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Summary In Western countries, most of the patients with hepatocellular carcinoma (HCC) are not eligible for curative treatments. Intra-arterial treatments have a palliative effect that could lead to extensive tumour necrosis and therefore have been widely used. Arterial embolization, Lipiodol-targeted chemoembolization and intra-arterial injection of radioactive iodine mixed with Lipiodol provided promising results in terms of tumoral growth, but were also responsible for severe side-effects, particularly in patients with cirrhosis. Their influence on survival has been assessed by randomized trials with contradictory results. In patients with advanced cases, embolization alone has limited or no influence on survival, and chemoembolization provided a beneficial effect mostly in patients with viral liver diseases, without liver failure, and with an adequate portal flux. The effects of radioactive iodine either in the treatment of advanced cases or the prevention of recurrences after a curative treatment must be investigated further. [ABSTRACT FROM AUTHOR]

Summary: Background: Liver fibrosis is often accompanied by steatosis, particularly in patients with non‐alcoholic fatty liver disease (NAFLD), and its non‐invasive characterisation is of utmost importance. Vibration‐controlled transient elastography is the non‐invasive method of choice; however, recent research suggests that steatosis may influence its diagnostic performance. Controlled Attenuation Parameter (CAP) added to transient elastography enables simultaneous assessment of steatosis and fibrosis. Aim: To determine how to use CAP in interpreting liver stiffness measurements. Methods: This is a secondary analysis of data from an individual patient data meta‐analysis on CAP. The main exclusion criteria for the current analysis were unknown aetiology, unreliable elastography measurement and data already used for the same research question. Aetiology‐specific liver stiffness measurement cut‐offs were determined and used to estimate positive and negative predictive values (PPV/NPV) with logistic regression as functions of CAP. Results: Two thousand and fifty eight patients fulfilled the inclusion criteria (37% women, 18% NAFLD/NASH, 42% HBV, 40% HCV, 51% significant fibrosis ≥ F2). Youden optimised cut‐offs were only sufficient for ruling out cirrhosis (NPV of 98%). With sensitivity and specificity‐optimised cut‐offs, NPV for ruling out significant fibrosis was moderate (70%) and could be improved slightly through consideration of CAP. PPV for significant fibrosis and cirrhosis were 68% and 55% respectively, despite specificity‐optimised cut‐offs for cirrhosis. Conclusions: Liver stiffness measurement values below aetiology‐specific cut‐offs are very useful for ruling out cirrhosis, and to a lesser extent for ruling out significant fibrosis. In the case of the latter, Controlled Attenuation Parameter can improve interpretation slightly. Even if cut‐offs are very high, liver stiffness measurements are not very reliable for ruling in fibrosis or cirrhosis. [ABSTRACT FROM AUTHOR]

Summary. A novel controlled attenuation parameter (CAP) has been developed for Fibroscan® to assess liver steatosis, simultaneously with liver stiffness measurement (LSM). We assessed CAP diagnostic accuracy in a large cohort of patients with chronic hepatitis C (CHC) virus. A total of 615 patients with CHC, who underwent both Fibroscan® and liver biopsy, were analysed. Fibrosis was graded using METAVIR score. Steatosis was categorized by visual assessment as S0: steatosis in <10% of hepatocytes, S1: 11-33%, S2: 34-66% and S3: 67-100%. Performances of CAP and liver stiffness were determined using receiver operating characteristic (ROC) curve analysis and cross-validated using the bootstrap method. The Obuchowski measure was used to assess overall accuracy of CAP and to differentiate between steatosis grades. In multivariate analysis, CAP was related to steatosis ( P < 10−15) independently of fibrosis stage (which was related to LSM). The areas under ROC curves using CAP to detect steatosis were 0.80 (95% CI, 0.75-0.84) for S ≥ S1, 0.86 (0.81-0.92) for S ≥ S2 and 0.88 (0.73-1) S = S3. CAP exhibited a good ability to differentiate steatosis grades (Obuchowski measure = 0.92). Performance of LSM for fibrosis assessment confirmed results from previous studies. CAP is a novel tool to assess the degree of steatosis and both fibrosis and steatosis can be evaluated noninvasively during the same procedure using Fibroscan®, in patients with CHC. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: The objective of this study was to assess the results and tolerance of radiofrequency ablation in patients with cirrhosis and hepatocellular carcinoma (HCC) older than 75 years. Patients and methods: Over a period of 9 years from January 2001, 235 patients with cirrhosis and 3 or less HCC≤5 cm of diameter were treated by radiofrequency ablation. Among them, 52 patients older than 75 years were selected for this study. Results: The mean age was 79.4±3. 5 years. There were 36 males, cirrhosis was classified Child-Pugh class A (n =52) related to alcohol (n =13), HCV infection (n =33), or other causes (n =6). The mean tumour diameter was 32.5±10,6mm, and 14 patients had a multifocal HCC. A complete ablation was obtained in 50/52 patients (96%). No severe complication occurred. The estimated overall survival rates were 62%, 52% and 36% at 3 years, 4 years and 5 years, respectively; it was similar to those observed in patients younger than 75 years. Conclusion: In patients with cirrhosis older than 75 years, radiofrequency ablation of 3 or less HCC≤5cm is well tolerated and survivals rates are similar to those of younger patients. [Copyright &y& Elsevier]

