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Background and Aim: The long-term prognosis of hepatocellular carcinoma (HCC) treated at a very-early-stage (the Barcelona Clinical Liver Cancer (BCLC) classification stage 0) was unclear, especially in terms of background liver disease., Methods: This single-center, retrospective study included 302 patients with BCLC stage 0 HCC treated with radiofrequency ablation (RFA) and followed for at least six months. We examined the impact of background liver disease on overall survival and recurrence., Results: The median age was 72 (range; 36-91) years; the median tumor diameter was 15 (range; 8-20) mm. The etiologies of background liver disease were hepatitis B virus infection (HBV) in 24 cases, hepatitis C virus infection (HCV) in 195 cases, and non-viral (NBNC) in 83 cases. Among the patients with HCV, 63 had achieved sustained virological response (SVR) by antiviral therapy (HCV SVR) before developing HCC (n = 37) or after HCC treatment (n = 26), and 132 had active HCV infection (HCV non-SVR). The median overall survival was 85 (95% CI; 72-98) months, and the median recurrence-free survival was 26 (95% CI; 20-30) months. Active infection with hepatitis C virus negatively contributed to overall survival (HR 2.91, 95% CI 1.31-3.60, p = 0.003) and recurrence-free survival (HR 1.47, 95% CI 1.06-2.05, p = 0.011)., Conclusions: The prognosis of RFA treatment for very early-stage HCC was favorable. Achieving SVR in hepatitis C was important for further prognosis improvement., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Namiki Izumi, Masayuki Kurosaki, and Kaoru Tsuchiya received lecture fees from Eisai, Bayer, Lilly, and Chugai.This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background & Aims: The presence of resistance-associated variants (RAVs) of hepatitis C virus (HCV) attenuates the efficacy of direct acting antivirals (DAAs). The objective of this study was to characterize the susceptibility of RAVs to interferon-based therapy., Methods: Direct and deep sequencing were performed to detect Y93H RAV in the NS5A region. Twenty nine genotype 1b patients with detectable RAV at baseline were treated by a combination of simeprevir, pegylated interferon and ribavirin. The longitudinal changes in the proportion of Y93H RAV during therapy and at breakthrough or relapse were determined., Results: By direct sequencing, Y93H RAV became undetectable or decreased in proportion at an early time point during therapy (within 7 days) in 57% of patients with both the Y93H variant and wild type virus at baseline when HCV RNA was still detectable. By deep sequencing, the proportion of Y93H RAV against Y93 wild type was 52.7% (5.8%- 97.4%) at baseline which significantly decreased to 29.7% (0.16%- 98.3%) within 7 days of initiation of treatment (p = 0.023). The proportion of Y93H RAV was reduced in 21 of 29 cases (72.4%) and a marked reduction of more than 10% was observed in 14 cases (48.7%). HCV RNA reduction was significantly greater for Y93H RAV (-3.65±1.3 logIU/mL/day) than the Y93 wild type (-3.35±1.0 logIU/mL/day) (p<0.001)., Conclusion: Y93H RAV is more susceptible to interferon-based therapy than the Y93 wild type.

Background/aims: To address the molecular mechanism for enhanced antiviral efficacy associated with a frequent dosing of interferon (IFN)-beta., Methods: Serum hepatitis C viral (HCV) dynamics, double-stranded RNA-activated protein kinase (PKR) mRNA and MxA mRNA levels in peripheral blood mononuclear cells (PBMC) were analyzed serially in 140 patients who were randomly assigned to a twice daily (3 MU bid) or once daily (6 MU qd) administration group., Results: In twice daily group, the rate of HCV decline during the second phase was 2-fold greater than in the once daily group (P=0.04). Peak PKR and MxA gene expression levels in the first phase (observed 4 h after a single administration) were 2-fold higher in the once daily group. However, the expression in the second phase was maintained at a significantly higher level in the twice daily group. Initial and peak expression levels were related to initial viral load. Basal expressions in PBMC were significantly correlated with those in the liver tissue (PKR, r=0.81; MxA, r=0.75, respectively, P<0.0001)., Conclusions: Our data suggest that elimination of HCV-infected cells is enhanced by twice daily dosing of IFN-beta, and that this enhanced effect is associated with a higher intracellular expression of PKR and MxA during the second phase.

