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Introduction: Traditional surveillance protocols do not adequately account for the decreasing risk of mortality over time in aggressive malignancies, such as bladder cancer. Rather, the risk of death depends on both the baseline risk of mortality and the time survived since treatment. We therefore evaluated the conditional survival of patients diagnosed with urothelial carcinoma of the bladder (UCB) following radical cystectomy (RC)., Patients and Methods: We identified patients aged 18 to 75 with Charlson 0-1 and pTany pN0-3 cM0 UCB diagnosed from 2006 to 2015 in the National Cancer Database and treated with RC. The 2- and 5-year conditional overall survival (COS)-i.e., the probability of surviving an additional 2- or 5-years given a specified time survived since treatment-was estimated using the Kaplan-Meier method. Multivariable Cox regression models with landmark time analysis were used to evaluate the associations of baseline characteristics with OS over time., Results: A total of 15,594 patients were included in the study. Median follow-up was 27.8 months. The 2- and 5-year COS for the overall cohort increased through 36 months follow-up and then plateaued. When stratified by pT and pN stage, the COS gain increased with higher pT and pN stage, demonstrating the greatest increase over time for patients with pTany N1-3 disease (5-year COS of 23% at baseline, 58% at 36-months, and 71% at 60-months). In multivariable Cox regression modeling, pT and pN stage were significantly associated with higher all-cause mortality at baseline (HR 3.27 for pT4, HR 2.57 for pT3 vs. ≤pT2; HR 2.26 for pN2-3, HR 1.77 for pN1 vs. pN0), but these associations were attenuated in magnitude with increasing landmark times of 36- and 60-months (HR 1.63 for pT4, HR 1.35 for pT3 vs. ≤pT2; HR 1.34 for pN2-3, HR 1.27 for pN1 vs. pN0). Our study is limited by the retrospective design and the lack of cancer-specific survival data., Conclusions: Risk of death after RC varies with time elapsed since treatment and disease stage. Accordingly, stage-specific COS may be used to improve prognostication and surveillance protocols., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Although pathologic lymph node involvement carries a poor prognosis in patients with urothelial carcinoma of the bladder (UCB), a subset of patients may demonstrate durable survival following surgical resection. To this end, there are limited contemporary data describing the natural history of UCB in patients with isolated lymph node involvement (cN0pN+) following radical cystectomy (RC) with pelvic lymph node dissection (PLND). We therefore utilized a large, nationwide oncology dataset to examine the natural history and outcomes of cN0 pN+ UCB after surgical resection., Materials and Methods: We identified patients in the National Cancer Database (NCDB) with cN0 pN+ cM0 UCB from 2006 to 2015 treated with RC and PLND. The associations of baseline characteristics with all-cause mortality (ACM) were evaluated using Cox regression., Results: A total of 2,884 patients formed the study cohort, including 42% with pN1 and 58% with pN2-3 disease. Of these, 606 (21%) received multiagent neoadjuvant chemotherapy, while 1,172 (41%) received postoperative adjuvant chemotherapy. A median of 15 (IQR 9-23) LNs were removed during PLND. The 5- and 7-year OS for the entire cohort were 20% and 17%, respectively. Compared to the overall cohort, patients surviving ≤5 years had lower pN stage (59% vs. 42% pN1) and lower pT stage (41% vs. 22% ≤pT2). On multivariable analysis, higher pT stage (HR 2.85, 95% CI 1.52-5.36 for pT3, HR 3.27, 95% CI 1.73-6.18 for pT4 vs. pT0), higher pN stage (HR 1.17, 95% CI 1.05-1.31 for pN2-3 vs. pN1), and increasing LN density (HR 2.37, 95% CI 1.88-2.99) were most strongly associated with increased ACM, while receipt of adjuvant chemotherapy (HR 0.61, 95% CI 0.55-0.68) was associated with reduced ACM., Conclusions: Although OS for patients with cN0 pN+ M0 UCB is poor, a subset of patients demonstrates durable long-term survival with 5- and 7-year OS of 20% and 17%, respectively. pT and pN stage represent important prognostic characteristics, while administration of adjuvant chemotherapy represents a potential therapeutic intervention associated with improved ACM., Competing Interests: Conflict of interest and funding The authors have no conflicts of interest to disclose. The National Cancer Data Base (NCDB) is a joint project of the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society. The CoC's NCDB and the hospitals participating in the CoC NCDB are the source of the de-identified data used herein; they have not verified and are not responsible for the statistical validity of the data analysis or the conclusions derived by the authors. