Growing evidence suggests that pretransplant alpha‐fetoprotein (AFP) predicts outcomes of hepatocellular carcinoma (HCC) patients treated with liver transplantation. We aimed to determine whether pretransplant AFP, Lens culinaris agglutinin‐reactive alpha‐fetoprotein (AFP‐L3), and des‐gamma‐carboxyprothrombin (DCP) predicted HCC recurrence after transplantation. A retrospective cohort study of 313 HCC patients undergoing transplantation between 2000 and 2008 was conducted, and 48 (15.3%) developed recurrence during a median follow‐up of 90.8 months. The 127 patients with available serum drawn before transplantation were included; they included 86 without recurrence and 41 with recurrence. Serum was tested for AFP, AFP‐L3%, and DCP in a blinded fashion with the μTASWako i30 immunoanalyzer. All biomarkers were significantly associated with HCC recurrence. The hazard ratios (HRs) were 3.5 [95% confidence interval (CI), 1.9‐6.7; P < 0.0001] for DCP ≥ 7.5 ng/mL and 2.8 (95% CI, 1.4‐5.4; P = 0.002) for AFP ≥ 250 ng/mL. The HR increased to 5.2 (95% CI, 2.3‐12.0; P < 0.0001) when AFP ≥ 250 ng/mL and DCP ≥7.5 ng/mL were considered together. When they were combined with the Milan criteria, the HR increased from 2.6 (95% CI, 1.4‐4.7; P = 0.003) for outside the Milan criteria to 8.6 (95% CI, 3.0‐24.6; P < 0.0001) for outside the Milan criteria and AFP ≥ 250 ng/mL and to 7.2 (95% CI, 2.8‐18.1; P < 0.0001) for outside the Milan criteria and DCP ≥7.5 ng/mL. Our findings suggest that biomarkers are useful for predicting the risk of HCC recurrence after transplantation. Using both biomarkers and the Milan criteria may be better than using the Milan criteria alone in optimizing the decision of liver transplantation eligibility. Liver Transpl 21:599–606, 2015. © 2015 AASLD.

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 a-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 non-hepatitis C virus patients with a relatively constitutive Cardif. Hepatic RIG-I, MDAS, 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 NVP. 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.

症例1は44歳女性．人間ドックにて肝腫瘍を指摘され，精査目的に入院．HBV, HCVなどウイルスマーカー陰性で肝機能異常は認めず，各種画像診断から肝血管筋脂肪腫（AML）を考え，経皮的腫瘍生検にて診断確定した．経過観察中にて腫瘍径の増大は認めていない．症例2は40歳女性．健診にて肝腫瘍を指摘され，各種画像診断でも肝細胞癌が否定できず，短期間に腫瘍径が増大したため左葉外側切除術を施行した．病理組織より肝血管筋脂肪腫と診断された．症例1, 2は最終診断では肝血管筋脂肪腫であったが，症例1では脂肪成分に富み典型的なAML所見であったのに対し，症例2は脂肪成分に乏しく診断困難であった．両者ともに肝静脈が流出血管として描出され，造影超音波検査が有用であった．

Session 1: HEPATITIS C THERAPY S7 predictive value for SVR at 4 weeks was 91% (41/45) for a ribavirin concentration 2 mg/l (p = 0.02).Correspondingly for the 12 weeks arm the PPV was 74% (25/34) (p = 0.12).In a multivariate analysis with SVR as outcome and ribavirin concentration at week 4 as independent variable, we included as covariates age, gender, fibrosis, baseline viral load, ribavirin dose in mg/kg, treatment duration and whether 80% of planed treatment was received.Ribavirin concentration at week 4 was an independent predictor of SVR (OR 2.3 95% CI 1.3-4.1,p = 0.002).Conclusion: Although 12 weeks of treatment was inferior to 24 weeks of treatment, a higher ribavirin concentration was associated with a significantly increased SVR.This indicates that a treatment regiment with ribavirin dose based on plasma concentration at week four could significantly improve treatment outcome.We propose this to be examined in a prospective randomized trial.

A 35-year-old woman was admitted to our hospital for right upper quadrant pain and multiple liver tumor were detected by diagnostic imaging. Tumors located near the surface of the liver which accompanied capsular retraction. Diagnostic laparoscopy showed multiple white tone tumors with retraction of the adjacent liver capsule. Tumor targeted biopsy was performed. The pathologic diagnosis of epithelioid hemangioendothelioma (EHE) was made by the positive staining of factor VIII-related antigen. EHE tend to locate in peripheral and extend to the liver capsule. Therefore, we face difficulties in getting biopsy sample safely. Here we report a useful case of laparoscopic examination and biopsy in the diagnosis of EHE.

