Updated on 2024/02/01

写真a

 
TAKAKI Akinobu
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Special-Appointment Professor
Position
Special-Appointment Professor
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Degree

  • Doctor (Medicine) ( Okayama University )

Research Interests

  • Gastroenterology

  • 消化器内科学

  • Gastroenterology

Research Areas

  • Life Science / Gastroenterology

Education

  • Okayama University   医学系研究科   内科学

    - 1994

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    Country: Japan

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  • Okayama University    

    - 1994

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  • Okayama University   医学部   医学科

    - 1990

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    Country: Japan

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  • Okayama University    

    - 1990

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Research History

  • - Associate Professor,Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Okayama University

    2012

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  • - 岡山大学医歯薬学総合研究科 准教授

    2012

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  • Senior Assistant Professor,Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Okayama University

    2010 - 2012

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  • 岡山大学医歯薬学総合研究科 講師

    2010 - 2012

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Professional Memberships

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Committee Memberships

  • 日本門脈圧亢進症学会   評議員  

    2019   

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  • 日本肝臓学会   評議員  

    2018   

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    Committee type:Academic society

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  • 厚生労働科学研究費補助金 難治性疾患政策研究事業 「難治性の肝・胆道疾患に関する調査研究」班   研究協力者  

    2016   

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    Committee type:Government

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  • 日本消化器病学会   学会評議員  

    2012   

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    Committee type:Academic society

    日本消化器病学会

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  • 日本消化器免疫学会   評議員  

    2011   

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    Committee type:Academic society

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  • 日本内科学会   中国支部評議員  

    2009   

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    Committee type:Academic society

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Papers

  • Detection of hepatocellular carcinoma during Fontan-associated liver disease follow-up: a report of three cases

    Hideki Onishi, Norihisa Toh, Teiji Akagi, Kenji Baba, Yasuhiro Kotani, Akinobu Takaki, Shingo Kasahara, Hiroshi Ito

    Clinical Journal of Gastroenterology   2023.11

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    Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    DOI: 10.1007/s12328-023-01892-w

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    Other Link: https://link.springer.com/article/10.1007/s12328-023-01892-w/fulltext.html

  • The prediction of early progressive disease in patients with hepatocellular carcinoma receiving atezolizumab plus bevacizumab. International journal

    Yasuto Takeuchi, Kazuhiro Nouso, Shin-Ichi Fujioka, Kazuya Kariyama, Haruhiko Kobashi, Shuji Uematsu, Akio Moriya, Hiroaki Hagihara, Hiroyuki Takabatake, Shinichiro Nakamura, Kazuhisa Yabushita, Tatsuya Kikuchi, Atsushi Oyama, Takuya Adachi, Nozomu Wada, Hideki Onishi, Hidenori Shiraha, Akinobu Takaki

    Cancer medicine   12 ( 17 )   17559 - 17568   2023.8

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    BACKGROUND AND AIMS: The IMbrave 150 trial revealed the usefulness of atezolizumab plus bevacizumab therapy in patients with unresectable hepatocellular carcinoma (HCC), making it now considered the first-line systemic chemotherapy agent for HCC. The present study investigated factors associated with early tumor progression of atezolizumab plus bevacizumab in patients with advanced HCC in real-world clinical practice. METHODS: A total of 184 HCC patients who received atezolizumab plus bevacizumab therapy were studied. We investigated the frequency of early progressive disease (e-PD; PD within 9 weeks) and analyzed the risk factors for e-PD. RESULTS: There were 47 patients (25.5%) diagnosed as e-PD. Patients with e-PD had a worse performance status (PS) and albumin-bilirubin (ALBI) and Child-Pugh (C-P) scores and a significantly higher rate of a systemic therapy than those with non-e-PD. A multivariate analysis showed that PS ≥1 (odds ratio [OR] = 4.5, 95% confidence interval [CI] = 1.9-10, p < 0.001), ALBI score ≥-2.30 (OR = 2.1, 95% CI = 1.0-4.5, p = 0.044) and the history of a systemic therapy (OR = 3.0, 95% CI = 1.4-6.4, p = 0.0038) were significant and independent determinants of e-PD. When examining the liver function trends in e-PD patients, the ALBI scores at 3 and 6 weeks after starting therapy were significantly higher than before the treatment (p < 0.001). CONCLUSIONS: The liver function and systemic therapy are useful predictors of e-PD in HCC patients treated with atezolizumab plus bevacizumab in real-world clinical practice.

    DOI: 10.1002/cam4.6369

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  • Disease Progression-Related Markers for Aged Non-Alcoholic Fatty Liver Disease Patients.

    Kosaku Morimoto, Yasuto Takeuchi, Akinobu Takaki, Nozomu Wada, Atsushi Oyama, Takuya Adachi, Hideki Onishi, Hidenori Shiraha, Hiroyuki Okada

    Acta medica Okayama   77 ( 4 )   377 - 385   2023.8

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    Liver fibrosis is an important phenomenon in non-alcoholic fatty liver disease (NAFLD) progression. Standard markers reflecting liver fibrosis, including the FIB-4 index, increase with age. This study aimed to identify fibrosis progression-related markers that are diagnostically beneficial even in aged individuals. Serum levels of pro- and anti-inflammatory cytokines were measured by multiple enzyme-linked immunosorbent assay. Two standard NAFLD or fibrosis progression-related markers - the FIB-4 index and APRI score - were analyzed along with cytokine levels to define the best approach to discriminate advanced fibrosis. Ninety-eight NAFLD patients were enrolled: 59 and 39 patients with fibrosis stages 1-2 and 3-4 respectively. In addition to the FIB-4 index and APRI score, the following factors showed significant differences between stages 1-2 and stages 3-4 in a multivariate analysis: platelet counts, IP-10, and RANTES. The fibrosis stage, FIB-4, APRI, PDGF-BB, and RANTES were related to the prognosis. In aged patients, IP-10, GM-CSF, and RANTES differed between stages 1-2 and stages 3-4. FIB-4 and APRI were beneficial for their correlation with fibrosis. However, to stratify either young or elderly advanced fibrosis patients, and to identify patients likely to have a bad outcome, RANTES was the best marker.

    DOI: 10.18926/AMO/65748

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  • Oxidative stress-related markers as prognostic factors for patients with primary sclerosing cholangitis in Japan. International journal

    Atsushi Oyama, Akinobu Takaki, Takuya Adachi, Nozomu Wada, Yasuto Takeuchi, Hideki Onishi, Hidenori Shiraha, Hiroyuki Okada, Motoyuki Otsuka

    Hepatology international   17 ( 5 )   1215 - 1224   2023.7

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    BACKGROUND/PURPOSE: Primary sclerosing cholangitis (PSC) is a rare chronic liver disease. The mechanisms and prediction of PSC progression are unclear. Recent investigations have shown that general conditions, such as oxidative stress, affect the course of chronic diseases. We investigated the clinical course and oxidative stress-related condition of PSC to determine prognostic factors. METHODS: We recruited 58 patients with PSC (mean age; 37.4 years, mean observation period; 1382 days) who visited our department from 2003 to 2021. Clinical characteristics were investigated to define prognostic factors. Oxidative stress status was evaluated using two types of markers: an oxidative stress marker (serum reactive oxygen metabolite; dROM) and an antioxidant marker (serum OXY adsorbent test; OXY). RESULTS: The revised Mayo risk, Child-Pugh, model for end-stage liver disease-sodium (MELD-Na) scores or fibrosis-related FIB-4 index significantly predicted poor overall survival. High intestinal immunoglobulin A (IgA) levels predicted poor survival. Among patients with high and intermediate revised Mayo risk scores, those with physiologically high dROM levels showed better survival than those with lower dROM levels. In this population, dROM was negatively correlated with AST and IgA, which are both correlated with survival. CONCLUSIONS: High and intermediate revised Mayo risk score group predicted a poor clinical course in PSC. Additionally, the Child-Pugh score, MELD-Na score, FIB-4 index, and serum IgA were significantly correlated with survival. In patients with high and intermediate revised Mayo risk scores, physiologically high oxidative stress status correlated with low IgA levels and a good prognosis.

    DOI: 10.1007/s12072-023-10557-2

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  • 肝生検により診断された播種性bacillus Calmette-Guerin(BCG)症の1例

    伊木 道子, 竹内 康人, 須江 真彦, 三宅 望, 足立 卓哉, 和田 望, 大西 秀樹, 白羽 秀則, 高木 章乃夫, 大塚 基之

    日本消化器病学会中国支部例会プログラム・抄録集   119回   62 - 62   2023.6

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  • 【肝胆膵領域におけるアルコール医学の新潮流】アルコール性肝障害の臨床研究における新知見 アルコール性肝障害における肝移植の現状

    高木 章乃夫, 竹内 康人, 八木 孝仁, 大塚 基之

    肝胆膵   86 ( 4 )   523 - 528   2023.4

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  • 肝硬変の成因と病態の推移 当院における肝硬変の成因と病態の推移

    足立 卓哉, 高木 章乃夫, 大山 淳史, 和田 望, 竹内 康人, 大西 秀樹, 白羽 英則

    肝臓   64 ( Suppl.1 )   A266 - A266   2023.4

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  • 肝癌における非薬物療法の最前線(手術,焼灼,TACE,放射線治療) 肝細胞癌の集学的治療における放射線治療の役割

    大西 秀樹, 竹内 康人, 高木 章乃夫

    肝臓   64 ( Suppl.1 )   A172 - A172   2023.4

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  • 肝硬変の成因と病態の推移 当院における肝硬変の成因と病態の推移

    足立 卓哉, 高木 章乃夫, 大山 淳史, 和田 望, 竹内 康人, 大西 秀樹, 白羽 英則

    肝臓   64 ( Suppl.1 )   A266 - A266   2023.4

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  • 当院における免疫チェックポイント阻害薬による免疫有害事象の臨床的特徴についての検討 肝障害を中心に

    須江 真彦, 竹内 康人, 大山 淳史, 足立 卓哉, 大西 秀樹, 白羽 英則, 高木 章乃夫

    日本消化器病学会雑誌   120 ( 臨増総会 )   A272 - A272   2023.3

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  • 膵癌化学療法における血中自己抗体を用いた治療効果予測の可能性

    松本 和幸, 高木 章乃夫, 高原 政宏, 小幡 泰介, 藤井 佑樹, 山崎 辰洋, 内田 大輔, 堀口 繁, 堤 康一郎, 加藤 博也

    日本消化器病学会雑誌   120 ( 臨増総会 )   A292 - A292   2023.3

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  • 急性肝炎が遷延し,死亡に至ったE型肝炎の一例

    安中 哲也, 高木 章乃夫, 大山 淳史, 足立 卓哉, 和田 望, 坂田 雅浩, 白羽 英則, 岡田 裕之

    肝臓   64 ( 2 )   101 - 101   2023.2

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  • History of Transcatheter Arterial Chemoembolization Predicts the Efficacy of Hepatic Arterial Infusion Chemotherapy in Hepatocellular Carcinoma Patients.

    Hideki Onishi, Kazuhiro Nouso, Akinobu Takaki, Atsushi Oyama, Takuya Adachi, Nozomu Wada, Yasuto Takeuchi, Hidenori Shiraha, Hiroyuki Okada

    Acta medica Okayama   76 ( 6 )   695 - 703   2022.12

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    This study sought to identify factors that are predictive of a therapeutic response to hepatic arterial infusion chemotherapy (HAIC) by focusing on the number of prior transcatheter arterial chemoembolization (TACE) sessions. To determine the parameters predicting a good response to HAIC, we retrospectively analyzed 170 patients with hepatocellular carcinoma (HCC) who received HAIC regimens comprising low-dose cisplatin combined with 5-fluorouracil (LFP) or cisplatin (CDDP) for the first time. In both the LFP and CDDP regimens, the response rates were significantly lower in patients with three or more prior TACE sessions than in those with two or fewer prior TACE sessions (LFP 57% versus 28%; p=0.01, CDDP 27% versus 6%; p=0.01). Multivariable logistic regression analysis revealed that the number of prior TACE sessions (≥ 3) was significantly associated with non-responder status (odds ratio 4.17, 95% Confidence Interval (CI) 1.76-9.86) in addition to the HAIC regimen. Multivariable analysis using the Cox proportional hazards model revealed that a larger number of prior TACE sessions (≥ 3) was a significant risk factor for survival (hazard ratio 1.60, 95% CI 1.12-2.29) in addition to Child-Pugh class, serum alpha-fetoprotein concentration, and maximum diameter of HCC. HCC patients who receive fewer prior TACE sessions (≤ 2) were found to be better responders to HAIC.

    DOI: 10.18926/AMO/64120

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  • Pathogenesis of Severe Liver Injury in Patients with Anorexia Nervosa: A Report of Two Cases and a Literature Review.

    Masahiro Sakata, Akinobu Takaki, Atsushi Oyama, Takuya Adachi, Nozomu Wada, Yasuto Takeuchi, Tetsuya Yasunaka, Hideki Onishi, Hidenori Shiraha, Hiroyuki Okada

    The Kurume medical journal   67 ( 2.3 )   121 - 129   2022.11

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    Anorexia nervosa (AN) can cause severe protein energy malnutrition and the consequent development of various organ disorders. AN is known to cause hepatic complications. We report two cases of starvation and refeeding-induced liver injury in patients with AN, and review the literature on the hepatic complications of AN. Acute liver injury can be induced by both starvation and refeeding, although the underlying pathomechanisms and management of liver injury differ between these two conditions. Clinicians should carefully identify the clinical features to ensure an accurate diagnosis and appropriate management of these conditions.

    DOI: 10.2739/kurumemedj.MS6723011

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  • 【内科医からみた肝移植,膵・膵島移植】肝移植 アルコール性肝疾患に対する肝移植から内科診療への発展

    高木 章乃夫, 松本 洋輔, 八木 孝仁

    肝胆膵   85 ( 5 )   671 - 676   2022.11

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  • 経皮的ラジオ波焼灼療法後の穿刺経路上に低分化型肝細胞癌の播種再発をきたした1例

    須江 真彦, 大山 淳史, 足立 卓哉, 和田 望, 竹内 康人, 大西 秀樹, 白羽 英則, 高木 章乃夫

    日本消化器病学会中国支部例会・日本消化器内視鏡学会中国支部例会プログラム・抄録集   118回・129回   107 - 107   2022.11

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  • ABO血液型不適合生体肝移植目的にリツキシマブを投与したところ肝機能が改善したACLFの一例

    三宅 望, 足立 卓哉, 須江 真彦, 大山 淳史, 和田 望, 竹内 康人, 大西 秀樹, 白羽 英則, 八木 孝仁, 廣瀬 享, 高木 章乃夫

    日本消化器病学会中国支部例会・日本消化器内視鏡学会中国支部例会プログラム・抄録集   118回・129回   109 - 109   2022.11

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  • 【内科医からみた肝移植,膵・膵島移植】肝移植 アルコール性肝疾患に対する肝移植から内科診療への発展

    高木 章乃夫, 松本 洋輔, 八木 孝仁

    肝胆膵   85 ( 5 )   671 - 676   2022.11

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  • 生検検体を用いた胆道癌におけるPD-L1発現の検討

    松本 和幸, 高木 章乃夫, 大原 利章, 藤澤 真義, 高原 政宏, 加藤 博也, 吉田 龍一, 楳田 祐三, 八木 孝仁, 松川 昭博

    日本消化器病学会雑誌   119 ( 臨増大会 )   A730 - A730   2022.10

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  • 生検検体を用いた胆道癌におけるPD-L1発現の検討

    松本 和幸, 高木 章乃夫, 大原 利章, 藤澤 真義, 高原 政宏, 加藤 博也, 吉田 龍一, 楳田 祐三, 八木 孝仁, 松川 昭博

    日本消化器病学会雑誌   119 ( 臨増大会 )   A730 - A730   2022.10

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  • 当院におけるintermediate stage HCCに対するAtezolizmab/Bevacizumab治療状況

    竹内 康人, 大山 淳史, 足立 卓哉, 和田 望, 大西 秀樹, 白羽 英則, 高木 章乃夫

    肝臓   63 ( Suppl.2 )   A601 - A601   2022.9

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  • 進行肝癌に対するアテゾリズマブ+ベバシズマブ併用療法とレンバチニブ治療のアルブミン値による効果の差

    足立 卓哉, 能祖 一裕, 大山 淳史, 和田 望, 竹内 康人, 大西 秀樹, 白羽 英則, 高木 章乃夫

    肝臓   63 ( Suppl.2 )   A585 - A585   2022.9

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  • 原発性硬化性胆管炎(PSC)の自然経過にみる2021年症例の特徴

    大山 淳史, 高木 章乃夫, 足立 卓哉, 和田 望, 竹内 康人, 大西 秀樹, 白羽 英則, 岡田 裕之

    肝臓   63 ( Suppl.2 )   A562 - A562   2022.9

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  • 進行肝癌に対するアテゾリズマブ+ベバシズマブ併用療法とレンバチニブ治療のアルブミン値による効果の差

    足立 卓哉, 能祖 一裕, 大山 淳史, 和田 望, 竹内 康人, 大西 秀樹, 白羽 英則, 高木 章乃夫

    肝臓   63 ( Suppl.2 )   A585 - A585   2022.9

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  • 原発性硬化性胆管炎(PSC)の自然経過にみる2021年症例の特徴

    大山 淳史, 高木 章乃夫, 足立 卓哉, 和田 望, 竹内 康人, 大西 秀樹, 白羽 英則, 岡田 裕之

    肝臓   63 ( Suppl.2 )   A562 - A562   2022.9

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  • 当院におけるintermediate stage HCCに対するAtezolizmab/Bevacizumab治療状況

    竹内 康人, 大山 淳史, 足立 卓哉, 和田 望, 大西 秀樹, 白羽 英則, 高木 章乃夫

    肝臓   63 ( Suppl.2 )   A601 - A601   2022.9

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  • 門脈血栓症の診断と治療 当院においてアンチトロンビンIII製剤を投与した門脈血栓症16症例の検討

    和田 望, 高木 章乃夫, 大山 淳史, 足立 卓哉, 竹内 康人, 大西 秀樹, 白羽 英則

    日本門脈圧亢進症学会雑誌   28 ( 3 )   95 - 95   2022.8

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  • 門脈肺高血圧症を合併した先天性胆道閉鎖症の葛西手術後胆汁うっ滞性肝硬変の一例

    大後戸 智也, 白羽 英則, 赤木 達, 内藤 貴教, 中村 一文, 大山 淳史, 足立 卓哉, 和田 望, 竹内 康人, 大西 秀樹, 高木 章乃夫

    日本門脈圧亢進症学会雑誌   28 ( 3 )   105 - 105   2022.8

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  • 投与ラインとetiology別の観点からみたアテゾリズマブ+ベバシズマブ治療とレンバチニブ治療の違いについて

    足立 卓哉, 能祖 一裕, 大山 淳史, 和田 望, 竹内 康人, 大西 秀樹, 白羽 英則, 高木 章乃夫, 岡田 裕之

    肝胆膵   85 ( 1 )   146 - 147   2022.7

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  • 肝性浮腫に対するトルバプタン治療の効果と予後予測について

    足立 卓哉, 高木 章乃夫, 岡田 裕之, 大山 淳史, 和田 望, 竹内 康人, 大西 秀樹, 白羽 英則

    肝臓   63 ( Suppl.1 )   A428 - A428   2022.4

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  • FALD(フォンタン術後肝障害)の疫学・病態・臨床-診療ガイドラインの確立を目指して Fontan循環による肝線維化・肝細胞癌発癌の現状とリスク因子

    大西 秀樹, 高木 章乃夫, 岡田 裕之

    肝臓   63 ( Suppl.1 )   A190 - A190   2022.4

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  • Risk factors for relapse of autoimmune hepatitis in Japan: A nationwide survey. International journal

    Atsushi Takahashi, Hiromasa Ohira, Kazumichi Abe, Mikio Zeniya, Masanori Abe, Teruko Arinaga-Hino, Nobuhiro Nakamoto, Akinobu Takaki, Jong-Hon Kang, Satoru Joshita, Yoshiyuki Suzuki, Kazuhiko Koike, Ayano Inui, Atsushi Tanaka

    Hepatology research : the official journal of the Japan Society of Hepatology   52 ( 7 )   597 - 602   2022.3

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    AIM: Some autoimmune hepatitis (AIH) patients experience relapse during their clinical course, and some risk factors for relapse have been identified previously using a relatively small sample size. The aim of the present study was to identify the risk factors for relapse in recently diagnosed AIH patients using a nationwide survey in Japan. METHODS: The nationwide survey performed in Japan in 2018 of AIH patients diagnosed between 2014 and 2017 was re-evaluated. A total of 614 patients who received corticosteroids were enrolled in the present study. Associations between relapse and patients' characteristics at diagnosis were evaluated using logistic regression analysis. RESULTS: Relapse was identified in 143 (23.3%) patients after remission. At the time of diagnosis of the disease, there were significant differences in the γ-glutamyl transpeptidase (γ-GTP) level, prevalence of liver cirrhosis, and degree of liver fibrosis. Multivariable logistic regression analysis showed that γ-GTP elevation and liver cirrhosis were significantly associated with relapse. CONCLUSION: The γ-GTP level at diagnosis could help identify AIH patients at higher risk of relapse. This article is protected by copyright. All rights reserved.

    DOI: 10.1111/hepr.13766

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  • 胆管結石発症に関する腸内細菌叢の解析

    松本 和幸, 高木 章乃夫, 岡田 裕之

    日本消化器病学会雑誌   119 ( 臨増総会 )   A317 - A317   2022.3

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  • 神経内分泌腫瘍肝転移における肝動脈塞栓療法の有効性の検討

    和田 望, 堀口 繁, 岡田 裕之, 大山 淳史, 足立 卓哉, 竹内 康人, 大西 秀樹, 白羽 英則, 高木 章乃夫

    日本消化器病学会雑誌   119 ( 臨増総会 )   A399 - A399   2022.3

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  • Diagnostic Utility of the PD-L1 Immunostaining in Biopsy Specimens of Patients with Biliary Tract Neoplasms. International journal

    Kazuyuki Matsumoto, Toshiaki Ohara, Masayoshi Fujisawa, Akinobu Takaki, Masahiro Takahara, Hironari Kato, Ryuichi Yoshida, Yuzo Umeda, Takahito Yagi, Akihiro Matsukawa, Hiroyuki Okada

    Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract   26 ( 6 )   1213 - 1223   2022.2

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    BACKGROUND: Anti-programmed death 1/programmed death ligand 1 (PD1/PD-L1) antibodies have been successfully used as treatment agents for several solid tumors; however, it is difficult to predict their effectiveness. We evaluated whether biopsy specimens could predict the positive status of PD-L1 in surgically resected tissue. METHODS: Among 91 patients who underwent tissue sampling with endoscopic or liver biopsy before surgery for biliary tract neoplasms in an academic center, 45 (49%) patients were selected for retrospective analysis because the quality and quantity of their biopsy specimens were adequate for histologic evaluation. We performed immunohistochemical staining to investigate the PD-L1 expression in both resected and biopsy specimens. The percentage of the positively stained cells was calculated for subsequent use in the correlation investigation. RESULTS: The biopsy methods were endoscopic retrograde cholangiopancreatography (ERCP) in 28 cases, percutaneous liver biopsy in 10 cases, and endoscopic ultrasound fine-needle aspiration in 7 cases. Among the 45 patients, when patients with > 10% positive tumor cells in surgically resected tissues were regarded as truly positive PD-L1, the positive and negative concordance rates between surgically resected tissues and biopsy samples were 56% (5/9) and 100% (36/36), respectively. With regard to the use of preoperative biopsy as a diagnostic tool, all (5/5) PD-L1-positive patients had a positive resected specimen. The accuracy of each biopsy method was as follows: ERCP, 89% (25/28); fine-needle aspiration, 86% (6/7); and liver biopsy, 100% (10/10). CONCLUSIONS: Biopsy samples could be a surrogate material for the assessment of the PD-L1 expression with substantial positive and high negative concordance rates.

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  • FALDに挑む Fontan関連肝腫瘍 肝細胞癌と良性肝結節

    大西 秀樹, 高木 章乃夫, 岡田 裕之

    日本成人先天性心疾患学会雑誌   11 ( 1 )   172 - 172   2022.1

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  • Study Protocol for a Trial: A Single-Arm, Open-Labeled Study Evaluating Transcatheter Arterial Embolization Plus Everolimus Combination Therapy for Patients With Liver Metastasis of Gastroenteropancreatic Neuroendocrine Tumors. International journal

    Yasuto Takeuchi, Hironari Kato, Shigeru Horiguchi, Atsushi Oyama, Takuya Adachi, Nozomu Wada, Hideki Onishi, Hidenori Shiraha, Akinobu Takaki

    Clinical Medicine Insights. Oncology   16   11795549221127750 - 11795549221127750   2022

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    BACKGROUND: The number of patients with non-functional neuroendocrine tumors (NETs) has increased recently, and the rate of liver metastasis of NETs is about 20% in patients at the first diagnosis. Transcatheter arterial embolization (TAE) and everolimus are therapies with reported efficacy, but few reports have described their combined treatment. We therefore aim to evaluate the efficacy and safety of combination therapy with everolimus and TAE in patients with liver metastasis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in a prospective study. METHODS: We design a single-arm, open-label, prospective study to evaluate the efficacy and safety of combination therapy with everolimus and TAE in patients with liver metastases of GEP-NETs. The study started in June 2021 at Okayama University Hospital and is expected to enroll 18 patients over a 2-year period. DISCUSSION: This study is a prospective study investigating a new treatment method for a rare disease called GEP-NETs. We may obtain useful information that contributes to the treatment guidelines in this study. However, NET is a rare disease, and although the number of cases is statistically established, it may not be possible to accurately assess causality.TRIAL REGISTRATION NUMBER: jRCT1061210015.

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  • A case of focal nodular hyperplasia with hepatic failure treated with liver transplantation.

    Tetsuya Yasunaka, Yasuto Takeuchi, Akinobu Takaki, Fukuo Kondo, Tomoharu Yoshizumi, Kenichi Kohashi, Atsushi Oyama, Takuya Adachi, Nozomu Wada, Hideki Onishi, Hidenori Shiraha, Hiroyuki Okada

    Clinical journal of gastroenterology   15 ( 1 )   171 - 176   2021.11

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    Focal nodular hyperplasia (FNH) is a benign nodular lesion, but because of its feature of portal tract vessel abnormality, it may induce portal hypertension. A 27-year-old woman was admitted with a fever. A large nodule with satellite lesions was found in the liver and cotton wool-like feature of arteries were detected on angiography. Technetium galactosyl serum albumin scintigraphy and diagnostic laparoscopy showed that the tumor site was functional, while the surrounding area was a non-functional fibrotic area. A biopsy specimen indicated that the nodular lesion was an FNH-like lesion. She experienced several instances of variceal rupture and suffered liver failure, receiving liver transplantation. The excised liver showed a centrally scarred area in the nodule, indicating that the diagnosis was FNH. We herein report this case as a rare case of FNH that progressed to liver failure.

    DOI: 10.1007/s12328-021-01529-w

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  • Circulating tumor DNA dynamics analysis in a xenograft mouse model with esophageal squamous cell carcinoma. International journal

    Hiroyuki Terasawa, Hideaki Kinugasa, Kazuhiro Nouso, Shumpei Yamamoto, Mami Hirai, Takehiro Tanaka, Akinobu Takaki, Hiroyuki Okada

    World journal of gastroenterology   27 ( 41 )   7134 - 7143   2021.11

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    BACKGROUND: It remains unclear which factors, such as tumor volume and tumor invasion, influence circulating tumor DNA (ctDNA), and the origin of ctDNA in liquid biopsy is always problematic. To use liquid biopsies clinically, it will be very important to address these questions. AIM: To assess the origin of ctDNA, clarify the dynamics of ctDNA levels, assess ctDNA levels by using a xenograft mouse after treatment, and to determine whether tumor volume and invasion are related to ctDNA levels. METHODS: Tumor xenotransplants were established by inoculating BALB/c-nu/nu mice with the TE11 cell line. Groups of mice were injected with xenografts at two or four sites and sacrificed at the appropriate time point after xenotransplantation for ctDNA analysis. Analysis of ctDNA was performed by droplet digital PCR, using the human telomerase reverse transcriptase (hTERT) gene. RESULTS: Mice given two-site xenografts were sacrificed for ctDNA at week 4 and week 8. No hTERT was detected at week 4, but it was detected at week 8. However, in four-site xenograft mice, hTERT was detected both at week 4 and week 6. These experiments revealed that both tumor invasion and tumor volume were associated with the detection of ctDNA. In resection experiments, hTERT was detected at resection, but had decreased by 6 h, and was no longer detected 1 and 3 d after resection. CONCLUSION: We clarified the origin and dynamics of ctDNA, showing that tumor volume is an important factor. We also found that when the tumor was completely resected, ctDNA was absent after one or more days.

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  • トルバプタンを導入した肝硬変患者における血管拡張抑制物質ADMA測定の意義

    竹内 康人, 大山 淳史, 足立 卓哉, 和田 望, 大西 秀樹, 白羽 英則, 高木 章乃夫, 岡田 裕之

    肝臓   62 ( Suppl.3 )   A740 - A740   2021.11

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  • Fontan関連肝疾患を背景に肝細胞腺腫を発症した一例

    國富 恵実, 大西 秀樹, 大山 淳史, 足立 卓哉, 和田 望, 竹内 康人, 白羽 英則, 高木 章乃夫, 岡田 裕之

    日本消化器病学会中国支部例会・日本消化器内視鏡学会中国支部例会プログラム・抄録集   116回・127回   85 - 85   2021.11

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  • アテゾリズマブ・ベバシズマブ併用療法の実臨床での治療効果

    足立 卓哉, 能祖 一裕, 大山 淳史, 和田 望, 竹内 康人, 大西 秀樹, 白羽 英則, 高木 章乃夫, 守屋 昭男, 小橋 春彦, 岩堂 昭太, 岡田 裕之

    肝臓   62 ( Suppl.3 )   A759 - A759   2021.11

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  • Transformation to diffuse large B-cell lymphoma with germinal center B-cell like subtype and discordant light chain expression in a patient with Waldenström macroglobulinemia/lymphoplasmacytic lymphoma.

    Hiroki Kobayashi, Noboru Asada, Yuria Egusa, Tomoka Ikeda, Misa Sakamoto, Masaya Abe, Daisuke Ennishi, Masahiro Sakata, Akinobu Takaki, Soichiro Kawahara, Yusuke Meguri, Hisakazu Nishimori, Nobuharu Fujii, Ken-Ichi Matsuoka, Yasuharu Sato, Tadashi Yoshino, Yoshinobu Maeda

    International journal of hematology   114 ( 3 )   401 - 407   2021.9

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    Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare indolent B-cell neoplasm, and a gain-of-function mutation in the myeloid differentiation primary response 88 (MYD88), L265P, is a commonly recurring mutation in patients with WM/LPL. Histological transformation of WM/LPL to an aggressive lymphoma such as diffuse large B-cell lymphoma (DLBCL) is rare, and transformed DLBCL has a worse prognosis than de novo DLBCL, partly because transformed DLBCL is mostly classified as non-germinal center B-cell-like (non-GCB) subtype. We herein describe a 75-year-old man with DLBCL with a history of WM/LPL. DLBCL in this patient showed the GCB subtype, and the light chain restriction of DLBCL was different from that of the antecedent WM/LPL, indicating that the two types of lymphoma cells had distinctive origins. However, DLBCL in this patient harbored the MYD88 L265P mutation, and polymerase chain reaction and Sanger sequencing of the DLBCL and WM/LPL for immunoglobulin heavy chain gene rearrangement suggested a clonal relationship between the two lymphomas. Since the outcome of transformed DLBCL is worse than for de novo DLBCL, it is important to evaluate the clonal relationship between primary WM/LPL and the corresponding transformed DLBCL, even if the DLBCL expresses a GCB subtype or discordant light chain restriction.

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  • トルバプタンによる腹水治療に伴う肝移植時状態の変化

    和田 望, 高木 章乃夫, 大山 淳史, 足立 卓哉, 竹内 康人, 大西 秀樹, 白羽 英則, 岡田 裕之

    肝臓   62 ( Suppl.2 )   A537 - A537   2021.9

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  • アテゾリズマブとベバシズマブの併用療法おける1stライン使用と2ndライン以降の使用の違いについて

    足立 卓哉, 能祖 一裕, 大山 淳史, 和田 望, 竹内 康人, 大西 秀樹, 白羽 英則, 高木 章乃夫, 狩山 和也, 岩堂 昭太, 守屋 昭男, 岡田 裕之

    肝臓   62 ( Suppl.2 )   A551 - A551   2021.9

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  • 急性肝不全に陥ることなく致死的経過を辿った急性E型肝炎の1例

    山内 菜緒, 安中 哲也, 高木 章乃夫, 日並 義統, 木野村 賢, 河原 明奈, 足立 卓哉, 大山 淳史, 和田 望, 竹内 康人, 大西 秀樹, 白羽 英則, 岡田 裕之

    肝臓   62 ( 8 )   463 - 470   2021.8

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  • 急性肝不全に陥ることなく致死的経過を辿った急性E型肝炎の1例

    山内 菜緒, 安中 哲也, 高木 章乃夫, 日並 義統, 木野村 賢, 河原 明奈, 足立 卓哉, 大山 淳史, 和田 望, 竹内 康人, 大西 秀樹, 白羽 英則, 岡田 裕之

    肝臓   62 ( 8 )   463 - 470   2021.8

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    症例は64歳,男性.過去の健診でビリルビン高値の指摘あり.家人に黄疸を指摘され,前医を受診,AST 1526U/l,ALT 2058U/lと肝障害を認め入院,ビリルビン上昇も伴っていたが,PT正常で急性肝不全には陥っていなかった.HEV RNA陽性が判明,肝生検で急性肝炎像を呈しており,急性E型肝炎として保存的加療となった.Transaminseは低下,PTも正常範囲を維持,HEV RNA陰性化したが高ビリルビン血症悪化,第75病日に転院.急性腎不全を合併,消化管出血,更に細菌性・真菌性敗血症を合併し,第169病日に死亡した.病理解剖にて,肝臓は萎縮もなく,肝細胞壊死や肝線維化は軽度で強い胆汁栓を認める所見であった.肝合成能は維持されるも胆汁うっ滞が遷延し,全身合併症により死亡したと考えられ,移植適応をどう考えていくかを含めて示唆に富む症例であり,報告する.(著者抄録)

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    Other Link: https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J00263&link_issn=&doc_id=20210811100004&doc_link_id=10.2957%2Fkanzo.62.463&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.62.463&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

  • Randomized controlled study to examine the efficacy of hepatic arterial infusion chemotherapy with cisplatin before radiofrequency ablation for hepatocellular carcinoma. International journal

    Atsushi Oyama, Kazuhiro Nouso, Kenichi Yoshimura, Yuki Morimoto, Shinichiro Nakamura, Hideki Onishi, Akinobu Takaki, Shouta Iwadou, Kazuya Kariyama, Kenji Kuwaki, Kazuhisa Yabushita, Kosaku Sakaguchi, Jyunichi Toshimori, Haruhiko Kobashi, Akio Moriya, Masaharu Ando, Hiroyuki Okada

    Hepatology research : the official journal of the Japan Society of Hepatology   51 ( 6 )   694 - 701   2021.6

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    AIM: Hepatic arterial infusion chemotherapy (HAIC) with cisplatin is beneficial to patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. This study aimed to examine the effect of HAIC with cisplatin before radiofrequency ablation (RFA) in patients with HCC. METHODS: This was a multicenter, single-blinded, randomized controlled study (UMIN000007267). Early-stage HCC patients were randomly assigned (1:1) to receive HAIC with cisplatin before RFA therapy (HAIC group) or RFA monotherapy (non-HAIC group). The primary end-point was recurrence-free survival. Efficacy analysis and safety analysis followed the intention-to-treat principle. RESULTS: Between August 2012 and July 2016, 74 patients were recruited. A total of 70 eligible patients were randomly assigned to the HAIC group (n = 35) and non-HAIC group (n = 35). Recurrence-free survival rates at 1 (3) year in the HAIC group and non-HAIC group were 82.9% (54.3%) and 74.3% (34.3%), respectively (hazard ratio [HR], 0.597; 95% confidence interval [CI], 0.320-1.091; p = 0.094]. Subgroup analysis showed that the beneficial effect of HAIC was observed in patients with a single nodule and Child-Pugh score 5. Intrahepatic distant recurrence-free survival rate in the HAIC group was significantly better than that in the non-HAIC group (HR, 0.468; 95% CI, 0.235-0.896; p = 0.022). Adverse events were observed in just two patients in the HAIC group (6%) - grade 2 cholecystitis and grade 2 hyperkalemia. CONCLUSIONS: HAIC with cisplatin before RFA did not significantly decrease recurrence in patients with early-stage HCC. However, it might be effective in preventing intrahepatic distant recurrence.

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  • Management of Cirrhotic Ascites under the Add-on Administration of Tolvaptan. International journal

    Takuya Adachi, Yasuto Takeuchi, Akinobu Takaki, Atsushi Oyama, Nozomu Wada, Hideki Onishi, Hidenori Shiraha, Hiroyuki Okada

    International journal of molecular sciences   22 ( 11 )   2021.5

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    Tolvaptan is a recently available diuretic that blocks arginine vasopressin receptor 2 in the renal collecting duct. Its diuretic mechanism involves selective water reabsorption by affecting the water reabsorption receptor aquaporin 2. Given that liver cirrhosis patients exhibit hyponatremia due to their pseudo-aldosteronism and usage of natriuretic agents, a sodium maintaining agent, such as tolvaptan, is physiologically preferable. However, large scale studies indicating the patients for whom this would be effective and describing management under its use have been insufficient. The appropriate management of cirrhosis patients treated with tolvaptan should be investigated. In the present review, we collected articles investigating the effectiveness of tolvaptan and factors associated with survival and summarized their management reports. Earlier administration of tolvaptan before increasing the doses of natriuretic agents is recommended because this may preserve effective arterial blood volume.

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  • Abnormal fucosylation of alpha-fetoprotein in patients with nonalcoholic steatohepatitis. International journal

    Kazuhiro Nouso, Yoshie Furubayashi, Kazuya Kariyama, Akiko Wakuta, Nozomi Miyake, Kanae Inoue, Yuta Nagai, Shiho Murakami, Takuya Adachi, Atsushi Oyama, Nozomu Wada, Yasuto Takeuchi, Masahiro Sakata, Tetsuya Yasunaka, Hideki Onishi, Hidenori Shiraha, Akinobu Takaki, Shohei Shiota, Satoshi Yasuda, Hidenori Toyoda, Miwa Kawanaka, Takashi Kumada, Hiroyuki Okada

    Hepatology research : the official journal of the Japan Society of Hepatology   51 ( 5 )   548 - 553   2021.5

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    AIM: Nonalcoholic steatohepatitis (NASH) is a risk factor for nonvirus-related hepatocellular carcinoma, which is increasing in prevalence. The aim of this study was to clarify the clinical application of fucosylated alpha-fetoprotein (AFP-L3) in the process of nonalcoholic fatty liver (NAFL) disease development. METHODS: Serum samples from 115 diabetes mellitus (DM), 36 NAFL, and 119 NASH patients were analyzed for AFP-L3 expression using raw data of a micro total analysis system. These data were then compared with the clinical characteristics of the patients. A validation study was also undertaken with 55 samples (17 NAFL and 38 NASH). RESULTS: Trace amounts of AFP-L3 were detected in 3.5%, 16.7%, and 58.0% of patients with DM, NAFL, and NASH, respectively. The odds ratio of AFP-L3 positivity for the diagnosis of NASH in multivariate analysis was 9.81 (95% confidence interval, 3.77-25.5). The rates in patients without fibrosis or with stage 1, stage 2, stage 3, and stage 4 fibrosis were 14.7%, 31.3%, 63.0%, 86.2%, and 100%, respectively. The rates were significantly increased according to the advancement of liver fibrosis (p < 0.001); however, no difference in the positive rate of AFP-L3 was observed between patients with and without fatty livers and between patients with normal and abnormal transaminase. The same relationship was also observed in the validation cohort. CONCLUSION: Abnormal fucosylation of AFP occurred in patients with NASH, so it could be useful for the screening of NASH in patients with DM, as well as for the differential diagnosis of NASH and the evaluation of fibrosis.

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  • 好中球性白血病との鑑別が問題となったアルコール性肝炎増悪による急性肝不全症例

    稲生 祥子, 安中 哲也, 高木 章乃夫, 大山 敦史, 足立 卓哉, 和田 望, 竹内 康人, 大西 秀樹, 白羽 英則, 岡田 裕之

    日本消化器病学会中国支部例会プログラム・抄録集   115回   88 - 88   2021.5

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  • Prediction of the prognosis of advanced hepatocellular carcinoma by TERT promoter mutations in circulating tumor DNA. International journal

    Mami Hirai, Hideaki Kinugasa, Kazuhiro Nouso, Shumpei Yamamoto, Hiroyuki Terasawa, Yuma Onishi, Atsushi Oyama, Takuya Adachi, Nozomu Wada, Masahiro Sakata, Tetsuya Yasunaka, Hideki Onishi, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada

    Journal of gastroenterology and hepatology   36 ( 4 )   1118 - 1125   2021.4

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    BACKGROUND ANDAIM: Human telomerase reverse transcriptase (TERT) promoter mutations were the most prevalent mutations in patients with hepatocellular carcinoma (HCC). We tried to detect the mutations with plasma circulating tumor DNA (ctDNA) in patients with advanced HCC and elucidated their clinical utility. METHODS: Circulating tumor DNA in plasma was extracted from 130 patients with advanced HCC who were treated with systemic chemotherapy (n = 86) or transcatheter arterial chemoembolization (n = 44), and TERT promoter mutations were examined with digital droplet polymerase chain reaction. The correlations between these mutations and the clinical outcome of patients were analyzed. RESULTS: Of the 130 patients examined, 71 patients (54.6%) were positive for TERT promoter mutations in ctDNA, of which 64 patients were -124bp G > A and 10 were -146bp G > A. The presence of TERT promoter mutations was correlated with large intrahepatic tumor size (P = 0.05) and high des-gamma carboxyprothrombin (P = 0.005). Overall survival of the patients with the mutations was significantly shorter than those without them (P < 0.001), and the patients with high (≥ 1%) fractional abundance of the mutant alleles showed shorter survival than those with low (< 1%) fractional abundance. Multivariate analysis revealed that TERT promoter mutation (hazard ratio [HR]: 1.94; 95% confidence interval [CI], 1.18-3.24; P < 0.01), systemic chemotherapy (HR: 2.38; 95% CI, 1.29-4.57; P < 0.01), and vascular invasion (HR: 2.16; 95% CI, 1.22-3.76; P < 0.01) were significant factors for poor overall survival. CONCLUSIONS: TERT promoter mutations in ctDNA were associated with short survival and could be a valuable biomarker for predicting the prognosis of patients with advanced HCC.

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  • 肝疾患移行期医療の現状と問題点 移行期医療におけるFontan関連肝疾患(FALD)診療の現状と問題

    大西 秀樹, 高木 章乃夫, 岡田 裕之

    肝臓   62 ( Suppl.1 )   A166 - A166   2021.4

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  • Differences in autoimmune hepatitis based on inflammation localization

    Atsushi Takahashi, Hiromasa Ohira, Kazumichi Abe, Mikio Zeniya, Masanori Abe, Teruko Arinaga-Hino, Takuji Torimura, Kaname Yoshizawa, Akinobu Takaki, Jong-Hon Kang, Yoshiyuki Suzuki, Nobuhiro Nakamoto, Ayano Inui, Atsushi Tanaka, Hajime Takikawa

    Medical Molecular Morphology   54 ( 1 )   8 - 13   2021.3

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    Histopathology is essential for the diagnosis and evaluation of disease activity of autoimmune hepatitis (AIH). We aimed to elucidate the characteristics of AIH from the localization of inflammation. We re-evaluated a nationwide survey that was performed in Japan in 2018 of AIH patients diagnosed between 2014 and 2017. A total of 303 patients were enrolled, and the clinical and treatment characteristics were compared between the patients with predominantly portal inflammation (230 patients) or lobular inflammation (73 patients). AIH patients with lobular inflammation had a higher probability of being diagnosed with acute hepatitis than those with portal inflammation. Liver enzyme levels were higher in patients with lobular inflammation, whereas immunoglobulin G levels were higher in patients with portal inflammation. The prevalence of an alanine aminotransferase level < 30 U/L after 6 months of treatment was significantly higher in patients with lobular inflammation than in those with portal inflammation (81.7% vs. 67.3%, P = 0.046). The localization of inflammation may be useful for evaluating the onset of AIH.

    DOI: 10.1007/s00795-020-00255-5

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  • The transition in the etiologies of hepatocellular carcinoma-complicated liver cirrhosis in a nationwide survey of Japan.

    Hirayuki Enomoto, Yoshiyuki Ueno, Yoichi Hiasa, Hiroki Nishikawa, Shuhei Hige, Yasuhiro Takikawa, Makiko Taniai, Toru Ishikawa, Kohichiroh Yasui, Akinobu Takaki, Koichi Takaguchi, Akio Ido, Masayuki Kurosaki, Tatsuya Kanto, Shuhei Nishiguchi

    Journal of gastroenterology   56 ( 2 )   158 - 167   2021.2

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    BACKGROUND: We recently reported the real-world changes in the etiologies of liver cirrhosis (LC) based on nationwide survey data and assessed the etiologies of LC with hepatocellular carcinoma (HCC). METHODS: Fifty-five participants from 68 institutions provided data on 23,637 patients with HCC-complicated LC. The changing trends in etiologies were assessed. We further analyzed the data from 29 hospitals that provided the annual number of newly identified HCC-complicated LC patients from 2008 to 2016 (N = 9362) without any missing years and assessed the transition in the real number of newly identified HCC-complicated LC cases. RESULTS: In the overall cohort, hepatitis C virus (HCV) infection (60.3%) and hepatitis B virus (HBV) infection (12.9%) were the leading and third-most common causes of HCC-complicated LC in Japan, respectively. HCV infection was found to be the leading cause throughout Japan. The rate of viral hepatitis-related HCC decreased from 85.3 to 64.4%. Among non-viral etiologies, notable increases were observed in nonalcoholic steatohepatitis (NASH)-related HCC (from 1.5 to 7.2%) and alcoholic liver disease (ALD)-related HCC (from 8.5 to 18.6%). Regarding the real number of newly diagnosed patients, the number of patients with viral hepatitis-related HCC decreased, while the number of patients with non-viral HCC, particularly NASH-related HCC, increased. CONCLUSIONS: Viral hepatitis has remained the main cause of HCC in Japan. However, the decrease in viral hepatitis-related HCC, particularly HCV-related HCC highly contributed to the etiological changes. In addition, the increased incidence of non-viral HCC, particularly NASH-related HCC, was involved in the changing etiologies of HCC-complicated LC in Japan.

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  • Lethal biliary congestive acute hepatitis e without acute liver failure: A case report

    Nao Yamauchi, Tetsuya Yasunaka, Akinobu Takaki, Yoshimune Hinami, Masaru Kinomura, Akina Kawahara, Takuya Adachi, Atsushi Oyama, Nozomu Wada, Yasuto Takeuchi, Hideki Onishi, Hidenori Shiraha, Hiroyuki Okada

    Acta Hepatologica Japonica   62 ( 8 )   463 - 470   2021

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    A 64-year-old man in whom benign hyperbilirubinemia had been identified was found to suffer from acute hepatitis E. Laboratory examination of the patient revealed high transaminase levels and hyperbilirubinemia, suggesting acute hepatitis, while the prothrombin time was within the normal range. The transaminase levels decreased and prothrombin time remained within the normal range; however, hyperbilirubinemia worsened to 39 mg/dl. The patient developed the complications of acute renal failure and sepsis, and eventually died. An autopsy was performed that showed no liver atrophy, liver fibrosis progression, or massive necrosis. The lung and kidney were revealed to be positive for fungal infection. The kidney was revealed to exhibit tubular conges-tion with bile. The present case offers information on the clinical course of acute hepatitis E in relatively elderly patients.

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  • High expression of a vascular stricture‐related marker is predictive of an early response to tolvaptan, and a low fractional excretion of sodium is predictive of a poor long‐term survival after tolvaptan administration for liver cirrhosis

    Takuya Adachi, Akinobu Takaki, Shuichi Sato, Hiroshi Tobita, Haruhiko Kobashi, Masaru Kinomura, Atsuko Nakatsuka, Atsushi Oyama, Nozomu Wada, Masahiro Sakata, Yasuto Takeuchi, Tetsuya Yasunaka, Hideki Onishi, Hidenori Shiraha, Hiroyuki Okada

    Hepatology Research   50 ( 12 )   1347 - 1354   2020.12

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    DOI: 10.1111/hepr.13573

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  • Quality of life among patients with autoimmune hepatitis in remission International journal

    Atsushi Takahashi, Masanori Abe, Tetsuya Yasunaka, Teruko Arinaga-Hino, Kazumichi Abe, Akinobu Takaki, Takuji Torimura, Mikio Zeniya, Kaname Yoshizawea, Jong-Hon Kang, Yoshiyuki Suzuki, Nobuhiro Nakamoto, Ayano Inui, Atsushi Tanaka, Hajime Takikawa, Hiromasa Ohira

    Medicine   99 ( 43 )   e22764 - e22764   2020.10

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    Health-related quality of life (HRQOL) is lower in individuals with autoimmune hepatitis (AIH) than in the general population. However, previous evaluations of HRQOL for AIH have included a broad range of disease activities. The aim of this study was to clarify HRQOL among patients with AIH in remission.We assessed HRQOL in patients with AIH in remission, patients with chronic hepatitis C (CHC) with eradicated hepatitis C virus (HCV) and patients with primary biliary cholangitis (PBC) using the Japanese version of the Chronic Liver Disease Questionnaire (CLDQ).Participants comprised 62 patients with AIH in remission, 39 patients with CHC with eradicated HCV and 66 patients with PBC. Median ages of patients were 63, 69, and 64 years, respectively. Overall score (5.6 vs 5.9, P = .02) and fatigue (5.2 vs 5.6, P = .01) and worry (5.6 vs 6.0, P = .01) domain scores of the CLDQ were significantly lower in patients with AIH in remission than in CHC with eradicated HCV, and similar to scores except for the systemic symptoms domain in patients with PBC. Disease duration was associated with lower scores on systemic symptoms and activity domains of the CLDQ in patients with AIH in remission.Patients with AIH in remission show impaired HRQOL associated with disease duration.

    DOI: 10.1097/md.0000000000022764

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  • 門脈圧亢進症性肺病変(肺高血圧症、肝肺症候群など) 肝硬変合併肺病変の移植後経過より見た病態

    大山 淳史, 高木 章乃夫, 安中 哲也, 足立 卓哉, 坂田 雅浩, 和田 望, 竹内 康人, 大西 秀樹, 白羽 英則, 岡田 裕之

    日本門脈圧亢進症学会雑誌   26 ( 3 )   102 - 102   2020.10

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  • Increasing incidence of acute autoimmune hepatitis: a nationwide survey in Japan. International journal

    Atsushi Takahashi, Hiromasa Ohira, Kazumichi Abe, Mikio Zeniya, Masanori Abe, Teruko Arinaga-Hino, Takuji Torimura, Kaname Yoshizawa, Akinobu Takaki, Jong-Hon Kang, Yoshiyuki Suzuki, Nobuhiro Nakamoto, Ayano Inui, Atsushi Tanaka, Hajime Takikawa

    Scientific reports   10 ( 1 )   14250 - 14250   2020.8

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    The Japanese diagnostic guidelines for autoimmune hepatitis (AIH) were proposed in 2014. This study aimed to determine the trends and characteristics of AIH based on a Japanese nationwide survey. Data for 796 patients who were newly diagnosed with AIH from 2014 to 2017 were collected from January to March, 2019 from 54 hospitals throughout Japan. Clinical characteristics, including treatment, were compared with those reported in a prior 2015 survey. The population had a median age of 63 years at diagnosis, and the male to female ratio was 1:5.3. The numbers of women was significantly lower in this survey than in the 2015 survey. Moreover, the incidence of AIH with histological acute hepatitis increased significantly from 11.0 to 21.7%. The changes in the laboratory findings, such as in transaminase and immunoglobulin G levels and antinuclear antibody titers, as well as in prednisolone treatment, reflected an increasing incidence of acute AIH. The clinical characteristics of AIH changed rapidly, in parallel with the increasing incidence of acute AIH. The elucidation and diagnosis of AIH with acute hepatitis are important in the management of AIH.

    DOI: 10.1038/s41598-020-71296-0

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  • Decreased Serum Antioxidant Marker is Predictive of Early Recurrence in the Same Segment after Radical Ablation for Hepatocellular Carcinoma.

    Taiko Muro, Shinichiro Nakamura, Akinobu Takaki, Hideki Onishi, Nozomu Wada, Tetsuya Yasunaka, Daisuke Uchida, Atsushi Oyama, Takuya Adachi, Hidenori Shiraha, Hiroyuki Okada

    Acta medica Okayama   74 ( 4 )   275 - 283   2020.8

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    Radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is a promising method for controlling tumors, although it does not entirely eliminate recurrence. Oxidative stress is associated with the progression of hepatocarcinogenesis, while also acting as an anticancer response. The objective of the present study was to investigate the factors influencing post-RFA outcomes. We recruited 235 newly diagnosed HCC patients who received RFA for single tumors. The patients with recurrence were sub-grouped into early and segmental recurrence groups. The characteristics of the sub-grouped patients were evaluated, including by measuring oxidative stress marker reactive oxygen metabolites and antioxidant marker OXY-adsorbent tests. The factors associated with poor survival were a high Child-Pugh score and early recurrence within 2 years in the same segment. The patients who experienced recurrence within 2 years in the same segment showed a larger tumor diameter than did others. According to a multivariate analysis, the OXY values were also significantly low in these patients. In conclusion, maintaining the antioxidant reservoir function with a high OXY value might be necessary to prevent early recurrence within the RFA-treated segment.

