Faculty Profiles - TAKAKI Akinobu

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

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

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

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

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

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

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

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

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

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

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

Language：English Publisher：Springer Tokyo

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

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

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

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

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

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

Language：English Publisher：BMJ PUBLISHING GROUP

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

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

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

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

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

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

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

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

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

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.

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

Language：English Publisher：WILEY

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

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)

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

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

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

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

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

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

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

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

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

Language：English Publisher：SPRINGER JAPAN KK

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

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

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

Language：English Publisher：WILEY

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<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.

DOI： 10.1111/jgh.13594

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

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

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

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

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

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

Language：English Publisher：WILEY

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 (> 30 mm, hazard ratio = 1.685, P = 0.043), high des-gamma-carboxyprothrombin (> 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.

DOI： 10.1111/jgh.13586

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

Language：English Publisher：INT SCIENTIFIC LITERATURE, INC

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

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

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

Language：English Publisher：SPRINGER

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

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

Language：English Publisher：WILEY-BLACKWELL

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<0.05). In the mouse models, the degree of mucosal injuries was lower in NC and NE than N (P<0.01). Serum d-ROM levels were lower in NC and NE than N (P<0.01), and OXY levels were higher in NC than N and NE (P<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

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

Language：Japanese Publisher：Japan Society of Hepatology

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.

DOI： 10.2957/kanzo.58.427

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

Language：English Publisher：JAPAN SOC INTERNAL MEDICINE

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

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

Language：Japanese Publisher：Japan Society of Hepatology

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

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

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

Language：English Publisher：JAPAN SOC INTERNAL MEDICINE

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.

DOI： 10.2169/internalmedicine.56.7002

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

Language：Japanese Publisher：(一財)日本消化器病学会

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

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

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

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

Language：English Publisher：SPANDIDOS PUBL LTD

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

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

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

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

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

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

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

Language：English Publisher：NATURE PUBLISHING GROUP

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

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

Language：English Publisher：WILEY

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<0.001), high AFP (>10ng/mL, RR=1.45, 95% CI=1.09-1.94, P<0.001) and high des--carboxyprothrombin (>40 mAU/mL, RR=1.52, 95% CI=1.13-2.02, P<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.

DOI： 10.1111/hepr.12636

【「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

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

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

Language：Japanese Publisher：(一社)日本移植学会

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.

DOI： 10.11386/jst.51.2-3_092

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

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

Language：English Publisher：WILEY-BLACKWELL

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.

DOI： 10.1111/jgh.13259

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

ONCOLOGY REPORTS 35 ( 5 ) 2576 - 2582 2016.5

Language：English Publisher：SPANDIDOS PUBL LTD

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

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

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

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

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

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

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

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

Language：English Publisher：BMJ PUBLISHING GROUP

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<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

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

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

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 >= 35 years, HBV DNA >= 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 >= 35 years with HBV DNA >= 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 > 0.05). Only small numbers of HCCs occurred in other patients. In CHB patients aged >= 35 years with HBV DNA >= 4 log copies/mL and positive HBeAg, ETV treatment is recommended for the suppression of HCC development.

DOI： 10.18926/AMO/53996

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

Language：English Publisher：NATURE PUBLISHING GROUP

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.

DOI： 10.1038/srep21721

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

Language：English Publisher：TAYLOR & FRANCIS LTD

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

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

Language：Japanese Publisher：Japanese Society of Gastroenterology

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.

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

Language：English Publisher：INT MEDICAL PRESS LTD

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.

DOI： 10.3851/IMP2976

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

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

Language：English Publisher：NATURE PUBLISHING GROUP

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

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

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

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

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

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

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

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

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

Language：English Publisher：WILEY-BLACKWELL

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 (>3), large tumor size (>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

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

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

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

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

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

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

Language：English Publishing type：Book review, literature introduction, etc. Publisher：MDPI AG

Hepatitis B often progresses to decompensated liver cirrhosis requiring orthotopic liver transplantation (OLT). Although newer nucleos(t)ide analogues result in >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 >80% without prevention, while >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

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

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

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

Language：English Publisher：LIPPINCOTT WILLIAMS & WILKINS

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

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

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

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

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

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

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

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

Entecavir Reduces Hepatocarcinogenesis in Patients With Chronic Hepatitis B

Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Kazuhide Yamamoto

GASTROENTEROLOGY 148 ( 4 ) S968 - S968 2015.4

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

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

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

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

Language：English Publisher：WILEY-BLACKWELL

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.

DOI： 10.1111/jgh.12711

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

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

Language：English Publishing type：Book review, literature introduction, etc. Publisher：WILEY-BLACKWELL

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

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

Language：English Publisher：SPRINGER

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 < 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 < 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.

DOI： 10.1007/s12072-014-9592-y

Liver cirrhosis; Advances in research and clinics

2015

【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

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

Akinobu Takaki, Kazuhide Yamamoto

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

Language：English Publisher：Baishideng Publishing Group Co

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

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

Language：English Publisher：JAPAN SOC INTERNAL MEDICINE

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)) >= 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 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.

DOI： 10.2169/internalmedicine.54.4889

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

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

Language：English

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

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

Language：English Publisher：WILEY-BLACKWELL

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

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

Language：English Publisher：WILEY-BLACKWELL

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

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

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/AMO/52894

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

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

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 > 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.

DOI： 10.18926/AMO/52898

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

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

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

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

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

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 < 0.01), among men who had sex with men (100%, p < 0.005), and among patients having sex with unspecified partners (44.8%, p < 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.

DOI： 10.18926/AMO/52790

【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

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

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

Language：English Publisher：ELSEVIER SCIENCE BV

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 > 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 < 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

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

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

Language：English Publishing type：Book review, literature introduction, etc. Publisher：MDPI AG

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

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

Language：English Publisher：WILEY-BLACKWELL

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

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

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

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

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

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

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

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

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

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

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

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

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

Language：English Publisher：WILEY-BLACKWELL

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

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

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

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)

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

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

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

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.

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

Language：English Publisher：WILEY-BLACKWELL

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 <= 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

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

Language：Japanese

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
2&lt
/inf&gt
&lt
80 mmHg and AaD0&lt
inf&gt
2&lt
/inf&gt
&gt
15 mmHg, reflecting intrapulmonary shunting. Four patients exhibited Pa0&lt
inf&gt
2&lt
/inf&gt
&lt
70 mmHg and orthodeoxia, defined as a fall in Pa0&lt
inf&gt
2&lt
/inf&gt
&gt
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
inf&gt
2&lt
/inf&gt
&lt
80 mmHg and AaD0&lt
inf&gt
2&lt
/inf&gt
&gt
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

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

Language：English Publisher：Springer-Verlag Tokyo

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

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

Language：English Publisher：Springer-Verlag Tokyo

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

Contradictory immune response in post liver transplantation hepatitis B and C

Akinobu Takaki, Takahito Yagi, Kazuhide Yamamoto

International Journal of Inflammation 2014 2014

Language：English Publishing type：Book review, literature introduction, etc. Publisher：Hindawi Publishing Corporation

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.

DOI： 10.1155/2014/814760

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

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

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

Language：English

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).

DOI： 10.1007/s00535-013-0763-8

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

Language：English Publishing type：Book review, literature introduction, etc.

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.

DOI： 10.3390/ijms141020704

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

Language：English

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.

DOI： 10.1371/journal.pone.0074861

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

Language：English Publisher：NATURE PUBLISHING GROUP

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.

DOI： 10.1038/bjc.2013.554

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

Language：English Publisher：SPRINGER JAPAN KK

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 < 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.

DOI： 10.1007/s00535-012-0732-7

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

Language：English Publisher：MDPI AG

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.

DOI： 10.3390/ijms141020877

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

Language：English

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.

DOI： 10.1111/hepr.12048

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

Language：English Publisher：WILEY-BLACKWELL

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.

DOI： 10.1111/hepr.12055

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

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

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

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

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

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

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

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

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

Language：English Publisher：WILEY-BLACKWELL

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.

DOI： 10.1111/jgh.12167

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

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

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

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

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

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

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

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

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

Language：English

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

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

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

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

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

Language：Japanese

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

Hydrogen as a treatment candidate for non-alcoholic steatohepatitis

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

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

Language：English Publisher：John Wiley and Sons Ltd

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.

DOI： 10.1016/j.molonc.2013.04.004

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

Language：English

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.

DOI： 10.1111/tri.12138

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

Language：English Publisher：BIOMED CENTRAL LTD

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

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

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

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

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

Language：English Publisher：WILEY-BLACKWELL

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.

DOI： 10.1002/ijc.27575

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

Language：English Publisher：WILEY-BLACKWELL

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 < 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 <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.

DOI： 10.1111/j.1872-034X.2012.01044.x

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

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

Language：English Publisher：BAISHIDENG PUBL GRP CO LTD

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.

DOI： 10.3748/wjg.v18.i44.6427

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

Language：English Publisher：WILEY-BLACKWELL

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

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

Language：English Publisher：WILEY-BLACKWELL

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 < 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 < 0.0001). Conclusions: des-?-carboxyl prothrombin production is associated with tumor angiogenesis in HCC.

DOI： 10.1111/j.1440-1746.2012.07173.x

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

Language：English Publisher：WILEY-BLACKWELL

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

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

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

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

Language：English Publisher：WILEY-BLACKWELL

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

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

Language：English Publisher：WILEY-BLACKWELL

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Language：English Publisher：SPRINGER TOKYO

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

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

B型肝炎腹腔鏡検査での赤色紋理は、B型慢性肝炎の肝発癌危険因子である

安中哲也, 池田房雄, 三宅康広, 白羽英則, 高木章乃夫, 藤岡真一, 小橋春彦, 山本和秀

肝臓 53 ( Suppl.1 ) A326 - A326 2012.4

肝癌基礎肝細胞癌において、カルボキシラーゼ活性低下は、SPARC発現を誘導し、細胞接着低下、EMT進行を引き起こす

白羽英則, 堀口繁, 岩室雅也, 片岡淳朗, 永原照也, 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 53 ( Suppl.1 ) A232 - A232 2012.4

C型肝炎臨床 C型慢性肝炎2型高ウイルス量症例に対するペグインターフェロンα+リバビリン併用療法の期間延長による治療効果改善の検討

難波真太郎, 池田房雄, 岩崎良章, 松下浩志, 森藤由記, 竹内康人, 安中哲也, 三宅康広, 高木章乃夫, 高口浩一, 荒木康之, 山本和秀

肝臓 53 ( Suppl.1 ) A357 - A357 2012.4

C型慢性肝炎に対するペグインターフェロンα+リバビリン併用療法における血清フェリチン値の検討

岩崎良章, 藤岡真一, 池田房雄, 橋本訓招, 荒木康之, 岡本良一, 高木敏行, 下江俊成, 宮武宏和, 高畠弘行, 芦田耕三, 狩山和也, 坂口孝作, 三宅康広, 高木章乃夫, 山本和秀, 岡山C型肝炎研究会

肝臓 53 ( Suppl.1 ) A528 - A528 2012.4

Streptozotocin投与NASH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, 松本和幸, 石川久, 津崎龍一郎, 安中哲也, 中司敦子, 小池和子, 三宅康広, 白羽英則, 和田淳

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

RUNX3の欠失はMRP発現を誘導しgemcitabine感受性に影響を与える

堀口繁, 白羽英則, 永原照也, 片岡淳朗, 岩室雅也, 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 109 ( 臨増総会 ) A335 - A335 2012.3

HEPATIC ANGIOSARCOMA WITH CHARACTERISTIC LAPAROSCOPIC FINDINGS

Tetsuya Yasunaka, Fusao Ikeda, Haruhiko Kobashi, Yasuhiro Miyake, Akinobu Takaki, Yoshiaki Iwasaki, Hajime Hada, Kazuhide Yamamoto, Masayuki Nakano

DIGESTIVE ENDOSCOPY 24 ( 2 ) 124 - 124 2012.3

Fulminant hepatitis: Who survives without liver transplantation?

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

HEPATOLOGY RESEARCH 42 ( 1 ) 60 - 67 2012.1

Language：English Publisher：WILEY-BLACKWELL

Aim: In order to rescue more patients with fulminant hepatitis (FH) in a setting of the shortage of liver grafts, it is important not only to determine the suitable timing for liver transplantation (LT) but also to reduce avoidable operations for patients surviving without LT. This study aimed to identify prognostic parameters for survival without LT in FH patients.
Methods: In 96 FH patients who did not receive LT, we examined prognostic parameters at the time of the diagnosis of FH, which were associated with patient's survival.
Results: Fifty-three patients (55%) were female. The median age was 48 years. At the time of the diagnosis of FH, hepatic coma grade was II in 63 patients (66%), III in 22 (23%) and IV in 11 (11%). Forty-six patients (48%) were in a state of systemic inflammatory response syndrome (SIRS). Four parameters of age (< 45 years), SIRS (no), direct bilirubin/total bilirubin ratio (> 0.65), and total bilirubin (< 12.0 mg/dL) were associated with patient's survival. Overall survival rate of eight patients ulfilling all four parameters were 88%. In 17 patients fulfilling any three parameters, 2-week, 4-week and overall survival rates were 82%, 77% and 71%, respectively. On the other hand, overall survival rate of 38 patients fulfilling any one parameter or none was less than 10%.
Conclusions: Patients fulfilling all four parameters will be successfully treated without LT. In patients fulfilling any three parameters, intensive care including artificial liver support in expectation of hepatic regeneration during a few weeks may be possible.

