Faculty Profiles - TAKAKI Akinobu

Papers - TAKAKI Akinobu

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Gastric peroral endoscopic myo-neurotomy as less-invasive bariatric surgery in porcine models: an experimental study

Kenta Hamada, Yasushi Yamasaki, Akinobu Takaki, Takehiro Tanaka, Hiroyuki Okada

iGIE 3 ( 3 ) 358 - 365 2024.9

Publishing type：Research paper (scientific journal)

Background and Aims: Obesity is a global health problem, and less-invasive treatments are warranted. We developed a novel endoscopic intervention named peroral endoscopic myo-neurotomy (POEM-N) that is performed at the greater curvature of the gastric antrum as a bariatric/metabolic procedure and assessed its feasibility using porcine models. Methods: Six live pigs were divided into 3 groups of 2: POEM-N with a high-fat diet (HFD) (POEM-N group); sham procedure with HFD (HF-control group); and sham procedure with normal diet (N-control group). All pigs were fed the diets for 2 weeks, underwent POEM-N or sham procedure, and were observed for 2 weeks after the procedure. The primary outcome was the safety and feasibility of POEM-N. Adverse events and histology of the area after POEM-N were evaluated to assess the procedure's safety and feasibility. Secondary outcomes were changes in body weight and glycolipid levels. Results: There was no severe worsening of vital signs during or after the POEM-N procedure. All pigs were well and food intake was good, with no delayed adverse events. Excessive storage of dietary residue, deformity of the gastric antrum, and fold concentration were observed after POEM-N, as expected. Histologic examination revealed hypertrophic regeneration of Auerbach's plexus, which regulates gastric peristalsis, in both POEM-N pigs. After the procedure, HFD-induced weight gain in the POEM-N pigs slowed, and the increase in serum and liver cholesterol levels was suppressed. Conclusions: We applied POEM-N as a bariatric/metabolic procedure and showed its safety and feasibility using porcine models.

DOI： 10.1016/j.igie.2024.06.002

Response to the letter: "Predictive factors for transition to conversion therapy in HCC using atezolizumab plus bevacizumab". International journal

Tatsuya Kikuchi, Yasuto Takeuchi, Kazuhiro Nouso, Kazuya Kariyama, Kenji Kuwaki, Junichi Toshimori, Shota Iwado, Akio Moriya, Hiroaki Hagihara, Hiroyuki Takabatake, Toshifumi Tada, Tetsuya Yasunaka, Masahiro Sakata, Masahiko Sue, Nozomi Miyake, Takuya Adachi, Nozomu Wada, Hideki Onishi, Hidenori Shiraha, Akinobu Takaki, Motoyuki Otsuka

Liver international : official journal of the International Association for the Study of the Liver 44 ( 7 ) 1736 - 1737 2024.7

Predictive factors for transition to conversion therapy in hepatocellular carcinoma using atezolizumab plus bevacizumab. International journal

Tatsuya Kikuchi, Yasuto Takeuchi, Kazuhiro Nouso, Kazuya Kariyama, Kenji Kuwaki, Junichi Toshimori, Shota Iwado, Akio Moriya, Hiroaki Hagihara, Hiroyuki Takabatake, Toshifumi Tada, Tetsuya Yasunaka, Masahiro Sakata, Masahiko Sue, Nozomi Miyake, Takuya Adachi, Nozomu Wada, Hideki Onishi, Hidenori Shiraha, Akinobu Takaki, Motoyuki Otsuka

Liver international : official journal of the International Association for the Study of the Liver 44 ( 6 ) 1456 - 1463 2024.6

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: To identify predictive factors associated with successful transition to conversion therapy following combination therapy with atezolizumab and bevacizumab in the treatment of unresectable hepatocellular carcinoma (HCC). METHODS: In total, 188 patients with HCC, who received atezolizumab plus bevacizumab combination therapy as the first-line chemotherapy, were studied. Patients who achieved complete response (CR) with systemic chemotherapy alone were excluded. Clinical factors possibly linked to successful transition to conversion therapy and the achievement of cancer-free status were identified. RESULTS: Fifteen (8.0%) patients underwent conversion therapy. In the conversion group, there was a significantly higher proportion of patients with Barcelona Clinic Liver Cancer (BCLC) stage A or B (73.3% versus [vs.] 45.1%; p = .03) and tended to have lower Child-Pugh scores and alpha-fetoprotein levels. Multivariate analysis revealed that BCLC stage was a predictive factor for the implementation of conversion therapy (A or B; odds ratio 3.7 [95% CI: 1.1-13]; p = .04). Furthermore, 10 (66.7%) patients achieved cancer-free status and exhibited a smaller number of intrahepatic lesions at the start of treatment (3.5 vs. 7; p < .01), and a shorter interval between systemic chemotherapy induction and conversion therapy (131 vs. 404 days; p < .01). In addition, the rate of achieving cancer-free status by undergoing surgical resection or ablation therapy was significantly higher (p = .03). CONCLUSION: BCLC stage was the sole predictive factor for successful transition to conversion therapy when using combination therapy with atezolizumab and bevacizumab to treat HCC. Furthermore, a small number of intrahepatic lesions and early transition to conversion therapy were associated with the achievement of cancer-free status.

