BACKGROUND AND AIMS:The ASAP algorithm incorporating Age, Sex, Alpha-fetoprotein (AFP), and prothrombin induced by vitamin K absence/antagonist II (PIVKA-II) has been shown to predict hepatocellular carcinoma (HCC) development. Our study evaluated the prognostic value of ASAP for early HCC recurrence after complete radiological response (CR) to locoregional therapy. METHODS:This single-center study enrolled patients with newly diagnosed HCC who achieved CR by ablation (MWTA) or chemoembolization (TACE) and available serum samples on the day of treatment. CR was evaluated by CT-scan 1 month after treatment. PIVKA-II and AFP levels were measured using Fujirebio assays. Patients were followed up every three months until recurrence, death, or last follow-up. RESULTS:127 patients with HCC (median age 66 years, 79 % male, 79 % with viral etiology) who achieved CR were enrolled. At time of treatment, median AFP and PIVKA-II levels were 6.6 ng/mL and 144 mAU/mL, respectively, while median ASAP score was 0.60. During follow-up, HCC recurred in 72 (56.7 %) patients (63 within 24 months, early recurrence). ASAP score was the sole independent predictor of early recurrence [HR 2.57 (95 % CI 1.50-4.40), p=0.001] and its new cutoff of 0.797 (AUC 66 %, sensitivity 57 %, specificity 75 %) outperformed other scores and biomarkers. CONCLUSIONS:The ASAP score accurately predicted early HCC recurrence post-CR, warranting further validation.

Background & Aims: In advanced hepatocellular carcinoma (HCC), neoplastic portal vein thrombosis (nPVT) and extrahepatic metastases could represent distinct manifestations of tumour burden. However, under first-line atezolizumab–bevacizumab (A+B), the relative prognostic weight of these features remains insufficiently explored. This study aimed to assess how vascular invasion and metastatic involvement influence clinical outcomes, including early decompensating events (EHD), in patients receiving A+B.Methods: Five hundred and six cirrhotic patients with unresectable HCC treated with first-line A+B within the prospective ARTE dataset were included. Patients were evaluated for the presence of nPVT and extrahepatic metastases. EHD was defined as new-onset ascites, encephalopathy, jaundice, or variceal bleeding within 12 weeks of treatment initiation. Primary endpoints were overall survival (OS), progression-free survival (PFS), and radiological progression.Results: nPVT was present in 331 patients (59.9%) and extrahepatic metastases in 185 (36.5%). EHD occurred in 53 patients (10.5%) and was strongly associated with nPVT (OR 3.13, 95% CI 1.71–6.44), even after adjustments for baseline liver function (Child-Pugh or ALBI grade), whereas metastases showed no association. Patients who developed EHD experienced markedly worse survival (median OS 8.2 vs 19.6 months, p<0.001) and shorter duration of treatment (3.5 months, IQR 1.4–9.8 vs 7.3 months, IQR 3.5–15.2).In time-dependent multivariable Cox analysis for OS, EHD (HR 1.85, 95% CI 1.27–2.70), ALBI grade ≥2 (HR 1.49, 95% CI 1.14–1.95), and AFP ≥400 ng/mL (HR 1.45, 95% CI 1.10–1.94) were independent predictors, whereas neither nPVT nor metastases retained significance after adjusting for liver function and EHD.Conversely, extrahepatic metastases were independently associated with radiological progression (HR 1.47, 95% CI 1.15–1.88) and shorter PFS (HR 1.40, 95% CI 1.05–1.64), while nPVT showed no association with either endpoint.Conclusions: Among patients treated with A+B, nPVT and metastases appear to influence prognosis through different pathways: nPVT primarily by predisposing to early hepatic decompensation, and metastases mainly by accelerating tumour progression. Once EHD occurs, its impact on survival outweighs that of both vascular invasion and metastatic spread, likely due to the shorter treatment duration observed in this group. These findings suggest that assessing early liver deterioration alongside baseline tumour pattern may improve early risk stratification in advanced HCC and help contextualise the prognostic relevance of nPVT and metastases under A+B therapy.

