Molecular Mechanisms Underlying Hepatocellular Carcinoma

Hepatocarcinogenesis is a complex process that remains still partly understood. That might be explained by the multiplicity of etiologic factors, the genetic/epigenetic heterogeneity of tumors bulks and the ignorance of the liver cell types that give rise to tumorigenic cells that have stem cell-like properties. The DNA stress induced by hepatocyte turnover, inflammation and maybe early oncogenic pathway activation and sometimes viral factors, leads to DNA damage response which activates the key tumor suppressive checkpoints p53/p21Cip1 and p16INK4a/pRb responsible of cell cycle arrest and cellular senescence as reflected by the cirrhosis stage. Still obscure mechanisms, but maybe involving the Wnt signaling and Twist proteins, would allow pre-senescent hepatocytes to bypass senescence, acquire immortality by telomerase reactivation and get the last genetic/epigenetic hits necessary for cancerous transformation. Among some of the oncogenic pathways that might play key driving roles in hepatocarcinogenesis, c-myc and the Wnt/β-catenin signaling seem of particular interest. Finally, antiproliferative and apoptosis deficiencies involving TGF-β, Akt/PTEN, IGF2 pathways for instance are prerequisite for cancerous transformation. Of evidence, not only the transformed liver cell per se but the facilitating microenvironment is of fundamental importance for tumor bulk growth and metastasis

Liver transplantation for alcoholic liver disease: a retrospective analysis of recidivism, survival and risk factors predisposing to alcohol relapse

Background and study aims : Alcoholic liver disease (ALD) is the second most common indication for liver transplantation. The aim of this study was to evaluate the alcohol relapse rate and long-term survival after liver transplantation for ALD and to identify risk factors predisposing to alcohol relapse. Patients and methods : Between 2000 and 2007, 108 patients transplanted for ALD in the Ghent University Hospital were included in this retrospective analysis. Relapse was defined as any drinking after transplantation, problem drinking as more than 2 units/day for women and 3 units/day for men. A wide range of variables was obtained from a questionnaire and medical records. Results : The mean follow-up was 55 months. Relapse was observed in 29%, 16% in problem drinking. The one-and five-year survival was 87% and 74% respectively. No significant difference in survival was found between non-relapsers, occasional drinkers and problem drinkers. The following risk factors were found to be significantly associated with relapse into problem drinking in an univariate analysis : a shorter pre-transplant abstinence period, the presence of a first degree relative with alcohol abuse and a higher number of prior attempts to quit. In multivariable analysis, the presence of a first degree relative with alcohol abuse was found associated with relapse into problem drinking. Conclusions : The presence of a first degree relative with alcohol abuse is a valuable pre-transplant variable evaluating an ALD patient's eligibility for liver transplantation. Other variables are also helpful to outline the broader context of the drinking behavior of the patient

What are non-inferiority drug trials?

Typically, clinical trials compare a new product or therapy with another that already exists to determine if the new one is as successful as, or better than, the existing one. In some studies, participants may be assigned to receive a placebo. Comparing a new product with a placebo can be the fastest and most reliable way to demonstrate the new product’s therapeutic effectiveness. However, placebos are not used if a patient would be put at risk, particularly in the study of treatments for serious illnesses by not having effective therapy. Most of non-inferiority studies compare new products with an approved therapy. The active-controlled trial with a non-inferiority design has gained popularity in recent years. They have methodological challenges, especially in determining the non-inferiority margin. Regulatory guidelines provide some general statements on how an NI trial should be conducted. In this narrative review based on scientific literature and papers, but also publications about clinical trials, we will define NI trial concepts, explain the main methodology of NI margin determination with its limitations and the potential margin of improvement

What are non-inferiority drug trials?

Typically, clinical trials compare a new product or therapy with another that already exists to determine if the new one is as successful as, or better than, the existing one. In some studies, participants may be assigned to receive a placebo. Comparing a new product with a placebo can be the fastest and most reliable way to demonstrate the new product’s therapeutic effectiveness. However, placebos are not used if a patient would be put at risk, particularly in the study of treatments for serious illnesses by not having effective therapy. Most of non-inferiority studies compare new products with an approved therapy. The active-controlled trial with a non-inferiority design has gained popularity in recent years. They have methodological challenges, especially in determining the non-inferiority margin. Regulatory guidelines provide some general statements on how an NI trial should be conducted. In this narrative review based on scientific literature and papers, but also publications about clinical trials, we will define NI trial concepts, explain the main methodology of NI margin determination with its limitations and the potential margin of improvement

What are non-inferiority drug trials?

Typically, clinical trials compare a new product or therapy with another that already exists to determine if the new one is as successful as, or better than, the existing one. In some studies, participants may be assigned to receive a placebo. Comparing a new product with a placebo can be the fastest and most reliable way to demonstrate the new product’s therapeutic effectiveness. However, placebos are not used if a patient would be put at risk, particularly in the study of treatments for serious illnesses by not having effective therapy. Most of non-inferiority studies compare new products with an approved therapy. The active-controlled trial with a non-inferiority design has gained popularity in recent years. They have methodological challenges, especially in determining the non-inferiority margin. Regulatory guidelines provide some general statements on how an NI trial should be conducted. In this narrative review based on scientific literature and papers, but also publications about clinical trials, we will define NI trial concepts, explain the main methodology of NI margin determination with its limitations and the potential margin of improvement

Surviving your genes-the role of PNPLA3 variation in end-stage liver disease

Fil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentin

Reconnaissance au travail (la)

