Nobuyoshi Fukushima

Microvascular Invasion in Patients with Hepatocellular Carcinoma and Its Predictable Clinicopathological Factors

BackgroundMacroscopic vascular invasion is known to be a poor prognostic factor in hepatocellular carcinoma (HCC). The aim of this study was to determine the outcomes and predictive factors after hepatic resection for HCC with microvascular invasion (MVI).MethodsOne hundred ten patients who underwent curative resection for HCC without macroscopic vascular invasion were included in this retrospective study. The risk factors of these patients for recurrence-free and disease-specific survival were investigated, and the clinicopathological factors predicting the presence of MVI were also determined.ResultsOf the 110 resected specimens, 49 (45%) had evidence of MVI. By univariate analysis, MVI was found to be statistically significantly associated with greater tumor size, gross classification, histological grade, and intrahepatic micrometastasis. Gross classification proved to be the only independent predictive factor for MVI by multiple logistic regression analysis. By multivariate analysis, cirrhosis and MVI were identified as independent risk factors for recurrence-free survival. The 5-year recurrence-free survival rates for patients with and without MVI were 20.8% and 52.6%, respectively. By multivariate analysis, the number of tumors, presence of MVI, and intrahepatic micrometastasis were identified as independent predictors of disease-specific survival. The 5-year disease-specific survival rates for patients with and without MVI were 59.3% and 92.0%, respectively.ConclusionsThe presence of MVI was the most important risk factor affecting recurrence and survival in HCC patients after curative resection. Furthermore, this study showed that gross classification of HCC can be very helpful in predicting the presence of MVI.

Surveillance program for early detection of hepatocellular carcinoma in Japan: results of specialized department of liver disease.

Objective Surveillance of cirrhotic patients enables early detection of hepatocellular carcinoma (HCC) and possibly prolongs survival. The aim of this study was to explore whether early-stage HCC can be detected earlier at a specialized department of liver disease than in other institutions. Methods The study subjects were 574 patients with HCC. Patients were subdivided into 3 groups according to the manner of HCC detection: group A, HCC was detected in 91 patients during periodic examination at Kurume University School of Medicine; group B, HCC was detected in 301 patients during periodic examination at other institutions; group C, HCC was detected incidentally or because of symptoms in 182 patients. Results The HCC detected in group A was significantly of smaller size (20.4 mm) compared with groups B (27.1 mm, P<0.0001) and C (57.8 mm, P<0.0001). The frequency of receiving treatment (surgery or local ablation therapy) was significantly higher in group A (73%) than in groups B (52%, P=0.002) and C (26%, P<0.0001). The 5-year survival rates were 52% for group A, 40% for group B, and 23% for group C, respectively. The survival of group A was significantly better than that of groups B (P=0.0157) and C (P<0.0001). Conclusions Surveillance for HCC at specialized Department of Liver Disease can detect early-stage HCC, resulting in a higher chance of receiving promising treatment.

Guidelines for the management of primary biliary cirrhosis: The Intractable Hepatobiliary Disease Study Group supported by the Ministry of Health, Labour and Welfare of Japan Guidelines for the management of primary biliary cirrhosis: The Intractable Hepatobiliary Disease Study Group supported by the Ministry of Health, Labour and Welfare of Japan

