Combination Immunotherapy for Hepatocellular Carcinoma: Where Are We Currently?
Semin Liver Dis DOI: 10.1055/s-0040-1722646The past decade has seen a rise in the availability of breakthrough therapeutic strategies for treatment of hepatocellular carcinoma (HCC). A tumor microenvironment in HCC is regulated by various immunotolerance mechanisms; therefore, therapeutic strategies aiming at disrupting tumor immune tolerance are becoming attractive curative options in HCC. Immune checkpoint inhibitors have demonstrated impressive effectiveness in HCC, including in sorafenib-unresponsive patients. Synergistic approaches with checkpoint inhibitors (anti-PD-1/PD-L1 and CTLA-4) and antiangiogenic drugs are bu...
Source: Seminars in Liver Disease - May 6, 2021 Category: Gastroenterology Authors: Uson Junior, Pedro Luiz Serrano Nagalo, Bolni Marius Ahn, Daniel H. Bekaii-Saab, Tanios Borad, Mitesh J. Tags: Review Article Source Type: research
Role of Biliary Organoids in Cholestasis Research and Regenerative Medicine
Semin Liver Dis DOI: 10.1055/s-0041-1728663Translational studies in human cholestatic diseases have for years been hindered by various challenges, including the rarity of the disorders, the difficulty in obtaining biliary tissue from across the spectrum of the disease stage, and the difficulty culturing and maintaining primary cholangiocytes. Organoid technology is increasingly being viewed as a technological breakthrough in translational medicine as it allows the culture and biobanking of self-organizing cells from various sources that facilitate the study of pathophysiology and therapeutics, including from individual pat...
Source: Seminars in Liver Disease - May 6, 2021 Category: Gastroenterology Authors: Soroka, Carol J. Roberts, Scott J. Boyer, James L. Assis, David N. Tags: Review Article Source Type: research
Potential of HBx Gene for Hepatocarcinogenesis in Noncirrhotic Liver
Semin Liver Dis DOI: 10.1055/s-0041-1723033Current treatments for hepatitis B virus (HBV) using nucleos(t)ide analogs cannot eliminate the risk of hepatocellular carcinoma (HCC) development. As HBV-associated HCC can develop even in the absence of liver cirrhosis, HBV is regarded to possess direct oncogenic potential. HBV regulatory protein X (HBx) has been identified as a primary mediator of HBV-mediated hepatocarcinogenesis. A fragment of the HBV genome that contains the coding region of HBx is commonly integrated into the host genome, resulting in the production of aberrant proteins and subsequent hepatocarcinogenesis. ...
Source: Seminars in Liver Disease - May 6, 2021 Category: Gastroenterology Authors: Sekiba, Kazuma Otsuka, Motoyuki Koike, Kazuhiko Tags: Review Article Source Type: research
Blinding in Clinical Trials for Chronic Liver Diseases
Semin Liver Dis DOI: 10.1055/s-0041-1723753Within the field of randomized clinical trials (RCTs), the randomized double-blind placebo-controlled clinical trial is considered the most efficient means of simultaneously assessing the efficacy and safety of a medical therapy in a single trial. While many RCTs are conducted without blinding (open label), it is rare to encounter a blinded trial that does not randomize its subjects. Clinical trials for chronic liver diseases have adopted many of the practices set forth by RCTs in other chronic diseases, but blinding has often been difficult to properly implement. This review exam...
Source: Seminars in Liver Disease - May 6, 2021 Category: Gastroenterology Authors: Ortiz, Vivian Ellenberg, Susan S. Weinberg, Ethan M. Tags: Review Article Source Type: research
Liver Transplantation Selection and Allocation Criteria for Hepatocellular Carcinoma: A European Perspective
Semin Liver Dis DOI: 10.1055/s-0041-1723032For patients with early-stage hepatocellular carcinoma (HCC), liver transplantation offers the best chance of cure. Over the past two decades, selection criteria to determine eligibility for liver transplantation have been constantly refined but a fair allocation strategy of liver grafts to HCC patients remains challenging. In Europe, over a dozen transplantation networks apply different liver transplantation criteria for HCC patients. In this review, we explore and compare candidate selection and liver graft allocation strategies for patients with HCC with a European perspective ...
