[Wilson's disease]

http://www.huveaux.fr/fr_santesite.aspWilson's disease is an autosomal recessive disorder of copper excess. This illness results from mutations of the ATP7B gene chromosome 13. The discovery of the gene allowed a better understanding of cytosolic copper trafficking its relationship with ceruloplasmin synthesis. Symptomatic patients may present with hepatic, neurologic or psychiatric forms. Clinical and phenotypic evidences provide only presumptive arguments for this disease which can be routinely assessed by molecular analysis. This disease can be efficiently treated by chelation and zinc therapy. Liver transplantation is the therapy to patients with hepatic fulminant course, or in those with relentless progression of hepatic dysfunction in spite of medical therapy

Patterns of chromosomal copy-number alterations in intrahepatic cholangiocarcinoma

International audienceBackground: Intrahepatic cholangiocarcinomas (ICC) are relatively rare malignant tumors associated with a poor prognosis. Recent studies using genome-wide sequencing technologies have mainly focused on identifying new driver mutations. There is nevertheless a need to investigate the spectrum of copy number aberrations in order to identify potential target genes in the altered chromosomal regions. The aim of this study was to characterize the patterns of chromosomal copy-number alterations (CNAs) in ICC. Methods: 53 patients having ICC with frozen material were selected. In 47 cases, DNA hybridization has been performed on a genomewide SNP array. A procedure with a segmentation step and a calling step classified genomic regions into copy-number aberration states. We identified the exclusively amplified and deleted recurrent genomic areas. These areas are those showing the highest estimated propensity level for copy loss (resp. copy gain) together with the lowest level for copy gain (resp. copy loss). We investigated ICC clustering. We analyzed the relationships between CNAs and clinico-pathological characteristics. Results: The overall genomic profile of ICC showed many alterations with higher rates for the deletions. Exclusively deleted genomic areas were 1p, 3p and 14q. The main exclusively amplified genomic areas were 1q, 7p, 7q and 8q. Based on the exclusively deleted/amplified genomic areas, a clustering analysis identified three tumors groups: the first group characterized by copy loss of 1p and copy gain of 7p, the second group characterized by 1p and 3p copy losses without 7p copy gain, the last group characterized mainly by very few CNAs. From univariate analyses, the number of tumors, the size of the largest tumor and the stage were significantly associated with shorter time recurrence. We found no relationship between the number of altered cytobands or tumor groups and time to recurrence. Conclusion: This study describes the spectrum of chromosomal aberrations across the whole genome. Some of the recurrent exclusive CNAs harbor candidate target genes. Despite the absence of correlation between CNAs and clinico-pathological characteristics, the co-occurence of 7p gain and 1p loss in a subgroup of patients may suggest a differential activation of EGFR and its downstream pathways, which may have a potential effect on targeted therapies

The Mw = 6.3, November 21, 2004, Les Saintes earthquake (Guadeloupe): Tectonic setting, slip model and static stress changes,

International audienceOn November 21, 2004, a magnitude 6.3 earthquake occurred offshore, 10 km south of Les Saintes archipelago in Guadeloupe (French West Indies). There were more than 30000 aftershocks recorded in the following two years, most of them at shallow depth near the islands of the archipelago. The main shock and its main aftershock of February 14, 2005 (Mw = 5.8) ruptured a NE-dipping normal fault (Roseau fault), mapped and identified as active from high-resolution bathymetric data a few years before. This fault belongs to an arc-parallel en echelon fault system that follows the inner edge of the northern part of the Lesser Antilles arc, accommodating the sinistral component of oblique convergence between the North American and Caribbean plates. The distribution of aftershocks and damage (destruction and landslides) are consistent with the main fault plane location and attitude. The slip model of the main shock, obtained by inverting jointly global broadband and local strong motion records, is characterized by two main slip zones located 5 to 10 km to the SE and NW of the hypocenter. The main shock is shown to have increased the Coulomb stress at the tips of the ruptured plane by more than 4 bars where most of the aftershocks occurred, implying that failures on fault system were mainly promoted by static stress changes. The earthquake also had an effect on volcanic activity since the Boiling Lake in Dominica drained twice, probably as a result of the extensional strain induced by the earthquake and its main aftershock

