研究者詳細 - 寺井　崇二

論文 - 寺井　崇二

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Guidance on the clinical application of extracellular vesicles. 国際誌

Shuji Terai, Motohiro Asonuma, Ayuko Hoshino, Masahiro Kino-Oka, Takahiro Ochiya, Kiyoshi Okada, Yoji Sato, Yuki Takahashi, Morikuni Tobita, Atsunori Tsuchiya

Regenerative therapy 29 43 - 50 2025年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Therapies using extracellular vesicles (EVs), exosomes, or cell culture supernatants containing EVs or exosomes (referred to as "EV therapies" in this Guidance) have garnered an increasing amount of interest. However, pharmaceutical products containing EVs as their main active ingredient are yet to receive regulatory approval. The "Basic points to consider regarding the preparation of extracellular vesicles and their clinical applications in Japan," was announced by the Japanese Society for Regenerative Medicine (JSRM) on March 10, 2021, with a specific focus on exosomes among EVs to promote high safety standards in this evolving field and facilitate the application of EV clinically. The Scientific Committee of the Pharmaceuticals and Medical Devices Agency and the Japanese Society for Extracellular Vesicles have issued reports and statements regarding treatment, resulting in a growing momentum toward treatment in Japan. This article summarized the basic items that should be recognized comprehensively for clinical practice in three categories: (1) risk profiling, (2) preparation (manufacturing) process and quality, and (3) verification of EVs checking items and effectiveness. This guideline will be revised in the future with technological innovations and new findings; nevertheless, it will serve as a guide for the development of treatments.

DOI： 10.1016/j.reth.2025.02.008

Safety of edoxaban for delayed bleeding in gastrointestinal endoscopic procedures with a high risk of bleeding. 国際誌

Ken-Ichi Mizuno, Junji Yokoyama, Osamu Shibata, Yuichi Kojima, Yuzo Kawata, Kazuya Takahashi, Kentaro Tominaga, Igarashi Satoshi, Hayashi Kazunao, Shuji Terai

DEN open 5 ( 1 ) e70018 2025年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: There are limited reports on the safety of gastrointestinal endoscopic procedures in individuals taking edoxaban, one of the direct oral anticoagulants. We clarified the incidence of delayed bleeding in patients who were on edoxaban in the perioperative period of gastrointestinal endoscopic procedures with a high risk of bleeding. METHODS: This was an investigator-initiated, single-center, open-label, prospective, single-arm study. Patients on warfarin or edoxaban undergoing endoscopy with a high risk of bleeding were enrolled from June 2018 to September 2021. Warfarin was replaced with edoxaban in patients on warfarin. Patients taking other direct oral anticoagulants, and antiplatelet drugs, were excluded. The primary endpoint was severe delayed bleeding (Common Terminology Criteria for Adverse Events [CTCAE] grades III-V) and the secondary endpoints included thromboembolism, all adverse events, any delayed bleeding (CTCAE grades I or II), and hospital stay durations. RESULTS: Twenty-one patients on edoxaban underwent high-risk endoscopy. Three cases (14%) experienced CTCAE grade III delayed bleeding, requiring endoscopic hemostasis. No CTCAE grade I-II delayed bleeding or thromboembolic events occurred. Cholangitis and aspiration pneumonia (conservatively treated) occurred during the hospital stay. The median length of hospital stay was 8 days (range 3-24 days). Patients with delayed bleeding had higher systolic blood pressure at admission and longer hospital stays. CONCLUSIONS: The delayed bleeding incidence in high-risk endoscopic procedures for patients on edoxaban was acceptable. Higher blood pressure may be associated with increased risk, but further research is needed.

DOI： 10.1002/deo2.70018

Coexistence of Relapsing Polychondritis, Crohn's Disease, and Pyoderma Gangrenosum Treated Successfully with Adalimumab: A Case Report and Literature Review.

Shun Yamazaki, Kentaro Tominaga, Kotaro Watanabe, Makoto Watanabe, Shuhei Kondo, Norihiro Sakai, Tomoaki Yoshida, Yuichi Kojima, Yusuke Watanabe, Yuzo Kawata, Naruhiro Kimura, Kazuya Takahashi, Hiroki Sato, Satoshi Ikarashi, Hiroteru Kamimura, Kazunao Hayashi, Shuji Terai

Internal medicine (Tokyo, Japan) 2025年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Relapsing polychondritis (RP) is a rare, progressive, immune-mediated systemic inflammatory disease of unknown etiology characterized by recurrent inflammation of cartilaginous structures. Approximately 30% of RP cases are associated with autoimmune disease. However, co-occurrence of RP and Crohn's disease (CD) has rarely been reported. We herein report a case of coexisting RP, CD, and pyoderma gangrenosum that was successfully treated with adalimumab in combination with methotrexate. We believe that this case and literature review will facilitate the accurate and prompt diagnosis and treatment of RP combined with CD and various other complications.

DOI： 10.2169/internalmedicine.5024-24

Current management and future perspectives of covert hepatic encephalopathy in Japan: a nationwide survey.

Takao Miwa, Mio Tsuruoka, Hajime Ueda, Tamami Abe, Hiroki Inada, Yoshimi Yukawa-Muto, Masatsugu Ohara, Taeang Arai, Yasuyuki Tamai, Hiroshi Isoda, Tomoko Tadokoro, Tatsunori Hanai, Takanori Ito, Nobuharu Tamaki, Akira Sakamaki, Yoshihiko Aoki, Fujimasa Tada, Sachiyo Yoshio, Hirokazu Takahashi, Asahiro Morishita, Tsuyoshi Ishikawa, Jun Inoue, Goki Suda, Chikara Ogawa, Masanori Atsukawa, Atsushi Hiraoka, Hidekatsu Kuroda, Tadashi Namisaki, Takashi Honda, Takumi Kawaguchi, Yasuhito Tanaka, Shuji Terai, Tadashi Ikegami, Hitoshi Yoshiji, Motoh Iwasa, Masahito Shimizu

Journal of gastroenterology 2025年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Covert hepatic encephalopathy (CHE) leads to devastating outcomes in patients with cirrhosis. This study aims to elucidate the current management and future perspectives of CHE in Japan. METHODS: A questionnaire-based cross-sectional study was conducted among physicians involved in managing cirrhosis in Japan. The primary aim was to elucidate the real-world management of CHE, including testing and treatment. Factors influencing the implementation of CHE testing were analyzed using a logistic regression model. Limitations and future perspectives for improving the management of CHE were also evaluated. RESULTS: Of 511 physicians surveyed, 93.9% recognized CHE as a significant problem, and 86.9% agreed that it should be tested. Overall, 62.8% of physicians tested for CHE, whereas 37.2% did not. Multivariable analysis identified institutional factors and certifying board as significant determinants of CHE test implementation. The Stroop (68.2%) and neuropsychiatric tests (57.5%) were the most commonly used methods of identifying CHE. Among those who tested for CHE, 87.7% treated CHE; the most common treatments were lactulose (81.5%), rifaximin (76.3%), and branched-chain amino acids (70.4%). Among non-testers, the primary barrier was the time requirement for testing. Proposals to encourage CHE testing included the development of simple tests and integration of multidisciplinary teams. CONCLUSIONS: Most physicians involved in cirrhosis care in Japan recognize CHE as a significant problem that warrants testing. However, testing for CHE remains limited by institutional factors and physician specialties. Time requirements for CHE testing are the primary barrier, and simple tests and multidisciplinary teams are recommended to enhance CHE management.

DOI： 10.1007/s00535-025-02232-0

Extremely Rare Isolated Small-Intestinal Polyp Diagnosed by Double-Balloon Endoscopy in an Asymptomatic Adult Patient. 国際誌

Kentaro Tominaga, Annenkov Alexey, Yuto Tanaka, Osamu Shibata, Yuichi Kojima, Yuzo Kawata, Nao Nakajima, Kazuya Takahashi, Hiroki Sato, Satoshi Ikarashi, Kazunao Hayashi, Ken-Ichi Mizuno, Shuji Terai

Clinical case reports 13 ( 3 ) e70255 2025年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

We present the first reported case of an isolated small-bowel intestinal juvenile polyp in an adult. This case is particularly noteworthy as it was asymptomatic, detected via computed tomography, localized by capsule endoscopy, and successfully resected via double-balloon endoscopy before the development of acute symptoms.

DOI： 10.1002/ccr3.70255

Targeted animal models for preclinical assessment of cellular and gene therapies in pancreatic and liver diseases: regulatory and practical insights. 国際誌

Hongjun Wang, Rachele Ciccocioppo, Shuji Terai, Sara Shoeibi, Gianluca Carnevale, Giulia De Marchi, Atsunori Tsuchiya, Soichi Ishii, Takafumi Tonouchi, Kaito Furuyama, Yuan Yang, Masaki Mito, Hiroyuki Abe, Rosanna Di Tinco, Vincenzo Cardinale

Cytotherapy 27 ( 3 ) 259 - 278 2025年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Cellular and gene therapy (CGT) products have emerged as a popular approach in regenerative medicine, showing promise in treating various pancreatic and liver diseases in numerous clinical trials. Before these therapies can be tested in human clinical trials, it is essential to evaluate their safety and efficacy in relevant animal models. Such preclinical testing is often required to obtain regulatory approval for investigational new drugs. However, there is a lack of detailed guidance on selecting appropriate animal models for CGT therapies targeting specific pancreatic and liver conditions, such as pancreatitis and chronic liver diseases. In this review, the gastrointestinal committee for the International Society for Cell and Gene Therapy provides a summary of current recommendations for animal species and disease model selection, as outlined by the US Food and Drug Administration, with references to EU EMA and Japan PMDA. We discuss a range of small and large animal models, as well as humanized models, that are suitable for preclinical testing of CGT products aimed at treating pancreatic and liver diseases. For each model, we cover the associated pathophysiology, commonly used metrics for assessing disease status, the pros and limitations of the models, and the relevance of these models to human conditions. We also summarize the use and application of humanized mouse and other animal models in evaluating the safety and efficacy of CGT products. This review aims to provide comprehensive guidance for selecting appropriate animal species and models to help bridge the gap between the preclinical research and clinical trials using CGT therapies for specific pancreatic and liver diseases.

DOI： 10.1016/j.jcyt.2024.11.008

Human placental extract improves liver cirrhosis in mice with regulation of macrophages and senescent cells. 国際誌

Natsuki Ishikawa, Yusuke Watanabe, Yuichirou Maeda, Tomoaki Yoshida, Naruhiro Kimura, Hiroyuki Abe, Akira Sakamaki, Hiroteru Kamimura, Takeshi Yokoo, Kenya Kamimura, Atsunori Tsuchiya, Shuji Terai

Regenerative therapy 28 509 - 516 2025年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: Cirrhosis is a disease with poor prognosis that requires the development of a novel therapeutic approach alternative to liver transplantation. In this study, we focused on the placenta and aimed to clarify the effects of human placental extract (HPE) on cirrhosis. METHODS: A mouse model of carbon tetrachloride-induced cirrhosis was used to evaluate the effect of HPE administration subcutaneously and compared with the control group (n = 8 for each group). In vitro and in vivo, real time-PCR and immunostaining were performed for HPE mechanistic analysis. Spatial transcriptomics was also performed for detailed analysis of the effect of HPE on cirrhosis. RESULTS: HPE administration improved serum ALT levels compared to control mice. Furthermore, there was a decrease in the number of senescent cells in the liver and the mRNA levels of secrete senescence-associated secretory phenotype factors and Cdkn2a (p16). In vitro, HPE induced macrophage polarization to the anti-inflammatory M2 phenotype. Spatial transcriptomics was also performed to analyze the underlying anti-inflammatory mechanism. The results showed that HPE strongly polarized macrophages to the M2 phenotype, especially in macrophage-rich regions in the liver. Gene expression pathway analysis using spatial transcriptomics also revealed the possibility of improving senescent cell-derived inflammation via mitochondrial function. CONCLUSIONS: HPE improves serum ALT levels via anti-inflammatory mechanisms in macrophages and senescent cells. HPE serves as a novel agent for cirrhosis treatment.

