Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death. Although the burden of alcohol- and NASH-related HCC is growing, chronic viral hepatitis (HBV and HCV) remains a major cause of HCC development worldwide. The pathophysiology of viral-related HCC includes liver inflammation, oxidative stress, and deregulation of cell signaling pathways. HBV is particularly oncogenic because, contrary to HCV, integrates in the cell DNA and persists despite virological suppression by nucleotide analogues. Surveillance by six-month ultrasound is recommended in patients with cirrhosis and in “high-risk” patients with chronic HBV infection. Antiviral therapy reduces the risks of development and recurrence of HCC; however, patients with advanced chronic liver disease remain at risk of HCC despite virological suppression/cure and should therefore continue surveillance. Multiple scores have been developed in patients with chronic hepatitis B to predict the risk of HCC development and may be used to stratify individual patient’s risk. In patients with HCV-related liver disease who achieve sustained virological response by direct acting antivirals, there is a strong need for markers/scores to predict long-term risk of HCC. In this review, we discuss the most recent advances regarding viral-related HCC.

Neoangiogenesis plays a crucial role in the progression of hepatocellular carcinoma (HCC), and concerns have been raised about the role of neoangiogenesis on the effectiveness of transarterial chemoembolization (TACE). In this study, we aimed to evaluate Vascular Endothelial Growth Factor (VEGF) and Hypoxia-Inducible Factor-1α (HIF-1α) as circulating prognostic biomarkers in HCC patients treated with TACE. Blood samples were collected from 163 patients before (t₀) and four weeks after TACE (t₁). Higher levels of VEGF after TACE were demonstrated (264.0 [78.7-450.8] vs. 278.6 [95.0-576.6] pg/mL; p < 0.0001). Responders to TACE had lower levels of VEGF than non-responders both at t₀ (200.0 [58.9-415.8] vs. 406.6 [181.4-558.6] pg/mL; p = 0.006) and at t₁ (257.3 [68.5-528.6] vs. 425.9 [245.2-808.3] pg/mL; p = 0.003), and in both groups there was an increase in VEGF compared to measurements before treatment (p = 0.001 and p = 0.005, respectively). VEGF was not associated with overall survival (OS), while patients with HIF-1α ≤ 0.49 ng/mL showed better prognosis (median OS 28.0 months [95% CI 19.7-36.3] vs. 17.0 months [95% CI 11.1-22.9]; p = 0.01). Moreover, HIF-1α was identified as an independent prognostic parameter. VEGF and HIF-1α can be considered useful prognostic biomarkers in HCC patients treated with TACE.

The systemic treatment of hepatocellular carcinoma (HCC) is changing rapidly. After a decade of tyrosine kinase inhibitors (TKIs), as the only therapeutic option for the treatment of advanced HCC, in the last few years several phase III trials demonstrated the efficacy of immune checkpoint inhibitors (ICIs). The combination of the anti-PD-L1 atezolizumab and the anti-vascular endothelial growth factor (VEGF) bevacizumab demonstrated the superiority over sorafenib and currently represents the standard of care treatment for advanced HCC. In addition, the combination of durvalumab (an anti-PD-L1) and tremelimumab (an anti-CTLA4) proved to be superior to sorafenib, and in the same trial durvalumab monotherapy showed non-inferiority compared to sorafenib. However, early reports suggest an influence of HCC etiology in modulating the response to these drugs. In particular, a lower effectiveness of ICIs has been suggested in patients with non-viral HCC (in particular non-alcoholic fatty liver disease). Nevertheless, randomized controlled trials available to date have not been stratified for etiology and data suggesting a possible impact of etiology in the outcome of patients managed with ICIs derive from subgroup not pre-specified analyses. In this review, we aim to examine the potential impact of HCC etiology on the response to immunotherapy regimens for HCC.

Background/Objectives: Despite advances in hepatocellular carcinoma (HCC) management, prognosis remains poor. Advanced-stage diagnosis often excludes curative treatments, and current biomarkers (e.g., alpha-fetoprotein [AFP]) have limited utility in early detection. Liquid biopsy has emerged as a promising cancer detection tool, with circulating cell-free DNA (ccfDNA) showing significant diagnostic potential. This proof-of-concept study aimed to investigate the potential role of tumor fraction (TF) within ccfDNA as a biomarker in HCC patients. Methods: A total of sixty patients were recruited, including thirteen with chronic liver disease (CLD), twenty-four with cirrhosis, and twenty-three with HCC. Plasma samples were collected, and ccfDNA was extracted for shallow whole genome sequencing (sWGS) analysis. The TF was calculated by focusing on somatic copy number alterations (SCNAs) within the ccfDNA. Results: Among patients with CLD and cirrhosis (n = 37), ctDNA was undetectable in all but one cirrhotic patient who exhibited a significant tumor fraction (TF) of 17% and subsequently developed HCC. Conversely, five out of twenty-three HCC patients (21.7%) displayed detectable ctDNA with TF levels ranging from 3.0% to 32.6%. Patients with detectable ctDNA were characterized by more aggressive oncological features, including a higher number of nodules (p = 0.005), advanced-stage disease (60% BCLC C, p = 0.010), and poorer response to therapy (80% PD, p = 0.001). Moreover, the overall survival (OS) was significantly reduced in patients with detectable ctDNA (median OS: 17 months; CI 95% 4.5–26.5) compared to those without (median OS: 24.0 months; CI 95% 7.0–66.0; log-rank p = 0.002). Conclusions: Our results suggest that the analysis of TF by sWGS is a promising non-invasive tool for the identification of HCC with aggressive clinical behavior, whereas it is not sensitive enough for early HCC detection. This molecular assay can improve prognostic stratification in HCC patients.

Background: Coagulation alterations may contribute to cirrhosis progression. We explored whether increased thrombomodulin-modified thrombin generation (TM-TG) was associated with first hepatic decompensation in compensated cirrhosis. Methods: We retrospectively analyzed a prospectively collected cohort of 171 patients with compensated cirrhosis. TM-TG was measured at enrolment. The primary endpoint was the first hepatic decompensation. Time-to-event analyses were performed using cause-specific Cox models, with Fine–Gray models as a complementary competing risk approach. Results: Median age was 66 years, 66.7% were male, and 90.1% were Child–Pugh A; 70 (40.9%) patients had large varices. During a median follow-up of 3.3 years, 37 patients (21.6%) developed first hepatic decompensation. The 1-year, 2-year, 3-year, and 5-year cumulative incidences were 4.7%, 11.5%, 17.8%, and 31.5%, respectively. Compared with patients who remained compensated, those who developed first hepatic decompensation had lower platelet count (56 vs. 111 × 10 ⁹ /L), higher MELD score (9.97 vs. 8.93), more frequent large varices (73% vs. 36%), higher ETP-TM (822 vs. 752 nM min), and more often an ETP ratio >0.80 (70.3% vs. 44.0%) (all p <0.05). In multivariable analyses, higher ETP-TM remained independently associated with first hepatic decompensation in models including MELD (HR 1.27; sHR 1.30), large varices (HR 1.24; sHR 1.30), and platelet count (HR 1.29; sHR 1.31) (all p 0.80 was independently associated with first hepatic decompensation in models including MELD (HR 2.81; sHR 2.9), large varices (HR 2.96; sHR 2.7), and platelet count (HR 3.41; sHR 3.32) (all p <0.05). Conclusion: In compensated cirrhosis, increased TM-TG is associated with the first hepatic decompensation, although confirmation in prospective studies is warranted.