation and workup of suspected bladder cancer, treatment of non-muscle-invasive urothelial bladder cancer, and treatment of metastatic urothelial bladder cancer because important updates have recently been made to these sections. Some important updates include recommendations for optimal treatment of non-muscle-invasive bladder cancer in the event of a bacillus Calmette-Guérin (BCG) shortage and details about biomarker testing for advanced or metastatic disease. The systemic therapy recommendations for second-line or subsequent therapies have also been revised. Treatment and management of muscle-invasive, nonmetastatic disease is covered in the complete version of the NCCN Guidelines for Bladder Cancer available at NCCN.org. Additional topics covered in the complete version include treatment of nonurothelial histologies and recommendations for nonbladder urinary tract cancers such as upper tract urothelial carcinoma, urothelial carcinoma of the prostate, and primary carcinoma of the urethra.

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: 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: 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.

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.)

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.)

Purpose: We report the outcomes in patients with muscle invasive bladder cancer from 2 institutions who experienced a clinically complete response to neoadjuvant platinum based chemotherapy and elected active surveillance. It was unknown whether conservative treatment could be safely implemented in these patients., Materials and Methods: We retrospectively reviewed the records of patients with muscle invasive bladder cancer at our institutions who elected surveillance following a clinically complete response to transurethral resection of bladder tumors and neoadjuvant chemotherapy from 2001 to 2017. A clinically complete response was defined as absent tumor on post-chemotherapy transurethral resection of bladder tumor, negative cytology and normal cross-sectional imaging., Results: In the 148 patients followed a median of 55 months (range 5 to 145) the 5-year disease specific, overall, cystectomy-free and recurrence-free survival rates were 90%, 86%, 76% and 64%, respectively. Of the patients 71 (48%) experienced recurrence in the bladder, including 16 (11%) with muscle invasive disease and 55 (37%) with noninvasive disease. Salvage radical cystectomy prevented cancer specific death in 9 of 12 patients (75%) who underwent cystectomy after muscle invasive relapse and in 13 of 14 (93%) after noninvasive relapse., Conclusions: We observed high rates of overall and disease specific survival with bladder preservation in patients who achieved a clinically complete response to neoadjuvant chemotherapy. These outcomes support the safety of active surveillance in carefully selected, closely monitored patients with muscle invasive bladder cancer. Future studies should aim to improve patient selection by identifying biomarkers predicting invasive relapse and developing novel imaging methods of early detection., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

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.)

The NCCN Clinical Practice Guidelines in Oncology for Bladder Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with bladder cancer. These NCCN Guidelines Insights discuss important updates to the 2018 version of the guidelines, including implications of the 8th edition of the AJCC Cancer Staging Manual on treatment of muscle-invasive bladder cancer and incorporating newly approved immune checkpoint inhibitor therapies into treatment options for patients with locally advanced or metastatic disease., (Copyright © 2018 by the National Comprehensive Cancer Network.)

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.

Micropapillary urothelial carcinoma (MPUC) is a rare but an aggressive variant of urothelial carcinoma. MPUC has been shown to commonly exhibit ERBB2 amplification and HER2 protein overexpression, but the frequency and distribution of these findings within micropapillary (MP) and not otherwise specified (NOS) components of tumors with mixed histology have not been addressed. Therefore, we evaluated ERBB2 amplification and HER2 expression in 43 MPUC cases by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Of the 35 tumors containing both MP and NOS components, ERBB2 amplification was present in both the MP and NOS components of 12 tumors (34.3%), in only the MP component of 11 tumors (31.4%), and exclusively in the NOS component of 4 tumors (11.4%). HER2 protein overexpression was significantly more commonly present in the MP component compared to the NOS component within the same tumor (68.6% versus 34.3%, P = .012). Overall, there was a moderately positive correlation between HER2 protein expression and ERBB2 amplification in both MP (ρ = 0.59, P < .001) and NOS (ρ = 0.70, P < .001) components. All MP/NOS areas with IHC score 3+ and none of MP/NOS areas with IHC score 0 were associated with ERBB2 amplification. We conclude that ERBB2 amplification and HER2 overexpression are preferentially but not exclusively identified in the MP component compared to the NOS component within the same tumor. Our findings identify the presence of intratumoral heterogeneity of ERBB2 amplification and HER2 expression in MPUC and provide grounds for further investigation into the mechanisms underlying the development of MPUC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background and Objectives: We evaluated the effect of re-resection with wide margins (undertaken because initial resection performed elsewhere was incomplete) on survival in patients with spermatic cord sarcoma (SCS)., Methods: After excluding those with metastatic disease and those not undergoing surgical intervention, the records of 72 consecutive patients treated for SCS between 1981 and 2011 at Memorial Sloan Kettering Cancer Center were reviewed. Recurrence-free survival (RFS) and cancer-specific survival were calculated using the Kaplan-Meier method for comparing between the 48 patients who underwent wide re-resection (WRR) within 5 months of diagnosis and the 24 who did not. The relationship of age, tumor size, tumor histology, adjuvant radiation, and wide re-resection with recurrence and death was assessed by univariate Cox regression., Results: WRR significantly improved RFS (hazard ratio [HR] 0.16, 95%CI 0.07-0.37; P < 0.0001), despite the fact that patients receiving WRR had higher-grade disease. Tumor-positive margins upon WRR were strongly associated with both disease recurrence (HR 5.56; 95%CI 1.14-27.11, P = 0.034) and death from cancer (HR 6.16, 95%CI 1.25-30.29; P = 0.025)., Conclusions: A WRR with negative margins is effective in the management of patients with SCS and leads to improved RFS., (© 2018 Wiley Periodicals, Inc.)

