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Background : Percutaneous radiofrequency ablation (RFA) is one of the main treatments of small hepatocellular carcinoma (HCC). However, it remains unclear whether this local treatment can induce systemic immune variations. Methods : We conducted a prospective study in a tertiary center including consecutive cirrhotic patients with unifocal HCC<5 cm treated by a first RFA between 2010 and 2014. Peripheral blood mononuclear cells were isolated on the day before (D0), day after (D1) and month after RFA (M1). Frequencies and phenotypes of myeloid cells, T cells, and NK cells were compared between timepoints. Overall recurrence and associated variables were estimated using Kaplan-Meier, log-rank and Cox proportional-hazards models. Results : 80 patients were included (69% male, median age: 67 years old). Main aetiologies of HCC were alcohol (51%), hepatitis C virus (45%), non-alcoholic steatohepatitis (36%) and hepatitis B virus (9%). Median overall survival was 55 months (M); median progression-free survival was 29.5M. Among innate immune populations, we observed variations between D0, D1 and M1 in NKp30+ NK cells (p < .0001) and in plasmacytoid dendritic cells (pDC, p < .01). Concerning adaptive immunity, we observed variations in CD8 Central Memory (p < .05) and CD28+ CD8 Central Memory (p < .01). An early dynamic (D0/D1) of activated NKp30 + NK cells was associated with a decreased overall recurrence (log-rank, p = .016, median delay 25.1 vs 40.6 months). In contrast, a late dynamic (D1/M1) of immature NK cells (CD56 bright ) and altered myeloid DC (PDL1 + ) was associated with an increased overall recurrence (log-rank, p = .011 and p = .0044, respectively). In multivariate analysis, variation of immature NK cells predicts tumor recurrence independently of classical clinical prognostic features (HR = 2.41, 95% CI: 1.15-5.057), p = .019). Conclusions : Percutaneous RFA of small HCC leads to systemic modifications of innate and adaptive immunity closely linked with overall tumor recurrence.

Background & Aims: We investigated the effectiveness of the protease inhibitors peginterferon and ribavirin in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis., Methods: In the Compassionate Use of Protease Inhibitors in Viral C Cirrhosis study, 511 patients with HCV genotype 1 infection and compensated cirrhosis who did not respond to a prior course of peginterferon and ribavirin (44.3% relapsers or patients with viral breakthrough, 44.8% partial responders, and 8.0% null responders) were given either telaprevir (n = 299) or boceprevir (n = 212) for 48 weeks. We assessed percentages of patients with sustained viral responses 12 weeks after therapy and safety. This observational study did not allow for direct comparison of the 2 regimens., Results: Among patients given telaprevir, 74.2% of relapsers, 40.0% of partial responders, and 19.4% of null responders achieved SVR12. Among those given boceprevir, 53.9% of relapsers, 38.3% of partial responders, and none of the null responders achieved SVR12. In multivariate analysis, factors associated with SVR12 included prior response to treatment response, no lead-in phase, HCV subtype 1b (vs 1a), and baseline platelet count greater than 100,000/mm(3). Severe adverse events occurred in 49.9% of cases, including liver decompensation, severe infections in 10.4%, and death in 2.2%. In multivariate analysis, baseline serum albumin level less than 35 g/L and baseline platelet counts of 100,000/mm(3) or less predicted severe side effects or death., Conclusions: Relatively high percentages of real-life, treatment-experienced patients with HCV genotype 1 infection and cirrhosis respond to the combination of peginterferon and ribavirin with telaprevir or boceprevir. However, side effects are frequent and often severe. Baseline levels of albumin and platelet counts can be used to guide treatment decisions. ClinicalTrials.gov number: NCT01514890., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: In phase III trials, the safety profile of triple therapy (pegylated interferon/ribavirin with boceprevir or telaprevir) seems to be similar in HCV treatment-experienced cirrhotic and non-cirrhotic patients, but few cirrhotics were included. We report the week 16 safety and efficacy analysis in a cohort of compensated cirrhotics treated in the French Early Access Programme., Methods: 674 genotype 1 patients, prospectively included, received 48 weeks of triple therapy. The analysis is restricted to 497 patients reaching week 16., Results: A high incidence of serious adverse events (40.0%), and of death and severe complications (severe infection or hepatic decompensation) (6.4%), and a difficult management of anaemia (erythropoietin and transfusion use in 50.7% and 12.1%) were observed. Independent predictors of anaemia < 8 g/dl or blood transfusion were: female gender (OR 2.19, 95% CI 1.11-4.33, p=0.024), no lead-in phase (OR 2.25, 95% CI 1.15-4.39, p=0.018), age ≥ 65 years (OR 3.04, 95% CI 1.54-6.02, p=0.0014), haemoglobin level (≤ 12 g/dl for females, ≤ 13 g/dl for males) (OR 5.30, 95% CI 2.49-11.5, p=0.0001). Death or severe complications were related to platelets count ≤ 100,000/mm(3) (OR 3.11, 95% CI 1.30-7.41, p=0.0105) and albumin <35 g/dl (OR 6.33, 95% CI 2.66-15.07, p=0.0001), with a risk of 44.1% in patients with both. However, the on-treatment virological response was high., Conclusions: The safety profile was poor and patients with platelet count ≤ 100,000/mm(3) and serum albumin <35 g/L should not be treated with the triple therapy., (Copyright © 2013. Published by Elsevier B.V.)