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The role of adjuvant chemotherapy (AC) in patients with locally advanced bladder cancer following radical cystectomy (RC) remains uncertain, with contemporary clinical trials underpowered and closed early due to low accrual., Objective: To conduct observational analyses designed to emulate a completed randomized trial of AC in patients with locally advanced bladder cancer., Design, Settings, and Participants: Based on EORTC 30994 eligibility criteria, we identified adult patients aged 35 to 75 with pT3/pT4 Nany M0 or Tany pN1-3 M0, R0 urothelial carcinoma of the bladder treated with RC and lymphadenectomy from 2006 to 2015 in the National Cancer Database., Outcome Measurements and Statistical Analysis: A propensity score for receipt of AC within 3 months of RC was estimated, and the associations of AC with overall survival were evaluated after reweighting by stabilized inverse probability of treatment weights., Results: Of the 2,416 patients who met inclusion criteria, 945 (39%) received AC after RC. After propensity score adjustment, baseline characteristics were well-balanced. Median follow-up was 26.0 months. After IPW-reweighting, overall survival was 43% vs. 36% at 5-years and 34% vs. 24% at 10-years, among those who did and did not receive AC, respectively (P < 0.01). In IPW-adjusted Cox regression models, AC was associated with improved all-cause mortality (HR 0.71; 95% CI 0.63-0.81; P < 0.01). Estimates were overall consistent in analyses that examined heterogeneity of treatment effects. Limitations include unmeasured confounding, selection bias, and lack of baseline renal function data., Conclusion: In observational analyses designed to emulate EORTC 30994, AC was associated with improved overall survival compared to observation after RC. Results were consistent across baseline patient and tumor characteristics., Competing Interests: Conflict of interest The authors have no conflicts of interest to disclose. The National Cancer Data Base (NCDB) is a joint project of the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society. The CoC's NCDB and the hospitals participating in the CoC NCDB are the source of the de-identified data used herein; they have not verified and are not responsible for the statistical validity of the data analysis or the conclusions derived by the authors., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The comparative effectiveness of radical cystectomy (RC) and trimodality therapy (TMT) for muscle-invasive bladder cancer remains uncertain, as no randomized data exist. A phase 3 trial (SPARE) was attempted in the UK, however, was deemed infeasible and closed., Objective: To emulate the SPARE trial using observational data., Design, Setting, and Participants: We identified patients aged 40 to 79 with cT2-3cN0cM0 urothelial carcinoma of the bladder diagnosed from 2006 to 2015 who were treated with multiagent neoadjuvant chemotherapy + RC with lymphadenectomy (RC arm) or multiagent chemotherapy + 3D conformal radiotherapy to the bladder (TMT arm) in the National Cancer Database., Outcome Measurements and Statistical Analysis: The primary outcome was overall survival (OS). We fit a flexible logistic regression model for treatment to estimate the propensity score, and then used inverse probability of treatment weights to evaluate the associations of treatment group with OS., Results and Limitations: A total of 2,048 patients were included, of whom 1,812 underwent RC and 236 underwent TMT. Median follow-up was 29.0 months. After propensity score adjustment, compared to TMT, RC was not associated with a statistically significant difference in OS (HR 0.87; 95% CI 0.64-1.19; P = 0.40). When examining heterogeneity of treatment effects, RC appeared to be associated with improved OS only for patients with cT3 disease. Similar results were observed in sensitivity analyses. Our study is limited by the retrospective design and the lack of cancer-specific survival data., Conclusions: In observational analyses designed to emulate the SPARE trial, there was no statistically significant difference in OS between RC and TMT. Heterogeneity of treatment effects suggested improved survival