    DOI: 10.18926/AMO/60364

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  • The Early Decline of α-Fetoprotein and Des-γ-Carboxy Prothrombin Predicts the Response of Hepatic Arterial Infusion Chemotherapy in Hepatocellular Carcinoma Patients. International journal

    Shumpei Yamamoto, Hideki Onishi, Akinobu Takaki, Atsushi Oyama, Takuya Adachi, Nozomu Wada, Masahiro Sakata, Tetsuya Yasunaka, Hidenori Shiraha, Hiroyuki Okada

    Gastrointestinal tumors   7 ( 3 )   83 - 92   2020.7

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    Introduction: Molecular targeting drugs are recommended as second-line treatment for intrahepatic advanced hepatocellular carcinoma (HCC). However, in Asia, hepatic arterial infusion chemotherapy (HAIC) is also considered as a second-line treatment because it improves the survival of responders. The aim of this study was to predict responders and non-responders to HAIC with low-dose cisplatin plus 5-fluorouracil (LFP) using tumor markers. Objective and Methods: The data of 47 patients who received LFP for the first time in our hospital were analyzed retrospectively. We evaluated the association between treatment response by Response Evaluation Criteria in Solid Tumors and the changing ratio of the serum concentration of α-fetoprotein (AFP), Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and des-γ-carboxy prothrombin (DCP) 2 weeks after LFP initiation. Results: The number of patients showing a complete response (CR), a partial response (PR), stable disease (SD), and progressive disease (PD) was 0 (0%), 20 (43%), 18 (38%), and 9 (19%), respectively. The AFP ratio showed significant positive correlations for PR vs. SD (p = 0.004) and PR vs. PD (p = 0.003). The DCP ratio correlated significantly for PR vs. SD (p = 0.02). The optimal cutoff values for responders were 0.79 for the AFP ratio and 0.53 for the DCP ratio. Prediction using both or either cutoff value showed 93% sensitivity, 53% specificity, a 94% negative predictive value, and a 57% positive predictive value. Conclusion: Optimal cutoff values for AFP and DCP ratios enable prediction of nonresponders to HAIC with LFP. This simple and early assessment method allows the use of HAIC and molecular targeting drugs for HCC treatment.

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  • ベルベリンによる慢性腸炎マウスの腸内細菌叢の変化

    高原 政宏, 高木 章乃夫, 平岡 佐規子, 安富 絵里子, 山本 峻平, 岡 昌平, 平井 麻美, 山崎 泰史, 井口 俊博, 衣笠 秀明, 原田 馨太, 岡田 裕之

    日本消化器病学会雑誌   117 ( 臨増総会 )   A275 - A275   2020.7

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  • 進行肝細胞癌に対する分子標的薬による治療効果及び肝予備能の変化

    足立 卓哉, 能祖 一裕, 大山 淳史, 和田 望, 坂田 雅浩, 安中 哲也, 大西 秀樹, 白羽 英則, 高木 章乃夫, 岡田 裕之

    日本消化器病学会雑誌   117 ( 臨増総会 )   A292 - A292   2020.7

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  • 肝性浮腫に対するトルバプタン効果予測と予後予測について

    足立 卓哉, 高木 章乃夫, 佐藤 秀一, 大山 淳史, 和田 望, 坂田 雅浩, 安中 哲也, 大西 秀樹, 白羽 英則, 岡田 裕之

    日本消化器病学会雑誌   117 ( 臨増総会 )   A371 - A371   2020.7

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  • 成人先天性心疾患におけるFontan関連肝疾患(FALD)の現状と問題点

    大西 秀樹, 高木 章乃夫, 能祖 一裕, 大山 淳史, 足立 卓哉, 和田 望, 坂田 雅浩, 安中 哲也, 白羽 英則, 岡田 裕之

    日本消化器病学会雑誌   117 ( 臨増総会 )   A369 - A369   2020.7

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  • Oxidative Stress Management in Chronic Liver Diseases and Hepatocellular Carcinoma. Reviewed International journal

    Daisuke Uchida, Akinobu Takaki, Atsushi Oyama, Takuya Adachi, Nozomu Wada, Hideki Onishi, Hiroyuki Okada

    Nutrients   12 ( 6 )   2020.5

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    Chronic viral hepatitis B and C and non-alcoholic fatty liver disease (NAFLD) have been widely acknowledged to be the leading causes of liver cirrhosis and hepatocellular carcinoma. As anti-viral treatment progresses, the impact of NAFLD is increasing. NAFLD can coexist with chronic viral hepatitis and exacerbate its progression. Oxidative stress has been recognized as a chronic liver disease progression-related and cancer-initiating stress response. However, there are still many unresolved issues concerning oxidative stress, such as the correlation between the natural history of the disease and promising treatment protocols. Recent findings indicate that oxidative stress is also an anti-cancer response that is necessary to kill cancer cells. Oxidative stress might therefore be a cancer-initiating response that should be down regulated in the pre-cancerous stage in patients with risk factors for cancer, while it is an anti-cancer cell response that should not be down regulated in the post-cancerous stage, especially in patients using anti-cancer agents. Antioxidant nutrients should be administered carefully according to the patients' disease status. In this review, we will highlight these paradoxical effects of oxidative stress in chronic liver diseases, pre- and post-carcinogenesis.

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  • 肝疾患における移行期医療 移行期医療におけるFontan関連肝疾患(FALD)の現状と問題点

    大西 秀樹, 高木 章乃夫, 岡田 裕之

    肝臓   61 ( Suppl.1 )   A139 - A139   2020.4

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  • REIC/Dkk-3遺伝子治療併用による肝癌治療の効果増強

    白羽 英則, 大山 淳史, 足立 卓哉, 和田 望, 坂田 雅浩, 安中 哲也, 大西 秀樹, 岡田 裕之, 高木 章乃夫

    肝臓   61 ( Suppl.1 )   A389 - A389   2020.4

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  • 肝性浮腫患者のトルバプタン効果と予後の予測

    足立 卓哉, 高木 章乃夫, 佐藤 秀一, 大山 淳史, 和田 望, 坂田 雅浩, 安中 哲也, 大西 秀樹, 白羽 英則, 岡田 裕之

    肝臓   61 ( Suppl.1 )   A350 - A350   2020.4

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  • Transition in the etiology of liver cirrhosis in Japan: a nationwide survey. Reviewed

    Hirayuki Enomoto, Yoshiyuki Ueno, Yoichi Hiasa, Hiroki Nishikawa, Shuhei Hige, Yasuhiro Takikawa, Makiko Taniai, Toru Ishikawa, Kohichiroh Yasui, Akinobu Takaki, Koichi Takaguchi, Akio Ido, Masayuki Kurosaki, Tatsuya Kanto, Shuhei Nishiguchi

    Journal of gastroenterology   55 ( 3 )   353 - 362   2020.3

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    BACKGROUND: To assess the recent real-world changes in the etiologies of liver cirrhosis (LC) in Japan, we conducted a nationwide survey in the annual meeting of the Japan Society of Hepatology (JSH). METHODS: We investigated the etiologies of LC patients accumulated from 68 participants in 79 institutions (N = 48,621). We next assessed changing trends in the etiologies of LC by analyzing cases in which the year of diagnosis was available (N = 45,834). We further evaluated the transition in the real number of newly identified LC patients by assessing data from 36 hospitals with complete datasets for 2008-2016 (N = 18,358). RESULTS: In the overall data, HCV infection (48.2%) was the leading cause of LC in Japan, and HBV infection (11.5%) was the third-most common cause. Regarding the transition in the etiologies of LC, the contribution of viral hepatitis-related LC dropped from 73.4 to 49.7%. Among the non-viral etiologies, alcoholic-related disease (ALD) and nonalcoholic steatohepatitis (NASH)-related LC showed a notable increase (from 13.7 to 24.9% and from 2.0 to 9.1%, respectively). Regarding the real numbers of newly diagnosed patients from 2008 to 2016, the numbers of patients with viral hepatitis-related LC decreased, while the numbers of patients with non-viral LC increased. CONCLUSIONS: HCV has remained the main cause of LC in Japan; however, the contribution of viral hepatitis as an etiology of LC is suggested to have been decreasing. In addition, non-viral LC, such as ALD-related LC and NASH-related LC, is suggested to have increased as etiologies of LC in Japan.

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  • Severe Colitis Caused by Hepatic Arterial Infusion Chemotherapy with Cisplatin for Hepatocellular Carcinoma.

    Shumpei Yamamoto, Hideki Onishi, Atsushi Oyama, Akinobu Takaki, Hiroyuki Okada

    Internal medicine (Tokyo, Japan)   59 ( 1 )   69 - 75   2020.1

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    A 78-year-old man with chronic hepatitis C underwent hepatectomy for hepatocellular carcinoma (HCC) 11 years prior to presentation. He was diagnosed with multiple intrahepatic recurrences of HCC with portal vein invasion and received hepatic arterial infusion chemotherapy (HAIC) with cisplatin. He developed abdominal pain, diarrhea, and blood-stained stool following treatment. Computed tomography revealed significant bowel wall thickening throughout the colon. Colonoscopy revealed reddish edematous mucosa with a reduced vascular pattern without ischemic changes. Conservative treatment with total parenteral nutrition improved his condition and his imaging findings. This is the first report of severe colitis following HAIC with cisplatin.

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  • Human Telomerase Reverse Transcriptase Gene Promoter Mutation in Serum of Patients with Hepatocellular Carcinoma. International journal

    Soichiro Ako, Kazuhiro Nouso, Hideaki Kinugasa, Hiroshi Matsushita, Hiroyuki Terasawa, Takuya Adachi, Nozomu Wada, Yasuto Takeuchi, Mari Mandai, Hideki Onishi, Fusao Ikeda, Hidenori Shiraha, Akinobu Takaki, Shinichi Fujioka, Tetsushige Mimura, Hiroyuki Okada

    Oncology   98 ( 5 )   311 - 317   2020

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    BACKGROUND: Mutations in the human telomerase reverse transcriptase (hTERT) gene promoter have been reported in hepatocellular carcinoma (HCC); however, analyses of these mutations in liquid biopsies have been technically difficult because of the high GC content of the regions of interest within this promoter. We evaluated the feasibility and prognostic value of hTERT promoter mutations identified in circulating cell-free DNA (cfDNA) from the serum of patients with HCC. OBJECTIVE: A cohort of HCC patients (n = 36) who were curatively treated by surgical resection between June 2003 and September 2014 were enrolled in this study. METHODS: The presence of hTERT promoter mutations in cfDNA from the patients' serum was analyzed via modified droplet digital polymerase chain reaction, and associations were sought between specific promoter mutations and patients' disease-free survival (DFS). RESULTS: The G>A hTERT mutation at -124 bp was detected in the serum of 25 patients (69%). Although no marked differences were observed between the characteristics of the serum mutation-positive and serum mutation-negative patient groups, the DFS of patients with the mutation was significantly shorter than that of the serum mutation-negative patients (p = 0.02). Among 18 clinicopathologic and background liver factors examined, the presence of the -124 bp G>A mutation was an independent and significant predictor of patients' DFS (hazard ratio = 3.01, 95% confidence interval 1.11-10.5, p = 0.03) in multivariate analyses. CONCLUSIONS: The -124 bp G>A hTERT promoter mutation was observed in the serum of 69% of HCC patients who underwent surgical resection and was an independent predictor of disease progression in HCC.

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  • A Phase I/Ib trial of Ad-REIC in liver cancer: study protocol. Reviewed International journal

    Oyama A, Shiraha H, Uchida D, Iwamuro M, Kato H, Takaki A, Ikeda F, Onishi H, Yasunaka T, Takeuchi Y, Wada N, Iwasaki Y, Sakata M, Okada H, Kumon H

    Future oncology (London, England)   15 ( 31 )   3547 - 3554   2019.11

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    This study will assess the safety and efficacy of the administration of adenoviral vector expressing the human-reduced expression in immortalized cells (Ad-REIC) to a liver tumor in patients with hepatocellular carcinoma (HCC) or liver metastasis of pancreatic cancer. A Phase I clinical study of Ad-REIC administration to a liver tumor in a patient with HCC or liver metastasis of pancreatic cancer will be conducted. The study is a single-arm, prospective, nonrandomized, noncomparative, open-label, single-center trial performed in Okayama University Hospital, Okayama, Japan. Ad-REIC will be injected into the liver tumor under ultrasound guidance. Ad-REIC administration will be repeated a total of three-times every 2 weeks. The primary end point is the dose-limiting toxicity and incidence of adverse events. The secondary end points are the objective response rate and disease control rate. This study aims to expand the indication of Ad-REIC by assessing its safety and efficacy in patients with HCC or liver metastasis of pancreatic cancer.

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  • The relationship between the PD-L1 expression of surgically resected and fine-needle aspiration specimens for patients with pancreatic cancer. Reviewed

    Matsumoto K, Ohara T, Fujisawa M, Takaki A, Takahara M, Tanaka N, Kato H, Horiguchi S, Yoshida R, Umeda Y, Fushimi S, Yagi T, Matsukawa A, Okada H

    Journal of gastroenterology   54 ( 11 )   1019 - 1028   2019.11

  • 膵癌におけるFNA検体と切除検体とのPD-L1発現の検討 Reviewed

    松本 和幸, 高木 章乃夫, 大原 利章, 藤澤 真義, 高原 政宏, 加藤 博也, 吉田 龍一, 楳田 祐三, 八木 孝仁, 松川 昭博, 岡田 裕之

    日本消化器病学会雑誌   116 ( 臨増大会 )   A826 - A826   2019.11

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  • 膵癌におけるFNA検体と切除検体とのPD-L1発現の検討

    松本 和幸, 高木 章乃夫, 大原 利章, 藤澤 真義, 高原 政宏, 加藤 博也, 吉田 龍一, 楳田 祐三, 八木 孝仁, 松川 昭博, 岡田 裕之

    日本消化器病学会雑誌   116 ( 臨増大会 )   A826 - A826   2019.11

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  • DAA治療後のSVR後発癌についての検討

    和田 望, 大山 淳史, 足立 卓哉, 坂田 雅浩, 安中 哲也, 大西 秀樹, 白羽 英則, 高木 章乃夫, 岡田 裕之

    肝臓   60 ( Suppl.3 )   A847 - A847   2019.11

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  • 原発性硬化性胆管炎(PSC)予後予測因子の検討

    大山 淳史, 高木 章乃夫, 足立 卓哉, 和田 望, 坂田 雅浩, 安中 哲也, 大西 秀樹, 白羽 英則, 岡田 裕之

    日本消化器病学会雑誌   116 ( 臨増大会 )   A849 - A849   2019.11

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  • レンバチニブで長期効果見込める肝細胞癌症例の特徴

    足立 卓哉, 能祖 一裕, 大山 淳史, 和田 望, 坂田 雅浩, 安中 哲也, 大西 秀樹, 白羽 英則, 高木 章乃夫, 狩山 和也, 岡田 裕之

    日本消化器病学会雑誌   116 ( 臨増大会 )   A781 - A781   2019.11

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  • 慢性炎症・癌ハイリスク状態対応の最前線 肝癌根治的ラジオ波後予後不良に関連する再発例での血清酸化ストレスマーカーの評価

    室 泰子, 高木 章乃夫, 中村 進一郎, 大西 秀樹, 岡田 裕之

    日本消化器病学会中国支部例会・日本消化器内視鏡学会中国支部例会プログラム・抄録集   112回・123回   68 - 68   2019.11

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  • 肝性浮腫に対するトルバプタン効果に寄与する血管内皮機能の検討

    足立 卓哉, 高木 章乃夫, 佐藤 秀一, 大山 淳史, 和田 望, 坂田 雅浩, 安中 哲也, 大西 秀樹, 白羽 英則, 岡田 裕之

    肝臓   60 ( Suppl.3 )   A853 - A853   2019.11

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  • 高齢者におけるDAA治療の現状

    和田 望, 大山 淳史, 足立 卓哉, 坂田 雅浩, 安中 哲也, 大西 秀樹, 池田 房雄, 白羽 英則, 高木 章乃夫, 岡田 裕之

    肝臓   60 ( Suppl.2 )   A657 - A657   2019.10

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  • The Efficacy and Safety of Steroids for Preventing Postembolization Syndrome after Transcatheter Arterial Chemoembolization of Hepatocellular Carcinoma. Reviewed

    Kuwaki K, Nouso K, Miyashita M, Makino Y, Hagihara H, Moriya A, Adachi T, Wada N, Yasunaka Y, Yasunaka T, Takeuchi Y, Onishi H, Nakamura S, Ikeda F, Shiraha H, Takaki A, Okada H

    Acta medica Okayama   73 ( 4 )   333 - 339   2019.8

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    Steroids are often administered at the time of transcatheter arterial chemoembolization (TACE), a standard treatment of hepatocellular carcinoma (HCC), with the expectation of preventing postembolization syndrome. Here we investigated the precise effects of steroids on TACE. We prospectively enrolled 144 HCC patients from 10 hospitals who underwent TACE. Three hospitals used steroids (steroid group, n=77) and the rest did not routinely use steroids (control group, n=67). The occurrence of adverse events and the algetic degree at 1-5 days post-treatment were compared between the groups. Fever (grades 0-2) after TACE was significantly less in the steroid group (56/21/0) compared to the control group (35/29/3, p=0.005, Cochran-Armitage test for trend). The suppressive effect of steroids against fever was prominent in females (p=0.001). Vomiting (G0/G1/ G2-) was also less frequent in the steroid group (70/5/2) versus the control group (53/10/3), but not significantly (p=0.106). The algetic degree and the grade of hematological adverse events, including hyperglycemia, did not differ between the groups. We conclude that the administration of steroids was useful for the prevention of adverse events after TACE in patients with HCC.

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  • Monitoring serum proangiogenic cytokines from hepatocellular carcinoma patients treated with sorafenib. Reviewed International journal

    Adachi T, Nouso K, Miyahara K, Oyama A, Wada N, Dohi C, Takeuchi Y, Yasunaka T, Onishi H, Ikeda F, Nakamura S, Shiraha H, Takaki A, Takabatake H, Fujioka SI, Kobashi H, Takuma Y, Iwadou S, Uematsu S, Takaguchi K, Hagihara H, Okada H, Okayama Liver, Cancer Group

    Journal of gastroenterology and hepatology   34 ( 6 )   1081 - 1087   2019.6

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    BACKGROUND AND AIM: Several factors, including proangiogenic cytokines, have been reported as predictive markers for the treatment effect of sorafenib in patients with hepatocellular carcinoma (HCC); however, most of them were determined based on one-time measurements before treatment. METHODS: We consecutively recruited 80 advanced HCC patients who were treated with sorafenib prospectively. Serum levels of eight proangiogenic cytokines and the appearance of adverse events were monitored periodically, and their correlations with the prognoses of the patients were evaluated. RESULTS: Among six significant risk factors for overall survival in univariate analyses, high angiopoietin-2 (hazard ratio, 2.06), high hepatocyte growth factor (hazard ratio, 2.08), and poor performance status before the treatment (hazard ratio, 2.48) were determined as independent risk factors. In addition, high angiopoietin-2 at the time of progressive disease was a marker of short post-progression survival (hazard ratio, 4.27). However, there was no significant variable that predicted short progression-free survival except the presence of hepatitis B virus surface antigen. CONCLUSIONS: Predictions of overall survival and post-progression survival were possible by periodically measuring serum proangiogenic cytokines, especially angiopoietin-2, in patients with HCC treated with sorafenib.

    DOI: 10.1111/jgh.14535

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  • 肝疾患の診断と治療 生体肝移植後経過より再考する肝硬変合併肺病変の評価

    大山 淳史, 高木 章乃夫, 安中 哲也, 足立 卓哉, 和田 望, 坂田 雅浩, 大西 秀樹, 白羽 英則, 吉田 龍一, 楳田 祐三, 中村 一文, 八木 孝仁, 岡田 裕之

    日本消化器病学会四国支部例会プログラム・抄録集   111回   47 - 47   2019.6

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  • THE RELATIONSHIP BETWEEN THE PD-L1 EXPRESSION OF SURGICAL RESECTED AND FINE-NEEDLE ASPIRATION SPECIMENS FOR PATIENTS WITH PANCREATIC CANCER Reviewed

    Matsumoto Kazuyuki, Ohara Toshiaki, Fujisawa Masayoshi, Takaki Akinobu, Takahara Masahiro, Kato Hironari, Horiguchi Shigeru, Matsukawa Akihiro, Okada Hiroyuki

    GASTROENTEROLOGY   156 ( 6 )   S758   2019.5

  • Paradoxical Roles of Oxidative Stress Response in the Digestive System before and after Carcinogenesis. Reviewed International journal

    Takaki A, Kawano S, Uchida D, Takahara M, Hiraoka S, Okada H

    Cancers   11 ( 2 )   2019.2

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    Oxidative stress is recognized as a cancer-initiating stress response in the digestive system. It is produced through mitochondrial respiration and induces DNA damage, resulting in cancer cell transformation. However, recent findings indicate that oxidative stress is also a necessary anticancer response for destroying cancer cells. The oxidative stress response has also been reported to be an important step in increasing the anticancer response of newly developed molecular targeted agents. Oxidative stress might therefore be a cancer-initiating response that should be downregulated in the precancerous stage in patients at risk of cancer but an anticancer cell response that should not be downregulated in the postcancerous stage when cancer cells are still present. Many commercial antioxidant agents are marketed as "cancer-eliminating agents" or as products to improve one's health, so cancer patients often take these antioxidant agents. However, care should be taken to avoid harming the anticancerous oxidative stress response. In this review, we will highlight the paradoxical effects of oxidative stress and antioxidant agents in the digestive system before and after carcinogenesis.

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  • Predictive Factors for Successful Vaccination Against Hepatitis B Surface Antigen in Patients Who Have Undergone Orthotopic Liver Transplantation. Reviewed

    Ikeda A, Takaki A, Yasunaka T, Oyama A, Adachi T, Wada N, Onishi H, Ikeda F, Shiraha H, Yoshida K, Kuise T, Nobuoka D, Yoshida R, Umeda Y, Yagi T, Fujiwara T, Okada H

    Acta medica Okayama   73 ( 1 )   41 - 50   2019.2

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    Post-orthotopic liver transplantation (OLT) hepatitis B recurrence is well-controlled with a nucleos(t)ide analogue and hepatitis B immunoglobulin (HBIG) combination, but the high cost and the potential risk of unknown infection associated with HBIG remain unresolved issues. Low-cost recombinant hepatitis B virus (HBV) vaccine administration is a potential solution to these problems. We retrospectively analyzed the rate and predictive factors of HBV vaccine success in 49 post-OLT patients: liver cirrhosis-type B (LC-B), n=28 patients; acute liver failure-type B (ALF-B), n=8; and non-HBV-related end-stage liver disease (non-B ESLD) who received a liver from anti-hepatitis B core antibody-positive donors, n=13. A positive anti-hepatitis B surface antibody response was achieved in 29% (8/28) of the LC-B group, 88% (7/8) of the ALF-B group, and 44% (4/9) of the adult non-B ESLD group. All four non-B ESLD infants showed vaccine success. The predictive factors for a good response in LC-B were young age, marital donor, and high donor age. ALF-B and non-B ESLD infants are thus good vaccination candidates. LC-B patients with marital donors are also good candidates, perhaps because the donated liver maintains an efficient immune memory to HBV, as the donors had already been infected in adulthood and showed adequate anti-HBV immune responses.

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  • Analysis of 307 cases with drug-induced liver injury between 2010 and 2018 in Japan. Reviewed

    Aiso M, Takikawa H, Tsuji K, Kagawa T, Watanabe M, Tanaka A, Sato K, Sakisaka S, Hiasa Y, Takei Y, Ohira H, Ayada M, Hashimoto E, Kaneko S, Ueno Y, Ohmoto K, Takaki A, Torimura T, Matsuzaki Y, Tajiri K, Yoneda M, Ito T, Kato N, Ikejima K, Mochida S, Yasuda H, Sakamoto N

    Hepatology research : the official journal of the Japan Society of Hepatology   49 ( 1 )   105 - 110   2019.1

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    DOI: 10.1111/hepr.13288

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  • [Adefovir Dipivoxil-induced Fanconi's Syndrome and Osteomalacia Following Multiple Bone Fractures in a Patient with Chronic Hepatitis B]. Reviewed

    Makita T, Kanzaki H, Onishi H, Ikeda A, Takaki A, Wada N, Takeuchi Y, Yasunaka T, Ikeda F, Shiraha H, Tanaka Y, Nishihara S, Murakawa K, Kitamura Y, Okada H, Sendo T

    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan   139 ( 4 )   641 - 645   2019

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    We herein present the case of a 66-year-old Japanese man with Fanconi's syndrome. He had been receiving adefovir dipivoxil (ADV) for the treatment of entecavir (ETV)-resistant chronic hepatitis B (CHB) for four years in his 8-year treatment of hepatocellular carcinoma (HCC), but was referred to our hospital after increased levels of bone pain in his ribs, knees, and ankles. Renal dysfunction, hypophosphatemia, and increased levels of bone alkaline phosphatase were found by a hematology test after admission for treatment of HCC. Radiography and 99m Tc-labeled hydroxymethylene diphosphonate (HMDP) scintigraphy revealed multiple insuficiency fractures in the ribs, knees, ankles, and heels. After switching from ADV to tenofovir disoproxil fumarate (TDF) and treatment with calcitriol and sodium dihydrogenphosphate, the patient's serum phosphate levels slightly increased and renal dysfunction did not improve, but after six months his clinical symptoms disappeared. To detect and prevent adverse effects from ADV, physicians and pharmacists should carefully monitor renal function and serum phosphate levels in patients with hepatitis B virus (HBV) treated for a long time with ADV.

    DOI: 10.1248/yakushi.18-00170

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  • Berberine improved experimental chronic colitis by regulating interferon-γ- and IL-17A-productive lamina propria CD4+ T cells through AMPK activation Reviewed International journal

    Takahara M, Takaki A, Hiraoka S, Adachi T, Shimomura Y, Matsushita H, Nguyen T, Koike K, Ikeda A, Takashima S, Yamasaki Y, Inokuchi T, Kinugasa H, Sugihara Y, Harada K, Eikawa S, Morita H, Udono H, Okada H

    Scientific Reports   9 ( 1 )   11934 - 11934   2019

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    The herbal medicine berberine (BBR) has been recently shown to be an AMP-activated protein kinase (AMPK) productive activator with various properties that induce anti-inflammatory responses. We investigated the effects of BBR on the mechanisms of mucosal CD4+T cell activation in vitro and on the inflammatory responses in T cell transfer mouse models of inflammatory bowel disease (IBD). We examined the favorable effects of BBR in vitro, using lamina propria (LP) CD4+ T cells in T cell transfer IBD models in which SCID mice had been injected with CD4+CD45RBhigh T cells. BBR suppressed the frequency of IFN-γ- and Il-17A-producing LP CD4+ T cells. This effect was found to be regulated by AMPK activation possibly induced by oxidative phosphorylation inhibition. We then examined the effects of BBR on the same IBD models in vivo. BBR-fed mice showed AMPK activation in the LPCD4+ T cells and an improvement of colitis. Our study newly showed that the BBR-induced AMPK activation of mucosal CD4+ T cells resulted in an improvement of IBD and underscored the importance of AMPK activity in colonic inflammation.

    DOI: 10.1038/s41598-019-48331-w

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  • Acquired partial lipoatrophy as graft-versus-host disease and treatment with metreleptin: two case reports. Reviewed

    Shibata Y, Nakatsuka A, Eguchi J, Miyamoto S, Masuda Y, Awazawa M, Takaki A, Yoshida R, Yagi T, Wada J

    Journal of medical case reports   12 ( 1 )   368   2018.12

  • 岡山県地域肝炎対策サポーター育成後の活動実態調査 肝炎医療コーディネーター活動と部署異動

    難波 志穂子, 池田 房雄, 秋山 文男, 石原 光将, 下村 泰之, 山崎 典子, 犬山 奈穂美, 小山 道弘, 亀川 勝典, 大久保 進之介, 長谷川 祐子, 岩井 賢司, 三喜 明子, 三浦 留美, 矢野 香苗, 藤井 洋輔, 大山 淳史, 足立 卓哉, 和田 望, 安中 幸, 安中 哲也, 大西 秀樹, 白羽 英則, 高木 章乃夫, 山野井 尚美, 岡田 裕之

    肝臓   59 ( 11 )   625 - 632   2018.11

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    岡山県では2011年より肝疾患に関わる部署の初任者を対象に肝炎医療研修会を実施し、受講者を地域肝炎対策サポーターと認定してきたが、厚生労働省の示す肝炎医療コーディネーターの役割を果たしているか不明であった。今回、認定者全員に調査票を郵送して、認定から現在までの肝炎に関する活動状況を調査した。地域肝炎対策サポーター298人中146人から回答を得た。回答者の56%が肝疾患関連部署に引き続き勤務し、3割が厚生労働省の示す肝炎医療コーディネーターの役割に合致することを確認した。回答者の24%は他部署へ異動していたが、その56%が日常業務と別に肝炎医療コーディネーター活動を行っており、部署の異動は非専門診療科に肝炎医療コーディネーター活動のできる人材を拡げる良い機会と考えられる。肝炎医療コーディネーターは医療圏の間で偏在を認めなかった。(著者抄録)

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  • Clinical features of autoimmune hepatitis with acute presentation: a Japanese nationwide survey.

    Satoru Joshita, Kaname Yoshizawa, Takeji Umemura, Hiromasa Ohira, Atsushi Takahashi, Kenichi Harada, Nguyen Canh Hiep, Koichi Tsuneyama, Masayoshi Kage, Masayuki Nakano, Jong-Hon Kang, Kazuhiko Koike, Mikio Zeniya, Tetsuya Yasunaka, Akinobu Takaki, Takuji Torimura, Masanori Abe, Osamu Yokosuka, Atsushi Tanaka, Hajime Takikawa

    Journal of gastroenterology   53 ( 9 )   1079 - 1088   2018.9

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    BACKGROUND: Autoimmune hepatitis (AIH) is characterized by progressive inflammation and necrosis of hepatocytes and eventually leads to a variety of phenotypes, including acute liver dysfunction, chronic progressive liver disease, and fulminant hepatic failure. Although the precise mechanisms of AIH are unknown, environmental factors may trigger disease onset in genetically predisposed individuals. Patients with the recently established entity of AIH with acute presentation often display atypical clinical features that mimic those of acute hepatitis forms even though AIH is categorized as a chronic liver disease. The aim of this study was to identify the precise clinical features of AIH with acute presentation. METHODS: Eighty-six AIH patients with acute presentation were retrospectively enrolled from facilities across Japan and analyzed for clinical features, histopathological findings, and disease outcomes. RESULTS: Seventy-five patients were female and 11 were male. Patient age ranged from adolescent to over 80 years old, with a median age of 55 years. Median alanine transaminase (ALT) was 776 U/L and median immunoglobulin G (IgG) was 1671 mg/dL. There were no significant differences between genders in terms of ALT (P = 0.27) or IgG (P = 0.51). The number of patients without and with histopathological fibrosis was 29 and 57, respectively. The patients with fibrosis were significantly older than those without (P = 0.015), but no other differences in clinical or histopathological findings were observed. Moreover, antinuclear antibody (ANA)-positive (defined as × 40, N = 63) and -negative (N = 23) patients showed no significant differences in clinical or histopathological findings or disease outcomes. Twenty-five patients experienced disease relapse and two patients died during the study period. ALP ≥ 500 U/L [odds ratio (OR) 3.20; 95% confidence interval (CI) 1.12-9.10; P < 0.030] and GGT ≥ 200 U/L (OR 2.98; 95% CI 1.01-8.77; P = 0.047) were identified as independent risk factors of disease relapse. CONCLUSIONS: AIH with acute presentation is a newly recognized disease entity for which diagnostic hallmarks, such as ALT, fibrosis, and ANA, are needed. Further investigation is also required on the mechanisms of this disorder. Clinicians should be mindful of disease relapse during patient care.

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  • 抗ドナーHLA抗体陽性の肝移植の短期・長期成績と問題点 抗ドナー抗体陽性生体肝移植の現状と問題点

    楳田 祐三, 八木 孝仁, 田中 健大, 吉田 龍一, 信岡 大輔, 杭瀬 崇, 吉田 一博, 安井 和也, 吉田 真里, 白川 靖博, 柳井 広行, 高木 章乃夫, 藤原 俊義

    移植   53 ( 総会臨時 )   257 - 257   2018.9

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  • Symptoms and health-related quality of life in Japanese patients with primary biliary cholangitis. Reviewed

    Yagi M, Tanaka A, Abe M, Namisaki T, Yoshiji H, Takahashi A, Ohira H, Komori A, Yamagiwa S, Kikuchi K, Yasunaka T, Takaki A, Ueno Y, Honda A, Matsuzaki Y, Takikawa H

    Scientific reports   8 ( 1 )   12542   2018.8

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  • Mixed HCV Infection of Genotype 1B and Other Genotypes Influences Non-response during Daclatasvir + Asunaprevir Combination Therapy.

    Nozomu Wada, Fusao Ikeda, Chizuru Mori, Koichi Takaguchi, Shin-Ichi Fujioka, Haruhiko Kobashi, Yoichi Morimoto, Kazuya Kariyama, Kosaku Sakaguchi, Noriaki Hashimoto, Akio Moriya, Mitsuhiko Kawaguchi, Hirokazu Miyatake, Hiroaki Hagihara, Junichi Kubota, Hiroki Takayama, Yasuto Takeuchi, Tetsuya Yasunaka, Akinobu Takaki, Yoshiaki Iwasaki, Hiroyuki Okada

    Acta medica Okayama   72 ( 4 )   401 - 406   2018.8

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    Daclatasvir (DCV) + asunaprevir (ASV) combination therapy has become available for patients with hepatitis C virus (HCV) serogroup 1 infection. We studied the efficacy of this therapy by focusing on the factors associated with sustained virological responses (SVR) including resistance-associated variants (RAVs) and mixed infection of different HCV genotypes. We enrolled 951 HCV serogroup 1-positive patients who received this combination therapy at our hospital or affiliated hospitals. The presence of RAVs in non-structural (NS) regions 3 and 5A was analyzed by direct sequencing. HCV genotypes were determined by PCR with genotype-specific primers targeting HCV core and NS5B regions. SVR was achieved in 91.1% of patients. Female sex, age > 70 years, and RAVs were significantly associated with non-SVR (p<0.01 for all). Propensity score-matching results among the patients without RAVs regarding sex, age, and fibrosis revealed that mixed HCV infection determined by HCV NS5B genotyping showed significantly lower SVR rates than 1B-mono infection (p=0.02). Female sex and RAVs were significant factors associated with treatment failure of this combination therapy for patients with HCV serogroup 1 infection. Mixed HCV infection other than 1B-mono infection would be useful for predicting treatment failure.

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  • Beneficial and Paradoxical Roles of Anti-Oxidative Nutritional Support for Non-Alcoholic Fatty Liver Disease. Reviewed International journal

    Uchida D, Takaki A, Adachi T, Okada H

    Nutrients   10 ( 8 )   2018.7

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    Oxidative stress is being recognized as a key factor in the progression of chronic liver disease (CLD), especially non-alcoholic fatty liver disease (NAFLD). Many NAFLD treatment guidelines recommend the use of antioxidants, especially vitamin E. Many prospective studies have described the beneficial effects of such agents for the clinical course of NAFLD. However, as these studies are usually short-term evaluations, lasting only a few years, whether or not antioxidants continue to exert favorable long-term effects, including in cases of concomitant hepatocellular carcinoma, remains unclear. Antioxidants are generally believed to be beneficial for human health and are often commercially available as health-food products. Patients with lifestyle-related diseases often use such products to try to be healthier without practicing lifestyle intervention. However, under some experimental NAFLD conditions, antioxidants have been shown to encourage the progression of hepatocellular carcinoma, as oxidative stress is toxic for cancer cells, just as for normal cells. In this review, we will highlight the paradoxical effects of antioxidants against NAFLD and related hepatocellular carcinoma.

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  • 進行肝細胞癌におけるソラフェニブ治療の長期生存症例と短期終了症例のそれぞれの特徴

    足立 卓哉, 能祖 一裕, 大山 淳史, 和田 望, 安中 幸, 竹内 康人, 安中 哲也, 大西 秀樹, 池田 房雄, 白羽 英則, 高木 章乃夫, 高口 浩一, 植松 周二, 高畠 弘行, 萩原 宏明, 岡田 裕之

    The Liver Cancer Journal   ( Suppl.1 )   77 - 77   2018.6

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  • New Left Lobe Transplantation Procedure with Caval Reconstruction Using an Inverted Composite Graft for Chronic Budd-Chiari Syndrome in Living-Donor Liver Transplantation—A Case Report Reviewed

    T. Yagi, K. Takagi, R. Yoshida, Yuzo Umeda, D. Nobuoka, T. Kuise, T. Fujiwara, A. Takaki

    Transplantation Proceedings   50 ( 4 )   1192 - 1195   2018.5

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    When the Budd-Chiari syndrome (BCS) lesion extends to the inferior vena cava (IVC) or the orifices of the hepatic vein, the thickened IVC and/or hepatic vein wall must be removed and IVC reconstruction is required in living-donor liver transplantation (LDLT). In various reports about IVC resection in LDLT for BCS, there are none about left lobe liver transplantation with reconstruction of the retrohepatic IVC (rhIVC). To overcome removal and reconstruction of the rhIVC in LDLT for BCS, we introduced a composite IVC graft that is applicable to both right and left lobe partial liver grafts for LDLT for BCS. Pathogenic IVC was removed together with the native liver between the lower edge of the right atrium and 5 cm above the renal vein junction with the use of venovenous bypass. The e-polytetrafluoroethylene graft was anastomosed to the suprarenal intact IVC. Then the native part was detached at the level of just above the renal junction. The composite graft was inverted and a half rim of the native part of the graft was anastomosed to the posterior wall of the right atrium. Next, the common venous orifice of the left lobe graft was anastomosed to the wall defect which was composed of the anterior wall of the right atrium and the distal end of the native part of the composite graft. In conclusion, our inverted composite graft technique will overcome the weak points of LDLT for BCS, such as incomplete removal of the pathogenic caval wall and reconstruction of the rhIVC.

    DOI: 10.1016/j.transproceed.2017.11.078

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  • Correction to: Efficacy and safety of glecaprevir/pibrentasvir in HCV-infected Japanese patients with prior DAA experience, severe renal impairment, or genotype 3 infection.

    Hiromitsu Kumada, Tsunamasa Watanabe, Fumitaka Suzuki, Kenji Ikeda, Ken Sato, Hidenori Toyoda, Masanori Atsukawa, Akio Ido, Akinobu Takaki, Nobuyuki Enomoto, Koji Kato, Katia Alves, Margaret Burroughs, Rebecca Redman, David Pugatch, Tami J Pilot-Matias, Preethi Krishnan, Rajneet K Oberoi, Wangang Xie, Kazuaki Chayama

    Journal of gastroenterology   53 ( 5 )   689 - 689   2018.5

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    Unfortunately, in the original publication of this article, the copyright line was incorrectly published in PDF as "© The Author(s) 2017" instead of "©The Author(s) 2017 This article is an open access publication" and also the CC-BY description was not included. The description should be as follows.

    DOI: 10.1007/s00535-017-1409-z

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  • A subclinical high tricuspid regurgitation pressure gradient independent of the mean pulmonary artery pressure is a risk factor for the survival after living donor liver transplantation. Reviewed International journal

    Saragai Y, Takaki A, Umeda Y, Matsusaki T, Yasunaka T, Oyama A, Kaku R, Nakamura K, Yoshida R, Nobuoka D, Kuise T, Takagi K, Adachi T, Wada N, Takeuchi Y, Koike K, Ikeda F, Onishi H, Shiraha H, Nakamura S, Morimatsu H, Ito H, Fujiwara T, Yagi T, Okada H

    BMC gastroenterology   18 ( 1 )   62 - 62   2018.5

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    BACKGROUND: Portopulmonary hypertension (POPH) is characterized by pulmonary vasoconstriction, while hepatopulmonary syndrome (HPS) is characterized by vasodilation. Definite POPH is a risk factor for the survival after orthotopic liver transplantation (OLT), as the congestive pressure affects the grafted liver, while subclinical pulmonary hypertension (PH) has been acknowledged as a non-risk factor for deceased donor OLT. Given that PH measurement requires cardiac catheterization, the tricuspid regurgitation pressure gradient (TRPG) measured by echocardiography is used to screen for PH and congestive pressure to the liver. We investigated the impact of a subclinical high TRPG on the survival of small grafted living donor liver transplantation (LDLT). METHODS: We retrospectively analyzed 84 LDLT candidates. Patients exhibiting a TRPG ≥25 mmHg on echocardiography were categorized as potentially having liver congestion (subclinical high TRPG; n = 34). The mean pulmonary artery pressure (mPAP) measured after general anesthesia with FIO20.6 (mPAP-FIO20.6) was also assessed. Patients exhibiting pO2 < 80 mmHg and an alveolar-arterial oxygen gradient (AaDO2) ≥ 15 mmHg were categorized as potentially having HPS (subclinical HPS; n = 29). The clinical course after LDLT was investigated according to subclinical high TRPG. RESULTS: A subclinical high TRPG (p = 0.012) and older donor age (p = 0.008) were correlated with a poor 40-month survival. Although a higher mPAP-FIO20.6 was expected to correlate with a worse survival, a high mPAP-FIO20.6 with a low TRPG was associated with high frequency complicating subclinical HPS and a good survival, suggesting a reduction in the PH pressure via pulmonary shunt. CONCLUSION: In cirrhosis patients, mPAP-FIO20.6 may not accurately reflect the congestive pressure to the liver, as the pressure might escape via pulmonary shunt. A subclinical high TRPG is an important marker for predicting a worse survival after LDLT, possibly reflecting congestive pressure to the grafted small liver.

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  • Risk Analysis for Invasive Fungal Infection after Living Donor Liver Transplantation: Which Patient Needs Potent Prophylaxis? Reviewed International journal

    Utsumi M, Umeda Y, Yagi T, Nagasaka T, Shinoura S, Yoshida R, Nobuoka D, Kuise T, Fuji T, Takagi K, Takaki A, Fujiwara T

    Digestive surgery   36 ( 1 )   59 - 66   2018.4

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    BACKGROUND: Invasive fungal infection (IFI) is associated with high mortality after living donor liver transplant (LDLT). The aim of this study was to identify the risk factors for post-LDLT IFI for early diagnosis and improvement of antifungal treatment outcome. METHODS: Risk analysis data were available for all 153 patients who underwent LDLT between January 2005 and April 2012. RESULTS: During the follow-up period (1,553 ± 73 days, range 20-2,946 days), 15 patients (9.8%) developed IFI classified as "proven" (n = 8) and "probable" (n = 7) with fungal pathogens including Candida spp. (n = 10), Aspergillus spp. (n = 4), and Trichosporon (n = 2). Of these patients, 7 patients with IFI died despite treatment. The 1-, 3-, and 5-year survival rates were lower in patients with IFI than those without IFI (66.7/59.3/44.4 vs. 90.4/85.7/81.8%, respectively; p = 0.0026). Multivariate analysis identified model for end-stage liver disease score of ≥26 (OR 16.0, p = 0.0012) and post-transplant acute kidney injury (RIFLE criteria I- or F-class; OR 4.87, p = 0.047) as independent risk factors for IFI. CONCLUSION: Preoperative recipients' status and postoperative kidney dysfunction can affect an occurrence of post-transplant IFI. These risk factors would be taken into consideration for designation of proper antifungal therapy.

    DOI: 10.1159/000486548

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  • Non-alcoholic fatty liver disease in patients with autoimmune hepatitis. International journal

    Atsushi Takahashi, Teruko Arinaga-Hino, Hiromasa Ohira, Kazumichi Abe, Takuji Torimura, Mikio Zeniya, Masanori Abe, Kaname Yoshizawa, Akinobu Takaki, Yoshiyuki Suzuki, Jong-Hon Kang, Nobuhiro Nakamoto, Tomoo Fujisawa, Atsushi Tanaka, Hajime Takikawa

    JGH open : an open access journal of gastroenterology and hepatology   2 ( 2 )   54 - 58   2018.4

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    BACKGROUND AND AIM: The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing all over the world. NAFLD develops in patients with liver disease, including patients with autoimmune hepatitis (AIH). NAFLD and AIH have some similar laboratory and histological findings. The aim of this study was to elucidate the characteristics of AIH patients with NAFLD. METHODS: We re-evaluated the nationwide survey performed in Japan in 2015 of AIH patients diagnosed between 2009 and 2013. RESULTS: A total of 1151 subjects (144 men and 1007 women) were enrolled in the present study. The overall prevalence of NAFLD was 17.0%. Compared to AIH without NAFLD, AIH patients with NAFLD had the following characteristics: (i) low female-to-male ratio, (ii) older age, (iii) mild elevation in hepatobiliary enzymes, (iv) histologically progressive fibrosis and mild plasma cell infiltration or mild lobular hepatitis, (v) lower prevalence of prednisolone administration and higher prevalence of ursodeoxycholic acid administration, (vi) higher levels of hepatic enzymes and immunoglobulin G after treatment, and (vii) similar prevalence of autoimmune and malignant complications. CONCLUSION: AIH patients with NAFLD have many features that are different from AIH patients without NAFLD. Understanding these differences is essential for the proper diagnosis and treatment of AIH patients with NAFLD.

    DOI: 10.1002/jgh3.12046

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  • Transcatheter Arterial Chemoembolization to Reduce Size of Hepatocellular Carcinoma before Radiofrequency Ablation. Reviewed

    Ako S, Nakamura S, Nouso K, Dohi C, Wada N, Morimoto Y, Takeuchi Y, Yasunaka T, Kuwaki K, Onishi H, Ikeda F, Shiraha H, Takaki A, Okada H

    Acta medica Okayama   72 ( 1 )   47 - 52   2018.2

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    Transcatheter arterial chemoembolization (TACE) is often performed before radiofrequency ablation (RFA) for the treatment of early-stage hepatocellular carcinoma (HCC). TACE prior to RFA can expand the ablated area and reduce the tumor size, facilitating complete ablation. However, the factors correlated with size reduction remain uncertain. The aim of this study was to identify the factors associated with size reduction by TACE and develop a formula to predict the reduction rate. A total of 100 HCC patients treated with TACE followed by RFA at least 20 days later were enrolled. The tumor size was measured at the time of TACE and RFA, and correlations between the reduction rate and 13 clinical factors were examined. A formula to predict the reduction rate was built using the factors obtained by the analysis. Reduction in the tumor size was observed in 69 nodules, and the median reduction rate was 16.2%. A multivariate regression analysis revealed that a large tumor size (p< 0.01) and a long interval between the therapies (p= 0.01) were factors for a high tumor reduction rate, with tumor size more strongly related to the degree of reduction. A size reduction of more than 10% can be expected by waiting 20 days after TACE when the size of the tumor at TACE is over 25 mm in diameter. The tumor size.

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  • 改訂自己免疫性肝炎・原発性胆汁性胆管炎診療ガイドライン Reviewed

    厚生労働科学研究費補助金, 難治性疾患政策研究事業, 難治性の肝, 胆道疾患に関する調査研究, 班, 自己免疫性肝炎分科会, 原発性胆汁性胆管炎分科会, 田中 篤, 大平 弘正, 高橋 敦史, 小森 敦正, 阿部 雅則, 姜 貞憲, 小池 和彦, 鈴木 義之, 髙木 章乃夫, 有永 照子, 島村 拓司, 中本 伸宏, 原田 憲一, 十河 剛, 乾 あやの, 藤澤 知雄, 吉澤 要, 玄田 拓哉, 銭谷 幹男, 下田 慎治, 竹山 康章, 向坂 彰太郎, 谷合 麻紀子, 橋本 悦子, 中村 稔, 浪崎 正, 吉治 仁志, 本多 彰, 松崎 靖司, 廣原 淳子, 山際 訓, 滝川 一

    肝臓   59 ( 4 )   211 - 216   2018

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  • Health-related quality of life in patients with autoimmune hepatitis: A questionnaire survey. International journal

    Atsushi Takahashi, Kei Moriya, Hiromasa Ohira, Teruko Arinaga-Hino, Mikio Zeniya, Takuji Torimura, Masanori Abe, Akinobu Takaki, Jong-Hon Kang, Ayano Inui, Tomoo Fujisawa, Kaname Yoshizawa, Yoshiyuki Suzuki, Nobuhiro Nakamoto, Kazuhiko Koike, Hitoshi Yoshiji, Aya Goto, Atsushi Tanaka, Zobair M Younossi, Hajime Takikawa

    PloS one   13 ( 10 )   e0204772   2018

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    AIM: Health-related quality of life is impaired in patients with autoimmune hepatitis, but the association between health-related quality of life and patients' backgrounds remains unknown. We assessed health-related quality of life in patients with autoimmune hepatitis and identified factors associated with its impairment. METHODS: We assessed health-related quality of life in patients with autoimmune hepatitis, patients with chronic hepatitis C, and healthy subjects using the Japanese version of the Chronic Liver Disease Questionnaire and the 36-Item Short Form Survey. We compared health-related quality of life in patients with autoimmune hepatitis with that of patients with chronic hepatitis C and healthy subjects. RESULTS: A total of 265 patients with autoimmune hepatitis, 88 patients with chronic hepatitis C, and 97 healthy subjects were enrolled; most patients were women. The median ages of patients were 65, 66, and 57 years, respectively. Of these patients with autoimmune hepatitis, 10.6% and 57.0% had cirrhosis and comorbid diseases, respectively. The overall Chronic Liver Disease Questionnaire scores (5.5 vs. 6.2, P < 0.001) and physical (48.1 vs. 54.2, P < 0.001) and mental (51.8 vs. 55.0, P = 0.004) component summaries of 36-Item Short Form Survey were significantly lower in patients with autoimmune hepatitis than in healthy subjects, and similar to scores in patients with chronic hepatitis C. Having cirrhosis, comorbid diseases, and treatment for autoimmune hepatitis were associated with impaired health-related quality of life among patients with autoimmune hepatitis. In particular, prednisolone use was associated with lower scores on the worry domain of the Chronic Liver Disease Questionnaire. CONCLUSIONS: Patients with autoimmune hepatitis showed impairment in health-related quality of life, which was associated with not only disease progression, but also comorbid diseases and treatment. Ways to improve health-related quality of life should be considered in patients with AIH when disease outcome is not favorable and when using prednisolone.

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  • 肝移植後C型肝炎再発に対するソホスブビル含有治療の有効性

    大山 淳史, 高木 章乃夫, 安中 哲也, 足立 卓哉, 池田 房雄, 和田 望, 竹内 康人, 大西 秀樹, 中村 進一郎, 白羽 英則, 高木 弘誠, 杭瀬 崇, 信岡 大輔, 吉田 龍一, 楳田 祐三, 吉田 真理, 有森 千聖, 八木 孝仁, 岡田 裕之

    肝臓   58 ( 11 )   599 - 604   2017.11

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    肝移植後C型肝炎に対するDirect Acting Antivirals(DAA)治療効果を検討した。Genotypelは29症例で、ダクラタスビル+アスナプレビル(DCV+ASV)5例、ソホスブビル+レジパスビル(SOF+LDV)25例(含DCV+ASV無効1例)、Genotype2が2症例でSOF+リバビリン治療を行った。DCV+ASVは5例中4例で治療完遂、3例でSustained viral response(SVR)24を達成。SOF+LDVは全例SVR24を達成、移植後2ヵ月以内の肝炎再燃例も含まれているが問題なく治療完遂可能であった。Genotype2はSVR24を達成。SOF中心レジメンで100%のSVR24達成率であり、移植後早期においても問題なくウイルス駆除達成可能であった。C型肝硬変の肝移植適応評価においてC型肝炎のネガティブインパクトはなくなったと言っても過言ではない。(著者抄録)

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  • Living Donor Liver Transplantation for Acute Liver Failure : Comparing Guidelines on the Prediction of Liver Transplantation. Reviewed

    Kazuhiro Yoshida, Yuzo Umeda, Akinobu Takaki, Takeshi Nagasaka, Ryuichi Yoshida, Daisuke Nobuoka, Takashi Kuise, Kosei Takagi, Tetsuya Yasunaka, Hiroyuki Okada, Takahito Yagi, Toshiyoshi Fujiwara

    Acta medica Okayama   71 ( 5 )   381 - 390   2017.10

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    Determining the indications for and timing of liver transplantation (LT) for acute liver failure (ALF) is essential. The King's College Hospital (KCH) guidelines and Japanese guidelines are used to predict the need for LT and the outcomes in ALF. These guidelines' accuracy when applied to ALF in different regional and etiological backgrounds may differ. Here we compared the accuracy of new (2010) Japanese guidelines that use a simple scoring system with the 1996 Japanese guidelines and the KCH criteria for living donor liver transplantation (LDLT). We retrospectively analyzed 24 adult ALF patients (18 acute type, 6 sub-acute type) who underwent LDLT in 1998-2009 at our institution. We assessed the accuracies of the 3 guidelines' criteria for ALF. The overall 1-year survival rate was 87.5%. The new and previous Japanese guidelines were superior to the KCH criteria for accurately predicting LT for acute-type ALF (72% vs. 17%). The new Japanese guidelines could identify 13 acute-type ALF patients for LT, based on the timing of encephalopathy onset. Using the previous Japanese guidelines, although the same 13 acute-type ALF patients (72%) had indications for LT, only 4 patients were indicated at the 1st step, and it took an additional 5 days to decide the indication at the 2nd step in the other 9 cases. Our findings showed that the new Japanese guidelines can predict the indications for LT and provide a reliable alternative to the previous Japanese and KCH guidelines.