Source: Seminars in Liver Disease - May 6, 2021 Category: Gastroenterology Authors: Moeckli, Beat Majno, Pietro Orci, Lorenzo A. Peloso, Andrea Toso, Christian Tags: Review Article Source Type: research
Hepatitis B Core-Related Antigen: From Virology to Clinical Application
Semin Liver Dis DOI: 10.1055/s-0041-1723088Hepatitis B core-related antigen (HBcrAg) is a composite measure of the serum levels of hepatitis B e antigen, hepatitis B core antigen, and a 22-kDa precore protein. It has been shown to reflect the level and transcriptional activity of covalently closed circular DNA in the liver. Longitudinal cohort studies have improved our understanding of the role of this novel viral marker in the natural history of chronic hepatitis B. HBcrAg kinetics reflect the response to peginterferon, and its role in defining guidelines for stopping peginterferon therapy has been evaluated. HBcrAg is a ...
Source: Seminars in Liver Disease - May 6, 2021 Category: Gastroenterology Authors: Lee, Hye Won Ahn, Sang Hoon Chan, Henry Lik-Yuen Tags: Review Article Source Type: research
Novel Mechanisms for Resolution of Liver Inflammation: Therapeutic Implications
Semin Liver Dis DOI: 10.1055/s-0041-1723031Traditional concepts have classically viewed resolution of inflammation as a passive process yet insight into the pathways by which inflammation is resolved has challenged this idea. Resolution has been revealed as a highly dynamic and active event that is essential to counteract the dysregulated inflammatory response that drives diverse disease states. Abrogation of the hepatic inflammatory response through the stimulation of proresolving mechanisms represents a new paradigm in the setting of chronic inflammatory-driven liver diseases. Elucidation of the role of different cells o...
Source: Seminars in Liver Disease - March 24, 2021 Category: Gastroenterology Authors: Kaufmann, Benedikt Reca, Agustina Kim, Andrea D. Feldstein, Ariel E. Tags: Review Article Source Type: research
Assessing Toxicity in Drug Trials in Liver Disease
Semin Liver Dis DOI: 10.1055/s-0041-1723030Since the early trials in viral hepatitis, more and more new drugs are being tested for use in various liver diseases. Since drug hepatotoxicity is a major cause of drugs under investigation not making it to market, the assessment of drug-induced liver injury in clinical trials of new drugs is crucial. This review will focus on the systems that are used to assess drug-induced liver injury in clinical trials and will discuss how some of these criteria are inappropriate or inaccurate in this function together with suggestions for improvement. [...] Thieme Medical Publishers, Inc. 33...
Source: Seminars in Liver Disease - March 8, 2021 Category: Gastroenterology Authors: Sherman, Morris Tags: Review Article Source Type: research
Gut –Liver Axis in Nonalcoholic Fatty Liver Disease: the Impact of the Metagenome, End Products, and the Epithelial and Vascular Barriers
Semin Liver Dis DOI: 10.1055/s-0041-1723752Nonalcoholic fatty liver disease (NAFLD) is a systemic, dynamic, heterogeneous, and multiaxis entity, the pathogenesis of which is still uncertain. The gut–liver axis is regulated and stabilized by a complex network encompassing a metabolic, immune, and neuroendocrine cross-talk between the gut, the microbiota, and the liver. Changes in the gut–liver axis affect the metabolism of lipids and carbohydrates in the hepatocytes, and they impact the balance of inflammatory mediators and cause metabolic deregulation, promoting NAFLD and its progression to nonalcoholic steatohepatitis...
Source: Seminars in Liver Disease - March 8, 2021 Category: Gastroenterology Authors: Gil-G ómez, Antonio Brescia, Paola Rescigno, Maria Romero-G ómez, Manuel Tags: Review Article Source Type: research
Organoids for the Study of Liver Cancer
Semin Liver Dis DOI: 10.1055/s-0040-1719176Liver cancer is the second most lethal malignancy worldwide. Cell lines and murine models are the most common tools for modeling human liver carcinogenesis. Most recently, organoids with a three-dimensional structure derived from primary tissues or cells have been applied to liver cancer research. Organoids can be generated from induced pluripotent stem cells, embryonic or adult, healthy or diseased tissues. In particular, liver organoids have been widely employed in mechanistic studies aimed at delineating the molecular pathways responsible for hepatocarcinogenesis. The introduct...