DOI： 10.1111/liv.15907

Impact of Nutritional Status on Neutrophil-to-Lymphocyte Ratio as a Predictor of Efficacy and Adverse Events of Immune Check-Point Inhibitors. International journal

Masahiko Sue, Yasuto Takeuchi, Shoichiro Hirata, Akinobu Takaki, Motoyuki Otsuka

Cancers 16 ( 10 ) 2024.5

Language：English Publishing type：Research paper (scientific journal)

The neutrophil -to-lymphocyte ratio (NLR) is useful for predicting the effectiveness of treatment with immune checkpoint inhibitors (ICIs) and immune-related adverse events (irAEs). Because a growing body of evidence has recently shown that the number of lymphocytes that comprise NLR fluctuates according to nutritional status, this study examined whether the usefulness of NLR varies in ICI treatment due to changes in nutritional status. A retrospective analysis was performed on 1234 patients who received ICI treatment for malignant tumors at our hospital. Progression-free survival (PFS) was significantly prolonged in patients with NLR < 4. Multivariate analysis revealed that the factors associated with the occurrence of irAE were NLR < 4 and the use of ipilimumab. However, when limited to cases with serum albumin levels <3.8 g/dL, lymphocyte counts significantly decreased, and the associations between NLR and PFS and between NLR and irAE occurrence disappeared. In contrast, when limited to the cases with serum albumin levels ≥3.8 g/dL, the associations remained, with significantly prolonged PFS and significantly increased irAE occurrence at NLR < 4. NLR may be a good predictive tool for PFS and irAE occurrence during ICI treatment when a good nutritional status is maintained.

DOI： 10.3390/cancers16101811

肝細胞癌の病態解明のためのトランスレーショナルリサーチ血清抗PD1自己抗体高値はアテゾリズマブ/ベバシズマブ治療予後不良の予測因子となる

高木章乃夫, 松本和幸, 佐々木裕貴, 須江真彦, 足立卓哉, 和田望, 竹内康人, 大西秀樹, 白羽英則, 大塚基之

日本消化器病学会雑誌 121 ( 臨増総会 ) A236 - A236 2024.3

Anti-PD-1 Autoantibody Predicts Survival of Patients With Hepatocellular Carcinoma Receiving Atezolizumab/Bevacizumab

Yuki Sasaki, Kazuyuki Matsumoto, Akinobu Takaki, Takuya Adachi, Masahiro Takahara, Keita Ozato, Yasuto Takeuchi, Masahiko Sue, Nozomi Miyake, Nozomu Wada, Hideki Onishi, Hidenori Shiraha, Takashi Oda, Koichiro Tsutsumi, Kazuhiro Nouso, Kazuya Kariyama, Hiroaki Hagihara, Akio Moriya, Motoyuki Otsuka

Gastro Hep Advances 3 ( 8 ) 1138 - 1147 2024.1

Publishing type：Research paper (scientific journal)

Background and Aims: Methods for predicting therapeutic response to immune checkpoint inhibitors in cancer therapy are in high demand. In patients with advanced hepatocellular carcinoma (HCC), atezolizumab (anti-programmed cell death-ligand 1 [PD-L1]) and bevacizumab (anti-vascular endothelial growth factor) combination therapy (Atezo/Bev therapy) is a first-line treatment. However, no reliable biomarkers are currently available to predict its efficacy. Here, we examined serum anti-PD-1 autoantibody levels as candidate biomarkers. Methods: We prospectively enrolled 63 patients with advanced HCC who received Atezo/Bev therapy. Serum anti-PD-1 autoantibody levels were measured before treatment using an indirect enzyme-linked immunosorbent assay. The correlation between the titers and response to therapy was statistically examined. Results: Serum anti-PD-1 autoantibody levels were not significantly associated with the treatment response in any patient. However, when examining only patients who received the Atezo/Bev as their first-line therapy, higher anti-PD-1 autoantibody levels were significantly associated with worse overall survival rates. The titer was an independent risk factor for poor prognosis (odds ratio [OR] = 7.8, P = .013), in addition to a higher neutrophil-to-lymphocyte ratio (OR = 7.1, P = .009) and lower albumin levels (OR = 14.2, P = .003). Conclusion: Serum anti-PD-1 autoantibody levels correlated with the overall survival rate in patients who received Atezo/Bev as first-line therapy. Serum anti-PD-1 autoantibody levels may serve as new biomarkers for predicting the efficacy of immune checkpoint inhibitors in patients with HCC.