La « reconnaissance » est devenue un nouvel enjeu de société. Le désir d’être reconnu envahit le monde du travail et imprègne les relations et les discours des individus. Reconnaissance de compétences, reconnaissance de la personne à travers son positionnement dans l’organisation, reconnaissance vis à vis de la hiérarchie et du groupe. Que revendiquet-on dans le monde du travail, quand on demande « une plus grande reconnaissance » ? quelles formes celle-ci peut-elle prendre, en particulier dans les démarches d’évaluation ou de validation de l’expérience ? Comment les entreprises abordent-elles ces attentes collectives et individuelles de reconnaissance

Two distinct subtypes of hepatitis B virus–related acute liver failure are separable by quantitative serum immunoglobulin M anti‐hepatitis B core antibody and hepatitis B virus DNA levels

Hepatitis B virus (HBV)‐related acute liver failure (HBV‐ALF) may occur after acute HBV infection (AHBV‐ALF) or during an exacerbation of chronic HBV infection (CHBV‐ALF). Clinical differentiation of the two is often difficult if a previous history of HBV is not available. Quantitative measurements of immunoglobulin M (IgM) anti–hepatitis B core antibody (anti‐HBc) titers and of HBV viral loads (VLs) might allow the separation of AHBV‐ALF from CHBV‐ALF. Of 1,602 patients with ALF, 60 met clinical criteria for AHBV‐ALF and 27 for CHBV‐ALF. Sera were available on 47 and 23 patients, respectively. A quantitative immunoassay was used to determine IgM anti‐HBc levels, and real‐time polymerase chain reaction (rtPCR) was used to determine HBV VLs. AHBV‐ALFs had much higher IgM anti‐HBc titers than CHBV‐ALFs (signal‐to‐noise [S/N] ratio median: 88.5; range, 0‐1,120 versus 1.3, 0‐750; P < 0.001); a cut point for a S/N ratio of 5.0 correctly identified 44 of 46 (96%) AHBV‐ALFs and 16 of 23 (70%) CHBV‐ALFs; the area under the receiver operator characteristic curve was 0.86 ( P < 0.001). AHBV‐ALF median admission VL was 3.9 (0‐8.1) log10 IU/mL versus 5.2 (2.0‐8.7) log10 IU/mL for CHBV‐ALF ( P < 0.025). Twenty percent (12 of 60) of the AHBV‐ALF group had no hepatitis B surface antigen (HBsAg) detectable on admission to study, wheras no CHBV‐ALF patients experienced HBsAg clearance. Rates of transplant‐free survival were 33% (20 of 60) for AHBV‐ALF versus 11% (3 of 27) for CHBV‐ALF ( P = 0.030). Conclusions: AHBV‐ALF and CHBV‐ALF differ markedly in IgM anti‐HBc titers, in HBV VLs, and in prognosis, suggesting that the two forms are, indeed, different entities that might each have a unique pathogenesis. (H EPATOLOGY 2011)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90152/1/24732_ftp.pd

Markers of Inflammation and Fibrosis in Alcoholic Hepatitis and Viral Hepatitis C

High levels of profibrinogenic cytokine transforming factor beta (TGF-β), metalloprotease (MMP2), and tissue inhibitor of matrix metalloprotease 1 (TIMP1) contribute to fibrogenesis in hepatitis C virus (HCV) infection and in alcohol-induced liver disease (ALD). The aim of our study was to correlate noninvasive serum markers in ALD and HCV patients with various degrees of inflammation and fibrosis in their biopsies. Methods. Serum cytokines levels in HCV-infected individuals in the presence or absence of ALD were measured. Student's-t-test with Bonferroni correction determined the significance between the groups. Results. Both tumor-necrosis-factor- (TNF)-α and TGF-β levels increased significantly with the severity of inflammation and fibrosis. TGF-β levels increased significantly in ALD patients versus the HCV patients. Proinflammatory cytokines' responses to viral and/or toxic injury differed with the severity of liver inflammation. A combination of these markers was useful in predicting and diagnosing the stages of inflammation and fibrosis in HCV and ALD. Conclusion. Therapeutic monitoring of TGF-β and metalloproteases provides important insights into fibrosis

Examination of the risk of reinfection with hepatitis C among injecting drug users who have been tested in Glasgow

Unsafe injecting practices put injecting drug users (IDUs) at repeat exposure to infection with the hepatitis C virus (HCV). It has not yet been determined if spontaneously clearing one's primary infection influences the risk of reinfection; our aim was to estimate the relative risk of reinfection in IDUs who have cleared the virus. We conducted a retrospective study using a large database of HCV test results covering Greater Glasgow Health Board during 1993–2007 to calculate rates of infection and reinfection in current/former IDUs. The relative risk of (re)infection in previously infected compared with never-infected IDUs was estimated using Poisson regression, adjusting for age at study entry, sex, and calendar period of test. Although the rate of reinfection in IDUs who were HCV antibody-positive, RNA-negative at baseline was lower (7/100 person-years, 95% CI: 5–9) than the rate of acute infection in IDUs who were HCV antibody-negative at baseline (10/100 person-years, 95% CI: 9–12), the risk of reinfection was not significantly different than the risk of initial infection (adjusted rate ratio = 0.78, 95% CI: 0.57–1.08). We found only weak evidence for a reduced risk of HCV reinfection in IDUs who had cleared their previous infection. Further research among those who have cleared infection through antiviral therapy is needed to help inform decisions regarding treatment of IDUs