Search Results (6,205)

Background/Objectives: The prevalence and management options of bland (non-neoplastic) portal vein thrombosis (PVT) in patients with hepatocellular carcinoma (HCC) are poorly characterized and data remain limited. Methods: We performed a retrospective analysis of a prospectively collected single-center cohort of 638 patients with HCC. Bland PVT was identified at baseline or during follow-up. Treatment exposure was modeled as time-varying to account for differences in timing of anticoagulation initiation. Results: Bland PVT was identified in 39 patients (25 at baseline and 14 during follow-up). Patients with PVT showed features of more advanced portal hypertension (lower platelet count and higher prevalence of ascites) and had a higher tumor burden (more often outside the Milan criteria; higher AFP). A total of 30 patients received anticoagulation. Anticoagulation was associated with partial or complete recanalization in 30% of cases at three months and with decrease in bilirubin, but was not associated with improved 1 year survival. Bleeding events occurred in four anticoagulated patients (13.3%). Conclusions: Bland PVT in HCC is associated with more severe liver disease. Our data indicate that anticoagulation in patients with HCC and concomitant bland PVT was generally well-tolerated and was associated with thrombus regression in one-third of cases. However, we did not observe an improved survival in patients on anticoagulation. Full article

The new therapeutic options now available for patients with hepatocellular carcinoma (HCC) have made their assessment more complex, especially due to the different stages of liver cirrhosis typically associated with this tumor. The management of the disease therefore requires an interdisciplinary approach aimed at identifying the most appropriate treatment based on the risk–benefit profile and residual liver function, as well as in relation to the patient’s age and potential for a full or partial recovery, risk of complications, and cancer recurrence. Another factor to be carefully considered in patients with hepatocellular carcinoma is the frequent comorbidities and the associated socio-health variables (substance abuse, addictions, unfavorable economic or family circumstances), which can impact patient management or the possibilities for long-term monitoring, thus influencing the choice of the most appropriate therapeutic pathway. The healthcare services offered in the Province of Salerno (Campania Region, Southern Italy) to ensure all possible diagnostic and therapeutic options for these patients can be difficult to access due to the territorial extension of the Local Health Authority, characterized by clinics and hospitals located in distant locations, as well as the potential fragmentation of expertise between the University Hospital and ambulatorial facilities or small hospitals. An interdisciplinary consensus conference on the management of patients with HCC has been set with the aim of involving clinicians and surgeons working in healthcare facilities located in Salerno and its Province for the optimal care and effective management of these patients, taking into account all the clinical characteristics of the disease and individual health needs or expectations, from the perspective of personalized medicine. Full article

Background: Statins have pleiotropic anti-inflammatory, antifibrotic, and potential antineoplastic effects. Although several studies have linked statin exposure to lower hepatocellular carcinoma (HCC) incidence, their effect on survival after HCC diagnosis remains uncertain. We evaluated whether statin therapy before HCC diagnosis was associated with overall survival in a real-world cohort. Methods: We performed a retrospective single-center cohort study of consecutive patients with HCC managed at a tertiary referral center between January 2000 and January 2025. Demographic, clinical, laboratory, tumor-related, and treatment variables were collected at diagnosis and during follow-up. Patients were classified according to statin use before HCC diagnosis. Overall survival (OS) was assessed using Kaplan–Meier analysis and Cox proportional hazards regression. Results: Overall, 190 patients were included; 172 (90.5%) were male, 136 (71.6%) had cirrhosis, and 42 (22.1%) received statins. Statin users more frequently had diabetes mellitus, elevated body mass index and arterial hypertension, but baseline liver function, alpha-fetoprotein levels, tumor burden, and treatment allocation were broadly comparable between groups. Among 159 patients with available survival data, statin users had longer OS than non-users (mean 82.5 vs. 41.7 months; median 57 vs. 31 months; log-rank p < 0.001). In univariate Cox analysis, statin therapy was associated with reduced mortality risk (HR 0.45, 95% CI 0.28–0.70, p < 0.001). This association remained significant across multivariable models adjusting for baseline liver function, tumor stage, vascular invasion, and diagnostic era. Conclusions: Pre-diagnostic statin therapy was independently associated with improved OS in patients with HCC. These hypothesis-generating findings warrant prospective multicenter validation and careful assessment of confounding by indication. Full article