Almost all patients achieved sustained virological response (SVR) by direct‐acting antivirals (DAA) therapy, but it is not clear as to what extent DAA therapy affects changes in liver fibrosis after achieving SVR. In this study, we investigated the changes of liver stiffness by magnetic resonance elastogaraphy (MRE) during DAA therapy. A total of 308 patients were enrolled in the study. Liver stiffness was measured twice before and after DAA treatment using MRE and time‐course change of liver stiffness was investigated. The median (interquartile range) values for liver stiffness were 4.2 (3.2–6.1) kPa at baseline and 3.3 (2.6–4.8) kPa at SVR, demonstrating a significant improvement (p <.01). A total of 44% of patients had no improvement in liver stiffness despite achieving SVR. In patients with advanced fibrosis (lower level of albumin [Alb] or histological fibrosis stage F4), it was difficult to improve liver stiffness. Except for Alb, there were no blood tests associated with nonimprovement in liver stiffness, making these cases difficult to predict. In conclusion, despite obtaining SVR, improvement in liver stiffness could not be obtained in some cases, especially in patients with advanced fibrosis. In these patients, liver stiffness must be followed even if SVR is obtained. Highlights: A total of 308 patients were received MRE before and after DAA therapy and changes in liver stiffness was examined.Liver stiffness significantly decreased after SVR in all patients, but 44% of patients had no improvement in liver stiffness.Improvement of liver stiffness was difficult to obtain in patients with advanced fibrosis (lower levels of albumin or histological fibrosis stage 4). [ABSTRACT FROM AUTHOR]

Aim: The albumin, bilirubin, and platelet (ABP) criteria was proposed to avoid screening endoscopy for detecting high‐risk varices (HRV) and it has high diagnostic accuracy. We carried out a retrospective cross‐sectional study to verify the diagnostic accuracy. Methods: A total of 610 patients with advanced fibrosis were enrolled in the study. ABP criteria are defined as follows: albumin >4.0 g/dL, bilirubin <22 μmol/L, and platelets >114 000/μL. Results: Background liver disease were hepatitis C/hepatitis B/non‐alcoholic fatty liver disease/others:405 (66.4%)/67 (10.5%)/78 (12.8%)/60 (10.3%). A total of 105 patients (17.2%) had HRV. In multivariate analysis, serum bilirubin <22 μmol/L (HR 2.00, 95% CI 1.2–3.4), albumin >4.0 g/dL (HR 2.56, 95% CI 1.7–3.8), and platelets >114 000/μL (HR 3.52, 95% CI 2.1–5.8) levels were independently associated with no presence of HRV. When the ABP criteria were examined, 200 patients (32.8%) fulfilled the criteria, and 194 patients had no HRV (positive predictive value 97.0%) When classified by etiologies (hepatitis C/hepatitis B/non‐alcoholic fatty liver disease), positive predictive value were 97.7/100/92.0%, respectively. Conclusions: The ABP criteria are easy to examine, because they use only standard laboratory tests, and they are available for screening patients who might avoid endoscopy regardless of etiologies. [ABSTRACT FROM AUTHOR]

Prediction of hepatocellular carcinoma (HCC) development after sustained virological response (SVR) is clinically important, and the usefulness of noninvasive markers for prediction HCC have been reported. The aim of this study was to compare the prediction accuracy for HCC development by noninvasive markers. A total of 346 patients with chronic hepatitis C without history of HCC who achieved SVR through direct‐acting antivirals were included. Magnetic resonance elastography (MRE) and serum fibrosis markers were measured 12 weeks after the end of treatment, and the subsequent HCC development was examined. The mean observation period was 26.4 ± 7.9 months, and 24 patients developed HCC. Area under the receiver operating characteristic curve of liver stiffness by MRE, Wisteria floribunda agglutinin‐positive mac‐2 binding protein and FIB‐4 for predicting HCC within 3 years was 0.743, 0.697 and 0.647, respectively. The 1/2/3‐year rates of HCC development in patients with liver stiffness ≥3.75 KPa were 6.6%, 11.9% and 14.5%, whereas they were 1.4%, 2.5% and 2.5% in patients with liver stiffness <3.75 KPa (P < 0.001). Multivariate analysis revealed that liver stiffness ≥3.75 was an independent predictive factor for HCC development (hazard ratio, 3.51; 95% confidence interval, 1.24‐9.99). In subgroup analysis, there were 132 patients who were <73 years old and had liver stiffness <3.75 KPa, and no HCC development was observed in these patients. Diagnostic accuracy for predicting HCC development was higher in MRE than serum fibrosis markers and measurement of liver stiffness by MRE could identify patients with high and low risk of HCC development after SVR. [ABSTRACT FROM AUTHOR]