Background and Aims: The management of comorbidities has gained relevance in hepatocellular carcinoma (HCC) due to improved long-term survival. Bevacizumab, an anti-VEGF drug, increases the risk of major adverse cardiac events (MACE). Identifying at-risk patients is crucial since anti-VEGF-free therapeutic alternatives are now available. This study aimed to assess whether the European Society of Cardiology (ESC) antiangiogenic risk score and the CARDIOSOR score (Carballo-Folgoso, 2021) predict MACE in patients with HCC treated with atezolizumab/bevacizumab (AB).Methods: We retrospectively analyzed prospectively collected data from the multicentric Italian ARTE dataset, including patients treated with AB for unresectable HCC between June 2022 and July 2025. MACE occurrence was evaluated using a competing risk regression, considering non-cardiovascular death as a competing event.Results: Among 538 patients (median age 69.8 years), the prevalence of arterial hypertension and obesity was 56.3% and 18.4%, respectively. Moreover 7.6% had chronic coronary artery disease. Median follow-up was 22.4 months (95% CI 21.0-24.2 months) and median overall survival 19.7 months (95% CI 17.1-22.3). Twenty MACE (3.7%) occurred: 8 cerebrovascular accidents, 7 acute coronary syndromes, 3 strokes, and 2 heart failures. The cumulative incidence of MACE was 10.6%, 3.7%, 2.6%, and 0.7% in very high, high, medium and low risk groups according to the ESC score (sHR 3.80, 95% CI 1.52–9.45, p=0.004). Patients with a high-risk CARDIOSOR score also had an increased risk of MACE (sHR 2.70, 95% CI 1.08–6.74, p=0.03). The two scores performed similarly when we analyzed the goodness of fit achieving an Akaike and Bayesian information criteria of 235 and 239 and 241 and 245.Conclusion: These findings suggest that the ESC and CARDIOSOR scores could be used to stratify the risk of MACE in patients receiving AB. These tools might inform clinicians and provide relevant information when evaluating the choice of the first line regimen.

BACKGROUND AND AIMS:Unlike other immune-based combinations for hepatocellular carcinoma (HCC), long-term data for atezolizumab-bevacizumab (AB) are lacking, as the IMbrave150 trial closed after a median follow-up of 15.6 months. Consequently, reports of long-term outcomes for AB rely mainly on real-world evidence. We evaluated long-term effectiveness, safety, and clinically relevant on-treatment events in a large prospective real-world cohort of patients treated with AB. APPROACH AND RESULTS:We analyzed 538 patients prospectively enrolled in the Italian ARTE database. Outcomes included overall survival (OS), safety, liver decompensation, rate of patients achieving drug-free disease-free status. On-treatment events were modelled as time-dependent covariates in Cox regression models. After a median follow-up of 24.2 months, median OS was 19.7 months (95% CI 17.2-22.2), with a 36-month survival rate of 30.0%. Independent factors influencing OS included ECOG-PS >0, ALBI grade >1, AFP >400 ng/mL, multinodularity, macrovascular invasion, and on-treatment events (objective response, progression, or liver decompensation). Grade ≥3 AEs occurred in 36.8% of patients; 5 late-onset severe toxicities arose beyond 24 months. Liver decompensation unrelated to tumor progression occurred in 14.1% patients. Eighty patients (14.9%) underwent surgical or locoregional procedures after the initiation of AB; 24 (4.4%) achieved a drug-free disease-free status. CONCLUSIONS:Our data confirmed the sustained effectiveness of AB without new safety concerns. Surgical/locoregional treatments after the start of AB and liver decompensation were common, highlighting the need for a multidisciplinary and integrated approach in advanced HCC.

BACKGROUND AND AIM:Dual immune checkpoint blockade with tremelimumab plus durvalumab (STRIDE) is an established first-line therapy for unresectable hepatocellular carcinoma (uHCC); however, real-world evidence on its safety, toxicity kinetics and liver function dynamics remains limited. We aimed to evaluate the tolerability and on-treatment changes in hepatic function and effectiveness in a multicentre cohort of patients treated with STRIDE in routine practice. METHODS:We conducted a retrospective analysis of prospectively collected data from 115 consecutive patients with uHCC treated with STRIDE across 12 centres in Lombardy, Italy. Clinical, biochemical and radiological variables were recorded at baseline and throughout the therapy. Adverse events were graded per CTCAE v5.0, and Child-Pugh was used to assess hepatic functional evolution. The temporal toxicity patterns were evaluated using smoothed hazard functions. Progression-free survival (PFS), overall survival (OS) and competing-risk cumulative incidences of progression and death were examined. RESULTS:The median follow-up was 8.9 months. More than 80% of the adverse events occurred within the first 2 months, and severe toxicities were infrequent. Child-Pugh deterioration from class A to B occurred in 7.8% of patients from baseline to day 28, increasing to 12.1% by day 56. PFS was 5.7 months; the median OS was not reached, with OS rates of 78.2% at 6 months and 53.3% at 18 months. Progression was the predominant early event, with a cumulative incidence of 49.2% at 6 months. CONCLUSIONS:In routine clinical practice, STRIDE shows reproducible effectiveness and a manageable safety profile, with an early and stabilising incidence of adverse events. Dynamic assessment of liver function shows that hepatic function declines modestly but is still clinically meaningful in affected patients.

