Faculty Profiles - TAKAKI Akinobu

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ソラフェニブ治療による長期生存例の検討

足立卓哉, 能祖一裕, 和田望, 森元裕貴, 竹内康人, 桑木健志, 大西秀樹, 中村進一郎, 白羽英則, 高木章乃夫, 山本和秀

肝臓 56 ( Suppl.2 ) A749 - A749 2015.9

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

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肝移植後の腎機能の経過と降圧療法について

高木章乃夫, 八木孝仁, 保田裕子, 安中哲也, 貞森裕, 篠浦先, 楳田祐三, 吉田龍一, 信岡大輔, 内海方嗣, 藤原俊義, 山本和秀

移植 50 ( 2-3 ) 292 - 292 2015.8

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

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

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

ACTA MEDICA OKAYAMA 69 ( 3 ) 137 - 144 2015.6

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

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

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

GASTROENTEROLOGY 148 ( 4 ) S1030 - S1030 2015.4

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

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REIC/Dkk-3遺伝子導入による肝細胞癌治療の検討

澤原大明, 内田大輔, 白羽英則, 永原照也, 岩室雅也, 片岡淳朗, 堀口繁, 竹内康人, 桑木健志, 大西秀樹, 中村進一郎, 高木章乃夫, 能祖一裕, 山本和秀

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

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

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

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

HEPATOLOGY INTERNATIONAL 9 ( 1 ) 105 - 112 2015.1

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

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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

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