Managements of recurrent hepatocellular carcinoma after liver transplantation: A systematic review

AIM: To investigate the efficacy(survival) and safety of treatments for recurrent hepatocellular carcinoma(HCC) in liver transplantation(LT) patients.METHODS: Literature search was performed on available online databases without a time limit until January 2015. Clinical studies describing survival after HCC recurrence in LT patients were retrieved for a fulltext evaluation. A total of 61 studies were selected: 13 case reports, 41 retrospective case series, and 7 retrospective comparative studies.RESULTS: Based on all included studies, the mean HCC recurrence rate was 16% of all LTs for HCC. A total of 1021 LT patients experienced HCC recurrence. The median time from LT to HCC recurrence was 13 mo(range 2-132 mo). The majority of patients(67%) presented with HCC extra-hepatic recurrences, involving lung, bone, adrenal gland, peritoneal lymph nodes, and rarely the brain. Overall survival after HCC recurrence was 12.97 mo. Surgical resection of localized HCC recurrence and Sorafenib for controlling systemic spread of HCC recurrence were associated with the higher survival rates(42 and 18 mo, res-pectively). However, Sorafenib, especially when combined with m TOR, was frequently associated with severe side effects that required dose reduction or discontinuation CONCLUSION: Management of recurrent HCC in LT patients is challenging and associated with poor prognosis independently of the type of treatment.

Endoscopic and histologic characteristics of serrated lesions

In recent years , a second pathway for colonic carcinogenesis , distinct from the adenomatous pathway, has been explored. This is referred to as serrated pathway and includes three types of polyp,characterised by a serrated appearance of the crypts:hyperplastic polyps(HP),sessile serrated adenomas(SSA)or lesions,and traditional serrated adenomas.Each lesion has its own genetic,as well as macroscopic and microscopic morphological features.Because of their flat aspect,their detection is easier with chromoendoscopy(carmin indigo or narrow-band imaging).However,as we show in this review,the distinction between SSA and HP is quite difficult.It is now recommended to resect in one piece as it is possible the serrated polyps with a control in a delay depending on the presence or not of dysplasia.These different types of lesion are described in detail in the present review in general population,in polyposis and in inflammatory bowel diseases patients.This review highlights the need to improve characterization and understanding of this way of colorectal cancerogenesis.

胰腺内分泌肿瘤:灌注CT评价的肿瘤血流反映了血管发生并与预后因素相关

目的 前瞻性评价胰腺内分泌肿瘤的多层CT灌注测定与组织学上肿瘤微血管密度的相关性，并确定不同分级的肿瘤其CT灌注参数是否有区别。方法 本研究获机构审查委员会批准和知情同意书。

Gender-related differences in irritable bowel syndrome: Potential mechanisms of sex hormones

According to epidemiological studies,twice as many women as men are affected by irritable bowel syndrome(IBS)in western countries,suggesting a role for sex hormones in IBS pathophysiology.Despite growing evidence about the implications of sex hormones in IBS symptom modulation,data on mechanisms by which they influence disease development are sparse.This review aims to determine the state of knowledge about the role of sex hormones in sensorimotor dysfunctions and to address the possible interplay of sex hormones with common risk factors associated with IBS.The scientific bibliography was searched using the following keywords:irritable bowel syndrome,sex,gender,ovarian hormone,estradiol,progesterone,testosterone,symptoms,pain,sensitivity,motility,permeability,stress,immune system,brain activity,spinal,supraspinal,imaging.Ovarian hormones variations along themenstrual cycle affect sensorimotor gastrointestinal function in both healthy and IBS populations.They can modulate pain processing by interacting with neuromodulator systems and the emotional system responsible for visceral pain perception.These hormones can also modulate the susceptibility to stress,which is a pivotal factor in IBS occurrence and symptom severity.For instance,estrogen-dependent hyper-responsiveness to stress can promote immune activation or impairments of gut barrier function.In conclusion,whereas it is important to keep in mind that ovarian hormones cannot be considered as a causal factor of IBS,they arguably modulate IBS onset and symptomatology.However,our understanding of the underlying mechanisms remains limited and studies assessing the link between IBS symptoms and ovarian hormone levels are needed to improve our knowledge of the disease evolution with regard to gender.Further studies assessing the role of male hormones are also needed to understand fully the role of sex hormones in IBS.Finally,investigation of brain-gut interactions is critical to decipher how stress,ovarian hormones,and female brain processing of pain can translate into gut dysfunctions.