Background/aim: Peripheral intrahepatic cholangiocarcinoma (ICC) occurring mainly in the absence of cirrhosis represents an increasing subgroup of primary liver tumors in Western countries. Histopathologic changes in the non-neoplastic liver in this context are not well characterized., Patients and Methods: We assessed the clinical characteristics and histopathologic changes in the distant nontumoral liver of 57 consecutive White patients (34 men, mean age 59 years) referred to one medical and one surgical liver institution over a 16-year period who developed a peripheral ICC in the absence of cirrhosis or bile duct disease., Results: High alcohol consumption was observed in 11 patients (20%), 38 patients (66%) had a BMI of 25 kg/m or more, 22 patients (40%) had diabetes, two patients had hepatitis B virus infection, two others had hepatitis C virus infection, three patients had genetic hemochromatosis, and two patients had cutaneous porphyria tarda. The distant nontumoral liver was normal in 10 patients (18%). The two main histopathologic changes observed were macrovesicular steatosis (>10% of hepatocytes) in 38 patients (66%), including 11 patients (19%) with steatohepatitis, and moderate or intense hepatocyte iron overload in 22 patients (38%)., Conclusion: This study shows a high prevalence of macrovesicular steatosis associated or not with steatohepatitis and iron overload in patients who develop peripheral ICC in the absence of cirrhosis or bile duct disease.

Unlabelled: Propranolol bears antioxidant, anti-inflammatory, and antiangiogenic properties and antitumoral effects and therefore is potentially active in the prevention of hepatocellular carcinoma (HCC). We retrospectively assessed the impact of propranolol treatment on HCC occurrence in a cohort of 291 patients with compensated viral C (HCV) cirrhosis, prospectively followed and screened for HCC detection. Of the 291 patients included in the cohort, 93 patients [50 males: mean age, 59.5 ± 12 years; body mass index (BMI), 25.7 ± 4.4 kg/m(2); and platelet count, 111 ± 53 Giga/L] developed esophageal varices (OV) or had OV at inclusion and 198 patients (111 males: mean age, 55.8 ± 13 years; BMI, 25.7 ± 5 kg/m(2); platelet count, 137 ± 59 Giga/L) did not. Among patients with OV, 50 received treatment by propranolol. During a median follow-up of 54 months interquartile range (32-82), 61 patients developed an HCC. The 3- and 5-year HCC incidence was 4% and 4%, and 10% and 20% for patients treated and not treated by propranolol, respectively (Gray test, P = 0.03). In multivariate analysis, propranolol treatment was associated with a decrease risk of HCC occurrence [HR, 0.25; 95% confidence interval (CI), 0.09-0.65; P = 0.004], and was the only independent predictive factor of HCC occurrence in patients with OV (HR, 0.16; CI, 0.06-0.45; P = 0.0005). The benefit of propranolol was further supported by propensity scores analyses., Conclusion: This retrospective long-term observational study suggests that propranolol treatment may decrease HCC occurrence in patients with HCV cirrhosis. These findings need to be verified by prospective clinical trial.

