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Liver transplantation is the only potentially curative option for unresectable hepatoblastoma. The introduction of platinum-based chemotherapy drastically improved the survival outcomes of patients with hepatoblastoma. However, the use of neoadjuvant chemotherapy and the optimal number of cycles required in patients listed for liver transplantation, as well as the potential use of adjuvant chemotherapy, remain unclear. Additionally, the shortage of donor liver grafts, along with the lack of clear consensus on the management of metastatic hepatoblastoma, makes the decision on whether to proceed to liver transplantation even more complex and challenging. Technological advances may optimize intraoperative imaging of both the primary tumor and metastatic sites, thus facilitating complete resection. Such improvements, along with the wider use of social media platforms to increase public awareness, could potentially pave the way for more optimal implementation of liver transplantation for the treatment of patients with unresectable hepatoblastoma. LESS      Full article

Nonalcoholic fatty liver disease (NAFLD) is a disease spectrum that spans simple steatosis, fibrosis, and ultimately cirrhosis, and is a leading cause of chronic liver disease globally. The severe variant of NAFLD, non-alcoholic steatohepatitis (NASH), is characterized by triglyceride accumulation within hepatocytes and the subsequent inflammatory pathway activation, ultimately progressing to cirrhosis in 10%-20% of patients. NASH is a known major risk factor for the development of hepatocellular carcinoma (HCC), and there is emerging data demonstrating the impact of NASH on immune subsets and the tumor microenvironment that may influence therapeutic response. This review describes the various ways in which the immune system is altered in patients with NASH. The innate immune system in NASH shows alterations in dendritic and Kupffer cells, impaired cytotoxicity of Natural Killer cells, and an accumulation of neutrophils. Additionally, there is emerging evidence emphasizing the role of the adaptive immune system in the development and progression of NASH, seen in the alteration of B-cells, T-cells, and NKT Cells. Due to the complex interplay of the immune system in NAFLD/NASH and its progression to HCC, many current treatments focus on targeting immune cells for HCC therapy. Recently, immune checkpoint inhibitors such as atezolizumab and bevacizumab have been approved as first-line therapy for unresectable HCC. Although an emerging field of research, further studies and clinical trials are needed to understand the complex interface of NASH, HCC and the immune response. LESS      Full article

Cholangiocarcinoma (CCA) is a highly lethal malignancy that comprises approximately 15% of all the primary liver tumors and 3% of gastrointestinal cancers. Diagnosis is often done when the disease is already at advanced stages, resulting in poor outcomes. Prevention of risk factors and early diagnosis are the cornerstones for improving survival. Early diagnosis is feasible in the setting of surveillance programs in patients at high risk of CCA such as patients with primary sclerosing cholangitis. Regrettably, surveillance of CCA in this population is hampered by the low diagnostic accuracy of current tumor markers at earlier stages, the difficulties of imaging techniques for the differential diagnosis between benign and malignant biliary strictures, and the need for invasive procedures for diagnostic confirmation. In this review we discuss the rationale for surveillance of CCA in high-risk populations, particularly patients with primary sclerosing cholangitis, the recommended tools for surveillance and diagnostic work-up, and future perspectives. LESS      Full article

Hepatocellular carcinoma (HCC) is the fifth most widespread cancer responsible for one fourth of cancer-related deaths globally. Persistent infection with hepatitis B virus (HBV) remains the main cause of HCC summing up to 50% of its causative etiology. Our recent studies, supported by findings from others, uncovered that HBV and its close relative woodchuck hepatitis virus (WHV) integrate into hepatocyte genome almost immediately, hence in minutes after infection. Retrotransposons and genes with translocation potential were found to be frequent sites of HBV insertions, suggesting a mechanism of HBV DNA spread across liver genome from the earliest stages after virus invasion. Many other genes were identified as the sites of early hepadnavirus merges in human hepatocyte-like lines infected de novo with HBV and in natural woodchuck WHV infection model. It was uncovered that head-to-tail joins (HTJs) prevail among the earliest virus-host fusions, implying their formation via the non-homologous-end-joining (NHEJ) pathway. Overlapping homologous junctions resulting from the micro-homology-mediated-overlapping-joining (MHMOJ) were rarely detected. Formation of the initial HTJs coincided with strong induction of reactive oxygen species (ROS) and transient appearance of inducible nitric oxide (iNOS). This was accompanied by cell DNA damage and activation of the poly(ADP-ribose) polymerase 1 (PARP1)-mediated host DNA repair machinery, which may explain predominant HTJ format of the first virus-host fusions. Identification of initial integration sites and resulting alterations in hepatocyte phenotype may pave a way to discovery of reliable markers of HBV-triggered HCC, including HCC resulting from occult HBV infection. Our research strongly argues that HBV is an ultimate human carcinogen capable of initiation of a pro-oncogenic process immediately after first contact with a susceptible host. LESS      Full article

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder worldwide. It comprises a spectrum of conditions that range from steatosis to non-alcoholic steatohepatitis, with progression to cirrhosis and hepatocellular carcinoma. Currently, there is no FDA-approved pharmacological treatment for NAFLD. The pathogenesis of NAFLD involves genetic and environmental/host factors, including those that cause changes in intestinal microbiota and their metabolites. In this review, we discuss recent findings on the relationship(s) of microbiota signature with severity of NAFLD and the role(s) microbial metabolites in NAFLD progression. We discuss how metabolites may affect NAFLD progression and their potential to serve as biomarkers for NAFLD diagnosis or therapeutic targets for disease management. LESS      Full article

Mutations involving CTNNB1, the gene encoding beta-catenin, and other molecular alterations that affect the Wnt/beta-catenin signaling pathway are exceptionally common in hepatocellular carcinoma. Several of these alterations have also been associated with scarcity of immune cells in the tumor microenvironment and poor clinical response to immune checkpoint inhibitor therapy. In light of these associations, tumor biomarkers of beta-catenin status could have the potential to serve as clinical predictors of immunotherapy outcome. This editorial review article summarizes recent pre-clinical and clinical research pertaining to associations between beta-catenin activation and diminished anti-tumor immunity. Potential non-invasive biomarkers that may provide a window into this oncogenic mechanism of immune evasion are also presented and discussed. LESS      Full article

The COVID-19 pandemic has led to the greatest worldwide health crisis in decades. The number of infected patients with severe SARS-CoV-2 (COVID-19) disease has overwhelmed the capacity of almost all health care systems around world. Hypoalbuminemia has now been reported in patients with severe disease seeking help in the emergency room because of COVID-19 infection. In the past, hypoalbuminemia was considered to be a negative prognostic marker, not only in patients with chronic liver disease, but also in patients with SARS and MERS infections. Albumin is the major serum protein synthesized by the liver. A low serum albumin level is an ominous clinical sign. Introduction of amino acids to a patient’s diet is of fundamental importance to hepatic albumin synthesis in different clinical situations. This highlights the importance of nutritional support during the early phases of COVID-19-infection. Furthermore, albumin synthesis in the hepatocyte is downregulated at a pretranslational level by the direct interaction of the major acute-phase cytokines which are released into the circulation during the cytokine “storm” induced by the viral effects on the lungs. Both mechanisms contribute to severe hypoalbuminemia which, combined with massive fluid losses due to the fever, is responsible for severe hypovolemia and shock commonly observed in patients with COVID-19 in critical care settings. LESS      Full article