Role of pro-and anti-inflammatory phenomena in the physiopathology of type 2 diabetes and obesity

In obesity, persistent low-grade inflammation is considered as a major contributor towards the progression to insulin resistance and type 2 diabetes while in lean subjects the immune environment is non-inflammatory. Massive adipose tissue(AT) infiltration by pro-inflammatory M1 macrophages and several T cell subsets as obesity develops leads to the accumulation-both in the AT and systemically-of numerous pro-inflammatory cytokines, including interleukin-1β(IL-1β), tumor necrosis factor a, IL-17 and IL-6 which are strongly associated with the progression of the obese phenotype towards the metabolic syndrome. At the same time, anti-inflammatory M2 macrophages and Th subsets producing the antiinflammatory cytokines IL-10, IL-5 and interferon-γ, including Th2 and T-reg cells are correlated to the maintenance of AT homeostasis in lean individuals. Here, we discuss the basic principles in the control of the interaction between the AT and infiltrating immune cells both in the lean and the obese condition with a special emphasis on the contribution of pro-and antiinflammatory cytokines to the establishment of the insulinresistant state. In this context, we will discuss the current knowledge about alterations in the levels on pro-and antiinflammatory cytokines in obesity, insulin resistance and type 2 diabetes mellitus, in humans and animal models. Finally, we also briefly survey the recent novel therapeutic strategies that attempt to alleviate or reverse insulin resistance and type 2 diabetes via the administration of recombinant inhibitory antibodies directed towards some pro-inflammatory cytokines.

Prevalence and virological profiles of hepatitis B infection in human immunodeficiency virus patients

AIM: To determine the prevalence of hepatitis B virus (HBV) in adult human immunodeficiency virus (HIV) patients with CD4+ T-cell count less than 500/mm 3 and without antiretroviral therapy; to describe different HBV-HIV coinfection virological profiles; and to search for factors associated with HBs antigen (HBsAg) presence in these HIV positive patients.METHODS: During four months (June through September 2006), 491 patients were received in four HIV positive monitoring clinical centers in Abidjan. Inclusion criteria: HIV-1 or HIV-1 and 2 positive patients, age ≥ 18 years, CD4+ T-cell count < 500/mL and formal and signed consent of the patient. Realized blood tests included HIV serology, CD4+ T-cell count, quantitative HIV RNA load and HBV serological markers, such as HBsAg and HBc antibody (anti-HBcAb). We performed HBeAg, anti-HBe antibody (anti-HBeAb), anti-HBc IgM and quantitative HBV DNA load in HBsAg positive patients. Anti-HBsAb had been tested in HIV patients with HBsAg negative and anti-HBcAb-positive. HBV DNA was also tested in 188 anti-HBcAb positive patients with HBsAg negative status and without anti-HBsAb. Univariate analysis (Pearsonχ 2 test or Fischer exact test) and multivariate analysis (backward step-wise selection logistic regression) were performed as statistical analysis. RESULTS: Mean age of 491 patients was 36 ± 8.68 years and 73.3% were female. Type-1 HIV was found in 97% and dual-type HIV (type 1 plus type 2) in 3%. World Health Organization (WHO) clinical stage was 1, 2, 3 and 4 respectively in 61 (12.4%), 233 (47.5%), 172 (35%) and 25 patients (5.1%). Median CD4+ T-cell count was 341/mm 3 (interquartile range: 221-470). One hundred and twelve patients had less than 200 CD4+ T-cell/mm 3 . Plasma HIV-1 RNA load was elevated (≥ 5 log 10 copies/mL) in 221 patients (45%). HBsAg and anti-HBcAb prevalence was respectively 13.4% and 72.9%. Of the 66 HBsAg positive patients, 22 were inactive HBV carriers (33.3%), 21 had HBeAg positive hepatitis (31.8%) and 20 had HBeAg negative hepatitis (30.3%). HBeAg and anti-HBeAb were indeterminate in 3 of them. Occult B infection prevalence (HBsAg negative, anti-HBcAb positive, anti-HBsAb negative and detectable HBV DNA) was 21.3%. Three parameters were significantly associated with the presence of HBsAg: male [odds ratio (OR): 2.2;P = 0.005; 95% confidence interval (CI): 1.3-3.8]; WHO stage 4 (OR: 3.2;P = 0.01;95% CI: 1.3-7.9); and aspartate aminotransferase (AST) level higher than the standard (OR: 1.9;P = 0.04; 95% CI: 1.02-3.8). CONCLUSION: HBV infection prevalence is high in HIV-positive patients. HBeAg positive chronic hepatitis and occult HBV infection are more frequent in HIVpositive patients than in HIV negative ones. Parameters associated with HBsAg positivity were male gender, AIDS status and increased AST level.

