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Concept: Hepatocellular carcinoma

326

Patients with chronic hepatitis C virus (HCV) infection and cirrhosis have higher risk for liver-related complications and have historically been more difficult to cure than patients without cirrhosis. We evaluated the safety and efficacy of ombitasvir/paritaprevir/ritonavir and dasabuvir, without ribavirin, for 12 weeks in patients with HCV GT1b infection and compensated cirrhosis.

Concepts: Cirrhosis, Hepatitis, Hepatocellular carcinoma, Hepatitis C, Hepatitis B, Hepatitis A, Hepatitis C virus, Wilson's disease

170

Hepatitis C Virus (HCV) infection is one of the most common etiological factors involved in fibrosis development and its progression to hepatocellular carcinoma (HCC). The pivotal role of hepatic stellate cells (HCSs) and extracellular matrix (ECM) in fibrogenesis is now certainly accepted, while the network of molecular interactions connecting HCV is emerging as a master regulator of several biological processes including proliferation, inflammation, cytoskeleton and ECM remodeling. In this study, the effects of HCV proteins expression on liver cancer cells, both pro-invasive and pro-fibrogenic phenotypes were explored. As a model of HCV infection, we used permissive Huh7.5.1 hepatoma cells infected with JFH1-derived ccHCV. Conditioned medium from these cells was used to stimulate LX-2 cells, a line of HSCs. We found that the HCV infection of Huh7.5.1 cells decreased adhesion, increased migration and caused the delocalization of alpha-actinin from plasma membrane to cytoplasm and increased expression levels of paxillin. The treatment of LX-2 cells, with conditioned medium from HCV-infected Huh7.5.1 cells, caused an increase in cell proliferation, expression of alpha-smooth muscle actin, hyaluronic acid release and apoptosis rate measured as cleaved poly ADP-ribose polymerase (PARP). These effects were accompanied in Huh7.5.1 cells by an HCV-dependent increasing of FAK activation that physically interacts with phosphorylated paxillin and alpha-actinin, and a rising of tumor necrosis factor alpha production/release. Silencing of FAK by siRNA reverted all effects of HCV infection, both those directed on Huh7.5.1 cells, and those indirect effects on the LX-2 cells. Moreover and interestingly, FAK inhibition enhances apoptosis in HCV-conditioned LX-2 cells. In conclusion, our findings demonstrate that HCV, through FAK activation, may promote cytoskeletal reorganization and a pro-oncogenic phenotype in hepatocyte-like cells, and a fibrogenic phenotype in HSCs.

Concepts: Protein, Gene, Cancer, Signal transduction, Cell membrane, Cirrhosis, Hepatocellular carcinoma, Hepatitis C

170

Transcatheter arterial chemoembolization (TACE) is the most widely used treatment option for unresectable hepatocellular carcinoma (HCC). Elevated serum YKL-40 level has been shown to predict poor prognosis in HCC patients undergoing resection. This study was designed to validate the prognostic significance of serum YKL-40 in patients with HCC undergoing TACE treatment.

Concepts: Lung cancer, Medical terms, Hepatocellular carcinoma, Hepatology, Radiology, Prognosis, Thought experiment, Transcatheter arterial chemoembolization

169

Hepatocellular carcinoma, the most frequent primary hepatic tumor, metastasizes in more than 50% of cases. However, parotid gland metastatic HCCs are very uncommon. We report a patient in whom the finding of a left parotid mass revealed metastatic HCC.

Concepts: Cancer, Oncology, Lung cancer, Cirrhosis, Hepatocellular carcinoma, Hepatitis C, Parotid gland, Warthin's tumor

164

To assess the technical safety and efficacy of transcatheter arterial chemoembolization (TACE) combined with immediate radiofrequency ablation (RFA) for large hepatocellular carcinomas (HCC) (maximum diameter ≥ 5 cm).

Concepts: Hepatocellular carcinoma, Hepatology, Radiology, Transcatheter arterial chemoembolization, Radiofrequency ablation

68

Liver cancer is highly fatal, and death rates in the United States are increasing faster than for any other cancer, having doubled since the mid-1980s. In 2017, it is estimated that the disease will account for about 41,000 new cancer cases and 29,000 cancer deaths in the United States. In this article, data from the Surveillance, Epidemiology, and End Results (SEER) Program and the National Center for Health Statistics are used to provide an overview of liver cancer incidence, mortality, and survival rates and trends, including data by race/ethnicity and state. The prevalence of major risk factors for liver cancer is also reported based on national survey data from the Centers for Disease Control and Prevention. Despite the improvement in liver cancer survival in recent decades, only 1 in 5 patients survives 5 years after diagnosis. There is substantial disparity in liver cancer death rates by race/ethnicity (from 5.5 per 100,000 in non-Hispanic whites to 11.9 per 100,000 in American Indians/Alaska Natives) and state (from 3.8 per 100,000 in North Dakota to 9.6 per 100,000 in the District of Columbia) and by race/ethnicity within states. Differences in risk factor prevalence account for much of the observed variation in liver cancer rates. Thus, in contrast to the growing burden, a substantial proportion of liver cancer deaths could be averted, and existing disparities could be dramatically reduced, through the targeted application of existing knowledge in prevention, early detection, and treatment, including improvements in vaccination against hepatitis B virus, screening and treatment for chronic hepatitis C virus infections, maintaining a healthy body weight, access to high-quality diabetes care, preventing excessive alcohol drinking, and tobacco control, at both the state and national levels. CA Cancer J Clin 2017. © 2017 American Cancer Society.