DOI： 10.1016/j.reth.2025.01.017

Small Intestinal Bacterial Overgrowth Is a Predictor of Overt Hepatic Encephalopathy in Patients with Liver Cirrhosis. 国際誌

Akira Sakamaki, Kunihiko Yokoyama, Hanako Yamazaki, Takuya Wakabayashi, Yuichi Kojima, Kentaro Tominaga, Atsunori Tsuchiya, Kenya Kamimura, Junji Yokoyama, Shuji Terai

Journal of clinical medicine 14 ( 5 ) 2025年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Objective: Liver cirrhosis (LC) progression induces intestinal microbiota abnormalities, such as small intestinal bacterial overgrowth (SIBO), and these changes lead to the inflow of gut pathogens and their degradation products into the vessels, causing cirrhotic complications such as hepatic encephalopathy (HE). Methods: To clarify the relationship between the development of overt HE and SIBO, we conducted a three-year observation after assessment of SIBO in patients with LC. Results: In the analysis of 107 patients, with a mean follow-up duration of 29.4 months, 31 were diagnosed with SIBO and 30 with covert HE. In the Cox multivariate regression analysis for prognosis, the Child-Pugh score, blood urea nitrogen level, and the Union for International Cancer Control (UICC) stage of hepatocellular carcinoma were derived using the following five factors: white blood cell count, blood urea nitrogen level, Child-Pugh score, UICC stage, and serum aspartate aminotransferase and alkaline phosphatase levels (p = 0.002, hazard ratio [HR] 3.733, 95% confidence interval [CI] 1.592-8.754, p = 0.001, HR 1.076, 95% CI 1.030-1.123, and p < 0.001, HR 2.767, 95% CI 1.780-4.302, respectively). Furthermore, in the Cox multivariate regression analysis for overt HE development, covert HE and methane-producing SIBO were derived using the following four factors: methane-producing SIBO, UICC stage, covert HE, and serum ammonia levels (p = 0.038, HR 5.008, 95% CI 1.096-22.892 and p = 0.006, HR 8.597, 95% CI 1.881-39.291, respectively). Conclusions: M-SIBO positivity was a significant predictor of overt HE.

DOI： 10.3390/jcm14051491

Pruritus in Chronic Cholestatic Liver Diseases, Especially in Primary Biliary Cholangitis: A Narrative Review. 国際誌

Tatsuo Kanda, Reina Sasaki-Tanaka, Naruhiro Kimura, Hiroyuki Abe, Tomoaki Yoshida, Kazunao Hayashi, Akira Sakamaki, Takeshi Yokoo, Hiroteru Kamimura, Atsunori Tsuchiya, Kenya Kamimura, Shuji Terai

International journal of molecular sciences 26 ( 5 ) 2025年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Patients with chronic cholestatic liver diseases often experience itch and struggle with this symptom. We discuss the mechanism of itch in patients with chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and others, and their therapies, including ileal bile acid transporter (IBAT) inhibitors. In patients with PBC, there are high serum/plasma concentrations of multiple factors, including bile salts, bilirubin, endogenous opioids, lysophosphatidic acid (LPA), autotaxin, and histamine. Bile salts, bilirubin, LPA, and autotaxin affect itch mediators in the skin and sensory nerves, while the endogenous opioid balance affects mediators in the spinal cord. Itch is sensitized by both the peripheral and central nervous systems. Both mechanisms are involved in itch in patients with chronic cholestatic liver disease. Although IBAT inhibitors have been approved for use in pediatric cholestatic conditions, such as progressive familial intrahepatic cholestasis and Alagille syndrome, IBAT inhibition seems to be a promising treatment for chronic refractory itch in patients with PBC. A traditional non-systematic review results in this narrative review. Multidisciplinary cooperation, involving hepatologists, dermatologists, and pharmacists, could provide better treatment for PBC patients suffering from refractory itch. In conclusion, we summarized the existing knowledge on itch caused by chronic cholestatic liver diseases, especially in PBC with a focus on the mechanisms and therapies. This narrative review provides the mechanisms and therapeutic options for itch in patients with chronic cholestatic liver diseases.

DOI： 10.3390/ijms26051883

Real-World Setting of Efficacy and Safety of 3 Years of Rifaximin Administration in Japanese Patients with Hepatic Encephalopathy: A Multicenter Retrospective Study. 国際誌

Hideto Kawaratani, Tadashi Namisaki, Yasuteru Kondo, Ryoji Tatsumi, Naoto Kawabe, Norikazu Tanabe, Akira Sakamaki, Kyoko Hoshikawa, Yoshihito Uchida, Kei Endo, Takumi Kawaguchi, Tsunekazu Oikawa, Yoji Ishizu, Shuhei Hige, Taro Takami, Shuji Terai, Yoshiyuki Ueno, Satoshi Mochida, Kazuhiko Koike, Hitoshi Yoshiji

Journal of clinical medicine 14 ( 4 ) 2025年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Background/Objectives: Rifaximin is a therapeutic agent for patients with hepatic encephalopathy (HE); however, there is little data on the effects of its long-term (>1 year) administration in Japanese patients with cirrhosis. The effects and safety of 3-year rifaximin treatment on HE was investigated in Japan. Methods: A total of 190 Japanese patients with cirrhosis who were continuously administered rifaximin for more than 1 year suffered overt or covert HE, which was diagnosed by a physician. Laboratory data were collected at baseline, 3, 6, 12, 18, 24, 30, and 36 months following rifaximin administration. We examined the cumulative overt HE incidences, overall survival rates, and hepatic functional reserves following rifaximin treatment. The occurrence of adverse events was also assessed. Results: The levels of ammonia improved significantly after 3 months of rifaximin administration, which continued for 3 years. Serum albumin and prothrombin activity also significantly improved 3 years after initiation of rifaximin treatment. Cumulative overt HE incidences were 12.1%, 19.7%, and 24.9% at 1, 2, and 3 years, respectively. The survival rates following rifaximin treatment were 100%, 88.9%, and 77.8% at 1, 2, and 3 years, respectively. In contrast, renal function and electrolytes did not change following rifaximin administration. Only three (1.6%) patients discontinued rifaximin therapy because of severe diarrhea after 1 year of rifaximin administration. No other serious adverse events were observed. Conclusions: Three years of continuous rifaximin (RFX) treatment was both effective and safe for patients with hepatic encephalopathy. Liver function improved and did not worsen during treatment.

DOI： 10.3390/jcm14041358

Combination therapies with immune checkpoint inhibitor-based combination therapies for hepatocellular carcinoma with major vascular invasion. 国際誌

Tatsuo Kanda, Reina Sasaki-Tanaka, Shuji Terai

Hepatology international 2025年2月

Correction: Watanabe et al. Pemafibrate Improves Alanine Aminotransferase Levels Independently of Its Lipid-Lowering Effect. <i>Livers</i> 2023, <i>3</i>, 562–568

Azuma Watanabe, Ryoko Horigome, Yumiko Nakatsuka, Shuji Terai

Livers 2025年2月

Hepatitis B virus infection and its treatment in Eastern Ethiopia 国際誌

Tatsuo Kanda, Reina Sasaki-Tanaka, Atsunori Tsuchiya, Shuji Terai

World Journal of Hepatology 17 ( 1 ) 99209 - 99209 2025年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Baishideng Publishing Group Inc.

Hepatitis B virus (HBV) infection causes acute and chronic hepatitis, compensated and decompensated cirrhosis, and hepatocellular carcinoma worldwide. The actual status of HBV infection and its treatment in certain regions of Asian and African countries, including Ethiopia, has not been well-documented thus far. Antiviral therapy for HBV infection can prevent the progression of HBV-related liver diseases and decrease the HBV-related symptoms, such as abdominal symptoms, fatigue, systemic symptoms and others. In Eastern Ethiopia, HBV-infected patients with cirrhosis were found to be positive for the HBV e antigen and to have a higher viral load than those without cirrhosis. Notably, 54.4% of patients practiced khat chewing and 18.1% consumed excessive amounts of alcohol. Tenofovir disoproxil fumarate effectively suppressed HBV DNA in those infected with HBV. It is important to elucidate the actual status of HBV infection in Eastern Ethiopia to eliminate HBV infection worldwide by 2030. HBV vaccination and the educational programs for Health Science students that provide practical strategies could help to reduce HBV infection in Eastern Ethiopia.

DOI： 10.4254/wjh.v17.i1.99209

Aligning cellular and molecular components in age-dependent tertiary lymphoid tissues of kidney and liver. 国際誌

Naoya Toriu, Yuki Sato, Hiroteru Kamimura, Takahisa Yoshikawa, Masaou Tanaka, Shinya Yamamoto, Shingo Fukuma, Masakazu Hattori, Shuji Terai, Motoko Yanagita

PloS one 20 ( 2 ) e0311193 2025年

記述言語：英語掲載種別：研究論文（学術雑誌）

Tertiary lymphoid tissues (TLTs) are ectopic lymphoid structures induced by multiple stimuli, including infection and tissue injuries; however, their clinical relevance in disease progression has remained unclear. We demonstrated previously that TLTs develop in mouse and human kidneys with aging and can be a potential marker of kidney injury and prognosis, and therapeutic targets. In addition, we found that two types of unique lymphocytes that emerge with aging, senescence-associated T cells and age-associated B cells, are essential for TLT formation in the kidney. Although TLTs develop with aging in other organs as well, their cellular and molecular components, and clinical significance remain unclear. In the present study, we found that TLTs developed in the liver with aging, and that their cellular and molecular components were similar to those in the kidneys. Notably, senescence-associated T cells and age-associated B cells were also present in hepatic TLTs. Furthermore, analysis of publicly available data on human liver biopsy transcriptomes revealed that the expression of TLT-related genes was elevated in the liver biopsy samples from hepatitis C virus (HCV)-infected patients compared with those without HCV infection and was associated with liver injury and fibrosis. Therefore, we analyzed liver biopsy samples from 47 HCV patients and found that TLTs were present in 87.2% of cases and that the numbers and stages of TLTs were higher in aged patients and cellular and molecular components of TLTs in humans were similar to those in mice. Our findings suggesting that age-dependent TLT formation is a systemic phenomenon across the tissues and aging is also a predisposing factor for TLT formation across organs.

DOI： 10.1371/journal.pone.0311193

Enrichment of Porphyromonas gingivalis in colonic mucosa-associated microbiota and its enhanced adhesion to epithelium in colorectal carcinogenesis: Insights from in vivo and clinical studies. 国際誌

Shunya Motosugi, Naoki Takahashi, Shuhei Mineo, Keisuke Sato, Takahiro Tsuzuno, Yukari Aoki-Nonaka, Nao Nakajima, Kazuya Takahashi, Hiroki Sato, Haruna Miyazawa, Koji Taniguchi, Shuji Terai, Koichi Tabeta

PloS one 20 ( 3 ) e0320383 2025年

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: The oral-gut axis is believed to play a role in the pathogenesis of colorectal cancer (CRC). Previous studies have demonstrated the transmission of oral microbiota to the gut, disrupting gut microbial balance and creating a protumorigenic microenvironment conducive to CRC progression. Fusobacterium nucleatum is a putative periodontal pathogen recognized as a specific bacterium that promotes CRC development. However, the possible involvement of other periodontal pathogens in CRC is poorly understood. This study aimed to explore the effects of ingested periodontal pathogens on experimental CRC in mice and elucidate the underlying mechanisms. METHODS: In this study, experimental colitis-induced CRC mouse models were used. The mice were orally administered periodontal pathogens (Porphyromonas gingivalis and Prevotella intermedia) three times a week during the experimental period. The CRC severity between the P. gingivalis-treated and P. intermedia-treated groups was compared. Lumen-associated microbiota (LAM) and mucosa-associated microbiota (MAM) were analyzed in both mouse and human samples. In vitro studies were conducted using intestinal epithelial cells to explore the possible mechanisms by which the periodontal pathogens affect the CRC development. RESULTS: The P. gingivalis-treated group exhibited significantly increased CRC severity compared to the other groups among azoxymethane/dextran sodium sulfate (AOM/DSS)-induced mouse models. The LAM and MAM exhibited distinct bacterial compositions, and P. gingivalis was enriched more in MAM than in LAM. In vitro adhesion assays revealed that P. gingivalis had higher adhesive capacity to intestinal epithelial cells than P. intermedia and indicated the possible involvement of gingipains in such a capacity. CONCLUSION: P. gingivalis is enriched in MAM, and its subsequent adhesion to intestinal epithelial cells is potentially involved in the progression of CRC.