Effects of ketogenic diet and ketone bodies on the cardiovascular system:Concentration matters

Ketone bodies have emerged as central mediators of metabolic health,and multiple beneficial effects of a ketogenic diet,impacting metabolism,neuronal pathologies and,to a certain extent,tumorigenesis,have been reported both in animal models and clinical research.Ketone bodies,endogenously produced by the liver,act pleiotropically as metabolic intermediates,signaling molecules,and epigenetic modifiers.The endothelium and the vascular system are central regulators of the organism’s metabolic state and become dysfunctional in cardiovascular disease,atherosclerosis,and diabetic micro-and macrovascular complications.As physiological circulating ketone bodies can attain millimolar concentrations,the endothelium is the first-line cell lineage exposed to them.While in diabetic ketoacidosis high ketone body concentrations are detrimental to the vasculature,recent research revealed that ketone bodies in the low millimolar range may exert beneficial effects on endothelial cell(EC)functioning by modulating the EC inflammatory status,senescence,and metabolism.Here,we review the long-held evidence of detrimental cardiovascular effects of ketoacidosis as well as the more recent evidence for a positive impact of ketone bodies—at lower concentrations—on the ECs metabolism and vascular physiology and the subjacent cellular and molecular mechanisms.We also explore arising controversies in the field and discuss the importance of ketone body concentrations in relation to their effects.At low concentration,endogenously produced ketone bodies upon uptake of a ketogenic diet or supplemented ketone bodies(or their precursors)may prove beneficial to ameliorate endothelial function and,consequently,pathologies in which endothelial damage occurs.

Effects of Institut Georges Lopez-1 and Celsior preservation solutions on liver graft injury

AIM: To compare Institut Georges Lopez(IGL-1) and Celsior preservation solutions for hepatic endothelium relaxation and liver cold ischemia reperfusion injury(IRI).METHODS: Two experimental models were used.In the first one, acetylcholine-induced endotheliumdependent relaxation(EDR) was measured in isolated ring preparations of rat hepatic arteries preserved or not in IGL-1 or Celsior solutions(24 h at 4 ℃).To determine nitric oxide(NO) and cyclooxygenase EDR, hepatic arteries were incubated with L-NG-nitroarginine methyl ester(L-NAME), an inhibitor of endothelium nitric oxide synthase(e NOS), or with L-NAME plus indomethacin, an inhibitor of cyclooxygenase.In the second experiment, rat livers were cold-stored in IGL-1 or Celsior solutions for 24 h at 4 ℃ and then perfused "ex vivo " for 2 h at 37 ℃.Liver injury was assessed by transaminase measurements, liver function by bile production and bromosulfophthalein clearance, oxidative stress by malondialdehyde levels and catalase activity and alterations in cell signaling pathways by pA kt, pA MPK, eN OS and MAPKs proteins level.RESULTS: After cold storage for 24 h with either Celsior or IGL-1, EDR was only slightly altered.Infreshly isolated arteries, EDR was exclusively mediated by NO.However, cold-stored arteries showed NOand COX-dependent relaxation.The decrease in NO-dependent relaxation after cold storage was significantly more marked with Celsior.The second study indicated that IGL-1 solution obtained better liver preservation and protection against IRI than Celsior.Liver injury was reduced, function was improved and there was less oxidative stress.IGL-1 solution activated Akt and AMPK, which was concomitant with increased eN OS expression and nitrite/nitrate levels.Furthermore, MAPKs kinases were regulated in livers preserved with IGL-1 solution since reductions in p-p38, p-ERK and p-JNK protein levels were observed.CONCLUSION: IGL-1 solution preserved NO-dependent relaxation better than Celsior storage solution and enhanced liver graft preservation.