Aim: Elastic fiber deposition is a cause of irreversibility of liver fibrosis. However, to date, its relevance to clinical features has not yet been clarified. This study aimed to clarify the correlation between non‐invasive markers of fibrosis and fiber quantity, including elastic fiber, obtained from computational analysis. Methods: This retrospective study included 270 patients evaluated by non‐invasive liver fibrosis assessment prior to liver biopsy. Of these patients, 95 underwent magnetic resonance elastography (MRE) and 244 were assessed with Wisteria floribunda agglutinin‐positive Mac‐2 binding protein (WFA+‐M2BP). Using whole‐slide imaging of Elastica van Gieson‐stained liver biopsy sections, the quantity of collagen, elastin, and total fiber (elastin + collagen) was determined. Results: The total fiber quantity showed significant linear correlation with fibrosis stage F0–F4. Collagen fiber quantity increased from stage F0 to F4, whereas elastic fiber quantity increased significantly only from stage F2 to F3. Spearman's rank correlation test revealed that non‐invasive liver fibrosis assessment significantly correlates with each fiber quantity, including correlation between total fiber quantity and the Fibrosis‐4 (FIB‐4) index (r = 0.361, P < 0.001), WFA+‐M2BP values (r = 0.404, P < 0.001), and liver stiffness value by MRE (r = 0.615, P < 0.001). Receiver operating characteristic (ROC) curve analyses revealed that the area under ROC for predicting higher elastic fiber (>3.6%) is 0.731 by FIB‐4 index, 0.716 by WFA+‐M2BP, and 0.822 by liver stiffness by MRE. Conclusion: Liver fibrosis correlates with fiber quantity through non‐invasive assessment regardless of fiber type, including elastic fiber. Moreover, MRE is useful for predicting high amounts of elastic fiber. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study is to clarify the value of serum Wisteria floribunda agglutinin‐positive Mac‐2 binding protein (WFA+‐M2BP) for predicting hepatocellular carcinoma (HCC) in chronic hepatitis C patients who achieved sustained virologic response (SVR) by therapy with interferon‐free, direct‐acting antivirals (DAAs). Methods: This is a retrospective cohort study that included 567 patients who underwent antiviral therapy with an interferon‐free DAA regimen and achieved SVR. Serum WFA+‐M2BP was measured after SVR. Factors predictive of HCC occurrence and recurrence were analyzed in the patients after stratification by previous treatment history of HCC. Results: Among 518 patients who had no history of HCC, 13 developed HCC. Post‐SVR WFA+‐M2BP ≥1.75 cut‐off index (C.O.I., P < 0.001) and α‐fetoprotein (AFP) level ≥6 ng/mL (P = 0.01) were significant predictors of HCC development. Multivariate analysis showed that post‐SVR WFA+‐M2BP ≥1.75 C.O.I. was an independent factor significantly associated with the development of HCC (hazard ratio [HR] 6.0; 95% confidence interval (CI), 1.8–19.4; P = 0.003). Among 49 patients who had a previous history of HCC, 22 had recurrence after SVR. Post‐SVR AFP ≥6 ng/mL was the only factor associated with recurrence‐free survival (HR 3.1; 95% CI, 1.3–7.5; P = 0.01). Conclusions: Post‐SVR WFA+‐M2BP is a predictive factor for the development of HCC in patients with no previous HCC history and treated with DAAs. Post‐SVR AFP was predictive for HCC recurrence after DAA therapy. [ABSTRACT FROM AUTHOR]

