PURPOSE: To evaluate the risk factors associated with positive surgical margins' (PSMs) location and their impact on disease-specific survival (DSS) in patients with bladder cancer (BCa) undergoing radical cystectomy (RC). METHODS: We analyzed a large multi-institutional cohort of patients treated with upfront RC for non-metastatic (cT1-4aN0M0) BCa. Multivariable binomial logistic regression analyses were used to assess the risk of PSMs at RC for each location after adjusting for clinicopathological covariates. The Kaplan-Meier method was used to estimate DSS stratified by margins' status and location. Log-rank statistics and Cox' regression models were used to determine significance. RESULTS: A total of 1058 patients were included and 108 (10.2%) patients had PSMs. PSMs were located at soft-tissue, ureter(s), and urethra in 57 (5.4%), 30 (2.8%) and 21 (2.0%) patients, respectively. At multivariable analysis, soft-tissue PSMs were independently associated with pathological stage T4 (pT4) (Odds ratio (OR) 6.20, p < 0.001) and lymph-node metastases (OR 1.86, p = 0.04). Concomitant carcinoma-in-situ (CIS) was an independent risk factor for ureteric PSMs (OR 6.31, p = 0.003). Finally, urethral PSMs were independently correlated with pT4-stage (OR 5.10, p = 0.01). The estimated 3-years DSS rates were 58.2%, 32.4%, 50.1%, and 40.3% for negative SMs, soft-tissue-, ureteric- and urethral PSMs, respectively (log-rank; p < 0.001). CONCLUSIONS: PSMs' location represents distinct risk factors' patterns. Concomitant CIS was associated with ureteric PSMs. Urethral and soft-tissue PSM showed worse DSS rates. Our results suggest that clinical decision-making paradigms on adjuvant treatment and surveillance might be adapted based on PSM and their location.

Department of Medical Oncology Claudius Regaud Institute Toulouse University Cancer Center Oncopole 31000 Toulouse France

Department of Medicine Surgery and Health Sciences Urological Clinic University of Trieste Trieste Italy

Department of Pathology Institut Curie 75005 Paris France

Department of Pathology Princess Margaret Cancer Center University Health Network University of Toronto Toronto ON Canada

Department of Surgical Oncology Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Plesmanlaan 121 1066 CX Amsterdam The Netherlands

Department of Surgical Oncology Princess Margaret Cancer Center University Health Network University of Toronto Toronto ON Canada

Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology and Pediatric Urology University Hospital Erlangen Friedrich Alexander University Erlangen Nurnberg Erlangen Germany

Department of Urology Caritas St Josef Medical Center University of Regensburg Regensburg Germany

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Urology Erasmus MC Cancer Institute University Medical Center Rotterdam The Netherlands

Department of Urology Fundacion Instituto Valenciano Oncologia Valencia Spain

Department of Urology St Franciscus Hospital Rotterdam The Netherlands

Department of Urology Turku University Hospital and University of Turku Turku Finland

Department of Urology University of Texas Southwestern Medical Center Dallas TX USA

Department of Urology Weill Cornell Medical College New York NY USA

Institut Curie CNRS UMR144 Molecular Oncology Team PSL Research University 75005 Paris France

Institute for Urology and Reproductive Health 1 M Sechenov 1st Moscow State Medical University Moscow Russia

Institute of Pathology University Hospital Erlangen Friedrich Alexander University Erlangen Nurnberg Erlangen Germany

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