Background & Aims: Genetic dimorphisms modulate the activities of several pro- or antioxidant enzymes, including myeloperoxidase (MPO), catalase (CAT), manganese superoxide dismutase (SOD2), and glutathione peroxidase 1 (GPx1). We assessed the role of the G(-463)A-MPO, T(-262)C-CAT, Ala16Val-SOD2, and Pro198Leu-GPx1 variants in modulating HCC development in patients with HCV-induced cirrhosis., Methods: Two hundred and five patients with HCV-induced, biopsy-proven cirrhosis but without detectable HCC at inclusion were prospectively followed-up for HCC development. The influence of various genotypes on HCC occurrence was assessed with the Kaplan-Meier method., Results: During follow-up (103.2±3.4 months), 84 patients (41%) developed HCC, and 66 died. Whereas the Ala16Val-SOD2 or Pro198Leu-GPx1 dimorphisms did not modulate the risk, HCC occurrence was increased in patients with either the homozygous GG-MPO genotype (HR=2.8 [1.7-4.4]; first quartile time to HCC occurrence: 45 vs. 96 months; LogRank <0.0001) or the homozygous CC-CAT genotype (HR=1.74 [1.06-2.82]; first quartile time to HCC occurrence: 55 vs. 96 months; LogRank=0.02). Compared to patients with neither of these two at risk factors, patients with only the CC-CAT genotype had a HR of 2.05 [0.9-4.6] (p=0.08) and patients with only the GG-MPO genotype had a HR of 3.8 [1.5-9.1] (p=0.002), while patients with both risk factors had an HR of 4.8 [2.2-10.4] (p<0.0001). However, only the GG-MPO genotype was independently associated with the HCC risk in multivariate Cox analysis., Conclusions: The high activity-associated GG-MPO genotype increases the rate of HCC occurrence in patients with HCV-induced cirrhosis., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Context: Insulin resistance plays a role in hepatocarcinogenesis and is decreased by metformin treatment., Objective: The aim of the study was to assess the influence of metformin treatment on the prognosis of compensated hepatitis C virus (HCV) cirrhosis in patients with type 2 diabetes., Design and Setting: We studied an observational prospective cohort (1988-2007) at a university hospital referral center., Patients: A total of 100 consecutive diabetic patients (53 men, age 61 ± 11 yr) with ongoing HCV cirrhosis and no contraindication for metformin were included in a screening program for hepatocellular carcinoma (HCC)., Main Outcomes: The patients were prospectively followed up for HCC incidence, liver-related death, or hepatic transplantation., Results: The level of platelet count was significantly lower in patients treated with metformin (n = 26) compared with those not treated with metformin (n = 74) [117 (interquartile range, 83-166) vs. 149 (105-192) Giga/liter, P = 0.045]. During a median follow-up of 5.7 (3.8-9.5) yr, one patient was lost to follow-up, 39 developed a HCC, and 33 died from liver causes or were transplanted. The 5-yr incidence of HCC was 9.5 and 31.2% (P = 0.001) and of liver-related death/transplantation, 5.9 and 17.4% (P = 0.013), in patients who received metformin treatment and in those who did not, respectively. In multivariate analysis, metformin treatment was independently associated with a decrease in HCC occurrence [hazard ratio, 0.19 (95% confidence interval, 0.04-0.79); P = 0.023] and liver-related death or transplantation [hazard ratio, 0.22 (95% confidence interval, 0.05-0.99); P = 0.049]., Conclusions: In patients with type 2 diabetes and HCV cirrhosis, use of metformin is independently associated with reduced incidence of HCC and liver-related death/transplantation.