Cirrhosis and liver transplantation in patients co-infected with HIV and hepatitis B or C:an observational cohort study

This study assessed the likelihood of referral for liver transplantation assessment in a prospective cohort of patients co-infected with HIV and hepatitis B or C with complications of cirrhosis. There were 141 co-infected patients from 11 UK centres with at least one complication of cirrhosis recorded (either decompensation or hepatocellular carcinoma) out of 772 identified with cirrhosis and/or HCC. Only 23 of these 141 (16.3%) were referred for liver transplantation assessment, even though referral is recommended for co-infected patients after the first decompensation episode

Safety and efficacy of protease inhibitors to treat hepatitis C after liver transplantation: A multicenter experience

Background & Aims: Protease inhibitors (PI) with peginterferon/ ribavirin have significantly improved SVR rates in HCV G1 patients. Their use to treat HCV recurrence after liver transplantation (LT) is a challenge. Methods: This cohort study included 37 liver transplant recipients (male, 92%, age 57 ± 11 years), treated with boceprevir (n = 18) or telaprevir (n = 19). The indication for therapy was HCV recurrence (fibrosis stage PF2 (n = 31, 83%) or fibrosing cholestatic hepatitis (n = 6, 16%). Results: Eighteen patients were treatment-naive, five were relapsers and fourteen were non-responders to dual therapy after LT. Twenty-two patients received cyclosporine and fifteen tacrolimus. After 12 weeks of PI therapy, a complete virological response was obtained in 89% of patients treated with boceprevir, and 58% with telaprevir (p = 0.06). The end of treatment virological response rate was 72% (13/18) in the boceprevir group and 40% (4/10) in the telaprevir group (p = 0.125). A sustained virological response 12 weeks after treatment discontinuation was observed in 20% (1/5) and 71% (5/7) of patients in the telaprevir and boceprevir groups, respectively (p = 0.24). Treatment was discontinued in sixteen patients (treatment failures (n = 11), adverse events (n = 5)). Infections occurred in ten patients (27%), with three fatal outcomes (8%). The most common adverse effect was anemia (n = 34, 92%), treated with erythropoietin and/ or a ribavirin dose reduction; thirteen patients (35%) received red blood cell transfusions. The cyclosporine dose was reduced by 1.8 ± 1.1-fold and 3.4 ± 1.0-fold with boceprevir and telaprevir, respectively. The tacrolimus dose was reduced by 5.2 ± 1.5-fold with boceprevir and 23.8 ± 18.2-fold with telaprevir. Conclusions: Our results suggest that triple therapy is effective in LT recipients, particularly those experiencing a severe recurrence. The occurrence of anemia and drug-drug interactions, and the risk of infections require close monitoring.

Liver transplantation for patients with human immunodeficiency virus and hepatitis C virus coinfection with special reference to hemophiliac recipients in Japan.

Liver transplantation for patients with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) remains challenging. The advent of highly active antiretroviral therapy (HAART) for HIV has reduced mortality from opportunistic infection related to acquired immunodeficiency syndrome dramatically, while about 50% of patients die of end-stage liver cirrhosis resulting from HCV. In Japan, liver cirrhosis frequently develops after HCV-HIV coinfection resulting from previously transfused infected blood products for hemophilia. The problems of liver transplantation for those patients arise from the need to control calcineurin inhibitor with HAART drugs, the difficulty of using interferon after liver transplantation with HAART, and the need to control intraoperative coagulopathy associated with hemophilia. We review published reports of liver transplantation for these patients in the updated world literature

Early liver transplantation for severe alcohol-related hepatitis not responding to medical treatment: a prospective controlled study