Aim To investigate, in a large number of cases at multiple institutions, the effects and limitations of antiviral therapy for hepatitis C following treatment of hepatocellular carcinoma (HCC) in clinical practice. Methods Retrospective analysis was performed of 112 patients who had received interferon (IFN) for treating hepatitis C following treatment of HCC and were registered with the Japanese Red Cross Liver Study Group. Factors that may influence recurrence and survival rates were investigated. Results Factors involved in prevention of recurrence were: surgical resection as HCC treatment, platelet and α-fetoprotein (AFP) levels prior to IFN administration, IFN adherence and post-IFN AFP level. Multivariate analysis showed post-IFN AFP level to be an independent factor. Factors involved in prolonging survival were: IFN adherence, IFN response (sustained viral response), pre-IFN alanine aminotransferase and AFP levels, post-IFN AFP level and absence of recurrence. Multivariate analysis showed absence of recurrence to be an independent factor. Although IFN adherence was involved in recurrence and survival, ribavirin adherence was not. IFN was suggested to be involved in preventing recurrence and improving survival due not only to its anti-viral effect, but also its antitumor effect. Conclusion Although complete prevention of HCC recurrence is difficult, the most important factor affecting first recurrence is the AFP level at 6 months after the conclusion of antiviral treatment. The survival rate improves dramatically if the hepatitis C virus is eliminated, but the most important factor for improving survival is absence of recurrence. [ABSTRACT FROM AUTHOR]

Aim The presence of resistance-associated variants (RAV) may attenuate the efficacy of direct-acting antivirals (DAA) in combination therapy for hepatitis C. The aim of this study was to characterize the NS3 and NS5A regions of hepatitis C virus (HCV) in naturally occurring RAV. Methods The NS3 and NS5A regions of HCV were amplified by nested polymerase chain reaction and their nucleotide sequences were determined by direct sequencing in 493 genotype 1b patients naive to DAA-based therapies. The effect of baseline RAV on response to pegylated interferon and ribavirin therapy was analyzed in 65 patients after stratification by interleukin (IL)-28B genotype. Results The incidence of RAV was 7.9% in NS3 (V36I/L, 1.2%; T54S, 2.8%; Q80K/R, 3.0%; A156S, 0.2%; and D168E/T, 2.4%) and 20.2% in NS5A (L31I/M, 2.2%; and Y93H, 19.0%). The incidence in interferon experienced and naive patients was similar. The incidence of Y93H in NS5A was significantly higher in the IL-28B TT genotype (rs8099917) than non-TT (27.1% vs 9.5%, P < 0.001). The virological response to pegylated interferon plus ribavirin therapy was not affected by the presence of RAV in IL-28B TT genotype. Conclusion RAV, especially Y93H in the NS5A region, were highly prevalent in DAA naive patients with genotype 1b HCV in Japan and were linked to IL-28B TT genotype. Interferon-based therapy could be an alternative for patients with RAV because these variants did not attenuate the response to that therapy. The analysis of RAV may impact the selection of the optimal treatment strategy. [ABSTRACT FROM AUTHOR]

The assessment of individual risk of fibrosis progression in patients with chronic hepatitis C is an unmet clinical need. Recent genome-wide association studies have highlighted several genetic alterations as predictive risk factors of rapid fibrosis progression in chronic hepatitis C. However, most of these results require verification, and whether the combined use of these genetic predictors can assess the risk of fibrosis progression remains unclear. Therefore, genetic risk factors associated with fibrosis progression were analyzed in 176 chronic hepatitis C patients who did not achieve sustained virological response by interferon-based therapy and linked to the fibrosis progression rate (FPR). FPR was determined in all patients by paired liver biopsy performed before and after therapy (mean interval: 6.2 years). Mean FPR in patients with IL28B (rs8099917) TG/GG and PNPLA3 (rs738409) CG/GG were significantly higher than in those with IL28B TT (FPR: 0.144 vs. 0.034, P < 0.001) and PNPLA3 CC (FPR: 0.10 vs. 0.018, P = 0.005), respectively. IL28B TG/GG [hazard ratio (HR): 3.9, P = 0.001] and PNPLA3 CG/GG (HR: 3.1, P = 0.04) remained independent predictors of rapid fibrosis progression upon multivariate analysis together with average alanine aminotransferase after interferon therapy ≥40 IU/l (HR: 4.2, P = 0.002). Based on these data, we developed a new clinical score predicting the risk of fibrosis progression (FPR-score). The FPR-score identified subgroups of patients with a low (FPR: 0.005), intermediate (FPR: 0.103, P < 0.001), and high (FPR: 0.197, P < 0.001) risk of fibrosis progression. In conclusion, IL28B and PNPLA3 genotypes are associated with rapid fibrosis progression, and the FPR-score identifies patients who has a high risk of fibrosis progression and require urgent antiviral treatment. [ABSTRACT FROM AUTHOR]