Summary. Liver steatosis is a main histopathological feature of Hepatitis C (HCV) infection because of genotype 3. Steatosis and/or mechanisms underlying steatogenesis can contribute to hepatocarcinogenesis. The aim of this retrospective study was to assess the impact of infection with HCV genotype 3 on hepatocellular carcinoma (HCC) occurrence in patients with ongoing HCV cirrhosis. Three hundred and fifty-three consecutive patients (193 men, mean age 58 ± 13 years), with histologically proven HCV cirrhosis and persistent viral replication prospectively followed and screened for HCC between 1994 and 2007. Log-rank test and Cox model were used to compare the actuarial incidence of HCC between genotype subgroups. The patients infected with a genotype 3 ( n = 25) as compared with those infected with other genotypes ( n = 328) had a lower prothrombin activity [78 (interquartile range 60-85) vs 84 (71-195) %, P = 0.03] and higher rate of alcohol abuse (48% vs 29%, P = 0.046). During a median follow-up of 5.54 years [2.9-8.6], 11/25 patients (44%) and 87/328 patients (26%) with a genotype 3 and non-3 genotype, respectively, develop a HCC. HCC incidences were significantly different among the genotype subgroups ( P = 0.001). The 5-year occurrence rate of HCC was 34% (95% CI, 1.3-6.3) and 17% (95% CI, 5.7-9.2) in genotype 3 and non-3 genotype groups, respectively ( P = 0.002). In multivariate analysis, infection with a genotype 3 was independently associated with an increased risk of HCC occurrence [hazard ratio 3.54 (95% CI, 1.84-6.81), P = 0.0002], even after adjustment for prothrombin activity and alcohol abuse [3.58 (1.80-7.13); P = 0.003]. For patients with HCV cirrhosis and ongoing infection, infection with genotype 3 is independently associated with an increased risk of HCC development. [ABSTRACT FROM AUTHOR]

Background Hepatic venous pressure gradient (HVPG) is the gold standard for assessing the presence and the severity of portal hypertension (PHT). Liver stiffness measurement (LSM) is a non-invasive method for liver fibrosis assessment. Aims To assess the relationship between LSM and HVPG in patients with compensated cirrhosis related to hepatitis C virus (HCV) or alcohol and to define the performance and the best cut-off of LSM for the diagnosis of PHT in these patients. Methods Between January 2004 and September 2006, we studied all the consecutive patients with compensated HCV or alcohol-related-cirrhosis referred for transjugular liver biopsy with HVPG measurement and LSM performed the same day. Results Ninety-two patients were eligible, 44 had HCV related-cirrhosis and 48 alcoholic cirrhosis. LSM was positively correlated to HVPG in both groups. The area under the receiver operating characteristic curve for the diagnosis of significant PHT was 0.76 ± 0.07 in HCV patients (best cut-off at 20.5 kPa) and 0.94 ± 0.03 (best cut-off at 34.9 kPa) in alcoholic patients. Conclusions Liver stiffness measurement and HVPG were significantly correlated in patients with compensated cirrhosis because of HCV infection or alcohol. LSM could predict significant PHT in both these groups of patients with a higher cut-off and a better performance in alcoholic patients. [ABSTRACT FROM AUTHOR]