Effects of glutamine supplementation on gut barrier,glutathione content and acute phase response in malnourished rats during inflammatory shock

AIM: To evaluate the effect of glutamine on intestinal mucosa integrity,glutathione stores and acute phase response in protein-depleted rats during an inflammatory shock. METHODS: Plasma acute phase proteins (APP),jejunal APP mRNA levels,liver and jejunal glutathione concentrations were measured before and one,three and seven days after turpentine injection in 4 groups of control,protein-restricted,protein-restricted rats supplemented with glutamine or protein powder. Bacterial translocation in mesenteric lymph nodes and intestinal morphology were also assessed. RESULTS: Protein deprivation and turpentine injection significantly reduced jejunal villus height,and crypt depths. Mucosal glutathione concentration significantly decreased in protein-restricted rats. Before turpentine oil,glutamine supplementation restored villus heights and glutathione concentration (3.24 ± 1.05 vs 1.72 ± 0.46 μmol/g tissue,P < 0.05) in the jejunum,whereas in the liver glutathione remained low. Glutamine markedly increased jejunal α1-acid glycoprotein mRNA level after turpentine oil but did not affect its plasma concentration. Bacterial translocation in protein-restricted rats was not prevented by glutamine or protein powder supplementation. CONCLUSION: Glutamine restored gut glutathione stores and villus heights in malnourished rats but had no preventive effect on bacterial translocation in our model.

Pseudomonas exotoxin antisense RNA selectively kills hepatitis B virus infected cells

AIM: To present an approach for selectively killing retrovirus-infected cells that combines the toxicity of Pseudomonas exotoxin (PE) and the presence of reverse transcriptase (RT) in infected cells. METHODS: PE antisense toxin RNA has palindromic stem loops at its 5' and 3' ends enabling self-primed generation of cDNA in the presence of RT. The RT activity expressed in retrovirus-infected cells converts "antisense-toxin-RNA" into a lethal toxin gene exclusively in these cells. RESULTS: Using cotransfection studies with PE-expressing RNAs and β-gal expressing reporter plasmids, we show that, in HepG2 and HepG2.2.15 hepatoma cells as well as in duck hepatitis B virus (DHBV) infected cells, HBV or DHBV-polymerase reverse transcribe a lethal cDNA copy of an antisense toxin RNA, which is composed of sequences complementary to a PE gene and eukaryotic transcription and translation signals. CONCLUSION: This finding may have important implications as a novel therapeutic strategy aimed at the elimination of HBV infection.

Transit time ultrasound perivascular flow probe technology is superior to MR imaging on hepatic blood flow measurement in a porcine model

Background: The hepatic hemodynamics is an essential parameter in surgical planning as well as in various disease processes. The transit time ultrasound(TTUS) perivascular flow probe technology is widely used in clinical practice to evaluate the hepatic inflow, yet invasive. The phase-contrast-MRI(PC-MRI) is not invasive and potentially applicable in assessing the hepatic blood flow. In the present study, we compared the hepatic inflow rates using the PC-MRI and the TTUS probe, and evaluated their predictive value of post-hepatectomy adverse events. Methods: Eighteen large white pigs were anaesthetized for PC-MRI and approximately 75% hepatic resection was performed under a unified protocol. The blood flow was measured in the hepatic artery(Qha), the portal vein(Qpv), and the aorta above the celiac trunk(Qca) using PC-MRI, and was compared to the TTUS probe. The Bland-Altman method was conducted and a partial least squares regression(PLS) model was implemented. Results: The mean Qpv measured in PC-MRI was 0.55 ± 0.12 L/min, and in the TTUS probe was 0.74 ± 0.17 L/min. Qca was 1.40 ± 0.47 L/min in the PC-MRI and 2.00 ± 0.60 L/min in the TTUS probe. Qha was 0.17 ± 0.10 L/min in the PC-MRI, and 0.13 ± 0.06 L/min in the TTUS probe. The Bland-Altman method revealed that the estimated bias of Qca in the PC-MRI was 32%(95% CI:-49% to 15%); Qha 17%(95% CI:-15% to 51%); and Qpv 40%(95% CI:-62% to 18%). The TTUS probe had a higher weight in predicting adverse outcomes after 75% resection compared to the PC-MRI( β= 0.35 and 0.43 vs β = 0.22 and 0.07, for tissue changes and premature death, respectively). Conclusions: There is a tendency of the PC-MRI to underestimate the flow measured by the TTUS probes. The TTUS probe measures are more predictive of relevant post-hepatectomy outcomes.