Background: We aimed to clarify the association between single nucleotide polymorphism (SNP) located near interleukin 28B and hepatocellular carcinoma (HCC). Methods: A cohort comprising 792 patients treated with interferon for chronic hepatitis C was investigated. SNPs at rs8099917 and rs12979860 were determined. Cumulative incidence and HCC risk were analyzed by Kaplan-Meier and Cox proportional hazard analyses for a mean follow-up period of 4.9 years. Fibrosis progression rate (FPR) was determined in these patients with a known time of infection ( n = 294). Results: Cumulative HCC incidence was significantly higher in rs8099917 nonTT (minor homozygote or heterozygote) patients than in rs8099917 TT (major homozygote) patients (20.8 vs. 10.5 % over 10 years, logrank test, p = 0.002). This difference was notable in patients infected with genotype 1 and those treated with pegylated interferon and ribavirin. Among nonSVRs, interferon had a limited effect in suppressing alanine aminotransferase (ALT) and/or α-fetoprotein (AFP) levels in nonTT patients. The suppression of these values after interferon therapy was associated with a lower incidence of HCC. FPR were similar in TT and nonTT patients. Conclusions: rs8099917 nonTT is related to higher HCC development in patients with HCV genotype 1 and those treated with pegylated interferon and ribavirin. Higher HCC incidence observed in nonTT patients partly results from the limited suppression of ALT and/or AFP by interferon in these patients. [ABSTRACT FROM AUTHOR]

Objectives: Recent reports indicated that reduced SLC22A7 (a gene-encoding organic anion transporter 2) expression in noncancerous liver tissue predicts hepatocellular carcinoma (HCC) recurrence after curative resection. Our study aimed to elucidate the association between SLC22A7 expression and HCC development in chronic hepatitis C patients. Methods: HCC recurrence after local ablation therapy and SLC22A7 expression in noncancerous liver tissue were analyzed in 20 patients. Subsequently, the association between de novo HCC development and SLC22A7 expression was examined at baseline in 38 hepatitis C patients without HCC who subsequently developed HCC as well as in 76 hepatitis C patients who did not develop HCC and were matched for age, gender and stage of fibrosis. Results: In the patients whose HCC had been cured, reduced SLC22A7 expression in noncancerous liver tissue was significantly associated with a high incidence of multifocal HCC recurrence. In patients without HCC at baseline, cumulative incidence of de novo HCC development was significantly higher with a reduced SLC22A7 expression than with a normal expression (p = 0.01). This difference remained significant among patients without known risk factors for HCC like age and advanced fibrosis. Conclusion: Reduced SLC22A7 expression in the liver indicates a significant risk for HCC development in chronic hepatitis C, independently of other risk factors. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aims: Peginterferon (PEG-IFN) + ribavirin (RBV combination therapy is the current standard of care for chronic hepatitis C. However, more than half of the patients cannot achieve sustained viral response (SVR). In Japan, the clinical benefit of retreatment with PEG-IFN + RBV combination re treatment is still unknown. Methods: We collected clinical data in 106 chronic hepatitis C patients who failed to achiev SVR with PEG-IFNα-2b + RBV combination therapy and were retreated with PEG-IFNα-2a + RBV. This retrospective stud examined the efficacy of retreatment with PEG-IFNα-2a RBV by evaluating the time to eradication of hepatitis C virus RNA, early virological response (EVR), and SVR. We compared the results of the previous therapy and retreatment in term of efficacy and analyzed the factors influencing SVR. Results: The SVR rates in the non-responders and relapsers were 11 and 53%, respectively. EVR and prolonged treatment duration were associated with SVR. We also found that a prior response to PEG-IFN + RBV therapy was more important than the Interleukin-28B genotype for predicting the response to retreatment. Conclusions: Retreatment with PEG-IFNcα-2a RBV should be considered for relapsers and partial responders. Our results suggest that prolonged administration is also favorable for EVR cases to attain a higher SVR. [ABSTRACT FROM AUTHOR]

