Transarterial chemoembolization versus sorafenib in patients with hepatocellular carcinoma and extrahepatic disease

BackgroundSorafenib is the recommended treatment for advanced hepatocellular carcinoma (HCC), but transarterial chemoembolization (TACE) is performed in individual cases with limited extrahepatic spread. The aim of this study was to compare the outcome of patients with HCC and extrahepatic disease (EHD) treated with sorafenib and TACE.MethodsA total of 172 patients with HCC and EHD treated with sorafenib (n = 98) or TACE (n = 74) at three German referral centers (Hannover, Mainz and Hamburg) were included in this study. In order to reduce selection bias, patients were matched for significant demographic differences using a propensity score analysis.ResultsPatients with liver cirrhosis, high…

Validation of the simplified Animal Naming Test as primary screening tool for the diagnosis of covert hepatic encephalopathy

Diagnosis of covert hepatic encephalopathy (CHE) is time consuming in clinical practice. Recently, a new diagnostic tool - the simplified Animal Naming Test (S-ANT1) - was presented with promising results in an Italian cohort. The aim of the present study was to validate S-ANT1 in a cohort of cirrhotic patients from a German tertiary referral centre.143 cirrhotic patients and 37 healthy controls were enrolled. Hepatic encephalopathy (HE) grade 1 (HE1) was clinically diagnosed according to the West-Haven Criteria. Critical flicker frequency and Psychometric Hepatic Encephalopathy Score were used to detect minimal HE (MHE). All participants were additionally examined by S-ANT1.58 (40.6%) pati…

Snapshot liver transcriptome in hepatocellular carcinoma

Lately, advances in high throughput technologies in biomedical research have led to a dramatic increase in the accessibility of molecular insights at different levels of cancer biology such as genome, epigenome, transcriptome, proteome, and others. Among the diverse biological layers, the transcriptome has been most extensively studied especially due to the successful and broad introduction of the microarray technology. The future prospect of broad disposability of deep sequencing technology will furthermore lead to a more sensitive detection of lowly expressed transcripts and to an increase in the number of newly identified transcripts, but also to increase the discovery and characterizati…

Generation and validation of syngeneic murine hepatoma cells bearing features of human HCC for rapid anti-HCC drug screening

Sequential (epi)genetic changes during liver cancer development and progression

Curcumin effectively inhibits oncogenic NF-κB signaling and restrains stemness features in liver cancer

Background & Aims The cancer stem cells (CSCs) have important therapeutic implications for multi-resistant cancers including hepatocellular carcinoma (HCC). Among the key pathways frequently activated in liver CSCs is NF-κB signaling. Methods We evaluated the CSCs-depleting potential of NF-κB inhibition in liver cancer achieved by the IKK inhibitor curcumin, RNAi and specific peptide SN50. The effects on CSCs were assessed by analysis of side population (SP), sphere formation and tumorigenicity. Molecular changes were determined by RT-qPCR, global gene expression microarray, EMSA, and Western blotting. Results HCC cell lines exposed to curcumin exhibited differential responses to curcumin a…

O100 : The hepatic microenvironment induces a CSC phenotype and determines the prognosis of HCC patients

Common variants in the HLA-DQ region confer susceptibility to idiopathic achalasia

Idiopathic achalasia is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus(1,2). This ultimately leads to massive dilatation and an irreversibly impaired megaesophagus. We performed a genetic association study in 1,068 achalasia cases and 4,242 controls and fine-mapped a strong MHC association signal by imputing classical HLA haplotypes and amino acid polymorphisms. An eight-residue insertion at position 227-234 in the cytoplasmic tail of HLA-DQ beta 1 (encoded by HLA-DQB1*05:03 and HLA-DQB1*06:01) confers the strongest risk for achalasia (P = 1.73 x 10(-19)). In addition, two amino acid substitutions in the. extracellular …

The addition of TACE to palliative chemotherapy is associated with extended survival in unresectable intrahepatic cholangiocarcinoma

Dynamics and predicted drug response of a gene network linking dedifferentiation with β-catenin dysfunction in hepatocellular carcinoma

Background & Aims Alterations of individual genes variably affect the development of hepatocellular carcinoma (HCC). Thus, we aimed to characterize the function of tumor-promoting genes in the context of gene regulatory networks (GRNs). Methods Using data from The Cancer Genome Atlas, from the LIRI-JP (Liver Cancer – RIKEN, JP project), and from our transcriptomic, transfection and mouse transgenic experiments, we identify a GRN which functionally links LIN28B-dependent dedifferentiation with dysfunction of β-catenin (CTNNB1). We further generated and validated a quantitative mathematical model of the GRN using human cell lines and in vivo expression data. Results We found that LIN28B and C…

Use of inhibitors of the renin-angiotensin system is associated with longer survival in patients with hepatocellular carcinoma.

Inhibition of the renin-angiotensin system (RAS) was associated with longer survival in patients with different solid malignancies.The objective of this study was to investigate the effect of RAS inhibitor (RASi) treatment (angiotensin-converting enzyme inhibitors or angiotensin-II-receptor blockers) on survival of patients with hepatocellular carcinoma (HCC).Patients diagnosed with HCC and Child-Pugh A between 1992 and 2013 who received sorafenib, experimental therapy, or best supportive care were eligible for the Vienna cohort. The Mainz cohort included patients with HCC and Child-Pugh A who received sorafenib treatment between 2007 and 2016. The association between RASi and overall survi…

Contribution of the Cancer Stem Cell Phenotype to Hepatocellular Carcinoma Resistance

The cancer stem cell (CSC) hypothesis is an increasingly accepted concept in cancer research that provides a plausible explanation for the considerable phenotypic and molecular heterogeneities observed in hepatocellular carcinoma (HCC) which hampers therapeutic progress. The hypothesis infers that CSCs share functional properties similar to adult stem cells, such as self-renewal and differentiation capacity, and are exclusively responsible for tumor evolution. By definition, CSCs are held responsible not only for tumor initiation and progression but also acquisition of chemoresistance and the fueling of relapse after therapy. Therefore, the CSC model has significant implications both for tr…

MYC Activates Stem-like Cell Potential in Hepatocarcinoma by a p53-Dependent Mechanism

Activation of c-MYC is an oncogenic hallmark of many cancers including liver cancer, and is associated with a variety of adverse prognostic characteristics. Despite a causative role during malignant transformation and progression in hepatocarcinogenesis, consequences of c-MYC activation for the biology of hepatic cancer stem cells (CSCs) are undefined. Here, distinct levels of c-MYC over-expression were established by using two dose-dependent tetracycline inducible systems in 4 hepatoma cell lines with different p53 mutational status. The CSCs were evaluated using side-population approach as well as standard in vitro and in vivo assays. Functional repression of p53 was achieved by lentivira…