DOI： 10.1111/j.1872-034X.2011.00894.x

脂肪肝,脂肪性肝炎(NAFLD,NASH)

山本和秀, 高木章乃夫

MEDICINAL 2 ( 4 ) 76 - 84 2012

SIRS Score Reflects Clinical Features of Non-Acetaminophen-Related Acute Liver Failure with Hepatic Coma

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

INTERNAL MEDICINE 51 ( 8 ) 823 - 828 2012

Language：English Publisher：JAPAN SOC INTERNAL MEDICINE

Objective In acetaminophen-induced acute liver failure (ALF), the hepatic coma grade worsens and mortality rates increase, as the number of systemic inflammatory response syndrome components fulfilled (SIRS score) increases. This study aimed to investigate the impact of SIRS score on clinical features of non-acetaminophen-related ALF.
Methods Ninety-nine patients with non-acetaminophen-related ALF with hepatic coma who did not undergo liver transplantation were investigated. Each patient was given a SIRS score of 0, 1, 2, 3 or 4 at the time of diagnosis.
Results At the diagnosis of ALF with hepatic coma, with the increase of SIRS score, hepatic coma grade and prothrombin activity were deteriorated. After the diagnosis of ALF with hepatic coma, 25 patients (25%) developed acute respiratory distress syndrome (ARDS), 31 patients (31%) developed disseminated intravascular coagulation (DIC), and 21 patients (22%) developed acute renal failure (ARF). Thirty-eight patients (38%) developed MOF. With the increase of SIRS score, frequencies of the development of ARDS, DIC and MOF increased. ARF was more frequently developed in patients with a SIRS score of 2 or higher. Overall, 36 patients (36%) survived. Overall survival rate was 66% in 29 patients with a score of 0, 43% in 21 patients with a score of 1, 17% in 29 patients with a score of 2 and 15% in 20 patients with a score of 3 or 4.
Conclusion SIRS score will be useful for predicting not only the overall survival but also the development of complications such as ARDS, DIC and MOF in non-acetaminophen-related ALF with hepatic coma.

DOI： 10.2169/internalmedicine.51.6686

Serum Levels of Soluble Adhesion Molecules as Prognostic Factors for Acute Liver Failure

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

DIGESTION 86 ( 2 ) 122 - 128 2012

Language：English Publisher：KARGER

Background/Aims: In patients with septic shock, the degree of liver dysfunction is correlated with serum levels of soluble intercellular adhesion molecule (sICAM)-1. We aimed to assess the usefulness of serum levels of soluble adhesion molecules as prognostic factors for acute liver failure (ALF). Methods: Serum levels of soluble platelet endothelial cell adhesion molecule (sPECAM)-1, sICAM-3, soluble endothelial (sE) selectin, sICAM-1, soluble platelet selectin, and soluble vascular cell adhesion molecule-1 on admission were measured in 37 ALF patients and 34 healthy controls. Results: Twenty-two ALF patients (59%) reached to fatal outcomes. Serum levels of sPECAM-1, sICAM-3, sE-selectin and sICAM-1 were higher in ALF patients than healthy controls. In 37 ALF patients, by the multivariate logistic regression analysis, ratio of direct to total bilirubin (per 0.1 increase; OR 0.11, 95% CI 0.01-0.99), serum sPECAM-1 level (per 100 ng/ml increase; OR 4.37, 95% CI 1.23-15.5) and serum sICAM-1 level (per 100 ng/ml increase; OR 0.49, 95% CI 0.27-0.89) were associated with fatal outcomes. Using receiver operating characteristics curve, each area under the curve of serum sPECAM-1 and sICMA-1 levels as prognostic factors was 0.71 and 0.74, respectively. Conclusion: Serum sPECAM-1 and sICAM-1 levels may be useful for predicting the prognosis of ALF. Copyright (c) 2012 S. Karger AG, Basel

DOI： 10.1159/000339496

Mizoribine, tacrolimus, and corticosteroid combination therapy successfully induces remission in patients with lupus nephritis

Kagawa Hidetoshi, Hiromasa Tsutomu, Hara Takayuki, Takaki Ayako, Yamanaka Ryutaro, Sada Ken-ei, Makino Hirofumi

Clinical and Experimental Nephrology 16 ( 5 ) 760 - 766 2012

核酸アナログ併用下、低用量HBIG・ワクチンによるB型肝炎ウイルスコントロール

高木章乃夫, 八木孝仁, 貞森裕, 松田浩明, 安中哲也, 篠浦先, 楳田祐三, 吉田龍一, 内海方嗣, 小池和子, 池田房雄, 三宅康広, 白羽英則, 保田裕子, 藤原俊義, 山本和秀

移植 46 ( 6 ) 660 - 660 2011.12

移植後肝疾患における末梢血制御性T細胞の頻度の検討

内海方嗣, 小池和子, 高木章乃夫, 八木孝仁, 渡辺信和, Napier Stephanie C, 貞森裕, 松田浩明, 篠浦先, 楳田祐三, 吉田龍一, 佐藤太祐, 三宅康広, 安中哲也, 山本和秀, 藤原俊義

移植 46 ( 6 ) 678 - 678 2011.12

理想的な肝移植チームの在りかた岡山大学病院における肝移植患者に対する全科横断的な取り組みアルコール性肝硬変患者に対する取り組みを中心に

吉田龍一, 八木孝仁, 貞森裕, 松田浩明, 篠浦先, 楳田祐三, 佐藤太佑, 内海方嗣, 高木章乃夫, 山本和秀, 松本洋輔, 河本泰信, 保田裕子, 清水千聖, 藤原俊義

移植 46 ( 6 ) 647 - 648 2011.12

血管新生関連サイトカインによる進行肝細胞癌の治療効果予測

宮原孝治, 能祖一裕, 衣笠秀明, 竹内康人, 友田健, 小林沙代, 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 52 ( Suppl.3 ) A810 - A810 2011.11

肝細胞癌におけるPIVKA-II産生とEpithelial-Mesenchymal Transition

白羽英則, 松原稔, 堀口繁, 岩室雅也, 片岡淳朗, 永原照也, 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 52 ( Suppl.3 ) A839 - A839 2011.11

HCV特異的免疫応答およびIL28B遺伝子近傍SNPからみたC型肝炎による生体肝移植後の臨床経過についての検討

津崎龍一郎, 高木章乃夫, 八木孝仁, 池田房雄, 貞森裕, 松田浩明, 篠浦先, 楳田祐三, 吉田龍一, 内海方嗣, 河合大介, 安中哲也, 小池和子, 藤原俊儀, 山本和秀

肝臓 52 ( Suppl.3 ) A858 - A858 2011.11

C型慢性肝炎に対するインターフェロン(IFN)療法における予後予測因子としてのQuality of life(QOL)スコアの解析

松下浩志, 池田房雄, 岩崎良章, 竹内康人, 森藤由記, 安中哲也, 三宅康広, 高木章乃夫, 山本和秀

肝臓 52 ( Suppl.3 ) A920 - A920 2011.11

C型慢性肝炎に対するインターフェロン単独長期投与における治療反応性と肝発癌の検討

岩崎良章, 高口浩一, 下村宏之, 下江俊成, 藤岡真一, 橋本訓招, 池田房雄, 三宅康広, 高木章乃夫, 山本和秀

肝臓 52 ( Suppl.3 ) A921 - A921 2011.11

SERUM FOLLISTATIN AS A PROGNOSTIC MARKER FOR HEPATOCELLULAR CARCINOMA

Kazuhiro Nouso, Takeshi Tomoda, Sayo Kobayashi, Koji Miyahara, Hiroaki Hagihara, Kenji Kuwaki, Hideki Onishi, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Kazuhide Yamamoto

HEPATOLOGY 54 1375A - 1376A 2011.10

劇症肝炎に対する肝移植の展望

吉田一博, 楳田祐三, 貞森裕, 松田浩明, 篠浦先, 吉田龍一, 高木章乃夫, 三宅康広, 保田裕子, 八木孝仁, 藤原俊義

移植 46 ( 総会臨時 ) 163 - 163 2011.10

THE RELATIONSHIPS OF PNPLA3 RS738409 POLYMORPHISM WITH THE ETIOLOGY OF LIVER DISEASES AND THE INCIDENCE OF HEPATOCELLULAR CARCINOMA

Yasuto Takeuchi, Fusao Ikeda, Yuki Moritou, Tetsuya Yasunaka, Yasuhiro Miyake, Akinobu Takaki, Yoshiaki Iwasaki, Kazuhide Yamamoto

HEPATOLOGY 54 1425A - 1425A 2011.10

改正臓器移植法後の脳死肝移植登録の現状と問題点

保田裕子, 楳田祐三, 清水千聖, 高木章乃夫, 八木孝仁

移植 46 ( 総会臨時 ) 163 - 163 2011.10

先天性胆道閉鎖症に対する葛西手術後に肝細胞癌を発症した30歳台前半女性の一例

太田茂, 高木章乃夫, 内海方嗣, 松田浩明, 大西秀樹, 池田房雄, 三宅康広, 中村進一郎, 白羽英則, 岩崎良章, 能祖一裕, 八木孝仁, 山本和秀

肝臓 52 ( Suppl.2 ) A614 - A614 2011.9

NBI(Narrow Band Imaging)による腹腔鏡診断

安中哲也, 小橋春彦, 池田房雄, 三宅康広, 白羽英則, 高木章乃夫, 山本和秀

Gastroenterological Endoscopy 53 ( Suppl.2 ) 2613 - 2613 2011.9

肝細胞癌におけるepithelial-mesenchymal transition制御(The regulatory mechanism for epithelial-mesenchymal transition in hepatocellular carcinoma)

白羽英則, 仁科慎一, 堀口繁, 片岡淳朗, 岩室雅也, 松原稔, 高岡伸行, 高木章乃夫, 大西秀樹, 中村進一郎, 能祖一裕, 山本和秀

日本癌学会総会記事 70回 256 - 256 2011.9

本学関連病院における急性B型肝炎の実態調査

安中哲也, 池田房雄, 三宅康広, 白羽英則, 高木章乃夫, 小橋春彦, 藤岡真一, 岡本良一, 狩山和也, 高山裕基, 宮武宏和, 守屋昭男, 高口浩一, 辰川匡史, 金吉俊彦, 坂田達朗, 高畠弘行, 守本洋一, 山田剛太郎, 山本和秀

肝臓 52 ( Suppl.2 ) A583 - A583 2011.9

C型肝炎におけるPNPLA3遺伝子の遺伝子多型と病態・インターフェロン治療効果の検討

森藤由記, 池田房雄, 岩崎良章, 高口浩一, 永野拓也, 妹尾知典, 馬場伸介, 竹内康人, 安中哲也, 三宅康広, 高木章乃夫, 小橋春彦, 山本和秀

日本消化器病学会雑誌 108 ( 臨増大会 ) A934 - A934 2011.9

C型慢性肝炎に対するペグインターフェロンα+リバビリン併用療法の期間延長投与による治療効果改善におけるIL28B、ITPA遺伝子多型の影響

池田房雄, 岩崎良章, 森藤由記, 安中哲也, 竹内康人, 三宅康広, 高木章乃夫, 高口浩一, 荒木康之, 山本和秀

日本消化器病学会雑誌 108 ( 臨増大会 ) A933 - A933 2011.9

C型慢性肝炎に対するペグインターフェロンα+リバビリン併用療法におけるIL28B遺伝子多型とウイルス動態の検討

岩崎良章, 池田房雄, 森藤由記, 竹内康人, 高木章乃夫, 三宅康広, 安中哲也, 高口浩一, 荒木康之, 山本和秀

肝臓 52 ( Suppl.2 ) A600 - A600 2011.9

肝硬変に対するインターフェロン治療血小板減少を伴うC型慢性肝炎・肝硬変症例へのインターフェロン治療に関するQOL評価の解析

安中哲也, 池田房雄, 三宅康広, 白羽英則, 高木章乃夫, 山本和秀

日本門脈圧亢進症学会雑誌 17 ( 3 ) 59 - 59 2011.8

生体肝移植後C型肝炎に対するオーダーメイド治療

高木章乃夫, 八木孝仁, 貞森裕, 松田浩明, 篠浦先, 楳田祐三, 佐藤太祐, 吉田龍一, 三宅康広, 山本和秀

日本門脈圧亢進症学会雑誌 17 ( 3 ) 168 - 168 2011.8

Proteomic Analysis Reveals Aberrant Retinol Metabolism in Hepatitis C Virus Subgenomic Replicon-Harboring Cells

Kazuko Koike, Akinobu Takaki, Nobuyuki Kato, Mamoru Ouchida, Tetsuya Yasunaka, Yasuhiro Miyake, Kazuhide Yamamoto

GASTROENTEROLOGY 140 ( 5 ) S972 - S972 2011.5

Hydrogen Rich Water Prevents Progression of NASH and Accompanying Hepatic Tumorigenesis in Mice

Daisuke Kawai, Akinobu Takaki, Tetsuya Yasunaka, Kazuko Koike, Yasuhiro Miyake, Hidenori Shiraha, Kazuhide Yamamoto

GASTROENTEROLOGY 140 ( 5 ) S703 - S703 2011.5

非アルコール性脂肪性肝炎(NASH)モデルマウスの病態進行に対する水素水の効果の検討

河合大介, 高木章乃夫, 松本和幸, 津崎龍一郎, 安中哲也, 中司敦子, 小池和子, 三宅康広, 白羽英則, 和田淳, 山本和秀

肝臓 52 ( Suppl.1 ) A259 - A259 2011.4

肝再生医学研究の新展開正常ヒト肝切除に伴う増殖因子の経時的変動生体肝移植ドナーにおける検討

松本和幸, 三宅康広, 楳田祐三, 松田浩明, 高木章乃夫, 貞森裕, 能祖一裕, 八木孝仁, 藤原俊義, 山本和秀

肝臓 52 ( Suppl.1 ) A118 - A118 2011.4

C型慢性肝炎に対するペグインターフェロンα-2a+リバビリン併用療法の解析

岩崎良章, 狩山和也, 藤岡真一, 荒木康之, 岡本良一, 橋本訓招, 下江俊成, 芦田耕三, 宮武宏和, 下村宏之, 谷口英明, 高畠弘行, 佐藤敦彦, 保崎泰弘, 妹尾知典, 松村周治, 中村進一郎, 川口憲二, 池田房雄, 三宅康広, 高木章乃夫, 小橋春彦, 山本和秀