DOI： 10.1371/journal.pone.0320383

Persistent body-weight change on achalasia and peroral endoscopic myotomy: a multicenter cohort study.

Kazuya Takahashi, Hiroki Sato, Yuto Shimamura, Hirofumi Abe, Hironari Shiwaku, Junya Shiota, Chiaki Sato, Takuya Satomi, Masaki Ominami, Yoshitaka Hata, Hisashi Fukuda, Ryo Ogawa, Jun Nakamura, Tetsuya Tatsuta, Yuichiro Ikebuchi, Shuji Terai, Haruhiro Inoue

Journal of gastroenterology 2024年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The distribution of body weight in patients with achalasia and after peroral endoscopic myotomy (POEM) has not been investigated. The role of body weight assessment after treatment remains unclear. METHODS: Using the multicenter achalasia cohort, the frequency of underweight (body mass index [BMI] < 18.5 kg/m2) and overweight (BMI ≥ 25.0 kg/m2) and their associated clinical characteristics were analyzed. After POEM, risk factors for insufficient- (underweight persistently) and excessive- (responded to overweight) weight gainers were investigated. The correlation between BMI-increase rate and severity of esophageal symptoms post-POEM was evaluated. RESULTS: Among 3,410 patients, 23.0% and 15.7% were underweight and overweight, respectively. Factors associated with underweight were higher age, female sex, severe symptoms, high lower esophageal sphincter (LES) pressure, and non-dilated esophagus (all p < 0.01). Longitudinal analyses revealed that weight gain post-POEM was achieved after a long duration (≥ 12 months; p < 0.01). In 528 patients post-POEM, the frequency of underweight reduced to 8.3% (p < 0.01). Risk factors for insufficient-weight gain (36.1% of underweight patients) included low BMI (p < 0.01) and high LES pressure (p = 0.03) and conversely for excessive-weight gain. Machine learning models based on patient characteristics successfully predicted insufficient- and excessive-weight gainers with an area under the curve value of 0.74 and 0.75, respectively. Esophageal symptoms post-POEM did not correlate with BMI increase. CONCLUSION: Underweight is not solely a condition of advanced achalasia. After POEM, insufficient- or excessive-weight gainers are not rare and can be predicted preoperatively. Body weight change is an independent nutrition parameter rather than a part of the assessment of residual esophageal symptoms.

DOI： 10.1007/s00535-024-02205-9

Dasatinib and Quercetin as Senolytic Drugs Improve Fat Deposition and Exhibit Antifibrotic Effects in the Medaka Metabolic Dysfunction-Associated Steatotic Liver Disease Model. 国際誌

Shunta Yakubo, Hiroyuki Abe, Yawen Li, Marina Kudo, Atsushi Kimura, Takuya Wakabayashi, Yusuke Watanabe, Naruhiro Kimura, Toru Setsu, Takeshi Yokoo, Akira Sakamaki, Hiroteru Kamimura, Atsunori Tsuchiya, Kenya Kamimura, Shuji Terai

Diseases (Basel, Switzerland) 12 ( 12 ) 2024年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Metabolic dysfunction-associated steatotic liver disease (MASLD) causes cellular senescence due to oxidative stress, endoplasmic reticulum stress, and ectopic fat deposition in the liver. Recently, dasatinib, an antitumor agent, and quercetin, a dietary supplement, were combined as a senolytic drug to eliminate senescent cells. Thus, this study aimed to examine the effects of dasatinib and quercetin administration on removing senescent cells and their therapeutic effects on MASLD in a medaka MASLD model. Dasatinib and quercetin were administered to a medaka MASLD model, which was fed a high-fat diet by dissolving them in aquarium water. The results revealed that senescent cells in the liver were increased in the HFD group but improved in the treatment group. Hematoxylin and eosin staining also showed that treatment improved fat deposition in hepatocytes. In addition, TGFβ1, a driver factor of fibrosis, was reduced in the treatment group. Dasatinib and quercetin eliminated senescent cells in MASLD, attenuated fat deposition, and suppressed fibrosis gene expression. The results indicate that dasatinib and quercetin as senolytic drugs are novel therapeutic agents that reduce MASLD.

DOI： 10.3390/diseases12120317

ROI Selection to Improve Prediction Performance of CNN for Cirrhosis Detection Using Ultrasound Images 査読

Kazuma Nakata, Yusuke Fujita, Yoshihiro Mitani, Yoshihiko Hamamoto, Makoto Segawa, Shuji Terai

2024 IEEE 13th Global Conference on Consumer Electronics (GCCE) 636 - 640 2024年11月

Factors involved in gastroesophageal varix-related events in patients with hepatitis C virus-related compensated and decompensated cirrhosis after direct-acting antiviral therapy. 国際誌

Yuki Tahata, Hayato Hikita, Satoshi Mochida, Nobuyuki Enomoto, Norifumi Kawada, Akio Ido, Daiki Miki, Masayuki Kurosaki, Hitoshi Yoshiji, Ryotaro Sakamori, Hidekatsu Kuroda, Hiroshi Yatsuhashi, Taro Yamashita, Yoichi Hiasa, Naoya Kato, Hisamitsu Miyaaki, Yoshiyuki Ueno, Yoshito Itoh, Kentaro Matsuura, Taro Takami, Yasuhiro Asahina, Goki Suda, Norio Akuta, Ryosuke Tateishi, Yasunari Nakamoto, Eiji Kakazu, Shuji Terai, Masahito Shimizu, Masanori Miyazaki, Yasutoshi Nozaki, Satoshi Sobue, Hiroki Yano, Tomokatsu Miyaki, Akihiro Moriuchi, Takeshi Hori, Kumiko Shirai, Kazuhiro Murai, Yoshinobu Saito, Takahiro Kodama, Tomohide Tatsumi, Tomomi Yamada, Tetsuo Takehara

Hepatology research : the official journal of the Japan Society of Hepatology 2024年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIM: The incidence of and factors involved in gastroesophageal varix-related events in hepatitis C virus-related cirrhosis patients, including decompensated cirrhosis, after direct-acting antiviral therapy are unclear. METHODS: We conducted a multicenter study using prospective data from 478 hepatitis C virus-related cirrhosis patients treated with direct-acting antiviral therapy from February 2019 to December 2021 at 33 Japanese hospitals. Gastroesophageal varices were classified as F1 (small-caliber), F2 (moderately enlarged), or F3 (markedly enlarged) according to the Japanese criteria. Patients without varix or with F1 without red color signs were defined as low-risk varix, and patients with ≥F2 or red color signs or a history of rupture were defined as high-risk varix. Varix-related events were defined as prophylactic treatment or rupture of gastroesophageal varix. RESULTS: The median age was 70 years, 43% of patients had decompensated cirrhosis, and 16% had high-risk varices (13% in compensated and 33% in decompensated, p < 0.001). Sustained virologic response rates were 94.9% for compensated cirrhosis and 91.3% for decompensated cirrhosis (p = 0.120). Across 35.7 months, 25 patients received prophylactic treatment, and four experienced varix rupture. The 3-year incidence rate of varix-related events was 6.2% (3.5% in compensated and 9.9% in decompensated, p = 0.001). In the multivariate analysis, high-risk varix (p < 0.001), high baseline gamma-glutamyl transpeptidase levels (p < 0.001), and virologic failure (p = 0.004) were significantly involved in varix-related events. CONCLUSIONS: The cumulative incidence rate of varix-related events was significantly higher in decompensated cirrhosis than in compensated cirrhosis. Baseline varix status, baseline gamma-glutamyl transpeptidase levels, and virologic response were related to varix-related events after direct-acting antiviral therapy.

DOI： 10.1111/hepr.14131

Association between Clinical Characteristics and Sarcopenia or Sarcopenic Obesity in Crohn's Disease.

Takumi Naruse, Hiroki Sato, Kazuya Takahashi, Chihiro Sato, Yuichi Kojima, Yuzo Kawata, Kentaro Tominaga, Ken-Ichi Mizuno, Shuji Terai

Internal medicine (Tokyo, Japan) 2024年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Objective Crohn's disease (CD) is a chronic inflammatory bowel disease that is associated with malnutrition. Sarcopenia is a malnutrition condition characterized by skeletal muscle loss that impairs the physical function. We investigated the clinical characteristics of patients with CD with sarcopenia and sarcopenic obesity (sarcopenic-o). Methods The body composition of patients with CD was evaluated using a bioelectrical impedance analysis. The clinical characteristics of patients with sarcopenia and sarcopenic-o were analyzed, and a predictive model for sarcopenia was developed. Patients: Patients with CD recruited from 2019 to 2021 were included. Results Among the 104 patients, 35 (33.7%) and 10 (9.6%) had sarcopenia and sarcopenic-o, respectively. In the sarcopenia group, the skeletal muscle index (SMI) and body mass index (BMI) were lower than those in the control group (SMI, 6.3 kg/m2 vs. 7.7 kg/m2, p<0.01; BMI, 18.8 kg/m2 vs. 22.6 kg/m2, p<0.01), whereas the Crohn's disease activity index (CDAI) was higher than in the control group (114.2 vs. 42.0, p<0.01). The predictive models of sarcopenia using the BMI and CDAI revealed high performance with areas under the receiver operating characteristic curve (AUC) of 0.87 and 0.72, respectively, and high specificity (0.94) and sensitivity (0.71), respectively. Sarcopenic-o patients could not be screened using the BMI (25 kg/m2), and the SMI and body fat percentage were negatively correlated in patients with sarcopenia (p<0.01). Conclusion Sarcopenia and sarcopenic-o are relatively common conditions among patients with CD. Sarcopenia can be predicted using the clinical parameters of BMI and CDAI. Sarcopenic-o can be a severe form of sarcopenia.

DOI： 10.2169/internalmedicine.4420-24

Diffuse Large B-cell Lymphoma with Severe Lactic Acidosis and Liver Failure: A Case Report and Literature Review.

Shun Yamazaki, Yusuke Watanabe, Kazuya Takahashi, Kentaro Tominaga, Satoshi Ikarashi, Takeshi Yokoo, Hiroteru Kamimura, Atsunori Tsuchiya, Shuji Terai

Internal medicine (Tokyo, Japan) 2024年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Among causes of liver failure, liver failure due to lymphocytic infiltration is rare. Unlike typical liver failure, some cases present with severe lactic acidosis and a poor prognosis. We herein report a case of diffuse large B-cell lymphoma with severe lactic acidosis and liver failure. We further discuss the characteristics of similar cases in the literature, suggesting that intrahepatic infiltration by hematological malignant cells should be considered as a differential diagnosis in the presence of severe lactic acidosis and liver failure. This study underscores the importance of early recognition and serves as a reference for future cases.

