Liver fibrosis is a major cause of morbidity and mortality worldwide due to chronic viral hepatitis and, more recently, from fatty liver disease associated with obesity. Hepatic stellate cell activation represents a critical event in fibrosis because these cells become the primary source of extracellular matrix in liver upon injury. Use of cell-culture and animal models has expanded our understanding of the mechanisms underlying stellate cell activation and has shed new light on genetic regulation, the contribution of immune signaling, and the potential reversibility of the disease. As pathways of fibrogenesis are increasingly clarified, the key challenge will be translating new advances into the development of antifibrotic therapies for patients with chronic liver disease.

The hemoglobin threshold for transfusion of red cells in patients with acute gastrointestinal bleeding is controversial. We compared the efficacy and safety of a restrictive transfusion strategy with those of a liberal transfusion strategy.

Hepatocellular carcinoma (HCC) is the most common primary liver tumor and the third greatest cause of cancer-related death worldwide, and its incidence is increasing. Despite the significant improvement in management of HCC over the past 30 years, there are no effective chemoprevention strategies, and only one systemic therapy has been approved for patients with advanced tumors. This drug, sorafenib, acts on tumor cells and the stroma. HCC develops from chronically damaged tissue that contains large amounts of inflammation and fibrosis, which also promote tumor progression and resistance to therapy. Increasing our understanding of how stromal components interact with cancer cells and the signaling pathways involved could help identify new therapeutic and chemopreventive targets.

Epigenetic deregulation has emerged as a driver in human malignancies. There is no clear understanding of the epigenetic alterations in hepatocellular carcinoma (HCC) and of the potential role of DNA methylation markers as prognostic biomarkers. Analysis of tumor tissue from 304 patients with HCC treated with surgical resection allowed us to generate a methylation‐based prognostic signature using a training‐validation scheme. Methylome profiling was done with the Illumina HumanMethylation450 array (Illumina, Inc., San Diego, CA), which covers 96% of known cytosine‐phosphate‐guanine (CpG) islands and 485,000 CpG, and transcriptome profiling was performed with Affymetrix Human Genome U219 Plate (Affymetrix, Inc., Santa Clara, CA) and miRNA Chip 2.0. Random survival forests enabled us to generate a methylation signature based on 36 methylation probes. We computed a risk score of mortality for each individual that accurately discriminated patient survival both in the training (221 patients; 47% hepatitis C–related HCC) and validation sets (n = 83; 47% alcohol‐related HCC). This signature correlated with known predictors of poor outcome and retained independent prognostic capacity of survival along with multinodularity and platelet count. The subset of patients identified by this signature was enriched in the molecular subclass of proliferation with progenitor cell features. The study confirmed a high prevalence of genes known to be deregulated by aberrant methylation in HCC (e.g., Ras association [RalGDS/AF‐6] domain family member 1, insulin‐like growth factor 2, and adenomatous polyposis coli) and other solid tumors (e.g., NOTCH3) and describes potential candidate epidrivers (e.g., septin 9 and ephrin B2). Conclusions: A validated signature of 36 DNA methylation markers accurately predicts poor survival in patients with HCC. Patients with this methylation profile harbor messenger RNA–based signatures indicating tumors with progenitor cell features. (Hepatology 2015;61:1945–1956)

Hepatocellular carcinoma (HCC) is a major health problem. Most patients with HCC experience a recurrence after resection/ablation or are diagnosed at advanced stages. Sorafenib remains the only approved systemic drug for these patients. Molecular therapies targeting signaling cascades involved in hepatocarcinogenesis have been explored in phase III clinical trials. However, none of the drugs tested have shown positive results in the first-line (brivanib, sunitinib, erlotinib, and linifanib) or second-line (brivanib, everolimus) setting after sorafenib progression. Reasons for failure are heterogeneous and include lack of understanding of critical drivers of tumor progression/dissemination, liver toxicity, flaws in trial design, or marginal antitumoral potency. These trials are also challenging time to progression as a surrogate endpoint of survival. Trials ongoing testing drugs head-to-head versus sorafenib in “all comers” might have difficulties in achieving superior results in the first line. Novel trials are also designed testing drugs in biomarker-based subpopulations of patients with HCC. Most common mutations, however, are undruggable, such as p53 and CTNNB1. Two types of studies are proposed: (i) phase II pivotal proof-of-concept studies testing drugs blocking potential oncogenic addiction loops, such as the one testing MEK inhibitors in RAS+ patients or amplification of FGF19 as a target; and (ii) phase II to III studies using biomarker-based trial enrichment for defining HCC subpopulations, such as the case of enriching for MET-positive tumors. These strategies have been deemed successful in breast, melanoma, and lung cancers, and are expected to change the landscape of trial design of HCC. Clin Cancer Res; 20(8); 2072–9. ©2014 AACR.