肝臓 52 ( Suppl.1 ) A306 - A306 2011.4

C型慢性肝炎(1型かつ高ウイルス量)に対するペグインターフェロンα+リバビリン併用療法におけるコア蛋白アミノ酸配列とIL28B遺伝子多型の検討

池田房雄, 岩崎良章, 安中哲也, 三宅康広, 高木章乃夫, 小橋春彦, 山本和秀

肝臓 52 ( Suppl.1 ) A309 - A309 2011.4

LONG-TERM EFFICACY AND IMPACT ON HEPATOCELLULAR CARCINOMA DEVELOPMENT OF NUCLEOSIDE ANALOGUE TREATMENT WITH LAMIVUDINE AND ENTECAVIR FOR CHRONIC HEPATITIS B AND CIRRHOSIS

H. Kobashi, Y. Miyake, F. Ikeda, T. Yasunaka, K. Nishino, A. Moriya, J. -I. Kubota, S. Nakamura, A. Takaki, K. Nouso, G. Yamada, K. Yamamoto

JOURNAL OF HEPATOLOGY 54 S291 - S292 2011.3

劇症肝炎患者の血清中における血管増殖因子レベルと予後

高山裕基, 三宅康広, 能祖一裕, 安中哲也, 池田房雄, 白羽英則, 高木章乃夫, 岩崎良章, 小橋春彦, 山本和秀

肝臓 52 ( 3 ) 220 - 220 2011.3

肝胆膵疾患の免疫病態の新たな展開 C型肝硬変生体部分肝移植後のHCV特異的免疫応答の変化についての検討

高木章乃夫, 岩崎良章, 八木孝仁, 山本和秀

消化器と免疫 47 ( 47 ) 41 - 43 2011.3

Language：Japanese Publisher：日本消化器免疫学会

生体肝移植後C型肝炎患者の有意な死亡リスク要因は高齢ドナーであった。インターフェロン投与が必要な活動性肝炎に至るリスク要因は有意なものはなかった。C型肝炎ウイルス(HCV)抗原特異的な免疫応答は、非移植症例ではウイルス排除群において強力であるが、慢性肝炎症例では病態にかかわらず弱かった。一方、移植後症例においては、ALTに代表される肝炎の程度の低い症例において免疫応答が高い傾向にあり、ウイルス駆除に成功した症例では高値となっていた。(著者抄録)

劇症肝炎患者の血清中における血管増殖因子レベルと予後

高山裕基, 三宅康広, 能祖一裕, 安中哲也, 池田房雄, 白羽英則, 高木章乃夫, 岩崎良章, 小橋春彦, 山本和秀

肝臓 51 ( Suppl.2 ) A581 - A581 2010.9

C型慢性肝炎(1型高ウイルス量)のコア領域アミノ酸置換例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Response-guided therapyの可能性

岩崎良章, 池田房雄, 高木章乃夫, 三宅康広, 安中哲也, 小橋春彦, 山本和秀

肝臓 51 ( Suppl.2 ) A594 - A594 2010.9

肝癌においてカルボキシラーゼ活性は、EMTを制御する(Gamma-glutamyl-carboxylase regulates epithelial-mesenchymal transition in hepatocellular carcinoma)

白羽英則, 仁科慎一, 松原稔, 堀口繁, 片岡淳朗, 岩室雅也, 高岡伸行, 上村雅之, 高木章乃夫, 能祖一裕, 山本和秀

日本癌学会総会記事 69回 120 - 120 2010.8

DES-GAMMA-CARBOXY PROTHROMBIN AND ANGIOGENESIS IN HEPATOCELLULAR CARCINOMA

H. Shiraha, S. Nishina, M. Matsubara, S. Horiguchi, M. Iwamuro, J. Kataoka, N. Takaoka, A. Takaki, K. Nouso, K. Yamamoto

TUMOR BIOLOGY 31 S93 - S93 2010.8

デンバーシャントにより二次性ネフローゼ症候群が悪化したと考えられるアルコール性肝硬変の一例

高木章乃夫, 岩崎良章, 安中哲也, 池田房雄, 三宅康広, 小橋春彦, 山本和秀

日本門脈圧亢進症学会雑誌 16 ( 2 ) 147 - 147 2010.8

高齢者肝疾患の治療適応と予後、何歳まで治療するべきか? 高齢者肝細胞癌の治療成績

能祖一裕, 小林功幸, 中村進一郎, 宮原孝治, 友田健, 小林沙代, 高山裕基, 大西秀樹, 歳森淳一, 萩原宏明, 桑木健志, 安中哲也, 池田房雄, 三宅康広, 白羽英則, 高木章乃夫, 山本和秀

日本高齢消化器病学会誌 13 ( 1 ) 89 - 89 2010.7

C型肝炎ウイルス蛋白による樹状細胞マーカーおよび機能変化の検討

高木章乃夫, 小池和子, 安中哲也, 岩崎良章, 三宅康広, 山本和秀

Minophagen Medical Review 55 ( 2 ) 168 - 172 2010.6

Language：Japanese Publisher：(株)ミノファーゲン製薬

HCV構成タンパクを樹状細胞(DC)と混合培養した場合の細胞表面マーカー発現の変化およびPPD特異的な、アロではなく自己のCD4 T細胞刺激能・サイトカイン産生能の変化を検討した。健常成人8例の末梢血よりCD14陽性細胞を回収した。GM-CSF、IL-4を加えて5日間培養し、未熟樹状細胞を樹立した。また、成熟樹状細胞は未熟樹状細胞にLPS添加して1日培養して作成した。CD86発現、IFNγ産生・IL17産生はHCV-NS4添加により低下したが、成熟刺激により回復した。Th2サイトカイン産生に差異はなく、制御性T細胞頻度も差異を認めなかった。よって、HCV-NS4により樹状細胞のTh1産生能・Th17産生能が低下した。

慢性肝炎・肝硬変・肝細胞癌症例における末梢血酸化ストレス度・抗酸化ストレス度の検討

高木章乃夫, 玉木直文, 小池和子, 安中哲也, 岩崎良章, 池田房雄, 三宅康広, 白羽英則, 小橋春彦, 森田学, 山本和秀

肝臓 51 ( Suppl.1 ) A181 - A181 2010.4

AFP20ng/mL以下の肝細胞癌におけるL3分画測定の意義

能祖一裕, 小林功幸, 中村進一郎, 高山裕基, 小林沙代, 大西秀樹, 歳森淳一, 萩原宏明, 桑木健志, 安中哲也, 池田房雄, 三宅康広, 白羽英則, 高木章乃夫, 岩崎良章, 小橋春彦, 山本和秀

肝臓 51 ( Suppl.1 ) A203 - A203 2010.4

自己免疫性肝疾患研究の進歩 CTLA4遺伝子の+49A/G多型は自己免疫性肝炎および原発性胆汁性肝硬変の疾患感受性に関連する

三宅康広, 安中哲也, 池田房雄, 中村進一郎, 白羽英則, 小林功幸, 高木章乃夫, 岩崎良章, 能祖一裕, 小橋春彦, 山本和秀

肝臓 51 ( Suppl.1 ) A58 - A58 2010.4

高齢者C型慢性肝炎(1型高ウイルス量)に対する低用量ペグインターフェロン+リバビリン併用療法の無作為化比較試験による検討

岩崎良章, 荒木康之, 岡本良一, 石井泰史, 橋本訓招, 高口浩一, 谷口英明, 永野拓也, 寺田亮, 守屋昭男, 池田房雄, 三宅康広, 高木章乃夫, 小橋春彦, 山本和秀

肝臓 51 ( Suppl.1 ) A162 - A162 2010.4

ラミブジン・アデフォビル併用治療抵抗性のB型慢性肝炎症例の検討

池田房雄, 小橋春彦, 馬場伸介, 高口浩一, 三好健司, 安中哲也, 三宅康広, 高木章乃夫, 岩崎良章, 山本和秀

肝臓 51 ( Suppl.1 ) A356 - A356 2010.4

消化器疾患と樹状細胞病態の解明と治療法の開発 C型肝炎ウイルス(HCV)構成遺伝子導入およびHCVタンパク添加による樹状細胞機能の変化

高木章乃夫, 小池和子, 安中哲也, 三宅康広, 白羽英則, 岩崎良章, 山本和秀

消化器と免疫 ( 46 ) 59 - 63 2010.3

Language：Japanese Publisher：日本消化器免疫学会

【目的】HCV構成タンパクを健常者樹状細胞に添加した場合の、細胞表面マーカー・サイトカイン産生能の変化を検討した。【方法】健常成人末梢血よりCD14陽性細胞を回収。樹状細胞を樹立後、HCV構成タンパクを添加。細胞表面マーカーの発現を比較、また自己CD4陽性T細胞と、PPDを加えて抗原特異的リンパ球増殖能、および、Th1・Th2・Th17サイトカイン産生の測定を行った。【結果】CD86発現、IFNγ産生・IL17産生はNS4添加により低下したが、成熟刺激により回復した。【結論】HCV-NS4により樹状細胞のTh1産生能・Th17産生能が低下する。(著者抄録)

男性同性愛者のインターネット・コミュニティを介してGenotype AのB型急性肝炎と大腸アメーバ症を合併感染したと考えられる2症例

小橋春彦, 安中哲也, 池田房雄, 恩地正浩, 三宅康広, 白羽英則, 高木章乃夫, 岩崎良章, 山本和秀

日本消化器病学会雑誌 107 ( 臨増総会 ) A405 - A405 2010.3

異常プロトロンビンの血管新生促進効果の検討

白羽英則, 松原稔, 山本和秀, 藤川達也, 仁科慎一, 堀口繁, 上村雅之, 高木章乃夫, 萩原宏明, 桑木健志, 歳森淳一, 大西秀樹, 中村進一郎, 小林功幸, 能祖一裕

日本消化器病学会雑誌 107 ( 臨増総会 ) A265 - A265 2010.3

輸入感染症としてのE型急性肝炎ネパール人留学生の1例

宮原孝治, 三宅康広, 安中哲也, 池田房雄, 高木章乃夫, 岩崎良章, 小橋春彦, 高橋和明, 姜貞憲, 山本和秀

日本消化器病学会雑誌 107 ( 臨増総会 ) A399 - A399 2010.3

劇症肝炎における各種予後予測モデルの評価

三宅康広, 高木章乃夫, 岩崎良章, 小橋春彦, 安中哲也, 池田房雄, 山本和秀

日本内科学会雑誌 99 ( Suppl. ) 166 - 166 2010.2

劇症肝炎に対する治療戦略劇症肝炎における新たな予後予測モデル

三宅康広, 高木章乃夫, 安中哲也, 池田房雄, 岩崎良章, 小橋はるひこ, 山本和秀

日本腹部救急医学会雑誌 30 ( 2 ) 274 - 274 2010.2

低用量HBIG・核酸アナログ併用によるHBV関連肝移植症例のHBV再発予防療法における血清HBcrAg、肝組織中HBV DNAの検討

安中哲也, 高木章乃夫, 八木孝仁, 岩崎良章, 貞森裕, 松田浩明, 篠浦先, 吉田龍一, 内海方嗣, 小池和子, 河合大介, 池田房雄, 三宅康広, 白羽英則, 小橋春彦, 山本和秀

肝臓 50 ( Suppl.3 ) A733 - A733 2009.10

腹腔鏡でびまん性肝紫斑症の所見を呈した肝血管肉腫の1例

安中哲也, 小橋春彦, 萩原宏明, 桑木健志, 歳森淳一, 大西秀樹, 池田房雄, 三宅康広, 白羽英則, 中村進一郎, 小林功幸, 高木章乃夫, 岩崎良章, 能祖一裕, 山本和秀

肝臓 50 ( Suppl.3 ) A764 - A764 2009.10

LOW-DOSE HEPATITIS B IMMUNOGLOBULIN AND NUCLEOS(T)IDE ANALOGUES THERAPY FOR POST-TRANSPLANTATION HEPATITIS B RESULTS IN LOW INTRAHEPATIC CCCDNA AND SERUM HBCRAG LEVELS

Tetsuya Yasunaka, Akinobu Takaki, Takahito Yagi, Masashi Utsumi, Ryuichi Yoshida, Daisuke Sato, Fusao Ikeda, Yasuhiro Miyake, Susumu Shinoura, Hidenori Shiraha, Hiroaki Matsuda, Hiroshi Sadamori, Yoshiaki Iwasaki, Kazuhiro Nouso, Haruhiko Kobashi, Kazuhide Yamamoto

HEPATOLOGY 50 ( 4 ) 552A - 552A 2009.10

核酸アナログによりB型肝炎ウイルス関連肝細胞癌の予後は改善されている

能祖一裕, 小林功幸, 中村進一郎, 大西秀樹, 歳森淳一, 萩原宏明, 桑木健志, 安中哲也, 池田房雄, 三宅康広, 白羽英則, 高木章乃夫, 岩崎良章, 山本和秀

肝臓 50 ( Suppl.2 ) A560 - A560 2009.9

非ホジキンリンパ腫に対する化学療法後にB型肝炎ウイルス再活性化による急性肝炎〜劇症肝炎を発症した3例発生予防策に関する考察

小橋春彦, 安中哲也, 池田房雄, 三宅康広, 高木章乃夫, 岩崎良章, 山本和秀, 品川克至

日本消化器病学会雑誌 106 ( 臨増大会 ) A878 - A878 2009.9

岡山県における肝炎診療連携ネットワーク構築と連携拠点病院活動の独自の工夫

小橋春彦, 安中哲也, 池田房雄, 高木章乃夫, 岩崎良章, 山本和秀, 糸島達也

肝臓 50 ( Suppl.2 ) A543 - A543 2009.9

肝細胞癌根治後におけるインターフェロン治療の再発予防効果メタ解析

三宅康広, 岩崎良章, 高木章乃夫, 池田房雄, 安中哲也, 能祖一裕, 山本和秀

日本消化器病学会雑誌 106 ( 臨増大会 ) A890 - A890 2009.9

肝細胞癌における異常プロトロンビン血管新生亢進作用(Des-gamma-carboxy prothrombin promotes growth and angiogenesis in hepatocellular carcinoma)

白羽英則, 田中盛富, 仁科慎一, 松原稔, 堀口繁, 藤川達也, 高岡伸行, 上村雅之, 高木章乃夫, 山本和秀

日本癌学会総会記事 68回 312 - 312 2009.8

当院における劇症肝炎肝移植症例の経過

高木章乃夫, 八木孝仁, 岩崎良章, 貞森裕, 松田浩明, 篠浦先, 楳田祐三, 佐藤太祐, 吉田龍一, 安中哲也, 三宅康広, 能祖一裕, 小橋春彦, 山本和秀