DOI： 10.2169/internalmedicine.4450-24

自験例から考察したHBV de novo再活性化診療のピットフォール

木村究, 横尾健, 吉田智彰, 渡邉雄介, 木村成宏, 阿部寛幸, 上村博輝, 坂牧僚, 上村顕也, 土屋淳紀, 寺井崇二

日本消化器病学会甲信越支部例会・日本消化器内視鏡学会甲信越支部例会抄録集 75回・97回 70 - 70 2024年10月

治療困難胆管結石に対する経口胆道鏡下治療の有用性

五十嵐聡, 林和直, 柴田理, 寺井崇二

Gastroenterological Endoscopy 66 ( Suppl.2 ) 2301 - 2301 2024年10月

「長期臨床経過を見据えた消化器疾患の治療・管理における工夫と課題」自己免疫性膵炎のステロイド治療導入後再燃例における臨床経過の検証

田中裕登, 柴田理, 五十嵐聡, 林和直, 寺井崇二

日本消化器病学会甲信越支部例会・日本消化器内視鏡学会甲信越支部例会抄録集 75回・97回 51 - 51 2024年10月

非切除肝門部領域胆管癌に対する内視鏡的胆管ステント留置術の検討

林和直, 柴田理, 五十嵐聡, 寺井崇二

Gastroenterological Endoscopy 66 ( Suppl.2 ) 2292 - 2292 2024年10月

Maid gene dysfunction promotes hyperobesity via the reduction of adipose tissue inflammation in Mc4r gene-deficient mice. 国際誌

Kyutaro Koyama, Akira Sakamaki, Shinichi Morita, Itsuo Nagayama, Marina Kudo, Yuto Tanaka, Naruhiro Kimura, Yoshihisa Arao, Hiroyuki Abe, Kenya Kamimura, Shuji Terai

Scientific reports 14 ( 1 ) 21126 - 21126 2024年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

The onset and progression mechanisms of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are being studied. We developed and analyzed a new mouse model of obesity by combining maternal Id-like molecule (Maid) and melanocortin-4 receptor (Mc4r) gene deletions. Four mice, each at 12 and 28 weeks of age, were analyzed for each genotype: Maid gene knockout, Mc4r gene knockout, combined Mc4r and Maid gene knockout, and Mc4r gene knockout with a high-fat diet. Mice with a combined deficiency of Mc4r and Maid gene showed significantly more severe obesity compared to all other genotypes, but no liver fibrosis or a decline in metabolic status were observed. In visceral white adipose tissue, Maid and Mc4r gene knockout mice had fewer CD11c-positive cells and lower mRNA expression of both inflammatory and anti-inflammatory cytokines. Furthermore, Maid and Mc4r gene knockout mice showed lower expression of adipocytokines in visceral white adipose tissue and uncoupling protein-1 in scapular brown adipose tissue. The expression of adipocytokines and uncoupling protein-1 is regulated by sympathetic nerve signaling that contribute severe obesity in Maid and Mc4r gene knockout mice. These mechanisms contribute hyperobesity in Maid and Mc4r gene knockout mice.

DOI： 10.1038/s41598-024-72217-1

症候性巨大肝嚢胞に対する嚢胞内洗浄併用の塩酸ミノサイクリン硬化療法が長期的効果を呈した1例

小川和也, 上村顕也, 石井壮一, 遠藤沙織, 石川夏生, 阿部寛幸, 坂牧僚, 寺井崇二

日本消化器病学会雑誌 121 ( 9 ) 769 - 776 2024年9月

記述言語：日本語出版者・発行元：(一財)日本消化器病学会

肝嚢胞は,増大して圧迫症状や閉塞性黄疸などをきたし,症候性となることがある.内科的治療として嚢胞穿刺排液,硬化療法があるが,再発率が高い.今回われわれは,15年以上の経過で徐々に増大して圧迫症状と閉塞性黄疸をきたした症候性巨大肝嚢胞に対して,嚢胞穿刺排液と嚢胞内洗浄を併用する塩酸ミノサイクリンによる経皮的硬化療法を施行し,著明な嚢胞縮小効果と症状改善を認めた症例を経験したので報告する.(著者抄録)

その他リンク： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J01118&link_issn=&doc_id=20240919370009&doc_link_id=%2Fck8syokb%2F2024%2F012109%2F009%2F0769-0776%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fck8syokb%2F2024%2F012109%2F009%2F0769-0776%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

PCPE-1, a brown adipose tissue-derived cytokine, promotes obesity-induced liver fibrosis. 国際誌

Yung Ting Hsiao, Yohko Yoshida, Shujiro Okuda, Manabu Abe, Seiya Mizuno, Satoru Takahashi, Hironori Nakagami, Ryuichi Morishita, Kenya Kamimura, Shuji Terai, Tin May Aung, Ji Li, Takaaki Furihata, Jing Yuan Tang, Kenneth Walsh, Akihito Ishigami, Tohru Minamino, Ippei Shimizu

The EMBO journal 2024年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Metabolic dysfunction-associated steatohepatitis (MASH, previously termed non-alcoholic steatohepatitis (NASH)), is a major complication of obesity that promotes fatty liver disease. MASH is characterized by progressive tissue fibrosis and sterile liver inflammation that can lead to liver cirrhosis, cancer, and death. The molecular mechanisms of fibrosis in MASH and its systemic control remain poorly understood. Here, we identified the secreted-type pro-fibrotic protein, procollagen C-endopeptidase enhancer-1 (PCPE-1), as a brown adipose tissue (BAT)-derived adipokine that promotes liver fibrosis in a murine obesity-induced MASH model. BAT-specific or systemic PCPE-1 depletion in mice ameliorated liver fibrosis, whereas, PCPE-1 gain of function in BAT enhanced hepatic fibrosis. High-calorie diet-induced ER stress increased PCPE-1 production in BAT through the activation of IRE-1/JNK/c-Fos/c-Jun signaling. Circulating PCPE-1 levels are increased in the plasma of MASH patients, suggesting a therapeutic possibility. In sum, our results uncover PCPE-1 as a novel systemic control factor of liver fibrosis.

DOI： 10.1038/s44318-024-00196-0

Urinary NGAL in gastrointestinal diseases can be used as an indicator of early infection in addition to acute kidney injury marker. 国際誌

Yuichi Kojima, Atsunori Tsuchiya, Masaki Mito, Yusuke Watanabe, Yuzo Kawata, Kentaro Tominaga, Shuji Terai

JGH open : an open access journal of gastroenterology and hepatology 8 ( 8 ) e70009 2024年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND AIM: Neutrophil gelatinase-associated lipocalin (NGAL) is characterized by increased expression before the rise in serum creatinine and has been used as a biomarker for the early prediction of acute kidney injury (AKI). However, there have been no comprehensive analyses of its significance in gastrointestinal diseases. This study aimed to analyze the usefulness of measuring urinary NGAL levels in patients with gastrointestinal diseases. METHODS: This study included 171 patients with a wide range of gastrointestinal diseases. Urinary NGAL levels were measured in all patients within 24 h of admission and 72 h later. RESULTS: Urinary NGAL levels were higher in patients with acute pancreatitis and acute cholangitis/cholecystitis than in those with other diseases. Although lower than in these diseases, urinary NGAL tends to be higher in inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, as well as in acute and chronic liver diseases, and is higher in liver cirrhosis as the Child-Pugh grade increases. Furthermore, we found that the group with higher urinary NGAL levels, which continued to increase over time, had worse hospital stays and prognosis. CONCLUSION: Urinary NGAL could be used as an indicator of infectious diseases rather than an indicator of AKI in inflammatory bowel diseases and cirrhosis, and could predict the prognosis of patients with gastrointestinal diseases.

DOI： 10.1002/jgh3.70009

【肝臓リハビリテーションの現状と問題点】

寺井崇二, 吉治仁志, 川口巧, 清水雅仁, 辻哲也

肝臓 65 ( 8 ) 351 - 367 2024年8月

Diagnosis and resolution of olmesartan-associated sprue-like enteropathy confirmed by capsule endoscopy: a case report and literature review.

Erina Kodama, Yuzo Kawata, Shun Yamazaki, Takanori Igarashi, Yuichi Kojima, Kentaro Tominaga, Junji Yokoyama, Terasu Honma, Shuji Terai

Clinical journal of gastroenterology 2024年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Herein, we describe a case of olmesartan-associated sprue-like enteropathy, in which improvement in villous atrophy was confirmed using small bowel capsule endoscopy. The patient was a 69-year-old woman who had persistent watery diarrhea (20 bowel movements/day) for 1 year and experienced a weight loss of 10 kg in the same period. Abdominal computed tomography revealed no abnormalities, and blood test results revealed no inflammatory reactions. Upper endoscopy and colonoscopy revealed villous atrophy in the duodenum and terminal ileum. As the patient was administered olmesartan for a long time and capsule endoscopy showed villous atrophy throughout the small bowel, she was diagnosed with olmesartan-associated sprue-like disease. Following the discontinuation of the medication, symptoms of diarrhea soon improved, and repeat capsule endoscopy indicated improvement in small intestinal villous atrophy. Olmesartan-associated sprue-like enteropathy should be considered a differential diagnosis in patients with severe chronic watery diarrhea. Our report is the first in which capsule endoscopy was performed multiple times over a long period for follow-up observation of improvements in the small intestine. In addition, our literature review regarding capsule endoscopy for olmesartan-associated enteritis might aid clinicians in the early diagnosis of the condition and the assessment of treatment efficacy.

DOI： 10.1007/s12328-024-02023-9

Automatic ROI Selection with Reliability Evaluation Method for Cirrhosis Detection using Ultrasound Images 査読

Kazuma Nakata, Yusuke Fujita, Yoshihiro Mitani, Yoshihiko Hamamoto, Makoto Segawa, Shuji Terai, Isao Sakaida

IEEJ Transactions on Electrical and Electronic Engineering 19 ( 7 ) 2024年7月

Inflammation of the liver, HCC development and HCC establishment 招待査読

Tatsuo Kanda, Reina Sasaki-Tanaka, Shuji Terai

Hepatology International 2024年6月

Fibulin-4 as a potential extracellular vesicle marker of fibrosis in patients with cirrhosis. 国際誌

Masaru Kumagai, Atsunori Tsuchiya, Yuan Yang, Nobutaka Takeda, Kazuki Natsui, Yui Natusi, Kei Tomiyoshi, Fusako Yamazaki, Yohei Koseki, Hiroki Shinchi, Naoko Imawaka, Ryo Ukekawa, Takahiro Nishibu, Hiroyuki Abe, Takako Sasaki, Koji Ueda, Shuji Terai

FEBS open bio 2024年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Chronic liver injury leads to decreased liver function and increased fibrosis. Fibrosis is not only associated with the development of portal hypertension and carcinogenesis, but with the occurrence of events and a poor prognosis, highlighting the importance of non-invasive fibrosis assessment in patients. In the present study, we searched for markers related to liver fibrosis via proteomic analysis of small extracellular vesicles (sEVs). In the discovery cohort, proteomic analysis was carried out in the sEVs extracted from the sera of 5 patients with decompensated cirrhosis, 5 patients with compensated cirrhosis, and 5 controls without liver disease. Interestingly, in this cohort, fibulin-4 was significantly associated with cirrhosis while in the validation cohort [formed by 191 patients: 7 patients without disease, 16 patients without liver disease (other diseases), 38 patients with chronic liver disease (CLD), 75 patients with cirrhosis of Child-Pugh class A (36 without hepatocellular carcinoma [HCC], 29 with HCC), and 65 patients with cirrhosis of Child-Pugh class B-C (39 without HCC, 26 with HCC)], fibulin-4/CD9 levels increased with cirrhosis progression. Furthermore, the fibulin-4/CD9 ratio was significantly higher in patients with varices. Immunostaining also revealed strong fibulin-4 expression in cholangiocytes within the fibrous areas and mesothelial cells in liver tissue blood vessels. Taken together, our results suggest that fibulin-4, essential for lysyl oxidase activation, might be a new liver fibrosis marker found in the sEVs of patients with cirrhosis.