DOI： 10.1016/j.gastha.2024.07.018

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

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

Clinical Journal of Gastroenterology 2023.11

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

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

Cancer medicine 12 ( 17 ) 17559 - 17568 2023.8

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1002/cam4.6369

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

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

Acta medica Okayama 77 ( 4 ) 377 - 385 2023.8

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.18926/AMO/65748

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

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

Hepatology international 17 ( 5 ) 1215 - 1224 2023.7

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1007/s12072-023-10557-2

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

伊木道子, 竹内康人, 須江真彦, 三宅望, 足立卓哉, 和田望, 大西秀樹, 白羽秀則, 高木章乃夫, 大塚基之

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

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

高木章乃夫, 竹内康人, 八木孝仁, 大塚基之

肝胆膵 86 ( 4 ) 523 - 528 2023.4

肝硬変の成因と病態の推移当院における肝硬変の成因と病態の推移

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

肝臓 64 ( Suppl.1 ) A266 - A266 2023.4

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

大西秀樹, 竹内康人, 高木章乃夫

肝臓 64 ( Suppl.1 ) A172 - A172 2023.4

肝硬変の成因と病態の推移当院における肝硬変の成因と病態の推移

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

肝臓 64 ( Suppl.1 ) A266 - A266 2023.4

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

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

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

膵癌化学療法における血中自己抗体を用いた治療効果予測の可能性

松本和幸, 高木章乃夫, 高原政宏, 小幡泰介, 藤井佑樹, 山崎辰洋, 内田大輔, 堀口繁, 堤康一郎, 加藤博也

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

急性肝炎が遷延し,死亡に至ったE型肝炎の一例

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

肝臓 64 ( 2 ) 101 - 101 2023.2

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

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

Acta medica Okayama 76 ( 6 ) 695 - 703 2022.12

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.18926/AMO/64120

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.2739/kurumemedj.MS6723011

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

高木章乃夫, 松本洋輔, 八木孝仁

肝胆膵 85 ( 5 ) 671 - 676 2022.11

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

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

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

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

三宅望, 足立卓哉, 須江真彦, 大山淳史, 和田望, 竹内康人, 大西秀樹, 白羽英則, 八木孝仁, 廣瀬享, 高木章乃夫

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

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

高木章乃夫, 松本洋輔, 八木孝仁

肝胆膵 85 ( 5 ) 671 - 676 2022.11

生検検体を用いた胆道癌におけるPD-L1発現の検討

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

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

生検検体を用いた胆道癌におけるPD-L1発現の検討

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

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

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

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

肝臓 63 ( Suppl.2 ) A601 - A601 2022.9

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

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

肝臓 63 ( Suppl.2 ) A585 - A585 2022.9

原発性硬化性胆管炎(PSC)の自然経過にみる2021年症例の特徴

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

肝臓 63 ( Suppl.2 ) A562 - A562 2022.9

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

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

肝臓 63 ( Suppl.2 ) A585 - A585 2022.9

原発性硬化性胆管炎(PSC)の自然経過にみる2021年症例の特徴

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

肝臓 63 ( Suppl.2 ) A562 - A562 2022.9

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

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

肝臓 63 ( Suppl.2 ) A601 - A601 2022.9

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

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

日本門脈圧亢進症学会雑誌 28 ( 3 ) 95 - 95 2022.8

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

大後戸智也, 白羽英則, 赤木達, 内藤貴教, 中村一文, 大山淳史, 足立卓哉, 和田望, 竹内康人, 大西秀樹, 高木章乃夫

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

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

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

肝胆膵 85 ( 1 ) 146 - 147 2022.7

肝性浮腫に対するトルバプタン治療の効果と予後予測について

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

肝臓 63 ( Suppl.1 ) A428 - A428 2022.4

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

大西秀樹, 高木章乃夫, 岡田裕之

肝臓 63 ( Suppl.1 ) A190 - A190 2022.4

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1111/hepr.13766

胆管結石発症に関する腸内細菌叢の解析

松本和幸, 高木章乃夫, 岡田裕之

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

神経内分泌腫瘍肝転移における肝動脈塞栓療法の有効性の検討

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

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

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1007/s11605-021-05197-6

FALDに挑む Fontan関連肝腫瘍肝細胞癌と良性肝結節

大西秀樹, 高木章乃夫, 岡田裕之

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

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

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

Clinical Medicine Insights. Oncology 16 11795549221127750 - 11795549221127750 2022

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1177/11795549221127750

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1007/s12328-021-01529-w

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.3748/wjg.v27.i41.7134

トルバプタンを導入した肝硬変患者における血管拡張抑制物質ADMA測定の意義

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

肝臓 62 ( Suppl.3 ) A740 - A740 2021.11

Fontan関連肝疾患を背景に肝細胞腺腫を発症した一例

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

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

アテゾリズマブ・ベバシズマブ併用療法の実臨床での治療効果

足立卓哉, 能祖一裕, 大山淳史, 和田望, 竹内康人, 大西秀樹, 白羽英則, 高木章乃夫, 守屋昭男, 小橋春彦, 岩堂昭太, 岡田裕之

肝臓 62 ( Suppl.3 ) A759 - A759 2021.11

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1007/s12185-021-03157-z

トルバプタンによる腹水治療に伴う肝移植時状態の変化

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

肝臓 62 ( Suppl.2 ) A537 - A537 2021.9

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

足立卓哉, 能祖一裕, 大山淳史, 和田望, 竹内康人, 大西秀樹, 白羽英則, 高木章乃夫, 狩山和也, 岩堂昭太, 守屋昭男, 岡田裕之

肝臓 62 ( Suppl.2 ) A551 - A551 2021.9

急性肝不全に陥ることなく致死的経過を辿った急性E型肝炎の1例

山内菜緒, 安中哲也, 高木章乃夫, 日並義統, 木野村賢, 河原明奈, 足立卓哉, 大山淳史, 和田望, 竹内康人, 大西秀樹, 白羽英則, 岡田裕之

肝臓 62 ( 8 ) 463 - 470 2021.8

急性肝不全に陥ることなく致死的経過を辿った急性E型肝炎の1例

山内菜緒, 安中哲也, 高木章乃夫, 日並義統, 木野村賢, 河原明奈, 足立卓哉, 大山淳史, 和田望, 竹内康人, 大西秀樹, 白羽英則, 岡田裕之

肝臓 62 ( 8 ) 463 - 470 2021.8

Language：Japanese Publisher：(一社)日本肝臓学会

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

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

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1111/hepr.13633

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

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

International journal of molecular sciences 22 ( 11 ) 2021.5

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.3390/ijms22115582

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1111/hepr.13626

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

稲生祥子, 安中哲也, 高木章乃夫, 大山敦史, 足立卓哉, 和田望, 竹内康人, 大西秀樹, 白羽英則, 岡田裕之

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

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1111/jgh.15227

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

大西秀樹, 高木章乃夫, 岡田裕之

肝臓 62 ( Suppl.1 ) A166 - A166 2021.4

Differences in autoimmune hepatitis based on inflammation localization

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

Medical Molecular Morphology 54 ( 1 ) 8 - 13 2021.3

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

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

DOI： 10.1007/s00795-020-00255-5

Other Link： https://link.springer.com/article/10.1007/s00795-020-00255-5/fulltext.html

