Leonardo Stella

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)

Tryptophan (Trp) metabolism lies at the intersection of nutrition, gut microbiota, mucosal immunology, and systemic inflammation—processes that play key roles in many gastrointestinal and extraintestinal diseases. Trp is an essential amino acid obtained through dietary intake. Beyond its role in protein synthesis, it is metabolized through three principal pathways: the kynurenine pathway, the serotonin/melatonin pathway, and microbial metabolism in the gut leading to indole and related derivatives. The kynurenine pathway represents the primary route of Trp degradation and is strongly linked to inflammatory signaling. The serotonin pathway is particularly important for gastrointestinal physiology, influencing motility, secretion, and visceral sensitivity. In parallel, microbial Trp metabolism produces metabolites that regulate epithelial barrier integrity, modulate mucosal immune responses, and contribute to communication along the gut–organ axes. Across different disease states, several recurring patterns emerge. Inflammatory conditions frequently shift Trp metabolism toward the kynurenine pathway through increased IDO1 or TDO activity, resulting in changes in kynurenine metabolites and in the kynurenine-to-tryptophan (Kyn/Trp) ratio. At the same time, reduced microbial production of indole derivatives may impair aryl hydrocarbon receptor signaling and weaken barrier-protective and immunoregulatory mechanisms. Alterations in the serotonin pathway are also associated with disturbances in gastrointestinal motility and gut–brain communication. Together, these observations highlight Trp metabolism as an important framework for understanding interactions between diet, microbiota, and host responses in health and disease. However, it is important to clarify that much of the currently available evidence remains associative or is derived primarily from preclinical models. This narrative review, based on literature retrieved from major biomedical databases (e.g., PubMed/MEDLINE, Scopus, and Web of Science), aims to provide an updated synthesis of current knowledge on Trp metabolism in disease pathophysiology. Furthermore, while we highlight potential translational applications—such as proposed biomarker development and targeted therapeutic strategies—these perspectives have been moderated to acknowledge the limited level of clinical validation established to date.

Background/Objectives: Hepatocellular carcinoma (HCC) is the sixth most diagnosed cancer worldwide and a leading cause of cancer-related mortality. The majority of cases arise in the setting of chronic liver disease, where immune checkpoint inhibitors (ICIs) have emerged as a cornerstone of systemic therapy for advanced disease. However, durable clinical benefit remains limited to a minority of patients, and reproducible biomarkers of ICI response are lacking. The gut–liver axis—encompassing bidirectional exchange of microbial products, metabolites, bile acids, and immune signals—has emerged as a biologically plausible determinant of both hepatocarcinogenesis and immunotherapy response. This narrative review synthesises current evidence on the role of the gut–liver axis in HCC and ICI response and proposes a unifying conceptual framework to resolve discrepancies in the existing literature. Methods: A narrative review was conducted through systematic searches of PubMed/MEDLINE, Embase, and Web of Science. Studies were selected based on relevance to the biological mechanisms, clinical associations, and experimental models underpinning gut–liver–immune interactions in HCC, with particular emphasis on studies providing mechanistic insight, addressing immunotherapy outcomes, or highlighting temporal and context-dependent effects. Results: Observational studies consistently associate higher microbial diversity and enrichment of homeostasis-promoting taxa—including Akkermansia, Bifidobacterium, and short-chain fatty acid-producing Ruminococcaceae—with ICI responsiveness in HCC. Functional microbial outputs, particularly short-chain fatty acids and secondary bile acids, exert mechanistically grounded effects on hepatic immune tone and T cell activity that are biologically proximate to ICI effector pathways. Therapeutic modulation of the gut–liver axis through probiotics, dietary interventions, faecal microbiota transplantation, and antibiotic exposure demonstrates context-dependent effects on immune activation and ICI outcomes, with timing and disease severity emerging as critical determinants. The limited reproducibility of microbiome-immunotherapy associations across cohorts is attributable primarily to the dynamic and treatment-sensitive nature of the gut–liver axis rather than a fundamental lack of mechanistic coupling. Conclusions: The gut–liver axis in HCC is best understood as a dynamic, treatment-sensitive system rather than a static baseline trait. This reframing shifts emphasis from single-timepoint taxonomic signatures toward functional and longitudinal readouts and provides a coherent rationale for the heterogeneity observed across existing studies. Longitudinal clinical studies incorporating mechanistic endpoints and functional biomarker assessment are needed to translate this framework into clinically actionable strategies for patient stratification and microbiota-targeted intervention in HCC immunotherapy.