TGFβ-activated kinase 1 (TAK1) is activated and predicts prognosis in hepatocellular carcinoma

Long-term observation of hepatocellular carcinoma recurrence after liver transplantation at a European transplantation centre

BACKGROUND: The recurrence of hepatocellular carcinoma (HCC) is the strongest survival-limiting factor after liver transplantation (LT) in patients with HCC. In the face of donor organ shortage, it is necessary to identify factors associated with HCC recurrence in order to maximize the utility of the available grafts. OBJECTIVE: To study the phenomenon of HCC recurrence after LT at a European transplantation centre over the past 20 years. METHODS: Data from 304 HCC patients who underwent LT were prospectively recorded. Clinical and pathological factors were assessed for their association with recurrence. RESULTS: Fifty-one patients (16.8%) had HCC recurrence after LT. Patients exceeding the…

Obere gastrointestinale Blutung mit hämorrhagischem Schock am Ende einer Urlaubsreise: Präklinische und innerklinische Versorgung eines gastrointestinalen Notfalls

ZusammenfassungNach der Rückkehr aus dem Urlaub wurde ein 55-jähriger Patient mit Teerstuhl und hämorrhagischem Schock im Zugabteil eines InterCity der Deutschen Bahn notfallmedizinisch versorgt und in ein Krankenhaus der Maximalversorgung eingeliefert. Hier erfolgte zunächst die weitere notfallmedizinische Behandlung, in deren Rahmen in der internistischen Notaufnahme in interdisziplinärer Zusammenarbeit eine Stabilisierung der Hämodynamik sowie die Sicherung der Atemwege und Atemfunktion erfolgten. Anschließend wurde eine Notfall-Endoskopie des oberen Gastrointestinaltrakts durchgeführt. Ursächlich für das hämorrhagische Schockgeschehen war eine arteriell spritzende, endoskopisch nicht zu…

MicroRNAs as Novel Targets in Liver Cancer: Facing the Clinical Challenge

Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths worldwide with a rising incidence in the western world. HCCs are characterized by a phenotypic and molecular heterogeneity that limits therapeutic progress. MicroRNAs play a major role for the pathogenesis and progression of liver cancer. As an essential part of the RNA interference machinery, microRNAs contribute to the regulation of many pro-oncogenic processes in HCC, including proliferation, migration, and survival. Therefore, these epigenetically active small molecules advanced to attractive targets for both diagnosis and therapy of liver cancer. Here, we will try to delineate the role of microRNAs during liver de…

Deconvolution of the cellular origin in hepatocellular carcinoma: Hepatocytes take the center stage.

The expression of biliary/progenitor markers by hepatocellular carcinoma (HCC) is often associated with poor prognosis and stem cell-like behaviors of tumor cells. Hepatocellular adenomas (HCA) also often express biliary/progenitor markers and frequently act as precursor lesions for HCC. However, the cell of origin of HCA and HCC that expresses these markers still remains unclear. Therefore, to evaluate if mature hepatocytes give rise to HCA and HCC tumors, and to understand the molecular pathways involved in tumorigenesis, we lineage-labeled hepatocytes by injecting adeno-associated virus (AAV) containing thyroxine-binding globulin (TBG) promoter driven-Cre into RosaYFP mice. Yellow fluore…

Impact of non-selective ß-blockers on hepatic encephalopathy in patients with liver cirrhosis

Non-selective β-blockers (NSBB) are frequently used for the treatment of portal hypertension and gastroesophageal varices in patients with liver cirrhosis; however prospective studies investigating the potential association between NSBB use and hepatic encephalopathy (HE) are still scarce. We investigated the potential association between NSBB use and the presence of covert HE (CHE) as well as the development of overt HE (OHE).224 patients with liver cirrhosis were included into this cohort study at two German centers and followed for a median of 364 days. CHE was diagnosed by pathological results in the PHES. Predictors for the presence of CHE or the development of OHE were analyzed using …

The Addition of Transarterial Chemoembolization to Palliative Chemotherapy Extends Survival in Intrahepatic Cholangiocarcinoma

Incidence and mortality of intrahepatic cholangiocarcinoma (iCCA) have been increasing continuously. Recent studies suggest that the combination of palliative chemotherapy (pCTX) and transarterial chemoembolization (TACE) improves overall survival (OS). This study aimed to evaluate the outcome of patients treated with TACE and pCTX in unresectable iCCA at our tertiary care center. A group of 14 patients was treated with both pCTX and TACE. The non-randomized control group of 59 patients received pCTX alone. Patients received a median of two pCTX lines in both groups. Those treated with TACE underwent a median number of 3.5 sessions. Median OS from the time of unresectability was 26.2 months…

Application of patient derived liver cancer cell lines for phenotypic characterization and therapeutic target identification

Raised serum Interleukin-6 identifies patients with liver cirrhosis at high risk for overt hepatic encephalopathy

BACKGROUND Systemic inflammation is a driving force for the development of hepatic encephalopathy and recent studies demonstrated that elevated Interleukin-6 (IL-6) serum levels are associated with the presence of minimal hepatic encephalopathy in patients with liver cirrhosis. AIM To test the hypothesis that IL-6 is a suitable marker to identify patients with liver cirrhosis at high risk for the development of overt hepatic encephalopathy. METHODS 201 patients were included into this prospective cohort study and were followed for a mean time of 322 days. Covert hepatic encephalopathy was diagnosed according to the West-Haven criteria (hepatic encephalopathy grade 1) and with the portosyste…

Ginkgo biloba induces different gene expression signatures of oncogenic pathways in malignant and non-malignant cells in the liver

Context-Dependent Role of NF-κB Signaling in Primary Liver Cancer—from Tumor Development to Therapeutic Implications

Chronic inflammatory cell death is a major risk factor for the development of diverse cancers including liver cancer. Herein, disruption of the hepatic microenvironment as well as the immune cell composition are major determinants of malignant transformation and progression in hepatocellular carcinomas (HCC). Considerable research efforts have focused on the identification of predisposing factors that promote induction of an oncogenic field effect within the inflammatory liver microenvironment. Among the most prominent factors involved in this so-called inflammation-fibrosis-cancer axis is the NF-κB pathway. The dominant role of this pathway for malignant transformation and progression…

Murine liver organoids as a genetically flexible system to study liver cancer in vivo and in vitro.