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

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

Journal of gastroenterology 56 ( 2 ) 158 - 167 2021.2

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1007/s00535-020-01748-x

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

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

Acta Hepatologica Japonica 62 ( 8 ) 463 - 470 2021

Publishing type：Research paper (scientific journal)

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

DOI： 10.2957/kanzo.62.463

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

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

Hepatology Research 50 ( 12 ) 1347 - 1354 2020.12

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

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

Medicine 99 ( 43 ) e22764 - e22764 2020.10

Language：English Publishing type：Research paper (scientific journal) Publisher：Ovid Technologies (Wolters Kluwer Health)

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

DOI： 10.1097/md.0000000000022764

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

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

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

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

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

Scientific reports 10 ( 1 ) 14250 - 14250 2020.8

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1038/s41598-020-71296-0

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

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

Acta medica Okayama 74 ( 4 ) 275 - 283 2020.8

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.18926/AMO/60364

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

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

Gastrointestinal tumors 7 ( 3 ) 83 - 92 2020.7

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1159/000506941

ベルベリンによる慢性腸炎マウスの腸内細菌叢の変化

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

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

進行肝細胞癌に対する分子標的薬による治療効果及び肝予備能の変化

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

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

肝性浮腫に対するトルバプタン効果予測と予後予測について

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

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

成人先天性心疾患におけるFontan関連肝疾患(FALD)の現状と問題点

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

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

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

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

Nutrients 12 ( 6 ) 2020.5

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.3390/nu12061576

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

大西秀樹, 高木章乃夫, 岡田裕之

肝臓 61 ( Suppl.1 ) A139 - A139 2020.4

REIC/Dkk-3遺伝子治療併用による肝癌治療の効果増強

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

肝臓 61 ( Suppl.1 ) A389 - A389 2020.4

肝性浮腫患者のトルバプタン効果と予後の予測

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

肝臓 61 ( Suppl.1 ) A350 - A350 2020.4

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

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

Journal of gastroenterology 55 ( 3 ) 353 - 362 2020.3

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1007/s00535-019-01645-y

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.2169/internalmedicine.3340-19

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

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

Oncology 98 ( 5 ) 311 - 317 2020

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1159/000506135

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.2217/fon-2019-0115

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

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

Journal of gastroenterology 54 ( 11 ) 1019 - 1028 2019.11

膵癌におけるFNA検体と切除検体とのPD-L1発現の検討 Reviewed

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

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

膵癌におけるFNA検体と切除検体とのPD-L1発現の検討

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

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

DAA治療後のSVR後発癌についての検討

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

肝臓 60 ( Suppl.3 ) A847 - A847 2019.11

原発性硬化性胆管炎(PSC)予後予測因子の検討

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

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

レンバチニブで長期効果見込める肝細胞癌症例の特徴

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

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

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

室泰子, 高木章乃夫, 中村進一郎, 大西秀樹, 岡田裕之

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

肝性浮腫に対するトルバプタン効果に寄与する血管内皮機能の検討

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

肝臓 60 ( Suppl.3 ) A853 - A853 2019.11

高齢者におけるDAA治療の現状

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

肝臓 60 ( Suppl.2 ) A657 - A657 2019.10

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

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

Acta medica Okayama 73 ( 4 ) 333 - 339 2019.8

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.18926/AMO/56935

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1111/jgh.14535

肝疾患の診断と治療生体肝移植後経過より再考する肝硬変合併肺病変の評価

大山淳史, 高木章乃夫, 安中哲也, 足立卓哉, 和田望, 坂田雅浩, 大西秀樹, 白羽英則, 吉田龍一, 楳田祐三, 中村一文, 八木孝仁, 岡田裕之

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

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

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

GASTROENTEROLOGY 156 ( 6 ) S758 2019.5

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

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

Cancers 11 ( 2 ) 2019.2

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.3390/cancers11020213

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

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

Acta medica Okayama 73 ( 1 ) 41 - 50 2019.2

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.18926/AMO/56457

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

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

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

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

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

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

Publishing type：Research paper (scientific journal)

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

DOI： 10.1248/yakushi.18-00170

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

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

Scientific Reports 9 ( 1 ) 11934 - 11934 2019

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1038/s41598-019-48331-w

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

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

Journal of medical case reports 12 ( 1 ) 368 2018.12

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

難波志穂子, 池田房雄, 秋山文男, 石原光将, 下村泰之, 山崎典子, 犬山奈穂美, 小山道弘, 亀川勝典, 大久保進之介, 長谷川祐子, 岩井賢司, 三喜明子, 三浦留美, 矢野香苗, 藤井洋輔, 大山淳史, 足立卓哉, 和田望, 安中幸, 安中哲也, 大西秀樹, 白羽英則, 高木章乃夫, 山野井尚美, 岡田裕之