Background: Effects of neoadjuvant immunotherapy (NIT) before liver resection are not well-described in hepatocellular carcinoma (HCC). Survival and R0 resection rates in HCC patients undergoing curative-intent resection with or without NIT were evaluated. Methods: A retrospective study of stage I-III HCC patients undergoing hepatectomy from the 2017–2022 National Cancer Database was performed. Patients receiving NIT were exactly matched 1:3 to non-NIT patients by clinical stage. Primary outcomes were margin positivity, 30- and 90-day mortality, and overall survival. Results: After matching 510 patients, 97 received NIT and 291 did not (non-NIT). Resections included segmental (178, 45.9%), lobar (149, 38.4%), and extended hepatectomy (61, 15.7%). The NIT group included ablation (6, 6.2%), radiation (25, 25.8%), and Y90 (18, 18.6%). The non-NIT group included 124 (42.6%) chemotherapy, 23 (7.9%) chemotherapy plus ablation, 31 (10.7%) chemotherapy plus radiation, four (1.4%) radiation, and 109 (37.5%) upfront surgery. NIT patients were treated more at high-volume (41.2% vs. 0%) and academic/research centers (85.4% vs. 50.5%). NIT R0 resection rates were higher (97.9% vs. 93.2%, p = 0.009). Median survival was higher in the NIT group (59.1 vs. 50.4 months, p = 0.002); 30- and 90-day mortality were similar. NIT was not independently associated with improved survival in multivariable Cox regression (HR 0.73, 95% CI [0.35, 1.55]), although the effect estimate indicates a protective effect may be present. Conclusions: NIT was associated with higher R0 resection rates and overall survival without increasing short-term mortality in selected patients at high-volume academic centers, but was not independently associated with survival when adjusting for confounders. As we continue to see increasing use of immunotherapy in the neoadjuvant setting, these findings should be considered hypothesis-generating and warrant prospective validation before widespread adoption for HCC. Full article

Hepatocellular carcinoma (HCC) remains a malignancy with poor prognosis and limited therapeutic targets. Emerging evidence suggests a critical role for iron metabolism and ferroptosis in tumor progression. However, the involvement of hematopoietic lineage cell-specific protein 1 (HAX1) in HCC, particularly its regulatory role in ferroptosis, remains largely unknown. Here, we report that HAX1 is significantly upregulated in HCC tissues and correlates with advanced pathological stages and poor patient survival, suggesting its potential as an oncogene. Functionally, HAX1 overexpression promotes the proliferation and migration of HCC cells, while its knockdown inhibits these malignant phenotypes. Mechanistically, we demonstrate that HAX1 acts as a negative regulator of ferroptosis. Silencing HAX1 sensitizes HCC cells to the ferroptosis inducer IKE, leading to abnormal accumulation of intracellular ferrous iron (Fe²⁺) and increased lipid reactive oxygen species (ROS). Conversely, HAX1 overexpression suppresses iron overload and lipid peroxidation. Furthermore, we reveal that HAX1 maintains redox homeostasis by regulating the GSH/GPX4 antioxidant pathway. Knockdown of HAX1 depletes reduced glutathione (GSH), reduces glutathione peroxidase activity, and downregulates key ferroptosis defense proteins, including GPX4, FSP1, and SLC7A11. Our findings identify HAX1 as a critical promoter of HCC progression that functions by inhibiting ferroptosis through the modulation of iron homeostasis and the GSH/GPX4 pathway. Targeting the HAX1-mediated anti-ferroptotic mechanism may represent a promising therapeutic strategy for HCC treatment. Full article