Aim: Hepatic steatosis is linked to development of hepatocellular carcinoma (HCC) in non-viral liver disease such as non-alcoholic steatohepatitis. The present study aimed to assess whether hepatic steatosis is associated with the development of HCC in chronic hepatitis C. Methods: We studied a retrospective cohort of 1279 patients with chronic hepatitis C who received interferon (IFN) therapy between 1994 and 2005 at a single regional hospital in Japan. Of these patients, 393 had a sustained virological response (SVR) and 886 had non-SVR to IFN therapy. After IFN therapy, these patients were screened for development of HCC every 6 months. The average period of observation was 4.5 years. Results: HCC developed in 68 patients. The annual incidence of HCC was 2.73% for patients with a steatosis grade of 10% or greater and 0.69% for patients with a steatosis grade of 0–9%. On multivariate analysis, higher grade of steatosis was a significant risk factor for HCC independent of older age, male sex, higher body mass index (BMI), advanced fibrosis stage and non-SVR to IFN therapy. The adjusted risk ratio of hepatic steatosis was 3.04 (confidence interval 1.82–5.06, P < 0.0001), which was higher than that of older age (1.09), male sex (2.12), non-SVR to IFN (2.43) and higher BMI (1.69). Conclusion: Hepatic steatosis is a significant risk factor for development of HCC in chronic hepatitis C independent of other known risk factors, which suggest the possibility that amelioration of hepatic steatosis may prevent hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]

Aim: Early disappearance of serum hepatitis C virus (HCV) RNA is the prerequisite for achieving sustained virological response (SVR) in peg-interferon (PEG-IFN) plus ribavirin (RBV) therapy for chronic hepatitis C. This study aimed to develop a decision tree model for the pre-treatment prediction of response. Methods: Genotype 1b chronic hepatitis C treated with PEG-IFN alpha-2b and RBV were studied. Predictive factors of rapid or complete early virological response (RVR/cEVR) were explored in 400 consecutive patients using a recursive partitioning analysis, referred to as classification and regression tree (CART) and validated. Results: CART analysis identified hepatic steatosis (<30%) as the first predictor of response followed by low-density-lipoprotein cholesterol (LDL-C) (≥100 mg/dL), age (<50 and <60 years), blood sugar (<120 mg/dL), and gamma-glutamyltransferase (GGT) (<40 IU/L) and built decision tree model. The model consisted of seven groups with variable response rates from low (15%) to high (77%). The reproducibility of the model was confirmed by the independent validation group ( r2 = 0.987). When reconstructed into three groups, the rate of RVR/cEVR was 16% for low probability group, 46% for intermediate probability group and 75% for high probability group. Conclusions: A decision tree model that includes hepatic steatosis, LDL-C, age, blood sugar, and GGT may be useful for the prediction of response before PEG-IFN plus RBV therapy, and has the potential to support clinical decisions in selecting patients for therapy and may provide a rationale for treating metabolic factors to improve the efficacy of antiviral therapy. [ABSTRACT FROM AUTHOR]

Background & Aims: Clinical significance of molecules involving innate immunity in treatment response remains unclear. The aim is to elucidate the mechanisms underlying resistance to antiviral therapy and predictive usefulness of gene quantification in chronic hepatitis C (CH-C). Methods: We conducted a human study in 74 CH-C patients treated with pegylated interferon α-2b and ribavirin and 5 nonviral control patients. Expression of viral sensors, adaptor molecule, related ubiquitin E3-ligase, and modulators were quantified. Results: Hepatic RIG-I, MDA5, LGP2, ISG15, and USP18 in CH-C patients were up-regulated at 2- to 8-fold compared with nonhepatitis C virus patients with a relatively constitutive Cardif. Hepatic RIG-I, MDA5, and LGP2 were significantly up-regulated in nonvirologic responders (NVR) compared with transient (TR) or sustained virologic responders (SVR). Cardif and RNF125 were negatively correlated with RIG-I and significantly suppressed in NVR. Differences among clinical responses in RIG-I/Cardif and RIG-I/RNF125 ratios were conspicuous (NVR/TR/SVR = 1.3:0.6:0.4 and 2.3:1.3:0.8, respectively). Like viral sensors, ISG15 and USP18 were significantly up-regulated in NVR (4-fold and 2.3-fold, respectively). Multivariate and receiver operator characteristic analyses revealed higher RIG-I/Cardif ratio, ISG15, and USP18 predicted NVR. Lower Cardif in NVR was confirmed by its protein level in Western blot. Also, transcriptional responses in peripheral blood mononuclear cells to the therapy were rapid and strong except for Cardif in not only a positive (RIG-I, ISG15, and USP18) but also in a negative regulatory manner (RNF125). Conclusions: NVR may have adopted a different equilibrium in their innate immune response. High RIG-I/Cardif and RIG-I/RNF125 ratios and ISG15 and USP18 are useful in identifying NVR. [Copyright &y& Elsevier]

