| Summary: | Abstract Background Bladder cancer (BC) is the ninth most prevalent cancer globally, with approximately 75% of cases classified as non-muscle-invasive bladder cancer (NMIBC). Although transurethral resection of bladder tumor (TURBT) is the standard treatment for NMIBC, there remains a considerable risk of postoperative residual tumors. Accurately identifying patients who require repeat transurethral resection of bladder tumor (Re-TURBT) remains a significant clinical challenge. Magnetic resonance imaging (MRI) exhibits high accuracy in detecting residual tumors after TURBT, aiding clinical decision-making. However, its relatively low specificity limits its clinical applicability. Urinary methylation markers, particularly those associated with H4 cluster protein 6 (H4C6) and Twist Family BHLH Transcription Factor 1 (TWIST1), have demonstrated high sensitivity and specificity in detecting bladder cancer, showing promising clinical performance. The combined detection of H4C6 and TWIST1 gene methylation provides a more reliable method for identifying residual tumors post-TURBT. Integrating the VI-RADS score with urine gene methylation analysis could complement each other, improving the accuracy of residual tumor detection and enhancing clinical applicability. Objective This study aimed to evaluate the predictive value of clinical/pathological factors, urinary H4C6 and TWIST1 gene methylation, and their combined performance in identifying postoperative residual tumors in NMIBC patients. Methods Morning urine samples from NMIBC patients at Zhongshan City People’s Hospital (June 2022–August 2024) were analyzed for H4C6 and TWIST1 methylation levels. Patients underwent MRI and Re-TURBT. Logistic regression was used to identify predictors of residual tumors, and a nomogram was developed. Model performance was evaluated using Receiver Operating Characteristic (ROC) curves and decision curve analysis (DCA). Results Among the 55 patients included in the study, the area under the ROC curve (AUC) for urinary H4C6 methylation was 0.698, whereas TWIST1 methylation had an AUC of 0.758. Combined dual-gene methylation yielded an AUC of 0.764. The AUC for VI-RADS scoring was 0.888. When dual-gene methylation and hematuria were combined with VI-RADS scores, the prediction model achieved an AUC of 0.972. DCA demonstrated that the prediction model offers substantial clinical benefit across a broad range of threshold probabilities. The combined prediction model of dual-gene methylation, hematuria, and VI-RADS scores offers a powerful non-invasive method to assist clinicians in identifying high-risk patients with residual tumors after TURBT, thereby reducing unnecessary Re-TURBT and improving patient management. Conclusion Urinary H4C6 and TWIST1 gene methylation, along with VI-RADS scoring, show high diagnostic performance in predicting residual tumors following TURBT in NMIBC patients. A combined prediction model incorporating dual-gene methylation, hematuria, and VI-RADS scores achieves superior discrimination, excellent calibration, and strong clinical utility.
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