DOI： 10.1002/2211-5463.13842

胆膵内視鏡検査・治療における工夫とトラブルシューティング当院における副乳頭アプローチカニュレーション

名古屋拓郎, 小川光平, 五十嵐聡, 林和直, 寺井崇二

ENDOSCOPIC FORUM for digestive disease 39 ( 2 ) 154 - 154 2024年6月

IgG4関連疾患における診断・治療困難例に対する取り組み自己免疫性膵炎のステロイド治療導入後再燃例における臨床経過の検証

小川光平, 名古屋拓郎, 五十嵐聡, 林和直, 寺井崇二

ENDOSCOPIC FORUM for digestive disease 39 ( 2 ) 148 - 148 2024年6月

Platelet-rich plasma-derived extracellular vesicles improve liver cirrhosis in mice. 国際誌

Yuichirou Maeda, Yusuke Watanabe, Natsuki Ishikawa, Tomoaki Yoshida, Naruhiro Kimura, Hiroyuki Abe, Akira Sakamaki, Hiroteru Kamimura, Takeshi Yokoo, Kenya Kamimura, Atsunori Tsuchiya, Shuji Terai

Regenerative therapy 26 1048 - 1057 2024年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: Cirrhosis remains a significant clinical challenge due to its poor prognosis and limited treatment options, creating a high unmet medical need for the development of novel therapies. In this study, we analyzed the effects of a novel approach to treat cirrhosis using platelet-rich plasma-derived extracellular vesicles (PRPEV) in mice. METHODS: PRPEV were collected from platelet-rich plasma using ultrafiltration, and their proteomes were analyzed. The carbon tetrachloride (CCl4)-induced cirrhosis model of mice was used to evaluate the effect of PRPEV administration and compared with the control group (n = 8). In vitro and in vivo mechanistic analyses of PRPEV administration were confirmed using real time-PCR and immunostaining. RESULTS: Gene ontology analysis based on the proteome revealed that PRPEV contain many factors associated with EV and immune responses. In vitro, PRPEV polarize macrophages into an anti-inflammatory phenotype. Following PRPEV administration, there was a decrease in serum alanine aminotransferase levels and reduction in liver fibrosis, while mRNA levels of regenerative factors were upregulated and transforming growth factor β-1 was downregulated. Furthermore, the number of anti-inflammatory macrophages in the liver increased. CONCLUSIONS: PRPEV may contribute to hepatocyte proliferation, anti-inflammation, and anti-fibrogenesis in the liver. This novel concept paves the way for cirrhosis treatment.

DOI： 10.1016/j.reth.2024.10.010

胆膵内視鏡検査・治療における工夫とトラブルシューティング当院における副乳頭アプローチカニュレーション

名古屋拓郎, 小川光平, 五十嵐聡, 林和直, 寺井崇二

ENDOSCOPIC FORUM for digestive disease 39 ( 2 ) 154 - 154 2024年6月

IgG4関連疾患における診断・治療困難例に対する取り組み自己免疫性膵炎のステロイド治療導入後再燃例における臨床経過の検証

小川光平, 名古屋拓郎, 五十嵐聡, 林和直, 寺井崇二

ENDOSCOPIC FORUM for digestive disease 39 ( 2 ) 148 - 148 2024年6月

Novel scale for evaluating the therapeutic efficacy of per-oral endoscopic myotomy in achalasia.

Kazuya Takahashi, Hiroki Sato, Yuto Shimamura, Hirofumi Abe, Hironari Shiwaku, Junya Shiota, Chiaki Sato, Kenta Hamada, Masaki Ominami, Yoshitaka Hata, Hisashi Fukuda, Ryo Ogawa, Jun Nakamura, Tetsuya Tatsuta, Yuichiro Ikebuchi, Shuji Terai, Haruhiro Inoue

Journal of gastroenterology 2024年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Symptom scales for achalasia after per-oral endoscopic myotomy (POEM) are lacking. This study aimed to propose a new scale based on the conventional Eckardt score (c-ES) and evaluate persistent symptoms that impair patients' quality of life (QOL) post-POEM. METHODS: Dysphagia, regurgitation, and chest pain frequencies were assessed using a 6-point scale modified-ES (m-ES) after POEM, with "occasional" symptoms on the c-ES further subdivided into three-period categories on m-ES. Symptom severity was further evaluated using a 5-point scale ranging from 1 to 5 points, with a score ≥ 3 points defined as persistent symptoms impairing QOL. We analyzed the correlation between the m-ES and severity score, diagnostic performance of the m-ES for persistent symptoms, and overlaps between each residual symptom. RESULTS: Overall, 536 patients (median follow-up period, 2.9 years) post-POEM were included in this multicenter study. Significant correlations were observed between the m-ES and severity scores for dysphagia (r = 0.67, p < 0.01), regurgitation (r = 0.73, p < 0.01), and chest pain (r = 0.85, p < 0.01). Twenty-six patients (4.9%) had persistent symptoms post-POEM, and 23 of them had m-ES-specific symptom frequency ≥ once a month, which was determined as the optimal frequency threshold for screening persistent symptoms. The total m-ES predicted persistent symptoms more accurately than the total c-ES (area under the curve: 0.95 vs. 0.79, p < 0.01). Furthermore, dysphagia and chest pain were the major residual symptoms post-POEM covering 91.4% of regurgitation. CONCLUSIONS: The new post-POEM scale successfully evaluated the QOL-based patient symptom severities. Our study implied the possibility of a simpler scale using residual dysphagia and chest pain.

DOI： 10.1007/s00535-024-02119-6

Liver Diseases: From Bench to Bedside 招待査読

Tatsuo Kanda, Reina Sasaki-Tanaka, Shuji Terai

International Journal of Molecular Sciences 25 ( 10 ) 5454 2024年5月

Acute on chronic liver failureモデルに対する肝細胞老化除去治療の基礎的検討

渡邉雄介, 土屋淳紀, 寺井崇二

肝臓 65 ( 5 ) 252 - 252 2024年5月

消化器救急疾患における診断・治療と課題当院における重症急性膵炎の予後・感染性被包化膵壊死合併の検討

柴田理, 林和直, 寺井崇二

日本消化器病学会甲信越支部例会・日本消化器内視鏡学会甲信越支部例会抄録集 74回・96回 35 - 35 2024年5月

A rare cause of esophageal stenosis: Compression due to a thoracic osteophyte. 国際誌

Suguru Miida, Yoshihisa Arao, Nobutaka Takeda, Shu Goto, Yuichi Kojima, Naruhiro Kimura, Kazunao Hayashi, Atsunori Tsuchiya, Shuji Terai

DEN open 4 ( 1 ) e260 2024年4月

記述言語：英語

Several cases of esophageal stenosis caused by cervical vertebral osteophytes have been reported; however, few reports of esophageal stenosis caused by thoracic osteophytes are available. We describe the case of an 86-year-old man with esophageal stenosis caused by a thoracic osteophyte near the tracheal bifurcation. An endoscopic ultrasonography examination was scheduled to determine the cause of acute pancreatitis; however, lacerations observed at the bifurcation following endoscope removal during prior esophagogastroduodenoscopy led us to cancel the ultrasonography to avoid potential esophageal perforation. A review of the present case and six similar previous cases of thoracic osteophyte-associated esophageal stenosis (identified via a systematic search of the PubMed database) demonstrated the clinical importance of a thoracic osteophyte near physiological esophageal stenosis. Esophagogastroduodenoscopy and computed tomography should be performed to screen for vertebral osteophytes before endoscopic ultrasonography, endoscopic retrograde cholangiopancreatography, and transesophageal echocardiography to avoid iatrogenic accidents.

DOI： 10.1002/deo2.260

ダサチニブ及びケルセチンは老化細胞除去剤としてMASHメダカモデルにおいて老化細胞を減少させ病態改善に寄与する

阿部寛幸, 弥久保俊太, 渡邉雄介, 木村成宏, 横尾健, 坂牧僚, 上村博輝, 土屋淳紀, 上村顕也, 寺井崇二

肝臓 65 ( Suppl.1 ) A514 - A514 2024年4月

Portal biliopathyにより胆管消失症候群を来したと考えられる一例

木村究, 上村博輝, 渡邉雄介, 五十嵐聡, 土屋淳紀, 寺井崇二, 佐久間康成, 大西康晴, 眞田幸弘, 脇屋太一, 平田雄大, 大豆生田尚彦

肝臓 65 ( Suppl.1 ) A301 - A301 2024年4月

顕性肝性脳症の発症予測における,呼気中水素・メタン分析によるSIBO診断の有用性の検討

坂牧僚, 横山邦彦, 若林拓哉, 阿部寛幸, 土屋淳紀, 上村顕也, 寺井崇二

肝臓 65 ( Suppl.1 ) A410 - A410 2024年4月

再生と老化研究のCutting edge-臨床への展開を踏まえて- S-005151の慢性肝疾患患者を対象にした第2相医師主導治験での線維化改善と肝機能改善効果の検証

土屋淳紀, 阿部寛幸, 寺井崇二

肝臓 65 ( Suppl.1 ) A78 - A78 2024年4月

顕性肝性脳症の発症予測における,呼気中水素・メタン分析によるSIBO診断の有用性の検討

坂牧僚, 横山邦彦, 若林拓哉, 阿部寛幸, 土屋淳紀, 上村顕也, 寺井崇二

肝臓 65 ( Suppl.1 ) A410 - A410 2024年4月

ダサチニブ及びケルセチンは老化細胞除去剤としてMASHメダカモデルにおいて老化細胞を減少させ病態改善に寄与する

阿部寛幸, 弥久保俊太, 渡邉雄介, 木村成宏, 横尾健, 坂牧僚, 上村博輝, 土屋淳紀, 上村顕也, 寺井崇二

肝臓 65 ( Suppl.1 ) A514 - A514 2024年4月

メダカを用いた脂肪性肝疾患の多臓器合併症の検討

上村顕也, 大越麻理奈, 木村淳史, 寺井崇二

肝臓 65 ( Suppl.1 ) A332 - A332 2024年4月

オルガノイドが切り拓く消化器病研究新時代組織常在型マクロファージを有する新規小腸オルガノイドの開発

冨永顕太郎, Wells James, 寺井崇二

日本消化器病学会雑誌 121 ( 臨増総会 ) A186 - A186 2024年3月

小腸腫瘍の内視鏡診断・治療の最前線当院における原発性小腸癌13例の臨床的特徴

小島雄一, 川田雄三, 冨永顕太郎, 寺井崇二

日本消化器病学会雑誌 121 ( 臨増総会 ) A77 - A77 2024年3月

当院における慢性膵炎に伴う膵仮性嚢胞の合併症治療

林和直, 五十嵐聡, 寺井崇二

日本消化器病学会雑誌 121 ( 臨増総会 ) A334 - A334 2024年3月

【膵癌基礎研究の最前線RELOADED】臓器選択的ハイドロダイナミック遺伝子導入法によるラット膵癌モデルの作製

柴田理, 上村顕也, 寺井崇二

胆と膵 45 ( 2 ) 123 - 126 2024年2月

記述言語：日本語出版者・発行元：医学図書出版(株)

われわれは,これまで臓器選択的なハイドロダイナミック遺伝子導入法(hydrodynamic gene delivery:HGD)の研究を行ってきた。本稿では,この方法論を用いた膵臓選択的なヒト膵発癌関連遺伝子導入による,野生型ラット由来の膵癌モデル動物の作製について総説する。変異型KRASG12D遺伝子を導入した個体は,HGD後4週間で主膵管内に膵管内上皮腫瘍性病変(pancreatic intra-epithelial neoplasia:PanIN)が発生し,また腺房-導管異形成(acinar-to-ductal metaplasia:ADM)を認めた。発癌性を高めた条件下では,5週時点でADMの範囲拡大とそれに連続する腺癌および著明な間質増生を認め,浸潤性膵癌へと発展し肝臓,リンパ節,皮下への転移をも認めた。野生型ラットを対象とする臓器選択的な遺伝子導入によりラット膵癌モデルが確立できた。その簡便性と再現性から,本モデルを活用する分子生物学的解析の進歩が早期診断法,新規治療法の開発に寄与すると考える。(著者抄録)

【慢性肝臓病の克服を目指して】肝臓リハビリテーションと再生医療の開発状況

上村博輝, 土屋淳紀, 寺井崇二

日本内科学会雑誌 113 ( 1 ) 69 - 75 2024年1月

An updated review on the treatment for diversion colitis and pouchitis, with a focus on the utility of autologous fecal microbiota transplantation and its relationship with the intestinal microbiota.