N-acetylcysteine and glycyrrhizin combination:Benefit outcome in a murine model of acetaminophen-induced liver failure

BACKGROUND Acetaminophen overdose is the most frequent cause of drug-induced liver failure in developed countries.Substantial progress has been made in understanding the mechanism of hepatocellular injury,but N-acetylcysteine remains the only effective treatment despite its short therapeutic window.Thus,other hepatoprotective drugs are needed for the delayed treatment of acetaminopheninduced hepatotoxicity.Our interest focused on glycyrrhizin for its role as an inhibitor of high mobility group box 1(HMGB1)protein,a member of the family of damage-associated molecular pattern,known to play an important pathological role in various diseases.AIM To investigate the efficacy of the N-acetylcysteine/glycyrrhizin combination compared to N-acetylcysteine alone in the prevention of liver toxicity.METHODS Eight-week-old C57BL/6J wild-type female mice were used for all our experiments.Mice fasted for 15 h were treated with acetaminophen(500 mg/kg)or vehicle(phosphate-buffered saline)by intraperitoneal injection and separated into the following groups:Glycyrrhizin(200 mg/kg);N-acetylcysteine(150 mg/kg);and N-acetylcysteine/glycyrrhizin.In all groups,mice were sacrificed 12 h following acetaminophen administration.The assessment of hepatotoxicity was performed by measuring plasma levels of alanine aminotransferase,aspartate aminotransferase and lactate dehydrogenase.Hepatotoxicity was also evaluated by histological examination of hematoxylin and eosin-stained tissues sections.Survival rates were compared between various groups using Kaplan-Meier curves.RESULTS Consistent with data published in the literature,we confirmed that intraperitoneal administration of acetaminophen(500 mg/kg)in mice induced severe liver injury as evidenced by increases in alanine aminotransferase,aspartate aminotransferase and lactate dehydrogenase but also by liver necrosis score.Glycyrrhizin administration was shown to reduce the release of HMGB1 and significantly decreased the severity of liver injury.Thus,the co-administration of glycyrrhizin and N-acetylcysteine was investigated.Administered concomitantly with acetaminophen,the combination significantly reduced the severity of liver injury.Delayed administration of the combination of drugs,2 h or 6 h after acetaminophen,also induced a significant decrease in hepatocyte necrosis compared to mice treated with N-acetylcysteine alone.In addition,administration of N-acetylcysteine/glycyrrhizin combination was associated with an improved survival rate compared to mice treated with only N-acetylcysteine.CONCLUSION We demonstrate that,compared to N-acetylcysteine alone,co-administration of glycyrrhizin decreases the liver necrosis score and improves survival in a murine model of acetaminophen-induced liver injury.Our study opens a potential new therapeutic pathway in the prevention of acetaminophen hepatotoxicity.

Predictors of Clostridium difficile infection severity in patients hospitalised in medical intensive care

