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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.  \n1 Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, 811 08 Bratislava, Slovakia; [stefan.harsanyi@fmed.uniba.sk](stefan.harsanyi@fmed.uniba.sk) (S.H.); [zuzana.varchulova@fmed.uniba.sk](zuzana.varchulova@fmed.uniba.sk) (Z.V.N.); [schwarzova27@uniba.sk](schwarzova27@uniba.sk) (L.N.); [lubos.danisovic@fmed.uniba.sk](lubos.danisovic@fmed.uniba.sk) (L.D.)  \n2 Institute of Forensic Medicine, Faculty of Medicine, Comenius University in Bratislava,  \n811 08 Bratislava, Slovakia; [sgalbavy@ousa.sk](sgalbavy@ousa.sk)  \n3 Department of Urology, Faculty of Medicine, Comenius University in Bratislava, 826 06 Bratislava, Slovakia  \n4 Institute of Anatomy, Faculty of Medicine, Comenius University in Bratislava, 811 08 Bratislava, Slovakia; [katarina.bevizova@fmed.uniba.sk](katarina.bevizova@fmed.uniba.sk)  \n* Correspondence: [stanislav.ziaran@fmed.uniba.sk](stanislav.ziaran@fmed.uniba.sk); Tel.: +421-2-48234-644  \nAbstract  \nBackground: Bladder cancer exhibits substantial heterogeneity, and accurate discrimination between non-muscle-invasive (NMIBC) and muscle-invasive disease (MIBC), as well as between low-grade (LG) and high-grade (HG) tumors, remains essential for appropriate clinical management. Established immunohistochemical (IHC) markers, such as p53, Ki- 67, and E-cadherin, could be used in a new setting, but standardized cut-off values and their combined predictive value remain unclear. This study aimed to identify optimal cut-offs for these markers and to evaluate whether biomarker combinations enhance the discrimination of tumor grade and stage. Methods: A retrospective dataset of 568 cases of bladder cancer was analyzed. For each case, the expression of p53, Ki-67, and E-cadherin was quantified, and tumors were classified as NMIBC or MIBC, and as LG or HG. ROCbased cut-off selection was performed using Youden’s J criterion with 10-fold stratified cross-validation. E-cadherin was modelled using an inverted scale to reflect biological loss. Logistic regression models were used to evaluate the discriminatory performance of single markers, two-marker combinations, and a three-marker model. Cross-validated AUC values and optimal thresholds were reported. Results: Ki-67 showed the strongest single-marker performance for predicting both MIBC (AUC 0.842) and HG disease (AUC 0.813), with optimal cut-offs of ≥40% and ≥30%, respectively. p53 demonstrated moderate discrimination (AUC 0.778 for MIBC and 0.776 for HG), while E-cadherin, evaluated on an inverted scale, showed acceptable performance (AUC 0.746 for MIBC; 0.780 for HG) . Combining markers yielded modest improvements, with the best performance observed for Ki-67 + E-cadherin (AUCs of 0.851 for MIBC and 0.838 for HG) . Conclusions: Ki-67 is the most effective single biomarker for distinguishing invasive and HG bladder cancer, while E-cadherin provides complementary value. A two-marker panel combining Ki-67 and E-cadherin, using appropriate cut-offs, offers the highest overall performance and may serve as a practical tool for enhanced pathological stratification.  \nKeywords: bladder cancer; p53; Ki-67; E-cadherin; cut-off analysis; ROC analysis; MIBC; tumor grade; biomarkers  \n1. Introduction  \nBladder cancer is one of the most common malignancies of the urinary tract. More than 600,000 new ca","cbCainCLJ2DHZFt0","https://ap.wps.com/l/cbCainCLJ2DHZFt0","pdf",6243805,11,"English","# Abstract\n## Background\n## Methods\n## Results\n## Conclusions\n# 1. Introduction","[{\"question\":\"What clinical problem does the study address in urothelial bladder cancer?\",\"answer\":\"The study addresses the need for accurate immunohistochemical discrimination between NMIBC and MIBC and between LG and HG tumors to support appropriate management.\"},{\"question\":\"How were optimal immunohistochemical cut-off values determined?\",\"answer\":\"Optimal cut-offs were selected using ROC-based analysis with Youden’s J criterion and 10-fold stratified cross-validation.\"},{\"question\":\"Which biomarker and which combination performed best for distinguishing disease grade and stage?\",\"answer\":\"Ki-67 showed the strongest single-marker performance for predicting MIBC and HG disease. The best combined performance was observed for the Ki-67 + E-cadherin two-marker panel using appropriate cut-offs.\"}]","Optimizing Ki-67 and E-Cadherin Thresholds for Improved Grade and Stage Classification in Urothelial Bladder Cancer | PDF",1790761902,28]