Kentaro Tominaga, Yuichi Kojima, Yuzo Kawata, Kazuya Takahashi, Hiroki Sato, Atsunori Tsuchiya, Kenya Kamimura, Shuji Terai

Bioscience of microbiota, food and health 43 ( 3 ) 162 - 169 2024年

記述言語：英語掲載種別：研究論文（学術雑誌）

Diversion colitis (DC) is characterized by mucosal inﬂammation in the defunctioned segment of the colon following a colostomy or ileostomy. The major causes of DC are an increase in the number of aerobic bacteria, a lack of short-chain fatty acids (SCFAs), and immune disorders in the diverted colon. However, its exact pathogenesis remains unknown. Various treatment strategies for DC have been explored, although none have been definitively established. Treatment approaches such as SCFAs, 5-aminosalicylic acid enemas, steroid enemas, and irrigation with fibers have been attempted, yielding various degrees of efficacies in mitigating mucosal inflammation. However, only individual case reports demonstrating the limited effect of the following therapies have been published: leukocytapheresis, dextrose (hypertonic glucose) spray, infliximab, an elemental diet, and coconut oil. The usefulness of probiotics for treating DC has recently been reported. Furthermore, fecal microbiota transplantation (FMT) has emerged as a promising treatment for DC. This review provides an update on the treatment strategies of DC, with a particular focus on FMT and its relationship with the intestinal microbiota. FMT may become the first choice of treatment for some patients in the future because of its low medical costs, ease of use, and minimal side effects. Furthermore, FMT can also be used for postoperative DC prophylaxis.

DOI： 10.12938/bmfh.2024-014

[A case of long-term efficacy of minocycline hydrochloride sclerotherapy combined with intra-cystic lavage for a symptomatic giant liver cyst].

Kazuya Ogawa, Kenya Kamimura, Soichi Ishii, Saori Endo, Natsuki Ishikawa, Hiroyuki Abe, Akira Sakamaki, Shuji Terai

Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology 121 ( 9 ) 769 - 776 2024年

記述言語：日本語掲載種別：研究論文（学術雑誌）

Herein, we report a case of a man with a large symptomatic hepatic cyst that gradually enlarged over a follow-up period of 15 years, which eventually caused epigastric fullness and obstructive jaundice. The patient underwent percutaneous cystic drainage followed by sclerotherapy using minocycline hydrochloride combined with intracystic lavage. The treatment resulted in a significant reduction in the hepatic cyst size, symptom improvement, and absence of recurrence for 670 days.

DOI： 10.11405/nisshoshi.121.769

Correction: Modulation of serotonin in the gut-liver neural axis ameliorates the fatty and fibrotic changes in non-alcoholic fatty liver. 国際誌

Masayoshi Ko, Kenya Kamimura, Takashi Owaki, Takuro Nagoya, Norihiro Sakai, Itsuo Nagayama, Yusuke Niwa, Osamu Shibata, Chiyumi Oda, Shinichi Morita, Atsushi Kimura, Ryosuke Inoue, Toru Setsu, Akira Sakamaki, Takeshi Yokoo, Shuji Terai

Disease models & mechanisms 16 ( 12 ) 2023年12月

Solid pseudopapillary neoplasm in a woman presenting with acute pancreatitis: a case report and review of literature.

Soichi Ishii, Hiroyuki Abe, Saori Endo, Shuhei Kondo, Nao Nakajima, Kazunao Hayashi, Akira Sakamaki, Takashi Kobayashi, Hajime Umezu, Shuji Terai

Clinical journal of gastroenterology 16 ( 6 ) 937 - 941 2023年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Solid pseudopapillary neoplasm (SPN) is a rare pancreatic tumor that typically affects young women in the body and tail of the pancreas. SPN is often asymptomatic in the early stages, so it is initially discovered as a large tumor. In this report, we experienced a case of a relatively small SPN discovered in the setting of acute pancreatitis. Because there have been few reports of SPN being discovered in the situation like our case, we report this case based on a review of the literature.

DOI： 10.1007/s12328-023-01850-6

【消化器領域における再生医療の現状と展望】間葉系幹細胞,細胞外小胞,ペプチドを用いた肝線維化改善・再生療法を目指して

土屋淳紀, 寺井崇二

日本消化器病学会雑誌 120 ( 12 ) 973 - 979 2023年12月

記述言語：日本語出版者・発行元：(一財)日本消化器病学会

肝硬変は多くの場合は,肝障害とそれに引き続く線維化にともなって形成される.そして線維化にともなう門脈圧亢進と肝機能低下からさまざまな症状を引きおこす.本邦では患者数が40万人いる疾患であるが,線維化改善薬が承認されていない現状がある.われわれは,内在の線維化改善・肝再生誘導システムを導き出すことに主眼を置き,線維化改善・再生促進療法の開発に間葉系幹細胞やその細胞外小胞,そしてペプチド製剤を用いて挑んでいる.本稿ではわれわれが進めてきた肝硬変への線維化改善・再生促進療法を目指した,基礎研究から治験までの流れを概説していきたい.(著者抄録)

その他リンク： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J01118&link_issn=&doc_id=20231218410003&doc_link_id=%2Fck8syokb%2F2023%2F012012%2F003%2F0973-0979%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fck8syokb%2F2023%2F012012%2F003%2F0973-0979%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

MC4R、Maid両遺伝子欠損マウスを用いた慢性アルコール性肝障害モデルマウスの開発

坂牧僚, 酒井規裕, 小川和也, 木村成宏, 荒生祥尚, 阿部寛幸, 上村顕也, 寺井崇二

アルコールと医学生物学 42 44 - 46 2023年12月

MC4R、Maid両遺伝子欠損マウスを用いた慢性アルコール性肝障害モデルマウスの開発

坂牧僚, 酒井規裕, 小川和也, 木村成宏, 荒生祥尚, 阿部寛幸, 上村顕也, 寺井崇二

アルコールと医学生物学 42 44 - 46 2023年12月

EUS-FNAが診断に有用であった原発性舌下腺癌に合併した多発膵腫瘍の1例

渡邊誠, 五十嵐聡, 渡邊浩太朗, 山崎駿, 酒井規裕, 渡邉雄介, 冨永顕太郎, 高橋一也, 上村博輝, 寺井崇二

日本消化器病学会甲信越支部例会・日本消化器内視鏡学会甲信越支部例会抄録集 73回・95回 68 - 68 2023年11月

炎症性腸疾患に対する新規治療とバイオ治療再考多剤使用歴のある潰瘍性大腸炎難治例の臨床的特徴

小島雄一, 川田雄三, 冨永顕太郎, 寺井崇二

日本消化器病学会甲信越支部例会・日本消化器内視鏡学会甲信越支部例会抄録集 73回・95回 41 - 41 2023年11月

小腸内細菌異常増殖症(SIBO)の病態と臨床顕性肝性脳症の発症予測における、呼気中水素・メタン分析によるSIBO診断の有用性の検討

坂巻僚, 横山邦彦, 若林拓哉, 小島雄一, 川田雄三, 冨永顕太郎, 水野研一, 上村顕也, 寺井崇二

日本小腸学会学術集会プログラム・抄録集 61回 26 - 26 2023年11月

小腸内細菌異常増殖症(SIBO)の病態と臨床顕性肝性脳症の発症予測における、呼気中水素・メタン分析によるSIBO診断の有用性の検討

坂巻僚, 横山邦彦, 若林拓哉, 小島雄一, 川田雄三, 冨永顕太郎, 水野研一, 上村顕也, 寺井崇二

日本小腸学会学術集会プログラム・抄録集 61回 26 - 26 2023年11月

Achalasia phenotypes and prediction of per-oral endoscopic myotomy outcomes using machine learning. 国際誌

Kazuya Takahashi, Hiroki Sato, Yuto Shimamura, Hirofumi Abe, Hironari Shiwaku, Junya Shiota, Chiaki Sato, Kenta Hamada, Masaki Ominami, Yoshitaka Hata, Hisashi Fukuda, Ryo Ogawa, Jun Nakamura, Tetsuya Tatsuta, Yuichiro Ikebuchi, Hiroshi Yokomichi, Shuji Terai, Haruhiro Inoue

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 2023年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: High-resolution manometry (HRM) and esophagography are used for achalasia diagnosis; however, achalasia phenotypes combining esophageal motility and morphology are unknown. Moreover, predicting treatment outcomes of per-oral endoscopic myotomy (POEM) in treatment-naïve patients remains an unmet need. METHODS: In this multicenter cohort study, we included 1,824 treatment-naïve patients diagnosed with achalasia. In total, 1,778 patients underwent POEM. Clustering by machine learning (ML) was conducted to identify achalasia phenotypes using patients' demographic data, including age, sex, disease duration, body mass index, and HRM/esophagography findings. ML models were developed to predict persistent symptoms (Eckardt score ≥3) and reflux esophagitis (RE) (Los Angeles grades A to D) after POEM. RESULTS: ML identified three achalasia phenotypes: phenotype 1, type I achalasia with a dilated esophagus (n=676; 37.0%); phenotype 2, type II achalasia with a dilated esophagus (n=203; 11.1%); phenotype 3, late-onset type I-III achalasia with a non-dilated esophagus (n=619, 33.9%). Types I and II achalasia in phenotypes 1 and 2 exhibited different clinical characteristics from those in phenotype 3, implying different pathophysiologies within the same HRM diagnosis. A predictive model for persistent symptoms exhibited an area under the curve (AUC) of 0.70. Pre-POEM Eckardt score ≥6 was the greatest contributing factor for persistent symptoms. The AUC for post-POEM RE was 0.61. CONCLUSION: Achalasia phenotypes combining esophageal motility and morphology indicated multiple disease pathophysiologies. ML helped develop an optimal risk stratification model for persistent symptoms with novel insights into treatment resistance factors.

DOI： 10.1111/den.14714

Improving diagnostic performance of coronavirus disease 2019 rapid antigen testing through computer-based feedback training using open-source experimental psychology software. 国際誌

Masato Matsuda, Kosuke Itoh, Takahiro Sugai, Yoshiki Hoshiyama, Toshiaki Kikuchi, Shuji Terai

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 2023年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: Rapid antigen testing (RAT) results are visually read as whether colored line is present or absent. The subjective interpretation potentially misses detecting weak lines due to lower analyte concentration in samples tested, requiring training. Although routine test experience has improved the result readout skills, it consumes time and resources. Therefore, we created a computer-based feedback training method using open-source experimental psychology software, wherein participants accumulate RAT result readout experience by repeatedly responding positive/negative to randomly presented pictures showing RAT results; then, they receive feedback on their answers as correct or incorrect and are asked to stare at the pictures again with the knowledge of correct answer. This study aimed to examine the training effects in improving the skills, using coronavirus disease 2019 (COVID-19) RAT. METHODS: Twenty-two medical technologists were randomly divided into two groups: the feedback-training and test-experience groups. Using several pictures showing positive and negative results of COVID-19 RAT, after examination of their initial result readout skills, feedback-training group received the feedback training, whereas test-experience group performed an equal number of tests without feedback to accumulate test experience, and their skills were examined again. The ratio of "positive" answers to the pictures showing positive results (i.e., hit rate) was statistically analyzed. RESULTS: The feedback-training group showed a significantly higher hit rate after their training, whereas the test-experience group did not. The feedback training effects were manifested in weak line detection. CONCLUSIONS: This computer-based feedback training method can be an effective tool for improving RAT result readout skills.