The rising incidence of cholangiocarcinoma (CCA) coupled with a low 5-year survival rate that remains below 10% delineates the urgent need for more effective treatment strategies. Although several recent studies provided detailed information on the genetic landscape of this fatal malignancy, versatile model systems to functionally dissect the immediate clinical relevance of the identified genetic alterations are still missing. To enhance our understanding of CCA pathophysiology and facilitate rapid functional annotation of putative CCA driver and tumor maintenance genes, we developed a tractable murine CCA model by combining the cyclization recombination (Cre)-lox system, RNA interference, …

Genetically flexible murine organoids for mechanistic and functional modeling of cholangiocarcinoma

Effektivität der sequentiellen systemischen Therapie bei Patienten mit einem fortgeschrittenen HCC - Erfahrungen aus dem klinischen Alltag

Next-Generation Genomic Profiling of Hepatocellular Adenomas: A New Era of Individualized Patient Care

Hepatocellular adenomas (HCAs) are clinically relevant benign liver lesions that commonly occur in women on hormonal contraceptives. In this issue of Cancer Cell, Pilati and colleagues present an integrative multi-“omics”-based analysis of HCA and identify recurrent genetic alterations associated with adenoma-carcinoma transition and new drugable targets.

Ginkgo biloba induces different gene expression signatures and oncogenic pathways in malignant and non-malignant cells of the liver

Ginkgo biloba (EGb761) is a widely used botanical drug. Several reports indicate that EGb761 confers preventive as well as anti-tumorigenic properties in a variety of tumors, including hepatocellular carcinoma (HCC). We here evaluate functional effects and molecular alterations induced by EGb761 in hepatoma cells and non-malignant hepatocytes. Hepatoma cell lines, primary human HCC cells and immortalized human hepatocytes (IH) were exposed to various concentrations (0-1000 μg/ml) of EGb761. Apoptosis and proliferation were evaluated after 72h of EGb761 exposure. Response to oxidative stress, tumorigenic properties and molecular changes were further investigated. While anti-oxidant effects w…

Cytoplasmic localization of the cell polarity factor scribble supports liver tumor formation and tumor cell invasiveness

The loss of epithelial cell polarity plays an important role in the development and progression of liver cancer. However, the specific molecular mechanisms supporting tumor initiation and progression are poorly understood. In this study, transcriptome data and immunofluorescence stains of tissue samples derived from hepatocellular carcinoma (HCC) patients revealed that overexpression associated with cytoplasmic localization of the baso-lateral cell polarity complex protein Scribble (Scrib) correlated with poor prognosis of HCC patients. In comparison to HCC cells stably expressing wildtype Scrib (ScribWT), mutated Scrib with enforced cytoplasmic enrichment (ScribP305L) induced AKT signaling…

Increased liver carcinogenesis and enrichment of stem cell properties in livers of Dickkopf 2 (Dkk2) deleted mice.

// Thorsten Maass 1 , Jens Marquardt 2 , Ju-Seog Lee 3 , Markus Krupp 4 , Peter Scholz-Kreisel 2 , Carolin Mogler 5 , Peter Schirmacher 5 , Martina Muller 1 , Heiner Westphal 6 , Peter R. Galle 2 , Andreas Teufel 1 1 Department of Internal Medicine I, University of Regensburg, Regensburg, Germany 2 I. Department of Medicine, University Medical Center Mainz, Mainz, Germany 3 Cancer Biology Program, MD Anderson Cancer Center, Houston, TX, USA 4 Department of Informatics, Johannes Gutenberg University Mainz, Mainz, Germany 5 Institute of Pathology, University of Heidelberg, Heidelberg, Germany 6 Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Develop…

Portal vein infiltration in patients with hepatocellular carcinoma: The relevance of correct classification.

e15651 Background: Portal vein invasion (PVI) is has a significant impact on the prognosis of patients with hepatocellular carcinoma (HCC). Patients with PVI are classified as stage C in the BCLC score and systemic therapy is recommended. Patients with minor PVI are frequently misclassified due to radiological challenges in determining malignant PVI or non-adherence to guidelines. The concept of resection or TACE in limited PVI is sometimes followed with the assumption of a negligible influence on survival. Aim of this study is the reevaluation of PVI and the analysis of the impact of a misclassification. Methods: 763 patients with HCC of a total of 1413 were extracted from the clinical re…

Loss of c-Met signaling sensitizes hepatocytes to lipotoxicity and induces cholestatic liver damage by aggravating oxidative stress.

Recent studies confirmed a critical importance of c-Met signaling for liver regeneration by modulating redox balance. Here we used liver-specific conditional knockout mice (MetKO) and a nutritional model of hepatic steatosis to address the role of c-Met in cholesterol-mediated liver toxicity. Liver injury was assessed by histopathology and plasma enzymes levels. Global transcriptomic changes were examined by gene expression microarray, and key molecules involved in liver damage and lipid homeostasis were evaluated by Western blotting. Loss of c-Met signaling amplified the extent of liver injury in MetKO mice fed with high-cholesterol diet for 30days as evidenced by upregulation of liver enz…

Molecular diagnosis and therapy of hepatocellular carcinoma (HCC): an emerging field for advanced technologies.

Despite great progress in diagnosis and management of hepatocellular carcinoma (HCC), the exact biology of the tumor remains poorly understood overall limiting the patients' outcome. Detailed analysis and characterization of the molecular mechanisms and subsequently individual prediction of corresponding prognostic traits would revolutionize both diagnosis and treatment of HCC and is the key goal of modern personalized medicine. Over the recent years systematic approaches for the analysis of whole tumor genomes and transcriptomes as well as epigenomes became affordable tools in translational research. This includes simultaneous analyses of thousands of molecular targets using microarray-bas…

Functional and genetic deconstruction of the cellular origin in liver cancer.

During the past decade, research on primary liver cancers has particularly highlighted the uncommon plasticity of differentiated parenchymal liver cells (that is, hepatocytes and cholangiocytes (also known as biliary epithelial cells)), the role of liver progenitor cells in malignant transformation, the importance of the tumour microenvironment and the molecular complexity of liver tumours. Whereas other reviews have focused on the landscape of genetic alterations that promote development and progression of primary liver cancers and the role of the tumour microenvironment, the crucial importance of the cellular origin of liver cancer has been much less explored. Therefore, in this Review, w…

Health-related quality of life in patients with compensated and decompensated liver cirrhosis.