Background: Hepatitis delta (HDV) is the most severe form of chronic viral hepatitis, with rapid progression to cirrhosis and hepatocellular carcinoma, and remains neglected in the Amazon Basin. The state of Acre, in the Western Brazilian Amazon, is endemic for HDV, with a high prevalence of genotype 3 (HDV-3). This study aimed to analyze epidemiological data, quantify HDV RNA, identify genotypes, and describe the phylogeny and phylogeography of HDV in Acre. Methods: This cross-sectional study included patients positive for HBsAg and anti-HDV under follow-up at the Specialized Assistance Service (SAE) in Rio Branco, Acre, between March and November 2023. Blood samples were collected for HDV RNA quantification using one-step RT-qPCR. Samples with detectable viremia (Ct ≤ 30) underwent Nested-PCR, Sanger sequencing, phylogenetic analysis (Maximum Likelihood), temporal signal evaluation, and Bayesian phylogeographic reconstruction. Results: Among 108 patients (median age 43; 55.6% female), HDV RNA was detected in 48.1%, with viral loads ranging from 140 to 24,000,000 copies/mL. Of these, 55.8% had >100,000 copies/mL. Genotyping (n = 41) identified exclusively HDV-3. Phylogenetic analysis revealed genetic heterogeneity among HDV-3 isolates, with the formation of two major phylogenetic clades. Bayesian analysis estimated tMRCA around 1818 and suggested dispersion from Amazonas to Acre and neighboring regions. Conclusion: HDV-3 predominates in Acre with high genetic diversity, indicating sustained viral circulation in the Western Amazon and reinforcing the need for improved surveillance and diagnosis. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) arises through heterogeneous pathways involving chronic hepatitis B virus infection, hepatitis C virus infection, alcohol-related liver disease, metabolic dysfunction-associated steatotic liver disease, fibrosis, cirrhosis, and environmental exposures. Genome-wide association studies (GWASs) have identified host germline loci associated with HCC susceptibility, but interpretation is complicated by aetiology, ancestry, liver disease stage, and the definition of controls. This narrative review examines current GWAS evidence for HCC, with emphasis on aetiology-specific susceptibility, functional interpretation, cross-disorder genetic effects, and clinical translation. Methods: Studies were identified through iterative searches of PubMed/PMC, publisher pages, academic search tools, and citation tracking, supplemented by targeted searches for major HCC-associated loci. Sources were chosen based on relevance to GWAS discovery, replication, meta-analysis, functional interpretation, polygenic risk modelling, or HCC risk stratification, rather than by a formal systematic review protocol. Results: Viral HCC studies most often implicate immune regulation and antigen presentation, including MICA, HLA-DQ, HLA-DQB1, HLA class I, HCP5, STAT4, DEPDC5, and FAM114A1. Alcohol-related, metabolic, and non-viral HCC studies more often implicate hepatic lipid metabolism, telomere biology, iron metabolism, steatosis, and cirrhosis-related pathways, including PNPLA3, TM6SF2, TERT, HSD17B13, APOE, HFE, and MTARC1. Recent studies increasingly combine GWASs with fine-mapping, functional annotation, transcriptomic analyses, and risk modelling. Conclusions: HCC genetic susceptibility is highly aetiology-specific and overlaps with other liver and metabolic disorders, but discoveries from genetic studies have not yet been translated into routine clinical practice. Future work should prioritise multi-ancestry cohorts, disease-stage-aware controls, functional validation, and prospectively tested genetic risk models. Full article

Background and Objectives: Sevoflurane, a widely used inhalational anesthetic, is frequently administered during hepatocellular carcinoma (HCC) surgery, including hepatic resection and orthotopic liver transplantation. Because such procedures often require prolonged anesthetic exposure, the potential influence of sevoflurane on HCC cell behavior is of clinical interest. We aimed to evaluate the effects of sevoflurane on the proliferation and migration of HepG2 cells in vitro and on tumor growth in a xenograft mouse model in vivo, and to explore whether hypoxia-inducible factor-1α (HIF-1α) might be involved in this process. Materials and Methods: For the in vitro experiments, HepG2 cells were exposed to room air (0%), 2%, or 4% sevoflurane. A scratch wound healing assay was used to assess cell migration, and the number of viable cells was quantified by hemocytometer counting on day 4 to estimate proliferation. For the in vivo experiments, BALB/c nude mice bearing HepG2 xenografts were exposed to room air, 2% sevoflurane, or 4% sevoflurane for 3 h, three times weekly for 5 weeks. Tumor size and tumor weight were measured at the end of the exposure period. HIF-1α protein levels in tumor tissue were measured by enzyme-linked immunosorbent assay (ELISA) in tumor lysates and normalized to total tumor protein as an exploratory mechanistic analysis. Given the small sample available for this endpoint, the analysis had limited sensitivity to detect modest differences. Results: When wound closure was quantified and pooled across the analyzable experiments, no statistically significant difference was detected among the room air, 2% sevoflurane, and 4% sevoflurane groups (day-2 closure 19.9 ± 32.1%, 22.1 ± 25.8%, and 22.3 ± 28.8%, respectively; repeated-measures ANOVA p = 0.82), with variability dominated by between-experiment rather than treatment differences. In the proliferation assay, the number of viable HepG2 cells on day 4 was significantly lower in the 2% sevoflurane group (62.6 ± 3.3 × 10⁵) than in the room air group (68.5 ± 4.2 × 10⁵; p < 0.05); the 4% sevoflurane group (66.0 ± 3.2 × 10⁵) showed an intermediate value that did not reach statistical significance. In the xenograft model, mean tumor size in the room air, 2% sevoflurane, and 4% sevoflurane groups was 7.1 ± 1.9, 2.7 ± 2.0, and 2.1 ± 0.9 cm³, respectively (p = 0.041 for room air vs. 2% sevoflurane; p = 0.034 for room air vs. 4% sevoflurane). Tumor weight was likewise lower in the sevoflurane groups (room air, 7.88 ± 2.2 g; 2% sevoflurane, 2.95 ± 2.1 g; 4% sevoflurane, 2.3 ± 1.6 g; p = 0.044 for room air vs. 2% sevoflurane; p = 0.067 for room air vs. 4% sevoflurane). No statistically significant differences in tumor HIF-1α protein levels were observed among the three groups. Conclusions: In this exploratory study, sevoflurane exposure was associated with reduced HepG2 xenograft tumor growth in vivo, whereas its in vitro effects were more limited: a reduction in viable cell number was observed only at 2% sevoflurane, and an effect on cell migration could not be confirmed when analyzed across experiments. Tumor HIF-1α levels did not differ significantly between groups, suggesting that other molecular pathways may be involved. Further mechanistic and clinical studies are warranted before any conclusions can be drawn about the relevance of these findings to the perioperative management of patients with HCC. Full article