肝臓 50 ( 8 ) 495 - 495 2009.8

PBCに伴う門脈圧亢進症をめぐって早期に食道静脈瘤合併した原発性胆汁性肝硬変症例の臨床的特徴、予後についての検討

池田房雄, 小橋春彦, 安中哲也, 窪田淳一, 庄司凡, 三宅康広, 高木章乃夫, 岩崎良章, 岡田裕之, 山本和秀

日本門脈圧亢進症学会雑誌 15 ( 1 ) 57 - 57 2009.8

B型慢性肝炎・肝硬変に対する核酸アナログ療法によるAFPの変化と肝細胞癌スクリーニングにおける診断的意義

小橋春彦, 安中哲也, 池田房雄, 三宅康広, 谷口英明, 白羽英則, 中村進一郎, 高木章乃夫, 小林功幸, 能祖一裕, 岩崎良章, 山本和秀

肝臓 50 ( Suppl.1 ) A193 - A193 2009.4

血管新生因子としての異常プロトロンビン in vivoにおける検討

白羽英則, 藤川達也, 仁科慎一, 松原稔, 田中盛富, 高岡伸行, 中西豊, 上村雅之, 上田直樹, 高木章乃夫, 山本和秀

肝臓 50 ( Suppl.1 ) A303 - A303 2009.4

生体肝移植後C型肝炎症例におけるPD-L2発現の検討

小池和子, 高木章乃夫, 八木孝仁, 岩崎良章, 貞森裕, 松田浩明, 安中哲也, 三宅康広, 池田房雄, 白羽英則, 小橋春彦, 能祖一裕, 山本和秀

肝臓 50 ( Suppl.1 ) A247 - A247 2009.4

1型かつ高ウイルス量の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治療抵抗例の解析

岩崎良章, 荒木康之, 大澤俊哉, 川口光彦, 三好健司, 岡本良一, 谷口英明, 高畠弘行, 池田房雄, 三宅康広, 高木章乃夫, 能祖一裕, 小橋春彦, 坂田達朗, 坂口孝作, 山本和秀

肝臓 50 ( Suppl.1 ) A349 - A349 2009.4

Matrix Metalloproteinase 3阻害による肝線維化抑制

高岡伸行, 上村雅之, 松原稔, 仁科慎一, 藤川達也, 田中盛富, 中西豊, 白羽英則, 高木章乃夫, 山本和秀

日本消化器病学会雑誌 106 ( 臨増総会 ) A368 - A368 2009.3

移植にて救命し得たC型肝炎ウイルスによると考えられる劇症肝炎の一例

神崎洋光, 高木章乃夫, 三宅康宏, 岩崎良章, 小橋春彦, 山本和秀, 水野憲治, 貞森裕, 八木孝仁, 田中紀章

日本消化器病学会雑誌 106 ( 臨増総会 ) A366 - A366 2009.3

生体肝移植後C型肝炎に再発予防は必要か? インターフェロン無治療症例の検討

高木章乃夫, 八木孝仁, 岩崎良章, 貞森裕, 松川啓義, 松田浩明, 篠浦先, 楳田祐三, 水野憲司, 佐藤太祐, 吉田龍一, 庄司凡, 小橋春彦, 田中紀章, 山本和秀

移植 44 ( 1 ) 134 - 134 2009.2

生体肝移植後B型肝炎再発予防としてのB型肝炎ウイルスワクチン効果

高木章乃夫, 八木孝仁, 岩崎良章, 貞森裕, 松川啓義, 松田浩明, 篠浦先, 楳田祐三, 田中紀章, 山本和秀

移植 44 ( 1 ) 134 - 135 2009.2

1型高ウイルス量のC型慢性肝炎に対するPEG-IFN+リバビリン併用療法の検討

岩崎良章, 荒木康之, 高口浩一, 谷口英明, 岡本良一, 藤岡真一, 高木章乃夫, 小橋春彦, 坂口孝作, 山本和秀

日本内科学会雑誌 98 ( Suppl. ) 116 - 116 2009.2

LOW-DOSE HEPATITIS B IMMUNOGLOBULIN WITH LAMIVUDINE FOR POST-TRANSPLANTATION HEPATITIS B VIRUS REACTIVATION AND MONTHLY HEPATITIS B VACCINE APPLICATION IS RELIABLE, COST-EFFECTIVE TREATMENT STRATEGIES

Akinobu Takaki, Takahito Yagi, Yoshiaki Iwasaki, Hirsohi Sadamori, Yuzo Umeda, Susumu Shinoura, Hiroaki Matsuda, Tetsuya Yasunaka, Yasuhiro Miyake, Haruhiko Kobashi, Noriaki Tanaka, Kazuhide Yamamoto

HEPATOLOGY 48 ( 4 ) 586A - 586A 2008.10

RUNX3は肝細胞癌の進展を抑制する(RUNX3 regulates development of hepatocellular carcinoma)

中西豊, 白羽英則, 田中盛富, 仁科慎一, 藤川達也, 松尾則行, 高岡伸行, 上村雅之, 高木章乃夫, 山本和秀

日本癌学会総会記事 67回 185 - 185 2008.9

twist発現が肝細胞癌の転移・移動能を制御する(Twist expression regulates migration and invasion in hepatocellular carcinoma)

白羽英則, 松尾則行, 田中盛富, 藤川達也, 高岡伸行, 中西豊, 仁科慎一, 上村雅之, 高木章乃夫, 山本和秀

日本癌学会総会記事 67回 184 - 184 2008.9

B型肝細胞癌根治治療後の長期予後に対する核酸アナログ療法の影響

小橋春彦, 小林功幸, 安中哲也, 中村進一郎, 高木章乃夫, 岩崎良章, 山本和秀

肝臓 49 ( Suppl.2 ) A532 - A532 2008.9

原因不明の急性肝不全に対し、生体肝移植を行った症例の検討

肝臓 49 ( 8 ) 414 - 415 2008.8

C型肝硬変生体部分肝移植後のHCV特異的免疫応答の変化についての検討

高木章乃夫, 岩崎良章, 八木孝仁, 貞森裕, 松田浩明, 篠浦先, 楳田祐三, 吉田龍一, 佐藤太祐, 水野憲司, 三宅康広, 小池和子, 小橋春彦, 山本和秀

日本臨床免疫学会会誌 31 ( 4 ) 299 - 299 2008.8

抗核抗体陰性自己免疫性肝炎例の臨床的特徴

三宅康広, 安中哲也, 池田房雄, 高木章乃夫, 岩崎良章, 小橋春彦, 山本和秀

日本臨床免疫学会会誌 31 ( 4 ) 338 - 338 2008.8

HBV/HCV感染症とその治療

岩崎良章, 小橋春彦, 高木章乃夫, 山本和秀

日本化学療法学会雜誌 = Japanese journal of chemotherapy 56 82 - 82 2008.5

A prospective and comparative cohort study on efficacy and drug resistance during long-term lamivudine treatment for various stages of chronic hepatitis B and cirrhosis

Tomohiro Nishida, Haruhiko Kobashi, Shin-Ichi Fujioka, Kozo Fujio, Kouichi Takaguchi, Hiroshi Ikeda, Mitsuhiko Kawaguchi, Masaharu Ando, Yasuyuki Araki, Toshihiro Higashi, Bon Shoji, Akinobu Takaki, Yoshiaki Iwasaki, Kohsaku Sakaguchi, Yasushi Shiratori, Kazuhide Yamamoto

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 23 ( 5 ) 794 - 803 2008.5

Language：English Publisher：WILEY-BLACKWELL

Background and Aims: A prospective, non-randomized cohort study on long-term lamivudine treatment, comparing efficacy, drug resistance, and prognosis for various stages of chronic hepatitis B virus ( HBV)- related liver disease was performed to elucidate the significance and indication of lamivudine for individual patients at each stage of disease.
Methods: A total of 158 cases consisting of 87 chronic hepatitis, 28 compensated cirrhosis, and 43 decompensated cirrhosis, with serum HBV-DNA > 5 log(10) copies/mL and with elevated alanine aminotransferase (ALT) over twice the upper normal limit or complications of hepatic insufficiency, were administered 100 mg of lamivudine daily and monitored for HBV markers, biochemistry, and prognosis.
Results: Lamivudine reduced HBV-DNA and ALT equally in all groups. Serum albumin, prothrombin time (%), and platelet count increased in all groups. The increased margin of albumin was the highest in the decompensated cirrhosis and higher in the compensated cirrhosis than the chronic hepatitis groups. Cumulative incidence of virologic breakthrough was 16%, 42%, 49%, and 53% at 12, 24, 36, and 48 months, respectively, and the strongest predictive factor for lamivudine resistance was persistent HBV-DNA at 3 months. Ascites, encephalopathy, and jaundice improved in the majority of patients with decompensated cirrhosis. On the other hand, hepatic failure developed or deteriorated in 10 patients after virologic breakthrough, and nine of them had decompensated cirrhosis.
Conclusions: Lamivudine was effective in reducing HBV-DNA and improving hepatic reserve at all stages and was most beneficial and significant for decompensated cirrhosis. Meanwhile, close monitoring of viral load and immediate rescue treatment for lamivudine resistance is necessary to prevent hepatic failure in decompensated cirrhosis.

DOI： 10.1111/j.1440-1746.2007.05240.x

B型肝炎ウイルスワクチンの今日的課題生体肝移植後B型肝炎再発予防としてのB型肝炎ウイルスワクチンの位置づけ

高木章乃夫, 八木孝仁, 岩崎良章, 貞森裕, 松川啓義, 松田浩明, 篠浦先, 楳田祐三, 庄司凡, 安中哲也, 小橋春彦, 田中紀章, 山本和秀

肝臓 49 ( Suppl.1 ) A76 - A76 2008.4

肝硬変の成因別実態

庄司凡, 小橋春彦, 安中哲也, 萩原, 桑木健志, 歳森淳一, 宮武宏和, 白羽英則, 中村進一郎, 高木章乃夫, 小林功幸, 岩崎良章, 山本和秀

肝臓 49 ( Suppl.1 ) A105 - A105 2008.4

カルボキシラーゼ活性低下による肝癌進展

白羽英則, 高岡伸行, 上田直樹, 藤川達也, 仁科慎一, 中西豊, 田中盛富, 松尾則行, 高木章乃夫, 山本和秀

肝臓 49 ( Suppl.1 ) A241 - A241 2008.4

A randomized trial of standard vs. dose-escalation dosing of ribavirin in combination therapy for chronic hepatitis c patients with genotype 1 and high viral load

Yoshiaki Iwasaki, Yasuyuki Araki, Ryo-ichi Okamoto, Hideaki Taniguchi, Yasuhiro Makino, Tohru Ohnishi, Hiroyuki Shimomura, Minoru Tomita, Kazuhisa Yabushita, Yasushi Ishii, Masaharu Ando, Kumaki Hashimoto, Hiroshi Ikeda, Kouichi Takaguchi, Akinobu Takaki, Haruhiko Kobashi, Kohsaku Sakaguchi, Yasushi Shiratori, Kazuhide Yamamoto

GASTROENTEROLOGY 134 ( 4 ) A788 - A789 2008.4

B型慢性肝炎・肝硬変に対するエンテカビル療法の長期効果と問題点

小橋春彦, 安中哲也, 高畠弘行, 坂田達朗, 田中弘教, 岡本良一, 橋本訓招, 庄司凡, 高木章乃夫, 岩崎良章, 山田剛太郎, 山本和秀

肝臓 49 ( Suppl.1 ) A336 - A336 2008.4

難治性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中止例の解析

岩崎良章, 荒木康之, 高口浩一, 谷口英明, 岡本良一, 川口光彦, 寺田亮, 大澤俊哉, 藤岡真一, 永野拓也, 喜田恵治, 高木章乃夫, 小橋春彦, 坂口孝作, 山本和秀

肝臓 49 ( Suppl.1 ) A312 - A312 2008.4

当科における過去18年間の薬物性肝障害の動向と問題点

小橋春彦, 庄司凡, 安中哲也, 谷口英明, 高木章乃夫, 岩崎良章, 山本和秀

肝臓 49 ( Suppl.1 ) A125 - A125 2008.4

A 27-year-old man who died of acute liver failure probably due to trichloroethylene abuse

Akinobu Takaki, Hideyuki Suzuki, Yoshiaki Iwasaki, Tomoko Takigawa, Keiki Ogino, Hiroaki Matsuda, Takahito Yagi, Motohiko Hanazaki, Hideki Nakatsuka, Hiroshi Katayama, Masaki Matsumi, Bon Shoji, Ryo Terada, Haruhiko Kobashi, Kohsaku Sakaguchi

JOURNAL OF GASTROENTEROLOGY 43 ( 3 ) 239 - 242 2008.3

Language：English Publisher：SPRINGER TOKYO

Acute liver failure from abuse of volatile substances is not usual. We encountered a case involving a 27-year-old man with acute liver and kidney failure followed by severe brain edema, probably caused by abuse of glue containing trichloroethylene. The clinical course was observed from the first day, when serum transaminases were normal, until death on day 12. The trichloroethylene metabolite trichloroacetate was detected in his urine.