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  • 肝炎ウイルス検査陽性患者に対する検査報告システムの効果的な運用方法 肝臓専門医受診率向上のさらなる工夫

    下村 泰之, 藤井 洋輔, 池田 房雄, 安中 哲也, 山崎 典子, 笠原 郁子, 犬山 奈穂美, 小山 道弘, 難波 志穂子, 竹内 康人, 和田 望, 桑木 健志, 大西 秀樹, 中村 進一郎, 白羽 英則, 高木 章乃夫, 岡田 裕之

    肝臓   58 ( 8 )   427 - 434   2017.8

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    非肝臓専門診療科で実施される肝炎ウイルス検査の結果が受検者に適切に説明されるように、当院では2013年に電子カルテ上で検査陽性を知らせるアラートの自動表示システムを導入した。このシステムを利用して担当医が説明した割合は28%と不十分であったため、検査実施診療科了解のもと検査陽性者へ検査報告書を郵送し、検査陽性者への報告率は89%と改善した。肝臓専門医への紹介状と返信用書類を同封、郵送半年後に肝臓専門医受診を確認できていない場合は再送し、肝炎専門医受診把握率は49%から72%に改善した(p<0.001)。検査報告書再送で肝精査の必要性に気づき肝臓専門医を受診し、肝炎治療を受けた症例もあった。肝炎ウイルス検査陽性者への報告を徹底することは肝臓専門医受診率の向上や適切な肝炎治療の受療に有用である。(著者抄録)

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  • Association between periodontitis and prognosis of pancreatobiliary tract cancer: A pilot study. Reviewed International journal

    Maruyama T, Tomofuji T, Machida T, Kato H, Tsutsumi K, Uchida D, Takaki A, Yoneda T, Miyai H, Mizuno H, Ekuni D, Okada H, Morita M

    Molecular and clinical oncology   6 ( 5 )   683 - 687   2017.5

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    Several studies have indicated that periodontitis is a risk factor for cancer. However, the association between periodontitis and the prognosis of pancreatobiliary tract cancer remains unclear. The aim of this pilot study was to investigate the association between periodontitis and prognosis of pancreatobiliary tract cancer. A total of 22 patients diagnosed with pancreatobiliary tract cancer were analyzed. Oral health status, including severity of periodontitis, general health status and biochemical serum markers were evaluated. The Kaplan-Meier method and Cox proportional hazards model were used to assess factors affecting the prognosis of pancreatobiliary tract cancer. The Kaplan-Meier analysis demonstrated that low body mass index, high concentration of serum C-reactive protein (CRP) and severe periodontitis were significant prognostic factors for survival rate. The Cox proportional hazards model revealed that serum carbohydrate antigen 19-9 concentration [hazard ratio (HR)=1.002; 95% confidence interval (CI): 1.000-1.004] and serum CRP concentration (HR=2.57; 95% CI: 1.15-5.74) were significantly associated with the prognosis of pancreatobiliary tract cancer. In addition, cancer patients with severe periodontitis had higher serum CRP concentrations compared with those without severe periodontitis. Therefore, severe periodontitis indirectly affected the prognosis of pancreatobiliary tract cancer through promoting systemic inflammation.

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  • 職域での出張肝臓病教室と同時開催の肝炎検診の意義

    難波 志穂子, 池田 房雄, 下村 泰之, 犬山 奈穂美, 大久保 進之介, 槇田 崇志, 長谷川 祐子, 岩井 賢司, 細羽 章子, 三浦 留美, 藤井 洋輔, 安中 哲也, 竹内 康人, 和田 望, 桑木 健志, 大西 秀樹, 中村 進一郎, 白羽 英則, 高木 章乃夫, 岡田 裕之

    肝臓   58 ( 5 )   304 - 306   2017.5

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    出張肝臓病教室では、岡山大学病院の肝疾患サポートチームが職域に出向き、職員全員を対象として肝炎検診受検や肝臓専門機関受診の重要性を説明した。12回の出張肝臓病教室を603人が受講し、アンケート回答に欠損のない565人の回答を分析した。肝臓病で通院中の人は3人(0.5%)、健康診断で今まで肝機能異常を指摘されたことがない人が468人(82.8%)、健康診断で肝臓に関する検査結果を意識してみていない人が263人(46.5%)であった。肝臓病教室を受講して肝炎ウイルス検査を受けようと思った人が300人(53.1%)、既に受けている人が154人(27.3%)で、111人(19.6%)は受けないと回答した。講演が職場の肝臓病に対する偏見や誤解の解消に非常に役立つと思った人が347人(61.4%)、少し役に立つと思った人が208人(36.8%)であった。出張肝臓病教室に参加した306名中288名(94.1%)が肝炎検診を受検し、HBs抗原陽性者3名(1%)、HCV抗体陽性者3名(1%)であった。陽性者6名全員が肝炎専門医療機関を受診した。

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  • Redox Signaling in NASH Reviewed

    A. Takaki, D. Uchida, K. Yamamoto

    Liver Pathophysiology: Therapies and Antioxidants   169 - 180   2017.3

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    The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is multifactorial and difficult to unify. The progression of benign nonalcoholic fatty liver (NAFL) to progressive nonalcoholic steatohepatitis (NASH) is acknowledged to be a multiple parallel hit process. Oxidative stress is one of the main factors that drives progression of NAFL to NASH, although it is also essential for vital cellular processes. Overaccumulation of long chain fatty acid results in mitochondrial ?-oxidation pathway activation followed by reactive oxygen species (ROS) production. ROS can mediate the oxidative stress response in hepatocytes, Kupffer cells, or hepatic stellate cells resulting in hepatocyte damage, and in proinflammatory and profibrogenic responses that should be well balanced. ROS detoxification pathway signaling is often damaged in NAFLD following ROS accumulation. Inactivation of pro-oxidant production pathways and activation of detoxifying signaling pathways are the required treatment approach.

    DOI: 10.1016/B978-0-12-804274-8.00012-6

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  • The Serum Oxidative/Anti-oxidative Stress Balance Becomes Dysregulated in Patients with Non-alcoholic Steatohepatitis Associated with Hepatocellular Carcinoma. Reviewed

    Yasuyuki Shimomura, Akinobu Takaki, Nozomu Wada, Tetsuya Yasunaka, Fusao Ikeda, Takayuki Maruyama, Naofumi Tamaki, Daisuke Uchida, Hideki Onishi, Kenji Kuwaki, Shinichiro Nakamura, Kazuhiro Nouso, Yasuhiro Miyake, Kazuko Koike, Takaaki Tomofuji, Manabu Morita, Kazuhide Yamamoto, Hiroyuki Okada

    Internal Medicine   Vol.56 ( No.3 )   243 - 251   2017.2

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    Objective Oxidative stress is associated with the progression of chronic liver disease. Non-alcoholic fatty liver disease (NAFLD) is also an oxidative stress-related disease. However, the oxidative/anti-oxidative balance has not been fully characterized in NAFLD. The objective of the present study was to investigate the balance between oxidative stress and the anti-oxidative activity in NAFLD, including non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC). Patients We recruited 69 patients with histologically proven NAFLD without HCC (NAFLD; n=58), and with NASH-related HCC (NASH-HCC; n=11). The 58 NAFLD patients included patients with non-alcoholic fatty liver (NAFL; n=14) and NASH (n=44). Methods The serum levels of reactive oxygen metabolites (ROM) and anti-oxidative markers (OXY) were determined and then used to calculate the oxidative index. The correlations among such factors as ROM, OXY, oxidative index, and clinical characteristics were investigated. Results In NAFLD, ROM positively correlated with the body mass index (BMI), hemoglobin A1c (HbA1c), C-reactive protein (CRP), and the histological grade or inflammatory scores, while only high HbA1c and CRP levels were significant factors that correlated with a higher ROM according to a multivariate analysis. OXY positively correlated with the platelet counts, albumin, and creatinine levels, while negatively correlating with age. However, it improved after treatment intervention. The oxidative index positively correlated with BMI, CRP, and HbA1c. The NASH-HCC patients exhibited a lower OXY than the NASH patients, probably due to the effects of aging. Conclusion Oxidative stress correlated with the levels of NASH activity markers, while the anti-oxidative function was preserved in younger patients as well as in patients with a well-preserved liver function. The NASH-HCC patients tended to be older and exhibited a diminished anti-oxidative function.

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  • Safety and Efficacy of Small Bowel Examination by Capsule Endoscopy for Patients before Liver Transplantation Reviewed

    Kawano Seiji, Takaki Akinobu, Iwamuro Masaya, Yasunaka Tetsuya, Kono Yoshiyasu, Miura Kou, Inokuchi Toshihiro, Kawahara Yoshiro, Umeda Yuzo, Yagi Takahito, Okada Hiroyuki

    BIOMED RESEARCH INTERNATIONAL   2017   2017

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    Background and Aims. Gastrointestinal surveillance is a requirement prior to liver transplantation (LT), but small intestine examination is not generally undertaken. The aim of the present studywas to evaluate the safety and efficacy of capsule endoscopy (CE) for patients with end-stage liver disease. Methods. 31 patients who needed LT were enrolled, and 139 patients who underwent CE over the same period of time acted as controls. Results. Frequency of successful achievement of evaluation of the full length of the small bowel, the mean gastric transit time, and the mean small bowel transit time were not significantly different between the two groups. Abnormalities in the small bowel were found in 26 patients. Comparative analysis revealed that history of EV rupture, history of EV treatment, red color sign of EV, and presence of PHG or HCC were significantly associated with patients with &gt;2 two such findings (high score group). Conclusions. Small bowel examination by CE in patients before liver transplantation could be performed safely and is justified by the high rate of abnormal lesions detected particularly in patients with history of EV therapy or bleeding, red color sign, and presence of PHG or HCC. This study was registered in the UMIN Clinical Trial Registry (UMIN 000008672).

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  • P2-10 慢性腸炎マウスモデルにおけるベルベリンの改善効果と作用機序の検討

    高原 政宏, 高木 章乃夫, 平岡 佐規子, 池田 愛璃, 足立 卓哉, 松下 浩志, 小池 和子, 岡田 裕之

    日本臨床免疫学会会誌   40 ( 4 )   311b - 311b   2017

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    <p>【背景】生薬であるベルベリン(BBR)は下痢止めとして臨床応用されているが,抗炎症など多彩な作用も有することが明らかになっている.BBRは細胞のエネルギーの調節因子であるAMPKを活性化させることが知られており,近年,このAMPKがT細胞を含む免疫細胞の応答に関わっていることが報告されている.【目的,方法】慢性腸炎マウスモデルを用いて,大腸炎粘膜のCD4+T細胞(LP CD4+T細胞)におけるBBRの抗炎症作用とその機序についての検証をin vitroおよびIn vivoで行う.1)CD4+CD45RBhighT細胞移入腸炎マウスのLPCD4+T細胞をPMA/Ionomysinで刺激し,IFN-γ産生細胞を誘導,BBRの効果について,AMPKの関与も含めて検討.2)上記腸炎マウスにBBRを含んだ餌を投与し,腸炎の抑制効果について検討.【結果】1)LP CD4+T細胞はBBRと共培養すると,IFN-γ産生細胞が優位に低下し,ウェスタンブロッティングでは,AMPKの活性化を認めた.次に,AMPKのagonistとantagonistを用いた培養系でIFN-γの産生を調べたところ,agonistで抑制,antagonistで増加を認めた.以上から,BBRにより活性化されたAMPKがIFN-γを制御していることが示唆された.2)上記腸炎マウスにBBRを経口投与した結果,腸炎は優位に抑制された.【結論】BBRは,慢性腸炎マウスモデルの腸炎を抑制し,その作用機序の一つとしてAMPKを介した機序が示唆された.</p>

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  • Serum Oxidative/anti-oxidative Stress Balance Is Dysregulated in Potentially Pulmonary Hypertensive Patients with Liver Cirrhosis: A Case Control Study. Reviewed

    Masako Terao, Akinobu Takaki, Takayuki Maruyama, Hiroki Oe, Tetsuya Yasunaka, Naofumi Tamaki, Kazufumi Nakamura, Takaaki Tomofuji, Takahito Yagi, Hiroshi Sadamori, Yuzo Umeda, Susumu Shinoura, Ryuichi Yoshida, Kazuhiro Nouso, Daisuke Ekuni, Kazuko Koike, Fusao Ikeda, Hidenori Shiraha, Manabu Morita, Hiroshi Ito, Toshiyoshi Fujiwara, Kazuhide Yamamoto

    Internal Medicine   Vol.54 ( No.22 )   2815 - 2826   2015.11

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    Objective Hepatopulmonary syndrome (HPS) is characterized by vascular dilatation and hyperdynamic circulation, while portopulmonary hypertension (POPH) is characterized by vasoconstriction with fibrous obliteration of the vascular bed. Vasoactive molecules such as nitric oxide (NO) are candidate factors for cirrhotic complications associated with these diseases. However, oxidative stress balance is not well characterized in HPS and POPH. The present objective is to investigate the oxidative stress and anti-oxidative stress balance and NO pathway balance in patients with potential HPS and POPH. Methods We recruited patients with decompensated cirrhosis (n=69) admitted to our hospital as liver transplantation candidates. Patients exhibiting partial pressure of oxygen lower than 80 mmHg and alveolar-arterial oxygen gradient (AaDO2) 15 mmHg were categorized as potentially having HPS (23 of 69 patients). Patients exhibiting a tricuspid regurgitation pressure gradient 25 mmHg were categorized as potentially having POPH (29 of 61 patients). Serum reactive oxygen metabolites were measured and anti-oxidative OXY-adsorbent test (OXY) were performed, and the balance of these tests was defined as the oxidative index. The correlation between these values and the clinical characteristics of the patients were assessed in a cross-sectional study. Results Potential HPS patients exhibited no correlation with oxidative stress markers. Potential POPH patients exhibited lower OXY (p=0.037) and higher oxidative index values (p=0.001). Additionally, the vascular NO synthase enzyme inhibiting protein, asymmetric dimethylarginine, was higher in potential POPH patients (p=0.049). The potential POPH patients exhibited elevated AaDO2, suggesting the presence of pulmonary shunting. Conclusion Potential POPH patients exhibited elevated oxidative stress with decreased anti-oxidative function accompanied by inhibited NO production. Anti-oxidants represent a candidate treatment for potential POPH patients.

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  • 当院における生体肝移植後の胆管狭窄に対する内視鏡治療

    友田 健, 加藤 博也, 内田 大輔, 秋元 悠, 松本 和幸, 山本 直樹, 堀口 繁, 堤 康一郎, 高木 章乃夫, 岡田 裕之, 八木 孝仁

    移植   50 ( 4-5 )   481 - 481   2015.10

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  • Hepatic stellate cells promote upregulation of epithelial cell adhesion molecule and epithelial-mesenchymal transition in hepatic cancer cells. Reviewed International journal

    Nagahara T, Shiraha H, Sawahara H, Uchida D, Takeuchi Y, Iwamuro M, Kataoka J, Horiguchi S, Kuwaki T, Onishi H, Nakamura S, Takaki A, Nouso K, Yamamoto K

    Oncology reports   34 ( 3 )   1169 - 1177   2015.9

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    Microenvironment plays an important role in epithelial-mesenchymal transition (EMT) and stemness of cells in hepatocellular carcinoma (HCC). Epithelial cell adhesion molecule (EpCAM) is known as a tumor stemness marker of HCC. To investigate the relationship between microenvironment and stemness, we performed an in vitro co-culture assay. Four HCC cell lines (HepG2, Hep3B, HuH-7 and PLC/PRF/5) were co-cultured with the TWNT-1 immortalized hepatic stellate cells (HSCs), which create a microenvironment with HCC. Cell proliferation ability was analyzed by flow cytometry (FCM) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, while migration ability was assessed by a wound healing assay. Expression of EpCAM was analyzed by immunoblotting and FCM. HCC cell lines were co-cultured with TWNT-1 treated with small interfering RNA (siRNA) for TGF-β and HB-EGF; we then analyzed proliferation, migration ability and protein expression using the methods described above. Proliferation ability was unchanged in HCC cell lines co-cultured with TWNT-1. Migration ability was increased in HCC cell lines (HepG2, Hep3B, HuH-7 and PLC/PRF/5) directly (216.2±67.0, 61.0±22.0, 124.0±66.2 and 51.5±40.3%) and indirectly (102.5±22.0, 84.6±30.9, 86.1±25.7 and 73.9±29.7%) co-cultured with TWNT-1 compared with the HCC uni-culture. Immunoblot analysis revealed increased EpCAM expression in the HCC cell lines co-cultured with TWNT-1. Flow cytometry revealed that the population of E-cadherin-/N-cadherin+ and EpCAM-positive cells increased and accordingly, EMT and stemness in the HCC cell line were activated. These results were similar in the directly and indirectly co-cultured samples, indicating that humoral factors were at play. Conversely, HCC cell lines co-cultured with siRNA‑treated TWNT-1 showed decreased migration ability, a decreased population of EpCAM-positive and E-cadherin-/N-cadherin+ cells. Taken together, humoral factors secreted from TWNT-1 promote upregulation of EpCAM and EMT in hepatic cancer cells.

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  • Effectiveness of Extending Treatment Duration in Therapy with Pegylated Interferon and Ribavirin for Genotype 2 Hepatitis C Virus Infection Reviewed

    Shintarou Nanba, Fusao Ikeda, Shin-ichi Fujioka, Yasuyuki Araki, Kouichi Takaguchi, Noriaki Hashimoto, Hiroyuki Seki, Akinobu Takaki, Yoshiaki Iwasaki, Kazuhide Yamamoto

    ACTA MEDICA OKAYAMA   69 ( 4 )   237 - 244   2015.8

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    The effectiveness of extending treatment duration as response guided therapy was previously reported for chronic hepatitis C (CHC) genotype 1, but is still controversial for genotype 2. The present study is a retrospective cohort study to investigate the effectiveness of extending treatment duration in therapy with pegylated interferon and ribavirin for patients with CHC genotype 2 by focusing on the timing at which patients obtained undetectable HCV RNA. A total of 306 patients who obtained undetectable HCV RNA by week 24 of treatment and completed 24 weeks of treatment were enrolled. Rapid virological response (RVR) to standard therapy was achieved by 122 patients (51%), and 89% of them obtained sustained virological response (SVR), while 69% of non-RVR patients achieved SVR. Non-RVR patients with undetectable HCV RNA at week 8, and insufficient adherence &lt; 80% pegylated interferon and ribavirin during the first 24 weeks, significantly improved their SVR rate by extended therapy. Among patients receiving extended therapy, drug adherences did not differ between SVR and non-SVR patients, indicating that extending treatment duration might compensate for insufficient antiviral effects due to insufficient drug adherences. This finding might be useful in creating a guideline for extending treatment duration for patients with CHC genotype 2.

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  • Serum N-glycan profiles in patients with intraductal papillary mucinous neoplasms of the pancreas Reviewed

    Yutaka Akimoto, Kazuhiro Nouso, Hironari Kato, Koji Miyahara, Chihiro Dohi, Yuki Morimoto, Hideaki Kinugasa, Takeshi Tomoda, Naoki Yamamoto, Koichiro Tsutsumi, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada, Maho Amano, Shin-Ichiro Nishimura, Kazuhide Yamamoto

    PANCREATOLOGY   15 ( 4 )   432 - 438   2015.7

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    Background/objectives: Diagnosing the invasiveness of intraductal papillary mucinous neoplasms (IPMNs) is difficult, especially by blood test. Alterations in serum glycan profiles have been reported for several cancers, but changes in serum glycan profiles have not been investigated in patients with IPMNs. The objectives of this study were to determine the serum N-glycan profile and to investigate its clinical utility in patients with IPMNs.
    Methods: We measured serum N-glycan profiles in 79 patients with IPMNs, including 13 invasive IPMNs, by performing comprehensive glycome analysis and assessed the relationship between N-glycan changes and clinical parameters.
    Results: Seventy glycans were identified and their expression profiles were significantly different depending on the cyst size, the presence of an enhancing solid component, and the histological grade of the IPMN. Nine glycans were highly expressed in patients with invasive IPMNs. The glycan m/z 3195, which is a fucosylated tri-antennary glycan, had the highest diagnostic value for distinguishing invasive IPMNs from non-invasive IPMNs (area under the receiver operating characteristic curve = 0.803). Multivariate analyses revealed high levels of m/z 3195 [odds ratio (OR), 20.5; 95% confidence interval (CI) 2.60-486.4] and the presence of enhancing solid components (OR, 35.8; 95% Cl, 5.39-409.6) were significant risk factors for invasive IPMNs.
    Conclusions: We performed a comprehensive evaluation of the changes in serum N-glycan profiles in patients with IPMNs for the first time. We determined that increased expression of fucosylated complex-type glycans, especially m/z 3195, is a potential marker for invasive IPMNs. Copyright (C) 2015, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.

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  • Prognostic Value of Altered N-Glycosylation of Circulating Glycoproteins in Patients With Unresectable Pancreatic Cancer Treated With Gemcitabine Reviewed

    Koji Miyahara, Kazuhiro Nouso, Yuki Morimoto, Hideaki Kinugasa, Hironari Kato, Naoki Yamamoto, Koichiro Tsutsumi, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Taku Nakahara, Yoshiaki Miura, Hidehisa Asada, Maho Amano, Shin-Ichiro Nishimura, Kazuhide Yamamoto

    PANCREAS   44 ( 4 )   551 - 556   2015.5

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    Objectives: The objectives of this study were to examine the whole serum N-glycan profile of patients with unresectable pancreatic cancer and to evaluate the ability of glycans to predict gemcitabine treatment efficacy and patient survival.
    Methods: We collected serum from 52 patients with advanced pancreatic cancer before they began gemcitabine monotherapy. The serum glycan profile was measured through comprehensive quantitative high-throughput glycome analysis and compared with the treatment efficacy and patient survival.
    Results: Of the 61 glycans detected, the serum levels of glycan 4310 (molecular weight [m/z] 1549.566), 6301 (m/z 2032.724), and 9200 (m/z 2010.692) were high in patients with a short time to tumor progression (TTP). Multivariate analysis revealed that a high glycan 9200 concentration was an independent risk factor for shorter TTP (hazard ratio, 2.11; 95% confidence interval, 1.07-4.17) and poor overall survival (hazard ratio, 2.56; 95% confidence interval, 1.08-6.19). The median TTP of patients with up-regulation of 9200 after gemcitabine treatment was shorter than for the remaining patients (91 vs 301 days; P = 0.0005). A similar relationship was observed for overall survival (median, 181 vs 561 days; P = 0.001).
    Conclusions: Glycan 9200 is a possible biomarker predicting gemcitabine efficacy survival in patients with unresectable pancreatic cancer.

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  • Randomized Trial of Peginterferon Alpha-2b Plus Low and Escalating Dose of Ribavirin in Patients With Chronic Hepatitis C With High Viral Load Genotype 1 Reviewed

    Yoshiaki Iwasaki, Yasuyuki Araki, Hideaki Taniguchi, Ryo-ichi Okamoto, Haruhiko Kobashi, Fusao Ikeda, Yasuhiro Miyake, Akinobu Takaki, Kazuhide Yamamoto

    JOURNAL OF MEDICAL VIROLOGY   87 ( 4 )   625 - 633   2015.4

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    It has been reported that elderly patients with chronic hepatitis C infection cannot tolerate standard combination therapy. In this randomized, controlled trial, the efficacy and safety of peginterferon alpha-2b plus a low and escalating dose of ribavirin in chronic hepatitis C patients with high viral load genotype 1 were investigated. Sixty-two patients were randomized into combination therapy with standard ribavirin dosing (group 1) or low and escalating ribavirin dosing (group 2). Patients were evaluated for safety and efficacy of treatment. There was no significant difference in the prevalence of virological response between the groups throughout the treatment as well as 24 weeks after treatment. However, the response in patients 60 years of age was higher in group 1 than in group 2 at early treatment phase (P=0.015). The prevalence of completion of therapy in patients 60 years of age tended to be higher in group 2 than in group 1 (50% vs. 0%, P=0.055). There was no significant difference in dose modification of peginterferon alpha-2b between the groups. However, dose modification of ribavirin was significantly more frequent in group 1 than in group 2 (60% vs. 24%, P=0.005). These data suggest that combination therapy with low and escalating dosing of ribavirin may be safer in elderly patients than that with standard dosing of ribavirin without impairing the treatment response. J. Med. Virol. 87:625-633, 2015. (c) 2015 Wiley Periodicals, Inc.

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  • Use of non-invasive serum glycan markers to distinguish non-alcoholic steatohepatitis from simple steatosis. Reviewed International journal

    Yamasaki Y, Nouso K, Miyahara K, Wada N, Dohi C, Morimoto Y, Kinugasa H, Takeuchi Y, Yasunaka T, Kuwaki K, Onishi H, Ikeda F, Miyake Y, Nakamura S, Shiraha H, Takaki A, Iwasaki Y, Amano M, Nishimura S, Yamamoto K

    Journal of gastroenterology and hepatology   30 ( 3 )   528 - 534   2015.3

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    BACKGROUND AND AIMS: Serum glycans have been reported to be promising diagnostic markers for many inflammatory diseases and cancers. The aims of this study were to investigate whole glycan expression in patients with non-alcoholic fatty liver diseases and to evaluate the potential use of glycan profiles as new clinical biomarkers to distinguish non-alcoholic steatohepatitis (NASH) from simple steatosis (SS). METHODS: We collected sera from 42 histologically proven NASH and 15 SS patients prior to treatment. Serum glycan profiles were measured by comprehensive, quantitative, high-throughput glycome analysis, and diagnostic values of serum glycans for NASH prediction were examined. RESULTS: Among the 41 serum glycans examined, the expression levels of 8 glycans in NASH were significantly higher than those of SS. Out of these eight glycans, three glycans (m/z 1955, 2032, and 2584) showed high areas under the receiver operating characteristic curve (0.833, 0.863, and 0.866, respectively) for distinguishing NASH from SS. In multivariate analyses with clinical parameters and serum glycans, these three glycans were significant predictive factors for distinguishing NASH from SS. The odds ratio of m/z 1955, 2032, and 2584 were 48.5, 6.46, and 11.8, respectively. These glycans also correlated significantly with lobular inflammation, ballooning, and fibrosis, but not with steatosis. CONCLUSION: We clearly demonstrated whole-serum glycan profiles in NASH patients, and the feasibility of serum glycans (m/z 1955, 2032, and 2584) as new noninvasive biomarkers for distinguishing NASH from SS.

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  • Alpha-fetoprotein before and after pegylated interferon therapy for predicting hepatocellular carcinoma development Reviewed

    Yasuto Takeuchi, Fusao Ikeda, Toshiya Osawa, Yasuyuki Araki, Kouichi Takaguchi, Youichi Morimoto, Noriaki Hashimoto, Kousaku Sakaguchi, Tatsuro Sakata, Masaharu Ando, Yasuhiro Makino, Shuji Matsumura, Hiroki Takayama, Hiroyuki Seki, Shintarou Nanba, Yuki Moritou, Tetsuya Yasunaka, Hideki Ohnishi, Akinobu Takaki, Kazuhiro Nouso, Yoshiaki Iwasaki, Kazuhide Yamamoto

    World Journal of Hepatology   7 ( 19 )   2220 - 2228   2015

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    AIM: To investigate factors that accurately predict hepatocellular carcinoma (HCC) development after antiviral therapy in chronic hepatitis C (CHC) patients. METHODS: CHC patients who received pegylated interferon and ribavirin were enrolled in this cohort study that investigated the ability of alpha-fetoprotein (AFP) to predict HCC development after interferon (IFN) therapy. RESULTS: Of 1255 patients enrolled, 665 developed sustained virological response (SVR) during mean follow-up period of 5.4 years. HCC was occurred in 89 patients, and 20 SVR patients were included. Proportional hazard models showed that HCC occurred in SVR patients showing AFP ≥ 5ng/mL before therapy and in non-SVR patients showing AFP ≥ 5ng/mL before and 1year after therapy besides older age, and low platelet counts. SVR patients showing AFP ≥ 5ng/mL before therapy and no decrease in AFP to &lt
    5ng/mL 1year after therapy had significantly higher HCC incidence than non-SVR patients showing AFP ≥ 5ng/ mL before therapy and decreased AFP (P = 0.043). AFP ≥ 5ng/mL before therapy was significantly associated with low platelet counts and high values of alanine aminotransferase (ALT) in stepwise logistic regression analysis. After age, gender, platelet count, and ALT was matched by propensity score, significantly lower HCC incidence was shown in SVR patients showing AFP &lt
    5ng/mL before therapy than in those showing AFP ≥ 5ng/mL. CONCLUSION: The criteria of AFP &lt
    5ng/mL before and 1year after IFN therapy is a benefical predictor for HCC development in CHC patients.

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  • Local recurrence and complications after percutaneous radiofrequency ablation of hepatocellular carcinoma: a retrospective cohort study focused on tumor location. Reviewed

    Toshimori J, Nouso K, Nakamura S, Wada N, Morimoto Y, Takeuchi Y, Yasunaka T, Kuwaki K, Ohnishi H, Ikeda F, Shiraha H, Takaki A, Yamamoto K

    Acta medica Okayama   69 ( 4 )   219 - 226   2015

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    DOI: 10.18926/AMO/53558

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    Other Link: http://search.jamas.or.jp/link/ui/2016215092

  • Polycythemia Vera Diagnosed after Esophageal Variceal Rupture.

    Yoshiyasu Kono, Akinobu Takaki, Hideo Gobara, Ken-Ichi Matsuoka, Masato Nishino, Hiroyuki Okada, Kazuhide Yamamoto

    Internal medicine (Tokyo, Japan)   54 ( 18 )   2395 - 9   2015

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    Polycythemia vera (PV) is a chronic myeloproliferative neoplasm that leads to hyperviscosity and the risk of thrombosis. We encountered the case of a young male Filipino patient diagnosed with PV after the rupture of esophageal varices. The complete blood cell count showed a slight increase in white blood cells. An abdominal computed tomography scan disclosed splenomegaly and occlusion of the portal vein and collateral vessels. A blood examination demonstrated an increase in all three blood cell lines within three months. Based on the presence of severe hypercellularity of the bone marrow and positivity for the JAK2V617F mutation, we finally diagnosed the patient with PV.

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  • Ultrastructural analysis of a gastric persimmon phytobezoar Reviewed

    Masaya Iwamuro, Haruo Urata, Masumi Furutani, Yoshinari Kawai, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada, Kazuhide Yamamoto

    CLINICS AND RESEARCH IN HEPATOLOGY AND GASTROENTEROLOGY   38 ( 4 )   E85 - E87   2014.9

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  • L-Carnitine Prevents Progression of Non-Alcoholic Steatohepatitis in a Mouse Model with Upregulation of Mitochondrial Pathway Reviewed

    Hisashi Ishikawa, Akinobu Takaki, Ryuichiro Tsuzaki, Tetsuya Yasunaka, Kazuko Koike, Yasuyuki Shimomura, Hiroyuki Seki, Hiroshi Matsushita, Yasuhiro Miyake, Fusao Ikeda, Hidenori Shiraha, Kazuhiro Nouso, Kazuhide Yamamoto

    PLOS ONE   9 ( 7 )   2014.7

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    Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease characterized by lobular inflammation, hepatocellular ballooning, and fibrosis with an inherent risk for progression to cirrhosis and hepatocellular carcinoma (HCC). Mitochondrial dysfunction appears to play a role in the progression from simple steatosis to NASH. L-carnitine (L-b-hydroxy-g-N-trimethylaminobutyric acid), an essential nutrient that converts fat into energy in mitochondria, has been shown to ameliorate liver damage. The aim of the present study was to explore the preventive and therapeutic effect of L-carnitine in NASH model mice. Eight-week-old male STAM mice, a NASH-cirrhosis-hepatocarcinogenic model, were divided into 3 experimental groups and fed as follows: 1) high-fat diet (HFD) (control group); 2) HFD mixed with 0.28% L-carnitine (L-carnitine group); and 3) HFD mixed with 0.01% alpha-tocopherol (alpha-tocopherol group). After 4 or 8 weeks, mice were sacrificed. Blood samples and livers were collected, and hepatic tumors were counted and measured. Livers were subjected to histological study, immunohistochemical staining of 4-hydroxynonenal and ferritin, determination of 8-OHdG levels, mRNA and protein expressions for multiple genes, and metabolomic analysis. The intestinal microbiome was also analyzed. L-carnitine increased hepatic expression of genes related to long-chain fatty acid transport, mitochondrial beta-oxidation, and antioxidant enzymes following suppression of hepatic oxidative stress markers and inflammatory cytokines in NASH, and mice treated with L-carnitine developed fewer liver tumors. Although alpha-tocopherol resulted in NASH improvement in the same manner as L-carnitine, it increased periodontitis-related microbiotic changes and hepatic iron transport-related gene expression and led to less effective for anti-hepatocarcinogenesis. Conclusion: L-carnitine prevents progression of non-alcoholic steatohepatitis in a mouse model by upregulating the mitochondrial beta-oxidation and redox system.

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  • Impact of Comorbid Hepatic Steatosis on Treatment of Chronic Hepatitis C in Japanese Patients and the Relationship with Genetic Polymorphism of IL28B, PNPLA3 and LDL Receptor Reviewed

    Yuki Moritou, Fusao Ikeda, Yoshiaki Iwasaki, Nobuynki Baba, Kouichi Takaguchi, Tomonori Senoh, Takuya Nagano, Yasuto Takeuchi, Tetsuya Yasunaka, Hideki Ohnishi, Yasuhiro Miyake, Akinobu Takaki, Kazuhiro Nouso, Kazuhide Yamamoto

    ACTA MEDICA OKAYAMA   68 ( 1 )   17 - 22   2014.2

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    The impact of hepatic steatosis on interferon therapy for patients with chronic hepatitis C (CHC) has been associated with single-nucleotide polymorphisms (SNP) of IL28B, patatin-like phospholipase domain-containing protein 3 (PNPLA3), and low-density lipoprotein (LDL) receptor. Whether this holds true for Japanese patients, however, remains unresolved. The present study prospectively enrolled 226 Japanese patients with CHC, and investigated the impact of hepatic steatosis and its related SNPs, including rs8099917 of IL28B, rs738409 of PNPLA3, and rs14158 of LDL receptor, on outcomes of peg-interferon and ribavirin therapy. In multivariate logistic regression analysis, significant factors affecting the severity of hepatic steatosis were high body mass index and the minor alleles of IL28B SNP (p = 0.020 and 0.039, respectively). The risk alleles of PNPLA3 SNP also showed weak association (p = 0.059). Severe steatosis and the minor alleles of IL28B SNP were significantly associated with null or partial virological response in patients with HCV genotype 1, as were female gender, and low LDL cholesterol (p = 0.049, and &lt;0.001, respectively). The SNP genotype of PNPLA3 and LDL receptor did not have a significant impact on therapeutic outcomes. With respect to the SNP sites examined, the SNP of PNPLA3 has a weak association with severe hepatic steatosis, but not with the outcome of interferon therapy.

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  • In Vitro Analysis of Gastric Phytobezoar Dissolubility by Coca-Cola, Coca-Cola Zero, Cellulase, and Papain Reviewed

    Masaya Iwamuro, Yoshinari Kawai, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada, Kazuhide Yamamoto

    JOURNAL OF CLINICAL GASTROENTEROLOGY   48 ( 2 )   190 - 191   2014.2

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    DOI: 10.1097/MCG.0b013e3182a39116

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  • Anti-programmed cell death-1 antibody as a new serological marker for type 1 autoimmune hepatitis Reviewed

    Kazuyuki Matsumoto, Yasuhiro Miyake, Hiroshi Matsushita, Atsuyuki Ohnishi, Fusao Ikeda, Hidenori Shiraha, Akinobu Takaki, Kazuhiro Nouso, Kazuhide Yamamoto

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   29 ( 1 )   110 - 115   2014.1

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    Background and AimRecently, the association of the dysfunction of programmed cell death (PD)-1 expressed on activated lymphocytes with the pathogenesis of autoimmune hepatitis (AIH) has been speculated. This study aimed to investigate the association of serum anti-PD-1 antibodies with clinical characteristics of type 1 AIH.
    MethodsSerum samples before the initiation of prednisolone treatment were obtained from 52 type 1 AIH patients, 24 patients with drug-induced liver injury (DILI), 30 patients with acute viral hepatitis (AVH), 11 patients with primary sclerosing cholangitis (PSC), and 62 healthy volunteers. Titers of serum anti-PD-1 antibodies were measured by indirect enzyme-linked immunosorbent assay. The cutoff level was represented by a mean absorbance+2 standard deviations in healthy volunteers.
    ResultsPrevalence of serum anti-PD-1 antibodies was 63% in type 1 AIH patients, 8% in DILI patients, 13% in AVH patients, 18% in PSC patients, and 3% in healthy volunteers. In type 1 AIH patients, titers of serum anti-PD-1 antibodies were correlated with serum levels of bilirubin (r=0.31, P=0.030) and alanine aminotransferase (r=0.31, P=0.027) but not serum immunoglobulin G levels. Positivity for serum anti-PD-1 antibodies was associated with the later normalization of serum alanine aminotransferase levels after the initiation of prednisolone and the disease relapse.
    ConclusionsSerum anti-PD-1 antibodies would be useful for the discrimination of type 1 AIH from DILI, AVH, and PSC as an auxiliary diagnostic marker. Furthermore, anti-PD-1 antibodies may be associated with clinical characteristics of type 1 AIH.

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  • Predictive impact of polymorphism of PNPLA3 on HCC development after interferon therapy in Japanese patients with chronic hepatitis C. Reviewed International journal

    Moritou Y, Ikeda F, Iwasaki Y, Baba N, Takaguchi K, Senoh T, Nagano T, Takeuchi Y, Yasunaka T, Ohnishi H, Miyake Y, Takaki A, Nouso K, Yamamoto K

    SpringerPlus   2 ( 1 )   251 - 251   2013.12

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    The impact of single-nucleotide polymorphisms (SNP) of patatin-like phospholipase domain-containing protein 3 (PNPLA3) on development of hepatocellular carcinoma (HCC) is not clarified for Japanese patients with chronic hepatitis C. The present study investigated the associations of rs738409 PNPLA3 with HCC development after the antiviral therapy with peg-interferon and ribavirin for Japanese patients with hepatitis C virus serotype 1 and high viral load. Of the 271 patients enrolled in the study, 20 patients developed HCC, during a median follow-up period of 4.6 years. Multivariate analysis in the proportional hazards models revealed that sex, body mass index, platelet counts, and alpha feroprotein (AFP) had significant associations with HCC development (p = 0.011, 0.029, 0.0002, and 0.046, respectively). Multivariate regression analysis revealed that PNPLA3 148 M was significantly associated with serum AFP level (p = 0.032), other than body mass index, platelet count, and alanine aminotransferase (p = 0.0006, 0.0002, and 0.037, respectively), and that serum AFP level was significantly associated with PNPLA3 148 M (p = 0.017). Serum AFP level is an important factor in predicting HCC development after the antiviral therapy for Japanese patients with chronic hepatitis C, the mechanism of which might involve its significant associations with the SNP genotype of PNPLA3.

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  • 自己免疫性肝胆膵疾患の病態解明の進歩 自己免疫性肝炎における新規自己抗体

    三宅 康広, 松本 和幸, 大西 敦之, 松下 浩志, 高木 章乃夫, 山本 和秀

    消化器と免疫   ( 49 )   3 - 6   2013.3

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    抑制性の補助刺激分子programmed cell death-1(PD-1)に対する血清中抗体価を間接ELISA法で測定した。抗PD-1抗体価は、薬物性肝障害(DILI)群や急性ウイルス性肝炎群、健常者群に比べて自己免疫性肝炎(AIH)群で高値であった。また、AIH群では、抗PD-1抗体価とビリルビンやトランスアミナーゼが正に相関しており、抗PD-1抗体陽性例では陰性例に比べて抗核抗体の陽性率が高かった。血清中抗PD-1抗体は、AIHとDILIの鑑別に有用であり、AIHの病態に関与している可能性が推測される。(著者抄録)

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  • Erratum: Risk factors for recurrence after transarterial chemoembolization for early-stage hepatocellular carcinoma (Journal of Gastroenterology (2012) DOI: 10.1007/s00535-011-0492-9) Reviewed

    Hideaki Kinugasa, Kazuhiro Nouso, Yasuto Takeuchi, Tetsuya Yasunaka, Hideki Onishi, Shin-Ichiro Nakamura, Hidenori Shiraha, Kenji Kuwaki, Hiroaki Hagihara, Fusao Ikeda, Yasuhiro Miyake, Akinobu Takaki, Kazuhide Yamamoto

    Journal of Gastroenterology   47 ( 4 )   489   2012.4

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    DOI: 10.1007/s00535-011-0508-5

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  • 我が国における自己免疫性肝疾患の現状と展開 自己免疫性肝炎の新規診断補助マーカーとしての抗PD-1抗体及び抗BTLA抗体

    三宅 康広, 松本 和幸, 高木 章乃夫, 山本 和秀

    肝臓   53 ( Suppl.1 )   A121 - A121   2012.4

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  • 急性肝不全症例における血清中可溶性接着分子の意義

    大西 敦之, 三宅 康広, 松本 和幸, 安中 哲也, 池田 房雄, 小池 和子, 高木 章乃夫, 山本 和秀

    日本消化器病学会雑誌   109 ( 臨増総会 )   A325 - A325   2012.3

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  • 急性肝不全における血清中可溶性接着分子の意義

    大西 敦之, 三宅 康広, 松本 和幸, 安中 哲也, 池田 房雄, 小池 和子, 高木 章乃夫, 山本 和秀

    日本内科学会雑誌   101 ( Suppl. )   218 - 218   2012.2

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  • Serum hepatitis B virus DNA before liver transplantation correlates with HBV reinfection rate even under successful low-dose hepatitis B immunoglobulin prophylaxis Reviewed

    Tetsuya Yasunaka, Akinobu Takaki, Takahito Yagi, Yoshiaki Iwasaki, Hiroshi Sadamori, Kazuko Koike, Satoshi Hirohata, Masashi Tatsukawa, Daisuke Kawai, Hidenori Shiraha, Yasuhiro Miyake, Fusao Ikeda, Haruhiko Kobashi, Hiroaki Matsuda, Susumu Shinoura, Ryuichi Yoshida, Daisuke Satoh, Masashi Utsumi, Teppei Onishi, Kazuhide Yamamoto

    HEPATOLOGY INTERNATIONAL   5 ( 4 )   918 - 926   2011.12

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    Purpose The combination of hepatitis B immunoglobulin (HBIg) and nucleos(t)ide analogues has been accepted as the best treatment to control hepatitis B recurrence after orthotopic liver transplantation (OLT). However, the optimal dose of HBIg remains unclear. We have previously reported that high-dose HBIg in the early period followed by low-dose HBIg with nucleos(t)ide analogues offers reliable and cost-effective control of hepatitis B recurrence. The aim of this study was to investigate intrahepatic hepatitis B virus (HBV) reinfection status with our clinically successful protocol.
    Methods We quantified levels of intrahepatic HBV covalently closed circular (ccc) deoxyribonucleic acid (DNA) and serum hepatitis B core-related antigen (HBcrAg), a new serological marker that can estimate intrahepatic cccDNA levels. Nucleos(t)ide analogues were administered in all cases.
    Results No patients showed recurrence of hepatitis B surface antigen (HBsAg) or HBV-DNA. However, HBV, cccDNA, and HBcrAg were positive in 57% and 48% of patients after OLT, respectively. Pre-OLT serum HBV-DNA and HBcrAg levels correlated linearly with post-OLT cccDNA levels (r = 0.534, P &lt; 0.05, and r = 0.634, P &lt; 0.05, respectively). High serum HBV-DNA and HBcrAg levels, particularly with &gt; 3 log(10) copies/mL and &gt; 4 log(10) IU/mL, respectively, at the time of OLT, were associated with high levels of post-OLT cccDNA. Even with our successful protocol, nearly half of patients showed HBV reinfection.
    Conclusions Patients with high serum HBV-DNA and HBcrAg levels before OLT (particularly &gt; 3 log(10) copies/mL and &gt; 4 log(10) IU/mL, respectively) should be followed with care for HBV recurrence.

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  • Stage of hepatocellular carcinoma is associated with periodontitis Reviewed

    Naofumi Tamaki, Akinobu Takaki, Takaaki Tomofuji, Yasumasa Endo, Kenta Kasuyama, Daisuke Ekuni, Tetsuya Yasunaka, Kazuhide Yamamoto, Manabu Morita

    JOURNAL OF CLINICAL PERIODONTOLOGY   38 ( 11 )   1015 - 1020   2011.11

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    Aim: Periodontitis induces overproduction of reactive oxygen species (ROS). This state increases circulating ROS levels and may affect hepatocellular carcinoma (HCC). The Japan Integrated Stage (JIS) score is a novel staging system for HCC. The objective of the present study was to compare JIS scores in HCC patients with and without periodontitis.
    Material and Methods: We recruited 64 HCC patients comprising 31 chronic periodontitis subjects (HCC + P) and 33 periodontally healthy controls (HCC + H). Their JIS scores were recorded. Serum levels of reactive oxygen metabolites (ROM) from HCC + P, HCC + H and healthy age-and gender-matched subjects with healthy gingiva (control, n = 15) were also assessed for circulating ROS levels.
    Results: The HCC + P and HCC + H groups had similar body mass index, habitual drinking and tobacco exposure data. The HCC + P group showed higher JIS scores than the HCC + H group (p = 0.027). Both the HCC + P and HCC + H groups had higher serum levels of ROM than controls (p &lt; 0.001), while serum levels of ROM in the HCC + P group were a further 25.8% higher than those in the HCC + H group (p &lt; 0.001).
    Conclusion: HCC patients with periodontitis had higher JIS score and circulating ROS level than HCC patients without periodontitis.

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  • Predicting the treatment effect of sorafenib using serum angiogenesis markers in patients with hepatocellular carcinoma Reviewed

    Koji Miyahara, Kazuhiro Nouso, Takeshi Tomoda, Sayo Kobayashi, Hiroaki Hagihara, Kenji Kuwaki, Junichi Toshimori, Hideki Onishi, Fusao Ikeda, Yasuhiro Miyake, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Kazuhide Yamamoto

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   26 ( 11 )   1604 - 1611   2011.11

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    Background and Aim: Sorafenib, the first agent demonstrated to have efficacy to improve the survival of patients with advanced hepatocellular carcinoma (HCC), is an active multikinase inhibitor affecting angiogenesis and tumor proliferation. We analyzed cytokines related to angiogenesis or cell proliferation, and tried to determine their utility as biomarkers of sorafenib treatment effect for HCC.
    Methods: Nine serum cytokines (angiopoietin-2 [Ang-2], follistatin, granulocyte colony-stimulating factor [G-CSF], hepatocyte growth factor [HGF], interleukin-8 [IL-8], leptin, platelet-derived growth factor-BB, platelet endothelial cell adhesion molecule-1, and vascular endothelial growth factor) were measured in 30 HCC patients treated with sorafenib, and the effects of treatment were compared using modified Response Evaluation Criteria in Solid Tumors.
    Results: All but IL-8 were significantly higher at baseline in patients with progressive disease. Progression-free survival was significantly shorter in patients with high levels of Ang-2, G-CSF, HGF, and leptin, and the hazard ratios were 2.51, 6.89, 2.55, and 4.14, respectively. As the number of cytokines at a high level increased, the treatment response deteriorated. Disease progression was seen in three of 12 (25.0%) patients with zero to two high biomarkers, two of six (33.3%) patients with 3-5 high biomarkers, and 10 of 12 (83.3%) patients with six to eight high biomarkers (P = 0.008). The prognosis of all patients with eight high biomarkers was progressive disease.
    Conclusion: High levels of serum cytokines at baseline were correlated with poor effects of sorafenib treatment in patients with HCC.

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  • 急性肝不全症例における血清中可溶性接着分子の意義

    大西 敦之, 三宅 康広, 松本 和幸, 高木 章乃夫, 小池 和子, 安中 哲也, 池田 房雄, 能祖 一裕, 山本 和秀

    肝臓   52 ( Suppl.3 )   A862 - A862   2011.11

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  • Hepatitis B virus core promoter mutations G1613A and C1653T are significantly associated with hepatocellular carcinoma in genotype C HBV-infected patients Reviewed

    Masashi Tatsukawa, Akinobu Takaki, Hidenori Shiraha, Kazuko Koike, Yoshiaki Iwasaki, Haruhiko Kobashi, Shin-Ichi Fujioka, Kohsaku Sakaguchi, Kazuhide Yamamoto

    BMC CANCER   11   458   2011.10

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    Background: Hepatitis B virus (HBV) is a major cause of hepatocarcinogenesis. To identify mutations relevant to hepatocellular carcinoma (HCC) development, we compared the full genome sequences of HBV from the sera of patients with and without HCC.
    Methods: We compared the full genome sequences of HBV isolates from 37 HCC patients (HCC group 1) and 38 patients without HCC (non-HCC group 1). We also investigated part of the core promoter region sequences from 40 HCC patients (HCC group 2) and 68 patients without HCC. Of the 68 patients who initially did not have HCC, 52 patients remained HCC-free during the follow-up period (non-HCC group 2), and 16 patients eventually developed HCC (pre-HCC group 2). Serum samples collected from patients were subjected to PCR, and the HBV DNA was directly sequenced.
    Results: All patients had genotype C. A comparison of the nucleotide sequences of the HBV genome between HCC group 1 and non-HCC group 1 revealed that the prevalence of G1613A and C1653T mutations in the core promoter region was significantly higher in the HCC group. These mutations tended to occur simultaneously in HCC patients. Multivariate analysis with group 2 revealed that the presence of HCC was associated with aging and the double mutation. Future emergence of HCC was associated with aging and the presence of a single G1613A mutation.
    Conclusions: G1613A and C1653T double mutations were frequently found in patients with HCC. A single G1613A mutation was associated with future emergence of HCC. These mutations may serve as useful markers in predicting HCC development.

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  • Stage of hepatocellular carcinoma is associated with periodontitis. Reviewed International journal

    Naofumi Tamaki, Akinobu Takaki, Takaaki Tomofuji, Yasumasa Endo, Kenta Kasuyama, Daisuke Ekuni, Tetsuya Yasunaka, Kazuhide Yamamoto, Manabu Morita

    Journal of Clinical Periodontology   Vol.38 ( No.11 )   1015 - 1020   2011.9

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    HCC patients with periodontitis had higher JIS score and circulating ROS level than HCC patients without periodontitis.

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  • Additive improvement induced by bezafibrate in patients with primary biliary cirrhosis showing refractory response to ursodeoxycholic acid Reviewed

    Yasuto Takeuchi, Fusao Ikeda, Shin-ichi Fujioka, Toshiyuki Takaki, Toshiya Osawa, Tetsuya Yasunaka, Yasuhiro Miyake, Akinobu Takaki, Yoshiaki Iwasaki, Haruhiko Kobashi, Kazuhide Yamamoto, Tatsuya Itoshima

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   26 ( 9 )   1395 - 1401   2011.9

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    Background and Aim: Ursodeoxycholic acid (UDCA) has been widely used in the treatment of patients with primary biliary cirrhosis (PBC). However, some patients are refractory to UDCA. The aim of this study is to clarify the additive improvement induced by bezafibrate in patients refractory to UDCA.
    Methods: This study was a prospective analysis of 37 consecutive PBC patients. All patients were treated first for 6 months with UDCA, and then with bezafibrate, if their alkaline phosphatase (ALP) levels did not decrease more than 40% or within the normal range after 6 months&apos; treatment with UDCA. Clinical parameters were monitored for the subsequent 24 months.
    Result: Twenty-two patients (59%) achieved improvement of ALP levels after the treatment with UDCA. Those patients (Group A) had significantly lower levels of ALP at diagnosis than those with abnormal ALP levels after 6 months&apos; treatment with UDCA (Group B; P = 0.020). They continued UDCA monotherapy, and maintained normal ALP levels at subsequent follow ups. However, immunoglobulin M (IgM) levels remained abnormal in eight patients, whose IgM levels at the time of diagnosis were significantly higher than those whose IgM were normalized after 6 months&apos; treatment with UDCA (P = 0.026). Those in Group B were treated additionally with bezafibrate, and 12 patients (80%) achieved normalALP and IgM levels within 12 months of commencement of therapy.
    Conclusion: Higher ALP level at diagnosis is one of the predictors for UDCA failure. Combination treatment of bezafibrate in addition to UDCA may be an effective treatment for PBC patients refractory to UDCA.