The lysine methyltransferase SMYD5 is an important regulator of development and has been implicated in multiple malignancies, such as heart disease, lung and gastric cancers, breast and hepatocellular carcinomas, and inflammatory bowel disease. Further, SMYD5 has been linked to the mild hypothermia response, RNA translation, and HIV-1 transcription. SMYD5 is ubiquitously expressed in lymphocytes and the fetal brain, retina, heart, gut, liver, and reproductive organs. Mechanistically, SMYD5 methylates histone residues H3K36, H3K37, and H4K20, as well as non-histone targets such as the ribosomal protein RPL40 and the HIV-1 Tat protein. Here, we review the literature on SMYD5, focusing on its epigenetic functions and its roles in development, cancer, and other biological processes. Full article

Background: Hepatocellular carcinoma (HCC) represents the most common primary liver cancer and a significant cause of global cancer-related mortality, with the majority of patients diagnosed at advanced or unresectable stages. Historically, tyrosine kinase inhibitor (TKI) monotherapies such as sorafenib and lenvatinib served as the primary systemic standard of care. However, the emergence of immune checkpoint inhibitor (ICPI)-based combinations has significantly transformed the treatment landscape. We aim to perform a comparative analysis of ICPI-based combination treatment versus TKI monotherapy among advanced HCC patients. Methods: This study utilized a reconstructed individual patient data (IPD) pooled analysis derived from nine phase 3 randomized clinical trials, adhering to PRISMA-IPD reporting guidelines. A total of 6161 patients were included in the analysis, which categorized treatment into five primary strategies: ICPI monotherapy, ICPI plus bevacizumab, dual ICPI therapy (duplet), ICPI plus TKI, and TKI monotherapy as the control group. The primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS) and the incidence of grade 3 or higher adverse events (AEs). Results: The analysis demonstrated that ICPI-based combinations provided a significant survival advantage over TKI monotherapy. Key hazard ratios (HRs) for OS compared to TKIs were 0.76 (95% CI: 0.67–0.85, p < 0.001) for dual ICPI, 0.76 (95% CI: 0.68–0.85, p < 0.001) for ICPI plus TKI, and 0.70 (95% CI: 0.61–0.81, p < 0.001) for ICPI plus bevacizumab. Median OS was numerically highest for ICPI plus TKI at 19.68 months and dual ICPI at 19.58 months compared to 14.84 months for the TKI group. Among FDA-approved regimens, nivolumab plus ipilimumab (NivoIpi) achieved the longest median OS of 24.08 months. From a safety standpoint, the ICPI plus TKI group had the highest incidence of grade 3/4 AEs at 69.1%. Conversely, TKI monotherapy showed a 50.1% incidence, while dual ICPI therapy exhibited the most favorable safety profile at 32.7%. Conclusions: ICPI-containing combination therapies are superior to TKI monotherapy for the first-line treatment of advanced HCC, providing marked improvements in survival outcomes. Dual ICPI therapy represents the most balanced approach between efficacy and safety, achieving high survival with the lowest rates of severe toxicity. Among approved options, NivoIpi exhibited a numerically favorable survival signal, while DurvaTreme offered the highest tolerability, supporting a personalized treatment approach based on individual patient risk factors and hepatic reserve. Full article