DOI： 10.1007/s00535-007-2146-5

Lamivudine treatment improves the prognosis of fulminant hepatitis B

Yasuhiro Miyake, Yoshiaki Iwasaki, Akinobu Takaki, Shin-ichi Fujioka, Kouichi Takaguchi, Hiroshi Ikeda, Haruhiko Kobashi, Kohsaku Sakaguchi, Yasushi Shiratori

INTERNAL MEDICINE 47 ( 14 ) 1293 - 1299 2008

Language：English Publisher：JAPAN SOC INTERNAL MEDICINE

Objective The efficacy of lamivudine for fulminant hepatitis B has been reported in Europe and West Asia. However, in these reports, the main infection genotype is D. Furthermore, if lamivudine improves survival, prognostic factors for fulminant hepatitis B may differ from those reported previously. The aim of this study was to clarify the prognostic factors and the efficacy of lamivudine for fulminant hepatitis B in Japan, where the main infection genotype is B.
Methods This study was a retrospective cohort study. We selected 37 consecutive patients with fulminant hepatitis due to acute hepatitis B virus infection. As 4 of them had received liver transplantation, the data of 33 patients with a median age of 45 (range, 20-74) years were analyzed.
Results Lamivudine was administered to 10 patients. There were no differences in clinical features at the time of the diagnosis of fulminant hepatitis B between patients treated with and without lamivudine. Survival rates of patients treated with and without lamivudine were 70% and 26%, respectively. Age (>= 45 years), systemic inflammatory response syndrome, and non-administration of lamivudine were associated with fatal outcomes. The survival rates of patients treated with and without lamivudine, who were in a state of systemic inflammatory response syndrome, were 50% and 9%, and in patients aged >= 45 years, 50% and 8%, respectively.
Conclusion This study suggests the efficacy of lamivudine for fulminant hepatitis B in the area where the main infection genotype is B. We consider that lamivudine is worth administering to patients with fulminant hepatitis B.

DOI： 10.2169/internalmedicine.47.1061

Gamma-Glutamyl-Carboxylase Regulates Development of Hepatocellular Carcinoma

Hidenori Shiraha, Tatsuya Fujikawa, Naoki Ueda, Nobuyuki Takaoka, Yutaka Nakanishi, Shigetomi Tanaka, Shin-ichi Nishina, Akinobu Takaki, Kazuhide Yamamoto

TUMOR BIOLOGY 29 41 - 41 2008

Hepatitis C virus could be eradicated with strong immune responses after withdrawing interferon treatment post living donor liver transplantation

Akinobu Takaki, Takahito Yagi, Yoshiaki Iwasaki, Hiroshi Sadamori, Kazuko Koike, Masashi Tatsukawa, Haruhiko Kobashi, Kohsaku Sakaguchi

HEPATOLOGY 46 ( 4 ) 533A - 533A 2007.10

30-P2-13 塩酸エピルビシンによる経カテーテル肝動脈内動注化学療法における副作用調査(副作用・有害事象,社会の期待に応える医療薬学を)

駒橋美妃, 松永尚, 高木章乃夫, 坂口孝作, 千堂年昭

日本医療薬学会年会講演要旨集 17 327 - 327 2007.9

Gamma-glutamyl carboxylase活性低下による肝細胞癌転移能の変化

高岡伸行, 白羽英則, 藤川達也, 上田直樹, 中西豊, 松尾則行, 田中盛富, 仁科慎一, 高木章乃夫, 坂口孝作

日本消化器病学会雑誌 104 ( 臨増大会 ) A679 - A679 2007.9

B型劇症肝炎における予後因子の解析

三宅康広, 高木章乃夫, 岩崎良章, 藤岡真一, 高口浩一, 池田弘, 小橋春彦, 坂口孝作

日本消化器病学会雑誌 104 ( 臨増大会 ) A682 - A682 2007.9

C型慢性肝炎に対するDose escalationによるペグインターフェロン+リバビリン併用療法の有用性

岩崎良章, 荒木康之, 岡本良一, 谷口英明, 牧野泰裕, 大西亨, 下村宏之, 冨田稔, 藪下和久, 石井泰史, 池田弘, 高木章乃夫, 小橋春彦, 坂口孝作, 白鳥康史

肝臓 48 ( Suppl.2 ) A421 - A421 2007.9

非アルコール性脂肪性肝炎(NASH)とアルコール性肝炎の腹腔鏡像及び臨床像の比較検討

庄司凡, 小橋春彦, 安中哲也, 寺田亮, 高木章乃夫, 岩崎良章, 坂口孝作

Gastroenterological Endoscopy 49 ( Suppl.2 ) 2380 - 2380 2007.9

腹腔鏡により診断した乳癌肝転移の化学療法に伴うpseudocirrhosisの1例

安中哲也, 小橋春彦, 萩原宏明, 桑木健志, 歳森淳一, 宮武宏和, 庄司凡, 三好健司, 寺田亮, 中村進一郎, 小林功幸, 高木章乃夫, 岩崎良章, 坂口孝作

Gastroenterological Endoscopy 49 ( Suppl.2 ) 2380 - 2380 2007.9

時間依存性共変量を用いた肝細胞癌患者の予後予測モデルの検討

桑木健志, 小林功幸, 中村進一郎, 岩堂昭太, 萩原宏明, 安中哲也, 歳森淳一, 宮武宏和, 寺田亮, 三好健司, 庄司凡, 高木章乃夫, 岩崎良章, 小橋春彦, 坂口孝作

日本消化器病学会雑誌 104 ( 臨増大会 ) A693 - A693 2007.9

RUNX3による肝癌細胞株における細胞移動能の抑制(RUNX3 inhibits cell migration in hepatocellular carcinoma cell line)

田中盛富, 白羽英則, 中西豊, 上田直樹, 高岡伸行, 松尾則行, 仁科慎一, 藤川達也, 上村雅之, 高木章乃夫, 坂口孝作

日本癌学会総会記事 66回 139 - 139 2007.8

特異な経過を辿った劇症B型肝炎の1例

田邊渉, 池田弘, 神野亜希子, 寺島禎彦, 菊池理, 前田有紀, 畑貴子, 山本直樹, 青山育雄, 酒井章裕, 清輔良江, 新井修, 大西秀樹, 金吉俊彦, 下村宏之, 高木章乃夫, 岩崎良章, 坂口孝作

肝臓 48 ( 8 ) 405 - 405 2007.8

生体肝移植術前管理としての感染コントロールの重要性

高木章乃夫, 八木孝仁, 岩崎良章, 貞森裕, 松川啓義, 松田浩明, 篠浦先, 楳田祐三, 成島道樹, 庄司凡, 寺田亮, 小橋春彦, 田中紀章, 坂口孝作

肝臓 48 ( Suppl.1 ) A237 - A237 2007.4

Limitation of combination therapy of peginterferon and ribavirin for older patients with chronic hepatitis C

Yoshiaki Iwasaki, Yasuyuki Araki, Kouichi Takaguchi, Hideaki Taniguchi, Ryoichi Okamoto, Mitsuhiko Kawaguchi, Ryo Terada, Toshiya Osawa, Shin-Ichi Fujioka, Takuya Nagano, Keiji Kita, Kazuhide Yamamoto, Akinobu Takaki, Haruhiko Kobashi, Kohsaku Sakaguchi, Yasushi Shiratori

GASTROENTEROLOGY 132 ( 4 ) A794 - A795 2007.4

1型高ウイルス量の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の解析

岩崎良章, 荒木康之, 高口浩一, 谷口英明, 岡本良一, 川口光彦, 寺田亮, 大澤俊哉, 藤岡真一, 永野拓也, 喜田恵治, 山本和秀, 高木章乃夫, 小橋春彦, 坂口孝作, 白鳥康史

肝臓 48 ( Suppl.1 ) A138 - A138 2007.4

Des-gamma-carboxyl prothrombin-promoted vascular endothelial cell proliferation and migrations

Tatsuya Fujikawa, Hidenori Shiraha, Naoki Ueda, Nobuyuki Takaoka, Yutaka Nakanishi, Noriyuki Matsuo, Shigetomi Tanaka, Shin-ichi Nishina, Mayumi Suzuki, Akinobu Takaki, Kohsaku Sakaguchi, Yasushi Shiratori

JOURNAL OF BIOLOGICAL CHEMISTRY 282 ( 12 ) 8741 - 8748 2007.3

Language：English Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Des-gamma-carboxyl prothrombin (DCP) is a well recognized tumor marker for hepatocellular carcinoma. Previously, we have demonstrated that DCP stimulates cell proliferation in hepatocellular carcinoma cell lines through Met-Janus kinase 1 signal transducer and activator of transcription 3 signaling pathway. In the present study, we demonstrated that DCP induces both cell proliferation and migration in human umbilical vein endothelial cells. DCP was found to bind with the kinase insert domain receptor (KDR), alternatively referred to as vascular endothelial growth factor receptor-2. Furthermore, DCP induced autophosphorylation of KDR and its downstream effector phospholipase C-gamma and mitogen-activated protein kinase (MAPK). To support these results, we showed that DCP-induced cell proliferation and cell migration were inhibited by KDR short interfering RNA, KDR kinase inhibitor, or MAPK inhibitor. In conclusion, these results indicate that DCP is a novel type of vascular endothelial growth factor that possesses potent mitogenic and migrative activities.

DOI： 10.1074/jbc.M609358200

A homosexual Japanese man with acute hepatitis due to hepatitis B virus genotype Ae, concurrent with amebic colitis

Yasuhiro Miyake, Yoshiaki Iwasaki, Shin Ishikawa, Masashi Tatsukawa, Toru Nawa, Jun Kato, Akinobu Takaki, Haruhiko Kobashi, Kohsaku Sakaguchi, Yasushi Shiratori

ACTA MEDICA OKAYAMA 61 ( 1 ) 35 - 39 2007.2

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

We report herein a case with acute hepatitis due to hepatitis B virus genotype Ale, concurrent with amebic colitis. A 39-year-old homosexual Japanese man was admitted to our hospital with jaundice. Laboratory tests showed an elevation of transaminase and positivity for hepatitis B surface antigen and IgM-type antibody to hepatitis B core antigen. The hepatitis B virus genotype was determined to be Ae. Furthermore, a mud-like stool with blood and mucous had sometimes been noted during the past 3 years, and amebic colitis was shown by colonofiberscopy during hospitalization. The patient was diagnosed with acute hepatitis B, concurrent with amebic colitis, and was successfully treated with lamivudine and metronidazole. In Japanese patients with acute hepatitis B virus genotype A infection, homosexual activity tends to be high. Furthermore, in Japanese homosexual men, amebiasis has been increasing. Thus, in Japanese patients with acute hepatitis B, a determination of genotype should be performed in order to investigate the route of transmission of hepatitis B virus, and a search for amebiasis should be performed in patients with acute hepatitis due to hepatitis B virus genotype A. Furthermore, education of homosexual men regarding hepatitis B virus, hepatitis B virus vaccination, and amebiasis is urgently required.

Short-term high-dose followed by long-term low-dose hepatitis B immunoglobulin and lamivudine therapy prevented recurrent hepatitis B after liver transplantation

Akinobu Takaki, Takahito Yagi, Yoshiaki Iwasaki, Hiroshi Sadamori, Hiroyoshi Matsukawa, Hiroaki Matsuda, Susumu Shinoura, Yuuzou Umeda, Yasuhiro Miyake, Ryou Terada, Haruhiko Kobashi, Kohsaku Sakaguchi, Noriaki Tanaka, Yasushi Shiratori

TRANSPLANTATION 83 ( 2 ) 231 - 233 2007.1

Language：English Publisher：LIPPINCOTT WILLIAMS & WILKINS

Hepatitis B immunoglobulin (HBIg) and lamivudine combination has been accepted as the best way to control hepatitis B recurrence after liver transplantation. However, the optimal dose of HBIg and the target titer of hepatitis B surface antibody (HBsAb) remain unclear. We report our satisfactory experience with high-dose HBIg in the early period followed by low-dose HBIg with lamivudine. Subjects comprised five patients with fulminant hepatitis (FH) and 18 patients with liver cirrhosis (LC) who underwent liver transplantation. HBIg at a dosage of 200 IU/kg per day was administered for one week postoperatively. Thereafter, HBIg was administered only for HBsAb titer < 100 IU/L. After six months, HBIg was withdrawn in FH and administered in LC only for HBsAb titer < 10 IU/L. Lamivudine was administered to two FH and all LC cases. Although two patients with LC showed transient hepatitis B surface antigen (HBsAg) recurrence, all patients remained HBsAg-negative at the final follow-up date. This method allows reliable and cost-effective control of hepatitis B recurrence.

DOI： 10.1097/01.tp.0000246310.75638.86

Contrast-enhanced ultrasonography depicts small tumor vessels for the evaluation of pancreatic tumors

Yuko Okamoto, Hirofumi Kawamoto, Akinobu Takaki, Etsuji Ishida, Tsuneyoshi Ogawa, Kenji Kuwaki, Yoshiyuki Kobayashi, Kohsaku Sakaguchi, Yasushi Shiratori

EUROPEAN JOURNAL OF RADIOLOGY 61 ( 1 ) 163 - 169 2007.1

Language：English Publisher：ELSEVIER IRELAND LTD

Objective: The aim of this study is to evaluate the efficacy of contrast-enhanced ultrasonography for the diagnosis of pancreatic tumors.
Materials and methods: Contrast-enhanced ultrasonography with Levovist was performed on 62 consecutive patients (53 with pancreatic cancer, 4 with islet cell tumor, 3 with inflammatory pancreatic tumor, and 2 with metastatic tumor). The vascular and perfusion image phases of the tumors were evaluated and compared with the findings of contrast-enhanced computed tomography.
Results: Contrast-enhanced ultrasonography showed tumor vessels around and/or in the tumor at the vascular image phase in 79% of pancreatic cancer patients (42/53). At the perfusion image phase, 96% of pancreatic cancers (51/53) were classified as hypo-enhancement type. However, tiny spotty or irregular heterogeneous enhanced lesions were found in 84% of hypo-enhanced pancreatic cancer patients (43/51). The presence of small vessels at the vascular image phase was closely correlated with the presence of these intratumor regional enhanced lesions at the perfusion image phase (K coefficient = 0.42). The sensitivity of contrast-enhanced ultrasonography (100%) for pancreatic cancer was superior to that of contrast-enhanced computed tomography (91%), but no significant difference was observed between the two (McNemar test: p = 0.063).
Conclusion: Contrast-enhanced ultrasonography with Levovist successfully visualizes fine vessels and enhancement in pancreatic tumors, and is useful for evaluating pancreatic tumors. (C) 2006 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.ejrad.2006.08.014

腫瘍マーカーの分子機能はどこまで解っているのか異常プロトロンビンの肝細胞癌進展における役割

白羽英則, 藤川達也, 上田直樹, 鈴木真由美, 高岡伸行, 高木章乃夫, 坂口孝作, 白鳥康史

日本臨床検査自動化学会会誌 32 ( 2 ) 164 - 165 2007

Clinical features of Japanese elderly patients with type 1 autoimmune hepatitis

Yasuhiro Miyake, Yoshiaki Iwasaki, Akinobu Takaki, Haruhiko Kobashi, Kohsaku Sakaguchi, Yasushi Shiratori

INTERNAL MEDICINE 46 ( 24 ) 1945 - 1949 2007

Language：English Publisher：JAPAN SOC INTERNAL MEDICINE

Objective In Caucasian type 1 autoimmune hepatitis patients with a main susceptibility of human leukocyte antigen DR3 and DR4, elderly patients have a higher frequency of concurrent autoimmune disease and cirrhosis at presentation. However, in Japanese patients, the disease is dominantly associated with DR4, and their clinical features may be different from those of previous reports. In this study, we assessed the clinical features of Japanese elderly patients with type 1 autoimmune hepatitis.
Methods We investigated 160 consecutive patients with type 1 autoimmune hepatitis, consisting of 34 elderly patients (65 years) and 126 younger patients (< 65 years).
Results There were no differences in form of clinical onset, frequencies of concurrent autoimmune disease, positive proportions of anti-nuclear antibody and/or anti-smooth muscle antibody, and human leukocyte antigen DR status between the two groups. However, the elderly patients had lower serum levels of albumin (p= 0.0049), and higher frequencies of cirrhosis (F4) and pre-cirrhosis (F3) (p= 0.014) compared with the younger patients. In contrast, in elderly patients, the cumulative incidental rate of the normalization of serum alanine aminotransferase levels within 6 months after the introduction of initial treatment was higher in those treated with prednisolone >= 20 mg/day than those treated only with ursodeoxycholic acid (p= 0.001).
Conclusion We speculate that more years may pass between the occurrence of the disease and the presentation in Japanese elderly patients than in younger patients, and we considered that, even in elderly patients, those with advanced fibrosis should be treated with prednisolone in order to prevent progress of the disease into liver failure.