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  • 急性肝不全症例における血清中可溶性接着分子の意義

    大西 敦之, 三宅 康広, 松本 和幸, 高木 章乃夫, 山本 和秀

    日本臨床免疫学会会誌   34 ( 4 )   316 - 316   2011.8

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  • Prognostic importance of fucosylated alpha-fetoprotein in hepatocellular carcinoma patients with low alpha-fetoprotein Reviewed

    Kazuhiro Nouso, Yoshiyuki Kobayashi, Shinichiro Nakamura, Sayo Kobayashi, Hiroki Takayama, Junichi Toshimori, Kenji Kuwaki, Hiroaki Hagihara, Hideki Onishi, Yasuhiro Miyake, Fusao Ikeda, Hidenori Shiraha, Akinobu Takaki, Yoshiaki Iwasaki, Haruhiko Kobashi, Kazuhide Yamamoto

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   26 ( 7 )   1195 - 1200   2011.7

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    Background and Aim: Fucosylated alpha-fetoprotein (AFP-L3) is known to be a marker of poor prognosis in patients with hepatocellular carcinoma (HCC). However, it has been difficult to measure AFP-L3 under low AFP (&lt;= 20 ng/mL). The aim of this study was to elucidate the role of AFP-L3 in HCC patients with low AFP conditions.
    Methods: One hundred and ninety six consecutive newly developed HCC patients with low AFP (&lt;= 20 ng/mL) were examined for serum AFP-L3 expression by a newly-developed micro-total analysis system that could stably measure AFP-L3 in low AFP circumstances, and its clinical importance was analyzed.
    Results: Positivity of AFP-L3 in HCC patients was 13.3% at a cut-off level of 10%. Five-year survivals of HCC patients with AFP-L3 (&lt; 10%) and AFP-L3 (&gt;= 10%) were 69.4% and 41.1%, respectively (P = 0.001). Among 18 clinical parameters, low alanine aminotransferase, large tumor size, presence of portal vein tumor thrombus, high AFP and high des-gamma carboxy prothrombin were observed in the high AFP-L3 (&gt;= 10%) group. Multivariate analysis revealed that high aspartate aminotransferase (AST) (risk ratio [RR] = 3.24, 95% confidence interval [Cl] = 1.27-8.26), the presence of ascites (RR = 3.44, 95% Cl = 1.22-9.34), multiple tumor number (RR = 3.06, 95% CI = 1.33-7.17), and high AFP-L3 (RR = 8.36, 95% Cl = 2.79-25.5) were risk factors for survival. High AFP-L3 was also a risk factor for survival in HCC patients who received radiofrequency ablation (P = 0.048).
    Conclusions: AFP-L3 is a strong prognostic factor for survival even in HCC patients with low AFP (&lt;= 20 ng/mL).

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  • Long-term outcome and hepatocellular carcinoma development in chronic hepatitis B or cirrhosis patients after nucleoside analog treatment with entecavir or lamivudine Reviewed

    Haruhiko Kobashi, Yasuhiro Miyake, Fusao Ikeda, Tetsuya Yasunaka, Ken Nishino, Akio Moriya, Jyunichi Kubota, Shinichiro Nakamura, Akinobu Takaki, Kazuhiro Nouso, Gotaro Yamada, Kazuhide Yamamoto

    HEPATOLOGY RESEARCH   41 ( 5 )   405 - 416   2011.5

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    Aim:
    We conducted this prospective study to elucidate the long-term outcome and incidence of hepatocellular carcinoma (HCC) development after nucleos(t)ide analog (NA) treatment in patients with chronic hepatitis B (CHB) or cirrhosis.
    Methods:
    CHB or cirrhosis patients without past NA treatment or HCC were started on entecavir (ETV) or lamivudine (LVD), and prospectively followed up with monthly blood tests, and with abdominal imaging every 6 months in CHB and every 3 months in cirrhosis patients.
    Results:
    A total of 256 subjects with CHB (n = 194) or cirrhosis (n = 62) received ETV (n = 129) or LVD (n = 127) for 4.25 years (range: 0.41-10.0). After NA treatment, serum HBV DNA, alanine aminotransferase and alpha-fetoprotein (AFP) dropped significantly, along with significant increases in serum albumin and prothrombin time. Drug-resistance developed in 60 cases in the LVD group and in only one case in the ETV group. HCC developed in 35 patients, and the incidence at years 1, 3, 5, 7 and 10 was significantly higher in patients with cirrhosis (8.1%, 17.5%, 43.2%, 46.7% and 53.4%, respectively) than chronic hepatitis (1.6%, 3.5%, 3.5%, 7.1% and 29.6%, respectively), with no difference between ETV and LVD. After NA treatment, the sensitivity/specificity for HCC of AFP and des-gamma-carboxy prothrombin (DCP) was 45.7%/97.3% and 33.3%/96.2%, respectively, with the specificity of AFP being higher than at baseline (64.4%), at the cut-off of 10 ng/mL.
    Conclusion:
    NA exerted a long-term efficacy and improved hepatic reservation in CHB and cirrhosis. After NA treatment, AFP dropped to lower than 10 ng/mL with marked elevation of specificity, leading to an earlier detection of HCC.

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  • Hepatocellular carcinoma occurring in hepatobiliary fibropolycystic disease Reviewed

    Hideaki Kinugasa, Kazuhiro Nouso, Yoshiyuki Kobayashi, Tetuya Yasunaka, Hideki Onishi, Shin-ichiro Nakamura, Hidenori Shiraha, Hiroki Takayama, Junichi Toshimori, Kenji Kuwaki, Hiroaki Hagihara, Yasuhiro Miyake, Fusao Ikeda, Akinobu Takaki, Haruhiko Kobashi, Kazuhide Yamamoto

    HEPATOLOGY RESEARCH   41 ( 3 )   277 - 281   2011.3

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    Congenital hepatic fibrosis (CHF) and bile duct hamartomas (von Meyenburg complexes) are hepatobiliary fibropolycystic diseases. There have been several reports of liver neoplasias arising in hepatobiliary fibropolycystic diseases. However, most of them were cholangiocarcinomas and cases involving hepatocellular carcinoma (HCC) are rare. A 51-year-old woman was found to have multiple hepatic tumors by ultrasonography and enhanced computed tomography (CT) during a regular work-up for the recurrence of lung cancer and thyroid cancer, which had been surgically removed 4 and 3 years ago, respectively. Nodules were observed at S3, S5, and S6 (2 cm in diameter). All of the nodules were hyperattenuated at the early arterial phase, and the main tumor at S5 showed hypoattenuation at the delayed phase on dynamic CT and magnetic resonance imaging (MRI). HCC was suspected from these findings. She also suffered from multiple small cystic lesions in the liver. The surgically removed liver showed HCC arising in CHF, which is a rare histological finding.

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  • 水素水はマウスにおけるNASHの進行を抑制する

    河合 大介, 高木 章乃夫, 山本 和秀, 松本 和幸, 津崎 龍一郎, 安中 哲也, 小池 和子, 三宅 康弘, 白羽 秀則

    日本消化器病学会雑誌   108 ( 臨増総会 )   A367 - A367   2011.3

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  • +49A/G polymorphism of cytotoxic T-lymphocyte antigen 4 gene in type 1 autoimmune hepatitis and primary biliary cirrhosis: A meta-analysis Reviewed

    Yasuhiro Miyake, Fusao Ikeda, Akinobu Takaki, Kazuhiro Nouso, Kazuhide Yamamoto

    HEPATOLOGY RESEARCH   41 ( 2 )   151 - 159   2011.2

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    Aim:
    Recently, the associations of +49A/G polymorphisms of cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene with the susceptibility to type 1 autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) have been reported; however these associations are yet to be fully elucidated. This study aimed to identify the associations of CTLA-4 gene +49A/G polymorphisms with the susceptibility to type 1 AIH and PBC by using a meta-analysis.
    Methods:
    PubMed was searched by using the following keywords: "autoimmune hepatitis AND (polymorphism OR polymorphisms)" or "primary biliary cirrhosis AND (polymorphism OR polymorphisms)". Meta-analyses of five studies including 526 patients with type 1 AIH and 631 controls and seven studies including 1500 patients with PBC and 2345 controls were performed.
    Results:
    For type 1 AIH, the odds ratio (OR) of G allele was 1.26 [95% confidence interval (CI) 1.06-1.51] although G/G homozygosity was not associated with the susceptibility to type 1 AIH. On the other hand, the OR of A/A homozygosity for type 1 AIH was 0.66 (95% CI 0.50-0.86). For PBC, the OR of G allele was 1.20 (95% CI 1.06-1.34). Furthermore, G/G homozygosity was significantly associated with the susceptibility to PBC (OR 1.29, 95% CI 1.01-1.66). The OR of A/A homozygosity for PBC was 0.81 (95% CI 0.70-0.94).
    Conclusions:
    This study suggests that CTLA-4 gene +49A/G polymorphisms may be associated with the susceptibility to type 1 AIH and PBC. Especially, while G/G genotype may be associated with the susceptibility to PBC, A/A genotype may be protective against type 1 AIH and PBC.

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  • Prognostic model for hepatocellular carcinoma with time-dependent factors. Reviewed

    Kuwaki K, Nouso K, Kobayashi Y, Nakamura S, Ito YM, Iwadou S, Hagihara H, Yasunaka T, Toshimori J, Miyatake H, Miyoshi K, Onishi H, Miyake Y, Shoji B, Takaki A, Shiraha H, Iwasaki Y, Kobashi H, Yamamoto K

    Acta medica Okayama   65 ( 1 )   11 - 19   2011.2

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    The purpose of this study was to build a prognostic model of hepatocellular carcinoma (HCC) using time-dependent covariates to re-evaluate the prognosis at any stage of the disease. The subjects were consecutive HCC patients who were treated at our institute between 1995 and 2007. We constructed time-fixed and time-dependent prognostic models with a training group (n=336) and compared the prognostic abilities between conventional Cancer of the Liver Italian Program (CLIP) scores, Japan Integrated Staging (JIS) scores, an Okuda classification, and our prognostic models in the testing group (n=227) with the c-index. The time-dependent prognostic model consisted of main tumor size, tumor number, portal vein invasion, distant metastasis, alpha-fetoprotein, des-gamma-carboxy prothrombin (DCP), bilirubin, and albumin and the weighted scores were set for each factor depending on the hazard ratio for the prognosis. The prognostic index was determined by summing the scores. The c-index values for the CLIP scores, JIS scores, Okuda classification, and our time-dependent model were 0.741, 0.727, 0.609, and 0.870, respectively. These results indicate that our time-dependent model can estimate the prognosis of HCC more precisely than traditional time-fixed models and can be used to re-predict the prognosis of HCC.

    DOI: 10.18926/AMO/43825

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  • Serum levels of platelet-derived growth factor-BB and vascular endothelial growth factor as prognostic factors for patients with fulminant hepatic failure Reviewed

    Hiroki Takayama, Yasuhiro Miyake, Kazuhiro Nouso, Fusao Ikeda, Hidenori Shiraha, Akinobu Takaki, Haruhiko Kobashi, Kazuhide Yamamoto

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   26 ( 1 )   116 - 121   2011.1

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    Background and Aims:
    In animal models for acute liver injury, the administration of some angiogenic factors such as vascular endothelial growth factor (VEGF) and granulocyte-colony stimulating factor (G-CSF) are shown to reduce liver injury and improve liver proliferative capacity. The aim of the present study was to assess the role of angiogenic factors in fulminant hepatic failure (FHF).
    Methods:
    Serum levels of nine angiogenic factors (angiopoietin-2, follistatin, G-CSF, hepatocyte growth factor [HGF], interleukin-8, leptin, platelet-derived growth factor [PDGF]-BB, platelet endothelial cell adhesion molecule-1 and VEGF) were measured using the Bio-Plex Protein Array System in 30 patients, 17 of whom were diagnosed with FHF, 13 with acute hepatitis (AH), and 20 controls.
    Results:
    Serum levels of PDGF-BB and VEGF were lower in FHF patients than AH patients and controls (PDGF-BB; 2050 +/- 1572 pg/mL vs 4521 +/- 2419 pg/mL vs 8506 +/- 5500 pg/mL, VEGF; 39 +/- 38 pg/mL vs 144 +/- 122 pg/mL vs 205 +/- 121 pg/mL). By using univariate logistic regression models, serum levels of PDGF-BB and VEGF were associated with poor outcomes. Serum PDGF-BB levels were strongly correlated with serum VEGF levels (r = 0.70). Furthermore, serum PDGF-BB levels were significantly correlated with platelet counts (r = 0.79), PT activity (r = 0.37) and D.Bil/T.Bil ratio (r = 0.50), while serum VEGF levels were significantly correlated with platelet counts (r = 0.68) and PT activity (r = 0.38).
    Conclusions:
    We consider that serum levels of PDGF-BB and VEGF are worth investigating as biomarkers for predicting outcomes of FHF patients.

    DOI: 10.1111/j.1440-1746.2010.06441.x

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  • Loss of runt-related transcription factor 3 expression leads hepatocellular carcinoma cells to escape apoptosis Reviewed

    Yutaka Nakanishi, Hidenori Shiraha, Shin-ichi Nishina, Shigetomi Tanaka, Minoru Matsubara, Shigeru Horiguchi, Masaya Iwamuro, Nobuyuki Takaoka, Masayuki Uemura, Kenji Kuwaki, Hiroaki Hagihara, Junichi Toshimori, Hideki Ohnishi, Akinobu Takaki, Shinichiro Nakamura, Yoshiyuki Kobayashi, Kazuhiro Nouso, Takahito Yagi, Kazuhide Yamamoto

    BMC CANCER   11   3   2011.1

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    Background: Runt-related transcription factor 3 (RUNX3) is known as a tumor suppressor gene for gastric cancer and other cancers, this gene may be involved in the development of hepatocellular carcinoma (HCC).
    Methods: RUNX3 expression was analyzed by immunoblot and immunohistochemistry in HCC cells and tissues, respectively. Hep3B cells, lacking endogenous RUNX3, were introduced with RUNX3 constructs. Cell proliferation was measured using the MTT assay and apoptosis was evaluated using DAPI staining. Apoptosis signaling was assessed by immunoblot analysis.
    Results: RUNX3 protein expression was frequently inactivated in the HCC cell lines (91%) and tissues (90%). RUNX3 expression inhibited 90 +/- 8% of cell growth at 72 h in serum starved Hep3B cells. Forty-eight hour serum starvation-induced apoptosis and the percentage of apoptotic cells reached 31 +/- 4% and 4 +/- 1% in RUNX3-expressing Hep3B and control cells, respectively. Apoptotic activity was increased by Bim expression and caspase-3 and caspase-9 activation.
    Conclusion: RUNX3 expression enhanced serum starvation-induced apoptosis in HCC cell lines. RUNX3 is deleted or weakly expressed in HCC, which leads to tumorigenesis by escaping apoptosis.

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  • Hepatic toxicity and prognosis in hepatitis C virus-infected patients with diffuse large B-cell lymphoma treated with rituximab-containing chemotherapy regimens: a Japanese multicenter analysis. Reviewed International journal

    Ennishi D, Maeda Y, Niitsu N, Kojima M, Izutsu K, Takizawa J, Kusumoto S, Okamoto M, Yokoyama M, Takamatsu Y, Sunami K, Miyata A, Murayama K, Sakai A, Matsumoto M, Shinagawa K, Takaki A, Matsuo K, Kinoshita T, Tanimoto M

    Blood   116 ( 24 )   5119 - 5125   2010.12

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    The influence of hepatitis C virus (HCV) infection on prognosis and hepatic toxicity in patients with diffuse large B-cell lymphoma in the rituximab era is unclear. Thus, we analyzed 553 patients, 131 of whom were HCV-positive and 422 of whom were HCV-negative, with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP)-like chemotherapy. Survival outcomes and hepatic toxicity were compared according to HCV infection. The median follow-up was 31 and 32 months for patients who were HCV-positive and HCV-negative, respectively. HCV infection was not a significant risk factor for prognosis (3-year progression-free survival, 69% vs 77%, P = .22; overall survival, 75% vs 84%, P = .07). Of 131 patients who were HCV-positive, 36 (27%) had severe hepatic toxicity (grade 3-4), compared with 13 of 422 (3%) patients who were HCV-negative. Multivariate analysis revealed that HCV infection was a significant risk factor for severe hepatic toxicity (hazard ratio: 14.72; 95% confidence interval, 6.37-34.03; P < .001). An exploratory analysis revealed that pretreatment transaminase was predictive of severe hepatic toxicity. HCV-RNA levels significantly increased during immunochemotherapy (P = .006). These results suggest that careful monitoring of hepatic function and viral load is indicated during immunochemotherapy for HCV-positive patients.

    DOI: 10.1182/blood-2010-06-289231

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    Other Link: http://orcid.org/0000-0003-1761-6314

  • Laparoscopic findings of reddish markings predict hepatocellular carcinoma in patients with hepatitis B virus-related liver disease. Reviewed

    Shoji B, Ikeda F, Fujioka S, Kobashi H, Yasunaka T, Miyake Y, Shiraha H, Takaki A, Nouso K, Iwasaki Y, Yamamoto K

    Journal of gastroenterology   45 ( 11 )   1172 - 1182   2010.11

  • Amino acid substitutions of hepatitis C virus core protein are not associated with intracellular antiviral response to interferon-α in vitro. Reviewed

    Ikeda F, Dansako H, Nishimura G, Mori K, Kawai Y, Ariumi Y, Miyake Y, Takaki A, Nouso K, Iwasaki Y, Ikeda M, Kato N, Yamamoto K

    Liver international : official journal of the International Association for the Study of the Liver   30 ( 9 )   1324 - 1331   2010.10

  • Hepatitis C virus NS4 protein impairs the Th1 polarization of immature dendritic cells Reviewed

    A. Takaki, M. Tatsukawa, Y. Iwasaki, K. Koike, Y. Noguchi, H. Shiraha, K. Sakaguchi, E. Nakayama, K. Yamamoto

    JOURNAL OF VIRAL HEPATITIS   17 ( 8 )   555 - 562   2010.8

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    Dendritic cells (DCs) in chronic hepatitis C patients display impaired function, although the details remain unclear. To investigate the hepatitis C virus (HCV) protein that has the most impact on DC function, we compared five recombinant proteins and seven HCV protein genes in modulating DC phenotype and function. Immature DCs (iDCs) were established from healthy donor peripheral blood monocytes with granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-4. Lipopolysaccharide was used to establish mature DCs (mDCs). Cells were then pulsed with HCV recombinant proteins or transfected with HCV plasmids and subsequently assayed for cell surface marker expression by flow cytometry. For cytokine and proliferative T-cell response analysis, DCs were cultured with autologous CD4 T cells and tuberculin purified protein derivative (PPD). Mean fluorescent intensity of CD86 was reduced in HCV protein-pulsed iDCs. Proliferative T-cell responses and Th1 cytokine concentrations were reduced with HCV nonstructural proteins (NS), particularly with HCV NS4. HCV nonstructural proteins, particularly NS4, change the iDC phenotype and reduce antigen-specific T-cell stimulatory function with Th1 cytokine reductions.

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  • Meta-analysis: interferon-alpha prevents the recurrence after curative treatment of hepatitis C virus-related hepatocellular carcinoma Reviewed

    Y. Miyake, A. Takaki, Y. Iwasaki, K. Yamamoto

    JOURNAL OF VIRAL HEPATITIS   17 ( 4 )   287 - 292   2010.4

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    Various clinical studies have indicated that interferon (IFN)-alpha treatment prevents the development of hepatocellular carcinoma (HCC) in people chronically infected with hepatitis C virus. However, it has been controversial whether IFN-alpha treatment prevents HCC recurrence. The aim of this study was to identify the preventive effect of IFN-alpha treatment after curative therapy of primary tumours within the Milan criteria (three or fewer nodules 3 cm or less in diameter or a single nodule of 5 cm or less) on HCC recurrence. We conducted a meta-analysis of five trials including 355 patients (167 patients received IFN-alpha treatment after curative therapy of primary tumours) and estimated relative risks (RRs) and 95% confidence intervals (CIs) for the effect of IFN-alpha on HCC recurrence according to the DerSimonian and Laird method. IFN-alpha treatment after curative therapy of primary tumours significantly prevented HCC recurrence (RR 0.33; 95%CI 0.19-0.58, P &lt; 0.0001) without a significant heterogeneity (Q = 4.52, P = 0.34). An evaluation using the Begg method suggested no evidence of publication bias. Sub-group analyses revealed that IFN-alpha treatment reduced HCC recurrence in two studies achieving sustained virologic response (SVR) rates &gt; 30% (RR 0.20; 95%CI 0.05-0.81, P = 0.02) and in three studies achieving SVR rates &lt; 30% (RR 0.44; 95%CI 0.23-0.84, P = 0.01). In conclusion, IFN-alpha treatment after curative treatment of primary tumour within Milan criteria may be effective for the prevention of HCC recurrence, and higher SVR rate may be associated with better preventive effect of IFN-alpha treatment on HCC recurrence.

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  • Clinical features of autoimmune hepatitis diagnosed based on simplified criteria of the International Autoimmune Hepatitis Group Reviewed

    Yasuhiro Miyake, Yoshiaki Iwasaki, Haruhiko Kobashi, Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Kazuhide Yamamoto

    DIGESTIVE AND LIVER DISEASE   42 ( 3 )   210 - 215   2010.3

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    Background: Recently, simplified diagnostic criteria for autoimmune hepatitis have been proposed. Aim: We aimed to evaluate usefulness of the simplified criteria.
    Methods: We applied the simplified criteria to 176 autoimmune hepatitis patients diagnosed according to the revised scoring system proposed in 1999 (original criteria). Furthermore, in order to compare predictabilities between these two diagnostic criteria, we included 168 patients with other liver disease than autoimmune hepatitis.
    Results: Of 176 autoimmune hepatitis patients, 85% were diagnosed with autoimmune hepatitis according to the simplified criteria, and patients diagnosed according to the simplified criteria showed a higher frequency of antinuclear antibodies and/or smooth muscle antibodies of 1:80 or greater and slightly higher serum levels Of immunoglobulin G than those diagnosed according to the original criteria. However, 30% of male patients, 23% of patients with acute presentation, 50% of patients showing histological acute hepatitis and 46% of patients negative for antinuclear antibodies at presentation were not diagnosed with autoimmune hepatitis according to the simplified criteria. The simplified criteria showed lower sensitivity (85% vs. 100%) and higher specificity (99% vs. 93%) for autoimmune hepatitis than the original criteria.
    Conclusions: The simplified criteria may be useless for the diagnosis of patients with atypical features, especially patients with histological acute hepatitis. (C) 2009 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

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  • Evolution of prognostic factors in hepatocellular carcinoma in Japan. Reviewed

    Nouso K, Kobayashi Y, Nakamura S, Kobayashi S, Toshimori J, Kuwaki K, Hagihara H, Onishi H, Miyake Y, Ikeda F, Shiraha H, Takaki A, Iwasaki Y, Kobashi H, Yamamoto K

    Alimentary pharmacology & therapeutics   31 ( 3 )   407 - 414   2010.2

  • Autoimmune hepatitis with acute presentation in Japan Reviewed

    Y. Miyake, Y. Iwasaki, H. Kobashi, T. Yasunaka, F. Ikeda, A. Takaki, K. Yamamoto

    DIGESTIVE AND LIVER DISEASE   42 ( 1 )   51 - 54   2010.1

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    Background: In Caucasians with autoimmune hepatitis, patients with acute presentation have autoimmune thyroiditis and histological zone 3 necrosis more frequently.
    Aim: We aimed at investigating clinical features of Japanese autoimmune hepatitis patients with acute presentation.
    Methods: Of 176 patients retrospectively reviewed, 53 were diagnosed with acute presentation.
    Results: Patients with acute presentation had higher serum levels of bilirubin and transaminase, lower frequencies of autoimmune thyroiditis and antinuclear antibodies of 1:160 or greater, and a higher frequency of zone 3 necrosis. Of the 53 patients with acute presentation, 10 showed histological acute hepatitis; however, advanced staging of fibrosis was found in 13 patients. In patients with acute presentation, those with histological acute hepatitis were younger than those with chronic hepatitis. The cumulative incidental rate of the normalization of serum alanine aminotransferase levels with prednisolone treatment was similar between patients with acute presentation and those with classical presentation.
    Conclusions: In line with previous results, zone 3 necrosis is a histological characteristic of autoimmune hepatitis with acute presentation. Autoimmune hepatitis with acute presentation includes not only histological acute hepatitis but also acute exacerbation of pre-existing chronic disease. On the other hand, Japanese patients with acute presentation may also have different clinical features from Caucasian patients. (C) 2009 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

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  • Acute Hepatitis due to Hepatitis E Virus Genotype 1 As an Imported Infectious Disease in Japan Reviewed

    Koji Miyahara, Yasuhiro Miyake, Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Yoshiaki Iwasaki, Haruhiko Kobashi, Jong-Hon Kang, Kazuaki Takahashi, Masahiro Arai, Kazuhide Yamamoto

    INTERNAL MEDICINE   49 ( 23 )   2613 - 2616   2010

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    An 18-year-old Nepalese man was admitted due to general malaise and anorexia a month after coming to Japan. Laboratory tests showed elevation of transaminase and positivity for IgM anti-HEV antibody. Serum HEV RNA was detected by RT-PCR amplifications. An HEV genome phylogenetic tree, constructed using an 821-nucleotide sequence in the open reading frame 1, indicated that the genotype was 1. HEV genotype 1 is epidemic in South Asia, Africa and South America, and the incidence of acute hepatitis due to HEV genotype 1 is low in Japan. Thereafter, attention should be paid to HEV genotype 1 infection as an imported infectious disease.

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  • Efficacy of ursodeoxycholic acid for Japanese patients with autoimmune hepatitis Reviewed

    Yasuhiro Miyake, Yoshiaki Iwasaki, Haruhiko Kobashi, Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Ryoichi Okamoto, Kouichi Takaguchi, Hiroshi Ikeda, Yasuhiro Makino, Masaharu Ando, Kohsaku Sakaguchi, Kazuhide Yamamoto

    HEPATOLOGY INTERNATIONAL   3 ( 4 )   556 - 562   2009.12

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    This study aimed to investigate the efficacy of ursodeoxycholic acid (UDCA) for Japanese patients with autoimmune hepatitis (AIH).
    One hundred forty-seven patients were investigated.
    As initial treatment, 25 patients received UDCA (300-600 mg/day) monotherapy (UDCA group), 40 received a combination of prednisolone (PSL) (a parts per thousand yen20 mg/day) and UDCA (combination group), 68 received PSL monotherapy (PSL group), and 14 received other treatments. During the follow-up, in the UDCA group, PSL was added to 8 of 12 patients failing to achieve the normalization of serum transaminase levels with UDCA monotherapy. Cumulative incidence of the normalization of serum transaminase levels was 64% in the UDCA group, 95% in the combination group, and 94% in the PSL group (log-rank test, P = 0.0001). UDCA group required longest periods until the normalization of serum transaminase levels. Eleven patients, who achieved persistent normalization of serum transaminase levels with UDCA monotherapy, did not reach liver failure or develop hepatocellular carcinoma for 49.7 (range = 13.4-137.3) months. Meanwhile, during the taper of PSL, doses of PSL at the initial relapse were lower in patients treated with PSL and UDCA than in those treated with PSL monotherapy, and initial relapse occurred earlier in patients treated with PSL monotherapy.
    UDCA monotherapy is effective for some Japanese AIH patients; however, UDCA monotherapy for patients with either high-grade inflammatory activity or poor residual capacity of liver function is not recommended because they may reach liver failure before achievement of remission. Meanwhile, additional use of UDCA during the taper of corticosteroids may be effective for the prevention of early relapse.

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  • HCVコア蛋白質のアミノ酸の違いとIFN応答性との関係についての培養細胞を用いた解析 Reviewed

    池田 房雄, 団迫 浩方, 西村 剛, 河合 良成, 有海 康雄, 池田 正徳, 高木 章乃夫, 岩崎 良章, 加藤 宣之, 山本 和秀

    肝臓   50 ( Suppl.2 )   A515 - A515   2009.9

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  • Clinical features of type 1 autoimmune hepatitis in adolescence and early adulthood Reviewed

    Yasuhiro Miyake, Yoshiaki Iwasaki, Haruhiko Kobashi, Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Ryoichi Okamoto, Kouichi Takaguchi, Hiroshi Ikeda, Yasuhiro Makino, Kohsaku Sakaguchi, Masaharu Ando, Kazuhide Yamamoto

    HEPATOLOGY RESEARCH   39 ( 8 )   766 - 771   2009.8

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    Aim:
    The peak age of the presentation of autoimmune hepatitis (AIH) is between 40 years and 50 years. Elderly patients have been reported to have higher frequencies of concurrent thyroid or rheumatic diseases and histological cirrhosis and a lower occurrence of treatment failure. In this study, we assessed the clinical features of Japanese type 1 AIH in adolescence and early adulthood.
    Methods:
    Fifteen patients aged &lt; 30 years (group 1) were compared with 79 patients aged between 40 years and 50 years (group 2).
    Results:
    At presentation, patients aged &lt; 30 years accounted for 9% of the study population. Although frequencies of extrahepatic concurrent autoimmune diseases were similar between groups 1 and 2, a tendency toward a lower frequency of concurrent autoimmune thyroiditis was shown in group 1 (0 vs. 18%, P = 0.08). Group 1 had a lower frequency of human leukocyte antigen DR4 (27 vs. 78%, P = 0.002), and histological acute hepatitis was shown more frequently in group 1 (27 vs. 4%, P = 0.002). However, there were no differences in frequencies of the normalization of serum transaminase levels after the introduction of corticosteroid treatment or relapse after the normalization of serum transaminase levels between the two groups.
    Conclusions:
    Japanese type 1 AIH patients in adolescence and early adulthood respond well to corticosteroid treatment. However, they may frequently show atypical features, and the diagnosis of type 1 AIH in adolescence and early adulthood may be difficult and should be made carefully.

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  • Twist expression promotes migration and invasion in hepatocellular carcinoma. Reviewed

    Matsuo N, Shiraha H, Fujikawa T, Takaoka N, Ueda N, Tanaka S, Nishina S, Nakanishi Y, Uemura M, Takaki A, Nakamura S, Kobayashi Y, Nouso K, Yagi T, Yamamoto K

    BMC cancer   9   240   2009.7

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  • Clinical features of antinuclear antibodies-negative type 1 autoimmune hepatitis Reviewed

    Yasuhiro Miyake, Yoshiaki Iwasaki, Haruhiko Kobashi, Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Ryoichi Okamoto, Kouichi Takaguchi, Hiroshi Ikeda, Yasuhiro Makino, Masaharu Ando, Kohsaku Sakaguchi, Kazuhide Yamamoto

    HEPATOLOGY RESEARCH   39 ( 3 )   241 - 246   2009.3

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    Antinuclear antibodies (ANA) are the main serologic markers of type 1 autoimmune hepatitis (AIH); however 20-30% of patients are negative for ANA. We assessed the clinical features of ANA-negative patients.
    A retrospective analysis was performed of 176 patients with type 1 AIH (153 females, median age 55 years). A diagnosis of AIH was made based on the revised scoring system proposed by the International Autoimmune Hepatitis Group. ANA titers were measured using a standard indirect immunofluorescence technique.
    Thirty-eight patients (22%) had low titers of ANA (1:40 or 1:80), and 114 (65%) had high titers (&gt;= 1:160). Of 24 ANA-negative patients, 15 were positive for smooth muscle antibodies (SMA). Three of nine both ANA- and SMA-negative patients developed ANA during follow-up. The other six were diagnosed based on histological characteristics. Thirteen ANA-negative patients relapsed after the normalization of serum alanine aminotransferase (ALT) levels. ANA-negative patients more frequently showed acute presentation and, at presentation, had lower serum immunoglobulin G levels, higher serum levels of bilirubin and transaminase, and higher frequencies of histological acute hepatitis and zone 3 necrosis than those with high titers. However, the frequency of advanced stage of fibrosis was similar. The response to corticosteroids was not different among the three groups.
    ANA-negative type 1 AIH shows acute-onset more frequently but may include not only acute autoimmune hepatitis, but also acute exacerbation of inactive chronic disease. Regarding the diagnosis of ANA-negative AIH, the determination of ANA during follow-up and the response to immunosuppressive treatment may be helpful.

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  • Feasibility and Findings of Colonoscopy for Living-donor Liver Transplant Candidates Reviewed

    Shin Ishikawa, Jun Kato, Motoaki Kuriyama, Koji Takemoto, Toshio Uraoka, Akinobu Takaki, Takahito Yagi, Kohsaku Sakaguchi

    JOURNAL OF CLINICAL GASTROENTEROLOGY   43 ( 1 )   69 - 74   2009.1

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    Background and Aims: Living-donor liver transplantation (LDLT) has been widely performed in patients with end-stage liver disease and hepatocellular carcinoma in Japan. Although extrahepatic cancer survey for LDLT candidates is absolutely required. few reports have indicated the optimal surveillance method for colorectal cancer. The aim Of this study is to investigate the feasibility and findings of colonoscopy before LDLT.
    Patients and Methods: Front January 2004 to August 2006. we prospectively, enrolled all of the scheduled LDLT candidates of our hospital for pretransplant colonoscopy examination.
    Results: A total of 81 patients were enrolled For colonoscopy. Of these patients. 67 (83%) could actually undergo colonoscopy. Patients who could bot undergo colonoscopy exhibited more impaired liver Function than those who Could (median Model End-State Liver Disease,core: 25.5 vs. 14.5. P = 0.0003). Among patients who underwent colonoscopy. observation of total colon was attained in 64 (96%). Neoplasia was found in 28 ,,) patients, including 4 patients with adenomas &gt;= 10 mm, 1 patient with adenomas with high-grade dysplasia. and 3 patients with invasive cancer. Patients who had advanced neoplasia (adenoma &gt;= 10 mm. adenomas with high-grade dysplasia. or invasive cancer) were likely to have a lower performance status (PS) (7/8 were PS 3) than those who did not (P = 0.054).
    Conclusions: Clinically, significant tumors were found in a considerable portion Of LDLT candidates. particularly in lower PS patients. Because immunosuppressive agents after transplantation may worsen malignant tumors. colonoscopy before transplantation is recommended in patients who can tolerate the procedure.

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  • Exon 2 deletion splice variant of gamma-glutamyl carboxylase causes des-gamma-carboxy prothrombin production in hepatocellular carcinoma cell lines. Reviewed

    Ueda N, Shiraha H, Fujikawa T, Takaoka N, Nakanishi Y, Suzuki M, Matsuo N, Tanaka S, Nishina S, Uemura M, Takaki A, Shiratori Y, Yamamoto K

    Molecular oncology   2 ( 3 )   241 - 249   2008.10

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    Using GGCX gene-specific real-time PCR, exon 2 deletion splice variant of vitamin K-dependent gamma-glutamyl carboxylase (GGCX) mRNA was identified in HCC cell lines. Expressions of wild type and exon 2 deletion variant of GGCX were analyzed with relevance to DCP production in HCC cell lines. Hep3B, HepG2, HuH1, HuH7, and PLC/PRF/5 produced DCP, while SK-Hep-1, HLE, HLF, and JHH1 produced no detectable level of DCP. DCP-producing cells expressed exon 2 deletion variant of GGCX mRNA and protein, while DCP-negative cells expressed no detectable level of exon 2 deletion variant of GGCX. These results suggest that exon 2 deletion splice variant of GGCX causes dysfunction of GGCX enzyme activity resulting in DCP production in HCC cell lines. (C) 2008 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.molonc.2008.06.004

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  • Human leukocyte antigen DR status and clinical features in Japanese patients with type 1 autoimmune hepatitis Reviewed

    Yasuhiro Miyake, Yoshiaki Iwasaki, Akinobu Takaki, Toru Onishi, Ryoichi Okamoto, Kouichi Takaguchi, Hiroshi Ikeda, Yasuhiro Makino, Haruhiko Kobashi, Kohsaku Sakaguchi, Yasushi Shiratori

    HEPATOLOGY RESEARCH   38 ( 1 )   96 - 102   2008.1

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    Aim: Human leukocyte antigen (HLA) DR status affects the clinical features of autoimmune hepatitis. In Caucasians, patients with DR3 have poorer outcomes. In Japan, the relationship between HLA DR status and clinical features has yet to be fully examined.
    Methods: We investigated 79 patients with type 1 autoimmune hepatitis who underwent liver biopsy and were screened for HLA DR status by the polymerase chain reaction sequence specific oligonucleotide hybridization method.
    Results: Fifty-five patients had DR4 and 23 had DR2. Thirteen patients had both DR2 and DR4. None had DR3. Of patients aged &lt; 30 years, 70% did not have DR4. A tendency toward higher serum levels of immunoglobulin G was seen in patients with DR4 compared to those without, while patients with neither DR2 nor DR4 had lower serum levels of immunoglobulin G than those with only DR2 and those with only DR4. Patients with DR2 had a lower frequency of concurrentautoimmune disease. Concurrence of thyroid disease was seen only in patients with DR4. The cumulative incidental rate of the normalization of serum alanine aminotransferase levels within six months after the introduction of corticosteroid treatment was not associated with HLA DR status.
    Conclusion: HLA DR status is considered to affect the clinical features of Japanese patients with type 1 autoimmune hepatitis. Japanese patients with DR2 may have different clinical features from others. In addition, diagnoses of type 1 autoimmune hepatitis should be made carefully in Japanese patients with neither DR2 nor DR4 and in those aged &lt; 30 years.

    DOI: 10.1111/j.1872-034X.2007.00204.x

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  • Relationship between the length of the predialysis period and the pathogenesis of diabetic end-stage renal failure

    Nakatsuka Atsuko, Kanzaki Motoko, Iwata Yasuyoshi, Takaki Akinobu, Ikeda Hiroshi, Fukushima Masaki

    Journal of Japanese Society for Dialysis Therapy   38 ( 8 )   1385 - 1390   2005

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    To examine the relationship between the length of the predialysis period and the pathogenesis of diabetic end-stage renal failure, we retrospectively studied 58 hemodialyzed patients (36 males, 22 females; 62.8±10.6 (SD) years). They were subgrouped into group A (n=34) or B (n=29), respectively, depending on whether hemodialysis was started less or more than 2 years after their serum creatinine concentration had reached 2mg/dL.<br>Group A patients were ten years younger than those of group B, and showed significantly higher urinary protein excretion, lower plasma albumin concentration, and larger renal size. The incidence of cerebral infarction was higher in group B. Multiple regression analysis demonstrated that the length of predialysis period was well correlated with both patients' age and renal size. These findings suggest that the major pathogenesis of renal failure is microangiopathic glomerulosclerosis in group A, and macroangiopathic nephrosclerosis in group B. The length of the predialysis period in each case must reflect the different involvements of these two mechanisums. Especially, in older hemodialyzed diabetic patients, the number of which has been increasing in recent years, nephrosclerosis may play a larger role in diabetic nephropathy.

    DOI: 10.4009/jsdt.38.1385

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  • [A case of focal segmental glomerulosclerosis(FSGS) complicated with chronic hepatitis B and treated with steroid and LDL apheresis]. Reviewed

    Takaki A, Nakatsuka A, Satou C, Iwata Y, Ikeda H, Fukushima M

    Nihon Jinzo Gakkai shi   44 ( 8 )   806 - 812   2002.12

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    A 52-year-old man was admitted to our hospital because of nephrotic syndrome. He had been monitored at our outpatient clinic for chronic hepatitis B, and had experienced histologically proven minimal change nephrotic syndrome at the ages of 40 and 51 years. Because of HBsAg positivity in his serum, steroid therapy was withheld in his earlier episodes and he recovered from nephrotic syndrome spontaneously. However, in the most recent episode the nephrotic syndrome was found difficult to control and the findings of renal biopsy showed FSGS, which is not expected in HBV-associated nephropathy. Finally, prednisolone was administered at the dose of 40 mg/day for four weeks, after which the dose was tapered. LDL apheresis was also administered three times because of the patient's incomplete response to prednisolone. His proteinuria was reduced from>10 g/day to<1 g/day, but the ALT levels and HBsAg titer increased. With stronger neominophagen C induction and very careful tapering of glucocorticoid, ALT levels and the HBsAg titer decreased. During the two-year period since the induction of glucocor ticoid therapy, urinary protein excretion has been maintained at less than 1 g/gcr, and ALT levels and HBsAg titer have not increased. We conclude that attention must be paid to dose modification of steroid therapy and strategies without immunosuppressive agents such as LDL apheresis should be considered in the case of treatment of nephrotic syndrome with HB virus.

    DOI: 10.14842/jpnjnephrol1959.44.806

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  • C型慢性肝炎における自己免疫現象

    坂口孝作, 河本博文, 高木章乃夫

    岡山医学会雑誌   105 ( 7-8 )   795-796   1993.8

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  • C型肝炎 自己免疫性肝炎とHCV

    坂口孝作, 河本博文, 高木章乃夫

    臨床消化器内科   7 ( 12 )   2007-2015   1992.11

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Books

  • 肝肺症候群(総説)

    高木章乃夫, 安中哲也, 大山淳史, 足立卓哉, 岡田裕之( Role: Joint author ,  筆頭著者)

    日本臨床社  2021.2 

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  • Liver Pathophysiology

    Elsevier Academic Press  2017 

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  • Immune mechanisms in non-alcoholic steatohepatitis (NASH).

    iConcept Press  2015 

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  • 肝疾患Review2006-2007

    日本メディカルセンター東京,東京  2006 

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  • 肝疾患Review2006-2007

    日本メディカルセンター東京,東京 

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MISC

  • 当院における免疫チェックポイント阻害薬による免疫有害事象の臨床的特徴についての検討-肝障害を中心に-

    須江真彦, 竹内康人, 大山淳史, 足立卓哉, 大西秀樹, 白羽英則, 高木章乃夫

    日本消化器病学会雑誌(Web)   120   2023

  • 進行肝癌に対する全身化学療法(アテゾリズマブ+ベバシズマブ併用療法,レンバチニブ治療,ソラフェニブ治療)の血清アルブミン値による効果の差

    足立卓哉, 能祖一裕, 須江真彦, 三宅望, 大山淳史, 和田望, 竹内康人, 大西秀樹, 白羽英則, 高木章乃夫

    日本肝がん分子標的治療研究会プログラム・抄録集   27th   2023

  • 生検検体を用いた胆道癌におけるPD-L1発現の検討

    松本和幸, 高木章乃夫, 大原利章, 藤澤真義, 高原政宏, 加藤博也, 吉田龍一, 楳田祐三, 八木孝仁, 松川昭博

    日本消化器病学会雑誌(Web)   119   2022

  • 肝細胞癌に対する肝移植適応拡大の実態

    高木章乃夫, 大西秀樹, 岡田裕之

    肝臓   63 ( Supplement 2 )   2022

  • 神経内分泌腫瘍肝転移における肝動脈塞栓療法の有効性の検討

    和田望, 堀口繁, 岡田裕之, 大山淳史, 足立卓哉, 竹内康人, 大西秀樹, 白羽英則, 高木章乃夫

    日本消化器病学会雑誌(Web)   119   2022

  • 当院における切除不能肝細胞癌に対するAtezolizmab/Bevacizumab治療状況

    竹内康人, 大山淳史, 足立卓哉, 和田望, 大西秀樹, 白羽英則, 高木章乃夫, 能祖一裕

    日本肝がん分子標的治療研究会プログラム・抄録集   26th   2022

  • 進行肝癌に対するアテゾリズマブ+ベバシズマブ併用療法とレンバチニブ治療の転移の有無における効果の差について

    足立卓哉, 能祖一裕, 大山淳史, 和田望, 竹内康人, 大西秀樹, 白羽英則, 高木章乃夫

    日本肝がん分子標的治療研究会プログラム・抄録集   26th   2022

  • 門脈血栓症に対してアンチトロンビンIII製剤を投与した13症例の経過

    田尻和也, 高木章乃夫, 増田修子, 稲生祥子, 大山淳史, 足立卓哉, 和田望, 竹内康人, 大西秀樹, 白羽英則, 岡田裕之

    日本門脈圧亢進症学会雑誌   27 ( 3 )   2021

  • 肝硬変治療の進歩に伴う肝移植時腹水・肝性脳症状態の変化

    高木章乃夫, 竹内康人, 大山淳史, 足立卓哉, 和田望, 大西秀樹, 白羽英則, 岡田裕之

    日本門脈圧亢進症学会雑誌   27 ( 3 )   2021

  • 高齢者においても有用な非侵襲的NAFLD線維化診断方法の探索

    森本光作, 竹内康人, 高木章乃夫, 大山淳史, 足立卓哉, 和田望, 大西秀樹, 白羽英則, 岡田裕之

    肝臓   62 ( Supplement 1 )   2021

  • 肝癌に対するREIC/Dkk-3遺伝子治療開発

    白羽英則, 大山淳史, 岩室雅也, 小橋真由, 足立卓哉, 和田望, 竹内康人, 安中哲也, 大西秀樹, 高木章乃夫, 岡田裕之

    肝臓   62 ( Supplement 1 )   2021

  • 進行肝細胞癌に対する分子標的薬による治療効果及び肝予備能の変化

    足立卓哉, 能祖一裕, 大山淳史, 和田望, 坂田雅浩, 安中哲也, 大西秀樹, 白羽英則, 高木章乃夫, 岡田裕之

    日本消化器病学会雑誌(Web)   117   2020

  • 進行肝細胞癌に対する分子標的治療薬治療における血管新生サイトカインと既存腫瘍マーカーの位置づけ

    足立卓哉, 能祖一裕, 大山淳史, 和田望, 坂田雅浩, 安中哲也, 大西秀樹, 白羽英則, 高木章乃夫, 岡田裕之

    肝臓   61 ( Supplement 2 )   2020

  • 糖尿病外来患者における慢性肝疾患スクリーニングマーカーの検討

    大山淳史, 高木章乃夫, 足立卓哉, 和田望, 坂田雅浩, 安中哲也, 大西秀樹, 白羽英則, 岡田裕之

    肝臓   61 ( Supplement 1 )   2020

  • 血管新生サイトカインは進行肝細胞癌に対するレンバチニブ治療の予測因子になりうる

    足立卓哉, 能祖一裕, 大山淳史, 和田望, 坂田雅浩, 安中哲也, 大西秀樹, 白羽英則, 高木章乃夫, 岡田裕之

    肝臓   61 ( Supplement 1 )   2020

  • 偶発的に指摘された肝粘液嚢胞性腫瘍(MCN)の1例

    大山淳史, 足立卓哉, 和田望, 竹内康人, 安中哲也, 大西秀樹, 白羽英則, 高木章乃夫, 岡田裕之

    日本消化器病学会中国支部例会プログラム・抄録集   114th   2020

  • 限局性結節性過形成と画像上鑑別困難であった孤立性甲状腺濾胞癌肝転移の一例

    久保遥祐, 小幡泰介, 森本光作, 大山淳史, 足立卓哉, 和田望, 竹内康人, 安中哲也, 大西秀樹, 白羽英則, 高木章乃夫, 西田賢司, 田中高志, 岡田裕之

    日本消化器病学会中国支部例会プログラム・抄録集   114th   2020

  • 成人先天性心疾患におけるFontan関連肝疾患(FALD)の現状と問題点

    大西秀樹, 高木章乃夫, 能祖一裕, 大山淳史, 足立卓哉, 和田望, 坂田雅浩, 安中哲也, 白羽英則, 岡田裕之

    日本消化器病学会雑誌(Web)   117   2020

  • 肝性浮腫に対するトルバプタン効果予測と予後予測について

    足立卓哉, 高木章乃夫, 佐藤秀一, 大山淳史, 和田望, 坂田雅浩, 安中哲也, 大西秀樹, 白羽英則, 岡田裕之

    日本消化器病学会雑誌(Web)   117   2020

  • ベルベリンによる慢性腸炎マウスの腸内細菌叢の変化

    高原政宏, 高原政宏, 高木章乃夫, 平岡佐規子, 安富絵里子, 山本峻平, 岡昌平, 平井麻美, 山崎泰史, 井口俊博, 衣笠秀明, 原田馨太, 岡田裕之

    日本消化器病学会雑誌(Web)   117   2020

  • 肝疾患の診断と治療 生体肝移植後経過より再考する肝硬変合併肺病変の評価

    大山 淳史, 高木 章乃夫, 安中 哲也, 足立 卓哉, 和田 望, 坂田 雅浩, 大西 秀樹, 白羽 英則, 吉田 龍一, 楳田 祐三, 中村 一文, 八木 孝仁, 岡田 裕之

    日本消化器病学会四国支部例会プログラム・抄録集   111回   47 - 47   2019.6

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  • 肝細胞癌に対する定位放射線治療の有用性

    大西 秀樹, 高木 章乃夫, 能祖 一裕, 大山 淳史, 足立 卓哉, 和田 望, 坂田 雅浩, 安中 哲也, 池田 房雄, 白羽 英則, 岡田 裕之

    肝臓   60 ( Suppl.1 )   A377 - A377   2019.4

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  • 肝細胞癌根治的治療後の無再発に寄与する因子としての酸化ストレスの重要性

    室 泰子, 高木 章乃夫, 中村 進一郎, 大山 淳史, 足立 卓哉, 和田 望, 安中 哲也, 大西 秀樹, 白羽 英則, 岡田 裕之

    肝臓   60 ( Suppl.1 )   A533 - A533   2019.4

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  • 膵癌におけるFNA検体と切除検体とのPD-L1発現の検討

    松本和幸, 高木章乃夫, 大原利章, 藤澤真義, 高原政宏, 加藤博也, 吉田龍一, 楳田祐三, 八木孝仁, 松川昭博, 岡田裕之

    日本消化器病学会雑誌(Web)   116   2019

  • ベルベリンは腸管粘膜CD4+T細胞のAMPKの活性化を介して炎症性サイトカインを制御しマウス慢性腸炎を改善させる

    高原政宏, 高木章乃夫, 平岡佐規子, 安富絵里子, 岡昌平, 平井麻美, 井口俊博, 小池和子, 岡田裕之

    日本臨床免疫学会総会プログラム・抄録集   47th   77   2019

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  • 肝性浮腫を有する病態に対するトルバプタン効果予測と予後予測について

    足立卓哉, 高木章乃夫, 佐藤秀一, 大山淳史, 和田望, 坂田雅浩, 安中哲也, 大西秀樹, 白羽英則, 岡田裕之

    日本門脈圧亢進症学会雑誌   25 ( 3 )   2019

  • Adefovir Dipivoxil-induced Fanconi’s Syndrome and Osteomalacia Following Multiple Bone Fractures in a Patient with Chronic Hepatitis B

    槇田崇志, 神崎浩孝, 大西秀樹, 池田愛璃, 高木章乃夫, 和田望, 竹内康人, 安中哲也, 池田房雄, 白羽英則, 田中雄太, 西原茂樹, 村川公央, 北村佳久, 岡田裕之, 千堂年昭

    YAKUGAKU ZASSHI (Web)   139 ( 4 )   2019

  • 急性E型肝炎の1例

    山内菜緒, 岡上昇太郎, 上田英次郎, 足立卓哉, 大山淳史, 和田望, 坂田雅浩, 安中哲也, 池田房雄, 白羽英則, 高木章乃夫, 岡田裕之

    日本消化器病学会中国支部例会プログラム・抄録集   111th   2019

  • 肝動注化学療法で奏功が期待できる肝細胞癌の臨床的特徴

    大西秀樹, 高木章乃夫, 和田望, 大山淳史, 足立卓哉, 坂田雅浩, 安中哲也, 白羽英則, 能祖一裕, 岡田裕之

    肝臓   60 ( Supplement 3 )   2019

  • 当院でのレゴラフェニブ使用症例の経過と効果症例の特徴

    足立 卓哉, 能祖 一裕, 大山 淳史, 和田 望, 安中 哲也, 大西 秀樹, 池田 房雄, 白羽 英則, 高木 章乃夫, 岡田 裕之

    The Liver Cancer Journal   10 ( Suppl.2 )   43 - 44   2018.12

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  • DCV+ASV併用療法でSVR24を達成した5ヵ月後に再燃を認めたC型慢性肝炎の一例

    和田 望, 池田 房雄, 大山 淳史, 足立 卓哉, 坂田 雅浩, 安中 哲也, 大西 秀樹, 白羽 英則, 高木 章乃夫, 岡田 裕之

    日本消化器病学会中国支部例会プログラム・抄録集   110回   119 - 119   2018.12

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  • 肝細胞癌に対するシスプラチン肝動注化学療法後に大腸炎を発症した一例

    山本 峻平, 大西 秀樹, 大山 淳史, 足立 卓哉, 和田 望, 坂田 雅浩, 安中 哲也, 池田 房雄, 白羽 英則, 能祖 一裕, 高木 章乃夫, 岡田 裕之

    日本消化器病学会中国支部例会プログラム・抄録集   110回   114 - 114   2018.12

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  • 抗ドナーHLA抗体陽性の肝移植の短期・長期成績と問題点 抗ドナー抗体陽性生体肝移植の現状と問題点

    楳田 祐三, 八木 孝仁, 田中 健大, 吉田 龍一, 信岡 大輔, 杭瀬 崇, 吉田 一博, 安井 和也, 吉田 真里, 白川 靖博, 柳井 広行, 高木 章乃夫, 藤原 俊義

    移植   53 ( 総会臨時 )   257 - 257   2018.9

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  • DAA治療後のSVR後発癌の特徴

    和田 望, 竹内 康人, 池田 房雄, 大山 淳史, 足立 卓哉, 安中 幸, 安中 哲也, 大西 秀樹, 白羽 英則, 高木 章乃夫, 岡田 裕之

    肝臓   59 ( Suppl.2 )   A672 - A672   2018.9

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  • 非アルコール性脂肪性肝疾患における遺伝子多型と非アルコール性脂肪肝炎関連因子の検討

    岩崎 良章, 池田 房雄, 中山 光, 和田 望, 安中 哲也, 高木 章乃夫, 岡田 裕之

    肝臓   59 ( Suppl.2 )   A684 - A684   2018.9

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  • 進行肝細胞癌におけるソラフェニブ治療の長期生存症例と短期終了症例のそれぞれの特徴

    足立 卓哉, 能祖 一裕, 大山 淳史, 和田 望, 安中 幸, 竹内 康人, 安中 哲也, 大西 秀樹, 池田 房雄, 白羽 英則, 高木 章乃夫, 高口 浩一, 植松 周二, 高畠 弘行, 萩原 宏明, 岡田 裕之

    The Liver Cancer Journal   ( Suppl.1 )   77 - 77   2018.6

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  • Efficacy and safety of glecaprevir/pibrentasvir in HCV-infected Japanese patients with prior DAA experience, severe renal impairment, or genotype 3 infection

    Hiromitsu Kumada, Tsunamasa Watanabe, Fumitaka Suzuki, Kenji Ikeda, Ken Sato, Hidenori Toyoda, Masanori Atsukawa, Akio Ido, Akinobu Takaki, Nobuyuki Enomoto, Koji Kato, Katia Alves, Margaret Burroughs, Rebecca Redman, David Pugatch, Tami J. Pilot-Matias, Preethi Krishnan, Rajneet K. Oberoi, Wangang Xie, Kazuaki Chayama

    Journal of Gastroenterology   53 ( 4 )   566 - 575   2018.4

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    Background: Once-daily, orally administered, co-formulated glecaprevir (NS3/4A protease inhibitor) and pibrentasvir (NS5A inhibitor) (G/P) demonstrated pangenotypic activity and high sustained virologic response (SVR) rates in studies outside Japan. Here we report safety and efficacy in a subset of Japanese patients with chronic HCV infection who received G/P 300/120 mg in a phase 3, open-label, multicenter study (CERTAIN-1). Methods: This analysis focuses on three difficult-to-treat subgroups: HCV GT1/2-infected patients who failed to achieve SVR after treatment with a direct acting antiviral (DAA)-containing regimen
    GT1/2-infected patients with severe renal impairment (estimated glomerular filtration rate &lt
     30 mL/min/1.73 m2)
    and GT3-infected patients. Patients in the renal impairment and GT3 cohorts were treatment-naive or interferon treatment-experienced. Noncirrhotic GT1/2-infected, DAA-naïve patients in the renal impairment cohort received G/P for 8 weeks
    all other patients were treated for 12 weeks. Primary outcome was SVR (HCV RNA &lt
     15 IU/mL) 12 weeks post-treatment (SVR12). Results: The study enrolled 33 GT1/2-infected patients who failed previous DAA treatment (four with cirrhosis)
    12 GT1/2-infected patients with severe renal impairment (two with cirrhosis)
    and 12 GT3-infected patients (two with cirrhosis). SVR12 was achieved by 31/33 (93.9%), 12/12 (100%), and 10/12 (83.3%) patients, respectively. One serious adverse event (fluid overload, not related to G/P) occurred in a patient on chronic intermittent hemodialysis. Conclusions: G/P achieved high SVR12 rates and was well tolerated in three difficult-to-treat patient subgroups with limited treatment options in Japan (DAA-experienced patients, patients with severe renal impairment, and GT3-infected patients). These results support the potential suitability of this regimen for these special populations in Japan.