Primary hepatic masses in dogs represent a heterogeneous group of lesions with variable biological behavior and challenging preoperative characterization. The objective of this retrospective study was to describe the clinical presentation, diagnostic findings, surgical management, and outcome of dogs with primary hepatic lesions treated surgically. Ten dogs with resectable hepatic lesions and no evidence of extrahepatic metastasis were included. Clinical records, imaging findings, histopathological diagnoses, treatment, and follow-up data were reviewed. Histopathological diagnoses included hepatocellular carcinoma (n = 3), nodular hyperplasia (n = 2), lobular hyperplasia (n = 1), hepatocellular adenoma (n = 1), undifferentiated sarcoma (n = 1), osteosarcoma (n = 1), and one case without a definitive histological diagnosis. Tumor size ranged from 3.3 to 18 cm. Both benign and malignant lesions were represented across this size range. Cytological findings were discordant with the final histopathological diagnosis in three dogs, whereas one sample was non-diagnostic due to blood contamination. Abdominal ultrasound identified solitary lesions in all evaluated dogs, although surgery revealed previously undetected multifocal disease in two cases. Six of the ten lesions involved the right medial hepatic lobe, although the small sample size precludes conclusions regarding lesion distribution. All dogs underwent surgical resection. Two perioperative deaths occurred secondary to postoperative renal failure. Among the surviving dogs, clinical status during follow-up was generally reported as improved compared with preoperative presentation, and survival times ranged from 4 to more than 730 days, including dogs with malignant neoplasms. Four dogs remained alive and disease-free at the end of the follow-up period (>730 days). This retrospective case series illustrates the clinical and pathological heterogeneity of primary hepatic masses in dogs. Discrepancies between preoperative assessment and intraoperative or histopathological findings were observed in some cases. Given the small sample size, heterogeneous diagnoses and non-standardized diagnostic workup, these observations should be interpreted cautiously and considered hypothesis-generating. Full article

Aflatoxins and fumonisins are two of the most prevalent and toxicologically significant mycotoxins contaminating global food supplies, particularly maize and groundnuts. Although several regulated mycotoxins contribute to food safety concerns, this review focuses on aflatoxins and fumonisins because they frequently co-occur in maize and maize products. Their widespread prevalence, distinct toxicological mechanisms, and combined health effects necessitate an integrated exposure and risk assessment. This review critically evaluates the current state of exposure assessment and its implications for human health. We examine the evolution of sample preparation techniques, highlighting the transition from traditional liquid–liquid extraction to advanced approaches such as QuEChERS and green extraction technologies that can handle the divergent physicochemical properties of lipophilic aflatoxins and hydrophilic fumonisins. Analytical methods are compared, from the robust but limited HPLC-FLD to the multi-analyte capabilities of LC-MS/MS and the emerging potential of aptamer-based biosensors. Furthermore, the review addresses the critical challenge of modified mycotoxins that evade routine detection yet may contribute to total toxicity. By synthesizing data on biomarkers of exposure and the mechanisms of co-exposure, we discuss the complex interplay between these toxins in the etiology of hepatocellular carcinoma and neural tube defects. The review concludes that mitigating the public health burden of mycotoxins requires a holistic strategy that integrates HRMS for non-targeted analysis with human biomonitoring to capture the accurate individual-level exposure. Full article

Background/Objectives: Poor outcomes in liver cancer are often driven by late-stage diagnoses and high recurrence rates following surgical resection, highlighting a critical clinical need for non-invasive surveillance tools. This proof-of-concept study investigates the utility of circulating extracellular vesicles (EVs) to track dynamic molecular shifts and monitor patient response following tumour resection. Methods: Small ribonucleic acid (RNA) sequencing was conducted on matched tumour tissue, tissue-derived EVs, and plasma EVs collected at the time of surgery from patients with liver cancer. To capture longitudinal transcriptomic changes, plasma EVs were also collected at a post-operative follow-up appointment. Results: At the time of surgery, the transcriptomic profile of circulating plasma EVs strongly correlated with both the matched tumour tissue and tissue-derived EVs, exhibiting substantial transcript overlap. However, at post-operative follow-up, the circulating EV cargo significantly diverged from the primary tumour profile. This loss of similarity was characterised by a distinct shift in RNA cargo, including 173 uniquely detected transcripts absent at baseline. Conclusions: Circulating EVs accurately reflect the local hepatic transcriptome at the time of surgery, but their profile dynamically and fundamentally diverges once the tumour is removed. This post-surgical divergence provides an initial proof-of-concept that utilising patients as their own internal control to longitudinally profile EV cargo may track the clearance of tumour signals and monitor post-surgical systemic changes, highlighting their potential utility for future longitudinal studies aimed at tracking cancer progression and recurrence. Full article

