Hepatocellular carcinoma (HCC) is a malignant tumor originating from hepatocytes, often developing against a backdrop of chronic inflammation and liver fibrosis. The primary risk factor for HCC is cirrhosis, and early detection is crucial for improving outcomes. Despite advances in treatment, the prognosis remains poor, with a 5-year survival rate of approximately 15%-38%. Growing evidence highlights the critical role of the tumor microenvironment (TME) in modulating tumor initiation, growth, progression, and, in some cases, suppression. The TME is a complex ecosystem composed of immune cells, cancer-associated fibroblasts, extracellular matrix components, and other factors such as growth factors and cytokines. By shaping tumor cell behavior, the TME facilitates immune evasion and contributes to resistance to treatment. Tumor-associated immune cells, including regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, contribute to immune suppression and progression. On the other hand, immune activation via immune checkpoint inhibition has shown promise in improving outcomes, especially when combined with other treatments such as transarterial chemoembolization (TACE), selective internal radiation therapy (SIRT), and systemic therapies. Studies have demonstrated the potential of targeting the TME to enhance treatment efficacy, with immune modulation emerging as a key therapeutic strategy. This review explores the complex interactions within the TME in HCC, highlighting its role in therapy resistance and immune evasion. It also discusses current therapeutic approaches to target the TME to improve clinical outcomes in HCC patients.

The hepatitis D virus (HDV) is a compact, enveloped, circular RNA virus that relies on hepatitis B virus (HBV) envelope proteins to initiate a primary infection in hepatocytes, assemble, and secrete new virions. Globally, HDV infection affects an estimated 12 million to 72 million people, carrying a significantly elevated risk of developing cirrhosis, liver failure, and hepatocellular carcinoma (HCC) compared to an HBV mono-infection. Furthermore, HDV-associated HCC often manifests at a younger age and exhibits more aggressive characteristics. The intricate mechanisms driving the synergistic carcinogenicity of the HDV and HBV are not fully elucidated but are believed to involve chronic inflammation, immune dysregulation, and the direct oncogenic effects of the HDV. Indeed, recent data highlight that the molecular profile of HCC associated with HDV is unique and distinct from that of HBV-induced HCC. However, the question of whether the HDV is an oncogenic virus remains unanswered. In this review, we comprehensively examined several crucial aspects of the HDV, encompassing its epidemiology, molecular biology, immunology, and the associated risks of liver disease progression and HCC development.

Familial combined hyperlipidemia (FCH) is a very common inherited lipid disorder, characterized by a high risk of developing cardiovascular (CV) disease and metabolic complications, including insulin resistance (IR) and type 2 diabetes mellitus (T2DM). The prevalence of non-alcoholic fatty liver disease (NAFLD) is increased in FCH patients, especially in those with IR or T2DM. However, it is unknown how precociously metabolic and cardiovascular complications appear in FCH patients. We aimed to evaluate the prevalence of NAFLD and to assess CV risk in newly diagnosed insulin-sensitive FCH patients. From a database including 16,504 patients, 110 insulin-sensitive FCH patients were selected by general practitioners and referred to the Lipid Center. Lipid profile, fasting plasma glucose and insulin were determined by standard methods. Based on the results of the hospital screening, 96 patients were finally included (mean age 52.2 ± 9.8 years; 44 males, 52 females). All participants underwent carotid ultrasound to assess carotid intima media thickness (cIMT), presence or absence of plaque, and pulse wave velocity (PWV). Liver steatosis was assessed by both hepatic steatosis index (HSI) and abdomen ultrasound (US). Liver fibrosis was non-invasively assessed by transient elastography (TE) and by fibrosis 4 score (FIB-4) index. Carotid plaque was found in 44 out of 96 (45.8%) patients, liver steatosis was found in 68 out of 96 (70.8%) and in 41 out of 96 (42.7%) patients by US examination and HSI, respectively. Overall, 72 subjects (75%) were diagnosed with steatosis by either ultrasound or HSI, while 24 (25%) had steatosis excluded (steatosis excluded by both US and HSI). Patients with liver steatosis had a significantly higher body mass index (BMI) compared to those without (p < 0.05). Steatosis correlated with fasting insulin (p < 0.05), liver stiffness (p < 0.05), BMI (p < 0.001), and inversely with high-density lipoprotein cholesterol (p < 0.05). Fibrosis assessed by TE was significantly associated with BMI (p < 0.001) and cIMT (p < 0.05); fibrosis assessed by FIB-4 was significantly associated with sex (p < 0.05), cIMT (p < 0.05), and atherosclerotic plaque (p < 0.05). The presence of any grade of liver fibrosis was significantly associated with atherosclerotic plaque in the multivariable model, independent of alcohol habit, sex, HSI score, and liver stiffness by TE (OR 6.863, p < 0.001). In our cohort of newly diagnosed, untreated, insulin-sensitive FCH patients we found a high prevalence of liver steatosis. Indeed, the risk of atherosclerotic plaque was significantly increased in patients with liver fibrosis, suggesting a possible connection between liver disease and CV damage in dyslipidemic patients beyond the insulin resistance hypothesis.

Data concerning the prevalence of hepatitis B virus (HBV) occult infection (OBI) varies greatly in the different studies according to the sensitivity and specificity of the diagnostic approaches and the HBV prevalence in the different populations examined. The clinical implications of OBI are still debated. While the impact of OBI in HBV transmission as well as in HBV reactivation under immunosuppression are well established, the role of OBI in liver disease and hepatocellular carcinoma (HCC) development are still not definitively elucidated. It has been hypothesized that OBI might contribute to worsening the liver disease course when other causes of liver damage co‐exist. Furthermore, much evidence suggests a role of OBI in the hepato‐carcinogenesis processes through both indirect and direct oncogenic mechanisms that might favour HCC development. Data on the OBI clinical implications mainly come from studies performed in patients with hepatitis C virus (HCV) infection. However, HCV prevalence has dramatically fallen in the past years also because of the advent of specific and highly effective direct acting antivirals, with a consequent abrupt change of the worldwide scenario of chronic liver disease. Information about OBI prevalence and possible clinical impact in non‐HCV‐related liver disease are fragmentary, and the objective of this review is to critically summarize the available data in this field.

Review Article Selective internal radiation therapy across Barcelona Clinic Liver Cancer (BCLC) stages of hepatocellular carcinoma: literature review Paul Vigneron, Maria Stella Franzè, Julia Chalaye, Vania Tacher, Anna Sessa, Alain Luciani, Hicham Kobeiter, Hélène Regnault, Ancuta Bejan, Julien Calderaro, Rami Rhaiem, Daniele Sommacale, Giovanni Raimondo, Vincent Leroy, Raffaele Brustia, Giuliana Amaddeo