AIM:To describe and analyse factors associated with Clostridium difficile infection(CDI)severity in hospitalised medical intensive care unit patients.METHODS:We performed a retrospective cohort study of 40 patients with CDI in a medical intensive care unit(MICU)at a French university hospital.We include patients hospitalised between January 1,2007and December 31,2011.Data on demographics characteristics,past medical history,CDI description was collected.Exposure to risk factors associated with CDI within 8 wk before CDI was recorded,including previous hospitalisation,nursing home residency,antibiotics,antisecretory drugs,and surgical procedures.RESULTS:All included cases had their first episode of CDI.The mean incidence rate was 12.94 cases/1000admitted patients,and 14.93,8.52,13.24,19.70,and8.31 respectively per 1000 admitted patients annually from 2007 to 2011.Median age was 62.9[interquartile range(IQR)55.4-72.40]years,and 13(32.5%)were women.Median length of MICU stay was 14.0d(IQR 5.0-22.8).In addition to diarrhoea,the clinical symptoms of CDI were fever(>38℃)in 23 patients,abdominal pain in 15 patients,and ileus in 1 patient.The duration of diarrhoea was 13.0(8.0-19.5)d.In addition to diarrhoea,the clinical symptoms of CDI were fever(>38℃)in 23 patients,abdominal pain in 15 patients,and ileus in 1 patient.Prior to CDI,38patients(95.0%)were exposed to antibiotics,and 12(30%)received at least 4 antibiotics.Fluoroquinolones,3rdgeneration cephalosporins,coamoxiclav and tazocillin were prescribed most frequently(65%,55%,40%and 37.5%,respectively).The majority of cases were hospital-acquired(n=36,90%),with 5 cases(13.9%)being MICU-acquired.Fifteen patients had severe CDI.The crude mortality rate within 30 d after diagnosis was 40%(n=16),with 9 deaths(9 over 16;56.3%)related to CDI.Of our 40 patients,15(37.5%)had severe CDI.Multivariate logistic regression showed that male gender[odds ratio(OR):8.45;95%CI:1.06-67.16,P=0.044],rising serum C-reactive protein levels(OR=1.11;95%CI:1.02-1.21,P=0.021),and previous exposure to fluoroquinolones(OR=9.29;95%CI:1.16-74.284,P=0.036)were independently associated with severe CDI.CONCLUSION:We report predictors of severe CDI not dependent on time of assessment.Such factors could help in the development of a quantitative score in ICU’s patients.

Genome-wide differences in hepatitis C-vs alcoholism-associated hepatocellular carcinoma

AIM:To look at a comprehensive picture of etiology- dependent gene abnormalities in hepatocellular carcinoma in Western Europe. METHODS:With a liver-oriented microarray,transcript levels were compared in nodules and cirrhosis from a training set of patients with hepatocellular carcinoma (alcoholism,12;hepatitis C,10)and 5 controls.Loose or tight selection of informative transcripts with an abnormal abundance was statistically valid and the tightly selected transcripts were next quantified by qRTPCR in the nodules from our training set(12+10) and a test set(6+7). RESULTS:A selection of 475 transcripts pointed to significant gene over-representation on chromosome 8 (alcoholism)or-2(hepatitis C)and ontology indicated a predominant inflammatory response(alcoholism)or changes in cell cycle regulation,transcription factors and interferon responsiveness(hepatitis C).A stringent selection of 23 transcripts whose differences betweenetiologies were significant in nodules but not in cirrhotic tissue indicated that the above dysregulations take place in tumor but not in the surrounding cirrhosis.These 23 transcripts separated our test set according to etiologies. The inflammation-associated transcripts pointed to limited alterations of free iron metabolism in alcoholic vs hepatitis C tumors. CONCLUSION:Etiology-specific abnormalities(chromo- some preference;differences in transcriptomes and related functions)have been identified in hepatocellular carcinoma driven by alcoholism or hepatitis C.This may open novel avenues for differential therapies in this disease.

Differences and similarities between mesenchymal stem cell and endothelial progenitor cell immunoregulatory properties against T cells

Bone-marrow-derived mesenchymal stem cells and endothelial progenitor cells have some interesting biological properties that make them unique for cell therapy of degenerative and cardiovascular disorders.Although both cell populations have been already studied and used for their regenerative potentials,recently their special immunoregulatory features have brought much more attention.Mesenchymal stem cells and endothelial progenitor cells have both proangiogenic functions and have been shown to suppress the immune response,particularly T cell proliferation,activation,and cytokine production.This makes them suitable choices for allogeneic stem cell transplantation.Nevertheless,these two cells do not have equal immunoregulatory activities.Many elements including their extraction sources,age/passage,expression of different markers,secretion of bioactive mediators,and some others could change the efficiency of their immunosuppressive function.However,to our knowledge,no publication has yet compared mesenchymal stem cells and endothelial progenitor cells for their immunological interaction with T cells.This review aims to specifically compare the immunoregulatory effect of these two populations including their T cell suppression,deactivation,cytokine production,and regulatory T cells induction capacities.Moreover,it evaluates the implications of the tumor necrosis factor alpha-tumor necrosis factor receptor 2 axis as an emerging immune checkpoint signaling pathway controlling most of their immunological properties.