Background & Aims: Mechanisms linking obesity and unfavourable outcomes in patients with viral hepatitis C (HCV) cirrhosis are not well understood. Obesity is associated with insulin resistance, increased leptin, and decreased adiponectin serum levels., Methods: We assessed the predictive value of those factors for the occurrence of hepatocellular carcinoma (HCC) and liver-related death or transplantation in a cohort of 248 patients (mean age 58 (12 years, BMI 25.4 ± 4.4 kg/m(2)) with compensated HCV cirrhosis and persistent infection prospectively followed and screened for HCC., Results: The mean baseline serum levels of adiponectin and leptin were 16.8 ± 15 mg/L and 16.8 ± 19 ng/ml, respectively. The mean homeostasis model assessment of insulin resistance (HOMA) index was 3.8 ± 3; median 2.9. After a median follow-up of 72 months, 61 patients developed HCC, 58 died of liver causes, and 17 were transplanted. The incidences (Kaplan Meier) of HCC were 7%, 18%, and 27% at 5 years (p=0.017) and of liver-related death or transplantation 15%, 15% and 29% (p=0.002) according to the lowest, middle and highest tertile of HOMA, respectively. In multivariate analysis, the HOMA index was associated with HCC occurrence (HR=1.10, [1.01-1.21] p=0.026) and was a strong predictor of liver-related death or transplantation (HR=1.13, [1.07-1.21] p<0.0001). Serum levels of adiponectin and leptin were not associated with the outcome., Conclusions: In patients with compensated HCV cirrhosis, insulin resistance but not serum levels of adiponectin and leptin predicted the occurrence of HCC and of liver-related death or transplantation., (Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Unlabelled: Alcohol increases reactive oxygen species (ROS) formation in hepatocyte mitochondria and by reduced nicotinamide adenine dinucleotide phosphate oxidases and myeloperoxidase (MPO) in Kupffer cells and liver-infiltrating neutrophils. Manganese superoxide dismutase (MnSOD) converts superoxide anion into hydrogen peroxide, which, unless detoxified by glutathione peroxidase or catalase (CAT), can form the hydroxyl radical with iron. Our aim was to determine whether Ala16Val-superoxide dismutase 2 (SOD2), G-463A-MPO, or T-262C-CAT dimorphisms modulate the risks of hepatocellular carcinoma (HCC) and death in alcoholic cirrhosis. Genotypes and the hepatic iron score were assessed in 190 prospectively followed patients with alcoholic cirrhosis. During follow-up (61.1 +/- 2.7 months), 51 patients developed HCC, and 71 died. The T-262C-CAT dimorphism did not modify hepatic iron, HCC, or death. The GG-MPO genotype did not modify iron but increased the risks of HCC and death. The hazard ratio (HR) was 4.7 (2.1-10.1) for HCC and 3.6 (1.9-6.7) for death. Carriage of one or two Ala-SOD2 allele(s) was associated with higher liver iron scores and higher risks of HCC and death. The 5-year incidence of HCC was 34.4% in patients with both the GG-MPO genotype and one or two Ala-SOD2 alleles, 5.1% in patients with only one of these two traits, and 0% in patients with none of these traits. Corresponding 5-year death rates were 37.6%, 11.6%, and 5%., Conclusion: The combination of the GG-MPO genotype (leading to high MPO expression) and at least one Ala-SOD2 allele (associated with high liver iron score) markedly increased the risks of HCC occurrence and death in patients with alcoholic cirrhosis.