肝臓 59 ( 11 ) 625 - 632 2018.11

Language：Japanese Publisher：(一社)日本肝臓学会

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

A case of celecoxib-induced multiple ulcers of the small intestine observed on capsule endoscopy

Yuki Aoyama, Sakuma Takahashi, Tomoki Inaba, Mariko Colvin, Shigenao Ishikawa, Masaki Wato, Yoshiyasu Kono, Seiji Kawano, Akinobu Takaki, Hiroyuki Okada

Gastroenterological Endoscopy 60 ( 10 ) 2297 - 2302 2018.10

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japan Gastroenterological Endoscopy Society

The patient was a 75-year-old man with melena. Capsule endoscopy revealed colonic diverticular bleeding as well as 2-to 3-mm erosions scattered in the small intestine. The colonic diverticular bleeding was treated by endoscopic clipping. Two months later, administration of celecoxib was started for knee pain. Nine months later, black stools and iron-deficiency anemia were observed, and multiple ulcers were found in the intestine on capsule endoscopy. The patient was diagnosed as having nonsteroidal anti-inflammatory drug-induced small intestinal ulcer. The cele-coxib therapy was discontinued, and administration of misoprostol, rebamipide, and polaprezinc was started. Capsule endoscopy performed three months after starting the treatment demonstrated improvement of the ulcers. Celecoxib is a cyclooxygenase-2 (COX-2) selective inhibitor and is considered to confer a low risk of mucosal injury, but the risk of mucosal injury may increase with chronic administration of celecoxib or combination therapy with a proton pump inhibitor. Therefore, careful attention should be paid to patients who are being treated with celecoxib.

DOI： 10.11280/gee.60.2297

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

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

Journal of gastroenterology 53 ( 9 ) 1079 - 1088 2018.9

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1007/s00535-018-1444-4

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

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

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

Scientific reports 8 ( 1 ) 12542 2018.8

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

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

Acta medica Okayama 72 ( 4 ) 401 - 406 2018.8

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.18926/AMO/56178

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

Uchida D, Takaki A, Adachi T, Okada H

Nutrients 10 ( 8 ) 2018.7

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.3390/nu10080977

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

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

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

Transplantation Proceedings 50 ( 4 ) 1192 - 1195 2018.5

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier USA

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

DOI： 10.1016/j.transproceed.2017.11.078

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

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

Journal of gastroenterology 53 ( 5 ) 689 - 689 2018.5

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1007/s00535-017-1409-z

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

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

BMC gastroenterology 18 ( 1 ) 62 - 62 2018.5

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1186/s12876-018-0793-z

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

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

Digestive surgery 36 ( 1 ) 59 - 66 2018.4

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1159/000486548

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1002/jgh3.12046

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

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

Acta medica Okayama 72 ( 1 ) 47 - 52 2018.2

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.18926/AMO/55662

改訂自己免疫性肝炎・原発性胆汁性胆管炎診療ガイドライン Reviewed

厚生労働科学研究費補助金, 難治性疾患政策研究事業, 難治性の肝, 胆道疾患に関する調査研究, 班, 自己免疫性肝炎分科会, 原発性胆汁性胆管炎分科会, 田中篤, 大平弘正, 高橋敦史, 小森敦正, 阿部雅則, 姜貞憲, 小池和彦, 鈴木義之, 髙木章乃夫, 有永照子, 島村拓司, 中本伸宏, 原田憲一, 十河剛, 乾あやの, 藤澤知雄, 吉澤要, 玄田拓哉, 銭谷幹男, 下田慎治, 竹山康章, 向坂彰太郎, 谷合麻紀子, 橋本悦子, 中村稔, 浪崎正, 吉治仁志, 本多彰, 松崎靖司, 廣原淳子, 山際訓, 滝川一

肝臓 59 ( 4 ) 211 - 216 2018

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

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

PloS one 13 ( 10 ) e0204772 2018

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1371/journal.pone.0204772

An activity survey of hepatitis medical care coordinators in Okayama prefecture, Japan

Shihoko Namba, Fusao Ikeda, Fumio Akiyama, Mitsumasa Ishihara, Yasuyuki Shimomura, Noriko Yamasaki, Naomi Inuyama, Michihiro Koyama, Katsunori Kamegawa, Shinnosuke Okubo, Yuko Hasegawa, Kenji Iwai, Akiko Sanki, Rumi Miura, Kanae Yano, Yosuke Fujii, Atsushi Ohyama, Takuya Adachi, Nozomu Wada, Yuki Yasunaka, Tetsuya Yasunaka, Hideki Onishi, Hidenori Shiraha, Akinobu Takaki, Hisami Yamanoi, Hiroyuki Okada

Acta Hepatologica Japonica 59 ( 11 ) 625 - 632 2018

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japan Society of Hepatology

Okayama prefecture has conducted seminars on viral hepatitis primarily for new staff members belonging to the department dealing with liver diseases in public health centers and hospitals
participants have been certified as “hepatitis medical care coordinators.” This survey was planned to (1) evaluate the viral hepatitis awareness activities they conducted after seminars using self-reported questionnaires and (2) clarify whether their knowledge and practices were appropriate to classify them as competent hepatitis medical care coordinators as per the Ministry of Health, Labor and Welfare in Japan. Among all 298 coordinators in the Okayama prefecture, 146 responded to the survey
84 worked at the same department and 45 matched the coordinator in their daily activities. Further, 36 were transferred to different departments and 20 conducted awareness activities as hepatitis medical care coordinators in addition to their daily responsibilities. Transfer of hepatitis medical care coordinators may help expand hepatitis awareness activities across different departments.