Compensated (Child-Pugh [CP] A) and decompensated (CP B/C) liver cirrhosis significantly differs in terms of impairment of health-related quality of life (HRQoL). However, sufficient data on potentially treatable factors associated with HRQoL in both stages of the disease are still lacking. Consequently, aims of this study were to determine differences in HRQoL between patients with compensated and decompensated liver cirrhosis and to identify potentially treatable factors associated with HRQoL.218 patients with liver cirrhosis were enrolled into this study. Chronic Liver Disease Questionnaire (CLDQ) was used to assess HRQoL. Covert hepatic encephalopathy (CHE) was diagnosed according to a …

Urinary ethyl glucuronide (uEtG) as a marker for alcohol consumption in liver transplant candidates: a real-world cohort

 In order to reduce alcohol relapse after liver transplantation (LT), the German national guidelines for waiting-list maintenance and organ allocation demand a minimum 6-month period of alcohol abstinence pre-LT, confirmed by measuring urinary ethyl glucuronide (uEtG). Between January 2015 and June 2016, uEtG was measured at least once in 339 cirrhotic patients with an indication for LT at the University Medical Center Mainz. uEtG was measured with an enzyme-linked immunosorbent assay (ELISA) screening test (cutoff value: 500 µg/L). For uEtG values ≥ 500 µg/L, liquid chromatography-mass spectrometry (LC-MS/MS) was performed as a confirmatory assay. Data were collected prospectively in a tra…

Severe metabolic alterations in liver cancer lead to ERK pathway activation and drug resistance

Background: The extracellular signal-regulated kinase (ERK) pathway regulates cell growth, and is hyper-activated and associated with drug resistance in hepatocellular carcinoma (HCC). Metabolic pathways are profoundly dysregulated in HCC. Whether an altered metabolic state is linked to activated ERK pathway and drug response in HCC is unaddressed. Methods: We deprived HCC cells of glutamine to induce metabolic alterations and performed various assays, including metabolomics (with 13C-glucose isotope tracing), microarray analysis, and cell proliferation assays. Glutamine-deprived cells were also treated with kinase inhibitors (e.g. Sorafenib, Erlotinib, U0126 amongst other MEK inhibitors). …

Improved prediction of survival by a risk factor-integrated inflammatory score in Sorafenib treated hepatocellular carcinoma

Background and aims Inflammation affects progression of hepatocellular carcinoma (HCC). We therefore postulate that systemic inflammatory markers could help to predict prognosis in HCC patients receiving sorafenib therapy. Methods Overall survival (OS) of HCC patients receiving palliative sorafenib treatment was correlated with the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), C-reactive protein to albumin ratio (CAR), Glasgow prognostic score (GPS) and the modified GPS (mGPS) along with clinicopathological parameters. Predictors of OS were assessed by multivariable Cox regression and receiver operating characteristics and area under the curve (ROC-AUC) analyses.…

RNA-Seq Atlas—a reference database for gene expression profiling in normal tissue by next-generation sequencing

Abstract Motivation: Next-generation sequencing technology enables an entirely new perspective for clinical research and will speed up personalized medicine. In contrast to microarray-based approaches, RNA-Seq analysis provides a much more comprehensive and unbiased view of gene expression. Although the perspective is clear and the long-term success of this new technology obvious, bioinformatics resources making these data easily available especially to the biomedical research community are still evolving. Results: We have generated RNA-Seq Atlas, a web-based repository of RNA-Seq gene expression profiles and query tools. The website offers open and easy access to RNA-Seq gene expression pr…

Cholesterol burden in the liver induces mitochondrial dynamic changes and resistance to apoptosis

Non-alcoholic fatty liver disease (NAFLD) encompasses a broad spectrum of histopathological changes ranging from non-inflammatory intracellular fat deposition to non-alcoholic steatohepatitis (NASH), which may progress into hepatic fibrosis, cirrhosis, or hepatocellular carcinoma. Recent data suggest that impaired hepatic cholesterol homeostasis and its accumulation are relevant to the pathogenesis of NAFLD/NASH. Despite a vital physiological function of cholesterol, mitochondrial dysfunction is an important consequence of dietary-induced hypercholesterolemia and was, subsequently, linked to many pathophysiological conditions. The aim in the current study was to evaluate the morphological a…

Recombinant human hepatocyte growth factor provides protective effects in cerulein-induced acute pancreatitis in mice.

Acute pancreatitis is a multifactorial disease associated with profound changes of the pancreas induced by release of digestive enzymes that lead to increase in proinflammatory cytokine production, excessive tissue necrosis, edema, and bleeding. Elevated levels of hepatocyte growth factor (HGF) and its receptor c-Met have been observed in different chronic and acute pancreatic diseases including experimental models of acute pancreatitis. In the present study, we investigated the protective effects induced by the recombinant human HGF in a mouse model of cerulein-induced acute pancreatitis. Pancreatitis was induced by 8 hourly administrations of supramaximal cerulein injections (50 µg/kg, ip…

Induction of Chromosome Instability by Activation of Yes-Associated Protein and Forkhead Box M1 in Liver Cancer

Background & Aims Many different types of cancer cells have chromosome instability. The hippo pathway leads to phosphorylation of the transcriptional activator yes-associated protein 1 (YAP1, YAP), which regulates proliferation and has been associated with the development of liver cancer. We investigated the effects of hippo signaling via YAP on chromosome stability and hepatocarcinogenesis in humans and mice. Methods We analyzed transcriptome data from 242 patients with hepatocellular carcinoma (HCC) to search for gene signatures associated with chromosomal instability (CIN); we investigated associations with overall survival time and cancer recurrence using Kaplan–Meier curves. We analyze…

The Role of Transforming Growth Factor-β in Human Hepatocarcinogenesis: Mechanistic and Therapeutic Implications From an Integrative Multiomics Approach

Epigenetic regulation of methionine adenosyltransferase 1A: a role for MicroRNA-based treatment in liver cancer?

MicroRNAs (miRNAs) and methionine adenosyltransferase 1A (MAT1A) are dysregulated in hepatocellular carcinoma (HCC), and reduced MAT1A expression correlates with worse HCC prognosis. Expression of miR-664, miR-485-3p, and miR-495, potential regulatory miRNAs of MAT1A, is increased in HCC. Knockdown of these miRNAs individually in Hep3B and HepG2 cells induced MAT1A expression, reduced growth, and increased apoptosis, while combined knockdown exerted additional effects on all parameters. Subcutaneous and intraparenchymal injection of Hep3B cells stably overexpressing each of this trio of miRNAs promoted tumorigenesis and metastasis in mice. Treatment with miRNA-664 (miR-664), miR-485-3p, and…

HILPDA is upregulated, predicts prognosis and promotes cancer progression in hepatocellular carcinoma

949 IDENTIFICATION OF TWO CLINICALLY DISTINCT SUBTYPES IN AUTOIMMUNE HEPATITIS BY COMPARATIVE FUNCTIONAL GENOMICS

Conclusion: Incidence of autoimmune hepatitis is increasing, as other autoimmune diseases in developed countries. The main recognised hypothesis is the ‘hygienist theory’ (improvement of hygien leading to a decrease in infections) with few putative non exclusive mechanisms involving antigenic competition, extension of immune regulation induced by exogenous bacterial antigen or Toll Like Receptors.