Concepts: Epidemiology, Cancer, United States, Cirrhosis, Hepatitis, Hepatocellular carcinoma, Hepatitis C, Hepatitis B

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Oncolytic viruses (OVs) represent promising, proinflammatory cancer treatments. Here, we explored whether OV-induced innate immune responses could simultaneously inhibit HCV while suppressing hepatocellular carcinoma (HCC). Furthermore, we extended this exemplar to other models of virus-associated cancer.

Concepts: Immune system, Cancer, Oncology, Innate immune system, Cirrhosis, Hepatocellular carcinoma, Hepatitis C, Viruses

38

Background Patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3 for whom treatment with peginterferon is not an option, or who have not had a response to prior interferon treatment, currently have no approved treatment options. In phase 2 trials, regimens including the oral nucleotide polymerase inhibitor sofosbuvir have shown efficacy in patients with HCV genotype 2 or 3 infection. Methods We conducted two randomized, phase 3 studies involving patients with chronic HCV genotype 2 or 3 infection. In one trial, patients for whom treatment with peginterferon was not an option received oral sofosbuvir and ribavirin (207 patients) or matching placebo (71) for 12 weeks. In a second trial, patients who had not had a response to prior interferon therapy received sofosbuvir and ribavirin for 12 weeks (103 patients) or 16 weeks (98). The primary end point was a sustained virologic response at 12 weeks after therapy. Results Among patients for whom treatment with peginterferon was not an option, the rate of a sustained virologic response was 78% (95% confidence interval [CI], 72 to 83) with sofosbuvir and ribavirin, as compared with 0% with placebo (P<0.001). Among previously treated patients, the rate of response was 50% with 12 weeks of treatment, as compared with 73% with 16 weeks of treatment (difference, -23 percentage points; 95% CI, -35 to -11; P<0.001). In both studies, response rates were lower among patients with genotype 3 infection than among those with genotype 2 infection and, among patients with genotype 3 infection, lower among those with cirrhosis than among those without cirrhosis. The most common adverse events were headache, fatigue, nausea, and insomnia; the overall rate of discontinuation of sofosbuvir was low (1 to 2%). Conclusions In patients with HCV genotype 2 or 3 infection for whom treatment with peginterferon and ribavirin was not an option, 12 or 16 weeks of treatment with sofosbuvir and ribavirin was effective. Efficacy was increased among patients with HCV genotype 2 infection and those without cirrhosis. In previously treated patients with genotype 3 infection, 16 weeks of therapy was significantly more effective than 12 weeks. (Funded by Gilead Sciences; POSITRON and FUSION ClinicalTrials.gov numbers, NCT01542788 and NCT01604850 , respectively.).

Concepts: Clinical trial, Virus, Hepatitis, Hepatocellular carcinoma, Interferon, Hepatitis C, Ribavirin, Hepatitis B

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BACKGROUND & AIMS: Integrating host and HBV characteristics, this study aimed to develop models for predicting long-term cirrhosis and hepatocellular carcinoma risk in chronic hepatitis B patients. METHODS: This analysis included HBsAg-seropositive and anti-HCV-seronegative participants from R.E.V.E.A.L.-HBV cohort. The newly-developed cirrhosis and hepatocellular carcinoma was ascertained through regular follow-up ultrasonography, computerized linkage with national health databases, and medical chart reviews. Two-thirds participants were allocated for risk model derivation and another one-third for model validation. The risk prediction model included age, gender, HBeAg serostatus, serum levels of HBV DNA, and alanine aminotransferase (ALT), quantitative serum HBsAg levels and HBV genotypes. The family history was included in prediction model for hepatocellular carcinoma additionally. Cox’s proportional hazards regression coefficients for cirrhosis and hepatocellular carcinoma predictors were converted into risk scores. The areas under receiver operating curve (AUROCs) were used to evaluate the performance of risk models. Results: Elder age, male, HBeAg, genotype C, and increasing levels of ALT, HBV DNA and HBsAg were all significantly associated with an increased risk of cirrhosis and hepatocellular carcinoma. The risk scores estimated from the derivation set could accurately categorize participants with low, medium and high cirrhosis and hepatocellular carcinoma risk in validation set (p<0.001). The AUROCs for predicting 3-, 5- and 10-year cirrhosis risk ranged 0.83-0.86 and 0.79-0.82 for the derivation and validation set, respectively. The AUROC for predicting 5-, 10-, 15-year risk of hepatocellular carcinoma ranged 0.86-0.89 and 0.84-0.87 in the derivation and validation set, respectively. CONCLUSIONS: The risk prediction models of cirrhosis and hepatocellular carcinoma by integrating host and HBV profiles have excellent prediction accuracy and discriminatory ability. They may be used for clinical management of chronic hepatitis B patients. (HEPATOLOGY 2013.).

Concepts: Regression analysis, Cirrhosis, Hepatitis, Hepatocellular carcinoma, Alanine transaminase, Hepatitis C, Hepatitis B, Hepatitis A

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Hepatitis C virus (HCV) is a major causative agent of severe liver disease including fibrosis, cirrhosis and liver cancer. Therapy has improved over the years, but continues to be associated with adverse side effects and variable success rates. Furthermore, a vaccine protecting against HCV infection remains elusive. Development of more effective intervention measures has been delayed by the lack of a suitable animal model. Naturally, HCV infects only humans and chimpanzees. The determinants of this limited host range are poorly understood in part due to difficulties of studying HCV in cell culture. Some progress has been made elucidating the barriers for the HCV lifecycle in non-permissive species which will help in the future to construct animal models for HCV infection, immunity and pathogenesis.

Concepts: Immune system, Model organism, Cirrhosis, Hepatocellular carcinoma, Hepatitis C, Hepatitis B, Hepatitis A, Liver disease