Transient and etiology-related transcription regulation in cirrhosis prior to hepatocellular carcinoma occurrence

AIM:To search for transcription dysregulation that could(1) differentiate hepatocellular carcinoma(HCC)-free from HCC-related cirrhosis(2) differentiate HCC-free cirrhosis related to HCV from that related to alcohol intake.METHODS:Using microarray analysis,we compared transcript levels in HCC-free cirrhosis(alcoholism:7;hepatitis C:7),HCC-associated cirrhosis(alcoholism:10;hepatitis C:10) and eight control livers.The identified transcripts were validated by qRT-PCR in an independent cohort of 45 samples(20 HCC-free cirrhosis;15 HCC-associated cirrhosis and 10 control livers).We also confirmed our results by immunohistochemistry.transcripts which differentiated between alcoholic-related cirrhosis,HCV-related cirrhosis and control livers.They mainly corresponded to down-regulation.Dysregulation of Signal Transduction and Activator of Transcription-3(STAT-3) was found along with related changes in STAT-3 targets which occurred in an etiology-dependent fashion in HCC-free cirrhosis.In contrast,in HCC,such transcription dysregulations were not observed.CONCLUSION:We report that transcriptional dysregulations exist in HCC-free cirrhosis,are transiently observed prior to detectable HCC onset and may be appear like markers from cirrhosis to HCC transition.

肝硬化:体素不相干运动的MR成像——初步研究

目的 回顾性评价并行采集呼吸门控扩散加权MR成像序列允许计算的基于纯分子（D）和灌注相关（D＊，f）的扩散参数，在体素不相干运动（IVIM）理论基础上，判断这些参数在肝硬化病人及无肝纤维化病人间是否不同。材料与方法 本回顾性研究经机构审查委员会同意并免除知情同意。IVIM扩散加权成像经三烷模型测试，

PI3K/SHIP2/PTEN pathway in cell polarity and hepatitis C virus pathogenesis

Hepatitis C virus(HCV) infects hepatocytes, polarized cells in the liver. Chronic HCV infection often leads to steatosis, fibrosis, cirrhosis and hepatocellular carcinoma, and it has been identified as the leading cause of liver transplantation worldwide. The HCV replication cycle is dependent on lipid metabolism and particularly an accumulation of lipid droplets in host cells. Phosphoinositides(PIs) are minor phospholipids enriched in different membranes and their levels are tightly regulated by specific PI kinases and phosphatases. PIs are implicated in a vast array of cellular responses that are central to morphogenesis, such as cytoskeletal changes, cytokinesis and the recruitment of downstream effectors to govern mechanisms involved in polarization and lumen formation. Important reviews of the literature identified phosphatidylinositol(Ptd Ins) 4-kinases, and their lipid products Ptd Ins(4)P, as critical regulators of the HCV life cycle. SH2-containing inositol polyphosphate 5-phosphatase(SHIP2), phosphoinositide 3-kinase(PI3K) and their lipid products Ptd Ins(3,4)P2 and Ptd Ins(3,4,5)P3, respectively, play an important role in the cell membrane and are key to the establishment of apicobasal polarity and lumen formation. In this review, we will focus on these new functions of PI3 K and SHIP2, and their deregulation by HCV, causing a disruption of apicobasal polarity, actin organization and extracellular matrix assembly. Finally we will highlight the involvement of this pathway in the event of insulin resistance and nonalcoholic fatty liver disease related to HCV infection.