DOI： 10.1016/j.jiac.2023.10.019

Complementary role of peripheral and central autonomic nervous system on insulin-like growth factor-1 activation to prevent fatty liver disease. 国際誌

Itsuo Nagayama, Kenya Kamimura, Takashi Owaki, Masayoshi Ko, Takuro Nagoya, Yuto Tanaka, Marina Ohkoshi, Toru Setsu, Akira Sakamaki, Takeshi Yokoo, Hiroteru Kamimura, Shuji Terai

Hepatology international 2023年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Insulin-like growth factor-1 (IGF-1) is involved in the pathology of non-alcoholic fatty liver disease (NAFLD) and ameliorates fatty infiltration in the liver. It is activated by growth hormone (GH); however, the role of GH-IGF-1 axis in NAFLD developmental phase has not been well identified. Therefore, in this study, we focused on the effect of IGF-1 in NAFLD pathology and GH excretion activation from the pituitary gland by peripheral autonomic neural pathways relaying liver-brain-gut pathway and by central neuropeptides. METHODS: GH and IGF-1 levels were assessed in wild-type and melanocortin-4 receptor knockout mice upon the development of diet-induced NAFLD. The contribution of the peripheral autonomic nervous system connecting the liver-brain-gut axis was assessed by its blockade using capsaicin and that of the central nervous system was assessed by the expression of hypothalamic brain-derived neurotrophic factor (BDNF) and corticotropin-releasing factor (CRH), which activates GH release from the pituitary gland. RESULTS: In the NAFLD mouse models, the levels of GH and IGF-1 increased (p < .05). Further, hepatic fatty infiltration was suppressed even under peripheral autonomic nervous system blockade (p < .001), which inhibited gastric ghrelin expression. In mice with peripheral autonomic nervous blockade, hypothalamic BDNF and CRH were inhibited (p < .05), resulting in GH and IGF-1 excretion, whereas other neuropeptides of somatostatin and cortistatin showed no changes. These complementary effects were canceled in melanocortin-4 receptor knockout mice, which diminished BDNF and CRH release control. CONCLUSIONS: Our study demonstrates that the release of IGF-1 by the nervous system is a key factor in maintaining the pathological homeostasis of NAFLD, suggesting its therapeutic potential.

DOI： 10.1007/s12072-023-10601-1

Analysis of distribution, collection, and confirmation of capacity dependency of small extracellular vesicles toward a therapy for liver cirrhosis. 国際誌

Nobutaka Takeda, Atsunori Tsuchiya, Masaki Mito, Kazuki Natsui, Yui Natusi, Yohei Koseki, Kei Tomiyoshi, Fusako Yamazaki, Yuki Yoshida, Hiroyuki Abe, Masayuki Sano, Taketomo Kido, Yusuke Yoshioka, Junichi Kikuta, Tohru Itoh, Ken Nishimura, Masaru Ishii, Takahiro Ochiya, Atsushi Miyajima, Shuji Terai

Inflammation and regeneration 43 ( 1 ) 48 - 48 2023年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The progression of liver fibrosis leads to portal hypertension and liver dysfunction. However, no antifibrotic agents have been approved for cirrhosis to date, making them an unmet medical need. Small extracellular vesicles (sEVs) of mesenchymal stem cells (MSCs) are among these candidate agents. In this study, we investigated the effects of sEVs of MSCs, analyzed their distribution in the liver post-administration, whether their effect was dose-dependent, and whether it was possible to collect a large number of sEVs. METHODS: sEVs expressing tdTomato were generated, and their uptake into constituent liver cells was observed in vitro, as well as their sites of uptake and cells in the liver using a mouse model of liver cirrhosis. The efficiency of sEV collection using tangential flow filtration (TFF) and changes in the therapeutic effects of sEVs in a volume-dependent manner were examined. RESULTS: The sEVs of MSCs accumulated mostly in macrophages in damaged areas of the liver. In addition, the therapeutic effect of sEVs was not necessarily dose-dependent, and it reached a plateau when the dosage exceeded a certain level. Furthermore, although ultracentrifugation was commonly used to collect sEVs for research purposes, we verified that TFF could be used for efficient sEV collection and that their effectiveness is not reduced. CONCLUSION: In this study, we identified some unknown aspects regarding the dynamics, collection, and capacity dependence of sEVs. Our results provide important fundamentals for the development of therapies using sEVs and hold potential implications for the therapeutic applications of sEV-based therapies for liver cirrhosis.

DOI： 10.1186/s41232-023-00299-x

機能性消化管疾患の病態解明と臨床応用腸管運動機能に関わる組織常在型マクロファージを有する腸管オルガノイドの開発

冨永顕太郎, Wells James, 寺井崇二

Gastroenterological Endoscopy 65 ( Suppl.2 ) 1809 - 1809 2023年10月

重症急性膵炎後Walled-off necrosisの内視鏡治療における最適なステントの選択

五十嵐聡, 林和直, 寺井崇二

Gastroenterological Endoscopy 65 ( Suppl.2 ) 2046 - 2046 2023年10月

高齢者の術後再建腸管結石例に対するダブルバルーン内視鏡下ERCPの検討

林和直, 五十嵐聡, 寺井崇二

Gastroenterological Endoscopy 65 ( Suppl.2 ) 2022 - 2022 2023年10月

自律神経経路を基軸とする脂肪性肝疾患の脂質代謝制御機構の解明と治療薬探索

上村顕也, 大脇崇史, 寺井崇二

日本消化器病学会雑誌 120 ( 臨増大会 ) A452 - A452 2023年10月

脂肪性肝疾患の個別化医療に向けた提案 NAFLDの病態進展に関わるエフェクターを標的とした治療法の開発

上村顕也, 薛徹, 寺井崇二

肝臓 64 ( Suppl.3 ) A743 - A743 2023年10月

Similarity of oncogenic protein expression in KRASG12D gene delivery-based rat pancreatic cancer model to that of human pancreatic cancer. 国際誌

Yuto Tanaka, Kenya Kamimura, Osamu Shibata, Kohei Ogawa, Chiyumi Oda, Hiroyuki Abe, Satoshi Ikarashi, Kazunao Hayashi, Takeshi Yokoo, Toshifumi Wakai, Shuji Terai

Biochemical and biophysical research communications 673 29 - 35 2023年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The development of effective therapies and biomarkers for pancreatic cancer is an unmet clinical need. To address this, we have developed an easy-to-use pancreatic cancer rat animal model via pancreas-targeted hydrodynamic gene delivery of human pancreatic cancer-related genes. Our study aimed to determine the molecular similarity between the pancreatic tumor in the rat model and human pancreatic cancer. METHODS: KRASG12D gene-expressing plasmid was delivered to the pancreas of wild type rats via pancreas-targeted hydrodynamic gene delivery as previously reported. Tissue samples were collected at 5 weeks after the first gene delivery. The tumors developed in the rats were assessed for the expression of oncogenic proteins that are involved in human pancreatic cancer development. RESULTS: The development of a tumor mimicking pancreatic ductal adenocarcinoma was confirmed. The expression levels of Cyclin D1, c-Jun, IL-33, and Zip4 proteins in the tumor were immunohistochemically assessed and the correlation of the proteins was confirmed. The expression pattern showed similarity to that of surgically resected human pancreatic cancer tissues. CONCLUSIONS: Our study findings showing a similar pattern of oncogenic protein expression in novel KRASG12D gene-induced rat pancreatic cancer model and human pancreatic cancer will be useful for establishing novel tumor markers and therapeutic options for pancreatic cancer.

DOI： 10.1016/j.bbrc.2023.06.057

Development and validation of machine learning model for predicting treatment responders in patients with primary biliary cholangitis. 国際誌

Naruhiro Kimura, Kazuya Takahashi, Toru Setsu, Yusuke Horibata, Yusuke Kaneko, Haruka Miyazaki, Kohei Ogawa, Yuzo Kawata, Norihiro Sakai, Yusuke Watanabe, Hiroyuki Abe, Hiroteru Kamimura, Akira Sakamaki, Takeshi Yokoo, Kenya Kamimura, Atsunori Tsuchiya, Shuji Terai

Hepatology research : the official journal of the Japan Society of Hepatology 2023年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: Ursodeoxycholic acid is the first-line treatment for primary biliary cholangitis, and treatment response is one of the factors predicting the outcome. To prescribe alternative therapies, clinicians might need additional information before deciphering the treatment response to ursodeoxycholic acid, contributing to a better patient prognosis. In this study, we developed and validated machine learning (ML) algorithms to predict treatment responses using pretreatment data. METHODS: This multicenter cohort study included collecting datasets from two data samples. Data 1 included 245 patients from 18 hospitals for ML development, and was divided into (i) training and (ii) development sets. Data 2 (iii: test set) included 51 patients from our hospital for validation. An extreme gradient boosted tree predicted the treatment response in the ML model. The area under the curve was used to evaluate the efficacy of the algorithm. RESULTS: Data 1 showed that patients complying with the Paris II treatment response had significantly lower serum alkaline phosphatase and total bilirubin levels than those who did not respond. Three factors, total bilirubin, total protein, and alanine aminotransferase levels were selected as essential variables for prediction. Data 2 showed that patients complying with the Paris II criteria had significantly high prothrombin time and low total bilirubin levels. The area under the curve of extreme gradient boosted tree was good for (ii) (0.811) and (iii) (0.856). CONCLUSIONS: We demonstrated the efficacy of ML in predicting the treatment response for patients with primary biliary cholangitis. Early identification of cases requiring additional treatment with our novel ML model may improve prognosis.

DOI： 10.1111/hepr.13966

多職種の肝炎医療コーディネーターとの連携による,院内におけるC型肝炎患者の拾い上げと紹介率向上の効果

荒生祥尚, 酒井規裕, 薛徹, 渡邉雄介, 木村成宏, 阿部寛幸, 坂牧僚, 上村博輝, 横尾健, 土屋淳紀, 上村顕也, 寺井崇二

肝臓 64 ( Suppl.2 ) A634 - A634 2023年9月

肝疾患に対する再生医療のNew normal New Normalへの提案肝硬変に対する線維化改善を目指したトランスレーショナルリサーチ

土屋淳紀, 渡邉雄介, 寺井崇二

肝臓 64 ( Suppl.2 ) A570 - A570 2023年9月

【肝疾患とサルコペニア】総論肝疾患とサルコペニア未来のリハビリテーション医療楽しくないと続かない

寺井崇二, 上村博輝

日本消化器病学会雑誌 120 ( 9 ) 701 - 708 2023年9月

記述言語：日本語出版者・発行元：(一財)日本消化器病学会

骨格筋は運動機能に関わる運動器としてだけでなく,さまざまなホルモン様の生理活性物質を分泌する内分泌臓器としての役割も果たしている.肝における代謝を考える場合に,臓器間ネットワークの視点から肝の代謝をとらえることはきわめて重要で,糖・脂質代謝には,肝,脂肪組織(内臓・皮下),筋肉(骨格筋)のネットワークのなかでとらえていく必要がある.2022年10月より日本肝臓学会の社会保険委員会にて肝臓リハビリテーションワーキンググループが作られ,その指針が2023年4月に公開された.サルコペニアにともなう,肝臓疾患における身体的・精神的影響を軽減させ,症状を調整し,生命予後を改善するため,今後この分野は肝臓分野のなかでも注視される領域である.(著者抄録)

その他リンク： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J01118&link_issn=&doc_id=20230921450001&doc_link_id=%2Fck8syokb%2F2023%2F012009%2F001%2F0701-0708%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fck8syokb%2F2023%2F012009%2F001%2F0701-0708%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

消化器病に対する低侵襲治療切除不能肝内胆管癌に対して肝動脈化学塞栓療法(TACE)および重粒子線治療を行った1例

内山敦司, 上村博輝, 木村莉菓, 佐藤千紘, 木村究, 渡邉雄介, 高橋一也, 五十嵐聡, 寺井崇二

ENDOSCOPIC FORUM for digestive disease 39 ( 1 ) 37 - 37 2023年9月

Repurposable Drugs for Immunotherapy and Strategies to Find Candidate Drugs. 国際誌

Norihiro Sakai, Kenya Kamimura, Shuji Terai

Pharmaceutics 15 ( 9 ) 2023年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Conventional drug discovery involves significant steps, time, and expenses; therefore, novel methods for drug discovery remain unmet, particularly for patients with intractable diseases. For this purpose, the drug repurposing method has been recently used to search for new therapeutic agents. Repurposed drugs are mostly previously approved drugs, which were carefully tested for their efficacy for other diseases and had their safety for the human body confirmed following careful pre-clinical trials, clinical trials, and post-marketing surveillance. Therefore, using these approved drugs for other diseases that cannot be treated using conventional therapeutic methods could save time and economic costs for testing their clinical applicability. In this review, we have summarized the methods for identifying repurposable drugs focusing on immunotherapy.