DOI： 10.2169/internalmedicine.46.0420

Combination of 5-FU and IFN alpha enhances IFN signaling pathway and caspase-8 activity, resulting in marked apoptosis in hepatoma cell lines

Kazuko Koike, Akinobu Takaki, Masashi Tatsukawa, Mayumi Suzuki, Hidenori Shiraha, Yoshiaki Iwasaki, Kohsaku Sakaguchi, Yasushi Shiratori

INTERNATIONAL JOURNAL OF ONCOLOGY 29 ( 5 ) 1253 - 1261 2006.11

Language：English Publisher：PROFESSOR D A SPANDIDOS

Interferon (IFN) combined with 5-Fluorouracil (5-FU) treatment has recently been reported to show beneficial effects in patients with advanced hepatocellular carcinoma. IFNa is usually provided for this combination therapy. In this study, we investigated the molecular mechanisms of apoptosis induction in hepatoma cell lines with IFNa and 5-FU combination therapy from the view point of 5-FU's additive effect on interferon-related signaling pathways. Five hepatoma cell lines (Hep3B, Huh7, HLE, PLC/PRF/5, and HepG2) were tested for apoptosis inducibility by IFN alpha in the absence or presence of 5-FU. Hep3B was the most apoptosis sensitive to IFN plus 5-FU treatment. The JAK/STAT pathway transcriptional factor ISRE was activated more synergistically when 5-FU was added to IFN alpha treatments. Caspase-3, -9, and especially caspase-8 activity was higher with IFN a plus 5-FU than IFN or 5-FU alone. Inhibition of caspase-8, -9, c-Jun N-terminal kinase (INK), phosphatidylinositide 3-kinase (PI3K), and p38 mitogen-activated protein kinase (p38 MAPK) revealed that caspase-8 inhibition was the most effective at decreasing the apoptotic effects of IFN and/or 5-FU. In JAK1 and ISGF3y-silenced Hep3B cells, the apoptosis induction and caspase-8 activation levels by IFN, even in combination with 5-FU, were abrogated. In conclusion, caspase-8 is the most important factor that controls IFN and 5-FU-induced apoptosis in hepatoma cell lines.

Endoscopic therapy for bleeding esophageal varices improves the outcome of Child C cirrhotic patients

Shinichiro Hori, Akinobu Takaki, Hiroyuki Okada, Akiko Fujiwara, Ryuta Takenaka, Chiho Makidono, Yasushi Shiratori

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 21 ( 11 ) 1704 - 1709 2006.11

Language：English Publisher：BLACKWELL PUBLISHING

Background and Aims: Bleeding from esophageal varices is one of the frequent severe complications arising in patients with liver cirrhosis. The management of esophageal varices is therefore important for patient survival. The purpose of this study was to clarify the predictive factors for mortality in patients with Child C cirrhosis presenting with variceal bleeding.
Methods: A retrospective analysis of 77 Child C cirrhotic patients with bleeding from esophageal varices was conducted. All patients received endoscopic therapy. Twenty-nine patients received endoscopic variceal ligation, and 48 patients received endoscopic injection sclerotherapy or endoscopic injection sclerotherapy with ligation. Univariate and multivariate analyses of clinical data were performed to identify the prognostic factors for survival for these 77 patients.
Results: Fifty-seven of 77 patients received endoscopic therapy within 24 h after variceal bleeding, and bleeding was controlled in 55 (96.5%). The remaining 20 patients received endoscopic therapy more than 24 h after bleeding. Higher bilirubin level and rebleeding were the predictive parameters for 6-week survival in the 77 patients, according to univariate and multivariate analysis. Higher bilirubin level, refractory ascites, and the presence of hepatocellular carcinoma were the predictive parameters for mortality in 77 patients as determined by multivariate analysis.
Conclusion: Endoscopic therapy was effective in controlling acute variceal bleeding of Child C cirrhotic patients. The prognosis of Child C stage patients presenting with variceal bleeding depended on the severity of liver damage and the presence of hepatocellular carcinoma.

DOI： 10.1111/1440-1746.2006.04267.x

Hepatitis C virus non-structural protein 4 downregulates differentiation and CD4 T cell stimulatory function of dendritic cells

Akinobu Takaki, Yoshiaki Iwasaki, Kazuko Koike, Masashi Tatsukawa, Hidenori Shiraha, Kohsaku Sakaguchi, Eiichi Nakayama, Yasushi Shiratori

HEPATOLOGY 44 ( 4 ) 308A - 309A 2006.10

Gamma-glutamyl carboxylase inhibits cell migration in hepatocellular carcinoma cell lines

Nobuyuki Takaoka, Hidenori Shiraha, Naoki Ueda, Shin-ichi Nishina, Tatsuya Fujikawa, Noriyuki Matsuo, Shigetomi Tanaka, Akinobu Takaki, Kohsaku Sakaguchi, Yasushi Shiratori

HEPATOLOGY 44 ( 4 ) 488A - 489A 2006.10

B型肝炎ウイルス関連肝疾患における生体部分肝移植前後の抗ウイルス療法ラミブジン併用低容量HBIG治療

高木章乃夫, 八木孝仁, 岩崎良章, 貞森裕, 松川啓義, 松田浩明, 篠浦先, 楳田祐二, 坂口孝作, 田中紀章, 白鳥康史

移植 41 ( 5 ) 489 - 489 2006.10

B型慢性肝炎の血清中HBV-DNA全長塩基配列の検討肝線維化の進展とゲノム変異

辰川匡史, 高木章乃夫, 白羽英則, 小池和子, 岩崎良章, 小橋春彦, 坂口孝作, 白鳥康史

肝臓 47 ( Suppl.2 ) A391 - A391 2006.9

Gamma-glutamyl carboxylase活性低下による肝細胞癌悪性化

高岡伸行, 白羽英則, 藤川達也, 上田直樹, 中西豊, 松尾則行, 田中盛富, 仁科慎一, 高木章乃夫, 坂口孝作, 白鳥康史

日本癌学会総会記事 65回 296 - 296 2006.9

腫瘍マーカーの分子機能はどこまで解っているのか異常プロトロンビンの肝細胞癌進展における役割

白羽英則, 藤川達也, 上田直樹, 鈴木真由美, 高岡伸行, 高木章乃夫, 坂口孝作, 白鳥康史

日本臨床検査自動化学会会誌 31 ( 4 ) 352 - 352 2006.9

自己免疫性肝炎患者における肝発癌と危険因子の解析

三宅康広, 岩崎良章, 庄司凡, 寺田亮, 高木章乃夫, 小橋春彦, 坂口孝作, 白鳥康史

日本消化器病学会雑誌 103 ( 臨増大会 ) A956 - A956 2006.9

非アルコール性脂肪性肝炎(NASH)の進行は性別・年齢に依存する

庄司凡, 岩崎良章, 寺田亮, 三宅康広, 高木章乃夫, 小橋春彦, 坂口孝作, 白鳥康史, 岡本良一

日本消化器病学会雑誌 103 ( 臨増大会 ) A934 - A934 2006.9

Early detection and quantification of lamivudine-resistant hepatitis B virus mutants by fluorescent biprobe hybridization assay in lamivudine-treated patients

Fumi Umeoka, Yoshiaki Iwasaki, Masayuki Matsumura, Akinobu Takaki, Haruhiko Kobashi, Masashi Tatsukawa, Hidenori Shiraha, Shin-ichi Fujioka, Kohsaku Sakaguchi, Yasushi Shiratori

JOURNAL OF GASTROENTEROLOGY 41 ( 7 ) 693 - 701 2006.6

Language：English Publisher：SPRINGER JAPAN KK

Background. Long-term lamivudine treatment induces the emergence of lamivudine-resistant hepatitis B virus (HBV). The objective of this study was to develop a fluorescent biprobe hybridization (FBH) assay for the detection and quantification of HBV mutants in the clinical course of lamivudine-treated patients and to evaluate its clinical usefulness. Methods. We developed an FBH assay to detect mutations in the HBV DNA polymerase gene. The assay's detection sensitivity was determined using a dilution series of wild-type/mutant plasmid DNA. Blood samples obtained from 27 lamivudine-treated patients were analyzed. Results. Mutant DNA levels as low as 10% of total HBV DNA were detected (sensitivity = 100%, specificity = 80%). HBV mutants were detected in five of the 27 patients during an average follow-up of 20 months after lamivudine administration. In one of the five patients, the YIDD mutant was detected at the initiation of lamivudine treatment, while the remaining four patients were identified as having YIDD mutants within 3 months after beginning lamivudine administration. Of the five patients with an HBV mutant, four developed breakthrough hepatitis more than 10 months after the detection of HBV mutants, following the reappearance or a re-increase of HBV DNA, characterized by a predominance of the mutant. The YIDD mutant was detected in one patient, even when the titer of the serum HBV DNA was below the detection limit of commercially available quantitative polymerase chain reaction. Conclusions. The FBH assay is an efficient method for detecting and quantifying HBV mutants, as early as 3 months after lamivudine administration.

DOI： 10.1007/s00535-006-1834-x

Addition of 5-FU enhances the IFN alpha induced signaling pathway and caspase-8 activities, resulting in marked apoptosis in hepatoma cell lines

Kazuko Koike, Akinobu Takaki, Masashi Tatsukawa, Hidenori Shiraha, Yoshiaki Iwasaki, Haruhiko Kobashi, Kohsaku Sakaguchi, Yasushi Shiratori

GASTROENTEROLOGY 130 ( 4 ) A832 - A832 2006.4

Short-term high-dose followed by long-term low-dose hepatitis B immune globulin and long-term lamivudine therapy prevented recurrent hepatitis B after living donor liver transplantation

Akinobu Takaki, Takahito Yagi, Yoshiaki Iwasaki, Hiroshi Sadamori, Hiroyoshi Matsukawa, Hiroaki Matsuda, Susumu Shinoura, Yuuzou Umeda, Haruhiko Kobashi, Kohsaku Sakaguchi, Noriaki Tanaka, Yasushi Shiratori

GASTROENTEROLOGY 130 ( 4 ) A790 - A790 2006.4

肝移植臨床の最前線生体部分肝移植後のC型ウイルス肝炎の再燃・再発時におけるHCV特異的免疫応答変化の検討

高木章乃夫, 八木孝仁, 岩崎良章, 小池和子, 辰川匡史, 白羽英則, 貞森裕, 松川啓義, 松田浩明, 篠浦先, 楳田祐三, 田中紀章, 白鳥康史

肝臓 47 ( Suppl.1 ) A53 - A53 2006.4

B型慢性肝炎発癌例と非発癌例の血清中HBV-DNA全長塩基配列の相違

辰川匡史, 高木章乃夫, 小池和子, 白羽英則, 小橋春彦, 岩崎良章, 坂口孝作, 白鳥康史

肝臓 47 ( Suppl.1 ) A150 - A150 2006.4

肝移植臨床の最前線 B型肝炎ウイルス関連肝疾患における生体部分肝移植前後の抗ウイルス療法ラミブジン併用低用量HBIG治療

高木章乃夫, 八木孝仁, 岩崎良章, 貞森裕, 松川啓義, 松田浩明, 篠浦先, 楳田祐三, 小橋春彦, 寺田亮, 三宅康広, 坂口孝作, 田中紀章, 白鳥康史

肝臓 47 ( Suppl.1 ) A52 - A52 2006.4

Response to steroid therapy in patients with sclerosing cholangitis associated with elevated IgG4 level

Ryo Terada, Hirofumi Kawamoto, Yasuhiro Miyake, Kohsaku Sakaguchi, Yoshiaki Iwasaki, Akinobu Takaki, Haruhiko Kobashi, Yoshiaki Kobayashi, Shin-Ichiro Nakamura, Kazuhide Yamamoto, Yasushi Shiratori

GASTROENTEROLOGY 130 ( 4 ) A721 - A721 2006.4

Double mutation in core promoter region of hepatitis B virus genotype C is associated with an increased risk of hepatocellular carcinoma

Masashi Tatsukawa, Akinobu Takaki, Kazuko Koike, Hidenori Shiraha, Haruhiko Kobashi, Yoshiaki Iwasaki, Yasushi Shiratori