Purpose: Bladder cancer is the sixth most common cancer in the United States, but is exceedingly rare in young patients, leading to a lack of accepted standards for diagnosis, treatment, and surveillance. We review our institutional experience with bladder urothelial neoplasms in pediatric and young adult patients summarizing presentation, treatment, and outcomes., Methods: Surgical pathology records at our institution were searched for cases of urothelial neoplasms among patients ≤25 years of age treated between January 1997 and September 2016. Cases submitted exclusively for pathology review were excluded. Diagnoses were confirmed based on pathologic examination using the 2004 World Health Organization classification system., Results: Thirty-four patients were identified with a mean age of 21.1 years (range 8-25 years), and median follow-up was 25.1 months (1-187 months). The male to female ratio was 1.83:1. The most common presenting symptom was hematuria (n=26; 76%). Diagnoses were invasive urothelial carcinoma (n=3), noninvasive urothelial carcinoma (n=24), PUNLMP (n=6), and urothelial papilloma (n=1). Noninvasive lesions were resected by cystoscopy, after which 12% (n=4) experienced complications (grade II or greater). One patient with stage IV invasive disease at diagnosis died, and 2 patients developed recurrences. Of those with noninvasive carcinoma, 29% (n=7) required repeat cystoscopy soon after initial TURBT at outside institutions, and 17% (n=4) had tumors downgraded from high-grade to low-grade after pathology review., Conclusion: Hematuria is the most common sign of bladder neoplasia in children and young adults and should be investigated by cystoscopy. The majority of urothelial neoplasms in these patients are noninvasive and can be successfully treated with transurethral resection., Level of Evidence: Level IV (Retrospective study with no comparison group)., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on systemic therapy for muscle-invasive urothelial bladder cancer, as substantial revisions were made in the 2017 updates, such as new recommendations for nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab. The complete version of the NCCN Guidelines for Bladder Cancer addresses additional aspects of the management of bladder cancer, including non-muscle-invasive urothelial bladder cancer and nonurothelial histologies, as well as staging, evaluation, and follow-up., (Copyright © 2017 by the National Comprehensive Cancer Network.)

Objectives: To evaluate the influence of lamina propria invasion type at initial transurethral resection (TUR) on restaging pathology., Materials and Methods: We reviewed prospectively maintained records of all patients with a high-grade pT1 nonmuscle invasive bladder cancer who underwent both initial and restaging TUR within 6 weeks at our center between 2001 and 2016. The pathology of second TUR specimens was analyzed with regard to the characteristics of lamina propria invasion found at initial resection., Results: We included 198 patients, with a median age of 70 years (interquartile range: 63-79). Muscle was present in the initial TUR specimen in 107 patients (54%). Pathology restaging was pT0 in 73 patients (37%), pTis in 44 (22%), pTa in 27 (14%), pT1 in 50 (25%), and pT2 in 4 (2%). Eighty-seven patients (44%) had tumors with minimal lamina propria invasion at initial TUR: 53 specimens (27%) had focal invasion (few malignant cells in the lamina propria); 15 specimens (7.6%) had superficial invasion (invasion of the lamina propria to the level of the muscularis mucosae [T1a]); and 19 specimens (10%) had multifocal superficial invasion (multiple areas of T1a). Of the patients with minimal lamina propria invasion, residual disease was found in 54 patients (62%). However, none of those patients had T2 disease., Conclusions: A significant number of patients with T1 tumors have residual disease at restaging TUR as do patients with minimal lamina propria invasion. The extent of T1 invasion does not eliminate the need for repeat TUR., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Radical cystectomy (RC) has become increasingly regionalized to high-volume hospitals. Our objective was to describe changes in regional market concentration and the distribution of RCs among hospitals, and examine how these changes affect patient travel distance to surgery., Materials and Methods: We used the surveillance, epidemiology, and end results-Medicare database to identify patients who had RC for bladder cancer from 2001 to 2011. We defined RC market concentration within each Hospital Referral Regions (HRR) in surveillance, epidemiology, and end results using the Hirschman-Herfindhal Index. We measured straight-line patient travel distance to the nearest cystectomy provider hospital and used linear regression to evaluate the effect of market concentration on travel distance for surgery. We performed a similar analysis on patients who had laparoscopic cholecystectomy as a comparator., Results: We identified 10,802 patients with bladder cancer who had RC. From 2001 to 2011, 40% of HRRs had a statistically significant increase in Hirschman-Herfindhal Index, 53% had no significant change and 7% had a statically significant decrease. The median patient travel distance increased significantly from 10.4 miles (interquartile range: 2.6-30.2) to 16 miles (interquartile range: 6.3-40.4, P<0.0001). Patients who lived in a highly concentrated HRR had to travel significantly further than patients who lived in an unconcentrated HRR (β = 37.5, P<0.001). These trends were not seen for laparoscopic cholecystectomy., Conclusions: Between 2001 and 2011, RC became increasingly regionalized to a small group of hospitals with a resultant increase in regional RC market concentration and patient travel distance. The clinical consequences on these changes to patients who require RC are uncertain., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Evaluate oncologic outcomes of patients with cT1 nested variant (NV) of urothelial carcinoma (UC) and compare with cases of pure UC of the bladder., Materials and Methods: We retrospectively identified 30 patients with NV who, between 1997 and 2012, underwent transurethral resection with T1 tumor stage, followed by restaging transurethral resection within 3 months confirming non-muscle-invasive disease. Radical cystectomy within 3 months of restaging transurethral resection was considered "early" treatment. We matched 3 patients with pure UC to each nested patient., Results: Median follow-up for survivors was 4.3 years from T1-staged transurethral resection. Patients with NV had no statistically significant difference in metastasis-free survival (P = .2) and cancer-specific survival (P = .2) compared with patients with pure UC. However, it is concerning that the rate of upstaging to bladder and/or lymph nodes was 54% in patients with NV who underwent early radical cystectomy, even after rigorous restaging., Conclusions: Although NV UC may be diagnosed at a higher stage, when stage matched we have not seen any statistical evidence that it is more aggressive than typical UC. Because patients with NV UC who are cT1 on restaging transurethral resection appear to have a higher propensity to develop nodal metastatic disease and a higher rate of upstaging, patients with cT1 NV UC on restaging biopsy may benefit from "early" radical cystectomy, whereas patients with 