    DOI: 10.1007/s00535-017-1396-0

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  • エンテカビル投与後のB型肝硬変患者の長期予後

    坂口 智紘, 竹内 康人, 和田 望, 安中 幸, 安中 哲也, 大西 秀樹, 池田 房雄, 白羽 英則, 高木 章乃夫, 岡田 裕之

    日本消化器病学会雑誌   115 ( 臨増総会 )   A390 - A390   2018.4

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  • 非アルコール性脂肪性肝疾患における酸化ストレス評価と発癌も見据えた最適な抗酸化療法の探索

    足立 卓哉, 高木 章乃夫, 下村 泰之, 大山 淳史, 和田 望, 安中 幸, 安中 哲也, 大西 秀樹, 池田 房雄, 白羽 英則, 岡田 裕之

    肝臓   59 ( Suppl.1 )   A522 - A522   2018.4

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  • 肝臓 治療 安全かつ確実なRFA治療を目指した超音波技術の工夫 RFAにおける部分的free-hand法の利点と、ファントムを用いた穿刺トレーニング

    中村 進一郎, 竹内 康人, 能祖 一裕, 大西 秀樹, 森井 和彦, 和田 望, 安中 幸, 白羽 英則, 高木 章乃夫, 岡田 裕之

    超音波医学   45 ( Suppl. )   S329 - S329   2018.4

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  • 若年成人の非アルコール性脂肪性肝疾患の経過における遺伝子多型の解析

    岩崎 良章, 中山 光, 池田 房雄, 和田 望, 安中 哲也, 高木 章乃夫, 岡田 裕之

    肝臓   59 ( Suppl.1 )   A353 - A353   2018.4

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  • Acute presentation of autoimmune hepatitis: a multicentre study with detailed histological evaluation in a large cohort of patients

    Hiep Nguyen Canh, Kenichi Harada, Hirofumi Ouchi, Yasunori Sato, Koichi Tsuneyama, Masayoshi Kage, Masayuki Nakano, Kaname Yoshizawa, Atsushi Takahashi, Masanori Abe, Jong-Hon Kang, Kazuhiko Koike, Ayano Inui, Tomoo Fujisawa, Akinobu Takaki, Teruko Arinaga-Hino, Takuji Torimura, Yoshiyuki Suzuki, Keiichi Fujiwara, Mikio Zeniya, Hiromasa Ohira, Atsushi Tanaka, Hajime Takikawa

    JOURNAL OF CLINICAL PATHOLOGY   70 ( 11 )   961 - 969   2017.11

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    Aims Although liver biopsy is crucial to diagnose and guide treatment decisions, a detailed histological analysis of autoimmune hepatitis (AIH) with clinically acute presentations has not yet been performed. This study aimed to characterise the histological features and explore potential histological hallmarks to diagnose the acute presentation of AIH.
    Methods We systematically evaluated liver specimens of 87 adult patients with acute presentation of AIH retrospectively enrolled from Japanese multicentre facilities. Each histological feature was predefined by consensus based on the diagnostic criteria.
    Results Key findings were that acute presentation of AIH revealed histological features of both acute hepatitis and chronic hepatitis accompanying various degrees of fibrosis. The prominent features were lobular necrosis/ inflammation (97.7%), plasma cell infiltration (96.4%), emperipolesis (89.3%), pigmented macrophages (84.5%), cobblestone appearance of hepatocytes (82.6%) and perivenular necroinflammatory activity, including centrilobular necrosis (81.4%).
    Conclusions The acute presentation of AIH represents the entire histological spectrum of acute hepatitis and chronic hepatitis with various activity grades and fibrosis stages that clinically correspond to acute-onset AIH and acute exacerbation of classic AIH, respectively. Although there are no pathognomonic features for the pathological diagnosis, the prominent presence of lobular and perivenular necroinflammatory activity, pigmented macrophages and cobblestone appearance of hepatocytes in addition to the classic AIH features, such as plasma cell infiltration and emperipolesis, are useful for the pathological diagnosis of the acute presentation of AIH.

    DOI: 10.1136/jclinpath-2016-204271

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  • 再発肝癌に対する治療戦略 Salvage transplantationの見極め

    楳田 祐三, 八木 孝仁, 吉田 龍一, 信岡 大輔, 杭瀬 崇, 国府島 健, 熊野 健二郎, 高木 弘誠, 吉田 真里, 高木 章乃夫, 藤原 俊義

    移植   52 ( 4-5 )   414 - 415   2017.11

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  • 肝生検で診断し得た非典型画像の悪性リンパ腫の1例

    坂口 智紘, 和田 望, 大山 淳史, 竹内 康人, 安中 哲也, 大西 秀樹, 池田 房雄, 中村 進一郎, 白羽 英則, 高木 章乃夫, 岡田 裕之

    肝臓   58 ( Suppl.3 )   A827 - A827   2017.11

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  • 酸化ストレスマーカーを指標とした肝硬変体液貯留患者のトルバプタン治療

    足立 卓哉, 高木 章乃夫, 佐藤 秀一, 大山 淳史, 和田 望, 安中 幸, 竹内 康人, 安中 哲也, 大西 秀樹, 池田 房雄, 中村 進一郎, 白羽 英則, 岡田 裕之

    肝臓   58 ( Suppl.3 )   A860 - A860   2017.11

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  • HCV関連肝細胞癌の根治後にInterferon-free治療を行った312症例の再発と予後の解析

    中村 進一郎, 能祖 一裕, 岡田 裕之, 大西 秀樹, 白羽 英則, 池田 房雄, 桑木 健志, 安中 哲也, 安中 幸, 竹内 康人, 和田 望, 大山 淳史, 高木 章乃夫, 藤岡 真一, 荒木 康之, 岩堂 昭太, 守本 洋一, 安東 正晴, 守屋 昭男, 萩原 宏明, 金吉 俊彦, 狩山 和也, 谷口 英明, 小橋 春彦, 熊田 卓, 豊田 秀徳, 本村 健太

    肝臓   58 ( Suppl.3 )   A812 - A812   2017.11

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  • 移植後C型肝炎に対するインターフェロンフリーDAA治療の高い効果

    大山 淳史, 高木 章乃夫, 安中 哲也, 足立 卓哉, 和田 望, 池田 房雄, 楳田 祐三, 吉田 龍一, 信岡 大輔, 杭瀬 崇, 高木 弘誠, 八木 孝仁, 岡田 裕之

    移植   52 ( 4-5 )   416 - 416   2017.11

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  • 腹腔鏡下肝生検による原発性胆汁性胆管炎の予後予測

    安中 哲也, 池田 房雄, 足立 卓哉, 和田 望, 安中 幸, 高木 章乃夫, 岩崎 良章, 岡田 裕之

    肝臓   58 ( Suppl.3 )   A907 - A907   2017.11

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  • Living Donor Liver Transplantation for Acute Liver Failure: Comparing Guidelines on the Prediction of Liver Transplantation

    Kazuhiro Yoshida, Yuzo Umeda, Akinobu Takaki, Takeshi Nagasaka, Ryuichi Yoshida, Daisuke Nobuoka, Takashi Kuise, Kosei Takagi, Tetsuya Yasunaka, Hiroyuki Okada, Takahito Yagi, Toshiyoshi Fujiwara

    ACTA MEDICA OKAYAMA   71 ( 5 )   381 - 390   2017.10

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    Determining the indications for and timing of liver transplantation (LT) for acute liver failure (ALF) is essential. The King's College Hospital (KCH) guidelines and Japanese guidelines are used to predict the need for LT and the outcomes in ALF. These guidelines' accuracy when applied to ALF in different regional and etiological backgrounds may differ. Here we compared the accuracy of new (2010) Japanese guidelines that use a simple scoring system with the 1996 Japanese guidelines and the KCH criteria for living donor liver transplantation (LDLT). We retrospectively analyzed 24 adult ALF patients (18 acute type, 6 sub-acute type) who underwent LDLT in 1998-2009 at our institution. We assessed the accuracies of the 3 guidelines' criteria for ALF. The overall 1-year survival rate was 87.5%. The new and previous Japanese guidelines were superior to the KCH criteria for accurately predicting LT for acute-type ALF (72% vs. 17%). The new Japanese guidelines could identify 13 acute-type ALF patients for LT, based on the timing of encephalopathy onset. Using the previous Japanese guidelines, although the same 13 acute-type ALF patients (72%) had indications for LT, only 4 patients were indicated at the 1st step, and it took an additional 5 days to decide the indication at the 2nd step in the other 9 cases. Our findings showed that the new Japanese guidelines can predict the indications for LT and provide a reliable alternative to the previous Japanese and KCH guidelines.

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  • Promising therapeutic efficacy of a novel reduced expression in immortalized cells/dickkopf-3 expressing adenoviral vector for hepatocellular carcinoma

    Hiroaki Sawahara, Hidenori Shiraha, Daisuke Uchida, Hironari Kato, Ryo Kato, Atsushi Oyama, Teruya Nagahara, Masaya Iwamuro, Shigeru Horiguchi, Koichiro Tsutsumi, Mari Mandai, Tetsushige Mimura, Nozomu Wada, Yasuto Takeuchi, Kenji Kuwaki, Hideki Onishi, Shinichiro Nakamura, Masami Watanabe, Masakiyo Sakaguchi, Akinobu Takaki, Kazuhiro Nouso, Takahito Yagi, Yasutomo Nasu, Hiromi Kumon, Hiroyuki Okada

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   32 ( 10 )   1769 - 1777   2017.10

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    Background and Aim: Reduced expression in immortalized cells (REIC)/dickkopf-3 (Dkk-3) is a tumor suppressor gene that is downregulated in various cancers. In our previous study of prostate cancer, the REIC/Dkk-3-expressing adenoviral vector (Ad-REIC) was found to induce cancer-selective apoptosis. This study recently developed a novel super gene expression (SGE) system and used this system to re-construct an Ad-REIC vector, termed the Ad-SGE-REIC, to achieve more effective therapeutic outcomes. In this study, the therapeutic effects of Ad-SGE-REIC on hepatocellular carcinoma (HCC) was assessed.
    Methods: Human HCC cell lines (HLE, Huh7, HepG2, HLF, SK-Hep1, and PLC), human HCC tissues, and mouse HCC cell line (Hepa1-6) were used in this study. REIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry. The relative cell viability and the apoptotic effect were examined in vitro, and the anti-tumor effects of Ad-SGE-REIC treatment were analyzed in the mouse xenograft model. This study additionally assessed anti-tumor immunological effects on the immunocompetent mice.
    Results: REIC/Dkk-3 expression was decreased in HCC cell lines and HCC tissues. Ad-SGE-REIC reduced cell viability and induced apoptosis in HCC cell lines (HLE and Huh7), inhibited tumor growth in the mouse xenograft model, and demonstrated in vivo anti-cancer immunostimulatory effects on the HCC cell line (Hepa1-6).
    Conclusions: Ad-SGE-REIC treatment not only enhanced cell killing effects in vitro but also elicited significant therapeutic effects, with tumor growth suppression, in vivo. REIC/Dkk-3 gene therapy using Ad-SGE-REIC potentially represents an innovative new therapeutic tool for HCC.

    DOI: 10.1111/jgh.13757

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  • Autoimmune hepatitis nationwide survey in Japan - subanalysis report

    Teruko Arinaga-Hino, Atsushi Takahashi, Takuji Torimura, Hiromasa Ohira, Mikio Zeniya, Masanori Abe, Kaname Yoshizawa, Akinobu Takaki, Yoshiyuki Suzuki, Jong-Hon Kang, Nobuhiro Nakamoto, Tomoo Fujisawa, Atsushi Tanaka, Hajime Takikawa

    HEPATOLOGY   66   194A - 194A   2017.10

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  • Pruritus, dryness, fatigue and health-related quality of life in Japanese patients with primary biliary cholangitis

    Minami Yagi, Atsushi Tanaka, Masanori Abe, Tadashi Namisaki, Hitoshi Yoshiji, Atsushi Takahashi, Hiromasa Ohira, Atsumasa Komori, Satoshi Yamagiwa, Kentaro Kikuchi, Tetsuya Yasunaka, Akinobu Takaki, Yoshiyuki Ueno, Akira Honda, Yasushi Matsuzaki, Hajime Takikawa

    HEPATOLOGY   66   179A - 179A   2017.10

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  • DAA治療によるSVR後発癌

    竹内 康人, 池田 房雄, 和田 望, 安中 幸, 安中 哲也, 大西 秀樹, 中村 進一郎, 白羽 英則, 高木 章乃夫, 岡田 裕之

    肝臓   58 ( Suppl.2 )   A578 - A578   2017.9

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  • 肝硬変に伴う軽症肺高血圧の病態分類と生体肝移植後生命予後に与える影響

    大山 淳史, 高木 章乃夫, 安中 哲也, 足立 卓哉, 和田 望, 竹内 康人, 大西 秀樹, 中村 進一郎, 白羽 英則, 信岡 大輔, 吉田 龍一, 楳田 祐三, 篠浦 先, 岡田 裕之, 八木 孝仁

    肝臓   58 ( Suppl.2 )   A650 - A650   2017.9

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  • 若年成人の非アルコール性脂肪性肝疾患における遺伝子多型と白血球分画の検討

    岩崎 良章, 中山 光, 池田 房雄, 和田 望, 安中 哲也, 高木 章乃夫, 岡田 裕之

    肝臓   58 ( Suppl.2 )   A636 - A636   2017.9

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  • 脾摘の功罪からみた生体肝移植における術前脾動脈塞栓術の意義

    楳田 祐三, 八木 孝仁, 吉田 龍一, 信岡 大輔, 杭瀬 崇, 國府島 健, 熊野 健二郎, 高木 弘誠, 伏見 卓郎, 友田 健, 吉田 真里, 加藤 博也, 高木 章乃夫, 藤原 俊義

    移植   52 ( 総会臨時 )   333 - 333   2017.8

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  • トルバプタンによる胸水腹水治療戦略 肝硬変患者の体液貯留に対するトルバプタン効果予測因子としての酸化ストレスマーカーの有用性

    足立 卓哉, 高木 章乃夫, 佐藤 秀一, 大山 淳史, 和田 望, 安中 幸, 竹内 康人, 安中 哲也, 大西 秀樹, 池田 房雄, 中村 進一郎, 白羽 英則, 岡田 裕之

    日本門脈圧亢進症学会雑誌   23 ( 3 )   65 - 65   2017.8

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  • 肝硬変 : 肝硬変の合併症 : 合併症に負けないマネージメント (特集 肝臓を診る : 肝臓病のキモ) -- (肝不全・肝硬変・肝細胞がん)

    高木 章乃夫, 安中 哲也, 川野 誠司, 岡田 裕之

    内科 = Internal medicine : 臨床雑誌   119 ( 6 )   1173 - 1176   2017.6

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    Other Link: http://search.jamas.or.jp/link/ui/2017264380

  • Autoimmune hepatitis in Japan: trends in a nationwide survey

    Atsushi Takahashi, Teruko Arinaga-Hino, Hiromasa Ohira, Takuji Torimura, Mikio Zeniya, Masanori Abe, Kaname Yoshizawa, Akinobu Takaki, Yoshiyuki Suzuki, Jong-Hon Kang, Nobuhiro Nakamoto, Tomoo Fujisawa, Koji Yonemoto, Atsushi Tanaka, Hajime Takikawa

    JOURNAL OF GASTROENTEROLOGY   52 ( 5 )   631 - 640   2017.5

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    A nationwide survey of autoimmune hepatitis (AIH) patients was performed in Japan in 2015. The aims of this study were to elucidate the trends and characteristics of AIH in Japan, in addition to identifying differences in AIH between acute hepatitis and chronic hepatitis.
    Questionnaires about patients with AIH diagnosed from 2009 to 2013 were sent to 437 hospitals or clinics with hepatology specialists.
    A total of 1682 patients were enrolled. The mean age at diagnosis was 60.0 years, and 87.1 % of patients were female. Serum immunoglobulin G levels were high, peaking at 1.5-2.0 g/dL. Histological diagnoses of chronic hepatitis, acute hepatitis, and cirrhosis were seen in 79.6, 11.7, and 6.7 % of patients respectively. In addition to elevation of aminotransferase levels, the frequencies of emperipolesis and human leukocyte antigen (HLA)-DR2 positivity were higher in patients with acute hepatitis than in those with chronic hepatitis. Approximately 80 % of patients were treated with corticosteroids, and in 97.7 % of them, their condition improved. Steroid pulse therapy was more frequently given to patients with acute hepatitis than to those with chronic hepatitis.
    In the present nationwide survey of AIH patients in Japan, patients with acute hepatitis had clinical features different from those of patients with chronic hepatitis.

    DOI: 10.1007/s00535-016-1267-0

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  • Prospective evaluation of the factors predicting the prognosis of advanced hepatocellular carcinoma (HCC) patients treated with sorafenib.

    Takuya Adachi, Kazuhiro Nouso, Koji Miyahara, Chihiro Dohi, Nozomu Wada, Yasuto Takeuchi, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Shinichiro Nakamura, Hidenori Shiraha, Koichi Takaguchi, Shuji Uematsu, Shouta Iwadou, Yoshitaka Takuma, Hiroaki Hagihara, Hiroyuki Takabatake, Akinobu Takaki, Hiroyuki Okada

    JOURNAL OF CLINICAL ONCOLOGY   35   2017.5

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    DOI: 10.1200/JCO.2017.35.15_suppl.e15674

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  • Dynamic computed tomography is useful for prediction of pathological grade in pancreatic neuroendocrine neoplasm

    Shigeru Horiguchi, Hironari Kato, Hidenori Shiraha, Koichiro Tsutsumi, Naoki Yamamoto, Kazuyuki Matsumoto, Takeshi Tomoda, Daisuke Uchida, Yutaka Akimoto, Syou Mizukawa, Takehiro Tanaka, Koichi Ichimura, Akinobu Takaki, Takahito Yagi, Hiroyuki Okada

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   32 ( 4 )   925 - 931   2017.4

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    Background and Aim Pathological grading is important in defining the therapeutic strategy in pancreatic neuroendocrine neoplasm (PNEN) but is difficult for unresectable cases. Endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) is useful in the diagnosis of PNEN, but its usefulness for pathological grading is not well established. No studies have examined the diagnostic ability of dynamic computed tomography (CT) for pathological grading of PNEN. We investigated the usefulness of EUS-FNA and dynamic CT in the diagnosis and pathological grading of PNEN.
    Methods In this retrospective study, 39 PNEN patients finally diagnosed via EUS-FNA and/or surgical resection underwent dynamic CT. Pathological samples were diagnosed based on WHO2010; staging was based on the European Neuroendocrine Tumor Society classification. The proportion of the quantification value in the tumor to the pancreatic parenchyma in arterial phase was defined as the CT ratio. Immunohistochemical staining with CD31 was performed to evaluate microvessel density (MVD). We evaluated the relationship between pathological grade, CT ratio, and MVD.
    Results By using EUS-FNA, 35 of 39 (90%) cases were diagnosed as PNEN. As for pathological grade, 15 of 35 (43%) cases could be identified correctly. CT ratio could predict pathological Grade 3 disease. The sensitivity, specificity, and diagnostic accuracy were 100%, 94%, and 95%. MVD was significantly correlated with CT ratio (r=0.83, P&lt;0.0001) and pathological grade (P=0.0074).
    Conclusions Computed tomography ratio has a relationship with pathological grade in PNEN, which would help decide therapeutic strategy in unresectable cases and cases in which pathological grading is difficult.

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  • 肝腫瘤に対する穿刺・治療の進歩 穿刺用マイクロコンベックスプローブに求められるもの

    中村 進一郎, 大西 秀樹, 桑木 健志, 竹内 康人, 白羽 英則, 和田 望, 安中 幸, 能祖 一裕, 高木 章乃夫, 岡田 裕之

    超音波医学   44 ( Suppl. )   S260 - S260   2017.4

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  • PREDICTION OF PROGNOSIS: RETREATMENT WITH TACE ON DEMAND IN PATIENTS WITH HCC

    Nozomu Wada, Kazuhiro Nouso, Shouta Iwado, Yasuto Takeuchi, Kenji Kuwaki, Hideki Onishi, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada

    GASTROENTEROLOGY   152 ( 5 )   S1174 - S1174   2017.4

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  • 肝硬変体液貯留に対するトルバプタンの効果予測因子としての酸化ストレスの重要性

    足立 卓哉, 高木 章乃夫, 佐藤 秀一, 大山 淳史, 下村 泰之, 和田 望, 竹内 康人, 安中 幸, 安中 哲也, 桑木 健志, 大西 秀樹, 池田 房雄, 中村 進一郎, 白羽 英則, 岡田 裕之

    肝臓   58 ( Suppl.1 )   A407 - A407   2017.4

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  • SUBCLINICAL PULMONARY HYPERTENSION IS A STRONG RISK OF POST LIVING DONOR LIVER TRANSPLANTATION SURVIVAL FOR LIVER CIRRHOSIS

    Yosuke Saragai, Akinobu Takaki, Yuzo Umeda, Tetsuya Yasunaka, Ryuji Kaku, Kazufumi Nakamura, Takahito Yagi, Susumu Shinoura, Ryuichi Yoshida, Daisuke Nobuoka, Takuya Adachi, Yasuyuki Shimomura, Nozomu Wada, Kenji Kuwaki, Fusao Ikeda, Hideki Onishi, Hidenori Shiraha, Shinichiro Nakamura, Hiroshi Ito, Toshiyoshi Fujiwara, Hiroyuki Okada

    GASTROENTEROLOGY   152 ( 5 )   S1122 - S1122   2017.4

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  • 非アルコール性脂肪性肝疾患におけるPNPLA3およびTM6SF2遺伝子多型の組織学的検討

    岩崎 良章, 池田 房雄, 中山 光, 下村 泰之, 和田 望, 安中 哲也, 高木 章乃夫, 岡田 裕之

    肝臓   58 ( Suppl.1 )   A383 - A383   2017.4

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  • Application of radiofrequency ablation for the treatment of intermediate-stage hepatocellular carcinoma

    Kazuhiro Nouso, Kazuya Kariyama, Shinichiro Nakamura, Ayano Oonishi, Akiko Wakuta, Atsushi Oyama, Soichiro Ako, Chihiro Dohi, Nozomu Wada, Yuki Morimoto, Yasuto Takeuchi, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   32 ( 3 )   695 - 700   2017.3

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    Background and Aim: Transcatheter arterial chemoembolization (TACE) is a standard therapy for the treatment of intermediate-stage hepatocellular carcinoma (HCC). In this study, we tried to elucidate the possibility of using radiofrequency ablation (RFA) as an alternative treatment of intermediate-stage HCC.
    Methods: Among 246 patients who were initially diagnosed with intermediate-stage HCC, 76 who were treated with TACE (TACE group) and 91 who were treated with RFA (RFA group) were enrolled in this study. The risk for survival was analyzed with the Cox Proportional Hazard Model, and the survival rates were compared using propensity score matching.
    Results: About half (50.6%) of the intermediate-stage HCC patients in the RFA group were diagnosed with Barcelona Clinic Liver Cancer substage-B1 (BCLC-B1) compared with only 19.7% of the patients in the TACE group. Survival of the RFA group was longer than that of TACE group in patients with BCLC-B1 and BCLC-B2. In contrast, no difference between groups was observed in patients with BCLC-B3/4. Multivariate analysis revealed that large tumor size (&gt; 30 mm, hazard ratio = 1.685, P = 0.043), high des-gamma-carboxyprothrombin (&gt; 100 mAU/mL, hazard ratio = 1.920, P = 0.012), and TACE group (hazard ratio = 1.896, P = 0.016) were significant risk factors for survival. Overall 3-year survival of the patients in the RFA group (69.5%) was significantly longer than that of patients in the TACE group (51.5%) after propensity score matching (P = 0.032). No significant adverse events were observed in either group.
    Conclusions: RFA was useful for the treatment of less advanced intermediate-stage HCC and could be an alternative to TACE in selected cases.

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  • Early Chimerism After Liver Transplantation Reflects the Clinical Course of Recurrent Hepatitis C

    Masashi Utsumi, Akinobu Takaki, Yuzo Umeda, Kazuko Koike, Stephanie C. Napier, Nobukazu Watanabe, Susumu Shinoura, Ryuichi Yoshida, Daisuke Nobuoka, Tetsuya Yasunaka, Takahiro Oto, Motoo Araki, Kazuhide Yamamoto, Toshiyoshi Fujiwara, Takahito Yagi

    ANNALS OF TRANSPLANTATION   22   156 - 165   2017.3

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    Background: Human leukocyte antigen (HLA) mismatch is a characteristic feature of post-orthotopic liver transplantation (OLT) hepatitis C. To investigate the importance of donor HLA-restricted immune cells in post-OLT hepatitis C recurrence, we analyzed the frequency of donor chimerism and the clinical course of post-OLT hepatitis C.
    Material/Methods: We analyzed peripheral blood chimerism in 11 HCV-reinfected patients with post-HLA mismatched OLT. Patients were divided into 2 groups: the OLT chronic hepatitis C (CHC) group (n=8), exhibiting active hepatitis C recurrence; and the OLT-persistently normal ALT (PNALT) group (n=3), without active hepatitis. Chimerism was analyzed by flow cytometry using donor-specific anti-HLA antibodies in peripheral blood mononuclear cells from 1-100 days after OLT. Kidney (n=7) and lung (n=7) transplant recipients were also analyzed for comparison. As immune cells from the donor liver might contribute to post-OLT chimerism, the characteristics of perfusates from donor livers (n=10) were analyzed and defined.
    Results: Donor-derived cells were frequently observed in liver and lung transplant recipients. The frequency of donor-derived cells from the B cell subset was significantly higher in peripheral blood from OLT-CHC group than in that of the OLT-PNALT group. B cells, however, were not the predominant subset in the perfusates, indicating that inflow of donor-derived cells alone did not cause the chimerism.
    Conclusions: Chimerism of B cells is frequent in liver transplant patients with early recurrence of hepatitis C. We propose that monitoring of early chimerism could facilitate early detection of chronic hepatitis C recurrence, although we need more cases to investigate.

    DOI: 10.12659/AOT.900494

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  • Loss of Runt-related transcription factor 3 induces resistance to 5-fluorouracil and cisplatin in hepatocellular carcinoma (vol 35, pg 2576, 2016)

    Junro Kataoka, Hidenori Shiraha, Shigeru Horiguchi, Hiroaki Sawahara, Daisuke Uchida, Teruya Nagahara, Masaya Iwamuro, Hiroki Morimoto, Yasuto Takeuchi, Kenji Kuwaki, Hideki Onishi, Shinichiro Nakamura, Akinobu Takaki, Kazuhiro Nouso, Takahito Yagi, Kazuhide Yamamoto, Hiroyuki Okada

    ONCOLOGY REPORTS   37 ( 3 )   1921 - 1921   2017.3

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    DOI: 10.3892/or.2017.5419

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  • Serum-inducible protein (IP)-10 is a disease progression-related marker for non-alcoholic fatty liver disease

    Nozomu Wada, Akinobu Takaki, Fusao Ikeda, Tetsuya Yasunaka, Masahiro Onji, Kazuhiro Nouso, Atsuko Nakatsuka, Jun Wada, Kazuko Koike, Koji Miyahara, Hidenori Shiraha, Kazuhide Yamamoto, Hiroyuki Okada

    HEPATOLOGY INTERNATIONAL   11 ( 1 )   115 - 124   2017.1

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    The molecular pathogenesis of non-alcoholic steatohepatitis (NASH) is not well defined. The objective of the present study was to identify disease progression-related cytokines and investigate the molecular pathogenesis of such changes in NASH.
    A study population of 20 non-alcoholic fatty liver (NAFL) and 59 NASH patients diagnosed by liver biopsy and 15 healthy volunteers was recruited. The serum pro- and anti-inflammatory cytokines were measured by a multiple enzyme-linked immunosorbent assay. The hepatic mRNA expressions of cytokines were measured by real-time PCR. A monocyte cell line was stimulated with Toll-like receptor (TLR) ligand under a high glucose and insulin condition, and cellular cytokine mRNA expression was quantified.
    One group of cytokines was higher in NAFL and NASH than in controls, while another group was higher in NASH than in NAFL and controls. The NASH-specific second group included interleukin (IL)-15 and interferon-gamma-inducible protein (IP)-10. In particular, IP-10 was higher in NAFL than in controls and higher in NASH than in NAFL and controls. The sensitivity to diagnose NASH was 90%, with specificity of 50%. Insulin resistance reflecting a high glucose and insulin condition resulted in higher IP-10 mRNA expression in the monocyte cell line only with concomitant TLR-2 stimulation.
    IP-10 is a sensitive marker of the need for liver biopsy. Insulin resistance with bacteria-related TLR-2 stimulation might induce IP-10 production from monocytes. Insulin resistance and intestinal barrier function should be intensively controlled to prevent progression from NAFL to NASH.

    DOI: 10.1007/s12072-016-9773-y

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  • Oxidative stress controlling agents are effective for small intestinal injuries induced by non-steroidal anti-inflammatory drugs

    Yoshiyasu Kono, Seiji Kawano, Akinobu Takaki, Yasuyuki Shimomura, Masahiro Onji, Hisashi Ishikawa, Sakuma Takahashi, Joichiro Horii, Sayo Kobayashi, Daisuke Kawai, Kazuhide Yamamoto, Hiroyuki Okada

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   32 ( 1 )   136 - 145   2017.1

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    Background and AimVideo-capsule endoscopy (VCE) has shown that intestinal ulcers are common in non-steroidal anti-inflammatory drugs (NSAIDs) users, although the mechanisms and management have not been clearly defined. To explore the contribution of oxidative stress and potential of anti-oxidants for NSAIDs-induced intestinal ulcers, we assessed human serum oxidative stress balance and the effect of anti-oxidants using a mouse model.
    MethodsA total of 30 NSAIDs users (17 aspirin and 13 non-aspirin users) received VCE. Serum reactive oxygen metabolite (d-ROM) and antioxidative OXY-adsorbent test (OXY) were measured. The indomethacin (IND)-induced mouse intestinal ulcer model was used to assess the effect of anti-oxidants. Eight-week-old mice were divided into four groups; control diet and diet including IND (N group), IND and L-carnitine (NC group), and IND and vitamin E (NE group).
    ResultsSerum OXY levels among non-aspirin users were lower in the mucosal injuries positive group than the negative group (P&lt;0.05). In the mouse models, the degree of mucosal injuries was lower in NC and NE than N (P&lt;0.01). Serum d-ROM levels were lower in NC and NE than N (P&lt;0.01), and OXY levels were higher in NC than N and NE (P&lt;0.01). The degeneration of intestinal mitochondria was mild in NC and NE. The serum KC/CXCL-1 level and hepatic expression of the anti-oxidant molecule Gpx4 were lower in NC than N.
    ConclusionsNon-aspirin NSAID-induced intestinal ulcers are related to decreased anti-oxidative stress function. Anti-oxidants, especially L-carnitine, are good candidates for intestinal ulcers.

    DOI: 10.1111/jgh.13424

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  • Sufficient management of alert system of positive test results for HBV and HCV infection in electronic medical chart for facilitating hepatological consultation

    Yasuyuki Shimomura, Yousuke Fujii, Fusao Ikeda, Tetsuya Yasunaka, Noriko Yamasaki, Ikuko Kasahara, Naomi Inuyama, Michihiro Koyama, Shihoko Namba, Yasuto Takeuchi, Nozomu Wada, Takeshi Kuwaki, Hideki Onishi, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada

    Acta Hepatologica Japonica   58 ( 8 )   427 - 434   2017

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    Alert for positive results of hepatitis tests in electronic medical chart is helpful for management of hepatitis carriers at non-hepatology departments. Further attempts for sufficient hepatological consultations in this alert system, such as explaining the test results to the subjects by mailing notification forms with referral to the hepatologists were adopted. The notification forms were re-mailed to the subjects without the reply in 6 months. Aggregate analysis by reviewing the charts of the subjects confirmed that the rate of hepatological consultation was improved from 49% to 72% with further attempts (p&lt
    0.001, the chi-square test). Mailing notification forms with referral to the hepatologists can be helpful for facilitating hepatological consultation in alert system of positive test results for HBV and HCV infection in electronic medical chart.

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  • Correction to

    Hiromitsu Kumada, Tsunamasa Watanabe, Fumitaka Suzuki, Kenji Ikeda, Ken Sato, Hidenori Toyoda, Masanori Atsukawa, Akio Ido, Akinobu Takaki, Nobuyuki Enomoto, Koji Kato, Katia Alves, Margaret Burroughs,Rebecca Redman, David Pugatch, Tami J. Pilot-Matias, Preethi Krishnan, Rajneet, K. Oberoi, Wangang Xie, Kazuaki Chayama

    Journal of Gastroenterology, Gastroenterologia Japonica   873 - 882   2017

  • Usefulness of the seminars on liver disease at workplace to improve work environment associated with viral hepatitis

    Shihoko Namba, Fusao Ikeda, Yasuyuki Shimomura, Naomi Inuyama, Shinnosuke Okubo, Takashi Makita, Yuko Hasegawa, Kenji Iwai, Akiko Hosoba, Rumi Miura, Yosuke Fujii, Tetsuya Yasunaka, Yasuto Takeuchi, Nozomu Wada, Takeshi Kuwaki, Hideki Onishi, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada

    Acta Hepatologica Japonica, Kanzo   58 ( 5 )   304 - 306   2017

  • Hepatic and Gastric Involvement in a Case of Systemic Sarcoidosis Presenting with Rupture of Esophageal Varices

    Hiroaki Saito, Masayasu Ohmori, Masaya Iwamuro, Takehiro Tanaka, Nozomu Wada, Tetsuya Yasunaka, Akinobu Takaki, Hiroyuki Okada

    INTERNAL MEDICINE   56 ( 19 )   2583 - 2588   2017

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    A 46-year-old woman presented with massive hematemesis, caused by the rupture of esophageal varices. The laboratory investigations showed pancytopenia, and imaging tests revealed hepatosplenomegaly and ascites. A diagnosis of systemic sarcoidosis was made based on biopsies of the liver, stomach, lungs, heart, and skin. Although fat deposition was predominant, non-caseating granuloma and cirrhotic changes were found in the liver. Non-caseating granuloma was also identified in a biopsy specimen from minute depressions of the gastric folds. This case illustrates the rare involvement of the digestive system in a case of systemic sarcoidosis.

    DOI: 10.2169/internalmedicine.8768-16

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  • A sofosbuvir-based direct-acting antiviral treatment regimen exhibits a strong protective effect against post-liver transplantation chronic hepatitis C recurrence

    Atsushi Oyama, Akinobu Takaki, Tetsuya Yasunaka, Takuya Adachi, Fusao Ikeda, Nozomu Wada, Yasuhito Takeuchi, Hideki Onishi, Shinichiro Nakamura, Hidenori Shiraha, Kosei Takagi, Takashi Kuise, Daisuke Nobuoka, Ryuichi Yoshida, Yuzo Umeda, Mari Yoshida, Chisato Arimori, Takahito Yagi, Hiroyuki Okada

    Acta Hepatologica Japonica   58 ( 11 )   599 - 604   2017

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    The efficacy and safety of anti-hepatitis C virus (HCV. direct-acting antivirals were evaluated in postorthotopic liver transplantation patients. There were 29 patients with HCV genotype 1 and 2 with genotype 2. Of the 29 genotype 1 patients, 5 received daclatasvir (DCV. + asunaprevir (ASV), and 25 received sofosbuvir (SOF. + ledipasvir (LDV), including 1 who had failed DCV + ASV. Both genotype 2 patients received SOF + ribavirin. Four patients with DCV + ASV completed the protocol, and 3 of them achieved a sustained viral re-sponse for 24 weeks (SVR24). All of the patients who received SOF + LDV and SOF + RBV achieved SVR24 with minor adverse events. In post-liver transplantation patients, SOF-based regimens showed highly satisfactory efficacy and safety.

    DOI: 10.2957/kanzo.58.599

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  • Safety and Efficacy of Small Bowel Examination by Capsule Endoscopy for Patients before Liver Transplantation (vol 2017, 8193821, 2017)

    Seiji Kawano, Akinobu Takaki, Masaya Iwamuro, Tetsuya Yasunaka, Yoshiyasu Kono, Kou Miura, Toshihiro Inokuchi, Yoshiro Kawahara, Yuzo Umeda, Takahito Yagi, Hiroyuki Okada

    BIOMED RESEARCH INTERNATIONAL   2017   406 - 410   2017

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    DOI: 10.1155/2017/6418529

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  • The Serum Oxidative/Anti-oxidative Stress Balance Becomes Dysregulated in Patients with Non-alcoholic Steatohepatitis Associated with Hepatocellular Carcinoma

    Yasuyuki Shimomura, Akinobu Takaki, Nozomu Wada, Tetsuya Yasunaka, Fusao Ikeda, Takayuki Maruyama, Naofumi Tamaki, Daisuke Uchida, Hideki Onishi, Kenji Kuwaki, Shinichiro Nakamura, Kazuhiro Nouso, Yasuhiro Miyake, Kazuko Koike, Takaaki Tomofuji, Manabu Morita, Kazuhide Yamamoto, Hiroyuki Okada

    INTERNAL MEDICINE   56 ( 2 )   243 - 251   2017

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    Objective Oxidative stress is associated with the progression of chronic liver disease. Non-alcoholic fatty liver disease (NAFLD) is also an oxidative stress-related disease. However, the oxidative/anti-oxidative balance has not been fully characterized in NAFLD. The objective of the present study was to investigate the balance between oxidative stress and the anti-oxidative activity in NAFLD, including non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC).
    Patients We recruited 69 patients with histologically proven NAFLD without HCC (NAFLD; n=58), and with NASH-related HCC (NASH-HCC; n=11). The 58 NAFLD patients included patients with non-alcoholic fatty liver (NAFL; n=14) and NASH (n=44).
    Methods The serum levels of reactive oxygen metabolites (ROM) and anti-oxidative markers (OXY) were determined and then used to calculate the oxidative index. The correlations among such factors as ROM, OXY, oxidative index, and clinical characteristics were investigated.
    Results In NAFLD, ROM positively correlated with the body mass index (BMI), hemoglobin A1c (HbA1c), C-reactive protein (CRP), and the histological grade or inflammatory scores, while only high HbA1c and CRP levels were significant factors that correlated with a higher ROM according to a multivariate analysis. OXY positively correlated with the platelet counts, albumin, and creatinine levels, while negatively correlating with age. However, it improved after treatment intervention. The oxidative index positively correlated with BMI, CRP, and HbA1c. The NASH-HCC patients exhibited a lower OXY than the NASH patients, probably due to the effects of aging.
    Conclusion Oxidative stress correlated with the levels of NASH activity markers, while the anti-oxidative function was preserved in younger patients as well as in patients with a well-preserved liver function. The NASH-HCC patients tended to be older and exhibited a diminished anti-oxidative function.

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  • Low-dose FP療法が奏効した切除不能混合型肝癌の1例

    加藤 小百合, 竹内 康人, 和田 望, 森元 裕貴, 桑木 健志, 大西 秀樹, 中村 進一郎, 白羽 英則, 高木 章乃夫, 岡田 裕之

    日本消化器病学会雑誌   113 ( 12 )   2050 - 2056   2016.12

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    症例は50歳代、女性。肝左葉を占める、肝内多発転移・門脈腫瘍塞栓をともなう混合型肝癌と診断された。肝細胞癌成分が有意と判断し、肝細胞癌に準じた化学療法を導入した。Sorafenib・CDDP肝動注療法では病勢と全身状態の悪化を認めたが、Low-dose FP(LFP)療法は奏効を認め、長期生存が得られている。今回LFP療法が、切除不能な混合型肝癌の治療の選択肢としても有効である可能性が示唆された。(著者抄録)

    DOI: 10.11405/nisshoshi.113.2050

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  • 肝移植1年後生存に関与する潜在的門脈肺高血圧症の重要性

    高木 章乃夫, 安中 哲也, 麻植 浩樹, 中村 進一郎, 大西 秀樹, 桑木 健志, 中村 一文, 楳田 祐三, 八木 孝仁, 岡田 裕之

    超音波医学   43 ( 6 )   776 - 777   2016.11

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  • 非小細胞肺癌切除症例における術前血漿中抗RPL29抗体価と予後

    山本 寛斉, 高木 章乃夫, 林 達朗, 古川 公之, 田尾 裕之, 枝園 和彦, 宗 淳一, 大谷 真二, 三好 健太郎, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 岡部 和倫, 三好 新一郎, 豊岡 伸一

    肺癌   56 ( 6 )   518 - 518   2016.11

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  • miR-1246 and miR-4644 in salivary exosome as potential biomarkers for pancreatobiliary tract cancer

    Tatsuya Machida, Takaaki Tomofuji, Takayuki Maruyama, Toshiki Yoneda, Daisuke Ekuni, Tetsuji Azuma, Hisataka Miyai, Hirofumi Mizuno, Hironari Kato, Koichiro Tsutsumi, Daisuke Uchida, Akinobu Takaki, Hiroyuki Okada, Manabu Morita

    ONCOLOGY REPORTS   36 ( 4 )   2375 - 2381   2016.10

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    Pancreatobiliary tract cancer is a highly fatal cancer. Detection of pancreatobiliary tract cancer is difficult because it lacks typical clinical symptoms and because of its anatomical location. Biomarker discovery is therefore important to detect pancreatobiliary tract cancer in its early stage. A study demonstrated that expression levels of miR-1246, miR-3976, miR-4306, and miR-4644 in serum exosomes were higher in pancreatic cancer patients than these levels in healthy control participants. Supposing that microRNA (miRNA) expression profiles in saliva are similar to those in serum, four miRNAs (miR-1246, miR-3976, miR-4306, and miR-4644) in salivary exosomes may also be useful for detection of pancreatobiliary tract cancer. In this study, it was examined whether these miRNAs could be used as biomarkers for pancreatobiliary tract cancer. Twelve pancreatobiliary tract cancer patients and 13 healthy control participants were analyzed as a cancer and a control group, respectively. Unstimulated whole saliva was collected, salivary exosomes were isolated, and total RNA was extracted. Using quantitative real-time PCR (RT-qPCR), the relative expression ratios of miR-1246 and miR-4644 were significantly higher in the cancer group than these ratios in the control group. Receiver operating characteristic (ROC) curves were constructed to analyze the discrimination power of these miRNAs. For miR-1246, the results yielded an area under the curve (AUC) of 0.814 (P=0.008). For miR-4644, the results yielded an AUC of 0.763 (P=0.026). For the combination of miR-1246 and miR-4644, the results yielded an increased AUC of 0.833 (P=0.005). This pilot study suggests that miR-1246 and miR-4644 in salivary exosomes could be candidate biomarkers for pancreatobiliary tract cancer.

    DOI: 10.3892/or.2016.5021

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  • 肝 C型肝炎についてup to date 肝移植後のC型肝炎ウイルス治療の進歩 ソホスブビル含有治療の有用性

    高木 章乃夫, 安中 哲也, 足立 卓哉, 池田 房雄, 篠浦 先, 楳田 祐三, 吉田 龍一, 信岡 大輔, 高木 弘誠, 八木 孝仁, 岡田 裕之

    移植   51 ( 総会臨時 )   223 - 223   2016.9

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  • 乏血性腫瘤におけるEOB-MRIを用いた肝癌の診断手順

    土肥 千紘, 能祖 一裕, 赤穂 宗一郎, 和田 望, 森元 裕貴, 竹内 康人, 桑木 健志, 大西 秀樹, 池田 房雄, 中村 進一郎, 白羽 英則, 高木 章乃夫, 岡田 裕之

    肝臓   57 ( Suppl.2 )   A610 - A610   2016.9

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  • 肝移植後の腎機能保持を狙った降圧戦略

    高木 章乃夫, 安中 哲也, 八木 孝仁, 篠浦 先, 楳田 祐三, 吉田 龍一, 信岡 大輔, 岡田 裕之

    移植   51 ( 総会臨時 )   237 - 237   2016.9

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  • 肝動注化学療法から分子標的薬への切り替えのタイミング 肝機能と早期治療効果判定の観点から

    大西 秀樹, 能祖 一裕, 中村 進一郎, 和田 望, 安中 幸, 竹内 康人, 安中 哲也, 桑木 健志, 白羽 英則, 高木 章乃夫, 岡田 裕之

    肝臓   57 ( Suppl.2 )   A562 - A562   2016.9

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  • 肝硬変に至らない原発性胆汁性肝硬変が続発性骨粗鬆症の成因となりうるか?

    關 杏奈, 池田 房雄, 宮武 宏和, 藤岡 真一, 安東 正晴, 高口 浩一, 和田 望, 森元 裕貴, 安中 幸, 竹内 康人, 安中 哲也, 桑木 健志, 大西 秀樹, 中村 進一郎, 白羽 英徳, 岩崎 良章, 能祖 一裕, 高木 章乃夫, 岡田 裕之

    日本消化器病学会雑誌   113 ( 臨増大会 )   A733 - A733   2016.9

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  • Novel REIC/Dkk-3-encoding adenoviral vector as a promising therapeutic agent for pancreatic cancer

    H. Sawahara, H. Shiraha, D. Uchida, H. Kato, T. Nagahara, M. Iwamuro, J. Kataoka, S. Horiguchi, M. Watanabe, M. Sakaguchi, A. Takaki, K. Nouso, Y. Nasu, H. Kumon, H. Okada

    CANCER GENE THERAPY   23 ( 8 )   278 - 283   2016.8

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    Reduced expression in immortalized cells (REIC)/dickkopf-3 (Dkk-3), a tumor suppressor gene, is downregulated in various cancers. We previously reported the tumor-inhibitory effects of the REIC/Dkk-3 gene, delivered by a conventional adenoviral vector (Ad-CAG-REIC) in pancreatic cancer. Here, we developed an Ad-REIC vector with a novel gene expression system, termed the super gene expression (SGE) system, and assessed its therapeutic effects relative to those of Ad-CAG-REIC in pantreatic cancer cells. Human pancreatic cancer cell lines ASPC1 and MIAPaCa2 were used. REIC/Dkk-3 expression was assessed by western blot analysis. Relative cell viability and apoptotic effects were examined in vitro. The anti-tumor effects of Ad-REIC treatment were assessed in the mouse xenograft model. Compared with Ad-CAG-REIC, Ad-SGE-REIC elicited a significant increase in REIC protein expression in the cells studied, Relative to Ad-CAG-REIC, Ad-SGE-REIC reduced cell viability and induced apoptosis in the ASPC1 and MIAPaCa2 cell lines in vitro, and achieved superior tumor growth inhibition in the mouse xenograft model. Compared with conventional Ad-REIC agents, Ad-SGE-REIC provided enhanced inhibitory effects against tumor growth. Our results indicate that Ad-SGE-REIC is an innovative therapeutic tool for pancreatic cancer.

    DOI: 10.1038/cgt.2016.31

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  • Potential of alpha-fetoprotein as a prognostic marker after curative radiofrequency ablation of hepatocellular carcinoma

    Chihiro Dohi, Kazuhiro Nouso, Koji Miyahara, Yuki Morimoto, Nozomu Wada, Hideaki Kinugasa, Yasuto Takeuchi, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada

    HEPATOLOGY RESEARCH   46 ( 9 )   916 - 923   2016.8

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    AimRecurrence of hepatocellular carcinoma (HCC) is observed frequently, even after curative treatments. The aim of this study is to elucidate the risk factors for recurrence of HCC after radiofrequency ablation (RFA), focusing on the carcinogenic potential of the liver assessed by -fetoprotein (AFP).
    MethodsWe enrolled 357 consecutive patients who underwent complete ablation by RFA for primary HCC (3cm, 3 tumors) and analyzed the correlation between 17 critical parameters, including AFP and HCC recurrence.
    ResultsRecurrence was observed in 236 patients during a mean observation period of 54.3months. Multivariate analysis revealed that multiple tumors (risk ratio [RR]=1.70, 95% confidence interval [CI]=1.27-2.26, P&lt;0.001), high AFP (&gt;10ng/mL, RR=1.45, 95% CI=1.09-1.94, P&lt;0.001) and high des--carboxyprothrombin (&gt;40 mAU/mL, RR=1.52, 95% CI=1.13-2.02, P&lt;0.005) were significantly correlated with recurrence. AFP was selected as a significant factor even when the cut-off level was set lower (5ng/mL). The risk of recurrence increased linearly according to the increase of the lowest AFP level after RFA and the adjusted ratios relative to AFP less than 5ng/mL were 1.56, 2.14, 2.57 and 3.13 in AFP 5-10ng/mL, 10-20ng/mL, 20-50ng/mL and over 50ng/mL, respectively. In addition, the recurrence rate was predicted by the AFP level after RFA, regardless of the level before the treatment.
    ConclusionAFP less than 5ng/mL after curative RFA was an important predictor of a better prognosis and was considered to indicate the low carcinogenic potential of the non-cancerous liver.