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 and aims: Patients with hepatocellular carcinoma (HCC) have a risk of malnutrition and sarcopenia of 65-90% and 39%, both associated with worse survival in early stages. The prevalence and impact of these conditions in patients with unresectable HCC (uHCC) candidates to immune-based therapy (IO) have not been investigated. We aimed to study nutritional status and muscular reserve in uHCC patients starting IO and their impact on overall survival (OS).Methods: Monocentric retrospective study of 106 consecutive patients treated with IO for uHCC. Nutritional scores (Prognostic Nutritional Index-PNI; Systemic Immune-inflammation Index-SII) and sarcopenia were evaluated on blood samples and CT within 1 month prior to IO.Sarcopenia was defined according to EASL-AASLD cut-off (EA cut-off) for Smooth Muscle Index (SMI) at L3 on CT. By ROC analysis and Youden’s Index, a new cut-off was determined for OS prediction.OS according to malnutrition and sarcopenia was assessed by Kaplan-Meier analysis, while predictors of OS by Cox models.Results: Patients were predominantly males (80%), with median age 69 years and BMI 25.3 kg/m2. Most patients had cirrhosis (92%) with preserved liver function (95% ALBI 1-2), varices in 33%. BCLC C HCC in 78%; 79% treated with atezolizumab-bevacizumab and 21% with durvalumab-tremelimumab.Patients “high risk” for malnutrition were 18% according to SII>752 × 10⁹ and 74% to PNI<50.Median SMI was 46.0 (IQR 32.8-54.0) for women, 47.5 (IQR 42.4-55.5) cm/m2 for men. Prevalence of sarcopenia was 63.4% according to EA cut-off and 59% to new cut-off (38.6 for women, 48.8 cm/m2 for men).A lower OS was observed in “high-risk” patients according to SII (6 (IQR 4-15) vs 20 (IQR 10-30) months; p<0.001; Fig.1) and PNI (15 (IQR 6-24) vs 29 (IQR 20-31) months; p=0.01). However, only SII >752 × 10⁹ independently predicted mortality (HR 2.94 (95%CI 1.62-5.37), p<0.001) at multivariable Cox analysis.A trend toward shorter OS was observed in sarcopenic patients, but the difference was not significant [EA cut-off: 14(6–30) vs 21(9–36) months, p=0.52; new cut-off: 14(6–27) vs 21(7–27) months, p=0.09](Fig.2). Notably, survival curves according to new cut-off diverged after 4 months, with no proportional hazards assumption violation (p=0.97), so we performed an exploratory multivariable analysis including sarcopenia (new cut-off) with liver function, sex and BCLC stage. LASSO-selected models with bootstrap validation confirmed stability of the identified predictors, suggesting sarcopenia as an independent predictor of mortality (HR 2.24 (IQR 1.21-4.14), p=0.01), potentially exerting a delayed effect, with male sex and bilirubin.Conclusion: Malnutrition estimated by SII is a predictor of mortality in patients undergoing IO for uHCC. Sarcopenia by our new cut-off shows a potential delayed effect on survival in exploratory analyses.

Objectives: The combination of atezolizumab plus bevacizumab (A+B) represents one of the standards first-line treatments for unresectable hepatocellular carcinoma (HCC). Metformin has garnered attention for its potential antitumour and immunomodulatory properties beyond glycaemic control. This study aimed to assess metformin's impact in patients with type 2 diabetes mellitus (T2DM) receiving A+B therapy. Methods: This retrospective analysis of a prospectively-maintained multicentre database included 523 patients with HCC treated with A+B from the ARTE (Atezolizumab-bevacizumab Real-life Experience for Treatment of Hepatocellular Carcinoma) dataset across 18 Italian centres (May 2020-January 2024). We evaluated objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and time to progression (TTP) using Cox regression analysis and Inverse Probability of Treatment Weighting (IPTW) to address confounding. Results: Among 523 patients, 341 (65.2%) did not have diabetes and 182 (34.8%) had T2DM. In the overall population, metformin showed no significant benefit for PFS (HR = 1.15, 95% CI [0.88-1.50], p = 0.316) or OS (HR = 1.28, 95% CI [0.94-1.74], p = 0.124). In the subgroup with T2DM (N = 180), metformin showed no significant benefit for PFS (HR = 1.41,95% CI [0.97-2.05], p = 0.069), OS (HR = 1.23, 95% CI [0.81-1.86], p = 0.333), or TTP (HR = 0.82, 95% CI [0.53-1.26], p = 0.363). IPTW analysis confirmed these negative findings. Conclusion: This study found no evidence of improved outcomes with metformin use in patients with HCC in particular with T2DM receiving A+B therapy. Routine metformin use should not be expected to enhance A+B efficacy based on current evidence.