We investigated whether an HCV NS3 protease quasispecies heterogeneity was associated with progression from viral cirrhosis to hepatocellular carcinoma (HCC). The NS3 protease quasispecies structure of 10 HCV-1b cirrhotic patients (controls) was compared with that of 10 paired HCV-1b cirrhotic patients who displayed progression to HCC (cases). NS3 protease genetic complexity and diversity did not differ significantly between cases and controls. Amino acid substitutions were detected at 20 (11%) and 25 (14%) sites in at least two variants of the NS3 protease in cases and controls, respectively. Significant differences in the percentage of substituted clones were observed for 10 NS3 sites. Mutations Y56F, I71V, T72I, Q86P, P89S, S101G/D, R117H, S122G/T/N, V132I and V170I were more frequently observed in the NS3 protease sequences of controls than in those of cases. Residue V107 was substituted in NS3 cases but not in controls. However, these differences did not allow the definition of a specific NS3 profile related to HCC occurrence. The NS3 secondary structure B1-1 previously identified as potentially predictive of HCC was identified with a higher frequency in cases quasispecies (84.2%) than in controls (55.9%; P < 0.05). Our results suggest that there may be a relationship to fibrosis progression when diversity parameters are considered together with secondary structure profiles. Further investigations are required to determine the cellular interactions of HCV NS3 protease in the context of carcinogenesis. [ABSTRACT FROM AUTHOR]

SELDI-based proteomic profiling of body fluids is currently in widespread use for cancer biomarker discovery. We have successfully used this technology for the diagnosis of hepatocellular carcinoma (HCC) in hepatitis C patients and now report its application to serial serum samples from 37 hepatitis C patients before development of HCC, with HCC and following radiofrequency ablation of the tumour. As with alpha-fetoprotein, an accepted biomarker for HCC, we hypothesised that HCC-associated proteomic features would ‘return to normal’ following successful treatment and the primary aim of our study was to test this hypothesis. Several SELDI peaks that changed significantly during HCC development were detected but they did not reverse following treatment. These data may be interpreted to suggest that the characteristic SELDI profile is not linearly related to tumour burden but may result from the progression of underlying liver disease or from the emergence of precancerous lesions. β2-Microglobulin, a protein previously reported to be markedly elevated in patients with HCV related HCC, was also the most significantly HCC associated proteomic feature (m/z 11720) in this study.British Journal of Cancer (2006) 95, 1379–1383. doi:10.1038/sj.bjc.6603429 www.bjcancer.com Published online 24 October 2006 [ABSTRACT FROM AUTHOR]

Little is known about the role of specific hepatitis C virus (HCV) CD8+ T cells in liver damage, especially for the progression of fibrosis, during the highly variable course of chronic C hepatitis. The aim of this study was to investigate the presence of HCV-specific CD8+ T cells in the liver of patients with chronic C hepatitis and to examine their clinical significance by relating the response to liver fibrosis and progression rate, serum viral load, serum aminotransferase levels, inflammatory activity and in situ characteristics of the intrahepatic infiltrate. Fifteen patients were prospectively included in the study. Intrahepatic lymphocytes were tested for interferon gamma (IFNg) production in response to HCV class I-restricted epitopic peptides using enzyme-linked immunospot analysis. Liver biopsy samples were evaluated for fibrosis, fibrosis progression rate, activity, and in situ number of CD8+ cytotoxic lymphocytes and apoptotic cells. An IFNg-specific CD8+ T-cell response was detected in the liver samples of 47% of patients which was significantly related to a lower stage of fibrosis ( P = 0.02) and a lower progression rate of fibrosis ( P = 0.01). It was neither related to the number of cytotoxic lymphocytes infiltrating the liver nor to hepatocyte apoptosis. In conclusion, our results indicate that the presence of HCV-specific IFNg-secreting T cells in the liver of patients with chronic C hepatitis is associated with low liver fibrosis and fibrosis progression rate, suggesting that these IFNg-secreting T cells might limit the progression of liver damage. [ABSTRACT FROM AUTHOR]