peer reviewedBackground: Early liver transplantation for severe alcohol-related hepatitis is an emerging treatment option. We aimed to assess the risk of alcohol relapse 2 years after early liver transplantation for alcohol-related hepatitis compared with liver transplantation for alcohol-related cirrhosis after at least 6 months of abstinence. Methods: We conducted a multicentre, non-randomised, non-inferiority, controlled study in 19 French and Belgian hospitals. All participants were aged 18 years or older. There were three groups of patients recruited prospectively: patients with severe alcohol-related hepatitis who did not respond to medical treatment and were eligible for early liver transplantation according to a new selection scoring system based on social and addiction items that can be quantified in points (early transplantation group); patients with alcohol-related cirrhosis listed for liver transplantation after at least 6 months of abstinence (standard transplantation group); patients with severe alcohol-related hepatitis not responding to medical treatment not eligible for early liver transplantation according to the selection score (not eligible for early transplantation group), this group did not enter any further liver transplantation processes. We also defined a historical control group of patients with severe alcohol-related hepatitis unresponsive to medical therapy and non-transplanted. The primary outcome was the non-inferiority of 2-year rate of alcohol relapse after transplantation in the early transplantation group compared with the standard transplantation group using the alcohol timeline follow back (TLFB) method and a prespecified non-inferiority margin of 10%. Secondary outcomes were the pattern of alcohol relapse, 2-year survival rate post-transplant in the early transplantation group compared with the standard transplantation group, and 2-year overall survival in the early transplantation group compared with patients in the not eligible for early transplantation group and historical controls. This trial is registered with ClinicalTrials.gov, NCT01756794. Findings: Between Dec 5, 2012, and June 30, 2016, we included 149 patients with severe alcohol-related hepatitis: 102 in the early transplantation group and 47 in the not eligible for early transplantation group. 129 patients were included in the standard transplantation group. 68 patients in the early transplantation group and 93 patients in the standard transplantation group received a liver transplant. 23 (34%) patients relapsed in the early transplantation group, and 23 (25%) patients relapsed in the standard transplantation group; therefore, the non-inferiority of early transplantation versus standard transplantation was not demonstrated (absolute difference 9·1% [95% CI –∞ to 21·1]; p=0·45). The 2-year rate of high alcohol intake was greater in the early transplantation group than the standard transplantation group (absolute difference 16·7% [95% CI 5·8–27·6]) The time spent drinking alcohol was not different between the two groups (standardised difference 0·24 [95% CI −0·07 to 0·55]), but the time spent drinking a large quantity of alcohol was higher in the early transplantation group than the standard transplantation group (standardised difference 0·50 [95% CI 0·17–0·82]). 2-year post-transplant survival was similar between the early transplantation group and the standard transplantation group (hazard ratio [HR] 0·87 [95% CI 0·33–2·26]); 2-year overall survival was higher in the early transplantation group than the not eligible for early transplantation group and historical controls (HR 0·27 [95% CI 0·16–0·47] and 0·21 [0·13–0·32]). Interpretation: We cannot conclude non-inferiority in terms of rate of alcohol relapse post-transplant between early liver transplantation and standard transplantation. High alcohol intake is more frequent after early liver transplantation. This prospective controlled study confirms the important survival benefit related to early liver transplantation for severe alcohol-related hepatitis; and this study provides objective data on survival and alcohol relapse to tailor the management of patients with severe alcohol-related hepatitis. Funding: The present study has been granted by the French Ministry of Health—Programme Hospitalier de Recherche Clinique 2010

SYNTHESIS: THE ONLINE TOOL PROVIDING EASY ACCESS AND SYSTEMATIC CROSS-CHECKING OF ALL USEFUL INFORMATION FOR AVALANCHE DANGER ASSESSMENT

International audienceHaving a clear vision of current and future snow and avalanche situation depends on a limited number of criteria widely accepted in our community. According whether it is carried out by a forecaster or a practitioner, this task nevertheless requires a significant amount of information to be cross-checked. Due to either lack of time or negligence, such a cross-checking is not systematically carried out. Here again, human factors sometimes prevail over common sense. The originality of our approach lies in the stated wish to make rational use of digital tools to automatize this task, or at least simplify it. For this reason, we have developed the SYNTHESIS tool, accessible via the www.data-avalanche.org platform. On the one hand, it provides an innovative graphical representation that overlays recent avalanche observations, snow tests results, the positions of automatic measuring stations, the danger level, and the critical slope aspects from official bulletins. On the other hand, SYNTHESIS, as suggested by the name, brings together in a single place all useful information available online: avalanche danger bulletins, slope gradients map, descriptions of recent avalanche observations as well as the map of avalanche areas' history, data from automatic measuring stations, and finally snow tests graphical representations. Such information corresponds to the six criteria of the CRISTAL approach. The objective of SYNTHESIS is not to produce an automatic avalanche danger assessment, but to simplify as much as possible data retrieving and exploitation tasks

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