GASTROENTEROLOGY 130 ( 4 ) A751 - A751 2006.4

B型慢性肝炎・肝硬変384例に対するラミブジン療法の長期成績特に耐性化予測,アデホビル併用,肝発癌について

小橋春彦, 西田知弘, 白鳥康史, 池田弘, 岡本良一, 荒木康之, 牧野泰裕, 岡本毅, 坂田達朗, 橋本訓招, 安東正晴, 奥新浩晃, 辰川匡史, 高木章乃夫, 岩崎良章, 高畠弘行, 坂口孝作

肝臓 47 ( Suppl.1 ) A232 - A232 2006.4

消化器疾患と自然免疫 C型肝炎ウイルス(HCV)構成遺伝子導入及びHCVタンパク貪食による樹状細胞サイトカイン産生能の変化

高木章乃夫, 岩崎良章, 白鳥康史

日本消化器病学会雑誌 103 ( 臨増総会 ) A59 - A59 2006.3

B型慢性肝炎の背景因子および治療目標による最適治療の選択

小橋春彦, 西田知弘, 白鳥康史, 辰川匡史, 庄司凡, 高木章乃夫, 岩崎良章, 坂口孝作

日本消化器病学会雑誌 103 ( 臨増総会 ) A233 - A233 2006.3

Long-term monitoring of platelet count, as a non-invasive marker of hepatic fibrosis progression and/or regression in patients with chronic hepatitis C after interferon therapy

H Taniguchi, Y Iwasaki, A Fujiwara, K Sakaguchi, A Moriya, PC Yu, A Takaki, SI Fujioka, H Shimornura, Y Shiratori

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 21 ( 1 ) 281 - 287 2006.1

Language：English Publisher：BLACKWELL PUBLISHING

Background: Platelet count has been shown to correlate with the hepatic fibrosis stage in chronic hepatitis C (CHC). The aim of the present study was to assess hepatic fibrosis progression or regression of CHC patients by long-term monitoring of the platelet count.
Methods: A total of 429 interferon (IFN)-treated CHC patients were studied. Follow-up data on the platelet count were collected every 6 months after IFN therapy. The IFN response was defined as follows: complete responders (CR, n = 121) demonstrating persistent clearance of serum hepatitis C virus (HCV) RNA; biochemical responders (BR, n = 94) demonstrating alanine aminotransferase (ALT) normalization for >= 6 months without eradication of HCV-RNA; and non-responder (NR, n = 214) demonstrating all other patterns.
Results: In comparison with the baseline level, mean platelet count increased in the CR group from 0.5 years after IFN therapy (for each point, P < 0.01), but significantly decreased in the NR group from I year after IFN therapy (for each point, P < 0.01). In the BR group, an increase in mean platelet count was observed from 0.5 to 3.5 years following IFN therapy (for each point, P < 0.01), followed by a gradual decrease.
Conclusion: An increase from baseline values in platelet count was observed, regardless of the presence of HCV-RNA, in both the CR and BR groups, suggesting the importance of ALT normalization in preventing hepatic fibrosis progression in IFN-treated CHC patients. (C) 2006 Blackwell Publishing Asia Pty Ltd.

DOI： 10.1111/j.1440-1746.2006.04201.x

目でみる診断学 Wilson病のKayser-Fleischerリング

高木章乃夫, 白鳥康史

成人病と生活習慣病院 36,4,350-351 2006

Des-gamma-carboxy prothrombin is an autologous growth factor for hepatocellular carcinoma

H. Shiraha, M. Suzuki, T. Fujikawa, N. Ueda, N. Takaoka, Y. Nakanishi, A. Takaki, Y. Shiratori

JOURNAL OF HEPATOLOGY 44 S117 - S117 2006

Novel splicing variant of the vitamin K-dependent gamma-glutamyl carboxylase (GGCX) causes des-gamma-carboxyl prothrombin production in human hepatocellular carcinoma cell lines

N. Ueda, H. Shiraha, T. Fujikawa, M. Suzuki, N. Takanka, Y. Nakanishi, A. Takaki, Y. Shiratori

JOURNAL OF HEPATOLOGY 44 S109 - S110 2006

Novel splicing variant of the vitamin K-dependent Fa-glutamyl carboxylase (GGCX) in human des-gamma-carboxyl prothrombin producing hepatocellular carcinoma cell lines

N Ueda, H Shiraha, T Fujikawa, M Suzuki, N Takaoka, A Takaki, S Nakamura, Y Shiratori

HEPATOLOGY 42 ( 4 ) 528A - 528A 2005.10

Virus側と宿主側からみたC型慢性肝炎治療の将来像 C型肝炎ウイルス(HCV)構成遺伝子導入及びHCVタンパク貪食による樹状細胞機能の変化

高木章乃夫, 岩崎良章, 白鳥康史

肝臓 46 ( Suppl.2 ) A370 - A370 2005.9

Virus側と宿主側からみたC型慢性肝炎治療の将来像 C型肝炎ウイルス(HCV)構成遺伝子導入及びHCVタンパク貪食による樹状細胞機能の変化

高木章乃夫, 岩崎良章, 白鳥康史

日本消化器病学会雑誌 102 ( 臨増大会 ) A569 - A569 2005.9

C型肝炎ウイルス(HCV)構成遺伝子導入及びHCVタンパク貪食による樹状細胞(DC)表面マーカー及び機能の変化

高木章乃夫, 辰川匡史, 小池和子, 白羽英則, 岩崎良章, 白鳥康史

肝臓 46 ( Suppl.1 ) A225 - A225 2005.5

肝細胞癌における異常プロトロンビンの増殖制御機構

白羽英則, 鈴木真由美, 藤川達也, 高岡伸行, 上田直樹, 高木章乃夫, 白鳥康史

肝臓 46 ( Suppl.1 ) A141 - A141 2005.5

B型慢性肝炎発癌例と非発癌例の血清中HBV-DNA全長塩基配列の相違

辰川匡史, 高木章乃夫, 白羽英則, 小池和子, 藤岡真一, 岩崎良章, 白鳥康史

肝臓 46 ( Suppl.1 ) A190 - A190 2005.5

Des-gamma-carboxy prothrombin is a potential autologous growth factor for hepatocellular carcinoma

M Suzuki, H Shiraha, T Fujikawa, N Takaoka, N Ueda, Y Nakanishi, K Koike, A Takaki, Y Shiratori

JOURNAL OF BIOLOGICAL CHEMISTRY 280 ( 8 ) 6409 - 6415 2005.2

Language：English Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Des-gamma-carboxyl prothrombin (DCP) is a well recognized tumor marker for hepatocellular carcinoma (HCC). In the present study, we demonstrate that DCP has a mitogenic effect on HCC cell lines. Purified DCP stimulated DNA synthesis of Hep3B and SK-Hep-1 cells in a dose-dependent manner. DCP was found to bind with cell surface receptor Met causing Met autophosphorylation and also to activate STAT3 signaling pathway through Janus kinase 1. Luciferase gene reporter analysis showed that DCP induced STAT3-related transcription. Small interfering RNAs against both STAT3 and Met abrogated DCP-induced cell proliferation. DCP did not affect the mitogen-activated protein kinase pathway, Myc signaling pathway, or phosphoinositide 3-kinase/Akt pathway. Based on these results, we believe that DCP acts as an autologous mitogen for HCC cell lines. The Met-Janus kinase 1-STAT3 signaling pathway may be a major signaling pathway for DCP-induced cell proliferation.

DOI： 10.1074/jbc.M406714200

Consciousness disturbance due to hypermagnesemia in two patients with chronic renal failure

【年齢・性差と肝胆膵疾患】年齢・性差と各種肝疾患 C型肝障害

平岡佐規子, 高木章乃夫, 白鳥康史

肝・胆・膵 51,2,199-204 2005

【ウイルス肝炎と肝移植】施設における現状と対策内科医より岡山大学病院において

高木章乃夫, 八木孝仁, 岩崎良章, 坂口孝作, 白鳥康史

今日の移植 18,2,213-215 2005

肝臓 C型肝炎ウイルス,病態,診断

高木章乃夫, 白鳥康史

Annual Review消化器2005巻 259-262 2005

【利尿薬の正しい使い方基礎と臨床】肝疾患と腹水

高木章乃夫, 白鳥康史

腎と透析 58,2,146-149 2005

Des-gamma-carboxy prothrombin is a potential autologous growth factor for hepatocellular carcinoma.

T Fujikawa, M Suzuki, H Shiraha, N Takaoka, N Ueda, Y Nakanishi, K Koike, A Takaki, Y Shiratori

HEPATOLOGY 40 ( 4 ) 602A - 603A 2004.10

B型慢性肝炎発癌例と非発癌例の血清中HBV DNA全長塩基配列の相違

辰川匡史, 高木章乃夫, 白羽英則, 小池和子, 藤岡真一, 岩崎良章, 白鳥康史

肝臓 45 ( Suppl.2 ) A451 - A451 2004.9

インターフェロンα8はα2よりもcaspaseを強く活性化し,抗癌剤による肝細胞癌株アポトーシスを誘導する

小池和子, 高木章乃夫, 辰川匡史, 白羽英則, 岩崎良章, 坂口孝作, 白鳥康史

肝臓 45 ( Suppl.2 ) A484 - A484 2004.9

肝細胞癌におけるRUNX3の発現とその機能解析

中西豊, 白羽英則, 上田直樹, 藤川達也, 鈴木真由美, 高岡伸行, 高木章乃夫, 白鳥康史

日本消化器病学会雑誌 101 ( 臨増大会 ) A811 - A811 2004.9

糖尿病は非B非C型肝癌の危険因子である

庄司凡, 岩崎良章, 大西秀樹, 朴成郁, 田中弘教, 松本栄二, 中村進一郎, 三宅康広, 小林功幸, 高木章乃夫, 藤岡真一, 坂口孝作, 白鳥康史

肝臓 45 ( Suppl.2 ) A518 - A518 2004.9

5-FU and IFN alpha8 combination treatment induce more severe apoptosis and caspase activities than 5-FU and IFN alpha2 treatment in hepatoma cell lines

K Koike, A Takaki, M Tatsukawa, Y Iwasaki, Y Shiratori

GASTROENTEROLOGY 126 ( 4 ) A598 - A598 2004.4

5-FUによる肝細胞癌株アポトーシス誘導に対するインターフェロン(IFN)α2とα8の増強効果の違いはcaspase活性化と関係する

小池和子, 高木章乃夫, 辰川匡史, 岩崎良章, 坂口孝作, 稲葉二朗, 窪田規一, 白鳥康史

肝臓 45 ( Suppl.1 ) A63 - A63 2004.4

原因不明の劇症肝炎における臨床像についての検討

三宅康広, 高木章乃夫, 岩崎良章, 白鳥康史

日本消化器病学会雑誌 101 ( 臨増総会 ) A158 - A158 2004.3

肝炎の自然史－C型肝炎

高木章乃夫, 小池和子, 辰川匡史, 岩崎良章, 白鳥康史

臨床と研究 81(8) 2004

HCV感染に対する宿主の免疫学的監視機構のメカニズム

高木章乃夫, 小池和子, 白鳥康史

日本臨床ウィルス性肝炎（上）-基礎・臨床研究の進歩- 62,7,143-146 2004

ウイルス肝炎新たな治療法－ウイルス肝炎の自然経過と治療指針－C型慢性肝炎の自然経過と治療方針

高木章乃夫, 小池和子, 岩崎良章, 白鳥康史

内科 93(3)、425-429 2004

C型肝炎治療の実際と展望

白鳥康史, 岩崎良章, 小林功幸, 高木章乃夫, 坂口孝作

日本医事新報 4145,1-16 2004

HBV感染に対する宿主の免疫学的監視機構と感染成立機序

高木章乃夫, 辰川匡史, 小池和子, 白鳥康史

日本臨床 62(8) 2004

B型肝炎ウイルス関連検査法 HBV Subtype決定法－分類とタイピングの実際

高木章乃夫, 辰川匡史, 白鳥康史

日本臨床 62(8)、149-152 2004

C型肝炎ウイルス（HCV)の分子免疫学 HCV感染時の免疫応答の程度とMHCClassIIの多型性との関連

小池和子, 高木章乃夫, 白鳥康史

日本臨床 62(7) 2004

Ⅱ.B型肝炎ウィルス(HBV)B型ウィルス肝炎の分子免疫学 HBV感染と免疫機序 HBV感染に対する宿主の免疫学的監視機構と感染成立機序

高木章乃夫, 辰川匡史, 小池和子, 白鳥康史

日本臨床ウィルス性肝炎（下）-基礎・臨床研究の進歩- 62,8,62-65 2004

Ⅱ.B型肝炎ウィルス(HBV)関連検査法 HBV subtype決定法 -分類とtypingの実際-

高木章乃夫, 辰川匡史, 白鳥康史

日本臨床ウィルス性肝炎（下）-基礎・臨床研究の進歩- 62,8,149-152 2004

【プライマリケア医のための肝臓疾患診療マニュアル】わが国におけるウィルス性慢性肝炎診療の現状と展望

三宅康広, 高木章乃夫, 白鳥康史

治療 86,9,2435-2440 2004

【病気と薬の説明ガイド2004】消化器疾患肝炎

高木章乃夫, 小池和子, 白鳥康史

薬局 55,999-1005 2004

【急性肝不全の概念と分類の見直し】「劇症肝炎に対する肝移植適応ガイドライン」の問題点について

三宅康広, 三好健司, 岡本良一, 森井和彦, 藤尾耕三, 大本昌樹, 池田弘, 小橋春彦, 牧野泰裕, 坂井宣之, 高口浩一, 荒木康之, 安東正晴, 喜田恵治, 高木章乃夫, 岩崎良章, 坂口孝作, 白鳥康史

消化器科 2004

【ウィルス肝炎新たな治療法】ウィルス肝炎の自然経過と治療指針 C型慢性肝炎の自然経過と治療方針

高木章乃夫, 小池和子, 岩崎良章, 白鳥康史

内科 93,3,425-429 2004

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

Journal of Japanese Society for Dialysis Therapy 37 ( 2 ) 163 - 168 2004

Language：Japanese Publisher：The Japanese Society for Dialysis Therapy

Consciousness disturbances in untreated end stage renal failure are referred to as uremic encephalopathy, which is now rare in Japan as dialysis therapy is readily available. We describe two chronic renal failure (CRF) patients who developed consciousness disturbances attributable to hypermagnesemia. Case 1. A 77-year-old man with CRF due to diabetic nephropathy was transferred to our hospital because of appetite loss and drowsiness. Serum creatinine and blood urea nitrogen (BUN) levels were 4.31 and 64mg/dL, respectively. The serum magnesium (Mg) level was found to be as high as 7.3mg/dL. The calcium level was 5.8mg/dL. He had cutaneous flushing and respiratory insufficiency caused by respiratory depression in addition to pneumonia. The serum Mg level decreased after hemodialysis with improvement of consciousness disturbances. However, the serum Mg level rose again on the next day, and an additional hemodialysis session was needed. Case 2. A 78-year-old woman with rheumatoid arthritis developed urinary tract infection which induced acute deterioration of CRF. She demonstrated general fatigue and disorientation. The serum Mg, creatinine and BUN levels were 7.1, 6.56 and 96mg/dL, respectively. Her consciousness level was normalized as the Mg levels decreased after three successive days of hemodialysis. Both of these patients demonstrated rather mild azotemia and developed consciousness disturbances during the use of magnesium oxide. Of our 78 patients starting hemodialysis in the past two years, only these two patients demonstrated toxic serum Mg levels. We suggest that the use of Mg can cause symptomatic hypermagnesemia in patients with acute deterioration of CRF, and that hypocalcemia may worsen the manifestations of hypermagnesemia. Conclusions: As Mg toxicity is a serious and potentially fatal condition, early and accurate diagnosis must be made especially in CRF patients with consciousness disturbances. Hemodialysis is effective for the treatment, but postdialysis rebound of the serum Mg level must be carefully observed.