Background: Standard treatment for BCG-refractory urothelial cancer is radical cystectomy. Identification of active agents is clearly warranted. Objective: To determine a safe dose of oral everolimus in combination with standard intravesical gemcitabine and to evaluate the efficacy of this combination. Methods: Patients with carcinoma in situ refractory to intravesical bacillus Calmette-Guérin and refusing cystectomy were eligible. Patients in the phase I part of the trial received one of three dose levels of oral everolimus. Patients also received a fixed dose of intravesical gemcitabine. Maintenance everolimus was given for 12 months in patients achieving a complete response confirmed by cystoscopy and cytology. Patients in phase II received continuous everolimus administered at 10 mg daily with intravesical gemcitabine followed by everolimus maintenance for 12 months of total therapy. The enrollment goal for the phase II was 33 patients. Results: 14 patients were enrolled in phase I of the trial. 23 patients were enrolled in phase II of the trial and 19 were evaluable for primary and secondary endpoints. Four patients withdrew consent prior to treatment initiation. Of the 19 patients evaluable for response, 3 (16%, 95% confidence interval [CI] 3% - 40%) were disease free at 1 yr. The probability of RFS was 20% (95% CI 5% - 42%) at 12 months. Ten patients out of 19 had grade 3 or greater toxicity events. Seven withdrew consent or were taken off study. Conclusions: Many patients withdrew, and enrollment was halted. Continuous oral everolimus plus intravesical gemcitabine was not well tolerated in this patient population where the threshold for tolerability is low.

Background: We sought to determine if idiographic, or self-defined, measures added to our understanding of patients with bladder cancer's quality of life (QOL) prior to radical cystectomy (RC). We tested whether idiographic measures increased prediction of global QOL beyond standard (nomothetic) measures of QOL components., Methods: We administered the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (QLQ)-C30 and QLQ-BLM30, and our own idiographic Quality of Life Appraisal Profile prior to RC. Idiographic measures included number of goal statements, distance from goal attainment, and ability to complete goal attainment activities. Multivariate linear regression was used to predict measures of global QOL and related constructs of life satisfaction and mental health., Results: Two hundred fiftheen patients reported a median of 8 (interquartile range [IQR] 6, 11) goals and half had an average goal attainment rating above 6.9 out of 10 (IQR 5.5, 8.2). On multivariable analysis, QLQ-C30 role functioning and QLQ-BLM30 future perspective explained 15.7% of the variability in preoperative global QOL. Including goal attainment and activity difficulty explained an additional 12% of global QOL variance. Smaller gains were seen on measures of global health, life satisfaction, mental health, and activity, suggesting that idiographic measures capture aspects of QOL distinct from health and functional status defined by nomothetic scales., Conclusions: Idiographic assessment of QOL added to prediction of global QOL above and beyond health-related components measured using nomothetic instruments. This self-defined information may be valuable in communicating with cancer patients about their QOL. Copyright © 2015 John Wiley & Sons, Ltd., (Copyright © 2015 John Wiley & Sons, Ltd.)