Aim: To assess the long-term clinical benefit of sustained virological response (SVR) in patients with hepatitis C virus (HCV) cirrhosis treated by antiviral therapy using mostly ribavirin plus interferon either standard or pegylated., Methods: One hundred and thirteen patients with uncomplicated HCV biopsy-proven cirrhosis, treated by at least one course of antiviral treatment > or = 3 mo and followed > or = 30 mo were included. The occurrence of linical events [hepatocellular carcinoma (HCC), decompensation and death] was compared in SVR and non SVR patients., Results: Seventy eight patients received bitherapy and 63 had repeat treatments. SVR was achieved in 37 patients (33%). During a mean follow-up of 7.7 years, clinical events occurred more frequently in non SVR than in SVR patients, with a significant difference for HCC (24/76 vs 1/37, P = 0.01). No SVR patient died while 20/76 non-SVR did (P = 0.002), mainly in relation to HCC (45%)., Conclusion: In patients with HCV-related cirrhosis, SVR is associated with a significant decrease in the incidence of HCC and mortality during a follow-up period of 7.7 years. This result is a strong argument to perform and repeat antiviral treatments in patients with compensated cirrhosis.

Objectives: The goal of this study was to estimate the additional value of liver stiffness measurement (LSM) with physicians' assessment of fibrosis based on epidemiological, clinical, and biological parameters., Methods: One hundred forty-two unselected patients with chronic hepatitis C were included. Liver biopsy and LSM were performed simultaneously. First, four physicians (two junior residents with limited experience in hepatology and two senior hepatologists) independently predicted the stage of fibrosis according to the METAVIR classification, using clinical, epidemiological, and biological data. For the second step, they were informed of LSM values and could modify their first evaluation if necessary. Finally, the two successive evaluations were compared with the histological fibrosis score., Results: Providing LSM values improved agreement between physicians and resulted in a better correlation between clinical impression and histological liver fibrosis. The diagnostic performances were only significantly improved with transient elastography for the diagnosis of cirrhosis where assessment improved in three of the four physicians (AUROC [area under receiver operating characteristic curve]: 0.76 vs 0.87, 0.80 vs 0.87, and 0.83 vs 0.89, all p < 0.05). Moreover, these performances were nearly similar for junior and senior physicians when LSM was provided with the AUROC ranging from 0.69 to 0.72 for significant fibrosis and 0.87 to 0.90 for cirrhosis., Conclusions: Providing LSM values to physicians results in a better estimation of liver fibrosis and a more accurate diagnosis of cirrhosis. Moreover, it allows physicians with limited experience to predict liver fibrosis as well as experienced hepatologists.

Background & Aims: Influence of being overweight and diabetes mellitus on the occurrence of hepatocellular carcinoma (HCC) in patients with cirrhosis has not been evaluated prospectively. The aim of this study was to show the predictive value of these factors in a cohort of 771 patients with well-compensated alcohol- or hepatitis C (HCV)-related cirrhosis who were screened prospectively for HCC., Methods: The predictive value for HCC occurrence was assessed by using the log-rank test and the Cox proportional hazards model. At enrollment, the mean age was 61.4 +/- 10 years and 431 patients were men. Cirrhosis was caused by alcohol (n = 478), HCV (n = 220), or the association of both factors (n = 73). The mean body mass index (BMI) was 25.4 kg/m(2) and 231 patients were diabetic., Results: During a mean follow-up period of 4.2 +/- 3 years, 220 patients developed HCC. In univariate analysis, a BMI of 25 kg/m(2) or more, diabetes, male sex, age older than 60 years, and HCV infection were risk factors for HCC. In multivariate analysis, predictive factors were a BMI between 25-30 kg/m(2) (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.4-2.7), BMI of 30 kg/m(2) or more (HR, 2.8; 95% CI, 2.0-4.0), diabetes (HR, 1.6; 95% CI, 1.2-2.1), age 60-70 years (HR, 2.4; 95% CI, 1.3-4.3), age older than 70 years (HR, 3.0; 95% CI, 1.7-5.5), male sex (HR, 2.0; 95% CI, 1.4-2.7), HCV (HR, 1.6; 95% CI, 1.1-2.2), and mixed (HR, 2.6; 95% CI, 1.7-4.0) etiology. We found a positive linear relationship between BMI level and HCC incidence during follow-up evaluation., Conclusions: Overweight and diabetes mellitus are associated with an increased risk of HCC occurrence in patients with HCV- or alcohol-related cirrhosis.