Background/Aims: Interferon (IFN) therapy leads to regression of hepatic fibrosis in chronic hepatitis C patients who achieve a sustained virologic response (SVR), while the beneficial effect is limited in those who fail to do so. The aim of the present study was to define factors associated with progression of fibrosis in patients who do not achieve a SVR.Methods: Fibrosis staging scores were compared between paired liver biopsies before and after IFN in 97 chronic hepatitis C patients who failed therapy. The mean interval between biopsies was 5.9 years. Factors associated with progression of fibrosis were analyzed.Results: Fibrosis progressed in 23%, remained unchanged in 47% and regressed in 29%. Steatosis and a high average alanine aminotransferase (ALT) between biopsies were independent factors for progression of fibrosis with risk ratios of 5.53 and 4.48, respectively. Incidence and yearly rate of progression of fibrosis was 64% and 0.22 +/- 0.29 fibrosis units per year in those with both risk factors compared to 8% and -0.04 +/- 0.17 fibrosis units per year in those negative for both factors.Conclusions: Hepatic steatosis and elevated ALT levels are risk factors for progression of fibrosis in chronic hepatitis C patients who fail to achieve a SVR to IFN therapy and therefore may be therapeutic targets to halt the potentially progressive disease. (C) 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Background and Aims: Agrin is a recently identified proteoglycan component of vascular and bile duct basement membranes in the liver.The selective deposition of agrin in tumor microvessels versus sinusoidal walls prompted us to investigate whether immunohistochemistry (IHC) for agrin may help to discriminate between benign and malignant hepatocellular lesions.We focused on the differential diagnostic problems often presented by hepatocellular adenomas (HAs) and dysplastic nodules.Our aim was to devise a novel immunohistochemical method that sensitively and selectively detects hepatocellular malignancy.Also, an attempt was made to interpret the observed agrin immunostaining patterns in the context of vascular changes, ductular reaction and parenchymal regeneration.Methods: Eighty-eight formalin-fixed, paraffin-embedded surgical specimens from 68 patients included 24 cirrhotic liver tissues, 10 cases with focal nodular hyperplasia (FNH), 8 large regenerative nodules, 18 lowgrade and 6 high-grade dysplastic nodules (LGDN and HGDN), 6 small HCCs, 21 HCCs, and 29 HAs.Immunoreactions for agrin and, when necessary, for CD34 were evaluated in a semi-quantitative fashion, and the outcome was compared with histological diagnosis.Results: In our method, agrin IHC was complemented with CD34 immunoreaction in ambiguous cases.This combination was found highly informative in the assessment of dignity (sensitivity 92.6%, specificity 91.8%).Whereas most benign lesions (regenerative nodules, LGDN, FNH, HA without cellular atypia) were clearly negative, the strength of immunoreactions and consequent ranking of the sample faithfully reflected the degree and extent of dysplasia in HA and HGDN.Malignant lesions were uniformly positive.Conclusion: Agrin IHC, besides allowing insight into a multitude of nonmalignant pathological processes such as ductular reaction and parenchymal regeneration, is a sensitive indicator of hepatocellular dysplasia and changes in vascular phenotype.Therefore, the admission of agrin to the immunohistochemical panel used in routine liver pathology is worth consideration.

This study investigated the molecular and pharmacokinetic mechanisms of the enhanced antiviral efficacy associated with pegylated interferon (PEG-IFN) alpha-2b and ribavirin. The study involved comparing the expression of serial double-stranded RNA-activated protein kinase (PKR) before and during treatment in 26 PEG-IFN alpha-2b and 26 conventional IFN alpha-2b recipients matched for age, body weight and dose of ribavirin. The pharmacokinetics of PEG-IFN alpha-2b and ribavirin was analysed in 15 of the 26 PEG-IFN recipients. There was a rapid increase in PKR expression in both treatment groups, although expression from day 2 onwards was maintained at a significantly higher level in the PEG-IFN recipients (P < 0.05). C-max of PEG-IFN occurred 12-48 h after the initial administration, with t(1/2) and C-min being 49 h and 190 pg/mL, respectively. In contrast to ribavirin, accumulation of PEG-IFN was minimal. There was no association between serum PEG-IFN and ribavirin levels and virological response. Although baseline expression of PKR before treatment was marginally higher in nonresponders (NRs), from day 2 onwards, sequential PKR expression in response to PEG-IFN was higher in sustained viral responders compared with the NRs (P < 0.05). Significant correlations were found between kinetics of PKR expression and viral decline rates in each phase of hepatitis C virus dynamics (first phase, r = 0.67, P = 0.0006; second phase, r = 0.67, P = 0.001). In conclusion, improvement in pharmacokinetics following pegylation led to higher intracellular PKR expression, which was associated with enhanced virological efficacy of PEG-IFN-based combination therapy. The concentrations of both ribavirin and PEG-IFN alpha-2b were not associated with viral response and PKR expression.