Recurrence of hepatocellular carcinoma (HCC) is frequently observed in patients with hepatitis C virus (HCV) infection and the incidence of HCC recurrence is as high as 20% in these patients even after a complete curative treatment is given for the HCC nodules. We report a 57-year-old female who was referred to our hospital for the treatment of a HCC nodule of 1.8 cm diameter in S5 and having liver cirrhosis of Child–Pugh A classification with HCV infection in April 1999. The HCC nodule showed hypervascularity by computed tomography during hepatic arteriography (CTHA) and was coagulated by microwave under peritoneoscopy. Complete necrosis was confirmed by enhanced-CT scan after microwave coagulation. Thereafter, interferon alfa-2b (3MU, twice weekly) was given but HCV RNA continued to be positive. Thereafter, recurrence of HCC was noted five times in S1, S2, S6; treatment by radiofrequency ablation was given four times; and transarterial chemoembolization was carried out once. Since January 2004, peg-interferon alfa-2a (90 µm/week) has been administered, and no recurrence has been detected until August 2005. She is currently 63 years old, and quite well. Five-year-survival rate in HCC patients treated by radiofrequency ablation is 62.7% in our hospital, however, the recurrence rate is as high as 26.4% per year in the patients with chronic HCV infection. It is a point of controversy when liver transplantation should be recommended in HCC patients with liver cirrhosis of Child-Pugh A classification having chronic HCV infection because of the high incidence of recurrence. [ABSTRACT FROM AUTHOR]

Abstract: The up-regulation of MUC1 protein is associated with malignant phenotype of cancer. We investigated the significance of KL-6, one of the MUC1 antigens, as a tumor marker in hepatitis C virus positive hepatocellular carcinoma (HCC). Serum KL-6 was determined in 203 patients with chronic hepatitis (CH), 47 patients with liver cirrhosis (LC) and 78 patients with HCC. KL-6 was higher in HCC compared to non-HCC (p =0.0005) and was higher in patients with multiple HCC nodules compared to a single nodule (p =0.02). There was no correlation between KL-6 and existent tumor markers for HCC such as alpha-fetoprotein, lens culinaris agglutinin-reactive alpha-fetoprotein or des-gamma-carboxyprothrombin. In the prospective analysis, the cumulative incidence of HCC was significantly greater in CH and LC patients with high initial KL-6 (above 400U/ml) compared to the others (p =0.02). Moreover, in the prospective observation of 25 patients whose HCC was completely cured by radiofrequency ablation therapy, the cumulative incidence of distant recurrences was significantly greater in patients with high initial KL-6 compared to the others (p =0.005). These results suggest that serum KL-6 could be a novel tumor marker in the diagnosis and the prediction of prognosis of HCC that may have additive value to the existent markers. [Copyright &y& Elsevier]

Objectives: A high virological response rate can often be shown to be obtained with PEG-IFN α-2b and ribavirin combination therapy in chronic hepatitis C patients. Viral dynamics have been utilized for the evaluation of antiviral effects, especially the exponential second decay slope, which represents the elimination of infected cells. Methods: Forty-nine patients were randomly assigned to the IFN α-2b group (n = 26) or the PEG-IFN α-2b group (n = 23). Ribavirin was administered equally to both groups. Measuring the serum concentration of HCVRNA, the exponential viral decay during phase 1 and 2 was calculated. Results: The exponential decay slope in phase 2 during the first 2 weeks was greater in the IFN α-2b group than in the PEG-IFN α-2b group; however, from weeks 3 to 4, it was greater in the PEG-IFN α-2b group than in the IFN α-2b group. Interestingly, in the PEG-IFN α-2b group, the exponential decay slope was greater from weeks 3 to 4 after initiating combination therapy than during the weeks 1-2 (p < 0.01), despite administration of the same PEG-IFN α-2b dose (1.5 µg/kg once weekly). Conclusions: In PEG-IFN α-2b and ribavirin combination therapy, elimination of infected cells may be pronounced following an increase in serum ribavirin concentration in chronic hepatitis C patients with genotype 1b infection and a high viral load. [ABSTRACT FROM AUTHOR]