Background: Lenvatinib has been approved in Italy since October 2019 as a first-line therapy for advanced hepatocellular carcinoma (HCC) and to date data on effectiveness and safety of lenvatinib are not available in our region. To fill this gap, we performed a multicentric analysis of the real-world treatment outcomes with the propensity score matching in a cohort of Italian patients with unresectable HCC who were treated with either sorafenib or lenvatinib. Aims and Methods: To evaluate the effectiveness of sorafenib and lenvatinib as primary treatment of advanced HCC in clinical practice we performed a multicentric analysis of the treatment outcomes of 288 such patients recruited in 11 centers in Italy. A propensity score was used to mitigate confounding due to referral biases in the assessment of mortality and progression-free survival. Results: Over a follow-up period of 11 months the Cox regression model showed 48% reduction of death risk for patients treated with lenvatinib (95% CI: 0.34– 0.81; p = 0.0034), compared with those treated with sorafenib. The median PFS was 9.0 and 4.9 months for lenvatinib and sorafenib arm, respectively. Patients treated with lenvatinib showed a higher percentage of response rate (29.4% vs 2.8%; p < 0.00001) compared with patients treated with sorafenib. Sorafenib was shown to be correlated with more HFSR, diarrhea and fatigue, while lenvatinib with more hypertension and fatigue. Conclusion: Our study highlighted for the first time the efficacy and safety of lenvatinib in an Italian cohort of patients.

Introduction: Immune check point inhibitors have recently entered the armamentarium of advanced hepatocellular carcinoma (HCC) treatment. Among them, the combination of atezolizumab plus bevacizumab has pushed it a step forward; however, a number of patients still present primary non-responses without any biomarker to predict responses to different options. Here, we aimed to identify a putative baseline biomarker to predict the response to atezolizumab–bevacizumab, by investigating whether baseline PD1+ and PD-L1+ peripheral granulocyte percentages might offer a non-invasive, cheap, and easily feasible assay. Methods: A prospective Italian cohort of 34 patients treated by atezolizumab–bevacizumab was tested to assay the baseline percentage of peripheral granulocytes and their PD1 and PD-L1 expression. The neutrophil to lymphocyte ratio (NLR) was also considered, and all data were compared with the clinical course of patients. Results: A low-baseline PD1+ peripheral granulocyte percentage turned out to predict responder patients (mean ±SD of PD1+ granulocyte percentage in responders versus non-responders: 9.9 ± 9.1 vs. 29.2 ± 17.6; student’s t-test, p < 0.01). In line, patients identified by a low PD1+ granulocyte percentage displayed a longer TTP (log-rank test, p < 0.0001). A lower granulocyte percentage on total white blood cells, irrespective of PD1 or PD-L1 expression, is also associated with responses to atezolizumab–bevacizumab (log-rank test, p < 0.05). No predictive value was observed for either the PD-L1+ granulocyte percentage or NLR. Conclusions: A low-baseline PD1+ peripheral granulocyte percentage is associated with responses to atezolizumab–bevacizumab treatment in advanced HCC. These findings encourage evaluating this minimally invasive, cheap, and easy test in further independent cohorts and outlining the relevance of innate immunity in the response to immune-checkpoint inhibitors.

Background: The Barcelona Clinic Liver Cancer (BCLC) system for HCC was updated in 2022. The aim of the study was to assess the suitability and impact on overall survival (OS) of BCLC_2022, along with “clinical decision-making” (CDM), using BCLC_2018 as a benchmark. Methods: We retrospectively evaluated 798 patients with de novo HCC followed prospectively from 2006 to 2022: 187 in BCLC 0, 371 in A, 132 in B, 87 in C, and 21 in D, all managed by a multidisciplinary team. Patients were followed until death or at the end of the follow-up period in December 2022. Results: The suitability of the algorithm increased from 51% for BCLC_2018 to 69% for BCLC_2022 (p<0.001). Among those treated with the newly introduced “lower priority options,” 22% were in BCLC 0 and 37% in A, showing lower rates of complete response (CR) and shorter OS compared to first-line treatments. In BCLC 0 and A, CDM was associated with a significant decrease in “downward stage migration” with BCLC_2022 (from 33% to 16%, p<0.001). Conversely, in BCLC B and C, “upward stage migration” correlated with higher CR rates and longer OS [63 (36–72) vs. 28 (18–44) months, p=0.003 in BCLC B; 21 (15–44) vs. 11 (4–25) months, p200 ng/mL, Child–Pugh score C, advanced BCLC stage, and noncurative treatment. Conclusions: BCLC_2022 and CDM provide greater flexibility in clinical practice without adversely affecting patient survival. Access to curative treatments improves the outcomes of selected patients in all stages.