BACKGROUND AND AIMS:Conflicting data on hepatocellular carcinoma (HCC) survival in people with HIV (PWH) may depend on tumour aggressiveness and access to curative treatments. We compared outcomes of two HCC cohorts according to HIV status. METHODS:Patients from four tertiary referral centers in Northern Italy with the first HCC diagnosis (2005-2023) were analysed. Clinical characteristics, treatment access, and overall survival (OS) were described by HIV status, using inverse probability treatment weighting and propensity score (IPTW/PS) methods. Cox regression models assessed mortality predictors and recurrence after initial treatment. RESULTS:Among 606 patients, 143 were PWH and 463 HIV-negative. PWH were younger (median age 53 vs. 68 years, p < 0.001), predominantly male (87% vs. 75%, p = 0.004), with a lower proportion of Child-Pugh A cirrhosis (71% vs. 76%, p = 0.01). Despite similar surveillance rates (91% vs. 88%), PWH more frequently presented with BCLC-C stage HCC (22% vs. 10%, p < 0.001). First-line curative treatments were offered to 47% of PWH and 60% of HIV-negative patients (p = 0.006), while second-line treatment rates were similar (42% vs. 44%, p = 0.91). During median follow-up of 32 (11-78) and 36 (19-84) months for PWH and HIV-negative subjects (p = 0.04), five-year OS was 43.4% versus 44.1% (p = 0.97), median OS was 48 [interquartile range (IQR) 15-127] versus 46 (IQR 21-109) months (p = 0.97). Multivariable analysis after IPTW/PS showed similar mortality (HR 1.03, 95% CI 0.52-1.99, p = 0.94) but a higher two-year recurrence rate in PWH (47.4% vs. 22.8%, p = 0.03). CONCLUSION:Despite more advanced tumours and higher recurrence, survival in PWH with HCC was similar. Access to curative treatments with aggressive downstaging strategies may counterbalance initial disadvantages.

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, p<0.001 in BCLC C]. Independent predictors of mortality included AFP >200 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.

Background:Preclinical models have shown that metabolic dysfunction-associated steatotic liver disease (MASLD)-related hepatocellular carcinoma (HCC) may exhibit reduced responsiveness to immunotherapy, especially for intrahepatic lesions due to liver tumor microenvironment. Radiological pattern of progression has been validated in clinical studies as a useful tool for predicting outcomes in HCC undergoing systemic treatments. Aims:The aim of this study was to determine whether MASLD influences the pattern of progression in patients treated with atezolizumab-bevacizumab. Methods:This multicenter, prospective study included patients with unresectable HCC receiving atezolizumab-bevacizumab. Progression patterns were defined as previously proposed. Patients were categorized as either MASLD or controls based on a recent multisocietal Delphi consensus statement. Multivariable models analyzed the risk of specific progression patterns and their impacts on post-progression survival (PPS) and overall survival (OS). A historical cohort treated with sorafenib was also analyzed to determine whether observed patterns were specific for atezolizumab-bevacizumab. Results:Four-hundred twenty patients were included (MASLD: n = 88, 21.0%). Time to progression (TTP) was shorter in MASLD compared to controls, due to an increased risk of intrahepatic growth (IHG - hazard ratio [HR] 1.739, 95% confidence interval [CI] 1.206-2.507, p = 0.003]). Neither etiology nor IHG predicted a different PPS. No differences between etiologies were found in OS. Etiology did not influence the pattern of progression under sorafenib in the historical cohort. Conclusion:IHG was more frequently associated with MASLD-HCC compared to controls, confirming preclinical data and suggesting biological differences between tumors, with potential implications for future research. MASLD should not be seen as a contraindication to immunotherapy.