Source: Seminars in Liver Disease - February 9, 2021 Category: Gastroenterology Authors: Wang, Haichuan Calvisi, Diego F. Chen, Xin Tags: Review Article Source Type: research
Management of Portal Vein Thrombosis in Cirrhosis
Semin Liver Dis DOI: 10.1055/s-0040-1722260While portal vein thrombosis (PVT) is a frequently encountered complication in the cirrhosis population, its management can be challenging for even the most experienced clinicians. Multiple factors must be considered with regards to management, including the degree of underlying portal hypertension and liver dysfunction, risks of therapies including anticoagulation and transjugular intrahepatic portosystemic shunt placement, and extent of the thrombosis. Interpreting the available literature to determine the best treatment strategy for any individual patient can be especially chal...
Source: Seminars in Liver Disease - February 9, 2021 Category: Gastroenterology Authors: Stotts, Matthew J. Wentworth, Brian J. Northup, Patrick G. Tags: Review Article Source Type: research
Insights into the Role of Granulocyte Colony-Stimulating Factor in Severe Alcoholic Hepatitis
Semin Liver Dis DOI: 10.1055/s-0040-1719177Alcohol use disorder is the predominant cause of chronic liver disease globally. The standard of care for the treatment of alcoholic hepatitis, corticosteroids, has been shown to provide a therapeutic response in ∼60% of carefully selected patients with a short-term survival benefit. The patients who do not respond to steroids, or are ineligible due to infections or very severe disease, have little options other than liver transplantation. There is, thus, a large unmet need for new therapeutic strategies for this large and sick group of patients. Granulocyte colony stimulating f...
Source: Seminars in Liver Disease - February 9, 2021 Category: Gastroenterology Authors: Kedarisetty, Chandan Kumar Kumar, Anupam Sarin, Shiv Kumar Tags: Review Article Source Type: research
Cellular Senescence in Liver Disease and Regeneration
Semin Liver Dis DOI: 10.1055/s-0040-1722262Cellular senescence is an irreversible cell cycle arrest implemented by the cell as a result of stressful insults. Characterized by phenotypic alterations, including secretome changes and genomic instability, senescence is capable of exerting both detrimental and beneficial processes. Accumulating evidence has shown that cellular senescence plays a relevant role in the occurrence and development of liver disease, as a mechanism to contain damage and promote regeneration, but also characterizing the onset and correlating with the extent of damage. The evidence of senescent mechanis...
Source: Seminars in Liver Disease - February 9, 2021 Category: Gastroenterology Authors: Ferreira-Gonzalez, Sofia Rodrigo-Torres, Daniel Gadd, Victoria L. Forbes, Stuart J. Tags: Review Article Source Type: research
Molecular Mechanisms of Hepatoblastoma
Semin Liver Dis DOI: 10.1055/s-0040-1722645Hepatoblastoma (HB) is the predominant primary liver tumor in children. While the prognosis is favorable when the tumor can be resected, the outcome is dismal for patients with progressed HB. Therefore, a better understanding of the molecular mechanisms responsible for HB is imperative for early detection and effective treatment. Sequencing analysis of human HB specimens unraveled the pivotal role of Wnt/β-catenin pathway activation in this disease. Nonetheless, β-catenin activation alone does not suffice to induce HB, implying the need for additional alterations. Perturbations ...
Source: Seminars in Liver Disease - January 20, 2021 Category: Gastroenterology Authors: Zhang, Yi Solinas, Antonio Cairo, Stefano Evert, Matthias Chen, Xin Calvisi, Diego F. Tags: Review Article Source Type: research
Intrahepatic Cholestasis of Pregnancy: Natural History and Current Management
Semin Liver Dis DOI: 10.1055/s-0040-1722264Intrahepatic cholestasis of pregnancy (ICP) is a common disorder in the second half of pregnancy characterized by pruritus and elevated serum bile acids (BAs) with spontaneous resolution after delivery. ICP carries a risk of adverse effects on the fetus which correlates with the degree of BA elevation. ICP occurs in genetically susceptible women as the reproductive hormones increase during pregnancy. Ursodeoxycholic acid is still considered the first-line treatment for ICP though it is of unproven benefit in preventing adverse effects on the fetus. Fetal complications, such as sti...
Source: Seminars in Liver Disease - January 20, 2021 Category: Gastroenterology Authors: Roediger, Rebecca Fleckenstein, Jaquelyn Tags: Review Article Source Type: research