Advanced hepatocellular carcinoma (HCC) has a dismal prognosis; however, the introduction of atezolizumab-bevacizumab combination has improved overall survival and novel immune checkpoint inhibitors are entering the clinics. Despite more therapeutic options being available, no biomarker guides treatment choice. Indeed, tissue-based analyses and complex analytical procedures hinder clinical translation. We explored the informativeness of a simple, non-invasive, repeatable cytofluorimetric assay on peripheral blood to predict response and survival in HCC patients treated with atezolizumab-bevacizumab. Twenty-five cirrhotic patients, 50 HCC patients undergoing atezolizumab-bevacizumab and an independent validation cohort of 25 HCC patients were subjected to a cytofluorimetric study of peripheral white blood cells (WBCs) to assess baseline programmed death-ligand 1-positive (PD-L1+) and cytotoxic T-lymphocyte antigen 4-positive (CTLA4+) cell percentage in the different populations and their early on-treatment variations. Immunophenotypes were evaluated against treatment response. RNA sequencing followed by RT-PCR validation were used to elucidate the molecular correlates of immunophenotypic observations. PD-L1+ cell percentage did not predict response either at baseline or when evaluating treatment-induced early changes. Conversely, the percentage of CTLA4+ lymphocytes at baseline showed a predictive significance (35.37 in responders versus 31.5 in non-responders, P = 0.03). More interestingly, the early CTLA4+ changes during treatment in lymphocytes (responders 0.95 versus non-responders 1.08, P = 0.05), monocytes (responders 0.95 versus non-responders 1.04, P = 0.03), granulocytes (responders 0.94 versus non-responders 1.14, P = 0.001) and, even stronger, the early CTLA4+ percentage change in the whole WBCs displayed a predictive significance in terms of time to progression (TTP) (P < 0.0001) and overall survival (OS) (P = 0.005). The immunophenotypic findings correlated with transcriptional modulation of CTLA4 target genes and genes involved in immune response. A repeatable, easy, non-invasive blood test predicts response to immunotherapy in patients with HCC, both in terms of TTP and OS. CTLA4+ cell percentage increase in non-responders suggests a possible resistance mechanism which deserves attention as a druggable target.

Background and aims: Hepatocellular carcinoma (HCC) patients frequently present with comorbidities that limit therapeutic options and increase mortality. This study evaluated the performance of the Charlson Comorbidity Index (CCI) and a modified CCI (mCCI) in stratifying patients with HCC to predict treatment allocation and survival. Methods: A retrospective single-center cohort study analyzed 401 patients with de novo HCC (74% male, median age 68 years, 80% Child–Pugh-Turcotte (CPT) A, 65% viral etiology, 70% Barcelona Clinic Liver Cancer stage (BCLC) 0/A). CCI and mCCI (with points related to HCC and chronic liver disease excluded), were calculated at diagnosis for each patient. The primary endpoint was overall survival (OS) estimated by Kaplan–Meier method and compared across mCCI classes; Cox uni/multivariable models were applied to identify predictors of mortality. The secondary aim was evaluating the association between mCCI and treatment allocation. Results: While CCI classified 94% of patients as “high-risk”, mCCI reclassified patients into “high-risk” (21%), “intermediate-risk” (48%), and “low-risk” (31%), demonstrating better stratification whilst maintaining a strong correlation with CCI (Kendall’s tau-b = 0.57, p < 0.001). BCLC B patients with “high-risk” mCCI exhibited significantly lower access to first-line curative treatment (14% vs. 47%, p = 0.03). Moreover, “high” or “intermediate-risk” patients according to mCCI experienced significantly shorter OS compared to “low-risk” (median OS 36 vs. 49 vs. 74 months, p < 0.001). “High-risk” and “intermediate-risk” mCCI classes were independent predictors of mortality, alongside alpha-fetoprotein, CPT and BCLC stage. Considering the items composing mCCI, age and cardiovascular diseases were independent predictors of mortality. Conclusions: mCCI provides a more accurate assessment of comorbidities than the standard CCI and is associated with survival, hence it can contribute to designing patient-tailored therapeutic strategies.

Background & Aims: The management of comorbidities has become increasingly relevant in unresectable hepatocellular carcinoma (uHCC) as immunotherapy prolongs survival. Atezolizumab plus bevacizumab (AB) is a standard first‐line option, but bevacizumab carries a risk of cardiovascular toxicities. Data on cardiovascular risk stratification in patients with cirrhosis remain limited. Identifying patients at increased cardiovascular risk is therefore clinically important, particularly given the availability of bevacizumab‐free alternatives. Methods: We retrospectively analysed prospectively collected data from the multicenter Italian ARTE database, including patients with uHCC treated with first‐line AB between June 2022 and July 2025. Traditional major adverse cardiovascular events (tMACE) were defined as acute coronary syndromes, heart failure, cerebrovascular events, or peripheral ischemia, while an extended composite (eMACE) additionally included venous thromboembolism and immune‐related myocarditis. Cardiovascular risk was stratified using the European Society of Cardiology (ESC) Cardio‐Oncology classification and the CARDIOSOR score. Competing‐risk analyses were performed considering treatment discontinuation as a competing event. Results: This study included 538 patients (median age 69.8 years). During follow‐up, 20 patients (3.7%) experienced tMACE, and 30 (5.6%) experienced eMACE. Patients assigned to the very high‐risk category by ESC criteria and those with a high‐risk CARDIOSOR score had a significantly increased risk of tMACE and eMACE. Both scores demonstrated a moderate ability to stratify cardiovascular risk (Harrell's c‐index 0.68 for ESC and 0.59 for CARDIOSOR). Conclusions: Cardiovascular adverse events were uncommon overall, but their incidence was not negligible in patients in high‐risk subgroups. Risk scores may help identify vulnerable subgroups and support patient‐tailored treatment strategies, including consideration of bevacizumab‐free regimens in selected cases. Trial Registration: Multicenter ARTE database (NCT06806579)