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape for hepatocellular carcinoma (HCC); however, a considerable proportion of patients do not achieve durable clinical benefits. This highlights the need for reliable predictive biomarkers, which are currently lacking. The accumulated evidence supports a relevant role of the gut–liver axis in modulating immunotherapy outcomes, and several studies have identified distinct microbial features associated with either responders or non-responders. Responders to immunotherapy frequently present with higher microbial diversity and enrichment of beneficial taxa, whereas the expansion of pro-inflammatory and pathogenic bacteria has been associated with primary resistance and increased treatment-related toxicity in non-responders. However, the available findings remain heterogeneous across cohorts, likely owing to differences in geography, diet, liver disease etiology, treatment regimens, and microbiome analytical methods. Machine-learning models integrating metagenomic and metabolomic data have shown encouraging results in defining microbial signatures associated with treatment outcomes, although variability among cohorts currently limits their clinical applicability and generalizability. Beyond microbial taxonomic composition, microbiota-derived metabolites—such as short-chain fatty acids, bile acids, inosine, and tryptophan catabolites—appear to play a crucial role in shaping the tumor microenvironment and host immune responses, thus representing additional candidate biomarkers, also due to the relative ease of their measurement. Finally, microbiota-targeted interventions are emerging as potential strategies to enhance immunotherapy efficacy. Overall, the gut microbiome and its metabolic activity represent promising tools, albeit still under investigation, for patient stratification and personalized management in HCC treated with ICIs. Therefore, this review aims to summarize and critically discuss the current evidence on gut microbiota-derived biomarkers of response and resistance to ICIs in HCC, with particular focus on microbial composition, microbiota-related metabolites, and emerging microbiome-based therapeutic strategies. This narrative review provides an updated overview of the role of gut microbiota as both a biomarker and a therapeutic target in patients with hepatocellular carcinoma (HCC) receiving immune checkpoint inhibitor (ICI) therapy.

Hepatocellular carcinoma (HCC) is the sixth most diagnosed cancer worldwide and represents the second cause of cancer-related death worldwide, according to the estimates by Global Cancer Observatory in 2020. Its prognosis is strictly associated with neoplastic stage and liver function. Several treatments are involved in the management of HCC, according to its stage and the patients’ performance status. The abscopal effect is a particular phenomenon taking place in locally advanced or in metastatic cancer, as a positive off-target result of ionizing radiation at a certain distance from the irradiated zone determining a systemic effect due to the increase in tumor immune response, and resulting in the shrinkage of neoplastic lesions with a subsequent increase in tumor prognosis. If future studies will allow one to master its etiological mechanisms and deliberately trigger them, it could represent a notable weapon in the treatment of hepatocellular carcinoma, particularly at advanced stages, in which sometimes it is able to positively modify the patients’ prognosis. The aim of this review is to evaluate the literature available on this intriguing topic and the characteristics of the mechanisms that originate the abscopal effect, the treatments that can elicit this phenomenon, and the possible relevant therapeutic implications.

Patient-derived organoids (PDOs) have emerged as promising preclinical models for studying tumor biology and testing therapeutic strategies in oncology. These three-dimensional culture systems retain key histological, genetic, and functional characteristics of the original tumors, offering a unique opportunity to advance personalized medicine approaches in liver cancer. In this study, we present the methodological framework and preliminary findings of a prospective study aimed at generating and characterizing PDOs from patients with hepatocellular carcinoma (HCC) undergoing surgical resection. Tumor specimens were processed using an optimized protocol for organoid derivation, expansion, and cryopreservation. We evaluated the success rate of organoid establishment and the histo-molecular fidelity to the parental tumor. These early results demonstrate promising engraftment efficiency and maintenance of tumor-specific markers across passages. Our work highlights the potential of PDOs as a reliable and scalable platform for translational research in HCC, setting the stage for future applications in drug screening and biomarker discovery.

