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Background: The heterogeneity of bladder cancers (BCs) is a major challenge for the development of novel therapies. However, given the high rates of recurrence and/or treatment failure, the identification of effective therapeutic strategies is an urgent clinical need., Objective: We aimed to establish a model system for drug identification/repurposing in order to identify novel therapies for the treatment of BC., Design, Setting, and Participants: A collection of commercially available BC cell lines (n = 32) was comprehensively characterized. A panel of 23 cell lines, representing a broad spectrum of BC, was selected to perform a high-throughput drug screen., Outcome Measurements and Statistical Analysis: Positive hits were defined as compounds giving >50% inhibition in at least one BC cell line., Results and Limitations: Amongst >1700 tested chemical compounds, a total of 471 substances exhibited antineoplastic effects. Clofarabine, an antimetabolite drug used as third-line treatment for childhood acute lymphoblastic leukaemia, was amongst the limited number of drugs with inhibitory effects on cell lines of all intrinsic subtypes. We, thus, reassessed the substance and confirmed its inhibitory effects on commercially available cell lines and patient-derived cell cultures representing various disease stages, intrinsic subtypes, and histologic variants. To verify these effects in vivo, a patient-derived cell xenograft model for urothelial carcinoma (UC) was used. Well-tolerated doses of clofarabine induced complete remission in all treated animals (n = 12) suffering from both early- and late-stage disease. We further took advantage of another patient-derived cell xenograft model originating from the rare disease entity sarcomatoid carcinoma (SaC). Similarly to UC xenograft mice, clofarabine induced subcomplete to complete tumour remissions in all treated animals (n = 8)., Conclusions: The potent effects of clofarabine in vitro and in vivo suggest that our findings may be of high clinical relevance. Clinical trials are needed to assess the value of clofarabine in improving BC patient care., Patient Summary: We used commercially available cell lines for the identification of novel drugs for the treatment of bladder cancer. We confirmed the effects of one of these drugs, clofarabine, in patient-derived cell lines and two different mouse models, thereby demonstrating a potential clinical relevance of this substance in bladder cancer treatment., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Context: While upper tract urothelial carcinoma (UTUC) share histological appearance with bladder cancer (BC), the former has differences in etiology and clinical phenotype consistent with characteristic molecular alterations., Objective: To systematically evaluate current genomic sequencing and proteomic data examining molecular alterations in UTUC., Evidence Acquisition: A systematic review using PubMed, Scopus, and Web of Science was performed in December 2019 according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement., Evidence Synthesis: A total of 46 publications were selected for inclusion in this report, including 13 studies assessing genome-wide alterations, 18 studies assessing gene expression or microRNA expression profiles, three studies assessing proteomics, one study assessing genome-wide DNA methylation, and 14 studies evaluating distinct pathway alteration patterns. Differences between sporadic and hereditary UTUC, and between UTUC and BC, as well as molecular profiles associated with exposure to aristolochic acid are highlighted. Molecular pathways relevant to UTUC biology, such as alterations in FGFR3, TP53, or microsatellite instability, are discussed. Our findings are limited by tumor and patient heterogeneity and different platforms used in the studies., Conclusions: Molecular events in UTUC and BC can be shared or distinct. Consequently, molecular subtypes differ according to location. Further work is needed to define the epigenomic and proteomic features of UTUC, and understand the mechanisms by which they shape the clinical behavior of UTUC., Patient Summary: We report the current data on the molecular alterations specific to upper tract urothelial carcinoma (UTUC), resulting from novel genomic and proteomic technologies. Although UTUC biology is comparable with that of bladder cancer, the rates and UTUC-enriched alterations support its uniqueness and the need for precision medicine strategies for this rare tumor type., (Copyright © 2020. Published by Elsevier B.V.)

Context: The optimal treatment of urothelial bladder cancer (UBC) with micropapillary (MP) variant histology is not clear., Objective: To review the current literature on disease characteristics and treatment outcomes of MP UBC., Evidence Acquisition: A systematic search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and the Cochrane Handbook for Systematic Reviews of Interventions. The primary end points were recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS)., Evidence Synthesis: We identified 758 reports comprising a total of 3154 patients, of which 28 and 15 articles were selected for qualitative and quantitative analysis, respectively. In patients with T1 MP UBC, the 5-yr CSS rates for early radical cystectomy (RC) ranged from 81% to 100%, while they were between 60% and 85% for transurethral resection of the bladder and Bacillus Calmette-Guérin (BCG). In studies reporting on neoadjuvant chemotherapy (NAC), the rates of complete pathological response (ypT0) ranged from 11% to 55%. Nevertheless, the use of NAC did not improve RFS (hazard ratio [HR] 1.23, 95% confidence interval [CI] 0.52-2.93, p=0.6), CSS (HR 0.9, 95% CI 0.48-1.7, p=0.8), or OS (HR 1.35, 95% CI 0.98-1.86, p=0.1). Fifty-three percent (95% CI 43-63%) of patients who underwent RC alone had locally advanced disease (≥pT3), and 43% (95% CI 33-52%) were harbouring lymph node metastases. MP component at RC was not significantly associated with worse RFS (HR 1.25, 95% CI 0.88-1.78, p=0.2), CSS (HR 0.96, 95% CI 0.57-1.6, p=0.9), or OS (HR 1.20, 95% CI 0.88-1.62, p=0.3) when adjusted for pathological features., Conclusions: While MP UBC is associated with clinicopathological features of advanced disease, it is not associated with worse survival outcomes in patients undergoing RC. NAC results in pathological downstaging in a significant number of patients. Nevertheless, this does not translate into better survival outcomes. The optimal treatment of patients with cT1 remains controversial., Patient Summary: Our results suggest that micropapillary urothelial bladder cancer does not necessarily mandate different treatment algorithms. Nevertheless, each case should be discussed individually considering other clinicopathological factors., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)