Inverted Apical CD24 and Weak EZH2 Expressions Are Phenotypic Characteristics of Pure Invasive Micropapillary Carcinoma of the Breast

Invasive micropapillary carcinomas (IMPC) of the breast account for less than 2% of all breast cancers and have been recently described as luminal B carcinomas. CD24, CD44, ALDH1 and EZH2 are commonly used as stem-cell markers that display differential expression as a function of stage and molecular type, but their pattern of expression according to this rare histological type remains poorly defined and unknown for EZH2. We assessed expression of these markers in a series of 28 micropapillary breast carcinomas and compared the results with those obtained in a series of luminal A (27 cases) and B (34 cases) invasive carcinomas not otherwise specified (IC-NST). CD24 and CD44 were expressed in most cases. However, CD24 was expressed at the inverted apical membrane in 85% of invasive micropapillary carcinoma and at the apical pole of gland-forming cells in 45% of luminal A (p-val = 6.8 × 10-4) and 13% of luminal B cases (p-val = 1.1 × 10-7). ALDH1 was expressed in the stroma in most tumors, but in only 25%, 11% and 15% in epithelial cells of IMPC, luminal A and B IC-NST, respectively. Nuclear expression of EZH2 was not observed in luminal A tumors, and was detected in 35% (12/34) of luminal B carcinomas (p-val = 6.1 × 10-3) and only 4% (1/28) of invasive micropapillary carcinomas. This series shows that invasive micropapillary carcinomas harbor a CD24-positive inverted apical pole associated with weak EZH2 expression, phenotypical characteristics that distinguish this entity from other luminal carcinomas.

Predictive factors for survival and score application in liver retransplantation for hepatitis C recurrence

AIM: To identify risk factors associated with survival in patients retransplanted for hepatitis C virus(HCV) recurrence and to apply a survival score to this population.METHODS: We retrospectively identified 108 patients retransplanted for HCV recurrence in eight European liver transplantation centers(seven in France, one in Spain). Data collection comprised clinical and laboratory variables, including virological and antiviral treatment data. We then analyzed the factors associated with survival in this population. A recently published score that predicts survival in retransplantation in patients with hepatitis C was applied. Because there are currently no uniform recommendations regarding selection of the best candidates for retransplantation in this setting, we also described the clinical characteristics of 164 patients not retransplanted, with F3, F4, or fibrosing cholestatic hepatitis(FCH) post-first graft presenting with hepatic decompensation. RESULTS: Overall retransplantation patient survival rates were 55%, 47%, and 43% at 3, 5, and 10 years, respectively. Patients who were retransplanted for advanced cirrhosis had survival rates of 59%, 52%, and 49% at 3, 5, and 10 years, while those retransplanted for FCH had survival rates of 34%, 29%, and 11%, respectively. Under multivariate analysis, and adjusting for the center effect and the occurrence of FCH, factors associated with better survival after retransplantation were: negative HCV viremia before retransplantation, antiviral therapy after retransplantation, non-genotype 1, a Model for End-stage Liver Disease(MELD) score < 25 when replaced on the waiting list, and a retransplantation donor age < 60 years. Although the numbers were small, in the context of the new antivirals era, we showed that outcomes in patientswho underwent retransplantation with undetectable HCV viremia did not depend on donor age and MELD score. The Andrés score was applied to 102 patients for whom all score variables were available, producing a mean score of 43.4(SD = 6.6). Survival rates after the date of the first decompensation post-first liver transplantation(LT1) in the liver retransplantation(re LT) group(94 patients decompensated) at 3, 5, and 10 years were 62%, 59%, and 51%, respectively, among 78 retransplanted individuals with advanced cirrhosis, and 42%, 32%, and 16% among 16 retransplanted individuals with FCH. In the non-re LT group with hepatic decompensation, survival rates were 27%, 18%, and 9% at 3, 5, and 10 years, respectively(P < 0.0001). Compared with non-retransplanted patients, retransplanted patients were younger at LT1(mean age 48 ± 8 years compared to 53 ± 9 years in the no re LT group, P < 0.0001), less likely to have human immunodeficiency virus(HIV) co-infection(4% vs 14% among no re LT patients, P = 0.005), more likely to have received corticosteroid bolus therapy after LT1(25% in re LT vs 12% in the no re LT group, P = 0.01), and more likely to have presented with sustained virological response(SVR) after the first transplantation(20% in the re LT group vs 7% in the no re LT group, P = 0.028).CONCLUSION: Antiviral therapy before and after retransplantation had a substantial impact on survival in the context of retransplantation for HCV recurrence, and with the new direct-acting antivirals now available, outcomes should be even better in the future.