Impact of Individual Components of the Metabolic Syndrome on the Outcome of Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib

<b><i>Background/Aim:</i></b> Individual components of the metabolic syndrome (MS) such as obesity or diabetes mellitus impair the prognosis of patients with hepatocellular carcinoma (HCC) following curative treatment approaches or transarterial therapies. The aim of this retrospective study was to assess the impact of these factors on the overall survival (OS) of patients with advanced HCC treated with sorafenib. <b><i>Methods:</i></b> Univariate and multivariate analyses were performed to assess the impact of individual components of the MS on the OS of 152 consecutive patients with advanced HCC treated with sorafenib. <b><i>Resu…

Development and Validation of a Prognostic Score to Predict Covert Hepatic Encephalopathy in Patients With Cirrhosis.

Diagnosis of covert hepatic encephalopathy (CHE) is challenging and often neglected in clinical practice. The aim of this study was to develop an easy-to-perform score to predict CHE in patients with cirrhosis.For the development or validation cohort of the proposed clinical CHE score, 142 or 96 consecutive patients with cirrhosis were prospectively enrolled. The Psychometric Hepatic Encephalopathy Score was used to detect minimal hepatic encephalopathy. All patients were examined with the simplified animal naming test and were asked to complete the Chronic Liver Disease Questionnaire. We followed the TRIPOD guideline for development, validation, and reporting of the proposed score.The clin…

Abstract 1902: Enrichment of putative cancer stem cells during anti-angiogenic therapies promotes relapse formation in hepatocellular carcinoma

Abstract Background and Aims: Activation of neo-angiogenic processes in hepatocellular carcinoma (HCC) during disease progression is frequently associated with poor clinical outcome. Consequently, inhibition of neo-angiogenesis is an effective treatment strategy for advanced HCC. However, development of chemoresistance is observed in the majority of patients. Compelling evidence suggest that cancer stem cells (CSCs) may contribute to the acquisition of resistant properties in many solid tumors, but their exact role in this process for HCC remains to be defined. Here, we evaluate the importance of CSCs in the development of resistance and relapse formation after exposure to different anti-an…

Hepatozelluläres Karzinom - molekulare Grundlagen und Zielmoleküle für die Therapie

Das hepatozellulare Karzinom zahlt zu den haufigsten Krebserkrankungen weltweit mit einer steigenden Inzidenz in westlichen Landern. Leberzellkarzinome zeichnen sich durch eine molekulare Vielfalt und ein schlechtes Therapieansprechen aus. Trotz groser Fortschritte in der Diagnostik und Behandlung des Leberzellkarzinoms in den letzten Jahren bleiben die Details der biochemischen Mechanismen weitestgehend unverstanden. Hierdurch wird die Entwicklung neuer Therapiestrategien erheblich erschwert. Die rasante Entwicklung von neuen Verfahren zur Analyse molekularer Mechanismen der Krebsentstehung auf verschiedenen molekularen Ebenen hat wesentlich zum Verstandnis der Hepatokarzinogenese beigetra…

High pretreatment static and dynamic alpha‐fetoprotein values predict reduced overall survival in hepatocellular carcinoma

Abstract Background Hepatocellular carcinoma is one of the most lethal cancers worldwide. Novel prognostic and/or predictive biomarkers are urgently needed to improve patient management. Alpha‐fetoprotein (AFP) is a well‐established and widely used biomarker for hepatocellular carcinoma. However, diagnostic accuracy of static AFP values is limited and the clinical potential is a matter of ongoing scientific discussion. Objective We here evaluated the prognostic impact of pretreatment static and dynamic AFP variables on overall survival of hepatocellular carcinoma patients in a Western cohort. Methods Patients with confirmed hepatocellular carcinoma (n = 809) treated at the Johannes Gutenber…

How COVID-19 kick-started online learning in medical education-The DigiMed study.

Background The coronavirus disease 2019 (COVID-19) pandemic led to far-reaching restrictions of social and professional life, affecting societies all over the world. To contain the virus, medical schools had to restructure their curriculum by switching to online learning. However, only few medical schools had implemented such novel learning concepts. We aimed to evaluate students’ attitudes to online learning to provide a broad scientific basis to guide future development of medical education. Methods Overall, 3286 medical students from 12 different countries participated in this cross-sectional, web-based study investigating various aspects of online learning in medical education. On a 7-…

Survival of patients with unresectable cholangiocarcinoma undergoing palliative chemotherapy - real world data from a German tertiary care center

Mitochondrial BAX Determines the Predisposition to Apoptosis in Human AML

Abstract Purpose: Cell-to-cell variability in apoptosis signaling contributes to heterogenic responses to cytotoxic stress in clinically heterogeneous neoplasia, such as acute myeloid leukemia (AML). The BCL-2 proteins BAX and BAK can commit mammalian cells to apoptosis and are inhibited by retrotranslocation from the mitochondria into the cytosol. The subcellular localization of BAX and BAK could determine the cellular predisposition to apoptotic death. Experimental Design: The relative localization of BAX and BAK was determined by fractionation of AML cell lines and patient samples of a test cohort and a validation cohort. Results: This study shows that relative BAX localization determine…

Hepatocyte growth factor induces a protective effect in cerulein-induced acute pancreatitis in mice

Surveillance of Hepatocellular Carcinoma and Diagnostic Algorithms in Patients with Liver Cirrhosis

<b><i>Background:</i></b> Hepatocellular carcinoma (HCC) is the most deadly complication of all major chronic liver diseases. Since early detection is the most significant determinant of overall survival, intense screening is of major importance. <b><i>Methods:</i></b> This overview is based on a systematic review of the available literature on HCC screening and surveillance in the PubMed database. <b><i>Results:</i></b> Over the last decades, major etiological risk factors were identified and the population at highest risk for the development of HCC was clearly defined. Screening in these patients has been repeatedly d…

The 9th Annual Conference of the International Liver Cancer Association (ILCA) 2015

The 9th International Liver Cancer Association Annual Conference was held from 4th to 6th September 2015 in Paris, France, and attracted a record breaking 900 participants from 51 different countries and 386 submitted abstracts from scientists around the globe. The congress provided a comprehensive overview of current developments in primary liver cancers (i.e., hepatocellular carcinoma and cholangiocarcinoma) and covered a broad range of topics from basic science to clinical studies. Following the success of immunotherapies in recent years, a preconference workshop on immunopathogenesis and immunotherapy in hepatocellular carcinoma also took place. This report will provide a subjective su…

385 MOLECULAR STAGES OF PDGFB DRIVEN LIVER FIBROSIS: LESONS FROM A TRANSGENIC MOUSE MODEL

underlying pathomechanisms is hampered by the lack of a suitable animal model. To circumvent this problem, we studied hepcidinknockout (KO) mice as a model of iron-overload associated liver disease. Methods: 6 and 12 month-old hepcidin-KO and -wild type (WT) mice fed 3% iron carbonyl-containing diet (Fe-diet) since four weeks of age were compared to age-matched WT and KO animals kept on standard diet. The liver phenotype was quantified serologically as well as morphometrically based on hematoxylin & eosin, Prussian blue and Sirius red stainings. Liver iron content was determined by atomic mass absorption. Liver fibrosis development was determined by collagen RT-PCR and hydroxyproline assay.…

Novel insights in the genetics of HCC recurrence and advances in transcriptomic data integration.