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  • 肝移植と門脈圧亢進症 肝移植1年後生存に関与する術前リスクとしての潜在的門脈肺高血圧症の重要性

    皿谷 洋祐, 高木 章乃夫, 足立 卓哉, 安中 哲也, 麻植 浩樹, 中村 一文, 楳田 祐三, 八木 孝仁, 岡田 裕之

    日本門脈圧亢進症学会雑誌   22 ( 3 )   101 - 101   2016.8

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  • 【「移植臓器における原疾患の再発」】 移植臓器におけるC型肝炎の再発

    高木 章乃夫, 安中 哲也, 信岡 大輔, 吉田 龍一, 楳田 祐三, 篠浦 先, 八木 孝仁

    移植   51 ( 2-3 )   92 - 99   2016.8

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    <p>Hepatitis C recurrence after orthotopic liver transplantation (OLT) has been accepted as a major problem after OLT. Recent progress in hepatitis C virus (HCV) treatment with the use of direct acting antivirals (DAA) has almost resolved this major issue, as 95-100% of non-OLT hepatitis C patients in Japan reach a sustained viral response (SVR). However, the SVR rate among post-OLT hepatitis C patients in the United States and Europe is reported to be 90% and 10% of these patients require an additional approach. As the pathogenesis of hepatitis C involves immunological responses, post OLT hepatitis C exhibits complex phenomena with immune regulating agents including prednisolone and calcineurin inhibitors and HLA-mismatch in the recipient immune system and the donor liver. The pathogenesis and the recent progress in post-OLT hepatitis C are described in this chapter.</p>

    DOI: 10.11386/jst.51.2-3_092

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  • 肝移植と門脈圧亢進症 肝移植予定患者における門脈圧亢進症性小腸炎の検討 前向きコホート研究の結果から

    川野 誠司, 高木 章乃夫, 安中 哲也, 楳田 祐三, 八木 孝仁, 岡田 裕之

    日本門脈圧亢進症学会雑誌   22 ( 3 )   101 - 101   2016.8

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  • Synergistic anti-pancreatic cancer immunological effects by treatment with reduced expression in immortalized cells/dickkopf-3 protein and peripheral blood mononuclear cells

    Daisuke Uchida, Hidenori Shiraha, Hironari Kato, Hiroaki Sawahara, Teruya Nagahara, Masaya Iwamuro, Junro Kataoka, Shigeru Horiguchi, Masami Watanabe, Akinobu Takaki, Kazuhiro Nouso, Yasutomo Nasu, Hiromi Kumon, Kazuhide Yamamoto

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   31 ( 6 )   1154 - 1159   2016.6

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    Background and AimReduced expression in immortalized cells/dickkopf-3 (REIC/DKK3) is a reported tumor suppressor gene and has potential to become an innovative therapy for various cancers. We examined the antitumor immunological effects of human REIC/DKK3 protein against pancreatic cancer.
    MethodsActivation of extracellular signal-regulated kinases 1 and 2, mammalian target of rapamycin, and signal transducer and activator of transcription 3 by REIC/DKK3 protein was assessed in human peripheral blood mononuclear cells using immunoblotting. Pancreatic cancer cell lines (AsPC-1 and MIA Paca-2) were cocultured with peripheral blood mononuclear cells, and the anticancer effects of REIC/DKK3 protein were assessed using the methyl thiazole tetrazolium, cytotoxicity, and enzyme-linked immunospot assays. The antitumor immunological effects of the combined treatment with REIC/DKK3 protein and peripheral blood mononuclear cells were also assessed in a pancreatic cancer model using non-obese diabetic/severe combined immunodeficiency mice.
    ResultsThe REIC/DKK3 protein activated extracellular signal-regulated kinases 1 and 2, mammalian target of rapamycin, and signal transducer and activator of transcription 3 in peripheral blood mononuclear cells. REIC/DKK3 protein inhibited in vitro cancer cell viability and enhanced cytotoxicity when incubated with peripheral blood mononuclear cells. REIC/DKK3 protein induced significant production of interferon gamma from lymphocytes incubated with pancreatic cancer cells, indicating that CD8+ T cells were activated in the peripheral blood mononuclear cells when cocultured with AsPC-1 and MIA Paca-2 in the presence of REIC/DKK3 protein. Combined treatment with REIC/DKK3 protein and peripheral blood mononuclear cells produced in vivo anticancer immunostimulatory effects on pancreatic cancer cells.
    ConclusionsThe REIC/DKK3 protein and peripheral blood mononuclear cells synergistically enhanced anticancer immunological effects against pancreatic cancer cells. The observed immunomodulatory effect of combined treatment likely occurs in adenovirus-mediated REIC/DKK3 gene therapy and provides important clues to the therapeutic mechanisms involving immune cells.

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  • Loss of Runt-related transcription factor 3 induces resistance to 5-fluorouracil and cisplatin in hepatocellular carcinoma

    Junro Kataoka, Hidenori Shiraha, Shigeru Horiguchi, Hiroaki Sawahara, Daisuke Uchida, Teruya Nagahara, Masaya Iwamuro, Hiroki Morimoto, Yasuto Takeuchi, Kenji Kuwaki, Hideki Onishi, Shinichiro Nakamura, Akinobu Takaki, Kazuhiro Nouso, Takahito Yagi, Kazuhide Yamamoto, Hiroyuki Okada

    ONCOLOGY REPORTS   35 ( 5 )   2576 - 2582   2016.5

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    Runt-related transcription factor 3 (RUNX3) is known to function as a tumor suppressor in gastric cancer and other types of cancers, including hepatocellular carcinoma (HCC). However, its role has not been fully elucidated. In the present study, we aimed to evaluate the role of RUNX3 in HCC. We used the human HCC cell lines Hep3B, Huh7 and HLF; RUNX3 cDNA was introduced into Hep3B and Huh7 cells, which were negative for endogenous RUNX3 expression, and RUNX3 siRNA was transfected into HLF cells, which were positive for endogenous RUNX3. We analyzed the expression of RUNX3 and multidrug resistance-associated protein (MRP) by immunoblotting. MTT assays were used to determine the effects of RUNX3 expression on 5-fluorouracil (5-FU) and cisplatin (CDDP) sensitivity. Finally, 23 HCC specimens resected from patients with HCC at Okayama University Hospital were analyzed, and correlations among immunohistochemical expression of RUNX3 protein and MRP protein were evaluated in these specimens. Exogenous RUNX3 expression reduced the expression of MRP1, MRP2, MRP3 and MRP5 in the RUNX3-negative cells, whereas knockdown of RUNX3 in the HLF cells stimulated the expression of these MRPs. An inverse correlation between RUNX3 and MRP expression was observed in the HCC tissues. Importantly, loss of RUNX3 expression contributed to 5-FU and CDDP resistance by inducing MRP expression. These data have important implications in the study of chemotherapy resistance in HCC.

    DOI: 10.3892/or.2016.4681

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  • Oxidative Stress Controlling Agents Are Effective for NSAIDs-Induced Small Intestinal Injuries

    Yoshiyasu Kono, Akinobu Takaki, Seiji Kawano, Hiroyuki Okada

    GASTROENTEROLOGY   150 ( 4 )   S693 - S693   2016.4

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  • Characteristics of HCC Patients With hTERT Promoter Mutation

    Soichiro Ako, Kazuhiro Nouso, Hideaki Kinugasa, Takuya Adachi, Chihiro Dohi, Yuuki Morimoto, Nozomu Wada, Yasuto Takeuchi, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Shinichi Fujioka, Hiroyuki Okada

    GASTROENTEROLOGY   150 ( 4 )   S1152 - S1152   2016.4

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  • The Pattern of Recurrence Associated With the Prognosis of the Patients With Hepatocellular Carcinoma After Radiofrequency Ablation

    Shinichiro Nakamura, Kazuhiro Nouso, Hideki Onishi, Kenji Kuwaki, Yasuto Takeuchi, Nozomu Wada, Yuuki Morimoto, Tetsuya Yasunaka, Yuki Yasunaka, Fusao Ikeda, Hidenori Shiraha, Akinobu Takaki, Kazuhide Yamamoto, Hiroyuki Okada

    GASTROENTEROLOGY   150 ( 4 )   S1135 - S1135   2016.4

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  • Serum IP-10 Is a Highly Sensitive Marker for Discriminating Non-Alcoholic Fatty Liver and Non-Alcoholic Steatohepatitis

    Nozomu Wada, Akinobu Takaki, Fusao Ikeda, Tetsuya Yasunaka, Masahiro Onji, Kazuko Koike, Kazuhiro Nouso, Hiroyuki Okada

    GASTROENTEROLOGY   150 ( 4 )   S1091 - S1091   2016.4

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  • データマイニング手法を用いた非侵襲的肝線維化診断法によるC型肝硬変症例の抽出

    桑木 健志, 中村 進一郎, 安中 幸, 竹内 康人, 安中 哲也, 大西 秀樹, 池田 房雄, 白羽 英則, 高木 章乃夫, 岡田 裕之

    超音波医学   43 ( Suppl. )   S673 - S673   2016.4

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  • Changes of Immunoglobulin-Bound Glycans in Patients With Gastro-Intestinal Cancers

    Chihiro Dohi, Kazuhiro Nouso, Soichiro Ako, Yuuki Morimoto, Koji Miyahara, Hideaki Kinugasa, Nozomu Wada, Yasuto Takeuchi, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada

    GASTROENTEROLOGY   150 ( 4 )   S614 - S614   2016.4

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  • Association of hepatic oxidative stress and iron dysregulation with HCC development after interferon therapy in chronic hepatitis C

    Shintaro Nanba, Fusao Ikeda, Nobuyuki Baba, Koichi Takaguchi, Tomonori Senoh, Takuya Nagano, Hiroyuki Seki, Yasuto Takeuchi, Yuki Moritou, Tetsuya Yasunaka, Hideki Ohnishi, Yasuhiro Miyake, Akinobu Takaki, Kazuhiro Nouso, Yoshiaki Iwasaki, Kazuhide Yamamoto

    JOURNAL OF CLINICAL PATHOLOGY   69 ( 3 )   226 - 233   2016.3

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    Background Oxidative stress may play pathogenic roles in the mechanisms underlying chronic hepatitis C (CHC). The impact of excessive oxidative stress and iron dysregulation on the development of hepatocellular carcinoma (HCC) after interferon therapy has not been established.
    Methods We investigated the impact of oxidative stress and iron deposition on HCC development after therapy with pegylated interferon (PegIFN)+ribavirin in CHC patients. Systemic and intracellular iron homeostasis was evaluated in liver tissues, peripheral blood mononuclear cells and sera.
    Results Of 203 patients enrolled, 13 developed HCC during the 5.6-year follow-up. High hepatic 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were significantly associated with HCC development in multivariate analysis (p=0.0012) which was also significantly correlated with severity of hepatic iron deposition before therapy (p&lt;0.0001). Systemic and intracellular iron regulators of hepcidin and F-box and leucine-rich repeat protein 5 (FBXL5) expression levels were significantly suppressed in CHC patients (p=0.0032 and p=0.016, respectively) despite their significantly higher levels of serum iron and ferritin compared with controls. However, intracellular iron regulators of FBXL5 and iron regulatory proteins were regulated in balance with hepatic iron deposition. Significant correlations were observed among IL-6, bone morphogenetic protein 6, hepcidin and ferroportin, as regards systemic iron regulation.
    Conclusions Measurement of hepatic oxidative stress before antiviral therapy is useful for the prediction of HCC development after interferon therapy. Low baseline levels of the intracellular iron regulators of FBXL5 in addition to a suppressed hepcidin level might be associated with severe hepatic iron deposition in CHC patients.

    DOI: 10.1136/jclinpath-2015-203215

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  • Association of hepatic oxidative stress and iron dysregulation with HCC development after interferon therapy in chronic hepatitis C

    Shintaro Nanba, Fusao Ikeda, Nobuyuki Baba, Koichi Takaguchi, Tomonori Senoh, Takuya Nagano, Hiroyuki Seki, Yasuto Takeuchi, Yuki Moritou, Tetsuya Yasunaka, Hideki Ohnishi, Yasuhiro Miyake, Akinobu Takaki, Kazuhiro Nouso, Yoshiaki Iwasaki, Kazuhide Yamamoto

    JOURNAL OF CLINICAL PATHOLOGY   69 ( 3 )   226 - 233   2016.3

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    Background Oxidative stress may play pathogenic roles in the mechanisms underlying chronic hepatitis C (CHC). The impact of excessive oxidative stress and iron dysregulation on the development of hepatocellular carcinoma (HCC) after interferon therapy has not been established.
    Methods We investigated the impact of oxidative stress and iron deposition on HCC development after therapy with pegylated interferon (PegIFN)+ribavirin in CHC patients. Systemic and intracellular iron homeostasis was evaluated in liver tissues, peripheral blood mononuclear cells and sera.
    Results Of 203 patients enrolled, 13 developed HCC during the 5.6-year follow-up. High hepatic 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were significantly associated with HCC development in multivariate analysis (p=0.0012) which was also significantly correlated with severity of hepatic iron deposition before therapy (p&lt;0.0001). Systemic and intracellular iron regulators of hepcidin and F-box and leucine-rich repeat protein 5 (FBXL5) expression levels were significantly suppressed in CHC patients (p=0.0032 and p=0.016, respectively) despite their significantly higher levels of serum iron and ferritin compared with controls. However, intracellular iron regulators of FBXL5 and iron regulatory proteins were regulated in balance with hepatic iron deposition. Significant correlations were observed among IL-6, bone morphogenetic protein 6, hepcidin and ferroportin, as regards systemic iron regulation.
    Conclusions Measurement of hepatic oxidative stress before antiviral therapy is useful for the prediction of HCC development after interferon therapy. Low baseline levels of the intracellular iron regulators of FBXL5 in addition to a suppressed hepcidin level might be associated with severe hepatic iron deposition in CHC patients.

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  • Entecavir Reduces Hepatocarcinogenesis in Chronic Hepatitis B Patients

    Tetsuya Yasunaka, Fusao Ikeda, Nozomu Wada, Yuki Morimoto, Shin-ichi Fujioka, Junichi Toshimori, Haruhiko Kobashi, Kazuya Kariyama, Yoichi Morimoto, Hiroki Takayama, Tomonori Seno, Koichi Takaguchi, Akio Moriya, Hirokazu Miyatake, Ryoichi Okamoto, Kazuhisa Yabushita, Akinobu Takaki, Kazuhide Yamamoto

    ACTA MEDICA OKAYAMA   70 ( 1 )   1 - 12   2016.2

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    Chronic hepatitis B (CHB) leads to cirrhosis and hepatocellular carcinoma (HCC). With a cohort of 1,206 CHB patients who visited Okayama University Hospital and related hospitals in 2011 and 2012, we compared the incidence rates of HCC among the patients grouped by age, hepatitis B virus (HBV) DNA, hepatitis B e antigen (HBeAg), and treatment. HCCs were observed in 115 patients with the median observation period of 1,687 days. Among the HCC patients aged &gt;= 35 years, HBV DNA &gt;= 4 log copies/mL and positive HBeAg at diagnosis (n = 184), the HCC incidence rate was 8.4% at 5 years in the entecavir (ETV)-treated patients, 21.8% in the lamivudine (LVD)-treated patients, and 26.4% among the patients not treated with drugs. The cumulative HCC incidence was significantly reduced in the ETV-treated patients compared to those treated with LVD or not treated (p = 0.013). Among the patients aged &gt;= 35 years with HBV DNA &gt;= 4 log copies/mL and negative HBeAg (n = 237), the cumulative HCC incidence was 14.6% in 5 years in ETV group and 13.9% among those not treated with a drug (p &gt; 0.05). Only small numbers of HCCs occurred in other patients. In CHB patients aged &gt;= 35 years with HBV DNA &gt;= 4 log copies/mL and positive HBeAg, ETV treatment is recommended for the suppression of HCC development.

    DOI: 10.18926/AMO/53996

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  • Insufficiency of phosphatidylethanolamine N-methyltransferase is risk for lean non-alcoholic steatohepatitis

    Atsuko Nakatsuka, Makoto Matsuyama, Satoshi Yamaguchi, Akihiro Katayama, Jun Eguchi, Kazutoshi Murakami, Sanae Teshigawara, Daisuke Ogawa, Nozomu Wada, Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Eijiro Watanabe, Jun Wada

    SCIENTIFIC REPORTS   6   2016.2

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    Although obesity is undoubtedly major risk for non-alcoholic steatohepatitis (NASH), the presence of lean NASH patients with normal body mass index has been recognized. Here, we report that the insufficiency of phosphatidylethanolamine N-methyltransferase (PEMT) is a risk for the lean NASH. The Pemt-/-mice fed high fat-high sucrose (HFHS) diet were protected from diet-induced obesity and diabetes, while they demonstrated prominent steatohepatitis and developed multiple liver tumors. Pemt exerted inhibitory effects on p53-driven transcription by forming the complex with clathrin heavy chain and p53, and Pemt-/-mice fed HFHS diet demonstrated prominent apoptosis of hepatocytes. Furthermore, hypermethylation and suppressed mRNA expression of F-box protein 31 and hepatocyte nuclear factor 4 alpha resulted in the prominent activation of cyclin D1. PEMT mRNA expression in liver tissues of NASH patients was significantly lower than those with simple steatosis and we postulated the distinct clinical entity of lean NASH with insufficiency of PEMT activities.

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  • Low frequency of drug-resistant virus did not affect the therapeutic efficacy in daclatasvir plus asunaprevir therapy in patients with chronic HCV genotype-1 infection

    Hideaki Kinugasa, Fusao Ikeda, Kouichi Takaguchi, Chizuru Mori, Takehiro Matsubara, Hidenori Shiraha, Akinobu Takaki, Yoshiaki Iwasaki, Shinichi Toyooka, Kazuhide Yamamoto

    ANTIVIRAL THERAPY   21 ( 1 )   37 - 44   2016

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    Background: The efficacy of a direct-acting antiviral agent (DAA) is compromised by the development of drug resistance. The associations between resistance-associated virus (RAV) and therapeutic outcomes have not been well-understood.
    Methods: A total of 30 patients with HCV genotype-1b were enrolled and treated for 24 weeks with asunaprevir (ASV) and daclatasvir (DCV). Viral sequences in non-structural (NS) regions 3 and 5A in serum and liver tissue before treatment were examined with direct sequencing, next-generation sequencing (NGS) and the PCR-invader method to evaluate the importance of drug-resistance in the prediction of the outcomes of ASV plus DCV therapy.
    Results: Of 30 patients (22 treatment-naive patients, 2 interferon-intolerant patients and 6 non-responders), 25 patients (83.3%) achieved sustained virological response (SVR) 24 weeks after the treatment. Viral breakthrough occurred in three treatment-naive patients and one non-responder. One treatment-naive patient experienced viral relapse. Among 25 patients without RAV, 24 obtained SVR, whereas 5 patients had RAV with a 1.3 to 88% frequency, resulting in various therapeutic outcomes. As for HCV compartments, similar RAVs were detected in serum and liver tissue for a patient obtaining SVR despite HCV NS5A Y93H and another developed viral breakthrough although no RAV was detected. Direct sequencing could not detect RAVs in low frequency (1.3 to 12%) for three of four patients.
    Conclusions: Low frequency of RAVs might not affect the outcomes of ASV plus DCV therapy. Deep sequencing and PCR-invader methods can detect clinically significant RAVs for ASV plus DCV therapy.

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  • Oxidative stress balance is dysregulated and represents an additional target for treating cholangiocarcinoma

    Daisuke Uchida, Akinobu Takaki, Hisashi Ishikawa, Yasuko Tomono, Hironari Kato, Koichiro Tsutsumi, Naofumi Tamaki, Takayuki Maruyama, Takaaki Tomofuji, Ryuichiro Tsuzaki, Tetsuya Yasunaka, Kazuko Koike, Hiroshi Matsushita, Fusao Ikeda, Yasuhiro Miyake, Hidenori Shiraha, Kazuhiro Nouso, Ryuichi Yoshida, Yuzo Umeda, Susumu Shinoura, Takahito Yagi, Toshiyoshi Fujiwara, Manabu Morita, Masaki Fukushima, Kazuhide Yamamoto, Hiroyuki Okada

    FREE RADICAL RESEARCH   50 ( 7 )   732 - 743   2016

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    Background: Pancreatico-biliary malignancies exhibit similar characteristics, including obesity-related features and poor prognosis, and require new treatment strategies. Oxidative stress is known to induce DNA damage and carcinogenesis, and its reduction is viewed as being favorable. However, it also has anti-infection and anti-cancer functions that need to be maintained. To reveal the effect of oxidative stress on cancer progression, we evaluated oxidative stress and anti-oxidative balance in pancreatic cancer (PC) and cholangiocarcinoma (CC) patients, as well as the effect of add-on antioxidant treatment to chemotherapy in a mouse cholangiocarcinoma model.
    Methods: We recruited 84 CC and 80 PC patients who were admitted to our hospital. Serum levels of reactive oxygen metabolites (ROM) and the anti-oxidative OXY-adsorbent test were determined and the balance of these tests was defined as an oxidative index. A diabetic mouse-based cholangiocarcinoma model was utilized to evaluate the effects of add-on antioxidant therapy on cholangiocarcinoma chemotherapy.
    Results: Serum ROM was higher and anti-oxidant OXY was lower in CC patients with poor outcomes. These parameters were not significantly different in PC patients. In mice, vitamin E administration induced antioxidant hemeoxygenase (HO)-1 protein expression in cancer tissue, while the number of stem-like cells increased. L-carnitine administration improved intestinal microbiome and biliary acid balance, upregulated the hepatic mitochondrial membrane uptake related gene Cpt1 in non-cancerous tissue, and did not alter stem-like cell numbers.
    Conclusion: Oxidative stress balance was dysregulated in cholangiocarcinoma with poor outcome. The mitochondrial function-supporting agent L-carnitine is a good candidate to control oxidative stress conditions.

    DOI: 10.3109/10715762.2016.1172071

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  • A case of unresectable combined hepatocellular cholangiocarcinoma showing favorable response to LFP therapy

    Sayuri Kato, Yasuto Takeuchi, Nozomu Wada, Yuuki Morimoto, Kenji Kuwaki, Hideki Ohnishi, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada

    Journal of Japanese Society of Gastroenterology   113 ( 12 )   2050 - 2056   2016

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    A woman in her 50s was admitted to our hospital because of multiple tumors detected in her liver. She was diagnosed with combined hepatocellular cholangiocarcinoma using gadolinium-ethoxybenzyldiethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) and biopsy of the liver tumors. We judged the tumors to be unresectable because they were found in both lobes of the liver, with a tumor thrombus being found in the main left portal vein. The pathological findings showed that the tumors exhibited characteristics of hepatocellular carcinoma Therefore, sorafenib was administered
    however, 6 months later, the disease progressed. Consequently, she received second-line chemotherapy with a one-shot intra-arterial injection of cisplatin, but this too was ineffective, and her general condition worsened. As hence, we changed the regimen to 5-fluorouracil continuous infusion and consecutive low dose cisplatin (LFP) therapy. After one cycle of chemotherapy with LFP, Gd-EOB-DTPA-enhanced MRI showed markedly decreased sizes and numbers of tumors. To date, she has completed six cycles of LFP therapy, and almost all her tumors are no longer visible on MRI. She has recovered to a good state and has achieved long-term survival. Thus, this case indicates that although LFP therapy is generally selected for cases of advanced hepatocellular carcinoma, it also appears to be effective for long-term disease control in cases of hepatocellular cholangiocarcinoma.

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  • 肝移植医療を地域と大学が一体としてまとめ上げた実績とさらなる発展

    八木孝仁, 篠浦 先, 楳田祐三, 吉田龍一, 信岡大輔, 杭瀬 崇, 渡辺信之, 高木弘誠, 須井健太, 藤原俊義, 高木章乃夫, 吉田真理, 保田裕子, 森松博史

    肝胆膵   72 ( 3 )   481 - 487   2016

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  • Beneficial impact of Gpnmb and its significance as a biomarker in nonalcoholic steatohepatitis

    Akihiro Katayama, Atsuko Nakatsuka, Jun Eguchi, Kazutoshi Murakami, Sanae Teshigawara, Motoko Kanzaki, Tomokazu Nunoue, Kazuyuki Hida, Nozomu Wada, Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Kazuhide Yamamoto, Hiroshi Kiyonari, Hirofumi Makino, Jun Wada

    SCIENTIFIC REPORTS   5   2015.11

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    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Gpnmb is classified as a type 1 membrane protein and its soluble form is secreted by ADAM10-mediated cleavage. Gpnmb mRNA was found in the Kupffer cells and white adipose tissues (WATs) and its upregulation in obesity was recently found. Here, we generated aP2 promoter-driven Gpnmb transgenic (Tg) mice and the overexpression of Gpnmb ameliorated the fat accumulation and fibrosis of the liver in diet-induced obesity model. Soluble form of Gpnmb in sera was elevated in Gpnmb Tg mice and Gpnmb concentrated in hepatic macrophages and stellate cells interacted with calnexin, which resulted in the reduction of oxidative stress. In the patients with non-alcoholic steatohepatitis, serum soluble GPNMB concentrations were higher compared with the patients with simple steatosis. The GPNMB is a promising biomarker and therapeutic target for the development and progression of NAFLD in obesity.

    DOI: 10.1038/srep16920

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  • 異なる経過をたどった多発肝転移合併脾臓原発血管肉腫の2例

    脇地 一生, 大西 秀樹, 能祖 一裕, 大山 淳史, 足立 卓哉, 下村 泰之, 和田 望, 森元 裕貴, 安中 幸, 竹内 康人, 安中 哲也, 桑木 健志, 池田 房雄, 中村 進一郎, 白羽 英則, 高木 章乃夫, 岡田 裕之

    肝臓   56 ( Suppl.3 )   A1122 - A1122   2015.11

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  • TACE後RFAまでの腫瘍縮小を目指した至適待機期間の探索

    赤穂 宗一郎, 中村 進一郎, 能祖 一裕, 和田 望, 森元 裕貴, 竹内 康人, 安中 哲也, 桑木 健志, 大西 秀樹, 池田 房雄, 白羽 英則, 高木 章乃夫, 岡田 裕之

    肝臓   56 ( Suppl.3 )   A954 - A954   2015.11

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  • 急性肝不全に対する内科的治療と肝移植の現状

    楳田 祐三, 賀来 隆治, 安中 哲也, 篠浦 先, 吉田 龍一, 信岡 大輔, 松崎 孝, 保田 裕子, 高木 章乃夫, 藤原 俊義, 八木 孝仁

    移植   50 ( 4-5 )   477 - 477   2015.10

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  • 初回および再肝移植後に脂肪性肝炎を発症した1例

    田中 健大, 田中 顕之, 柳井 広之, 篠浦 先, 楳田 祐三, 吉田 龍一, 高木 章乃夫, 藤原 俊義, 八木 孝仁

    移植   50 ( 4-5 )   551 - 551   2015.10

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  • 岡山大学病院ICUにおける急性肝不全に対する肝移植までのBridging Therapyについて

    賀来 隆治, 楳田 祐三, 松崎 孝, 柴田 麻里, 篠浦 先, 吉田 龍一, 信岡 大輔, 保田 裕子, 高木 章乃夫, 八木 孝仁, 森松 博史

    移植   50 ( 4-5 )   477 - 478   2015.10

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  • Serum oxidative-anti-oxidative stress balance is dysregulated in patients with non-alcoholic steatohepatitis and related hepatocellular carcinoma

    Yasuyuki Shimomura, Akinobu Takaki, Nozomu Wada, Daisuke Uchida, Yasuto Takeuchi, Tetsuya Yasunaka, Fusao Ikeda, Hideki Onishi, Kenji Kuwaki, Shinichiro Nakamura, Kazuhiro Nouso, Yasuhiro Miyake, Kazuko Koike

    HEPATOLOGY   62   1297A - 1297A   2015.10

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  • Alteration of N-glycan profiles in patients with chronic hepatitis and hepatocellular carcinoma

    Koji Miyahara, Kazuhiro Nouso, Chihiro Dohi, Yuki Morimoto, Hideaki Kinugasa, Nozomu Wada, Yasuto Takeuchi, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Yasuhiro Miyake, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Maho Amano, Shin-Ichiro Nishimura, Kazuhide Yamamoto

    HEPATOLOGY RESEARCH   45 ( 9 )   986 - 993   2015.9

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    AimMost of the modification of N-glycosylation reported in cancers including hepatocellular carcinoma (HCC) were based on the examinations of a small number of patients or particular proteins. The aim of this study is to reveal changes in whole serum N-glycan profiles systematically during the process of hepatocarcinogenesis and to elucidate their clinical application.
    MethodsWe analyzed sera from 105 patients with chronic hepatitis/liver cirrhosis (CH/LC) and age-/sex-matched healthy volunteers (HLT), as well as from 114 patients with HCC. Serum N-glycan profiles were measured comprehensively by a new, quantitative, high-throughput method and compared with clinical parameters.
    ResultsThe total amount of N-glycan expression was significantly higher in patients with CH/LC than in HLT; however, no differences were observed between CH/LC and HCC patients. In HCC patients, multi-antennary glycans with fucose residues, particularly m/z 3195, were increased compared with CH/LC patients. The expression of m/z 3195 was high, especially in patients with a high number of intrahepatic lesions (&gt;3), large tumor size (&gt;3cm), macroscopic vascular invasion or metastasis. The ratio of pairs of glycans on the same path of the biosynthesis pathway (m/z 3195/1914) showed a higher area under the receiver-operator curve of 0.810 than any other single glycan to distinguish HCC from CH/LC.
    ConclusionWe demonstrate the full spectrum of the alterations of serum N-glycans comprehensively in patients with liver disease, and elucidate the possible use of glycans as novel biomarkers of liver disease progression.

    DOI: 10.1111/hepr.12441

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  • 移植医療におけるHCV治療up-to-date 肝移植後C型肝炎における免疫抑制性T細胞とキメリズムの病態への影響

    高木 章乃夫, 内海 方嗣, 篠浦 先, 楳田 祐三, 吉田 龍一, 信岡 大輔, 杭瀬 崇, 高木 弘誠, 安中 哲也, 保田 裕子, 八木 孝仁

    移植   50 ( 総会臨時 )   207 - 207   2015.9

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  • 移植医療人の役割分担と協調はどうあるべきか 外科医、内科医、コーディネーターの関係

    八木 孝仁, 篠浦 先, 楳田 祐三, 吉田 龍一, 信岡 大輔, 杭瀬 崇, 渡辺 信之, 高木 弘誠, 須井 健太, 木村 祐司, 藤原 俊義, 吉田 真理, 保田 裕子, 高木 章乃夫

    移植   50 ( 総会臨時 )   219 - 219   2015.9

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  • ソラフェニブ治療による長期生存例の検討

    足立 卓哉, 能祖 一裕, 和田 望, 森元 裕貴, 竹内 康人, 桑木 健志, 大西 秀樹, 中村 進一郎, 白羽 英則, 高木 章乃夫, 山本 和秀

    肝臓   56 ( Suppl.2 )   A749 - A749   2015.9

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  • 肝臓移植における血管吻合とくに非顕微鏡的肝動脈再建と肝静脈・下大静脈置換の手技

    八木 孝仁, 篠浦 先, 楳田 祐三, 吉田 龍一, 信岡 大輔, 杭瀬 崇, 渡辺 信之, 高木 弘誠, 須井 健太, 木村 祐司, 藤原 俊義, 吉田 真理, 保田 裕子, 高木 章乃夫

    移植   50 ( 総会臨時 )   197 - 197   2015.9

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  • 肝移植術前管理と肝移植後の難治性腹水におけるトルバプタンの有効性

    楳田 祐三, 八木 孝仁, 高木 章乃夫, 篠浦 先, 吉田 龍一, 信岡 大輔, 安中 哲也, 渡辺 信之, 杭瀬 崇, 高木 弘誠, 保田 裕子, 藤原 俊義

    移植   50 ( 総会臨時 )   336 - 336   2015.9

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  • Molecular Mechanisms to Control Post-Transplantation Hepatitis B Recurrence

    Akinobu Takaki, Tetsuya Yasunaka, Takahito Yagi

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   16 ( 8 )   17494 - 17513   2015.8

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    Hepatitis B often progresses to decompensated liver cirrhosis requiring orthotopic liver transplantation (OLT). Although newer nucleos(t)ide analogues result in &gt;90% viral and hepatitis activity control, severely decompensated patients still need OLT because of drug-resistant virus, acute exacerbation, or hepatocellular carcinoma. Acute hepatitis B is also an indication for OLT, because it can progress to fatal acute liver failure. After OLT, the hepatitis B recurrence rate is &gt;80% without prevention, while &gt;90% of transplant recipients are clinically controlled with combined hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogue treatment. However, long-term HBIG administration is associated with several unresolved issues, including limited availability and extremely high cost; therefore, several treatment protocols with low-dose HBIG, combined with nucleos(t)ide analogues, have been investigated. Another approach is to induce self-producing anti-hepatitis B virus (HBV) antibodies using an HBV envelope (HBs) antigen vaccine. Patients who are not HBV carriers, such as those with acutely infected liver failure, are good candidates for vaccination. For chronic HBV carrier liver cirrhosis patients, a successful vaccine response can only be achieved in selected patients, such as those treated with experimentally reduced immunosuppression protocols. The present protocol for post-OLT HBV control and the future prospects of newer treatment strategies are reviewed.

    DOI: 10.3390/ijms160817494

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  • 肝移植後の腎機能の経過と降圧療法について

    高木 章乃夫, 八木 孝仁, 保田 裕子, 安中 哲也, 貞森 裕, 篠浦 先, 楳田 祐三, 吉田 龍一, 信岡 大輔, 内海 方嗣, 藤原 俊義, 山本 和秀

    移植   50 ( 2-3 )   292 - 292   2015.8

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  • 生体肝移植におけるリスク因子としての高齢ドナーと背景疾患との関連性

    楳田 祐三, 高木 弘誠, 杭瀬 崇, 内海 方嗣, 信岡 大輔, 吉田 龍一, 篠浦 先, 保田 裕子, 高木 章乃夫, 藤原 俊義, 八木 孝仁

    移植   50 ( 2-3 )   248 - 249   2015.8

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  • Enhancement of Programmed Death Ligand 2 on Hepatitis C Virus Infected Hepatocytes by Calcineurin Inhibitors

    Kazuko Koike, Akinobu Takaki, Takahito Yagi, Yoshiaki Iwasaki, Tetsuya Yasunaka, Hiroshi Sadamori, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Sato, Daisuke Nobuoka, Masashi Utsumi, Yasuhiro Miyake, Fusao Ikeda, Hidenori Shiraha, Toshiyoshi Fujiwara, Kazuhide Yamamoto

    TRANSPLANTATION   99 ( 7 )   1447 - 1454   2015.7

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    Background. Post orthotopic liver transplantation (OLT) viral hepatitis is an immunological condition where immune cells induce hepatitis during conditions of immune-suppression. The immune-regulatory programmed death-1 (PD-1)/PD-ligand 1 system is acknowledged to play important roles in immune-mediated diseases. However, the PD-1/PD-L2 interaction is not well characterized, with PD-L2 also exhibiting an immunostimulatory function. We hypothesized that this atypical molecule could affect the recurrence of post-OLT hepatitis. To test this hypothesis, we conducted immunohistochemical staining analysis and in vitro analysis of PD-L2. Methods. The expression of PD-L2 was evaluated in liver biopsy specimens from patients with chronic hepatitis B (n = 15), post-OLT hepatitis B (n = 8), chronic hepatitis C (n = 48), and post-OLT hepatitis C (CH-C-OLT) (n = 14). The effect of calcineurin inhibitors (CNIs) and hepatitis C virus (HCV) on PD-L2 expression was investigated in hepatoma cell lines. Results. The PD-L2 was highly expressed on CH-C-OLT hepatocytes. Treatment of hepatoma cell lines with CNIs resulted in increased PD-L2 expression, especially in combination with HCV core or NS3 protein. Transfection of cell lines with PD-L2 containing plasmid resulted in high intercellular adhesion molecule-1 (ICAM-1) expression, which might enhance hepatitis activity. Conclusions. The PD-L2 is highly expressed on CH-C-OLT hepatocytes, whereas HCV proteins, in combination with CNIs, induce high expression of PD-L2 resulting in elevated expression of ICAM-1. These findings demonstrate the effect of CNIs on inducing PD-L2 and subsequent ICAM-1 expression, effects that may produce inflammatory cell infiltration in post-OLT hepatitis C.

    DOI: 10.1097/TP.0000000000000572

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  • Aberrant Expression of Keratin 7 in Hepatocytes as a Predictive Marker of Rapid Progression to Hepatic Failure in Asymptomatic Primary Biliary Cirrhosis

    Hiroyuki Seki, Fusao Ikeda, Shintaro Nanba, Yuki Moritou, Yasuto Takeuchi, Tetsuya Yasunaka, Hideki Onishi, Yasuhiro Miyake, Akinobu Takaki, Kazuhiro Nouso, Yoshiaki Iwasaki, Minoru Nakamura, Kazuhide Yamamoto

    ACTA MEDICA OKAYAMA   69 ( 3 )   137 - 144   2015.6

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    A predictive marker of the rapid progression to hepatic failure is desired for patients with asymptomatic primary biliary cirrhosis (aPBC). We performed a systematic cohort analysis of 101 patients diagnosed as having aPBC and the rapid progression to liver failure in some, by focusing on cholestasis. Cholestasis was assessed by aberrant keratin7 (K-7) expressions in the patients' hepatocytes. Intralobular expressions of K-7 were found in 9 of the 101 patients. The grades of K-7 expression were significantly associated with the levels of alanine aminotransferase, alkaline phosphatase, and total bilirubin at the time of diagnosis, but not with bile duct loss or cholestasis. Stepwise logistic regression analysis revealed that high grades of K-7 expression correlated positively with high levels of total bilirubin. During the follow-up period, 8 patients developed jaundice, and the mean period until the development of jaundice was 5.2 years. The proportional hazards models for the risk of developing jaundice identified a high grade of aberrant K-7 expression in hepatocytes as the only significant risk factor. Aberrant K-7 expression in hepatocytes can be used as an additional marker to predict rapid progression to liver failure in patients with aPBC at the time of diagnosis.

    DOI: 10.18926/AMO/53520

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  • Local Recurrences and Complications After Percutaneous Radiofrequency Ablation of Hepatocellular Carcinoma: Analysis Focused on Tumor Locations

    Junichi Toshimori, Kazuhiro Nouso, Shinichiro Nakamura, Nozomu Wada, Yuki Morimoto, Yasuto Takeuchi, Kenji Kuwaki, Tetsuya Yasunaka, Hideki Onishi, Fusao Ikeda, Hidenori Shiraha, Akinobu Takaki, Kazuhide Yamamoto

    GASTROENTEROLOGY   148 ( 4 )   S1030 - S1030   2015.4

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  • Serum N-Glycan Profiles in Patients With Intraductal Papillary Mucinous Neoplasms of Pancreas

    Yutaka Akimoto, Kazuhiro Nouso, Hironari Kato, Koji Miyahara, Chihiro Dohi, Yuki Morimoto, Hideaki Kinugasa, Takeshi Tomoda, Naoki Yamamoto, Koichiro Tsutsumi, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada, Maho Amano, Shin-ichiro Nishimura, Kazuhide Yamamoto

    GASTROENTEROLOGY   148 ( 4 )   S518 - S518   2015.4

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  • Alteration of Serum N-Glycan Profile in Patients With Hepatocellular Carcinoma and Their Clinical Application

    Kazuhiro Nouso, Koji Miyahara, Chihiro Dohi, Yuki Morimoto, Hideaki Kinugasa, Nozomu Wada, Yasuto Takeuchi, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Maho Amano, Shin-Ichiro Nishimura, Kazuhide Yamamoto

    GASTROENTEROLOGY   148 ( 4 )   S1022 - S1022   2015.4

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  • Oxidative Stress Balance Is Dysregulated in Cholangiocarcinoma That Could Be Improved With L-Carnitine Administration

    Daisuke Uchida, Akinobu Takaki, Yasuko Tomono, Kazuhide Yamamoto

    GASTROENTEROLOGY   148 ( 4 )   S967 - S967   2015.4

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  • 腫瘍マーカーの推移から見た肝動注化学療法の早期治療効果予測

    大西 秀樹, 能祖 一裕, 中村 進一郎, 和田 望, 竹内 康人, 桑木 健志, 白羽 英則, 高木 章乃夫, 山本 和秀

    肝臓   56 ( Suppl.1 )   A522 - A522   2015.4

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  • C型慢性肝炎に対するアスナプレビル・ダクラタスビル(第3相治験)の臨床的特徴から看護支援の検討

    難波 志穂子, 池田 房雄, 人部 友, 黒田 智, 千堂 年昭, 白羽 英則, 高木 章乃夫, 山本 和秀

    肝臓   56 ( Suppl.1 )   A505 - A505   2015.4

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  • Entecavir Reduces Hepatocarcinogenesis in Patients With Chronic Hepatitis B

    Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Kazuhide Yamamoto

    GASTROENTEROLOGY   148 ( 4 )   S968 - S968   2015.4

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  • 非アルコール性脂肪性肝疾患における血清Irisinの検討

    岩崎 良章, 池田 房雄, 下村 泰之, 和田 望, 森元 裕貴, 竹内 康人, 安中 哲也, 三宅 康広, 高木 章乃夫, 山本 和秀

    肝臓   56 ( Suppl.1 )   A348 - A348   2015.4

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  • TLR4, TLR9, and NLRP3 in biliary epithelial cells of primary sclerosing cholangitis: Relationship with clinical characteristics

    Hiroshi Matsushita, Yasuhiro Miyake, Akinobu Takaki, Tetsuya Yasunaka, Kazuko Koike, Fusao Ikeda, Hidenori Shiraha, Kazuhiro Nouso, Kazuhide Yamamoto

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   30 ( 3 )   600 - 608   2015.3

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    Background and AimInappropriate innate immune responses have been suggested to contribute to the pathogenesis of primary sclerosing cholangitis (PSC). We evaluated the associations of expressions of toll-like receptor (TLR) 4, TLR9, and nucleotide-binding oligomerization domain-containing protein (NOD)-like receptor family pyrin domain containing 3 (NLRP3) in the biliary epithelial cells (BECs) with clinical features of PSC patients.
    MethodsWe retrospectively evaluated the expressions of TLR4, TLR9, and NLRP3 in the intrahepatic BECs by immunohistochemical staining in 21 PSC patients and 10 normal controls. In PSC, 17 patients underwent liver biopsy, and, in the other four patients, liver specimens were obtained at the time of liver transplantation.
    ResultsTLR9 expressions in BECs were higher in PSC patients than in normal controls. TLR9 expressions were correlated with Ludwig fibrosis scores in PSC patients. TLR4 and NLRP3 expressions were similar between PSC patients and normal controls. Seventeen PSC patients undergoing liver biopsy were followed up during a median period of 55.7 months. Four reached to liver transplantation and four developed cholangiocarcinoma. Patients developing cholangiocarcinoma showed lower NLRP3 expressions than the others. Patients reaching to liver transplantation showed higher TLR9 expressions. Expression levels of TLR9 and NLRP3 were not correlated with liver biochemical tests and Mayo risk scores.
    ConclusionsIn PSC, excessive immune responses through TLR9 signaling may be associated with the disease progression. Insufficient immune response through NLRP3 signaling may be associated with the development of cholangiocarcinoma. Evaluation of TLR9 and NLRP3 expressions in BECs may be useful for predicting the prognosis as an auxiliary marker.

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  • REIC/Dkk-3遺伝子導入による肝細胞癌治療の検討

    澤原 大明, 内田 大輔, 白羽 英則, 永原 照也, 岩室 雅也, 片岡 淳朗, 堀口 繁, 竹内 康人, 桑木 健志, 大西 秀樹, 中村 進一郎, 高木 章乃夫, 能祖 一裕, 山本 和秀

    日本消化器病学会雑誌   112 ( 臨増総会 )   A345 - A345   2015.3

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  • Safe and cost-effective control of post-transplantation recurrence of hepatitis B

    Akinobu Takaki, Takahito Yagi, Kazuhide Yamamoto

    HEPATOLOGY RESEARCH   45 ( 1 )   38 - 47   2015.1

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    A combination of hepatitis B immunoglobulin (HBIG) and nucleoside/nucleotide analogs (NUC) is the current standard of care for controlling hepatitis B recurrence after orthotopic liver transplantation (OLT). However, long-term HBIG administration is associated with several unresolved issues, including limited availability and extremely high cost, and thus several protocols for treatment with low-dose HBIG combined with NUC or HBIG-free regimens have been developed. This article reviews recent advances in post-OLT hepatitis B virus (HBV) control and future methodological directions. New NUC such as entecavir, tenofovir or lamivudine plus adefovir dipivoxil combinations induce a very low frequency of viral resistance. The withdrawal of HBIG after several months of OLT under new NUC continuation also has permissible effects. Even after HBV reactivation, NUC can usually achieve viral control when viral markers are strictly followed up. Another approach is to induce self-producing anti-HBV antibodies via vaccination with a hepatitis B surface antigen vaccine. However, HBV vaccination is not sufficiently effective in patients to treat liver cirrhosis type B after OLT because immune tolerance to the virus has already continued for several decades. Trials of its safety and cost-effectiveness are required. This review advocates a safe and economical approach to controlling post-OLT HBV recurrence.

    DOI: 10.1111/hepr.12368

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  • Efficacy of hepatic arterial infusion chemotherapy in combination with irradiation for advanced hepatocellular carcinoma with portal vein invasion

    Hideki Onishi, Kazuhiro Nouso, Shinichiro Nakamura, Kuniaki Katsui, Nozomu Wada, Yuki Morimoto, Koji Miyahara, Yasuto Takeuchi, Kenji Kuwaki, Tetsuya Yasunaka, Yasuhiro Miyake, Hidenori Shiraha, Akinobu Takaki, Yoshiyuki Kobayashi, Kohsaku Sakaguchi, Susumu Kanazawa, Kazuhide Yamamoto

    HEPATOLOGY INTERNATIONAL   9 ( 1 )   105 - 112   2015.1

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    The presence of portal vein tumor thrombosis (PVTT) is a poor prognostic factor for patients with hepatocellular carcinomas (HCC). The purpose of this study was to determine the treatment effect of irradiation in combination with hepatic arterial infusion chemotherapy (HAIC) for these patients.
    We retrospectively examined the outcome of 67 HCC patients with PVTT of the main trunk or first branch who received HAIC alone or with concurrent irradiation for PVTT (CCRT).
    Thirty-four patients received HAIC, and 33 patients received CCRT. The time to progression (TTP) of PVTT in the CCRT group was significantly longer than in the HAIC group (p &lt; 0.01), and the TTP of intrahepatic nodules in the CCRT group tended to be longer than in the HAIC group (p = 0.06). The objective response rates of intrahepatic nodules (52 vs. 18 %, p &lt; 0.01) and PVTT (45 vs. 18 %, p = 0.01) were both significantly higher in the CCRT group than in the HAIC group, respectively. No significant difference in overall survival was found between the two groups (p = 0.14); however, the median survival time in the CCRT group was longer than that in the HAIC group (12.4 vs. 5.7 months, respectively).
    CCRT might be a promising treatment for advanced-stage HCC with PVTT. CCRT prolonged the TTP of intrahepatic nodules and PVTT, and it improved the objective response rate of intrahepatic nodules and PVTT.

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  • Serum Oxidative/anti-oxidative Stress Balance Is Dysregulated in Potentially Pulmonary Hypertensive Patients with Liver Cirrhosis: A Case Control Study

    Masako Terao, Akinobu Takaki, Takayuki Maruyama, Hiroki Oe, Tetsuya Yasunaka, Naofumi Tamaki, Kazufumi Nakamura, Takaaki Tomofuji, Takahito Yagi, Hiroshi Sadamori, Yuzo Umeda, Susumu Shinoura, Ryuichi Yoshida, Kazuhiro Nouso, Daisuke Ekuni, Kazuko Koike, Fusao Ikeda, Hidenori Shiraha, Manabu Morita, Hiroshi Ito, Toshiyoshi Fujiwara, Kazuhide Yamamoto

    INTERNAL MEDICINE   54 ( 22 )   2815 - 2826   2015

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    Objective Hepatopulmonary syndrome (HPS) is characterized by vascular dilatation and hyperdynamic circulation, while portopulmonary hypertension (POPH) is characterized by vasoconstriction with fibrous obliteration of the vascular bed. Vasoactive molecules such as nitric oxide (NO) are candidate factors for cirrhotic complications associated with these diseases. However, oxidative stress balance is not well characterized in HPS and POPH. The present objective is to investigate the oxidative stress and anti-oxidative stress balance and NO pathway balance in patients with potential HPS and POPH.
    Methods We recruited patients with decompensated cirrhosis (n = 69) admitted to our hospital as liver transplantation candidates. Patients exhibiting partial pressure of oxygen lower than 80 mmHg and alveolararterial oxygen gradient (AaDO(2)) &gt;= 15 mmHg were categorized as potentially having HPS (23 of 69 patients). Patients exhibiting a tricuspid regurgitation pressure gradient &gt;= 25 mmHg were categorized as potentially having POPH (29 of 61 patients). Serum reactive oxygen metabolites were measured and anti-oxidative OXY-adsorbent test (OXY) were performed, and the balance of these tests was defined as the oxidative index. The correlation between these values and the clinical characteristics of the patients were assessed in a cross-sectional study.
    Results Potential HPS patients exhibited no correlation with oxidative stress markers. Potential POPH patients exhibited lower OXY (p = 0.037) and higher oxidative index values (p = 0.001). Additionally, the vascular NO synthase enzyme inhibiting protein, asymmetric dimethylarginine, was higher in potential POPH patients (p = 0.049). The potential POPH patients exhibited elevated AaDO(2), suggesting the presence of pulmonary shunting.
    Conclusion Potential POPH patients exhibited elevated oxidative stress with decreased anti-oxidative function accompanied by inhibited NO production. Anti-oxidants represent a candidate treatment for potential POPH patients.

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  • Liver cirrhosis; Advances in research and clinics

    2015

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  • 【腸内細菌up to date:今まさに明らかになりつつある全身疾患への影響】 腸内細菌と肝疾患

    Pharma Medica   2015

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  • Control of oxidative stress in hepatocellular carcinoma: Helpful or harmful?

    Akinobu Takaki, Kazuhide Yamamoto

    World Journal of Hepatology   7 ( 7 )   968 - 979   2015

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    Oxidative stress is becoming recognized as a key factor in the progression of chronic liver disease (CLD) and hepatocarcinogenesis. The metabolically important liver is a major reservoir of mitochondria that serve as sources of reactive oxygen species, which are apparently responsible for the initiation of necroinflammation. As a result, CLD could be a major inducer of oxidative stress. Chronic hepatitis C is a powerful generator of oxidative stress, causing a high rate of hepatocarcinogenesis among patients with cirrhosis. Non-alcoholic steatohepatitis is also associated with oxidative stress although its hepatocarcinogenic potential is lower than that of chronic hepatitis C. Analyses of serum markers and histological findings have shown that hepatocellular carcinoma correlates with oxidative stress and experimental data indicate that oxidative stress increases the likelihood of developing hepatocarcinogenesis. However, the results of antioxidant therapy have not been favorable. Physiological oxidative stress is a necessary biological response, and thus adequate control of oxidative stress and a balance between oxidative and anti-oxidative responses is important. Several agents including metformin and L-carnitine can reportedly control mechanistic oxidative stress. This study reviews the importance of oxidative stress in hepatocarcinogenesis and of control strategies for the optimal survival of patients with CLD and hepatocellular carcinoma.

    DOI: 10.4254/wjh.v7.i7.968

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  • 門脈圧亢進症の病態と治療 基礎から臨床へ 門脈圧亢進症における心肺機能と酸化ストレスについての検討(共著)

    高木章乃夫, 寺尾正子, 安中哲也, 白羽英則, 中村進一郎, 麻植浩樹, 中村一文, 岡田裕之

    日本門脈圧亢進症学会雑誌   21 ( 3 )   67 - 67   2015

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  • A multicenter survey of enteroscopy for the diagnosis of intestinal follicular lymphoma. International journal

    Masaya Iwamuro, Hiroyuki Okada, Seiji Kawano, Junji Shiode, Ryuta Takenaka, Atsushi Imagawa, Tomoki Inaba, Seiyu Suzuki, Mamoru Nishimura, Motowo Mizuno, Masashi Araki, Tomohiko Mannami, Toru Ueki, Haruhiko Kobashi, Haruka Fukatsu, Shouichi Tanaka, Akiyoshi Omoto, Yoshinari Kawai, Takashi Kitagawa, Tatsuya Toyokawa, Katsuyoshi Takata, Tadashi Yoshino, Akinobu Takaki, Kazuhide Yamamoto

    Oncology letters   10 ( 1 )   131 - 136   2015

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    The importance of enteroscopy examinations to investigate the entire length of the small intestines has been emphasized in follicular lymphoma patients with intestinal involvement. The aim of the present study was to determine the current state of enteroscopy examinations, including the performance rate, and the prevalence of small intestinal lesions in a patient population in Japan. A retrospective multicenter survey of 17 institutions collected the case information of 110 follicular lymphoma patients with gastrointestinal involvement. The results of the enteroscopy examinations were reviewed, and in order to identify potential factors affecting the performance rate of enteroscopy, patient gender, age at lymphoma diagnosis, histopathological grade, clinical stage, the date of the initial diagnosis and the annual volume of enteroscopy at the institution were compared between the patients who underwent one or more enteroscopy procedures and the patients who did not undergo enteroscopy. A total of 34 patients (30.9%) underwent enteroscopy, and 24 of these (70.6%) presented with involvement in the jejunum and/or ileum. It was found that more patients diagnosed in recent years and more patients treated at an ultra-high volume institution (≥101 enteroscopy examinations/year) underwent an enteroscopy. In conclusion, although the prevalence of small intestinal lesions was high (70.6%) in the follicular lymphoma patients presenting with intestinal involvement, the performance rate of enteroscopy was only 30.9%, and thus the majority of the patients have not undergone enteroscopy examinations. Further investigation is required to define the clinical significance of enteroscopy at the initial diagnostic work-up and during the follow-up period of these patients.