Background: Oncolytic viruses (OVs), a promising anti-cancer therapeutic, replicate more efficiently in cancer cells rather than in healthy cells due to the alterations in antiviral response mechanisms and dysregulation of signaling pathways. Vesicular stomatitis virus (VSV) is known for low pathogenicity, tropism to various cancer cells, and the ability to lyse cells in the hypoxic tumor microenvironment (TME). Targeted delivery of immune checkpoint and co-stimulatory molecules can enhance the anti-tumor immune response and remodel the immunosuppressive TME. The aim of this study was to compare the activity of rVSV-GFP with rVSV, encoding the programmed cell death protein 1 (PD-1) and tumor necrosis factor ligand superfamily member 9 (4-1BBL). Methods: The oncolytic efficacy of these rVSV variants used at 10⁵, 10⁶, and 10⁷ TCID50 was evaluated at 24 and 48 h post-infection by flow cytometry in a panel of mouse and human cancer cell lines. Quantitative real-time polymerase chain reaction (qPCR) was used to evaluate mRNA expression levels of certain genes at 12 and 48 h post-infection. Results: Murine hepatocellular carcinoma (H22) and human melanoma (A375) or human lung carcinoma (A549) were the most sensitive to rVSV therapy cell lines. The higher relative expression of the antiviral response genes RIG-I and IFIT1 within each biological species (mouse or human) correlated with lower sensitivity to rVSV. No such effect was observed for the type I interferons (IFNs), despite their proposed key role in resistance to OV therapy. Conclusions: H22, A375, and A549 are more susceptible to the oncolytic activity of the novel rVSV-PD-1-4-1BBL. Full article

Background and Aims: To develop an inclusive, predictive framework for hepatocellular carcinoma patients, beyond what the Barcelona Clinic Liver Cancer (BCLC) staging system captures alone, non-invasive scores have emerged as potential contributors. Among them, the CRAFITY score (CRP and AFP in ImmunoTherapY), originally developed for immunotherapy-treated HCC populations, and the Platelet-Albumin-Bilirubin (PALBI) score have shown promising prognostic performance in selected cohorts. Likewise, the macrotrabecular-massive (MTM) histological subtype has been identified as a strong independent predictor of tumor recurrence, particularly in surgical series; whether it retains the prognostic significance in a mixed-treatment cohort remains unexplored. We aimed to evaluate the independent prognostic performance of CRAFITY and PALBI across all HCC treatment modalities, determine MTM prevalence and assess whether histological subtyping adds prognostic value beyond these readily available clinical scores. Methods: The study included 500 consecutive, pathologically confirmed HCC patients at a tertiary gastroenterology center in Cluj-Napoca, Romania. MTM subtype was defined as >50% macrotrabecular architectural pattern on histological review by two senior pathologists. Overall survival (OS) and recurrence-free survival (RFS) were assessed by Kaplan–Meier analysis and multivariable Cox regression. A random survival forest (RSF) model was constructed to identify dominant prognostic predictors. Results: MTM was identified in 14 patients (2.8%) and did not independently predict OS (HR 0.94, 95% CI 0.49–1.81, p = 0.85) or recurrence (OR 3.78, p = 0.116). In this heterogeneous cohort spanning multiple treatment modalities, CRAFITY (HR 1.68, 95% CI 1.42–1.98, p < 0.001) and PALBI (HR 1.51, 95% CI 1.22–1.87, p < 0.001) were strong independent predictors of OS after BCLC stage. RSF analysis confirmed this hierarchy with a C-index of 0.734. Conclusions: CRAFITY and PALBI demonstrated strong, independent predictive performance for a large, underrepresented, heterogenous Eastern European HCC cohort. In contrast, MTM subtype showed limited prognostic value in this cohort. The results support the broader applicability of CRAFITY beyond its original immunotherapy context and underline the low prevalence of MTM subtype. Full article