Background & Aims: In approximately 70% of patients with hepatocellular carcinoma (HCC) treated by resection or ablation, disease recurs within 5 years. Although gene expression signatures have been associated with outcome, there is no method to predict recurrence based on combined clinical, pathology, and genomic data (from tumor and cirrhotic tissue). We evaluated gene expression signatures associated with outcome in a large cohort of patients with early stage (Barcelona-Clinic Liver Cancer 0/A), single-nodule HCC and heterogeneity of signatures within tumor tissues. Methods:We assessed 287 HCC patients undergoing resection and tested genome-wide expression platforms using tumor (n = 287)…

Safety and efficacy of afatinib as add-on to standard therapy of gemcitabine/cisplatin in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, phase I trial with an extensive biomarker program

Background To date, the cornerstone of treatment in patients with advanced or metastatic cholangiocarcinoma (CCA) is systemic chemotherapy based on a combination of gemcitabine and a platinum derivative. Other therapeutic approaches including targeted agents and tyrosine kinase inhibitors (TKI) have demonstrated disappointing results, highlighting the complexity of CCA. Recently, drugs aiming at the inhibition of HER-receptors have shown first therapeutic benefit in patients with late stage disease. The aim of this phase I study was to test the dose level toxicities (DLTs), safety and efficacy of afatinib, a highly specific panErbB family receptor TKI, in chemotherapy naive patients with ad…

Epigenetic modifications precede molecular alterations and drive human hepatocarcinogenesis

Development of primary liver cancer is a multistage process. Detailed understanding of sequential epigenetic alterations is largely missing. Here, we performed Infinium Human Methylation 450k BeadChips and RNA-Seq analyses for genome-wide methylome and transcriptome profiling of cirrhotic liver (n = 7), low- (n = 4) and high-grade (n = 9) dysplastic lesions, and early (n = 5) and progressed (n = 3) hepatocellular carcinomas (HCC) synchronously detected in 8 patients with HCC with chronic hepatitis B infection. Integrative analyses of epigenetically driven molecular changes were identified and validated in 2 independent cohorts comprising 887 HCCs. Mitochondrial DNA sequencing was further em…

Vitamin A deficiency is associated with disease severity in patients with liver cirrhosis

A Phase I dose-escalation study of third-line regorafenib with trifluridine/tipiracil in metastatic colorectal cancer

Aim: To determine a recommended Phase II dose of the oral fluoropyrimidine trifluridine/tipiracil (FTD/TPI) combined with the multi-kinase inhibitor regorafenib (REG) in refractory metastatic colorectal cancer patients. Materials & methods: A conventional 3 + 3 dose finding design was used. FTD/TPI was administered on days 1–5 and 8–12 of a 28-day cycle, REG on days 2–22. Two dose levels were used: FTD/TPI 25 mg/m2 b.i.d. + REG 120 mg/d, then escalated to FTD/TPI 35 mg/m2 b.i.d. + REG 120 mg/d. Results: In total, 12 patients were treated at two dose levels. Three dose-limiting toxicities were observed; all were grade 3 hypertension causally attributed to REG. Recommended Phase II dose …

The role of molecular enrichment on future therapies in hepatocellular carcinoma

Summary Hepatocellular carcinomas (HCCs) are characterised by considerable phenotypic and molecular heterogeneity. Treating HCC and designing clinical trials are particularly challenging because co-existing liver disease, present in most patients, limits aggressive therapeutic options. Positive results in recent phase III clinical trials have confirmed the high value of anti-angiogenic therapies for HCC in both first (sorafenib and lenvatinib) and second line (regorafenib and cabozantinib) treatment modalities. However, failure of several large randomised controlled clinical trials over the last 10 years underlines the necessity for innovative treatment strategies and implementation of tran…

Cluster of differentiation 44 promotes osteosarcoma progression in mice lacking the tumor suppressor Merlin.

Merlin is a versatile tumor suppressor protein encoded by the NF2 gene. Several lines of evidence suggest that Merlin exerts its tumor suppressor activity, at least in part, by forming an inhibitory complex with cluster of differentiation 44 (CD44). Consistently, numerous NF2 mutations in cancer patients are predicted to perturb the interaction of Merlin with CD44. We hypothesized that disruption of the Merlin-CD44 complex through loss of Merlin, unleashes putative tumor- or metastasis-promoting functions of CD44. To evaluate the relevance of the Merlin-CD44 interaction in vivo, we compared tumor growth and progression in Cd44-positive and Cd44-negative Nf2-mutant mice. Heterozygous Nf2-mut…

Activation of tumor initiating cells during anti-angiogenic therapies promotes tumor progression and relapse formation in hepatocellular carcinoma

Regulation of microRNAs and their role in liver development, regeneration and disease

Abstract Since their discovery more than a decade ago microRNAs have been demonstrated to have profound effects on almost every aspect of biology. Numerous studies in recent years have shown that microRNAs have important roles in development and in the etiology and progression of disease. This review is focused on microRNAs and the roles they play in liver development, regeneration and liver disease; particularly chronic liver diseases such as alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, viral hepatitis and primary liver cancer. The key microRNAs identified in liver development and chronic liver disease will be discussed together with, where pos…

Loss of organic cation transporter 3 (Oct3) leads to enhanced proliferation and hepatocarcinogenesis

// Johanna Vollmar 1 , Anja Lautem 2 , Ellen Closs 3 , Detlef Schuppan 4 , Yong Ook Kim 4 , Daniel Grimm 1 , Jens U. Marquardt 1 , Peter Fuchs 1 , Beate K. Straub 5 , Arno Schad 5 , Dirk Grundemann 6 , Jorn M. Schattenberg 1 , Nadine Gehrke 1 , Marcus A. Worns 1 , Jan Baumgart 7 , Peter R. Galle 1 and Tim Zimmermann 1 1 Department of Internal Medicine, Gastroenterology and Hepatology, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany 2 Department of Hepatobiliary and Transplantation Surgery, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany 3 Department of Pharmacology, University Medical Center, Johannes Gutenberg-University Mainz, …

Outcome Prediction of Covert Hepatic Encephalopathy in Liver Cirrhosis: Comparison of Four Testing Strategies

INTRODUCTION: Despite the negative impact of covert hepatic encephalopathy on the outcome of patients with liver cirrhosis, data regarding the ability of different testing strategies to predict overt hepatic encephalopathy (OHE) development and mortality are limited. This study aimed to compare the ability of Psychometric Hepatic Encephalopathy Score (PHES), critical flicker frequency (CFF), simplified animal naming test (S-ANT1), and clinical covert hepatic encephalopathy (CCHE) score to predict OHE development and mortality. METHODS: A total of 224 patients with liver cirrhosis were tested with different testing strategies and prospectively followed up regarding clinically relevant outcom…

Regorafenib with TAS-102 (REGOTAS) in metastatic colorectal cancer patients who progressed after at least two standard therapies: Efficacy and safety results of a multicenter phase I study (REMETY).