DOI： 10.4009/jsdt.37.163

Ⅰ.C型肝炎ウィルス(HCV) C型ウィルス肝炎の分子免疫学体液性免疫 HCV感染時の免疫応答の程度とMHC classⅡの多型性との関連

小池和子, 高木章乃夫, 白鳥康史

日本臨床ウィルス性肝炎（上）-基礎・臨床研究の進歩- 62,7,147-150 2004

肝炎の自然史-C型肝炎

高木章乃夫, 小池和子, 辰川匡史, 岩崎良章, 白鳥康史

臨床と研究 81,8,1233-1236 2004

病気と薬の説明ガイド2004－消化器疾患肝炎

高木章乃夫, 小池和子, 白鳥康史

薬局 55:999-1005 2004

急性肝不全の概念と分類の見直し－劇症肝炎に対する肝移植適応ガイドラインの問題点について

三宅康弘, 三好健司, 岡本良一, 森井和彦, 藤尾耕三, 大本昌樹, 池田弘, 小橋春彦, 牧野泰裕, 坂井宣之, 高口浩一, 荒木康之, 安東正晴, 喜田恵治, 高木章乃夫, 岩崎良章, 坂口孝作, 白鳥康史

消化器科 38(1) 2004

消化器疾患と免疫－基礎－肝臓の免疫装置と免疫担当細胞

高木章乃夫, 小池和子, 白鳥康史

消化器科 35(11) 2004

肝炎の臨床よりの問題臨床的諸問題の展開と今後の展望

高木章乃夫, 岩崎良章, 白鳥康史

肝疾患Review 2004 25-38 2004

肝炎の臨床よりの問題－臨床的諸問題の展開と今後の展望

高木章乃夫, 岩崎良章, 白鳥康史

肝疾患Review 25-38 2004

Effects of pulsing procedure of interleukin-12 in combination with interleukin-2 on the activation of peripheral blood lymphocytes derived from patients with hepatocellular carcinoma

T Sawayama, K Sakaguchi, T Senoh, T Ohta, M Nishimura, A Takaki, T Tsuji, Y Shiratori

ACTA MEDICA OKAYAMA 57 ( 6 ) 285 - 292 2003.12

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

In patients with hepatocellular carcinoma (HCC), natural killer (NK) cell activity decreases significantly, and the reduced activity may be associated with the progression of HCC. In this study we evaluated the effects of pulsing with interleukin (IL)-2 and/or IL-12 on the activation of freshly isolated peripheral blood lymphocytes (PBL) derived from patients with HCC. PBL obtained from 9 HCC patients, 4 liver cirrhosis patients, and 9 normal subjects were cultured in the presence of IL-2 and/or IL-12. After 24h of incubation, the levels of interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha presented in the supernatants were determined by enzyme-linked immunosorbent assay (ELISA). The IFN-gamma and TNF-alpha production of PBL pulsed by a combination of IL-2 and IL-12 was significantly higher than those of PBL stimulated by either IL-2 or IL-12 alone. The mRNA encoding perforin, granzyme B, as well as IFN-gamma and TNF-alpha, were markedly enhanced in PBL stimulated with a combination of IL-12 and IL-2. The pulsing procedure of IL-12 in combination with IL-2 resulted in the increase of IFN-gamma and TNF-alpha, and the expression of perforin and granzyme B mRNA in PBL obtained from HCC patients, as well as in those obtained from normal subjects. These results indicate that adoptive immunotherapy based on PBL pulsed with a combination of IL-2 and IL-12 may be a promising adjunctive strategy for HCC treatment.

DOI： 10.18926/AMO/32813

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

紫外線照射にて蛍光赤血球を認めた骨髄性プロトポルフィリンの1例

庄司凡, 藤岡真一, 守屋昭男, 寺田亮, 朴成郁, 高木章乃夫, 岩崎良章, 白鳥康史

岡山済生会総合病院雑誌 35 104 - 105 2003.12

インターフェロンαサブタイプによる肝癌細胞株アポトーシス誘導効果の相違

高木章乃夫, 小池和子, 白羽英則, 岩崎良章, 坂口孝作, 稲葉二朗, 窪田規一, 白鳥康史

日本免疫学会総会・学術集会記録 33 331 - 331 2003.11

Interferon alpha 8 and 2 show differential activation of apoptosis pathway and growth factor pathway in human hepatoma cell lines.

A Takaki, K Koike, H Shiraha, Y Iwasaki, K Sakaguchi, N Inaba, K Kubota, Y Shiratori

HEPATOLOGY 38 ( 4 ) 406A - 406A 2003.10

C型肝炎ウイルス構成遺伝子導入による樹状細胞HLA及びCostimulatory molecule発現の変化についての検討

高木章乃夫, 小池和子, 白羽英則, 岩崎良章, 中山睿一, 白鳥康史

肝臓 44 ( Suppl.2 ) A433 - A433 2003.9

Des-gamma-carboxy prothrombin is an autocrine mitogen for hepatocellular carcinoma

M Suzuki, H Shiraha, T Fujikawa, N Takaoka, A Takaki, Y Nakanishi, N Ueda, K Koike, K Sakaguchi, Y Shiratori

GASTROENTEROLOGY 124 ( 4 ) A285 - A285 2003.4

インターフェロンαサブタイプによる肝癌細胞アポトーシス誘導能の相違と,細胞内情報伝達系及びアポトーシス関連遺伝子の変化の関連

高木章乃夫, 小池和子, 白羽英則, 岩崎良章, 坂口孝作, 白鳥康史

肝臓 44 ( Suppl.1 ) A168 - A168 2003.4

インターフェロンαサブタイプによる肝癌細胞アポトーシス誘導能の相違インターフェロンα2とα8で異なる細胞内情報伝達系とアポトーシス関連遺伝子の連係

高木章乃夫, 小池和子, 白羽英則, 岩崎良章, 白鳥康史

日本消化器病学会雑誌 100 ( 臨増総会 ) A150 - A150 2003.3

C型肝炎治療の実際と展望

白鳥康史, 医歯学総合研究科, 消化器肝臓感染症内科学, 岩崎良章, 小林功幸, 高木章乃夫, 坂口孝作

日本医事新報 1-10 2003

【消化器疾患と免疫】基礎肝臓の免疫装置と免疫担当細胞

高木章乃夫, 医歯学総合研究科, 消化器肝臓感染症内科, 小池和子, 白鳥康史

現代医療 35,11,2504-2508 2003

【内科キーワード2003】肝・胆・膵インターフェロン治療と肝線維化緩解

坂口孝作, 消化器肝臓感染症内科, 高木章乃夫, 河本博文, 白鳥康史

内科 91,6,1074 2003

約25年の経過で肝硬変に進展した体質性黄疸の一例

藤田英行, 医学部, 学科, 藤岡真一, 寺田亮, 馬場伸介, 中西豊, 朴成郁, 高木章乃夫, 岩崎良章, 山本和秀, 白鳥康史

日本消化器内視鏡学会雑誌 2003

【ウイルス肝炎診療update】 HCVの構造と研究の進歩 HCVと免疫

高木章乃夫, 消化器肝臓感染症内科学, 小池和子, 白鳥康史

臨床医 29,5,633-635 2003

TAKAKI Akinobu, NAKATSUKA Atsuko, SATOU Chikage, IWATA Yasuyoshi, IKEDA Hiroshi, FUKUSHIMA Masaki

Jpn J Nephrol 44 ( 8 ) 806 - 812 2002

Language：Japanese Publisher：Japanese Society of Nephrology

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

糖尿病性腎症に合併したANCA関連急速進行性糸球体腎炎の1例

中司敦子, 佐藤千景, 岩田康義, 高木章乃夫, 福島正樹, 津嘉山朝達, 西崎哲一

腎と透析 2002

【肝炎 EBMに基づく最新の知見と最新の治療】ウイルス肝炎における肝線維化とその臨床的意義

高木章乃夫, 医歯総合研究, 消化器肝臓感染症内科, 白鳥康史

Medical Practice 19,6,973-975 2002

ANCA関連腎炎の治療と予後に関する検討

中司敦子, 高木章乃夫, 岩田康義, 福島正樹

倉敷中央病院年報 2002

アンギオテンシン変換酵素阻害剤(ACE-I)投与中に発生した急性腎不全症例の検討

高木章乃夫, 岩田康義, 佐藤千景, 江口潤, 中司敦子, 福島正樹

ICUとCCU 2002

Cellular immune responses persist and humoral responses decrease two decades after recovery from a single-source outbreak of hepatitis C

Akinobu Takaki, Manfred Wiese, Geert Maertens, Erik Depla, Ulrike Seifert, Anke Liebetrau, Jeffery L. Miller, Michael P. Manns, Barbara Rehermann

Nature Medicine 6 ( 5 ) 578 - 582 2000.5

Language：English

As acute hepatitis C virus (HCV) infection is clinically inapparent in most cases, the immunologic correlates of recovery are not well defined. The cellular immune response is thought to contribute to the elimination of HCV- infected cells and a strong HCV-specific T-helper-cell (Th) response is associated with recovery from acute hepatitis C (ref. 2). However, diagnosis of resolved hepatitis C is based at present on the detection of HCV-specific antibodies and the absence of detectable HCV RNA, and detailed comparison of the humoral and cellular immune response has been hampered by the fact that patient cohorts as well as HCV strains are usually heterogeneous and that clinical data from acute-phase and long-term follow-up after infection generally are not available. We studied a cohort of women accidentally exposed to the same HCV strain of known sequence and found that circulating HCV-specific antibodies were undetectable in many patients 18-20 years after recovery, whereas HCV-specific helper and cytotoxic T-cell responses with an interferon (IFN)-γ-producing (Tc1) phenotype persisted. The data indicate these HCV-specific CD4+ and CD8+ T cells are biomarkers for a prior HCV exposure and recovery. Because of undetectable antibodies against HCV, the incidence of self-limited HCV infections and recovery may be underestimated in the general population.

DOI： 10.1038/75063

Increase in CD95 (Fas/APO-1)-positive CD4+ and CD8+ T cells in peripheral blood derived from patients with autoimmune hepatitis or chronic hepatitis C with autoimmune phenomena

Shin Ogawa, Kohsaku Sakaguchi, Akinobu Takaki, Kunihiro Shiraga, Tomoyuki Sawayama, Hirokazu Mouri, Manabi Miyashita, Norio Koide, Takao Tsuji

Journal of Gastroenterology and Hepatology (Australia) 15 ( 1 ) 69 - 75 2000

Language：English Publisher：Blackwell Publishing

Background: The expressions of CD95 (Fas/APO-1) and Bcl-2 are determinants of apoptosis in normal lymphocytes, and abnormalities in their expressions might contribute to the induction of autoimmunity. In this study, we examined the expressions of CD95 and Bcl-2 on freshly isolated T and B cells from patients with autoimmune hepatitis (AIH) or chronic hepatitis C associated with autoimmune phenomena (CH-C(AI)). Methods: The CD95 and Bcl-2 expressions within CD4+ T, CD8+ T, and CD19+ B cell subsets were analysed by two-colour flow cytometry. Results: The surface expression of CD95 was significantly high in both the CD4+ T and CD8+ T cell subsets derived from the patients with AIH and those with CH-C(AI), compared with expression in patients with CH-C and normal subjects. The increase in CD95 expression was associated with the phenotypic conversion of naive CD45RO- to primed CD45RO+ CD4+T cells. Bcl-2 was detected in the vast majority of peripheral T and B cells. There was no significant difference in the percentage of Bcl2- positive cells in the CD4+T cell, CD8+T cell and CD19+ B cell subsets among the patient groups and normal subjects. Conclusions: These results indicate that an increase in CD4+T cells expressing CD45RO and CD95 marks an important subset of AIH and CH-C(AI) patients. These expanded CD95+ CD45RO+ primed T cells most likely reflect a continuous antigen-specific or non- specific activation oft lymphocytes, and/or the persistent presence of activated lymphocytes as a consequence of abnormalities in the peripheral deletion of activated lymphocytes. These persistently activated lymphocytes might play a role in the induction of autoimmunity in AIH and CH-C(AI). (C) 2000 Blackwell Science Asia Pty Ltd.

DOI： 10.1046/j.1440-1746.2000.02044.x