Hepatocellular carcinoma (HCC) is characterized by a complex disruption of hemostatic balance, increasing the risk of both thrombotic and hemorrhagic events. Thrombotic complications, most notably portal vein thrombosis (PVT) and venous thromboembolism (VTE), have a significant impact on clinical outcomes and therapeutic strategies. Cirrhosis contributes to the precarious equilibrium between pro- and anticoagulant forces through impaired synthesis of coagulation factors, endothelial dysfunction, and systemic inflammation. In the presence of HCC tumor-driven mechanisms, such as tissue factor expression, extracellular vesicle release, platelet activation, and suppression of fibrinolysis exacerbate this prothrombotic state. In this scenario, advanced diagnostic tools such as thrombin generation assay (TGA) and rotational thromboelastometry (ROTEM) offer a more accurate assessment of coagulation dynamics than conventional tests, enabling better risk stratification especially for therapeutic purposes. Anticoagulant therapy has demonstrated clinical benefit in selected cases of non-malignant PVT and VTE, particularly when liver function is preserved. While prophylactic strategies are still under investigation, data suggest they may be safely implemented in selected surgical patients. In the setting of immunotherapy, especially regimens involving anti-VEGF agents, anticoagulation may be considered with careful management of bleeding risk due to portal hypertension. An individualized approach to anticoagulation, supported by functional coagulation testing, is gaining acceptance as a means to safely reduce thrombotic burden and potentially improve outcomes in patients with HCC.

Background and Aims: Hepatitis C virus (HCV) is a key driver of hepatocellular carcinoma (HCC). However, the impact of HCV eradication on systemic therapy remains unclear. We aimed to assess the safety and efficacy of direct‐acting antivirals (DAA) in patients treated with Atezolizumab plus Bevacizumab (AtezoBev). Methods: This retrospective multicentre study included patients with HCV‐related unresectable/advanced HCC treated with AtezoBev between 2021 and 2024. Three groups of patients were compared: Group A ( n = 22), concurrent DAA with AtezoBev; Group B ( n = 95), antiviral therapy before AtezoBev; and Group C ( n = 22), active infection. Results: Group A showed the longest median overall survival (42.8 months) compared to Group B (26.8 months; p = 0.03) and Group C (19.7 months; p = 0.01). Time to progression and progression‐free survival were significantly prolonged in Group A versus Groups B and C. Moreover, Group A exhibited a higher disease control rate than the other groups. Post‐DAA decompensation rates were significantly lower in Group A (4.5%) compared to Groups B (26.3%) and C (36.4%). Treatment‐related adverse events of grade ≥ 3 were similar across groups. In the multivariate competing risk analysis with adjustment for time‐dependent variables, achieving sustained virologic response during AtezoBev showed a protective effect against liver decompensation (sHR 0.02, p = 0.003) or tumour progression (sHR 0.14, p = 0.009), and was also associated with reduced mortality (HR 0.29, p = 0.005). Conclusions: Achieving a SVR during AtezoBev seems to improve oncologic outcomes and reduce liver decompensation in patients with unresectable/advanced HCC. An integrated therapeutic approach can optimise systemic treatment efficacy, particularly in patients eligible for conversion strategies. Trial Registration: Protocol ID: 5890

Introduction: The potential for curative conversion with immunotherapy-based systemic treatment used with noncurative intent in patients with hepatocellular carcinoma (HCC) remains debated. This study aimed to provide a reliable epidemiological snapshot of response patterns to atezolizumab plus bevacizumab (AB) therapy, with a focus on curative conversion rates. Methods: Patients with HCC undergoing first-line noncurative AB or lenvatinib (LENV, used as reference) from 2019 to 2023 were included, using centre-level aggregate data from a broad international consortium. The primary endpoint was the curative conversion rate, differentiating potential conversion (PC) – when objective response (OR) resulted in a consistent decrease in tumour burden and alpha-fetoprotein levels – from actual conversion (AC), when OR led to curative treatment. Secondary endpoints included OR, under-conversion (UC; [PC – AC]/OR) rates, and crude survival rates of AC patients. A meta-analytic approach was employed to analyse aggregate data. Results: Forty-eight international centres treating 2,379 patients with HCC with a noncurative intent (1,401 with AB and 978 with LENV) were included. A significant discrepancy was observed between PC (16% and 13% for AB and LENV, p = 0.03) and AC rates (3% for both AB and LENV, p = 0.14). UC rates remained similarly high (40% and 36% for AB and LENV, p = 0.93), despite differing OR rates (29% and 24% for AB and LENV, p = 0.01). Subgroup and meta-regression analyses did not identify any clear treatment, centre, or patient patterns that explained the high UC rate. The 3-year survival rate for the 72 patients who underwent a curative conversion after AB was 93%. Conclusions: Although patients treated with AB achieved higher OR and PC rates than those treated with LENV, AC remained similarly low, highlighting a potentially worrisome UC phenomenon in real life, also with novel immunotherapy-based combinations.