Chronic liver diseases complications generally occur when fibrosis progresses to cirrhosis. It is recognised that some patients do not progress while others develop significant fibrosis. Factors influencing the fibrosis progression rate are especially studied in chronic hepatitis C. Among many identified factors, the most important are those warranted a medical action such as alcohol consumption, obesity, other metabolic disorders and immunosuppression in case of HIV-HCV coinfection. Especially, in case of chronic liver disease, regular alcohol consumption should be avoided; overweight and metabolic disorders should be controlled. The control of liver damage aetiologies could decrease or even stop fibrosis progression.

Background: Although partial splenic embolization (PSE) has been proposed in patients with cirrhosis in cases when thrombocytopenia or neutropenia may cause clinical manifestations or if there are contra-indications to other therapeutic procedures, there are limited data on long-term outcome. We provide a retrospective review of results and the tolerance of all PSE procedures in patients with cirrhosis in our department., Patients and Methods: Thirty-two consecutive patients with cirrhosis were included over a 6 year period. Indications for PSE were as follows: (1) severe cytopenia preventing necessary antiviral treatment (n=14), percutaneous destruction of hepatocellular carcinoma (n=8) or major surgery (n=3), severe purpura (n=3); (2) painful splenomegaly (n=4). After superselective catheterization, embolization was performed with up to 50% reduction of splenic blood flow., Results: Thrombocyte and leucocyte counts increased markedly (185% and 51% at 1 month; 95% and 30% at 6 months). Thirty-one and 20 patients had platelet count >80,000/mm3 at months 1 and 6 vs only one before PSE. Overall, the aim of PSE was achieved in 27 patients (84%) (planned treatment: 20/25; disappearance of purpura and splenic pain: 7/7). Severe complications occurred in five patients (16%): transient ascites (n=2), splenic and/or portal vein thrombosis (n=2) that resolved after anticoagulation therapy, and splenic abscess (n=2) leading to death. These two patients had splenic necrosis >70%., Conclusion: In patients with cirrhosis, PSE may resolve cytopenia and the clinical complications related to hypersplenism or splenomegaly. However, due to a high risk of severe complications, particularly splenic abscess, the indications of PSE should be very limited and the extent of necrosis should be strictly controlled during the PSE procedure.

Aim: To investigate the feasibility and efficacy of hepatitis C virus screening in drug users in an addiction out-patient unit., Patients and Methods: All patients followed in an addiction out-patient unit were asked to undergo anti-hepatitis C virus antibody testing; further evaluation and treatment if indicated, were offered to positive patients. When treatment was initiated (Metavir score >=F2), patients were followed-up both by the hepatologist and the out-patient unit physician., Results: Between July 1997 and September 2000, 404 consecutive patients (310 men, mean age: 32, alcohol intake >=50 g per day in 51%, 94% in opiate substitution program) were included. Sixty-six per cent (269/404) of patients agreed to undergo HCV antibodies testing: 84% had a positive test. 68% of these patients accepted ALT serum measurement and 120 had indications for liver biopsy. Eighty-eight liver biopsies were performed, showing severe fibrosis (Metavir score F3 or F4) in 20 cases (22%). Ethanol intake was significantly correlated to fibrosis (P<0.05). Antiviral treatment was indicated in 47 patients but was only initiated in 27 due to patient refusal (n=7) or contraindication (n=13). Treatment had to be discontinued in 12 cases because of psychiatric side effects (depression: n=3; delirium: n=3; severe irritability: n=3; relapse with heroin injection: n=3). Finally, only 5 patients were sustained responders., Conclusion: Despite the high seroprevalence of HCV antibodies in this unit, the benefits of antiviral therapy are low due to high drop out rate. Ethanol withdrawal should be the highest priority in these patients.