Andrade, RitaPerez-Rojas, Judithda Silva, Sílvia GomesMiskinyte, MiglaQuaresma, Margarida CFrazão, Laura PPeixoto, CarolinaCubells, AlmudenaMontalvá, Eva MFigueiredo, AntónioCipriano, AugustaGonçalves-Reis, MariaProença, DanielaFolgado, AndréPereira-Leal, José BOliveira, Rui CaetanoPinto-Marques, HugoTralhão, José GuilhermeBerenguer, MarinaCardoso, Joana2025-10-212025-10-212025-02-02Cancers (Basel) . 2025 Feb 2;17(3):500. doi: 10.3390/cancers17030500.http://hdl.handle.net/10400.17/5189Background/objectives: Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths rising worldwide. This is leading to an increased demand for liver transplantation (LT), the most effective treatment for HCC in its initial stages. However, current patient selection criteria are limited in predicting recurrence and raise ethical concerns about equitable access to care. This study aims to enhance patient selection by refining the HepatoPredict (HP) tool, a machine learning-based model that combines molecular and clinical data to forecast LT outcomes. Methods: The updated HP algorithm was trained on a two-center dataset and assessed against standard clinical criteria. Its prognostic performance was evaluated through accuracy metrics, with additional analyses considering tumor heterogeneity and potential sampling bias. Results: HP outperformed all clinical criteria, particularly regarding negative predictive value, addressing critical limitations in existing selection strategies. It also demonstrated improved differentiation of recurrence-free and overall survival outcomes. Importantly, the prognostic accuracy of HP remained largely unaffected by intra-nodule and intra-patient heterogeneity, indicating its robustness even when biopsies were taken from smaller or non-dominant nodules. Conclusions: These findings support the usage of HP as a valuable tool for optimizing LT candidate selection, promoting fair organ allocation and enhancing patient outcomes through integrated analysis of molecular and clinical data.engHCC CHBPTHCC ANPATHCCHepatoPredictLiver TransplantLiver BiopsyPrognostic TestMulti-Target Genomic AssayTumor Heterogeneitytext10.3390/cancers17030500.39941867