158 Background: The multi-kinase inhibitor regorafenib (REGO) and oral fluoropyrimidine TAS-102 (TAS) show efficacies as single agents in treatment of refractory metastatic CRC patients (pts). We conducted a conventional 3+3 dose finding to determine a recommended phase II dose (RP2D) of its combination REGOTAS and efficacy in 3-4.-line. Methods: Eligible patients with ECOG 0-1, measurable mCRC, not amenable to surgery had at least 3rd-line treatments. Prior fluoropyrimidine-based and anti-VEGF (R) combinations were mandatory, and anti-EGFR for RAS WT tumors. TAS was given on days 1-5 and 8-12 (28-days cycle); REGO on days 2-22 (dose levels see table below). The following major AE categori…

SnapShot: Hepatocellular carcinoma.

Hepatocellular carcinoma is the sixth most common cancer globally and the second most lethal cancer worldwide. This SnapShot depicts the molecular and morphological features of this heterogeneous disease, as well as outlines associated prognostic factors, current and emerging therapies, and challenges ahead.

Clinical Predictors for Poor Quality of Life in Patients With Covert Hepatic Encephalopathy.

Background Current EASL/AASLD guidelines recommend treatment of covert hepatic encephalopathy (HE) only in symptomatic patients, for example, in those with impaired quality of life or with affected driving abilities. Goals Because testing for impaired quality of life is time consuming, the aim of the present study was to identify simple clinical predictors for poor quality of life in patients with covert HE (CHE). Study In total, 139 cirrhotic in- and outpatients without a history of overt hepatic encephalopathy were enrolled. Diagnosis of HE grade 1 (HE1) was diagnosed clinically according to the West-Haven Criteria. Critical flicker frequency and the Psychometric Hepatic Encephalopathy Sc…

Die Leberfunktion vor Lebertransplantation bestimmt das Überleben nach Lebertransplantation beim hepatozellulären Karzinom

Next generation sequencing of HCC from European and Asian HCC cohorts. Back to p53 and Wnt/β-catenin

Hepatocellular carcinoma (HCC) is the most common pri- mary liver malignancy. Here, we performed high-resolution copy- number analysis on 125 HCC tumors and whole-exome sequencing on 24 of these tumors. We identified 135 homozygous deletions and 994 somatic mutations of genes with predicted functional conse- quences. We found new recurrent alterations in four genes (ARID1A, RPS6KA3, NFE2L2 and IRF2) not previously described in HCC. Func- tional analyses showed tumor suppressor properties for IRF2, whose inactivation, exclusively found in hepatitis B virus (HBV)-related tumors, led to impaired TP53 function. In contrast, inactivation of chromatin remodelers was frequent and predominant in al…

Deletion of organic cation transporter Oct3 promotes hepatic fibrosis via upregulation of TGFβ

Organic cation transporters (OCT) are responsible for the intracellular uptake and detoxification of a broad spectrum of endogenous and exogenous substrates. OCTs are downregulated in cholestasis, fibrosis, and hepatocellular carcinoma, but the underlying molecular mechanisms and downstream effects of OCT deletion are unknown. Oct3-knockout ( Oct3−/−; FVB.Slc22a3tm10pb) and wild-type (WT; FVB) mice were subject to escalating doses of carbon tetrachloride (CCl4) or thioacetamide (TAA) for 6 wk to induce advanced parenchymal liver fibrosis. Secondary biliary fibrosis was generated by bile duct ligation. Liver fibrosis was assessed by hydroxyproline determination, quantitative Sirius red morp…

Next-Generation Sequencing: Application in Liver Cancer—Past, Present and Future?

Hepatocellular Carcinoma (HCC) is the third most deadly malignancy worldwide characterized by phenotypic and molecular heterogeneity. In the past two decades, advances in genomic analyses have formed a comprehensive understanding of different underlying pathobiological layers resulting in hepatocarcinogenesis. More recently, improvements of sophisticated next-generation sequencing (NGS) technologies have enabled complete and cost-efficient analyses of cancer genomes at a single nucleotide resolution and advanced into valuable tools in translational medicine. Although the use of NGS in human liver cancer is still in its infancy, great promise rests in the systematic integration of different …

Application of Patient-Derived Liver Cancer Cells in Personalized Treatment Approach: Phenotypic Characterization and Therapeutic Target Identification

Differential effect of TGF-β family members on proliferation and migration in primary liver cancer

Prospective evaluation of the impact of covert hepatic encephalopathy on quality of life and sleep in cirrhotic patients

BACKGROUND Minimal hepatic encephalopathy (HE) and HE grade 1 (HE1) according to the West Haven criteria have recently been grouped as one entity named-covert HE- (CHE). Data regarding the impact of CHE on health-related quality of life (HRQoL) and sleep quality are controversial. AIM First, to determine whether CHE affects HRQoL and sleep quality of cirrhotic patients and second, whether minimal HE (MHE) and HE1 affect HRQoL and sleep quality to a comparable extent. METHODS A total of 145 consecutive cirrhotic patients were enrolled. HE1 was diagnosed clinically according to the West Haven criteria. Critical flicker frequency and the Psychometric Hepatic Encephalopathy Score were used to d…

Integrative genomic analyses identified 14-3-3 zeta as a potential molecular driver of sorafenib resistance in HCC patients

The Co‐mutational Spectrum Determines the Therapeutic Response in Murine FGFR2 Fusion‐Driven Cholangiocarcinoma

Background and aims Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer and a highly lethal malignancy. Chemotherapeutic options are limited, but a considerable subset of patients harbors genetic lesions for which targeted agents exist. Fibroblast growth factor receptor 2 (FGFR2) fusions belong to the most frequent and therapeutically relevant alterations in ICC, and the first FGFR inhibitor was recently approved for the treatment of patients with progressed, fusion-positive ICC. Response rates of up to 35% indicate that FGFR-targeted therapies are beneficial in many but not all patients. Thus far, no established biomarkers exist that predict resistance or r…

Targeting tumor-initiating cells and compensatory YAP pathway to overcome sorafenib resistance in hepatocellular carcinoma

Application of patient-derived liver cancer cells for phenotypic characterization and therapeutic target identification.