THE JAPANESE VERSION of the clinical practice guidelines for primary biliary cirrhosis (PBC) was developed in 2012 by the Intractable Hepatobiliary Disease Study Group, with the support of the Ministry of Health, Labour and Welfare of Japan, for the use of general physicians, gastroenterologists and hepatologists who treat patients with PBC. In preparation for developing the guidelines, the study group reviewed recent studies that provided important evidence or that were published in leading journals with a high impact factor, in addition to considering the formal consensus of experts on PBC or related subjects. Using the core keywords “primary biliary cirrhosis,” a PubMed search was conducted for English-language clinical trials, randomized clinical trials (RCTs) and meta-analyses that were published from January 1998 to December 2009 and that addressed treatment of PBC and its complications, follow-up, indication of and time of consultation for liver transplantation, or time of consultation with specialists. Medical systems and other culture-specific factors in Japan were also taken into account. Members of the task force exchanged ideas frequently during the drafting process to try and establish a consensus. The final draft was made after collecting comments from the public and all the committee members. The level of evidence (LE; Table 1) and the grade of recommendation (GR; Table 2) were based on the Medical Information Network Distribution Service in Japan (MINDS). After being modified by recent literatures published since 2010, the present English version of the guidelines was developed in order to spread our ideas and exchange opinions with physicians who are involved in the management of PBC patients overseas. *Working Subgroup (English version) for Clinical Practice Guidelines for Primary Biliary Cirrhosis (in alphabetical order): Atsumasa Komori, Clinical Research Center, National Hospital Organization Nagasaki Medical Center; Atsushi Tanaka, Department of Medicine, Teikyo University School of Medicine; Hajime Takikawa, Department of Medicine, Teikyo University School of Medicine; §Hirohito Tsubouchi, Digestive Disease and Life-style Related Disease, Kagoshima University Graduate School of Medical and Dental Sciences and Kagoshima City Hospital; †Hiromi Ishibashi, International University of Health and Welfare/Fukuoka Sanno Hospital and Clinical Research Center, National Hospital Organization Nagasaki Medical Center; Hiroto Egawa, Department of Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University; Junko Hirohara, Third Department of Internal Medicine, Kansai Medical University; Ken Shirabe, Department of Surgery and Science, Kyushu University; Kenichi Harada, Department of Human Pathology, Kanazawa University Graduate School of Medicine; Makoto Nakamuta, Department of Gastroenterology, National Hospital Organization Kyushu Medical Center; Mikio Zeniya, Department of Gastroenterology, Jikei University Graduate School of Medicine; Minoru Nakamura, Clinical Research Center, National Hospital Organization Nagasaki Medical Center and Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences; Nobuyoshi Fukushima, Department of Gastroenterology, National Hospital Organization Kyushu Medical Center; Shinji Shimoda, Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University; Shotaro Sakisaka, Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine; Toshio Morizane, Japan Council for Quality Health Care; Yasuaki Takeyama, Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine; ‡Yasuni Nakanuma, Department of Human Pathology, Kanazawa University Graduate School of Medicine; Yoshiyuki Ueno, Department of Gastroenterology, Yamagata University Faculty of Medicine (†Chairperson of the Working Group, ‡Chairperson of the PBC Subcommittee, §Chairperson of the Intractable Hepatobiliary Disease Study Group). **Correspondence: Hiromi Ishibashi, Fukuoka Sanno Hospital, International University of Health and Welfare, 3-6-45 Momochihama, Sawara-ku, Fukuoka, 814-0001, Japan. Email: hiishibashi-gi@umin.ac.jp bs_bs_banner

Genetic polymorphisms in CTLA4 and SLC4A2 are differentially associated with the pathogenesis of primary biliary cirrhosis in Japanese patients

BackgroundAnti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis (PBC). In order to dissect the genetic basis for the production of these autoantibodies, as well as the development and progression of PBC in Japanese patients, we examined single nucleotide polymorphisms (SNPs) in cytotoxic T-lymphocyte antigen 4 (CTLA4) and solute carrier family 4 anion exchanger, member 2 (SLC4A2), which have been associated with the pathogenesis of PBC in Caucasian patients.MethodsFour SNPs for both CTLA4 and SLC4A2 were genotyped, using the polymerase chain reaction–restriction fragment length polymorphism method and TaqMan assay, in 450 Japanese PBC patients and 371 sex-matched healthy controls.ResultsThe CTLA4 rs231775, rs3087243, and rs231725 SNPs were significantly associated with PBC susceptibility. The CTLA4 rs231725 SNP was significantly associated with progression to late-stage disease. The CTLA-4 haplotype 1 (rs231775 G, rs231777 C, rs3087243 G, rs231725 A; GCGA) was a risk factor for PBC susceptibility but a protective factor for PBC progression. Conversely, the CTLA-4 haplotype 2 (ACAG) was a protective and risk factor, respectively, for PBC susceptibility and progression. In addition, the CTLA4 rs231777 SNP and haplotype 3 (ATGG) was significantly associated with anti-gp210 antibody production, while SLC4A2 haplotype 4 (rs2069443 A, rs2303933 G, rs2303937 A, rs2303941 T; AGAT) and haplotype 3 (AAGC) were significantly associated with PBC susceptibility and anti-centromere antibody production, respectively.ConclusionsCTLA4 and SLC4A2 genetic polymorphisms are differentially associated with PBC development and progression, as well as anti-gp210 or anti-centromere antibody production, in Japanese PBC patients.

Phosphorylated Smad2 and Smad3 signaling: Shifting between tumor suppression and fibro-carcinogenesis in chronic hepatitis C.

Insight into hepatic fibrogenesis and carcinogenesis (fibro‐carcinogenesis) caused by hepatitis C virus (HCV) infection has come from recent analyses of transforming growth factor (TGF)‐β signaling. TGF‐β type I receptor and pro‐inflammatory cytokine‐activated kinases differentially phosphorylate Smad2 and Smad3 to create C‐terminally (C), linker (L) or dually (L/C) phosphorylated (p) isoforms. This study aimed to elucidate how HCV infection affected hepatic fibro‐carcinogenesis, particularly via phospho‐Smad signaling.