DOI： 10.2957/kanzo.59.625

肝移植後C型肝炎再発に対するソホスブビル含有治療の有効性

大山淳史, 高木章乃夫, 安中哲也, 足立卓哉, 池田房雄, 和田望, 竹内康人, 大西秀樹, 中村進一郎, 白羽英則, 高木弘誠, 杭瀬崇, 信岡大輔, 吉田龍一, 楳田祐三, 吉田真理, 有森千聖, 八木孝仁, 岡田裕之

肝臓 58 ( 11 ) 599 - 604 2017.11

Language：Japanese Publisher：(一社)日本肝臓学会

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

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J00263&link_issn=&doc_id=20171128110001&doc_link_id=10.2957%2Fkanzo.58.599&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.58.599&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

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

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

Acta medica Okayama 71 ( 5 ) 381 - 390 2017.10

Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.18926/AMO/55435

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

下村泰之, 藤井洋輔, 池田房雄, 安中哲也, 山崎典子, 笠原郁子, 犬山奈穂美, 小山道弘, 難波志穂子, 竹内康人, 和田望, 桑木健志, 大西秀樹, 中村進一郎, 白羽英則, 高木章乃夫, 岡田裕之

肝臓 58 ( 8 ) 427 - 434 2017.8

Language：Japanese Publisher：(一社)日本肝臓学会

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

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J00263&link_issn=&doc_id=20170830080001&doc_link_id=10.2957%2Fkanzo.58.427&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.58.427&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.3892/mco.2017.1220

職域での出張肝臓病教室と同時開催の肝炎検診の意義

難波志穂子, 池田房雄, 下村泰之, 犬山奈穂美, 大久保進之介, 槇田崇志, 長谷川祐子, 岩井賢司, 細羽章子, 三浦留美, 藤井洋輔, 安中哲也, 竹内康人, 和田望, 桑木健志, 大西秀樹, 中村進一郎, 白羽英則, 高木章乃夫, 岡田裕之

肝臓 58 ( 5 ) 304 - 306 2017.5

Language：Japanese Publisher：(一社)日本肝臓学会

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

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J00263&link_issn=&doc_id=20170601230005&doc_link_id=10.2957%2Fkanzo.58.304&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.58.304&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Redox Signaling in NASH Reviewed

A. Takaki, D. Uchida, K. Yamamoto

Liver Pathophysiology: Therapies and Antioxidants 169 - 180 2017.3

Language：English Publishing type：Part of collection (book) Publisher：Elsevier

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

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

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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

Oxidative stress in nonalcoholic steatohepatitis

Akinobu Takaki, Daisuke Uchida, Kazuhide Yamamoto

Reactive Oxygen Species in Biology and Human Health 349 - 361 2017.1

Language：English Publishing type：Part of collection (book) Publisher：CRC Press

Nonalcoholic fatty liver disease (NAFLD) is a disease with increasing prevalence that is potentially lethal after decades of persistent fat toxicity on the liver and accompanying organs. The pathogenesis for the progression of benign nonalcoholic fatty liver (NAFL) to progressive nonalcoholic steatohepatitis (NASH) is acknowledged as a multiple parallel hit process, including fat deposition, genetic factors, insulin resistance, and oxidative stress. Oxidative stress is one of the main pathogenic factors driving the progression of NAFL to NASH. Excessive accumulation of long chain fatty acids results in activation of the mitochondrial b-oxidation pathway and consequent reactive oxygen species (ROS) production. ROS can mediate oxidative stress responses in hepatocytes, Kupffer cells and hepatic stellate cells (HSCs), resulting in hepatocyte damage as well as proinflammatory and profibrogenic responses. ROS detoxification pathway signaling is often damaged in NAFLD following ROS accumulation. Inactivation of the prooxidant production pathway is presently the primary treatment strategy. However, as oxidative stress is an essential response in living organisms, a new treatment strategy that activates toxic oxidative stress detoxifying pathways while maintaining essential oxidative stress responses is preferred.

DOI： 10.1201/b20228

Corrigendum to "Safety and Efficacy of Small Bowel Examination by Capsule Endoscopy for Patients before Liver Transplantation"

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 6418529 2017.1

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

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

BIOMED RESEARCH INTERNATIONAL 2017 2017

Language：English Publishing type：Research paper (scientific journal) Publisher：HINDAWI LTD