Primary liver cancer (PLC) ranks among the most lethal solid cancers worldwide due to lack of effective biomarkers for early detection and limited treatment options in advanced stages. Development of primary culture models that closely recapitulate phenotypic and molecular diversities of PLC is urgently needed to improve the patient outcome. Long-term cultures of 7 primary liver cancer cell lines of hepatocellular and cholangiocellular origin were established using defined culture conditions. Morphological and histological characteristics of obtained cell lines and xenograft tumors were analyzed and compared to original tumors. Time course analyses of transcriptomic and genomic changes were…

Liver Resection for Intrahepatic Cholangiocarcinoma—Single-Center Experience with 286 Patients Undergoing Surgical Exploration over a Thirteen Year Period

Background: Intrahepatic cholangiocarcinoma (iCCA) accounts for about 10% of primary liver cancer. Surgery is the only potentially curative treatment. We report on our current series of 229 consecutive hepatic resections for iCCA, which is one of the largest Western single-center series published so far. Methods: Between January 2008 to December 2020, a total of 286 patients underwent 307 surgical explorations for intended liver resection of iCCA at our department. Data were analyzed with regard to (1) preoperative treatment of tumor, (2) operative details, (3) perioperative morbidity and mortality, (4) histopathology, (5) outcome measured by tumor recurrence, treatment of recurrence and su…

GDF11 exhibits tumor suppressive properties in hepatocellular carcinoma cells by restricting clonal expansion and invasion.

Growth differentiation factor 11 (GDF11) has been characterized as a key regulator of differentiation in cells that retain stemness features, despite some controversies in age-related studies. GDF11 has been poorly investigated in cancer, particularly in those with stemness capacity, such as hepatocellular carcinoma (HCC), one of the most aggressive cancers worldwide. Here, we focused on investigating the effects of GDF11 in liver cancer cells. GDF11 treatment significantly reduced proliferation, colony and spheroid formation in HCC cell lines. Consistently, down-regulation of CDK6, cyclin D1, cyclin A, and concomitant upregulation of p27 was observed after 24 h of treatment. Interestingly,…

Functional inhibition of Oct leads to HNF4α upregulation

Organic cation transporters (human, OCT; mouse, Oct) are responsible for the intracellular uptake and detoxification of a broad spectrum of endogenous and exogenous substrates. The OCT1 gene SLC22A1 (human; mouse, Scl22a1) is transactivated by hepatocyte nuclear factor 4α (human, HNF4α; mouse, Hnf4α). HNF4α is a master regulator of hepatocyte differentiation and is frequently associated with hepatocellular carcinoma (HCC). In addition, the downregulation of HNF4α is associated with enhanced fibrogenesis. Our recent study revealed that hepatocarcinogenesis and fibrosis were enhanced with the loss of Oct3 (gene, Slc22a3). Notably, differences in Hnf4α expression, and in cholestasis and fibros…

The impact of patient and tumour baseline characteristics on the overall survival of patients with advanced hepatocellular carcinoma treated with sorafenib.

Abstract Background Impact of patient and tumour baseline characteristics on the overall survival is not well characterized in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. Aims/methods Univariate/multivariate analyses were conducted to identify retrospectively the impact of baseline characteristics on the survival of 110 patients with advanced HCC treated with sorafenib. Results Median survival of the whole cohort was 6.7 months, median survival in Child-Pugh A, B, C patients was 10.5, 6.1 and 3.0 months and median survival of patients with Barcelona Clinic Liver Cancer (BCLC) stage C/D was 6.8/2.6 months. Presence of ascites, presence of macrovascular invas…

PD-8 Regorafenib with TAS-102 in metastatic colorectal cancer patients who progressed after at least two standard therapies: Efficacy and safety results of a multicenter phase I study (REMETY)

Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers.

Background and aims Carriage of rs738409:G in patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with carriage of PNPLA3 rs738409:G. This study explores the risk associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC. Approach and results Variants in HSD17B13 and PNPLA3 were genotyped in 6,171 participants, including 1,03…

Liver vein infiltration in patients with hepatocellular carcinoma in a large German cohort

Sequential transcriptome analysis of human liver cancer indicates late stage acquisition of malignant traits

Background & Aims Human hepatocarcinogenesis is as a multi-step process starting from dysplastic lesions to early carcinomas (eHCC) that ultimately progress to HCC (pHCC). However, the sequential molecular alterations driving malignant transformation of the pre-neoplastic lesions are not clearly defined. This lack of information represents a major challenge in the clinical management of patients at risk. Methods We applied next-generation transcriptome sequencing to tumor-free surrounding liver (n=7), low- (n=4) and high-grade (n=9) dysplastic lesions, eHCC (n=5) and pHCC (n=3) from 8 HCC patients with hepatitis B infection. Integrative analyses of genetic and transcriptomic changes were pe…

Sirtuin-6-dependent genetic and epigenetic alterations are associated with poor clinical outcome in hepatocellular carcinoma patients

Sirtuin 6 (SIRT6) is a member of the sirtuin family of NAD+–dependent deacetylases. Genetic deletion of Sirt6 in mice results in a severe degenerative phenotype with impaired liver function and premature death. The role of SIRT6 in development and progression of hepatocellular carcinoma is currently unknown. We first investigated SIRT6 expression in 153 primary human liver cancers and in normal and cirrhotic livers using microarray analysis. SIRT6 was significantly down-regulated in both cirrhotic livers and cancer. A Sirt6 knockout (KO) gene expression signature was generated from primary hepatoctyes isolated from 3-week-old Sirt6-deficient animals. Sirt6-deficient hepatocytes showed up-re…

Redox Regulation by HGF/c-Met in Liver Disease

Reactive oxygen species (ROS) have gained considerable attention in recent years because of their direct involvement in the regulation of multiple physiological and pathological processes. Under normal conditions, ROS have an important role in cell signaling and function as essential mediators of cell homeostasis. However, imbalance between ROS and antioxidant systems induces oxidative stress, which leads to cell and tissue damage. The cellular redox modulation by hepatocyte growth factor (HGF) and its receptor c-Met in the liver has been studied extensively in the past. The generation of liver-specific c-Met–knockout mice has allowed to demonstrate the fundamental importance of HGF/c-Met i…