with RC only for cT3 disease., Competing Interests: Conflict of interest The authors have no conflicts of interest to disclose. The National Cancer Data Base (NCDB) is a joint project of the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society. The CoC's NCDB and the hospitals participating in the CoC NCDB are the source of the de-identified data used herein; they have not verified and are not responsible for the statistical validity of the data analysis or the conclusions derived by the authors., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To investigate the oncological impact of incidental prostate cancer (iPCa) found during radical cystoprostatectomy (RCP) on overall survival (OS) prognosis of urothelial carcinoma of the bladder (BCa)., Patients and Methods: A total of 122 RCP cases resected between 2002 and 2012 at our center were included for study. Survival of BCa patient was compared using the Kaplan-Meier method and the log-rank test. Cox proportional hazards regression models were used to analyze the impact of iPCa on the 5-year overall mortality of BCa patients after RCP., Results: Among the 122 BCa cases that underwent RCP, 38 cases (31.1%) had iPCa, in which, 17 cases (44.7%) were identified as clinically significant iPCa (csPCa). BCa patients with iPCa were older (71 vs 64 years, p = 0.004) and had higher preoperative PSA level (3.1 ng/mL vs 1.4 ng/mL, p = 0.017) when compared to those without iPCa. Cases with iPCa showed a more favorable 5-year OS than cases without iPCa, although this difference did not reach statistical significance (p = 0.219). When excluding the higher risk cases with Gleason score (GS) ≥ 4 + 3 and/or preoperative PSA > 10 ng/mL, BCa patients with iPCa showed a significantly longer OS than cases without iPCa on univariate analysis (p = 0.044), but not on multivariate analysis (p = 0.125)., Conclusion: Our results demonstrated that the frequent findings of low-risk iPCa in BCa patients could indicate the potential possibility of shared pathogenesis pathways between iPCa and BCa. Future study with a larger cohort is warranted to validate this result.

The tumors of 20 patients with multifocal primary transitional cell carcinoma of the bladder or lymph node metastases were examined for molecular genetic defects which we have previously found to be present in > 50% of invasive tumors. These included loss of heterozygosity (LOH) of chromosome 9, which occurs in superficial as well as invasive bladder tumors, and LOH of chromosome 17p and p53 mutations, which are commonly found only in invasive tumors. Analysis of multiple or recurrent primary tumors in 7 patients for these markers was generally consistent with recently published data that the tumors are monoclonal in origin and that p53 mutations occur as a late event in the generation of invasive bladder cancers. Comparison of the primary tumors and metastases to regional lymph nodes in 14 patients demonstrated a complete concordance between the molecular genetic defects present, showing that LOH of chromosomes 9 and 17p and p53 mutations occurred in the primary tumors before metastasis. Because of the importance of chromosome 9 in bladder cancer, we mapped the location of a putative tumor suppressor gene by restriction fragment length polymorphism analysis of 123 cases obtained in this and earlier studies. Most of the tumors showed LOH for more than one marker on chromosome 9. Results of mapping of 4 tumors with partial deletion of chromosome 9 suggests that the tumor suppressor gene is located between 9p12 and 9q34.1.

Forty-three transitional cell carcinomas of the bladder of differing grades and stages were examined for reduction to homozygosity for chromosomes 9q, 11p, and 17p. Allelic loss of chromosome 9q was seen in 24 of 38 informative grades II, III, and IV tumors providing further evidence for a bladder tumor suppressor gene on this chromosome. In contrast to the grade-independent involvement of chromosome 9q, allelic losses of chromosomes 11p and 17p were seen only in grade III and IV tumors. The results with chromosome 17p were particularly striking and showed that 0 of 10 grade II versus 20 of 31 grade III and IV tumors had allelic losses for this chromosome harboring the p53 tumor suppressor gene often mutated in other human cancers. The data suggest that cumulative genetic damage is sustained in transitional cell carcinomas and that one of the underlying molecular mechanisms distinguishing low grade from high grade tumors involves chromosome 17p.