Add‐on therapy of pitavastatin and eicosapentaenoic acid improves outcome of peginterferon plus ribavirin treatment for chronic hepatitis C

Despite the use of pegylated‐interferon (peg‐IFN) plus ribavirin combination therapy, many patients infected with hepatitis C virus (HCV)‐1b remain HCV‐positive. To determine whether addition of pitavastatin and eicosapentaenoic acid (EPA) is beneficial, the “add‐on” therapy option (add‐on group) was compared retrospectively with unmodified peg‐IFN/ribavirin therapy (standard group). Association of host‐ or virus‐related factors with sustained virological response was assessed. In HCV replicon cells, the effects of pitavastatin and/or EPA on HCV replication and expression of innate‐immunity‐ and lipid‐metabolism‐associated genes were investigated. In patients infected with HCV‐1b, sustained virological response rates were significantly higher in the add‐on than standard group. In both groups, sustained virological response rates were significantly higher in patients with genotype TT of IL‐28B (rs8099917) than in those with non‐TT genotype. Among the patients with non‐TT genotype, sustained virological response rates were markedly higher in the add‐on than standard group. By multivariate analysis, genome variation of IL28B but not add‐on therapy remained as a predictive factor of sustained virological response. In replicon cells, pitavastatin and EPA suppressed HCV replication. Activation of innate immunity was obvious in pitavastatin‐treated cells and EPA suppressed the expression of sterol regulatory element binding protein‐1c and low‐density lipoprotein receptor. Addition of pitavastatin and EPA to peg‐IFN/ribavirin treatment improved sustained virological response in patients infected with HCV‐1b. Genotype variation of IL‐28B is a strong predictive factor in add‐on therapy. J. Med. Virol. 85:250–260, 2013.

Adipocytokine involvement in hepatocellular carcinoma after sustained response to interferon for chronic hepatitis C

Aim:  Interferon (IFN) dramatically reduces the risk of hepatocellular carcinoma (HCC) after a sustained virological response (SVR) to chronic hepatitis C (CH‐C). However, HCC still develops in some patients after SVR. To evaluate metabolic factors in patients with HCC occurring after SVR and to determine whether insulin resistance and adipocytokines were involved in this etiology.

The incidence of hepatocellular carcinoma associated with hepatitis C infection decreased in Kyushu area

Summary Background The incidence of hepatocellular carcinoma (HCC) in Japan has still been increasing. The aim of the present study was to analyze the epidemiological trend of HCC in the western area of Japan, Kyushu. Material/Methods A total of 10,010 patients with HCC diagnosed between 1996 and 2008 in the Liver Cancer study group of Kyushu (LCSK), were recruited for this study. Cohorts of patients with HCC were categorized into five year intervals. The etiology of HCC was categorized to four groups as follows; B: HBsAg positive, HCV-RNA negative, C: HCV-RNA positive, HBsAg negative, B+C: both of HBsAg and HCV-RNA positive, nonBC: both of HBsAg and HCV-RNA negative. Results B was 14.8% (1,485 of 10,010), whereas 68.1% (6,819 of 10,010) had C, and 1.4% (140 of 10,010) had HCC associated with both viruses. The remaining 1,566 patients (15.6%) did not associate with both viruses. Cohorts of patients with HCC were divided into six-year intervals (1996–2001 and 2002–2007). The ratio of C cases decreased from 73.1% in 1996–2001 to 64.9% in 2002–2007. On the other hand, B and -nonBC cases increased significantly from 13.9% and 11.3% in 1996–2001 to 16.2% and 17.6% in 2002–2007, respectively. Conclusions The incidence of hepatocellular carcinoma associated with hepatitis C infection decreased after 2001 in Kyushu area. This change was due to the increase in the number and proportion of the HCC not only nonBC patients but also B patients.

CD34+ cell therapy is safe and effective in slowing the decline of hepatic reserve function in patients with decompensated liver cirrhosis

Preclinical studies in rodent models of chronic liver fibrosis have shown that transplantation of peripheral blood (PB) CD34+ cells leads to hepatic regeneration and a reduction of liver fibrosis by suppressing hepatic stellate cell activity and increasing matrix metalloproteinase activity. The aim of this study was to examine the safety and clinical efficacy of intrahepatic transplantation of autologous granulocyte colony‐stimulating factor (G‐CSF)‐mobilized PB‐CD34+ cells in patients with decompensated liver cirrhosis.

Genome-wide association studies identify PRKCB as a novel genetic susceptibility locus for primary biliary cholangitis in the Japanese population

&NA; A previous genome‐wide association study (GWAS) performed in 963 Japanese individuals (487 primary biliary cholangitis [PBC] cases and 476 healthy controls) identified TNFSF15 (rs4979462) and POU2AF1 (rs4938534) as strong susceptibility loci for PBC. In this study, we performed GWAS in additional 1,923 Japanese individuals (894 PBC cases and 1,029 healthy controls), and combined the results with the previous data. This GWAS, together with a subsequent replication study in an independent set of 7,024 Japanese individuals (512 PBC cases and 6,512 healthy controls), identified PRKCB (rs7404928) as a novel susceptibility locus for PBC (odds ratio [OR] = 1.26, P = 4.13 × 10‐9). Furthermore, a primary functional variant of PRKCB (rs35015313) was identified by genotype imputation using a phased panel of 1,070 Japanese individuals from a prospective, general population cohort study and subsequent in vitro functional analyses. These results may lead to improved understanding of the disease pathways involved in PBC, forming a basis for prevention of PBC and development of novel therapeutics.