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

DOI： 10.1155/2017/8193821

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

高原政宏, 高木章乃夫, 平岡佐規子, 池田愛璃, 足立卓哉, 松下浩志, 小池和子, 岡田裕之

日本臨床免疫学会会誌 40 ( 4 ) 311b - 311b 2017

Language：Japanese Publisher：日本臨床免疫学会

<p>【背景】生薬であるベルベリン（BBR）は下痢止めとして臨床応用されているが，抗炎症など多彩な作用も有することが明らかになっている．BBRは細胞のエネルギーの調節因子であるAMPKを活性化させることが知られており，近年，このAMPKがT細胞を含む免疫細胞の応答に関わっていることが報告されている．【目的，方法】慢性腸炎マウスモデルを用いて，大腸炎粘膜のCD4⁺T細胞（LP CD4⁺T細胞）におけるBBRの抗炎症作用とその機序についての検証をin vitroおよびIn vivoで行う．1）CD4⁺CD45RB^highT細胞移入腸炎マウスのLPCD4⁺T細胞をPMA/Ionomysinで刺激し，IFN-γ産生細胞を誘導，BBRの効果について，AMPKの関与も含めて検討．2）上記腸炎マウスにBBRを含んだ餌を投与し，腸炎の抑制効果について検討．【結果】1）LP CD4⁺T細胞はBBRと共培養すると，IFN-γ産生細胞が優位に低下し，ウェスタンブロッティングでは，AMPKの活性化を認めた．次に，AMPKのagonistとantagonistを用いた培養系でIFN-γの産生を調べたところ，agonistで抑制，antagonistで増加を認めた．以上から，BBRにより活性化されたAMPKがIFN-γを制御していることが示唆された．2）上記腸炎マウスにBBRを経口投与した結果，腸炎は優位に抑制された．【結論】BBRは，慢性腸炎マウスモデルの腸炎を抑制し，その作用機序の一つとしてAMPKを介した機序が示唆された．</p>

DOI： 10.2177/jsci.40.311b

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.2169/internalmedicine.54.4889

当院における生体肝移植後の胆管狭窄に対する内視鏡治療

友田健, 加藤博也, 内田大輔, 秋元悠, 松本和幸, 山本直樹, 堀口繁, 堤康一郎, 高木章乃夫, 岡田裕之, 八木孝仁

移植 50 ( 4-5 ) 481 - 481 2015.10

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

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

Oncology reports 34 ( 3 ) 1169 - 1177 2015.9

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.3892/or.2015.4126

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

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

ACTA MEDICA OKAYAMA 69 ( 4 ) 237 - 244 2015.8

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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

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

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

PANCREATOLOGY 15 ( 4 ) 432 - 438 2015.7

Language：English Publishing type：Research paper (scientific journal) Publisher：KARGER

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

DOI： 10.1016/j.pan.2015.05.470

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

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

PANCREAS 44 ( 4 ) 551 - 556 2015.5

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

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

DOI： 10.1097/MPA.0000000000000321

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

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

DOI： 10.1002/jmv.24097

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：3

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

DOI： 10.1111/jgh.12726

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

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

Acta medica Okayama 69 ( 4 ) 219 - 226 2015

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：Baishideng Publishing Group Co

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

DOI： 10.4254/wjh.v7.i19.2220

Polycythemia Vera Diagnosed after Esophageal Variceal Rupture.

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

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

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.2169/internalmedicine.54.4687

Ultrastructural analysis of a gastric persimmon phytobezoar Reviewed

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

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

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

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

PLOS ONE 9 ( 7 ) 2014.7

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

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

DOI： 10.1371/journal.pone.0100627

Controlling oxidative stress in non-alcoholic steatohepatitis (NASH)

Akinobu Takaki, Daisuke Kawai, Kazuhide Yamamoto

Oxidative Stress: Causes, Role in Diseases and Biological Effects 139 - 176 2014.4

Language：English Publishing type：Part of collection (book) Publisher：Nova Science Publishers, Inc.

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) representing simple steatosis of the liver. Multiple hits, including genetic differences, fat accumulation, insulin resistance and intestinal microbiota changes, account for the progression NASH. NAFLD is strongly associated with obesity, which induces adipokine secretion, endoplasmic reticulum (ER) and oxidative stress at the cellular level, and induces hepatic steatosis, inflammation and fibrosis. Among these factors, oxidative stress is considered a key contributor to the progression from NAFL to NASH. Although several clinical trials have shown that anti-oxidative therapy with vitamin E can effectively control the effects of hepatitis in the short term, the long-term effects remains obscure. Several trials of long-term anti-oxidant protocols aimed at treating cerebrovascular diseases or cancer development have failed to demonstrate benefits. This might be attributed to the non-selective anti-oxidant properties or excessive anti- oxidative effects of these drugs. Molecular hydrogen has recently been identified as an effective antioxidant that specifically reduces cytotoxic reactive oxygen species (ROS). Several diseases associated with oxidative stress, such as ischemia reperfusion injury of brain or heart, Parkinson's disease, post-chemotherapeutic renal injury, or transplant rejection, are responsive to hydrogen. The progress of NASH and transition of NASH to hepatocellular carcinoma can be controlled using hydrogen-rich water in mouse models. Long-term clinical intervention is required to control this complex lifestyle-related disease.

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

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

ACTA MEDICA OKAYAMA 68 ( 1 ) 17 - 22 2014.2

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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