    DOI: 10.3892/ol.2015.3251

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  • 肝炎ウイルススクリーニング検査陽性患者に対する検査報告システムの構築による肝臓専門医受診率向上への取り組み

    下村泰之, 池田房雄, 能祖一裕, 高木章乃夫, 渡邊都貴子, 岩月啓氏, 草野展周, 合地 明, 山本和秀

    肝臓   56 ( 4 )   137 - 143   2015

  • Prevention of vagotonia and pain during radiofrequency ablation of liver tumors

    Shinichiro Nakamura, Kazuhiro Nouso, Hideki Onishi, Kenji Kuwaki, Hiroaki Hagihara, Yasuto Takeuchi, Nozomu Wada, Yuki Morimoto, Koji Miyahara, Tetsuya Yasunaka, Fusao Ikeda, Yasuhiro Miyake, Yoshiyuki Kobayashi, Hidenori Shiraha, Shinichi Ishikawa, Akinobu Takaki, Kazuhide Yamamoto

    HEPATOLOGY RESEARCH   44 ( 13 )   1367 - 1370   2014.12

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    Radiofrequency ablation (RFA) is frequently used to treat early stage hepatocellular carcinoma. Two of the most cumbersome side-effects of the ablation procedure are intractable pain and vagotonia when deep sedation is not used. We describe local injection of anesthetic into Glisson's sheath as a new technique for overcoming these problems. Lidocaine was injected into Glisson's sheath when radiofrequency ablation of hepatocellular carcinomas, which were located adjacent to Glisson's sheath, could not be continued due to severe pain (n=8) or bradycardia (n=3). In all three patients who showed vagotonia with bradycardia during the ablations, injection of lidocaine prevented bradycardia, allowing completion of the radiofrequency ablation. Pain was reduced in all eight patients who experienced pain during ablation. No side-effects were observed during the procedures. Injection of anesthetic into Glisson's sheath is simple and effective for reducing intractable pain and vagotonia associated with RFA.

    DOI: 10.1111/hepr.12321

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  • Prevention of vagotonia and pain during radiofrequency ablation of liver tumors

    Shinichiro Nakamura, Kazuhiro Nouso, Hideki Onishi, Kenji Kuwaki, Hiroaki Hagihara, Yasuto Takeuchi, Nozomu Wada, Yuki Morimoto, Koji Miyahara, Tetsuya Yasunaka, Fusao Ikeda, Yasuhiro Miyake, Yoshiyuki Kobayashi, Hidenori Shiraha, Shinichi Ishikawa, Akinobu Takaki, Kazuhide Yamamoto

    HEPATOLOGY RESEARCH   44 ( 13 )   1367 - 1370   2014.12

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    Radiofrequency ablation (RFA) is frequently used to treat early stage hepatocellular carcinoma. Two of the most cumbersome side-effects of the ablation procedure are intractable pain and vagotonia when deep sedation is not used. We describe local injection of anesthetic into Glisson's sheath as a new technique for overcoming these problems. Lidocaine was injected into Glisson's sheath when radiofrequency ablation of hepatocellular carcinomas, which were located adjacent to Glisson's sheath, could not be continued due to severe pain (n=8) or bradycardia (n=3). In all three patients who showed vagotonia with bradycardia during the ablations, injection of lidocaine prevented bradycardia, allowing completion of the radiofrequency ablation. Pain was reduced in all eight patients who experienced pain during ablation. No side-effects were observed during the procedures. Injection of anesthetic into Glisson's sheath is simple and effective for reducing intractable pain and vagotonia associated with RFA.

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  • Involvement of platelets in extrahepatic metastasis of hepatocellular carcinoma

    Yuki Morimoto, Kazuhiro Nouso, Nozomu Wada, Yasuto Takeuchi, Hideaki Kinugasa, Koji Miyahara, Tetsuya Yasunaka, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Yasuhiro Miyake, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Kazuhide Yamamoto

    HEPATOLOGY RESEARCH   44 ( 14 )   E353 - E359   2014.12

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    AimRecently, a relationship between platelets and cancer metastasis has been reported. The aim of this study is to elucidate the risk factors for extrahepatic metastasis (EHM), with emphasis on association with platelets in patients, with hepatocellular carcinoma (HCC).
    MethodsWe examined risk factors for EHM in 1613 consecutive, newly diagnosed HCC patients by logistic regression analysis (case-control study). We also examined the factors by Cox proportional hazard model in a retrospective cohort fashion in 803 patients who received non-curative treatment for HCC.
    ResultsIn the case-control study, multivariate analysis revealed that high platelet counts (odds ratio [OR]=4.84; 95% confidence interval [CI]=1.29-29.54; P=0.01), high tumor number and the presence of macroscopic vascular invasion were significantly associated with EHM. In the cohort study, EHM was diagnosed in 71 patients during the study period (mean observation time=23.3 months). On multivariate analysis, high tumor number, high des--carboxyprothrombin (DCP) and Child-Pugh class A were significantly correlated with EHM, and the patients with high platelet counts tended to develop EHM (OR=1.73; 95% CI=0.99-3.14; P=0.055).
    ConclusionHCC patients with high platelet counts, as well as large numbers of tumors, high serum DCP and Child-Pugh class A, are at risk for EHM.

    DOI: 10.1111/hepr.12315

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  • Nursing Support Increases the Efficacy of Interferon Therapy in Patients with Chronic Hepatitis C

    Shihoko Namba, Kayoko Miyake, Fusao Ikeda, Tomoko Hazama, Yu Hitobe, Noriko Yamasaki, Hidenori Shiraha, Akinobu Takaki, Kazuhiro Nouso, Yoshiaki Iwasaki, Kazuhide Yamamoto

    ACTA MEDICA OKAYAMA   68 ( 5 )   263 - 268   2014.10

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    Nursing support might help patients with chronic hepatitis C (CHC) remain in good mental and physical condition during interferon (IFN) therapy. However, the effects of nursing support have not been studied adequately in this context. This case-control study evaluated the effects of nursing support during IFN therapy. Twenty-four CHC patients who received pegylated IFN and ribavirin were enrolled. Nurses advised patients on the maintenance of their mental and physical condition at weekly visits, based on the results of written questionnaires. An additional 24 patients who received IFN therapy without nursing support and who were matched for age, sex, platelet count, viral serogroup and IFN regimen were selected with propensity score matching as controls. The patients with nursing support during IFN therapy achieved higher sustained virological responses (79%) than those without nursing support (58%). Adherence to the IFN and ribavirin regimens at 24 weeks of therapy were slightly higher in the patients with nursing support than those without it, but these differences were not statistically significant. Adherence to ribavirin after 24 weeks of therapy was significantly higher in those with nursing support than those without it (93% and 66%, p = 0.045). These results suggested that nursing support services could contribute to the virological responses of CHC patients by promoting drug-regimen adherence.

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  • Hepatitis C Virus-specific T-cell Response Correlates with Hepatitis Activity and Donor IL28B Genotype Early after Liver Transplantation

    Ryuichiro Tsuzaki, Akinobu Takaki, Takahito Yagi, Fusao Ikeda, Kazuko Koike, Yoshiaki Iwasaki, Hidenori Shiraha, Yasuhiro Miyake, Hiroshi Sadamori, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Nobuoka, Masashi Utsumi, Eiichi Nakayama, Toshiyoshi Fujiwara, Kazuhide Yamamoto

    ACTA MEDICA OKAYAMA   68 ( 5 )   291 - 302   2014.10

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    It is not known how the immune system targets hepatitis C virus (HCV)-infected HLA-mismatched hepatocytes under immune-suppressed conditions after orthotopic liver transplantation (OLT). In addition, the relationship between the HCV-specific immune response and IL28B variants as predictors of HCV clearance has not been well-characterized. We determined the IL28B polymorphisms for 57 post-OLT HCV carriers, and we assessed the HCV-specific immune responses by measuring the peripheral blood mononuclear cell-derived HCV-specific interferon-gamma (IFN-gamma) response using an enzyme-linked immunospot assay. At 1-3 years after OLT, patients with no active hepatitis showed higher total spots on the immunospot assay. At &gt; 3 years after OLT, patients with resolved HCV showed higher levels of core, NS3, NS5A, and total spots compared to the chronic hepatitis patients. The IL28B major genotype in the donors correlated with higher spot counts for NS5A and NS5B proteins at 1-3 years after OLT. In the post-OLT setting, the HCV-specific immune response could be strongly induced in patients with no active hepatitis with an IL28B major donor or sustained virological response. Strong immune responses in the patients with no active hepatitis could only be maintained for 3 years and diminished later. It may be beneficial to administer IFN treatment starting 3 years after OLT, to induce the maximum immunological effect.

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  • 非B非C肝癌の臨床的特徴

    竹内 康人, 能祖 一裕, 和田 望, 桑木 健志, 大西 秀樹, 中村 進一郎, 白羽 英則, 高木 章乃夫, 山本 和秀

    肝臓   55 ( Suppl.2 )   A633 - A633   2014.9

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  • γ-secretase inhibitorによるNotch経路阻害は膵癌幹細胞を阻害し抗癌剤治療効果を増強する可能性がある

    堀口 繁, 白羽 英則, 内田 大輔, 永原 照也, 片岡 淳朗, 岩室 雅也, 加藤 博也, 高木 章乃夫, 能祖 一裕, 山本 和秀

    日本消化器病学会雑誌   111 ( 臨増大会 )   A951 - A951   2014.9

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  • テラプレビルにおける早期皮疹へのcytokineの関与について

    和田 望, 池田 房雄, 下村 泰之, 森元 裕貴, 竹内 康人, 安中 哲也, 三宅 康広, 高木 章乃夫, 岩崎 良章, 白藤 宜紀, 山本 和秀

    肝臓   55 ( Suppl.2 )   A658 - A658   2014.9

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  • Prevalence and Outcomes of Acute Hepatitis B in Okayama, Japan, 2006-2010

    Nozomu Wada, Tetsuya Yasunaka, Fusao Ikeda, Sohji Nishina, Masaaki Korenaga, Keisuke Hino, Shin-ichi Fujioka, Toshiya Osawa, Tatsuya Itoshima, Miwa Kawanaka, Gotaro Yamada, Kazuya Kariyama, Hiroki Takayama, Junichi Kubota, Yoichi Morimoto, Takaaki Mizushima, Haruhiko Yamashita, Hiroaki Tanioka, Yuji Negoro, Junichi Toshimori, Haruhiko Kobashi, Atsushi Hirano, Yasuo Itano, Akinobu Takaki, Kazuhide Yamamoto

    ACTA MEDICA OKAYAMA   68 ( 4 )   243 - 247   2014.8

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    Hepatitis B virus (HBV) is one of the major viruses causing acute hepatitis. Recently, the incidence of acute hepatitis with genotype A has been increasing in Japan. The aim of this study was to investigate acute hepatitis B (AHB) in Okayama prefecture, with special attention to HBV genotype A. AHB patients who visited one of 12 general hospitals in Okayama prefecture between 2006 and 2010 were retrospectively analyzed. Over the course of the study period, 128 patients were diagnosed with AHB. Sexual transmission was supposed in the majority of patients (78 patients, 61%), including 59 (76%) having sex with heterosexual partners. The genotypes of HEY were assessed in 90 patients (70%), of whom 27 patients were infected with genotype A, 5 with genotype B, and 58 with genotype C. The prevalence of genotype A was significantly higher among male patients (28.7%), aged 20-29 (35.6%, p &lt; 0.01), among men who had sex with men (100%, p &lt; 0.005), and among patients having sex with unspecified partners (44.8%, p &lt; 0.005). Genotype A was not a significant factor associated with delayed HBsAg disappearance. Caution should be exercised with regard to sexually transmissible diseases in order to slow the pandemic spread of AHB due to genotype A.

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  • 【肝胆膵領域の光学医療;一見に如かず】 肝臓領域の腹腔鏡検査 代表的な肝疾患腹腔鏡アトラス(後世に残る図譜として)

    安中 哲也, 池田 房雄, 下村 泰之, 和田 望, 森元 裕貴, 三宅 康広, 白羽 英則, 高木 章乃夫, 能祖 一裕, 岩崎 良章, 山本 和秀

    肝・胆・膵   69 ( 2 )   169 - 176   2014.8

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  • Loss of runt-related transcription factor 3 induces gemcitabine resistance in pancreatic cancer (vol 7, pg 840, 2013)

    Shigeru Horiguchi, Hidenori Shiraha, Teruya Nagahara, Jyunnro Kataoka, Masaya Ituamuro, Minoru Matsubara, Shinichi Nishina, Hironari Kato, Akinobu Takaki, Kazuhiro Nouso, Takehiro Tanaka, Koichi Ichimura, Takahito Yagi, Kazuhide Yamamoto

    MOLECULAR ONCOLOGY   8 ( 5 )   1054 - 1054   2014.7

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    DOI: 10.1016/j.molonc.2014.03.007

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  • Frequency of regulatory T-cell and hepatitis C viral antigen-specific immune response in recurrent hepatitis C after liver transplantation

    Masashi Utsumi, Akinobu Takaki, Yuzo Umeda, Kazuko Koike, Stephanie C. Napier, Nobukazu Watanabe, Hiroshi Sadamori, Susumu Shinoura, Ryuichi Yoshida, Daisuke Nobuoka, Tetsuya Yasunaka, Eiichi Nakayama, Kazuhide Yamamoto, Toshiyoshi Fujiwara, Takahito Yagi

    TRANSPLANT IMMUNOLOGY   31 ( 1 )   33 - 41   2014.6

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    Introduction: Regulatory T (Treg) and type 1 regulatory T (Tr1) cells facilitate hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT). However, their frequencies and effects on HCV-specific immune responses have not been well investigated.
    Methods: We determined Treg and Tr1 frequencies in OLT patients with hepatitis C and assessed their associations with HCV-specific T cell responses. These patients comprised the following groups: an early post-transplantation group (n = 14); an OLT-chronic active hepatitis C group (n = 14) with active hepatitis C (alanine aminotransferase of &gt; upper limit of normal/positive for HCV-RNA); an OLT-persistently normal alanine aminotransferase group (n = 12) without active hepatitis C (not interferon/positive for HCV-RNA); and an OLT-sustained viral response group (n = 6) with sustained viral responses using interferon treatment (negative for HCV-RNA). The frequencies of HCV-specific CD4+ T cells that secreted interferon-gamma were determined by enzyme-linked immunosorbent spot assay (except for the OLT early group).
    Results: Treg and Tr1 frequencies were low during the early post-transplantation period. OLT patients with sustained viral responses had lower Treg frequencies than those with chronic hepatitis C, whereas Tr1 frequencies were significantly reduced in OLT patients with persistently normal alanine aminotransferase levels compared to those with chronic hepatitis C (p &lt; 0.05). Treg frequencies positively correlated with HCV NS3 antigen-specific interferon-gamma responses, which corresponded to HCV clearance.
    Conclusions: Increased Treg frequencies and reduced HCV-NS3 antigen-specific responses recovered after viral eradication in post-OLT chronic hepatitis C patients. Reduced Tr1 frequencies were associated with hepatitis activity control, which may facilitate controlling chronic hepatitis C in patients after OLT. (C) 2014 Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.trim.2014.05.006

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  • 膵癌におけるγセクレターゼ阻害剤を用いた幹細胞抑制による抗癌剤増強効果の検討

    堀口 繁, 白羽 英則, 内田 大輔, 永原 照也, 片岡 淳朗, 岩室 雅也, 加藤 博也, 高木 章乃夫, 能祖 一裕, 山本 和秀

    膵臓   29 ( 3 )   553 - 553   2014.6

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  • Molecular Mechanisms and New Treatment Strategies for Non-Alcoholic Steatohepatitis (NASH)

    Akinobu Takaki, Daisuke Kawai, Kazuhide Yamamoto

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   15 ( 5 )   7352 - 7379   2014.5

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    Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD), in which most patients exhibit non-progressive, non-alcoholic fatty liver (NAFL) attributable to simple steatosis. Multiple hits, including genetic differences, fat accumulation, insulin resistance and intestinal microbiota changes, account for the progression of NASH. NAFLD is strongly associated with obesity, which induces adipokine secretion, endoplasmic reticulum (ER) and oxidative stress at the cellular level, which in turn induces hepatic steatosis, inflammation and fibrosis. Among these factors, gut microbiota are acknowledged as having an important role in initiating this multifactorial disease. Oxidative stress is considered to be a key contributor in the progression from NAFL to NASH. Macrophage infiltration is apparent in NAFL and NASH, while T-cell infiltration is apparent in NASH. Although several clinical trials have shown that antioxidative therapy with vitamin E can effectively control hepatitis pathology in the short term, the long-term effects remain obscure and have often proved to be ineffective in many other diseases. Several long-term antioxidant protocols have failed to reduce mortality. New treatment modalities that incorporate current understanding of NAFLD molecular pathogenesis must be considered.

    DOI: 10.3390/ijms15057352

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  • Potential of adenovirus-mediated REIC/Dkk-3 gene therapy for use in the treatment of pancreatic cancer

    Daisuke Uchida, Hidenori Shiraha, Hironari Kato, Teruya Nagahara, Masaya Iwamuro, Junro Kataoka, Shigeru Horiguchi, Masami Watanabe, Akinobu Takaki, Kazuhiro Nouso, Yasutomo Nasu, Takahito Yagi, Hiromi Kumon, Kazuhide Yamamoto

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   29 ( 5 )   973 - 983   2014.5

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    Background and AimThe reduced expression in immortalized cells REIC/the dickkopf 3 (Dkk-3) gene, tumor suppressor gene, is downregulated in various malignant tumors. In a prostate cancer study, an adenovirus vector carrying the REIC/Dkk-3 gene (Ad-REIC) induces apoptosis. In the current study, we examined the effects of REIC/Dkk-3 gene therapy in pancreatic cancer.
    MethodsREIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry in the pancreatic cancer cell lines (ASPC1, MIAPaCa2, Panc1, BxPC3, SUIT-2, KLM1, and T3M4) and pancreatic cancer tissues. The Ad-REIC agent was used to investigate the apoptotic effect in vitro and antitumor effects in vivo. We also assessed the therapeutic effects of Ad-REIC therapy with gemcitabine.
    ResultsThe REIC/Dkk-3 expression was lost in the pancreatic cancer cell lines and decreased in pancreatic cancer tissues. Ad-REIC induced apoptosis and inhibited cell growth in the ASPC1 and MIAPaCa2 lines in vitro, and Ad-REIC inhibited tumor growth in the mouse xenograft model using ASPC1 cells. The antitumor effect was further enhanced in combination with gemcitabine. This synergistic effect may be caused by the suppression of autophagy via the enhancement of mammalian target of rapamycin signaling.
    ConclusionsAd-REIC induces apoptosis and inhibits tumor growth in pancreatic cancer cell lines. REIC/Dkk-3 gene therapy is an attractive therapeutic tool for pancreatic cancer.

    DOI: 10.1111/jgh.12501

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  • NASH肝硬変における肝移植後の経過

    高木 章乃夫, 八木 孝仁, 池田 房雄, 保田 裕子, 安中 哲也, 貞森 裕, 篠浦 先, 楳田 祐三, 吉田 龍一, 信岡 大輔, 内海 方嗣, 藤原 俊義, 山本 和秀

    移植   49 ( 1 )   155 - 155   2014.5

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  • 生体肝移植におけるドナー年齢限界の見極めと個別化治療戦略

    楳田 祐三, 八木 孝仁, 貞森 裕, 高木 章乃夫, 篠浦 先, 吉田 龍一, 信岡 大輔, 内海 方嗣, 保田 裕子, 高木 弘誠, 藤原 俊義

    移植   49 ( 1 )   80 - 81   2014.5

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  • 再肝移植症例に対する肝腎同時移植経験と、本邦の複数臓器分配におけるMELD scoreのもつ問題点

    八木 孝仁, 信岡 大輔, 篠浦 先, 保田 裕子, 高木 章乃夫, 吉田 龍一, 内海 方嗣, 楳田 祐三, 高木 弘誠, 貞森 裕, 藤原 俊義, 佐藤 大輔

    移植   49 ( 1 )   69 - 70   2014.5

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  • 劇症肝炎に対する肝移植

    楳田 祐三, 貞森 裕, 高木 章乃夫, 篠浦 先, 吉田 龍一, 信岡 大輔, 内海 方嗣, 高木 弘誠, 保田 裕子, 藤原 俊義, 八木 孝仁

    移植   49 ( 1 )   165 - 165   2014.5

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  • 肝移植術後における真菌感染症に対する危険因子の解析

    内海 方嗣, 楳田 祐三, 貞森 裕, 篠浦 先, 吉田 龍一, 信岡 大輔, 高木 弘誠, 保田 裕子, 高木 章乃夫, 藤原 俊義, 八木 孝仁

    移植   49 ( 1 )   95 - 95   2014.5

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  • 当院におけるC型肝硬変治療

    安中 哲也, 高木 章乃夫, 保田 裕子, 池田 房雄, 岩崎 良章, 八木 孝仁, 山本 和秀

    移植   49 ( 1 )   76 - 76   2014.5

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  • 肝疾患の病態と糖鎖抗原の意義 網羅的糖鎖解析による肝細胞癌バイオマーカーの検討

    宮原 孝治, 能祖 一裕, 森元 裕貴, 衣笠 秀明, 和田 望, 竹内 康人, 安中 哲也, 桑木 健志, 大西 秀樹, 池田 房雄, 三宅 康弘, 中村 進一郎, 白羽 英則, 高木 章乃夫, 天野 麻穂, 西村 紳一郎, 山本 和秀

    肝臓   55 ( Suppl.1 )   A154 - A154   2014.4

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  • 肝癌におけるNotchシグナル活性化とその治療ターゲットとしての可能性

    白羽 英則, 片岡 淳朗, 堀口 繁, 岩室 雅也, 永原 照也, 内田 大輔, 仁科 慎一, 竹内 康人, 桑木 健志, 大西 秀樹, 中村 進一郎, 高木 章乃夫, 能祖 一裕, 山本 和秀

    肝臓   55 ( Suppl.1 )   A229 - A229   2014.4

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  • C型慢性肝炎に対する抗ウイルス療法における血清フェリチン値とIL28B遺伝子多型の検討

    岩崎 良章, 池田 房雄, 小橋 春彦, 藤岡 真一, 橋本 訓招, 坂口 孝作, 荒木 康之, 岡本 良一, 馬場 伸介, 谷口 英明, 宮武 宏和, 高畠 弘行, 芦田 耕三, 三宅 康広, 高木 章乃夫, 山本 和秀

    肝臓   55 ( Suppl.1 )   A220 - A220   2014.4

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  • 当院での肝炎ウイルス検査陽性患者に対する取り組み

    下村 泰之, 池田 房雄, 難波 真太郎, 關 博之, 安中 哲也, 高木 章乃夫, 能祖 一裕, 岩崎 良章, 山本 和秀

    肝臓   55 ( Suppl.1 )   A352 - A352   2014.4

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  • 慢性C型肝炎における8-OHdGと鉄代謝関連因子の関連と肝発癌予測因子としての有用性の検討

    難波 真太郎, 池田 房雄, 馬場 伸介, 高口 浩一, 妹尾 知典, 永野 拓也, 関 博之, 安中 哲也, 高木 章乃夫, 岩崎 良章, 山本 和秀

    肝臓   55 ( Suppl.1 )   A237 - A237   2014.4

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  • Efficacy of sorafenib beyond first progression in patients with metastatic hepatocellular carcinoma

    Koji Miyahara, Kazuhiro Nouso, Yuki Morimoto, Yasuto Takeuchi, Hiroaki Hagihara, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Yasuhiro Miyake, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Shouta Iwadou, Yoshiyuki Kobayashi, Koichi Takaguchi, Yoshitaka Takuma, Hiroyuki Takabatake, Kohsaku Sakaguchi, Kazuhide Yamamoto

    HEPATOLOGY RESEARCH   44 ( 3 )   296 - 301   2014.3

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    Aim
    We investigated whether continuous sorafenib administration keeps suppressing the growth of hepatocellular carcinoma (HCC) after first progressive disease (PD), and whether it prolongs patients' survival.
    Methods
    The size of metastatic lesions was measured in 36 patients with advanced HCC treated with sorafenib. The tumor growth rates before and after radiological PD as well as survival were compared between the patients who continued (n = 23) and stopped (n = 13) sorafenib at first radiological PD.
    Results
    The growth rate did not differ between before and after PD in patients who continued sorafenib, while it increased after PD in patients who stopped sorafenib at PD (P = 0.002). Survival beyond first progression was longer in patients who continued sorafenib than in those who stopped it at PD (P = 0.012), and this tendency was observed even when the analysis was limited to Child-Pugh class A patients (P = 0.085).
    Conclusion
    Sorafenib administration beyond first radiological PD could continuously suppress HCC growth and may have survival benefit.

    DOI: 10.1111/hepr.12123

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  • Efficacy of sorafenib beyond first progression in patients with metastatic hepatocellular carcinoma

    Koji Miyahara, Kazuhiro Nouso, Yuki Morimoto, Yasuto Takeuchi, Hiroaki Hagihara, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Yasuhiro Miyake, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Shouta Iwadou, Yoshiyuki Kobayashi, Koichi Takaguchi, Yoshitaka Takuma, Hiroyuki Takabatake, Kohsaku Sakaguchi, Kazuhide Yamamoto

    HEPATOLOGY RESEARCH   44 ( 3 )   296 - 301   2014.3

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    Aim
    We investigated whether continuous sorafenib administration keeps suppressing the growth of hepatocellular carcinoma (HCC) after first progressive disease (PD), and whether it prolongs patients' survival.
    Methods
    The size of metastatic lesions was measured in 36 patients with advanced HCC treated with sorafenib. The tumor growth rates before and after radiological PD as well as survival were compared between the patients who continued (n = 23) and stopped (n = 13) sorafenib at first radiological PD.
    Results
    The growth rate did not differ between before and after PD in patients who continued sorafenib, while it increased after PD in patients who stopped sorafenib at PD (P = 0.002). Survival beyond first progression was longer in patients who continued sorafenib than in those who stopped it at PD (P = 0.012), and this tendency was observed even when the analysis was limited to Child-Pugh class A patients (P = 0.085).
    Conclusion
    Sorafenib administration beyond first radiological PD could continuously suppress HCC growth and may have survival benefit.

    DOI: 10.1111/hepr.12123

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  • γセクレターゼ阻害剤を用いた膵癌幹細胞治療についての検討

    堀口 繁, 白羽 英則, 内田 大輔, 永原 照也, 岩室 雅也, 片岡 淳朗, 加藤 博也, 高木 章乃夫, 能祖 一裕, 山本 和秀

    日本消化器病学会雑誌   111 ( 臨増総会 )   A289 - A289   2014.3

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  • 画像・組織所見と臨床像が解離したB型劇症肝炎の1例

    池田 弘, 田邊 渉, 詫間 義隆, 高畠 弘行, 守本 洋一, 山本 博, 能登原 憲司, 高木 章乃夫, 岩崎 良章

    倉敷中央病院年報   76   85 - 92   2014.3

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    Language:Japanese   Publisher:(公財)大原記念倉敷中央医療機構倉敷中央病院  

    症例は28歳女性.38℃台の発熱,嘔気,全身倦怠感にて発症.近医で感冒と診断され解熱薬を内服.第3病日より褐色尿を認め,黄疸も出現したため第6病日に当院に緊急入院.入院時,HBs抗原・IgM-HBc抗体陽性.トランスアミナーゼの著明な上昇とプロトロンビン(PT)活性の低下(14%)を認めるも,意識は清明で肝萎縮も認めなかった.lamivudine内服,ステロイドパルス療法で入院翌日にはトランスアミナーゼ値は急速に低下し,肝萎縮も認めなかったが,PT活性は14%と改善せず,急激な意識レベルの低下を認めたために移植施設に転院.転院後は,3回の血漿交換で肝不全から急速に離脱した.第16病日にはHBs抗原は陰性化し,第33病日に行った肝生検では広汎肝壊死は認めず,急性肝炎回復期の像であった.臨床経過から本例の肝不全および意識障害には一過性の強いエネルギー代謝抑制による肝臓および脳の機能抑制が関与したと推測された.(著者抄録)

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  • C型慢性肝炎患者のインスリン抵抗性に対するペグインターフェロン治療の影響について

    下村 泰之, 池田 房雄, 竹内 康人, 安中 哲也, 萩原 宏明, 高木 章乃夫, 岩崎 良章, 山本 和秀

    日本消化器病学会雑誌   111 ( 臨増総会 )   A363 - A363   2014.3

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  • Long-term Observation of Osteomalacia Caused by Adefovir-Induced Fanconi's Syndrome

    Tomohiro Terasaka, Eijiro Ueta, Hirotaka Ebara, Koichi Waseda, Yoshihisa Hanayama, Akinobu Takaki, Tomoko Kawabata, Hitoshi Sugiyama, Ko Hidani, Fumio Otsuka

    ACTA MEDICA OKAYAMA   68 ( 1 )   53 - 56   2014.2

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    A 64-year-old man suffering polyarthralgia and bone pain was referred to our hospital. Renal dysfunction, hypophosphatemia and increased levels of bone alkaline phosphatase were found. The patient's serum creatinine level had gradually increased after the initiation of adefovir dipivoxil administration for hepatitis B. In agreement with multifocal uptakes of bone scintigraphy, iliac bone biopsy revealed an abnormal increase in osteoid tissues. Reducing the dose of adefovir and initiating the administration of eldecalcitol were effective for reducing proteinuria and glucosuria, and for ameliorating bone pain with an increase in serum phosphate level. This case first showed a clinical course of hypophosphatemic osteomalacia caused by secondary Fanconi's syndrome for 8 years after adefovir administration. Early diagnosis is important for the reversibility of bone damage and for a better renal prognosis.

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  • Assessment of health-related quality of life and how it predicts the outcome of pegylated interferon and ribavirin therapy for chronic hepatitis C

    Hiroshi Matsushita, Fusao Ikeda, Yoshiaki Iwasaki, Hiroyuki Seki, Shintaro Nanba, Yasuto Takeuchi, Yuki Moritou, Tetsuya Yasunaka, Hideki Onishi, Yasuhiro Miyake, Akinobu Takaki, Kazuhiro Nouso, Kazuhide Yamamoto

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   29 ( 2 )   337 - 343   2014.2

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    Background and Aim: Chronic infection with hepatitis C virus (HCV) decreases health-related quality of life (HRQOL). The present study was planned to investigate the impact of HRQOL of patients with chronic hepatitis C (CHC) on the outcomes of therapy with pegylated interferon and ribavirin (RBV), in addition to IL28B polymorphisms.
    Methods: The present study enrolled 228 CHC patients and assessed their HRQOLs prospectively with the 36-item short-form health survey.
    Results: The patients with CHC have lower physical HRQOL status than the general population (P = 0.037, the Z-test). The patients with advanced liver diseases exhibited further decreases in HRQOL (P = 0.036, Spearman's rank correlation coefficient). The score of total HRQOL was significantly lower in the group with sustained virological response (SVR) to the therapy with pegylated interferon and RBV than the non-SVR group (P = 0.031, the Mann-Whitney U-test), with significantly lower scores of mental component and its comprising subscales in the SVR group. Stepwise multivariate logistic regression analysis showed that low HRQOL score &lt;= 400 points was significantly associated with SVR (odds ratio = 2.4, P = 0.013), independently from high platelet counts, low HCV RNA, favorable single-nucleotide polymorphism type of IL28B, and HCV serotype 2. The patients with low HRQOL score will have significantly less decrease in HRQOL score by 4 weeks of the treatment than those with high HRQOL score at baseline (P = 0.0045).
    Conclusion: HRQOL is one of the significant predictor of the outcomes of therapy with pegylated interferon and RBV independently from IL28B polymorphism.

    DOI: 10.1111/jgh.12337

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  • Hepatopulmonary syndrome in Japanese liver cirrhosis patients

    Hayami Okada, Akinobu Takaki, Takahito Yagi, Tetsuya Yasunaka, Tatsuhiro Gotoda, Hiroki Oe, Kazufumi Nakamura, Shuichi Sato, Hiroshi Sadamori, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Masashi Utsumi, Daisuke Nobuoka, Yuko Yasuda, Fusao Ikeda, Yasuhiro Miyake, Hiroshi Ito, Toshiyoshi Fujiwara, Kazuhide Yamamoto

    Acta Hepatologica Japonica   55 ( 3 )   143 - 154   2014

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    Hepatopulmonary syndrome is characterized by hypoxemia induced by intrapulmonary vascular dilatations associated with hepatic diseases. We evaluated the frequency and case presentations revealed by general screening before liver transplantation. Sixty-one patients underwent arterial blood gas analysis in both upright and supine positions. Of these, 27 patients (44%) showed Pa0&lt
    inf&gt
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    80 mmHg and AaD0&lt
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    15 mmHg, reflecting intrapulmonary shunting. Four patients exhibited Pa0&lt
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    70 mmHg and orthodeoxia, defined as a fall in Pa0&lt
    inf&gt
    2&lt
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    5% or 4 mmHg in an upright position. Finally, two patients showed hepatopulmonary syndrome, with positive findings on perfusion lung scanning. Both patients with hepatopulmonary syndrome had liver cirrhosis type C with habitual alcohol drinking and smoking. Potential pulmonary shunt patients with Pa0&lt
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    80 mmHg and AaD0&lt
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    15 mmHg exhibited higher model for end-stage liver disease scores. Care should be taken regarding hepatopulmonary syndrome during liver cirrhosis management in Japanese patients. © 2014 The Japan Society of Hepatology.

    DOI: 10.2957/kanzo.55.143

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  • A case of fulminant liver failure associated with hepatitis C virus

    Hiromitsu Kanzaki, Akinobu Takaki, Takahito Yagi, Fusao Ikeda, Tetsuya Yasunaka, Kazuko Koike, Yasuhiro Miyake, Yoshiaki Iwasaki, Kazuhiro Nouso, Hiroshi Sadamori, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Masashi Utusmi, Toshiyoshi Fujiwara, Kazuhide Yamamoto

    Clinical Journal of Gastroenterology   7 ( 2 )   170 - 174   2014

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    Fulminant hepatitis due to acute hepatitis C virus (HCV) infection is rarely observed. We present a case study of a 21-year-old male patient who developed HCV-associated fulminant hepatitis after receiving steroid pulse therapy for optic neuritis. Despite daily plasmapheresis, the disease progressed to irreversible liver failure with grade 3 hepatic encephalopathy by the 6th day after symptom onset. The patient received a liver transplant on the 8th day. Serum anti-HCV antibody was negative at that time, but became positive on the 12th day. Positive HCV RNA in the serum at admission was reported after transplantation. Positive changes in anti-HCV antibodies and acute hepatitis with massive necrosis in the histology of the explanted liver indicated fulminant hepatitis due to acute HCV infection. Because of severe hepatitis recurrence, he started 12 months of interferon therapy on the 48th day, and obtained sustained virological response. His anti-HCV antibodies became negative again by 1.5 years after cessation of therapy. HCV genomes recovered from the patient's serum on the 7th and 48th days revealed 2 different clones out of 20 clones with 30 % amino acid difference in hypervariable region 1 of HCV second envelope glycoprotein. One of the 2 clones expanded further after liver transplantation. We conclude that early diagnosis of HCV-associated fulminant hepatitis requires the detection of HCV RNA in the serum. Severe hepatitis recurrence after liver transplantation might occur in patients with fulminant hepatitis due to HCV because of its monoclonal expansion. © 2014 Springer.

    DOI: 10.1007/s12328-014-0454-x

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  • A case of Wilson's disease with characteristic laparoscopic findings

    Shin-Ichiro Muro, Tetsuya Yasunaka, Nozomu Wada, Yuki Morimoto, Fusao Ikeda, Hidenori Shiraha, Akinobu Takaki, Kazuhiro Noso, Hiroaki Iwasaki, Kazuhide Yamamoto

    Clinical Journal of Gastroenterology   7 ( 2 )   175 - 179   2014

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    A 44-year-old male was pointed out liver function abnormality by medical check-up. Blood examination and computed tomography showed liver cirrhosis. Then, he was referred to our hospital for further examination. After blood test, viral markers revealed previous infection of hepatitis B virus (HBV). We estimated the etiology of his liver disease as previous HBV infection. On laparoscopic examination, his liver surface was nodular with mixed yellowish nodules and ash gray to copper-colored nodules in the diameter of 3-10 mm. There were large regenerative nodules in segments 3 and 4. Large regenerative nodules and irregular steatosis were contradictory to HBV-related liver cirrhosis, so then we supposed Wilson's disease. The amount of copper excretion in the urine was 326.6 μg (&gt
    100 μg/24 h). After D-penicillamine administration, urinary copper excretion increased to 2151.5 μg/24 h. Though hepatic copper concentration was 174.5 μg/g wet tissue (&gt
    200 μg/g wet tissue), his laboratory data fulfilled the Leipzig diagnostic criteria proposed by EASL. Laparoscopic examination with liver biopsy has advantages to survey many disease-specific findings on liver surface and to obtain adequate liver sample. Laparoscopic examination is one of the effective procedures for diagnosing relatively rare liver disease like Wilson's disease. © 2014 Springer.

    DOI: 10.1007/s12328-014-0465-7

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  • A case of fulminant liver failure associated with hepatitis C virus

    Hiromitsu Kanzaki, Akinobu Takaki, Takahito Yagi, Fusao Ikeda, Tetsuya Yasunaka, Kazuko Koike, Yasuhiro Miyake, Yoshiaki Iwasaki, Kazuhiro Nouso, Hiroshi Sadamori, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Masashi Utusmi, Toshiyoshi Fujiwara, Kazuhide Yamamoto

    Clinical Journal of Gastroenterology   7 ( 2 )   170 - 174   2014

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    Fulminant hepatitis due to acute hepatitis C virus (HCV) infection is rarely observed. We present a case study of a 21-year-old male patient who developed HCV-associated fulminant hepatitis after receiving steroid pulse therapy for optic neuritis. Despite daily plasmapheresis, the disease progressed to irreversible liver failure with grade 3 hepatic encephalopathy by the 6th day after symptom onset. The patient received a liver transplant on the 8th day. Serum anti-HCV antibody was negative at that time, but became positive on the 12th day. Positive HCV RNA in the serum at admission was reported after transplantation. Positive changes in anti-HCV antibodies and acute hepatitis with massive necrosis in the histology of the explanted liver indicated fulminant hepatitis due to acute HCV infection. Because of severe hepatitis recurrence, he started 12 months of interferon therapy on the 48th day, and obtained sustained virological response. His anti-HCV antibodies became negative again by 1.5 years after cessation of therapy. HCV genomes recovered from the patient's serum on the 7th and 48th days revealed 2 different clones out of 20 clones with 30 % amino acid difference in hypervariable region 1 of HCV second envelope glycoprotein. One of the 2 clones expanded further after liver transplantation. We conclude that early diagnosis of HCV-associated fulminant hepatitis requires the detection of HCV RNA in the serum. Severe hepatitis recurrence after liver transplantation might occur in patients with fulminant hepatitis due to HCV because of its monoclonal expansion. © 2014 Springer.

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  • Contradictory immune response in post liver transplantation hepatitis B and C

    Akinobu Takaki, Takahito Yagi, Kazuhide Yamamoto

    International Journal of Inflammation   2014   2014

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    Hepatitis B and C often progress to decompensated liver cirrhosis requiring orthotopic liver transplantation (OLT). After OLT, hepatitis B recurrence is clinically controlled with a combination of hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogues. Another approach is to induce self-producing anti-hepatitis B virus (HBV) antibodies using a HBV envelope antigen vaccine. Patients who had not been HBV carriers such as acutely infected liver failure or who received liver from HBV self-limited donor are good candidate. For chronic HBV carrier patients, a successful response can only be achieved in selected patients such as those treated with experimentally reduced immunosuppression protocols or received an anti-HBV adaptive memory carrying donor liver. Hepatitis C virus (HCV) reinfects transplanted livers at a rate of &gt
    90%. HCV reinfected patients show different severities of hepatitis, from mild and slowly progressing to severe and rapidly progressing, possibly resulting from different adaptive immune responses. More than half the patients require interferon treatment, although the success rate is low and carries risks for leukocytopenia and rejection. Managing the immune response has an important role in controlling recurrent hepatitis C. This study aimed to review the adaptive immune response in post-OLT hepatitis B and C.

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  • L-carnitine prevents progression of non-alcoholic steatohepatitis in a mouse model with upregulation of mitochondrial pathway

    Hisashi Ishikawa, Akinobu Takaki, Kazuhide Yamamoto

    HEPATOLOGY   60 ( 7 )   761A - 761A   2014

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    DOI: 10.1371/journal.pone.0100627

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  • Entecavir reduces the incidence of hepatocellular carcinoma in patients with chronic hepatitis B

    Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Tomonori Seno, Koichi Takaguchi, Kazuhide Yamamoto

    HEPATOLOGY   60   1096A - 1096A   2014

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  • Which patients respond best to hepatitis B vaccination after a hepatitis B virus-related liver transplantation?

    Akinobu Takaki, Takahito Yagi, Tetsuya Yasunaka, Hiroshi Sadamori, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Sato, Daisuke Nobuoka, Masashi Utsumi, Yuko Yasuda, Eiichi Nakayama, Yasuhiro Miyake, Fusao Ikeda, Hidenori Shiraha, Kazuhiro Nouso, Toshiyoshi Fujiwara, Kazuhide Yamamoto

    Journal of Gastroenterology   48 ( 12 )   1373 - 1383   2013.12

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    Background: A combination of hepatitis B immunoglobulin and nucleos(t)ide analogues is the current standard of care for controlling hepatitis B recurrence after orthotopic liver transplantation (OLT). However, frequent immunoglobulin treatment is expensive and inconvenient. This study investigated the efficacy of hepatitis B virus (HBV) vaccination in preventing the recurrence of hepatitis B after living donor OLT. Methods: Twenty-seven patients who had undergone living donor OLT participated in the study
    five had acute HBV infected liver failure (ALF-OLT) and 22 had HBV related liver cirrhosis (LC-OLT). Hepatitis B surface antigen (HBsAg)-containing vaccine was administered to them for at least 1 year after transplantation and continued once monthly for up to 36 months post-OLT. Patients who had anti-HBs antibody titers above 100 mIU/mL for a minimum of 6 months without immunoglobulin administration were defined as good responders
    the others were defined as poor responders. Interferon-γ enzyme-linked immunospot assays against HBs and HBc antigens were used to assay cellular immune responses. Results: All five of the ALF-OLT patients had good responses after a median of four (range 2.5-5) vaccinations. Nine of the 22 LC-OLT patients had good responses after a median of 19 (range 11.5-30) vaccinations. Among the LC-OLT group, those with livers donated by relatively higher-aged, marital and high-titer anti-HBs antibody donors were good responders. LC-OLT patients classed as good responders showed interferon-γ responses comparable to those of the ALF-OLT patients. Conclusions: The ALF-OLT and LC-OLT patients who received livers from relatively higher-aged, marital, high-titer anti-HBs antibody donors were the best candidates for HBV vaccine administration. Boosting donors before transplantation may facilitate later vaccine response of the recipients. © 2013 The Author(s).

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  • Multiple hits, including oxidative stress, as pathogenesis and treatment target in non-alcoholic steatohepatitis (NASH)

    Akinobu Takaki, Daisuke Kawai, Kazuhide Yamamoto

    International Journal of Molecular Sciences   14 ( 10 )   20704 - 20728   2013.10

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    Multiple parallel hits, including genetic differences, insulin resistance and intestinal microbiota, account for the progression of non-alcoholic steatohepatitis (NASH). Multiple hits induce adipokine secretion, endoplasmic reticulum (ER) and oxidative stress at the cellular level that subsequently induce hepatic steatosis, inflammation and fibrosis, among which oxidative stress is considered a key contributor to progression from simple fatty liver to NASH. Although several clinical trials have shown that anti-oxidative therapy can effectively control hepatitis activities in the short term, the long-term effect remains obscure. Several trials of long-term anti-oxidant protocols aimed at treating cerebrovascular diseases or cancer development have failed to produce a benefit. This might be explained by the non-selective anti-oxidative properties of these drugs. Molecular hydrogen is an effective antioxidant that reduces only cytotoxic reactive oxygen species (ROS) and several diseases associated with oxidative stress are sensitive to hydrogen. The progress of NASH to hepatocellular carcinoma can be controlled using hydrogen-rich water. Thus, targeting mitochondrial oxidative stress might be a good candidate for NASH treatment. Long term clinical intervention is needed to control this complex lifestyle-related disease. © 2013 by the authors
    licensee MDPI, Basel, Switzerland.

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  • Serum Glycan Markers for Evaluation of Disease Activity and Prediction of Clinical Course in Patients with Ulcerative Colitis

    Koji Miyahara, Kazuhiro Nouso, Shunsuke Saito, Sakiko Hiraoka, Keita Harada, Sakuma Takahashi, Yuki Morimoto, Sayo Kobayashi, Fusao Ikeda, Yasuhiro Miyake, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada, Maho Amano, Kazuko Hirose, Shin-Ichiro Nishimura, Kazuhide Yamamoto

    PLoS ONE   8 ( 10 )   e74861-e74861   2013.10

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    Background:The aims of this study were to determine the change of whole-serum N-glycan profile in ulcerative colitis (UC) patients and to investigate its clinical utility.Methods:We collected serum from 75 UC patients at the time of admission and the same number of age/sex-matched healthy volunteers. Serum glycan profile was measured by comprehensive quantitative high-throughput glycome analysis and was compared with disease activity and prognosis.Results:Out of 61 glycans detected, 24 were differentially expressed in UC patients. Pathway analysis demonstrated that highly sialylated multi-branched glycans and agalactosyl bi-antennary glycans were elevated in UC patients
    in addition, the glycan ratio m/z 2378/1914, which also increased in UC, showed the highest Area under Receiver Operating Characteristic curve (0.923) for the diagnosis of UC. Highly sialylated multi-branched glycans and the glycan ratio m/z 2378/1914 were higher in the patients with total colitis, Clinical Activity Index &gt
    10, Mayo endoscopic score 3, or a steroid-refractory status. In particular, the glycan ratio m/z 2378/1914 (above median) was an independent prognostic factor for the need for an operation (hazard ratio, 2.67
    95% confidence interval, 1.04-7.84).Conclusions:Whole-serum glycan profiles revealed that the glycan ratio m/z 2378/1914 and highly sialylated multi-branched glycans increase in UC patients, and are correlated with disease activity. The glycan ratio m/z 2378/1914 was an independent predictive factor of the prognosis of UC. © 2013 Miyahara et al.

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  • Pro-angiogenic cytokines for prediction of outcomes in patients with advanced hepatocellular carcinoma

    K. Miyahara, K. Nouso, Y. Morimoto, Y. Takeuchi, H. Hagihara, K. Kuwaki, H. Onishi, F. Ikeda, Y. Miyake, S. Nakamura, H. Shiraha, A. Takaki, M. Honda, S. Kaneko, T. Sato, S. Sato, S. Obi, S. Iwadou, Y. Kobayashi, K. Takaguchi, K. Kariyama, Y. Takuma, H. Takabatake, K. Yamamoto

    BRITISH JOURNAL OF CANCER   109 ( 8 )   2072 - 2078   2013.10

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    Background: We previously reported that expressions of the pro-angiogenic cytokines angiopoietin-2 (Ang-2), follistatin, granulocyte colony-stimulating factor, hepatocyte growth factor, leptin, platelet-derived growth factor-BB, platelet endothelial cell adhesion molecule-1, and vascular endothelial growth factor were associated with the response to sorafenib in patients with advanced hepatocellular carcinoma (HCC). The aim of the present study is to examine the same relationship in a larger cohort.Methods: In the current retrospective cohort study, we measured serum levels of the eightcytokines in 120 consecutive HCC patients who were treated with sorafenib. We evaluated the effects of increased expression of serum cytokines on progression-free survival (PFS) and overall survival (OS).Results: Elevated expression of Ang-2 correlated both with significantly shorter PFS (hazard ratio (HR), 1.84; 95% confidence interval (CI), 1.21-2.81), and OS (HR, 1.95; 95% CI, 1.21-3.17). Patients with more than three cytokines expressed above the median similarly had significantly shorter PFS (HR, 1.98; 95% CI, 1.30-3.06) and OS (HR, 1.94; 95% CI, 1.19-3.22). Differences in OS were evident in cases with the evidence of macroscopic vascular invasion or extrahepatic metastasis.Conclusion: High expression of Ang-2 or more than cytokines in serum is associated with poor PFS and OS in HCC patients treated with sorafenib.

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  • Clinical utility of high-throughput glycome analysis in patients with pancreatic cancer

    Kazuhiro Nouso, Maho Amano, Yoichi M. Ito, Koji Miyahara, Yuki Morimoto, Hironari Kato, Koichiro Tsutsumi, Takeshi Tomoda, Naoki Yamamoto, Shinichiro Nakamura, Sayo Kobayashi, Kenji Kuwaki, Hiroaki Hagihara, Hideki Onishi, Yasuhiro Miyake, Fusao Ikeda, Hidenori Shiraha, Akinobu Takaki, Taku Nakahara, Shin-Ichiro Nishimura, Kazuhide Yamamoto

    JOURNAL OF GASTROENTEROLOGY   48 ( 10 )   1171 - 1179   2013.10

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    Most of the glycan changes reported in cancers were based on the examinations of a small number of patients or particular proteins. The aim of this study was to determine the changes of the serum N-glycan profile comprehensively in a large number of pancreatic cancer patients and investigate its clinical utility.
    Glycan levels in the serum of 92 pancreatic cancer patients and 243 healthy volunteers (HLT) were examined by comprehensive quantitative high-throughput glycome analysis and were compared with clinical parameters.
    Out of 66 glycans detected, 15 were differentially expressed in pancreatic cancer, and 10 out of the 15 glycans were significantly up-regulated in cases with distant metastasis. There was a clear increase in overall expression of serum glycans, especially highly-branched glycans with fucose moieties, in pancreatic cancer. Among these 15 glycans, a tri-antennary complex type glycan (m/z 3195) showed the highest area under the receiver operating characteristic curve (AUROC = 0.799) for the diagnosis of pancreatic cancer. The ratio of pairs of glycans on the same path of the biosynthesis pathway (m/z 3195/1914) was found to be significantly higher in pancreatic cancer than in HLT (median = 1.11 and 0.41, respectively; p &lt; 0.0001, AUROC = 0.831). For this pair ratio, the hazard ratio for survival (2.60, 95 % CI = 1.44-4.79) was higher than that of any single glycan and 1-year survival of patients with a high and low ratio was 36.9 and 69.2 %, respectively, (p = 0.001).
    Comprehensive glycome analysis can be used to know the presence of pancreatic cancer, distant metastasis, and patient prognosis, simultaneously.

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  • Serial Changes of Serum Growth Factor Levels and Liver Regeneration after Partial Hepatectomy in Healthy Humans

    Kazuyuki Matsumoto, Yasuhiro Miyake, Yuzo Umeda, Hiroshi Matsushita, Hiroaki Matsuda, Akinobu Takaki, Hiroshi Sadamori, Kazuhiro Nouso, Takahito Yagi, Toshiyoshi Fujiwara, Kazuhide Yamamoto

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   14 ( 10 )   20877 - 20889   2013.10

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    This study aimed to investigate the associations of the serial changes of serum levels of various growth factors with liver regeneration after hepatectomy in healthy liver donors. Sixteen healthy liver donors who underwent conventional liver resection were included. Serum levels of various growth factors before hepatectomy and on postoperative day (POD) 1, 3, 5 and 7 were measured. Liver volume data calculated by multi-detector computed tomography using workstation. The ratio of remnant liver volume on POD 0 to liver volume before the operation was 51% +/- 20%. The ratio of liver volume on POD 14 to liver volume on POD 0 were inversely correlated with remnant liver volume on POD 0 (r = -0.91). The ratio of liver volume on POD 14 to liver volume on POD 0 were significantly correlated with serum hepatocyte growth factor (HGF) levels on POD 1 (r = 0.54), serum leptin levels on POD 1 (r = 0.54), and serum macrophage colony-stimulating factor (M-CSF) levels on POD 5 (r = 0.76) and POD 7 (r = 0.80). These results suggest that early-phase elevation of serum levels of HGF, leptin and M-CSF may be associated with the acceleration of liver regeneration after hepatectomy in humans.

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  • Serum oxidative-anti-oxidative stress balance is dysregulated in patients with hepatitis C virus-related hepatocellular carcinoma

    Mamoru Nishimura, Akinobu Takaki, Naofumi Tamaki, Takayuki Maruyama, Hideki Onishi, Sayo Kobayashi, Kazuhiro Nouso, Tetsuya Yasunaka, Kazuko Koike, Hiroaki Hagihara, Kenji Kuwaki, Shinichiro Nakamura, Fusao Ikeda, Yoshiaki Iwasaki, Takaaki Tomofuji, Manabu Morita, Kazuhide Yamamoto

    Hepatology Research   43 ( 10 )   1078 - 1092   2013.10

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    Aim: Oxidative stress is associated with progression of chronic liver disease (CLD). This association is best established in chronic hepatitis C. However, the anti-oxidative state is not well characterized. The objective of the present study was to investigate the balance of oxidative and anti-oxidative stress in CLD patients. Methods: We recruited a study population of 208 patients, including healthy volunteers (HV
    n=15), patients with hepatitis B virus (HBV)-related CLD without or with hepatocellular carcinoma (HBV-non-HCC, n=25, and HBV-HCC, n=50, respectively), and patients with hepatitis C virus (HCV)-related CLD without or with HCC (HCV-non-HCC, n=49, and HCV-HCC, n=69, respectively). Serum levels of reactive oxygen metabolites (ROM) and anti-oxidative markers (OXY-adsorbent test
    OXY) were determined, and the balance of these values was used as the oxidative index. Correlations among ROM, OXY, oxidative index and clinical characteristics were investigated. Results: Patients with CLD exhibited elevated ROM and oxidative index compared to HV. Among patients with CLD, HCV positive status correlated with increased ROM. In CLD, HCV-HCC patients exhibited the highest ROM levels. Among HCV-related CLD patients, lower OXY correlated with HCC positive status, but was recovered by eradication of HCC. In HCV-HCC, lower OXY correlated with high PT-INR. Conclusion: HCV positive CLD patients displayed higher oxidative stress and HCV-HCC patients displayed lower anti-oxidative state. Anti-oxidative state depression was associated with liver reservoir-related data in HCV-HCC and could be reversed with HCC eradication. © 2012 The Japan Society of Hepatology.

