Beyond Single Biomarkers: A Multidimensional Risk Score for Improved Post-Transplant Prognosis Prediction in Hepatocellular Carcinoma

Abstract

Introduction Inflammation- and nutrition-related biomarkers are associated with prognosis in hepatocellular carcinoma (HCC), but most studies have focused on single markers. This study aimed to develop and internally validate a multidimensional inflammatory-nutritional risk score (RS) for predicting post-transplant outcomes in HCC patients. Materials and methods This single-center retrospective cohort included 239 patients with pathologically confirmed HCC who underwent liver transplantation between April 2013 and July 2023. Fourteen preoperative inflammation- and nutrition-related markers were calculated from laboratory data obtained within one week before transplantation. A bootstrap LASSO-Cox framework with 2000 resampling iterations was used to identify stable prognostic markers, and those selected in >70% of iterations were retained for the primary RS. Overall survival (OS) and recurrence-free survival (RFS) were assessed. Model performance was evaluated using Cox regression, C-index, time-dependent ROC analysis, calibration, decision curve analysis, and bootstrap optimism-corrected internal validation. Results During a median follow-up of 53 months, 83 OS events and 89 RFS events occurred. Four markers, including fibrinogen-to-albumin ratio, gamma-glutamyl transpeptidase-to-prealbumin ratio, gamma-glutamyl transpeptidase-to-albumin ratio, and aspartate aminotransferase-to-neutrophil ratio index, were selected to construct the primary RS. Patients with high RS had significantly worse OS and RFS than those with low RS, and RS remained independently associated with both outcomes in multivariable Cox analyses. Adding RS improved prognostic performance beyond Milan criteria, Hangzhou criteria, UCSF criteria, and clinicopathological models incorporating alpha-fetoprotein, tumor burden, portal vein tumor thrombus, and microvascular invasion. The final RS-plus clinicopathological model achieved apparent C-indices of 0.766 for OS and 0.759 for RFS, with bootstrap optimism-corrected C-indices of 0.756 and 0.749, respectively. Conclusion A four-marker inflammatory-nutritional RS based on routinely available preoperative biomarkers was independently associated with OS and RFS after liver transplantation for HCC and provided incremental prognostic information beyond established criteria and clinicopathological factors. Because the RS-plus model incorporates microvascular invasion, it should be interpreted as a postoperative prognostic tool. External validation is required before clinical application.