DOI： 10.18926/AMO/52139

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

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

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

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

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

DOI： 10.1111/jgh.12340

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

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

SpringerPlus 2 ( 1 ) 251 - 251 2013.12

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1186/2193-1801-2-251

自己免疫性肝胆膵疾患の病態解明の進歩自己免疫性肝炎における新規自己抗体

三宅康広, 松本和幸, 大西敦之, 松下浩志, 高木章乃夫, 山本和秀

消化器と免疫 ( 49 ) 3 - 6 2013.3

Language：Japanese Publisher：日本消化器免疫学会

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

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

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

Journal of Gastroenterology 47 ( 4 ) 489 2012.4

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

三宅康広, 松本和幸, 高木章乃夫, 山本和秀

肝臓 53 ( Suppl.1 ) A121 - A121 2012.4

急性肝不全症例における血清中可溶性接着分子の意義

大西敦之, 三宅康広, 松本和幸, 安中哲也, 池田房雄, 小池和子, 高木章乃夫, 山本和秀

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

急性肝不全における血清中可溶性接着分子の意義

大西敦之, 三宅康広, 松本和幸, 安中哲也, 池田房雄, 小池和子, 高木章乃夫, 山本和秀

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

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

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

HEPATOLOGY INTERNATIONAL 5 ( 4 ) 918 - 926 2011.12

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

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

DOI： 10.1007/s12072-011-9265-z

Stage of hepatocellular carcinoma is associated with periodontitis Reviewed

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

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

DOI： 10.1111/j.1600-051X.2011.01777.x

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

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

DOI： 10.1111/j.1440-1746.2011.06887.x

急性肝不全症例における血清中可溶性接着分子の意義

大西敦之, 三宅康広, 松本和幸, 高木章乃夫, 小池和子, 安中哲也, 池田房雄, 能祖一裕, 山本和秀

肝臓 52 ( Suppl.3 ) A862 - A862 2011.11

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

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

BMC CANCER 11 458 2011.10

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

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

DOI： 10.1186/1471-2407-11-458

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

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

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

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

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

DOI： 10.1111/j.1440-1746.2011.06737.x

急性肝不全症例における血清中可溶性接着分子の意義

大西敦之, 三宅康広, 松本和幸, 高木章乃夫, 山本和秀

日本臨床免疫学会会誌 34 ( 4 ) 316 - 316 2011.8

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

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

DOI： 10.1111/j.1440-1746.2011.06720.x

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

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

HEPATOLOGY RESEARCH 41 ( 5 ) 405 - 416 2011.5

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

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

DOI： 10.1111/j.1872-034X.2011.00785.x

Hepatocellular carcinoma occurring in hepatobiliary fibropolycystic disease Reviewed

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

HEPATOLOGY RESEARCH 41 ( 3 ) 277 - 281 2011.3

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

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

DOI： 10.1111/j.1872-034X.2010.00761.x

水素水はマウスにおけるNASHの進行を抑制する

河合大介, 高木章乃夫, 山本和秀, 松本和幸, 津崎龍一郎, 安中哲也, 小池和子, 三宅康弘, 白羽秀則

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

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

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

HEPATOLOGY RESEARCH 41 ( 2 ) 151 - 159 2011.2

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

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

DOI： 10.1111/j.1872-034X.2010.00757.x

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

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

Acta medica Okayama 65 ( 1 ) 11 - 19 2011.2

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.18926/AMO/43825

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL PUBLISHING, INC

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

DOI： 10.1111/j.1440-1746.2010.06441.x

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

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

BMC CANCER 11 3 2011.1

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

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

DOI： 10.1186/1471-2407-11-3

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

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

Blood 116 ( 24 ) 5119 - 5125 2010.12

Language：English Publishing type：Research paper (scientific journal) Publisher：24

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

DOI： 10.1182/blood-2010-06-289231

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

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

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

Journal of gastroenterology 45 ( 11 ) 1172 - 1182 2010.11

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

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

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

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

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

DOI： 10.1111/j.1365-2893.2009.01213.x

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL PUBLISHING, INC

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

DOI： 10.1111/j.1365-2893.2009.01181.x

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

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

DOI： 10.1016/j.dld.2009.06.013

Evolution of prognostic factors in hepatocellular carcinoma in Japan. Reviewed

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

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

Autoimmune hepatitis with acute presentation in Japan Reviewed

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

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

DOI： 10.1016/j.dld.2009.04.009

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

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

INTERNAL MEDICINE 49 ( 23 ) 2613 - 2616 2010

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC INTERNAL MEDICINE

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

DOI： 10.2169/internalmedicine.49.4221

Efficacy of ursodeoxycholic acid for Japanese patients with autoimmune hepatitis Reviewed

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

HEPATOLOGY INTERNATIONAL 3 ( 4 ) 556 - 562 2009.12

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

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

DOI： 10.1007/s12072-009-9155-9

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

池田房雄, 団迫浩方, 西村剛, 河合良成, 有海康雄, 池田正徳, 高木章乃夫, 岩崎良章, 加藤宣之, 山本和秀

肝臓 50 ( Suppl.2 ) A515 - A515 2009.9

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

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

HEPATOLOGY RESEARCH 39 ( 8 ) 766 - 771 2009.8

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL PUBLISHING, INC

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

DOI： 10.1111/j.1872-034X.2009.00510.x

Twist expression promotes migration and invasion in hepatocellular carcinoma. Reviewed

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

BMC cancer 9 240 2009.7

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

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

HEPATOLOGY RESEARCH 39 ( 3 ) 241 - 246 2009.3

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL PUBLISHING, INC

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

DOI： 10.1111/j.1872-034X.2008.00454.x

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

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

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

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

Molecular oncology 2 ( 3 ) 241 - 249 2008.10

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

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

DOI： 10.1016/j.molonc.2008.06.004

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

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

HEPATOLOGY RESEARCH 38 ( 1 ) 96 - 102 2008.1

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING

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

DOI： 10.1111/j.1872-034X.2007.00204.x

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

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

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

Language：Japanese Publisher：The Japanese Society for Dialysis Therapy

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

DOI： 10.4009/jsdt.38.1385

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

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

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

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

C型慢性肝炎における自己免疫現象

坂口孝作, 河本博文, 高木章乃夫

岡山医学会雑誌 105 ( 7-8 ) 795-796 1993.8

C型肝炎自己免疫性肝炎とHCV

坂口孝作, 河本博文, 高木章乃夫

臨床消化器内科 7 ( 12 ) 2007-2015 1992.11

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