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  • Evaluation of the effect of sorafenib using serum NX-des-gamma-carboxyprothrombin in patients with hepatocellular carcinoma

    Koji Miyahara, Kazuhiro Nouso, Yuki Morimoto, Takeshi Tomoda, Sayo Kobayashi, Yasuto Takeuchi, Hiroaki Hagihara, Kenji Kuwaki, Hideki Ohnishi, Fusao Ikeda, Yasuhiro Miyake, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Kazuhide Yamamoto

    HEPATOLOGY RESEARCH   43 ( 10 )   1064 - 1070   2013.10

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    AimDes--carboxyprothrombin (DCP) is known to be increased by the use of sorafenib for the treatment of hepatocellular carcinoma (HCC), despite its therapeutic efficacy. In addition to the tumor progression, hypoxia that impairs vitamin K uptake is known to induce DCP and this mechanism may explain DCP elevation by sorafenib. In this study, we tried to evaluate the effect of sorafenib treatment using a new marker, NX-DCP, which is specific to vitamin K absence.
    MethodsSerum DCP and NX-DCP were measured in 50 consecutive HCC patients before and 1 week after starting sorafenib, and compared with the treatment effect using the modified Response Evaluation Criteria in Solid Tumors guidelines.
    ResultsDCP and NX-DCP increased 1.58- (median, range 0.21-28.7) and 1.20-fold (median, range 0.41-14.2) after the administration of sorafenib, respectively. The increases of both markers were less than twofold in approximately half of the patients (low-elevation group). However, 12 patients showed over twofold increase of both DCP and NX-DCP (double-elevation group), and eight patients showed over twofold increase of DCP alone (DCP-elevation group). The disease control rate (DCR) of the DCP-elevation group (12.5%) was significantly lower than those of the double-elevation group (75.0%, P=0.020) and the low-elevation group (60.0%, P=0.042). Progression-free survival (PFS) was significantly shorter in the DCP-elevation group than in the double-elevation group (P=0.006) and the low-elevation group (P=0.001).
    ConclusionNX-DCP in combination with DCP could be a useful biomarker of sorafenib treatment for advanced HCC.

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  • Strong hepatitis C virus-specific T-cell immune responses correlate with lower hepatitis activities and donor IL28B major genotype in the early period after living donor liver transplantation

    Ryuichiro Tsuzaki, Akinobu Takaki, Takahito Yagi, Fusao Ikeda, Kazuko Koike, Yoshiaki Iwasaki, Hidenori Shiraha, Yasuhiro Miyake, Hirsohi Sadamori, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Masashi Utsumi, Daisuke Nobuoka, Toshiyoshi Fujiwara, Kazuhide Yamamoto

    HEPATOLOGY   58   1048A - 1048A   2013.10

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  • Nucleoside analogue treatment can not reduce the incidence of hepatocellular carcinoma in patients with chronic hepatitis B

    Tetsuya Yasunaka, Fusao Ikeda, Nozomu Wada, Yuuki Morimoto, Kenji Kuwaki, Akinobu Takaki, Kazuhide Yamamoto

    HEPATOLOGY   58   671A - 671A   2013.10

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  • Frequency of regulatory T cell and HCV antigen specific immune response in recurrent hepatitis C after liver transplantation

    Akinobu Takaki, Masashi Utsumi, Kazuko Koike, Takahito Yagi, Nobukazu Watanabe, Ryuichiro Tsuzaki, Hirsohi Sadamori, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Nobuoka, Tetsuya Yasunaka, Hidenori Shiraha, Kazuhide Yamamoto

    HEPATOLOGY   58   1178A - 1178A   2013.10

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  • Prediction of Survival in Patients with Hepatocellular Carcinoma Treated with Sorafenib by Comprehensive Serum Glycan Analysis

    Kazuhiro Nouso, Koji Miyahara, Yuuki Morimoto, Yasuto Takeuchi, Hiroaki Hagihara, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Yasuhiro Miyake, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Koichi Takaguchi, Takahisa Sato, Shinpei Sato, Shuntaro Obi, Kazuko Hirose, Maho Amano, Shin-Ichiro Nishimura, Kazuhide Yamamoto

    HEPATOLOGY   58   1242A - 1242A   2013.10

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  • Predictive impacts of alpha-fetoprotein levels on development of hepatocellular carcinoma during interferon therapy for chronic hepatitis C

    Yasuto Takeuchi, Fusao Ikeda, Tetsuya Yasunaka, Yasuhiro Miyake, Akinobu Takaki, Kazuhiro Nouso, Yoshiaki Iwasaki, Kazuhide Yamamoto

    HEPATOLOGY   58   1128A - 1129A   2013.10

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  • 肝細胞癌遠隔転移と血小板の関係

    森元 裕貴, 能祖 一裕, 和田 望, 竹内 康人, 宮原 孝治, 萩原 宏明, 桑木 健志, 安中 哲也, 大西 秀樹, 三宅 康広, 中村 進一郎, 白羽 英則, 高木 章乃夫, 山本 和秀

    肝臓   54 ( Suppl.2 )   A638 - A638   2013.9

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  • TACE不応症例への治療戦略の検討

    和田 望, 能祖 一裕, 中村 進一郎, 森元 裕貴, 竹内 康人, 安中 哲也, 萩原 宏明, 桑木 健志, 大西 秀樹, 白羽 英則, 高木 章乃夫, 山本 和秀

    肝臓   54 ( Suppl.2 )   A641 - A641   2013.9

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  • 肝細胞におけるCK7の発現はPBCの予後予測に有用である

    関 博之, 池田 房雄, 竹内 康人, 森藤 由記, 難波 真太郎, 安中 哲也, 三宅 康広, 高木 章乃夫, 岩崎 良章, 山本 和秀

    肝臓   54 ( Suppl.2 )   A646 - A646   2013.9

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  • Prognotic impact of serum follistatin in patients with hepatocellular carcinoma

    Takeshi Tomoda, Kazuhiro Nouso, Koji Miyahara, Sayo Kobayashi, Hideaki Kinugasa, Junki Toyosawa, Hiroaki Hagihara, Kenji Kuwaki, Hideki Onishi, Shinichiro Nakamura, Fusao Ikeda, Yasuhiro Miyake, Hidenori Shiraha, Akinobu Takaki, Kazuhide Yamamoto

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   28 ( 8 )   1391 - 1396   2013.8

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    Background and Aim: Follistatin (FST) is a glycoprotein expressed in most organs, which interacts with activins or other members of the transforming growth factor beta family. Recently, several reports have shown that FST regulates a variety of processes during tumor progression. Here, serum FST in patients with liver diseases was measured, and its clinical utility as a biomarker was assessed.
    Methods: Serum was collected from 162 patients (91 hepatocellular carcinoma [HCC], 43 liver cirrhosis, and 28 chronic hepatitis) as well as from 16 healthy volunteers. FST was quantified by enzyme-linked immunosorbent assays, and levels were compared with clinical parameters including survival of the HCC patients.
    Results: Median serum FST levels in HCC, liver cirrhosis, chronic hepatitis, and healthy volunteers were 1168, 1606, 1324, and 1661 pg/mL, respectively, not significantly different. In HCC patients, higher serum FST was associated with greater age, hepatitis C virus antibody-negativity, large tumor size, g-glutamyl transpeptidase, des-gamma carboxyprothrombin and presence of portal vein tumor thrombus. Survival of HCC patients with high FST levels was significantly shorter than for those with low levels (P = 0.004). Multivariate analysis revealed that in addition to large tumor size and presence of portal vein thrombus, high FST levels were independently correlated with poor prognosis (hazard ratio = 2.41, 95% confidence interval = 1.16-5.00, P = 0.02).
    Conclusions: Serum FST levels are significantly associated with HCC prognosis and could represent a predictive biomarker in this disease.

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  • 移植医療における看護師が抱える倫理的ジレンマ 遺伝性疾患に対する肝移植におけるレシピエント移植コーディネーターのあり方

    保田 裕子, 安中 哲也, 楳田 祐三, 高木 章乃夫, 八木 孝仁

    移植   48 ( 総会臨時 )   267 - 267   2013.8

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  • アルコール性肝硬変患者に対する肝移植適応基準確立に向けた岡山大学病院での取組み

    吉田 龍一, 高木 弘誠, 内海 方嗣, 信岡 大輔, 楳田 祐三, 篠浦 先, 貞森 裕, 保田 裕子, 高木 章乃夫, 藤原 俊義, 八木 孝仁

    移植   48 ( 総会臨時 )   309 - 309   2013.8

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  • 法改正後の肝移植紹介患者の経過より分かる現状の生体と脳死の選択

    高木 章乃夫, 保田 裕子, 八木 孝仁, 安中 哲也, 貞森 裕, 篠浦 先, 楳田 祐三, 白羽 英則, 能祖 一裕, 藤原 俊義, 山本 和秀

    日本門脈圧亢進症学会雑誌   19 ( 3 )   184 - 184   2013.8

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  • カルニチン及びビタミンE投与による酸化ストレスとNASH病態改善の関連

    石川 久, 高木 章乃夫, 松下 浩志, 津崎 龍一郎, 小池 和子, 三宅 康広, 白羽 英則, 山本 和秀

    肝臓   54 ( Suppl.1 )   A389 - A389   2013.4

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  • ソラフェニブ中止に伴う腫瘍進展に関する検討

    宮原 孝治, 能祖 一裕, 森元 裕貴, 竹内 康人, 和田 望, 萩原 宏明, 安中 哲也, 桑木 健志, 大西 秀樹, 池田 房雄, 三宅 康広, 中村 進一郎, 白羽 英則, 高木 章乃夫, 山本 和秀

    肝臓   54 ( Suppl.1 )   A115 - A115   2013.4

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  • 肝癌におけるRUNX3発現低下はNotchシグナルを介し癌幹細胞化とEMTを制御する

    白羽 英則, 片岡 淳朗, 堀口 繁, 岩室 雅也, 永原 照也, 内田 大輔, 仁科 慎一, 高木 章乃夫, 萩原 宏明, 桑木 健志, 大西 秀樹, 中村 進一郎, 能祖 一裕, 山本 和秀

    肝臓   54 ( Suppl.1 )   A151 - A151   2013.4

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  • 脂肪性肝疾患における血中Fetuin-Aの検討

    岩崎 良章, 池田 房雄, 安中 哲也, 竹内 康人, 森藤 由記, 森元 裕貴, 三宅 康広, 高木 章乃夫, 山本 和秀

    肝臓   54 ( Suppl.1 )   A308 - A308   2013.4

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  • C型慢性肝炎患者におけるインターフェロン治療前AFP値と肝発癌予測

    竹内 康人, 池田 房雄, 安中 哲也, 三宅 康広, 高木 章乃夫, 岩崎 良章, 藤岡 真一, 大澤 俊哉, 宮武 和宏, 荒木 康之, 牧野 泰祐, 谷口 英明, 妹尾 知典, 高口 浩一, 松村 周治, 真鍋 康二, 山本 和秀

    肝臓   54 ( Suppl.1 )   A130 - A130   2013.4

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  • The impact of patatin-like phospholipase domain-containing protein 3 polymorphism on hepatocellular carcinoma prognosis

    Yasuto Takeuchi, Fusao Ikeda, Yuki Moritou, Hiroaki Hagihara, Tetsuya Yasunaka, Kenji Kuwaki, Yasuhiro Miyake, Hideki Ohnishi, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Yoshiaki Iwasaki, Kazuhiro Nouso, Kazuhide Yamamoto

    Journal of Gastroenterology   48 ( 3 )   405 - 412   2013.3

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    Background The single nucleotide polymorphism (SNP) rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3) is associated with hepatic fat accumulation and disease progression in patients with nonalcoholic fatty liver disease and alcoholic liver disease (ALD). This study was conducted to determine whether PNPLA3 rs738409 SNPs affect development and prognosis of hepatocellular carcinoma (HCC) in patients with various liver diseases. Methods We enrolled 638 consecutive Japanese patients newly diagnosed with HCC between 2001 and 2010: 72 patients with hepatitis B virus (HBV), 462 with hepatitis C virus (HCV), and 104 with non-B non-C (NBNC). Results NBNC patients exhibited large tumors of advanced TNM stages at HCC diagnosis, and had significantly poorer prognosis than HBV or HCV patients (P&lt
    0.001 and &lt
    0.001, respectively
    log-rank test). The G/G genotype of PNPLA3 rs738409 SNP had significantly higher distribution in NBNC patients (P&lt
    0.001) and was significantly associated with higher body mass index (BMI) and an increased aspartate aminotransferase to platelet ratio index. No significant differences were observed in survival with differences in PNPLA3 SNP genotypes among the patients, although ALD patients with the G/G genotype of PNPLA3 SNP and low BMI had significantly poorer survival than those with high BMI (P = 0.028). Conclusions The G/G genotype of PNPLA3 rs738409 SNP was more frequently distributed, and associated with BMI and fibrosis among NBNC-HCC patients but not among HBV or HCV patients. These genotypes might affect HCC prognosis in ALD patients, but not in HBV, HCV, or NAFLD patients. © Springer 2012.

    DOI: 10.1007/s00535-012-0647-3

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  • 肝癌EMTマーカーとしてのPIVKA-II

    白羽 英則, 堀口 繁, 岩室 雅也, 片岡 淳朗, 永原 照也, 内田 大輔, 高木 章乃夫, 萩原 宏明, 桑木 健志, 大西 秀樹, 中村 進一郎, 能祖 一裕, 山本 和秀

    日本消化器病学会雑誌   110 ( 臨増総会 )   A387 - A387   2013.2

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  • RUNX3欠失はmultidrug resistant protein発現を介してgemcitabine感受性に影響を与える

    堀口 繁, 白羽 英則, 内田 大輔, 永原 照也, 片岡 淳朗, 岩室 雅也, 松原 稔, 加藤 博也, 高木 章乃夫, 能祖 一裕, 八木 孝仁, 山本 和秀

    日本消化器病学会雑誌   110 ( 臨増総会 )   A210 - A210   2013.2

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  • 原発性硬化性胆管炎の病態における自然免疫の関与

    松下 浩志, 三宅 康広, 山本 和秀, 池田 房雄, 小池 和子, 白羽 英則, 高木 章乃夫, 能祖 一裕

    日本消化器病学会雑誌   110 ( 臨増総会 )   A339 - A339   2013.2

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  • A case of childhood autoimmune hepatitis of cirrhotic stage manifested by anemia

    Shinichiro Muro, Tetsuya Yasunaka, Yuuki Morimoto, Fusao Ikeda, Hidenori Shiraha, Akinobu Takaki, Kazuhiro Nouso, Kazuhide Yamamoto

    Acta Hepatologica Japonica   54 ( 10 )   698 - 704   2013

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    A 15 years-old boy was pointed out anemia by the medical checkup. Further blood test revealed hepatobiliary enzymes abnormality. Computed tomography showed hepatosplenomegaly. He was diagnosed as autoimmune hepatitis (AIH) based on presence of anti-nuclear antibody and high level of IgG. He was treated with oral prednisolone (PSL: 20 mg/day) administration, and admitted to our hospital for further examination. We performed liver biopsy, and diagnosed as AIH of cirrhotic stage. The improvement of the liver dysfunction was insufficient So he was treated with PSL: 40 mg/day and combined use of azathioprine, however these medications were still ineffective. Then, He was treated with pulsed methylpredonisolone (mPSL) therapy. Liver dysfunction improved after the treatment. This case is the boy who had neither abdominal symptoms nor jaundice and was diagnosed as AIH manifested by anemia Because childhood AIH sometimes diagnosed as advanced stage, accurate diagnosis including liver biopsy and enough immunosuppression therapy is important. © 2013 The Japan Society of Hepatology.

    DOI: 10.2957/kanzo.54.698

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  • 8.NASHに対する水素分子の有用性

    高木章乃夫, 山本和秀

    Hepatology Practice第二巻   2 ( 2 )   376 - 379   2013

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  • Hydrogen as a treatment candidate for non-alcoholic steatohepatitis

    125 ( 3 )   201 - 204   2013

  • Loss of runt-related transcription factor 3 induces gemcitabine resistance in pancreatic cancer

    Shigeru Horiguchi, Hidenori Shiraha, Teruya Nagahara, Jyunnro Kataoka, Masaya Iwamuro, Minoru Matsubara, Shinichi Nishina, Hironari Kato, Akinobu Takaki, Kazuhiro Nouso, Takehiro Tanaka, Koichi Ichimura, Takahito Yagi, Kazuhide Yamamoto

    Molecular Oncology   7 ( 4 )   840 - 849   2013

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    Background &amp
    Aim: Runt-related transcription factor 3 (RUNX3) is a tumor suppressor gene that is expressed in gastric and other cancers including pancreatic cancer. However, the precise function of RUNX3 in pancreatic cancer has not been fully elucidated. In this study, we aimed to determine the effect of decreased RUNX3 expression in pancreatic cancer. Methods: This study included 36 patients with primary pancreatic cancer, who had undergone pancreaticoduodenectomy. All patients were treated with 1000mg/m2 gemcitabine after the surgery. The pancreatic cancer cell lines PANC-1, MIAPaCa-2, BxPC-3, SUIT-2, and KLM-1 were used for immunoblotting analysis of RUNX3 and multidrug resistance protein (MRP) expressions. Ectopic RUNX3 expression was achieved by cDNA transfection of the cells, and small interfering RNA (siRNA) against RUNX3 was used to knock down endogenous RUNX3. Cell growth in the presence of gemcitabine was assessed using the MTT assay. Results: Patients with RUNX3-positive and RUNX3-negative pancreatic cancer had a median survival of 1006 and 643 days, respectively. Exogenous RUNX3 expression reduced the expression of MRP1, MRP2, and MRP5 in endogenous RUNX3-negative cells, whereas RUNX3 siRNA increased the expressions of these genes in endogenous RUNX3-positive cells. Exogenous RUNX3 expression decreased gemcitabine IC50 in RUNX3-negative cells. Conclusion: Loss of RUNX3 expression contributes to gemcitabine resistance by inducing MRP expression, thereby resulting in poor patient survival. © 2013 Federation of European Biochemical Societies.

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  • Risk factors for acute renal injury in living donor liver transplantation: evaluation of the RIFLE criteria. International journal

    Masashi Utsumi, Yuzo Umeda, Hiroshi Sadamori, Takeshi Nagasaka, Akinobu Takaki, Hiroaki Matsuda, Susumu Shinoura, Ryuichi Yoshida, Daisuke Nobuoka, Daisuke Satoh, Tomokazu Fuji, Takahito Yagi, Toshiyoshi Fujiwara

    Transplant international : official journal of the European Society for Organ Transplantation   26 ( 8 )   842 - 52   2013

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    Acute renal injury (ARI) is a serious complication after liver transplantation. This study investigated the usefulness of the RIFLE criteria in living donor liver transplantation (LDLT) and the prognostic impact of ARI after LDLT. We analyzed 200 consecutive adult LDLT patients, categorized as risk (R), injury (I), or failure (F), according to the RIFLE criteria. ARI occurred in 60.5% of patients: R-class, 23.5%; I-class, 21%; and F-class, 16%. Four patients in Group-A (normal renal function and R-class) and 26 patients in Group-B (severe ARI: I- and F-class) required renal replacement therapy (P < 0.001). Mild ARI did not affect postoperative prognosis regarding hospital mortality rate in Group A (3.2%), which was superior to that in Group B (15.8%; P = 0.0015). Fourteen patients in Group B developed chronic kidney disease (KDIGO stage 3/4). The 1-, 5- and 10-year survival rates were 96.7%, 90.6%, and 88.1% for Group A and 71.1%, 65.9%, and 59.3% for Group B, respectively (P < 0.0001). Multivariate analysis revealed risk factors for severe ARI as MELD ≥ 20 [odds ratio (OR) 2.9], small-for-size graft (GW/RBW <0.7%; OR 3.1), blood loss/body weight >55 ml/kg (OR 3.7), overexposure to calcineurin inhibitor (OR 2.5), and preoperative diabetes mellitus (OR 3.2). The RIFLE criteria offer a useful predictive tool after LDLT. Severe ARI, defined beyond class-I, could have negative prognostic impact in the acute and late postoperative phases. Perioperative treatment strategies should be designed and balanced based on the risk factors for the further improvement of transplant prognosis.

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  • A preliminary study for constructing a bioartificial liver device with induced pluripotent stem cell-derived hepatocytes

    Masaya Iwamuro, Hidenori Shiraha, Shuhei Nakaji, Masumi Furutani, Naoya Kobayashi, Akinobu Takaki, Kazuhide Yamamoto

    BIOMEDICAL ENGINEERING ONLINE   11   e93-e93   2012.12

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    Background: Bioartificial liver systems, designed to support patients with liver failure, are composed of bioreactors and functional hepatocytes. Immunological rejection of the embedded hepatocytes by the host immune system is a serious concern that crucially degrades the performance of the device. Induced pluripotent stem (iPS) cells are considered a desirable source for bioartificial liver systems, because patient-derived iPS cells are free from immunological rejection. The purpose of this paper was to test the feasibility of a bioartificial liver system with iPS cell-derived hepatocyte-like cells.
    Methods: Mouse iPS cells were differentiated into hepatocyte-like cells by a multi-step differentiation protocol via embryoid bodies and definitive endoderm. Differentiation of iPS cells was evaluated by morphology, PCR assay, and functional assays. iPS cell-derived hepatocyte-like cells were cultured in a bioreactor module with a pore size of 0.2 mu m for 7 days. The amount of albumin secreted into the circulating medium was analyzed by ELISA. Additionally, after a 7-day culture in a bioreactor module, cells were observed by a scanning electron microscope.
    Results: At the final stage of the differentiation program, iPS cells changed their morphology to a polygonal shape with two nucleoli and enriched cytoplasmic granules. Transmission electron microscope analysis revealed their polygonal shape, glycogen deposition in the cytoplasm, microvilli on their surfaces, and a duct-like arrangement. PCR analysis showed increased expression of albumin mRNA over the course of the differentiation program. Albumin and urea production was also observed. iPS-Heps culture in bioreactor modules showed the accumulation of albumin in the medium for up to 7 days. Scanning electron microscopy revealed the attachment of cell clusters to the hollow fibers of the module. These results indicated that iPS cells were differentiated into hepatocyte-like cells after culture for 7 days in a bioreactor module with a pore size of 0.2 mu m.
    Conclusion: We consider the combination of a bioreactor module with a 0.2-mu m pore membrane and embedded hepatocytes differentiated from iPS cells to be a promising option for bioartificial liver systems. This paper provides the basic concept and preliminary data for an iPS cell-oriented bioartificial liver system. PACS code: 87. Biological and medical physics, 87.85.-d Biomedical engineering, 87.85.Lf Tissue engineering, 87.85.Tu Modeling biomedical systems.

    DOI: 10.1186/1475-925X-11-93

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  • Eradication of Hepatitis C Virus Subgenomic Replicon by Interferon Results in Aberrant Retinol-Related Protein Expression

    Kazuko Koike, Akinobu Takaki, Nobuyuki Kato, Mamoru Ouchida, Hirotaka Kanzaki, Tetsuya Yasunaka, Hidenori Shiraha, Yasuhiro Miyake, Kazuhide Yamamoto

    ACTA MEDICA OKAYAMA   66 ( 6 )   461 - 468   2012.12

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    Hepatitis C virus (HOT) infection induces several changes in hepatocytes, such as oxidative stress, steatosis, and hepatocarcinogenesis. Although considerable progress has been made during recent years, the mechanisms underlying these functions remain unclear. We employed proteomic techniques in HCV replicon-harboring cells to determine the effects of HCV replication on host-cell protein expression. We examined two-dimensional electrophoresis (2-DE) and mass spectrometry to compare and identify differentially expressed proteins between HCV subgenomic replicon-harboring cells and their "cured" cells. One of the identified proteins was confirmed using enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Full-length HCV genome RNA replicating and cured cells were also assessed using ELISA. Replicon-harboring cells showed higher expression of retinal dehydrogenase 1 (RALDH-1), which converts retinol to retinoic acid, and the cured cells showed higher expression of retinol-binding protein (RBP), which transports retinol from the liver to target tissues. The alteration in RBP expression was also confirmed by ELISA and Western blot analysis. We conclude that protein expression profiling demonstrated that HCV replicon eradication affected retinol-related protein expression.

    DOI: 10.18926/AMO/49042

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  • Runt-related transcription factor 3 reverses epithelial-mesenchymal transition in hepatocellular carcinoma

    Shigetomi Tanaka, Hidenori Shiraha, Yutaka Nakanishi, Shin-Ichi Nishina, Minoru Matsubara, Shigeru Horiguchi, Nobuyuki Takaoka, Masaya Iwamuro, Junro Kataoka, Kenji Kuwaki, Hiroaki Hagihara, Junichi Toshimori, Hideki Ohnishi, Akinobu Takaki, Shinichiro Nakamura, Kazuhiro Nouso, Takahito Yagi, Kazuhide Yamamoto

    INTERNATIONAL JOURNAL OF CANCER   131 ( 11 )   2537 - 2546   2012.12

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    Loss or decreased expression of runt-related transcription factor 3 (RUNX3), a tumor suppressor gene involved in gastric and other cancers, has been frequently observed in hepatocellular carcinoma (HCC). The objective of this study was to identify the regulatory mechanism of the epithelialmesenchymal transition (EMT) by RUNX3 in HCC. Human HCC cell lines, Hep3B, Huh7, HLF and SK-Hep1, were divided into low- and high-EMT lines, based on their expression of TWIST1 and SNAI2, and were used in this in vitro study. Ectopic RUNX3 expression had an anti-EMT effect in low-EMT HCC cell lines characterized by increased E-cadherin expression and decreased N-cadherin and vimentin expression. RUNX3 expression has previously been reported to reduce jagged-1 (JAG1) expression; therefore, JAG1 ligand peptide was used to reinduce EMT in RUNX3-expressing low-EMT HCC cells. Immunohistochemical analyses were performed for RUNX3, E-cadherin, N-cadherin and TWIST1 in 33 human HCC tissues, also divided into low- and high-EMT HCC, based on TWIST1 expression. E-cadherin expression was correlated positively and N-cadherin expression was correlated negatively with RUNX3 expression in low-EMT HCC tissues. Correlations between EMT markers and RUNX3 mRNA expression were analyzed using Oncomine datasets. Similarly, mRNA expression of E-cadherin was also significantly correlated with that of RUNX3 in low-EMT HCC, while mRNA expression of JAG1 was negatively correlated with that of RUNX3. These results suggest a novel mechanism by which loss or decreased expression of RUNX3 induces EMT via induction of JAG1 expression in low-EMT HCC.

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  • Clinical utility of serum fucosylated hemopexin in Japanese patients with hepatocellular carcinoma

    Sayo Kobayashi, Kazuhiro Nouso, Hideaki Kinugasa, Yasuto Takeuchi, Takeshi Tomoda, Koji Miyahara, Hiroaki Hagihara, Kenji Kuwaki, Hideki Onishi, Shinichiro Nakamura, Fusao Ikeda, Yasuhiro Miyake, Hidenori Shiraha, Akinobu Takaki, Kazuhide Yamamoto

    HEPATOLOGY RESEARCH   42 ( 12 )   1187 - 1195   2012.12

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    Aim: Hepatocellular carcinoma (HCC) is a common clinical problem all over the world. Fucosylated hemopexin (Fuc-Hpx) is a newly reported glycoprotein for the diagnosis of HCC, however, its clinical implications are unclear. The aim of this study was to elucidate the clinical utility of Fuc-Hpx in Japanese patients with HCC.
    Methods: The sera from 331 HCC patients, 45 with liver cirrhosis (LC), 85 with chronic hepatitis (CH) and 22 healthy people were examined for the expression of Fuc-Hpx; the level was compared with clinical parameters as well as hemopexin (Hpx) expression. The expressions of Fuc-Hpx in 12 HCC tissues and corresponding adjacent non-cancerous liver tissues were also examined.
    Results: No correlation was observed between Hpx and Fuc-Hpx level. The median Fuc-Hpx levels in healthy people and CH, LC and HCC patients were 3.8, 3.7, 6.1 and 7.6 AU/mL, respectively (CH vs LC, P = 0.002; CH vs HCC, P &lt; 0.001; LC vs HCC, P = 0.02). Multivariate analysis revealed that low albumin, low prothrombin time and the presence of HCC were significantly correlated with high Fuc-Hpx (P = 0.013, =0.001 and &lt;0.001, respectively). Among the HCC patients, albumin was correlated with high Fuc-Hpx; however, none of the tumor factors, such as tumor size, tumor number and tumor stage, was correlated with Fuc-Hpx level. The expression of Fuc-Hpx in cancer tissue was not different from that in non-cancerous tissue.
    Conclusion: Fuc-Hpx is a valuable biomarker for HCC but it might be a marker for hypercarcinogenic liver rather than a marker for tumor-bearing liver.

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  • Low peripheral blood treg and high HCV specific interferon gamma production achieved after eradication of HCV after liver transplantation

    Kazuko Koike, Akinobu Takaki, Masashi Utsumi, Tetsuya Yasunaka, Yasuhiro Miyake, Takahiro Yagi, Kazuhide Yamamoto

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   27   275 - 275   2012.12

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  • Diagnostic role of 18F-fluorodeoxyglucose positron emission tomography for follicular lymphoma with gastrointestinal involvement

    Masaya Iwamuro, Hiroyuki Okada, Katsuyoshi Takata, Katsuji Shinagawa, Shigeatsu Fujiki, Junji Shiode, Atsushi Imagawa, Masashi Araki, Toshiaki Morito, Mamoru Nishimura, Motowo Mizuno, Tomoki Inaba, Seiyu Suzuki, Yoshinari Kawai, Tadashi Yoshino, Yoshiro Kawahara, Akinobu Takaki, Kazuhide Yamamoto

    WORLD JOURNAL OF GASTROENTEROLOGY   18 ( 44 )   6427 - 6436   2012.11

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    AIM: To investigate the capacity for 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) to evaluate patients with gastrointestinal lesions of follicular lymphoma.
    METHODS: This retrospective case series consisted of 41 patients with follicular lymphoma and gastrointestinal involvement who underwent 18F-FDG-PET and endoscopic evaluations at ten different institutions between November 1996 and October 2011. Data for endoscopic, radiological, and biological examinations performed were retrospectively reviewed from clinical records. A semi-quantitative analysis of 18F-FDG uptake was performed for each involved area by calculating the maximum standardized uptake value (SUVmax). Based on the positivity of 18F-FDG uptake in the gastrointestinal lesions analyzed, patients were subdivided into two groups. To identify potential predictive factors for 18F-FDG positivity, these two groups were compared with respect to gender, age at diagnosis of lymphoma, histopathological grade, pattern of follicular dendritic cells, mitotic rate, clinical stage, soluble interleukin-2 receptor levels detected by 18F-FDG-PET, lactate dehydrogenase (LDH) levels, hemoglobin levels, bone marrow involvement, detectability of gastrointestinal lesions by computed tomography (CT) scanning, and follicular lymphoma international prognostic index (FLIPI) risk.
    RESULTS: Involvement of follicular lymphoma in the stomach, duodenum, jejunum, ileum, cecum, colon, and rectum was identified in 1, 34, 6, 3, 2, 3, and 6 patients, respectively. No patient had esophageal involvement. In total, 19/41 (46.3%) patients exhibited true-positive 18F-FDG uptake in the lesions present in their gastrointestinal tract. In contrast, false-negative 18F-FDG uptake was detected in 24 patients (58.5%), while false-positive 18F-FDG uptake was detected in 5 patients (12.2%). In the former case, 2/19 patients had both 18F-FDG-positive lesions and 18F-FDG-negative lesions in the gastrointestinal tract. In patients with 18F-FDG avidity, the SUVmax value of the involved gastrointestinal tract ranged from 2.6 to 17.4 (median: 4.7). For the 18F-FDG-negative (n = 22) and -positive (n = 19) groups, there were no differences in the male to female ratios (10/12 vs 4/15, P = 0.186), patient age (63.6 +/- 2.4 years vs 60.1 +/- 2.6 years, P = 0.323), presence of histopathological grade 1 vs 2 (20/2 and 17/2, P = 1.000), follicular dendritic cell pattern (duodenal/nodal: 13/5 vs 10/3, P = 1.000), mitotic rate (low/ partly high, 14/1 vs 10/3, P = 0.311), clinical stage according to the Ann Arbor system (stages I E and II E/other, 15/7 vs 15/4, P = 0.499), clinical stage according to the Lugano system (stages I and II-1/other, 14/8 vs 14/5, P = 0.489), soluble interleukin-2 receptor levels (495 +/- 78 vs 402 +/- 83, P = 0.884), LDH levels (188 +/- 7 vs 183 +/- 8, P = 0.749), hemoglobin levels (13.5 +/- 0.3 vs 12.8 +/- 0.4, P = 0.197), bone marrow involvement (positive/negative, 1/8 vs 1110, P = 1.000), detectability by CT scanning (positive/negative, 1/16 vs 4/13, P = 0.335), and FLIPI risk (low risk/other, 16/6 vs 13/6, P = 0.763), respectively in each case.
    CONCLUSION: These findings indicate that it is not feasible to predict 18F-FDG-avidity. Therefore, 18F-FDG-PET scans represent a complementary modality for the detection of gastrointestinal involvements in follicular lymphoma patients, and surveillance of the entire gastrointestinal tract by endoscopic examinations is required. (C) 2012 Baishideng. All rights reserved.

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  • Hepatitis B e antigen predicts delayed reduction of HBV DNA without viral breakthrough with adefovir dipivoxil and lamivudine: A 5-year study of patients with hepatitis B with lamivudine resistance

    Fusao Ikeda, Nobuyuki Baba, Koichi Takaguchi, Junichi Kubota, Kenji Miyoshi, Shin-ichi Fujioka, Yuki Moritou, Yasuto Takeuchi, Tetsuya Yasunaka, Yasuhiro Miyake, Akinobu Takaki, Yoshiaki Iwasaki, Haruhiko Kobashi, Kazuhide Yamamoto

    JOURNAL OF MEDICAL VIROLOGY   84 ( 10 )   1562 - 1570   2012.10

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    To clarify the factors associated with delayed reduction of HBV DNA during combination treatment with adefovir dipivoxil (ADV) and lamivudine (LAM) for patients with LAM-resistant hepatitis B virus (HBV), factors including patient characteristics, viral mutations, and drug metabolism were investigated during a 5-year observation period. Delayed reduction of HBV DNA was defined as delayed viral response of detectable HBV DNA after 3 years of combination therapy. Of 67 consecutive patients, 47 attained undetectable HBV DNA after 3 years of combination therapy, and the mean therapeutic duration was 5 years (range: 3.08.4 years). The patients with delayed viral response had high levels of HBV DNA and HBe antigen, while those with negative or low levels of HBe antigen were also negative for HBV DNA, even if they had high levels of HBV DNA. In the multivariate analysis with the proportional hazards model, a high baseline level of HBe antigen was negatively associated with viral decline to an undetectable level (P?=?0.013). A higher baseline of HBe antigen corresponded to a lower annual decline in HBV DNA (R?=?-0.38, P?=?0.004). No patients showed ADV-resistant mutations in the HBV reverse transcriptase region. Trough concentrations of LAM and ADV showed no clear associations with viral response. HBe antigen levels at the initiation of therapy, and reductions in these levels during therapy are predictive of the therapeutic response to combination therapy with ADV and LAM for patients with LAM-resistant HBV. J. Med. Virol. 84:15621570, 2012. (c) 2012 Wiley Periodicals, Inc.

    DOI: 10.1002/jmv.23371

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  • Des-gamma-carboxyl prothrombin is associated with tumor angiogenesis in hepatocellular carcinoma

    Minoru Matsubara, Hidenori Shiraha, Jyunro Kataoka, Masaya Iwamuro, Shigeru Horiguchi, Shin-ichi Nishina, Nobuyuki Takaoka, Masayuki Uemura, Akinobu Takaki, Shinichiro Nakamura, Yoshiyuki Kobayashi, Kazuhiro Nouso, Kazuhide Yamamoto

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   27 ( 10 )   1602 - 1608   2012.10

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    Background and Aim: Hepatocellular carcinoma (HCC) is a hypervascular tumor, and angiogenesis plays an important role in its development. Previously, we demonstrated that des-?-carboxyl prothrombin (DCP) promotes both cell proliferation and migration of human umbilical vein endothelial cells (HUVECs) by inducing the autophosphorylation of kinase insert domain receptor (KDR). In the present study, DCP-associated tumor angiogenesis was assessed by comparing hypovascular and common hypervascular HCC. Methods: The solitary HCCs of 827 patients were classified into two groups according to the tumor density at the arterial phase of a dynamic computed tomography scan; the initial clinical data of patients with the hyper- and hypovascular types were compared. The HCC tissues from 95 tumors were analyzed by immunohistochemical staining for DCP and phosphorylated KDR, and intratumoral microvessel density (MVD) was analyzed to evaluate microvessel angiogenesis. Results: The serum DCP levels (320 +/- 3532 mAU/mL) and tumor size (18.4 +/- 9.0 mm) of patients with hypervascular HCC were significantly greater than those with hypovascular HCC (38.7 +/- 80 mAU/mL and 14.6 +/- 5.2 mm, P &lt; 0.001). Immunohistochemical analysis revealed that the expressions of DCP and phospho-KDR were significantly greater in hypervascular HCC (71.4% and 31.0%, respectively) than in hypovascular HCC (7.6% and 5.7%, respectively). Intratumoral MVD was significantly correlated with DCP (r = 0.48, P &lt; 0.0001). Conclusions: des-?-carboxyl prothrombin production is associated with tumor angiogenesis in HCC.

    DOI: 10.1111/j.1440-1746.2012.07173.x

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  • Peritoneovenous shunting for refractory ascites results in worsening of nephrotic syndrome

    Akinobu Takaki, Yohei Maeshima, Takahito Yagi, Akihiro Katayama, Norikazu Hinamoto, Shigeru Akagi, Hitoshi Sugiyama, Takeshi Tomoda, Yoshiaki Iwasaki, Tetsuya Yasunaka, Fusao Ikeda, Yasuhiro Miyake, Haruhiko Kobashi, Atsushi Hirano, Hirofumi Makino, Kazuhide Yamamoto

    HEPATOLOGY RESEARCH   42 ( 10 )   1048 - 1053   2012.10

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    Peritoneovenous shunt (PVS) is accepted as a treatment for refractory ascites due to liver cirrhosis. Infection is a well-known complication of shunting. However, the effects of PVS in terms of complications for renal disease are unclear. We encountered a case involving a 52-year-old man with alcoholic liver cirrhosis and complications of nephrotic syndrome that were worsened by PVS. He received PVS for refractory ascites due to alcoholic liver cirrhosis before coming to our hospital for evaluation for liver transplantation. Nephrotic syndrome was then identified due to cirrhosis-related membranoproliferative glomerulonephritis (MPGN). Prednisolone was administrated at 60 mg/day for MPGN. On day 5, he showed grade IV hepatic encephalopathy (West Haven criteria). Tapering prednisolone and intestinal cleansing with lactulose treatment improved hepatic encephalopathy, but hyperammonemia persisted and the PVS was removed. After shunt removal, urinary protein levels decreased from 46 g/day to 0.30.5 g/day and ammonia levels decreased. PVS may increase the excretion of urinary protein and increase ammonia levels in patients with complications of glomerulonephritis.

    DOI: 10.1111/j.1872-034X.2012.01012.x

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  • Low frequency of Tr1 in peripheral blood correlated with persistent normal ALT in chronic hepatitis C after liver transplantation

    Akinobu Takaki, Kazuko Koike, Masashi Utsumi, Takahito Yagi, Hirsohi Sadamori, Tetsuya Yasunaka, Kazuhide Yamamoto

    HEPATOLOGY   56   527A - 528A   2012.10

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  • Laparoscopic Findings of Reddish Markings Predict Hepatocellular Carcinoma in HBeAg Positive Chronic Hepatitis B Patients

    Tetsuya Yasunaka, Fusao Ikeda, Yasuhiro Miyake, Akinobu Takaki, Shin-ichi Fujioka, Haruhiko Kobashi, Kazuhide Yamamoto

    AMERICAN JOURNAL OF GASTROENTEROLOGY   107   S145 - S145   2012.10

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  • Hydrogen-rich water prevents progression of nonalcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice

    Daisuke Kawai, Akinobu Takaki, Atsuko Nakatsuka, Jun Wada, Naofumi Tamaki, Tetsuya Yasunaka, Kazuko Koike, Ryuichiro Tsuzaki, Kazuyuki Matsumoto, Yasuhiro Miyake, Hidenori Shiraha, Manabu Morita, Hirofumi Makino, Kazuhide Yamamoto

    HEPATOLOGY   56 ( 3 )   912 - 921   2012.9

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    Oxidative stress is a strong contributor to the progression from simple fatty liver to nonalcoholic steatohepatitis (NASH). Molecular hydrogen is an effective antioxidant that reduces cytotoxic reactive oxygen species. In this study, we investigated the effects of hydrogen-rich water and the drug pioglitazone on the progression of NASH in mouse models. A methionine-cholinedeficient (MCD) diet mouse model was prepared. Mice were divided into three experimental groups and fed for 8 weeks as follows: (1) MCD diet + control water (CW group); (2) MCD diet + hydrogen-rich water (HW group); and (3) MCD diet mixed with pioglitazone (PGZ group). Plasma alanine aminotransferase levels, hepatic expression of tumor necrosis factor-a, interleukin-6, fatty acid synthesisrelated genes, oxidative stress biomarker 8-hydroxydeoxyguanosine (8-OHdG), and apoptosis marker terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate nick-end labeling (TUNEL)positive cells in the liver were decreased in the HW and PGZ groups. The HW group showed a smaller decrease in hepatic cholesterol; however, stronger antioxidative effects in serum and lower peroxisome proliferator-activated receptor-a expression in the liver were seen in comparison with the PGZ group. We then investigated the effects of hydrogen in the prevention of hepatocarcinogenesis in STAM mice, known as the NASH-related hepatocarcinogenesis model. Eight-week-old male STAM mice were divided into three experimental groups as follows: (1) control water (CW-STAM); (2) hydrogen-rich water (HW-STAM); and (3) pioglitazone (PGZ-STAM). After 8 weeks, hepatic tumors were evaluated. The number of tumors was significantly lower in the HW-STAM and PGZ-STAM groups than in the CW-STAM group. The maximum tumor size was smaller in the HW-STAM group than in the other groups. Conclusion: Consumption of hydrogen-rich water may be an effective treatment for NASH by reducing hepatic oxidative stress, apoptosis, inflammation, and hepatocarcinogenesis. (HEPATOLOGY 2012;56:912921)

    DOI: 10.1002/hep.25782

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  • Diagnostic usefulness of precise examinations with intraductal ultrasonography, peroral cholangioscopy and laparoscopy of immunoglobulin G4-related sclerosing cholangitis

    Shigeru Horiguchi, Fusao Ikeda, Hidenori Shiraha, Naoki Yamamoto, Ichiro Sakakihara, Yasuhiro Noma, Koichiro Tsutsumi, Hironari Kato, Hiroaki Hagihara, Tetsuya Yasunaka, Shinichiro Nakamura, Haruhiko Kobashi, Hirofumi Kawamoto, Kazuhide Yamamoto

    DIGESTIVE ENDOSCOPY   24 ( 5 )   370 - 373   2012.9

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    Herein, a case of immunoglobulin G4 (IgG4)-related sclerosing cholangitis is reported. IgG4 was diagnosed based on observations from peroral cholangioscopy and laparoscopy, and these methods are proposed for definitive and precise diagnosis of this disease. A 76-year-old male patient with inguinal Paget's disease had intrahepatic bile duct dilatations detected with computed tomography at his periodic check-up. Magnetic resonance cholangiography showed stenosis of the upper common bile duct and poststenotic dilatation of left intrahepatic bile ducts. The portal tract and bilateral intrahepatic bile ducts were surrounded by a low-density area, facing a tumor-like lesion at segment 2. Cytological examinations of the stenotic and dilated lesions revealed no cellular atypia. Histological examination of the tumor showed normal liver tissue with infiltration of lymphocytes, indicating an inflammatory pseudotumor. Peroral cholangioscopy excluded the possibility of biliary cancer and indicated that the stenotic legion was of submucosal, not mucosal, origin. Laparoscopic observations showed discoloration with wide yellowish-white lobular markings and wide depressed lesions at segments 2 and 7. Liver histology showed mild cholangitis with infiltration of IgG4-positive plasma cells around the bile ducts. Serum IgG4 levels were elevated. From these findings, the patient was diagnosed with IgG4-related sclerosing cholangitis. After treatment with prednisolone, blood liver enzymes and IgG4 rapidly normalized, bile duct dilatations improved, and the hepatic pseudotumor disappeared. The cholangitis did not recur. In this case, biliary cancer was ruled out by observation with peroral cholangioscopy, and the spread of cholangitis in the liver periphery was verified with laparoscopy; this information could not be obtained with other modalities.

    DOI: 10.1111/j.1443-1661.2012.01300.x

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  • 非B非C肝癌の予後及び特徴

    竹内 康人, 能祖 一裕, 萩原 宏明, 安中 哲也, 桑木 健志, 大西 秀樹, 池田 房雄, 中村 進一郎, 白羽 英則, 三宅 康広, 高木 章乃夫, 山本 和秀

    肝臓   53 ( Suppl.2 )   A765 - A765   2012.9

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  • 当院における肝細胞癌に対する生体肝移植症例の検討

    高木 章乃夫, 八木 孝仁, 貞森 裕, 安中 哲也, 篠浦 先, 楳田 祐三, 吉田 龍一, 佐藤 太祐, 信岡 大輔, 内海 方嗣, 中村 進一郎, 能祖 一裕, 保田 裕子, 三浦 公, 藤原 俊義, 山本 和秀

    移植   47 ( 4-5 )   340 - 340   2012.9

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  • 移植後B型肝炎に対するHBVワクチンの有用性についての検討

    高木 章乃夫, 八木 孝仁, 安中 哲也, 貞森 裕, 小池 和子, 篠浦 先, 楳田 祐三, 吉田 龍一, 佐藤 太祐, 信岡 大輔, 内海 方嗣, 吉田 一博, 三宅 康広, 保田 裕子, 藤原 俊義, 山本 和秀

    移植   47 ( 4-5 )   341 - 341   2012.9

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  • B型肝炎ウイルスに対して免疫寛容状態にある移植後患者でのHBVワクチンの効果

    高木 章乃夫, 八木 孝仁, 安中 哲也, 貞森 裕, 篠浦 先, 楳田 祐三, 保田 裕子, 山本 和秀

    移植   47 ( 総会臨時 )   264 - 264   2012.9

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  • Streptozotocin投与NASH発癌モデルマウスにおける病態進行と水素水投与の有効性の検討

    河合 大介, 高木 章乃夫, 山本 和秀, 中司 敦子, 和田 淳, 玉木 直文, 安中 哲也, 小池 和子, 津崎 龍一郎, 松本 和幸, 三宅 康広, 白羽 英則, 森田 学, 槇野 博史

    日本消化器病学会雑誌   109 ( 臨増大会 )   A708 - A708   2012.9

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  • 改正臓器移植法後の脳死肝移植の現状と問題点

    楳田 祐三, 八木 孝仁, 貞森 裕, 高木 章乃夫, 篠浦 先, 吉田 龍一, 信岡 大輔, 佐藤 太祐, 内海 方嗣, 保田 裕子, 藤原 俊義

    移植   47 ( 総会臨時 )   254 - 254   2012.9

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  • C型慢性肝炎の肝脂肪化におけるPNPLA3の関与についての検討

    和田 望, 池田 房雄, 竹内 康人, 森藤 由紀, 湧田 暁子, 安中 哲也, 三宅 康広, 馬場 伸介, 狩山 和也, 妹尾 知典, 高木 章乃夫, 永野 拓也, 高口 浩一, 岩崎 良章, 山本 和秀

    肝臓   53 ( Suppl.2 )   A743 - A743   2012.9

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  • C型慢性肝炎に対するペグインターフェロン・リバビリン併用療法におけるテプレノン併用の無作為化比較試験による検討

    岩崎 良章, 荒木 康之, 橋本 訓招, 下江 俊成, 高口 浩一, 石田 清隆, 岡本 良一, 坂口 孝作, 狩山 和也, 小橋 春彦, 難波 真太郎, 池田 房雄, 三宅 康広, 高木 章乃夫, 山本 和秀

    肝臓   53 ( Suppl.2 )   A750 - A750   2012.9

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  • 当院における急性・慢性肝不全に対する脳死肝移植の現状

    安中 哲也, 高木 章乃夫, 保田 裕子, 八木 孝仁, 吉田 龍一, 楳田 祐三, 三宅 康広, 篠浦 先, 貞森 裕, 山本 和秀

    日本門脈圧亢進症学会雑誌   18 ( 3 )   157 - 157   2012.8

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  • 膵癌において、CD44の発現は、RUNX3発現は逆相関する(CD44 expression correlates negatively with runt-related transcription factor 3 in pancreatic ductal adenocarcinoma)

    堀口 繁, 白羽 英則, 内田 大輔, 永原 照也, 岩室 雅也, 片岡 淳朗, 加藤 博也, 高木 章乃夫, 能祖 一裕, 山本 和秀

    日本癌学会総会記事   71回   179 - 180   2012.8

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  • C型肝硬変症例に対するペグインターフェロン・リバビリン併用療法の成績

    安中 哲也, 池田 房雄, 岩崎 良章, 三宅 康広, 高木 章乃夫, 山本 和秀

    日本門脈圧亢進症学会雑誌   18 ( 3 )   150 - 150   2012.8

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  • 臓器移植法案改正後、急性肝不全に対する肝移植適応はどう変わったか? 当院における急性肝不全に対する脳死肝移植の現状

    安中 哲也, 高木 章乃夫, 保田 裕子, 八木 孝仁, 吉田 龍一, 楳田 祐三, 三宅 康広, 篠浦 先, 貞森 裕, 山本 和秀

    肝臓   53 ( 7 )   449 - 450   2012.7

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  • Hepatitis B Vaccine Repeat After Liver Transplantation Succeeds in Type-B Cirrhotics With Marital, High-Hbs-Antibody Donors

    Akinobu Takaki, Takahito Yagi, Hiroshi Sadamori, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Sato, Masashi Utsumi, Tetsuya Yasunaka, Kazuhide Yamamoto

    GASTROENTEROLOGY   142 ( 5 )   S998 - S998   2012.5

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  • Risk factors for recurrence after transarterial chemoembolization for early-stage hepatocellular carcinoma

    Hideaki Kinugasa, Kazuhiro Nouso, Yasuto Takeuchi, Tetsuya Yasunaka, Hideki Onishi, Shin-ichiro Nakamura, Hidenori Shiraha, Kenji Kuwaki, Hiroaki Hagihara, Fusao Ikeda, Yasuhiro Miyake, Akinobu Takaki, Kazuhide Yamamoto

    JOURNAL OF GASTROENTEROLOGY   47 ( 4 )   421 - 426   2012.4

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    Radiofrequency ablation (RFA) is a standard therapy for the treatment of hepatocellular carcinoma (HCC) with 3 or fewer tumors of up to 3 cm (early-stage HCC); when RFA is unsuccessful or unfeasible, transcatheter arterial chemoembolization (TACE) has often been performed. However, little information about the outcome of TACE for early-stage HCC has been reported and it is hard to decide whether to perform additional treatment following TACE in these difficult conditions. The aim of this study was to determine the risk factors for local or intrahepatic distant recurrence after TACE in early-stage HCC.
    Among 1,560 newly diagnosed HCC patients who were admitted to Okayama University Hospital, 43 patients with early-stage HCC who received only TACE in at least one nodule were enrolled in this study. We analyzed the risk factors for local and distant recurrence by the Cox proportional hazard model.
    The local recurrence rates and intrahepatic distant recurrence rates at 3 months, 6 months, and 1 year were 18.6, 33.4, and 61.8%, and 2.8, 2.8, and 10.2%, respectively. Among 12 parameters examined as possible risk factors for recurrence, heterogeneous Lipiodol uptake (risk ratio 3.38; 95% confidence interval 1.14-10.60) and high serum des-gamma-carboxy prothrombin (DCP) (2.58; 1.03-7.14) were significantly correlated with local recurrence, and the presence of multiple tumors (10.64; 1.76-93.75) was significantly correlated with intrahepatic distant recurrence.
    Heterogeneous Lipiodol uptake, high serum DCP, and multiple tumors are risk factors for recurrence in patients with early-stage HCC who have undergone palliative TACE.

    DOI: 10.1007/s00535-011-0492-9

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  • 肝癌臨床 HCV関連肝細胞癌の遺伝子学的成因についての検討

    竹内 康人, 池田 房雄, 森藤 由記, 萩原 宏明, 安中 哲也, 桑木 健志, 三宅 康広, 大西 秀樹, 中村 進一郎, 白羽 英則, 高木 章乃夫, 岩崎 良章, 能祖 一裕, 山本 和秀

    肝臓   53 ( Suppl.1 )   A263 - A263   2012.4

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  • B型肝炎 腹腔鏡検査での赤色紋理は、B型慢性肝炎