Early diagnosis of hepatocellular carcinoma (HCC) is the key to the delivery of effective therapies. The conventional serological diagnostic test, estimation of serum alpha-fetoprotein (AFP) lacks both sensitivity and specificity as a screening tool and improved tests are needed to complement ultrasound scanning, the major modality for surveillance of groups at high risk of HCC. We have analysed the serum proteome of 182 patients with hepatitis C-induced liver cirrhosis (77 with HCC) by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI). The patients were split into a training set (84 non-HCC, 60 HCC) and a 'blind' test set (21 non-HCC, 17 HCC). Neural networks developed on the training set were able to classify the blind test set with 94% sensitivity (95% CI 73-99%) and 86% specificity (95% CI 65-95%). Two of the SELDI peaks (23/23.5 kDa) were elevated by an average of 50% in the serum of HCC patients (P<0.001) and were identified as kappa and lambda immunoglobulin light chains. This approach may permit identification of several individual proteins, which, in combination, may offer a novel way to diagnose HCC. [ABSTRACT FROM AUTHOR]

Background: Liver cirrhosis may lead to hepatocellular carcinoma (HCC), regardless of its cause. Genetic and/or environmental factors may modulate the risk of HCC. Mutations in the HFE gene are responsible for genetic haemochromatosis, a condition known to be associated with liver cirrhosis, HCC, or both. It has recently been suggested that the C282Y HFE gene mutation may be more frequent in patients with HCC that have developed in the non-cirrhotic liver than in the general population. Whether or not HFE gene mutations are associated with an increased risk of HCC in patients with cirrhosis is unknown. Aim: To assess the prevalence of HFE gene mutations in cirrhotic patients with and without HCC. Patients and methods: A total of 133 consecutive cirrhotic patients with HCC were prospectively studied for the presence of C282Y and H63D mutations. The control group consisted of 100 cirrhotic patients without HCC. We used restriction enzyme digestion of polymerase chain reaction amplified genomic DNA for determination of HFE genotypes. Iron loading was assessed on non-tumoral liver biopsy samples from 89 patients with HCC and 73 patients without HCC. Results: The prevalence of C282Y heterozygotes was similar in patients with and without HCC (5% v 4%, respectively; p=0.65) and did not differ from that expected in the general population. None of the HCC patients was found to be homozygous for C282Y or H63D, nor compound heterozygous. The prevalence of H63D heterozygotes was similar in patients with and without HCC (31% v 38%, respectively; p=0.25). No relation was detected between HFE genotypes and hepatic iron loading in patients with or without HCC. Conclusion: C282Y and H63D mutations do not appear to be associated with an increased risk of HCC in patients with cirrhosis. [ABSTRACT FROM AUTHOR]

Summary. Interferon-alpha (IFN) monotherapy results in sustained virological clearance in a minority of patients with chronic hepatitis C. The aim of this study was to assess the effect of a reinforced regimen combining ribavirin and high-dose IFN for 48 weeks compared with a nonreinforced regimen combining a standard IFN regimen and ribavirin for 24 weeks in nonresponders with chronic hepatitis C. A total of 231 patients with chronic hepatitis C and previous nonresponse to IFN monotherapy were randomized. The reinforced group (n = 114) received IFN-2b 6 million units (MU) thrice weekly (TIW) and ribavirin for 48 weeks, and the nonreinforced group (n = 117) received IFN-2b 3 MU TIW and ribavirin for 24 weeks. The main outcome measure was a sustained virological response, defined as negative serum hepatitis C virus (HCV)-RNA 24 weeks following the end of treatment. This endpoint was determined in 98 patients of the reinforced group and 105 patients of the nonreinforced group. At the end of follow-up, a sustained virological response was observed in 29 of the 98 patients (29.6%) in the reinforced group vs 16 of the 105 patients (15.2%) in the nonreinforced group (P = 0.014). In multivariate analysis, factors associated with a sustained virological response were treated with a reinforced regimen [odds ratio (OR) 2.9; P = 0.06] and genotype 2 or 3 (OR 8.8; P < 0.0002). A total of 160 patients had paired biopsies before and after treatment. Histological activity improvement was observed in 32 of 80 patients (40%) and fibrosis worsening in 26 of 80 patients (33%) in the reinforced group vs 13 of 80 (16%) and 19 of 80 (24%) in the nonreinforced group (P = 0.30 and 0.20, respectively). Hence in nonresponders, a high-dose 48-week regimen of IFN and ribavirin combination was more effective than a regimen with interferon at lower dose and ribavirin for 24 weeks only. [ABSTRACT FROM AUTHOR]

Examines the prevalence of serum hepatitis C virus antibodies in patients with Hashimoto's thyroiditis. Assessment on thyroid function using standard radioimmunoassay; Detection of receptor antibodies for thyroid stimulating hormone using radioreceptor assay; Use of laser nephelometry in immunoglobulin assays.