DOI： 10.3390/pharmaceutics15092190

【ここまで進んだ肝硬変診療】肝硬変症の次世代治療の開発抗線維化治療と肝再生療法

寺井崇二, 土屋淳紀, 渡邊雄介, 阿部寛幸

臨床消化器内科 38 ( 10 ) 1329 - 1333 2023年8月

記述言語：日本語出版者・発行元：(株)日本メディカルセンター

＜文献概要＞肝硬変症に対する,抗線維化・再生誘導薬の治験の開発が進んできた.肝臓は他臓器と違い再生力をもつことが特徴である.一つの大きな治療コンセプトとして,肝硬変になった肝臓に対して線維化を改善し,いかに内在の肝臓再生力を誘導するかが重要である.また肝臓領域においては,臨床現場において各種,肝線維化評価の方法も開発されてきた.今後,開発される各種薬剤のmode of actionを理解しながら,適切な治験の実施が求められる.そのなかで,肝硬変のどの病態に対してどのような治療を開発していくかが重要である.

【ここまで進んだ肝硬変診療】肝硬変症の次世代治療の開発抗線維化治療と肝再生療法

寺井崇二, 土屋淳紀, 渡邊雄介, 阿部寛幸

臨床消化器内科 38 ( 10 ) 1329 - 1333 2023年8月

記述言語：日本語出版者・発行元：(株)日本メディカルセンター

＜文献概要＞肝硬変症に対する,抗線維化・再生誘導薬の治験の開発が進んできた.肝臓は他臓器と違い再生力をもつことが特徴である.一つの大きな治療コンセプトとして,肝硬変になった肝臓に対して線維化を改善し,いかに内在の肝臓再生力を誘導するかが重要である.また肝臓領域においては,臨床現場において各種,肝線維化評価の方法も開発されてきた.今後,開発される各種薬剤のmode of actionを理解しながら,適切な治験の実施が求められる.そのなかで,肝硬変のどの病態に対してどのような治療を開発していくかが重要である.

Correction: Medaka as a model for human nonalcoholic steatohepatitis. 国際誌

Toshihiko Matsumoto, Shuji Terai, Toshiyuki Oishi, Shinya Kuwashiro, Koichi Fujisawa, Naoki Yamamoto, Yusuke Fujita, Yoshihiko Hamamoto, Makoto Furutani-Seiki, Hiroshi Nishina, Isao Sakaida

Disease models & mechanisms 16 ( 7 ) 2023年7月

細胞および細胞外小胞で拓く創薬モダリティ細胞外小胞を用いた肝硬変に対する線維化改善、修復療法の開発

土屋淳紀, 寺井崇二

日本DDS学会学術集会プログラム予稿集 39回 101 - 101 2023年7月

BCL11B expression in hepatocellular carcinoma relates to chemosensitivity and clinical prognosis. 国際誌

Hiroyuki Abe, Kenya Kamimura, Shujiro Okuda, Yu Watanabe, Jun Inoue, Yutaka Aoyagi, Toshifumi Wakai, Ryo Kominami, Shuji Terai

Cancer medicine 12 ( 14 ) 15650 - 15663 2023年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: B-cell lymphoma/leukemia 11B (BCL11B) is a subunit of SWI/SNF chromatin remodeling complexes and functions in cell cycle regulation and apoptosis upon DNA replication stress and damages via transcription. Many malignancies were reported to exhibit changes in BCL11B gene expression; however, no study has focused on the relationship between BCL11B and hepatocellular carcinoma, which potentially exhibits DNA replication stress and damages upon its oncogenesis. Thus, in this study, we examined the molecular characterization of BCL11B expression in hepatocellular carcinoma. METHODS AND RESULTS: The cumulative progression-free survival and overall survival were significantly longer in the clinical cases of BCL11B-negative hepatocellular carcinoma than BCL11B-positve cases. Microarray and real-time PCR analyses in hepatocellular carcinoma cell lines indicated a correlation between BCL11B and GATA6, a gene reported to be correlated with oncogenic activities and resistance to anthracycline, which is often used for hepatocellular carcinoma chemotherapy. Consequently, BCL11B-overexpressing cell lines exhibited resistance to anthracycline in cell growth assays and the resistance has been evidenced by the increased expression of BCL-xL in cell lines. The results were supported by the analyses of human HCC samples showing the correlation between BCL11B and GATA6 expressions. DISCUSSIONS AND CONCLUSION: Our results indicated that overexpression of BCL11B amplifies GATA6 expression in hepatocellular carcinoma in vitro and in vivo that leads to anti-apoptotic signal activation, and induces resistance to chemotherapy, which influenced the postoperative prognosis.

DOI： 10.1002/cam4.6167

Portal venous gas caused by barium swallow examination: An extremely rare clinical finding. 国際誌

Takuya Wakabayashi, Kentaro Tominaga, Akira Sakamaki, Shuji Terai

Clinical case reports 11 ( 7 ) e7480 2023年7月

記述言語：英語

We found an extremely rare case of PVG after a barium swallow examination. This may be related to vulnerable intestinal mucosa in the patient undergoing prednisolone treatment. Conservative therapy should be considered for patients with PVG without bowel ischemia or perforation. Caution should be exercised during barium examination undergoing prednisolone treatment.

DOI： 10.1002/ccr3.7480

細胞および細胞外小胞で拓く創薬モダリティ細胞外小胞を用いた肝硬変に対する線維化改善、修復療法の開発

土屋淳紀, 寺井崇二

日本DDS学会学術集会プログラム予稿集 39回 101 - 101 2023年7月

エンドトキシン吸着療法を行い救命し得た重症胆道感染症の2例

齋藤征爾, 坂田純, 滝沢一泰, 三浦宏平, 石川博補, 廣瀬雄己, 安藤拓也, 安部舜, 宗岡悠介, 田島陽介, 市川寛, 島田能史, 阿部寛幸, 小川光平, 寺井崇二, 若井俊文

新潟医学会雑誌 137 ( 7 ) 243 - 248 2023年7月

記述言語：日本語出版者・発行元：新潟医学会

重症胆道感染症から敗血症性ショックに至った症例に対してエンドトキシン吸着療法(polymyxin-direct hemoperfusion:PMX-DHP)を行い,急性期から脱却後に手術を施行し得た2例を経験したので報告する.症例1は79歳の男性で,発熱と呼吸困難を主訴に救急外来を受診した.呼吸数36回/分,経皮的動脈血酸素飽和度81%(room air),心拍数71回/分,血圧85/61mmHgとショック状態であった.腹部造影CT検査で胆嚢結石と総胆管の拡張を認め,総胆管結石による重症急性胆管炎と診断した.気管内挿管と急速輸液,ノルアドレナリンの持続静注を開始し,経皮経肝胆道ドレナージを行なったが,敗血症性ショックが遷延したためPMX-DHPを施行した.PMX-DHP開始後4時間程度で循環動態は安定し,ノルアドレナリンの投与を終了した.急性胆管炎発症から3病日目に人工呼吸器管理を終了し,15病日目に内視鏡下に総胆管結石を採石した.29病日目に自宅へ退院となった.発症から3ヵ月後に腹腔鏡下胆嚢摘出術を施行した.術後2年2ヵ月が経過した現在,胆道感染症の再発なく経過している.症例2は86歳の女性で,大動脈弁置換術後のため入院加療中であった.術後21病日目に発熱し,呼吸数34回/分,経皮的動脈血酸素飽和度96%(酸素8L/分投与下),心拍数125回/分,血圧85/41mmHgとショック状態となった.腹部造影CT検査で腫大した胆嚢と周囲の脂肪織濃度の上昇を認め,重症急性胆嚢炎と診断した.急速輸液,ノルアドレナリンの持続静注を開始し,経皮経肝胆嚢ドレナージを施行した.敗血症性ショックが遷延したためPMX-DHPを施行し,血圧は上昇傾向となった.急性胆嚢炎発症から3病日目にノルアドレナリンの投与を終了できた.46病日目にリハビリ目的に他院へ転院となった.発症から3ヵ月後に開腹下胆嚢摘出術を施行した.術後1年6ヵ月が経過した現在,胆道感染症の再発なく経過している.重症胆道感染症により循環動態が不安定な症例では,PMX-DHPは支持療法として治療選択肢の1つになり得る.(著者抄録)

エンドトキシン吸着療法を行い救命し得た重症胆道感染症の2例

齋藤征爾, 坂田純, 滝沢一泰, 三浦宏平, 石川博補, 廣瀬雄己, 安藤拓也, 安部舜, 宗岡悠介, 田島陽介, 市川寛, 島田能史, 阿部寛幸, 小川光平, 寺井崇二, 若井俊文

新潟医学会雑誌 137 ( 7 ) 243 - 248 2023年7月

記述言語：日本語出版者・発行元：新潟医学会

重症胆道感染症から敗血症性ショックに至った症例に対してエンドトキシン吸着療法(polymyxin-direct hemoperfusion:PMX-DHP)を行い,急性期から脱却後に手術を施行し得た2例を経験したので報告する.症例1は79歳の男性で,発熱と呼吸困難を主訴に救急外来を受診した.呼吸数36回/分,経皮的動脈血酸素飽和度81%(room air),心拍数71回/分,血圧85/61mmHgとショック状態であった.腹部造影CT検査で胆嚢結石と総胆管の拡張を認め,総胆管結石による重症急性胆管炎と診断した.気管内挿管と急速輸液,ノルアドレナリンの持続静注を開始し,経皮経肝胆道ドレナージを行なったが,敗血症性ショックが遷延したためPMX-DHPを施行した.PMX-DHP開始後4時間程度で循環動態は安定し,ノルアドレナリンの投与を終了した.急性胆管炎発症から3病日目に人工呼吸器管理を終了し,15病日目に内視鏡下に総胆管結石を採石した.29病日目に自宅へ退院となった.発症から3ヵ月後に腹腔鏡下胆嚢摘出術を施行した.術後2年2ヵ月が経過した現在,胆道感染症の再発なく経過している.症例2は86歳の女性で,大動脈弁置換術後のため入院加療中であった.術後21病日目に発熱し,呼吸数34回/分,経皮的動脈血酸素飽和度96%(酸素8L/分投与下),心拍数125回/分,血圧85/41mmHgとショック状態となった.腹部造影CT検査で腫大した胆嚢と周囲の脂肪織濃度の上昇を認め,重症急性胆嚢炎と診断した.急速輸液,ノルアドレナリンの持続静注を開始し,経皮経肝胆嚢ドレナージを施行した.敗血症性ショックが遷延したためPMX-DHPを施行し,血圧は上昇傾向となった.急性胆嚢炎発症から3病日目にノルアドレナリンの投与を終了できた.46病日目にリハビリ目的に他院へ転院となった.発症から3ヵ月後に開腹下胆嚢摘出術を施行した.術後1年6ヵ月が経過した現在,胆道感染症の再発なく経過している.重症胆道感染症により循環動態が不安定な症例では,PMX-DHPは支持療法として治療選択肢の1つになり得る.(著者抄録)

その他リンク： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00990&link_issn=&doc_id=20240628120003&doc_link_id=%2Fdg3nigta%2F2023%2F013707%2F003%2F0243-0248%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2023%2F013707%2F003%2F0243-0248%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Machine learning prediction model for treatment responders in patients with primary biliary cholangitis. 国際誌

Naruhiro Kimura, Kazuya Takahashi, Toru Setsu, Shu Goto, Suguru Miida, Nobutaka Takeda, Yuichi Kojima, Yoshihisa Arao, Kazunao Hayashi, Norihiro Sakai, Yusuke Watanabe, Hiroyuki Abe, Hiroteru Kamimura, Akira Sakamaki, Takeshi Yokoo, Kenya Kamimura, Atsunori Tsuchiya, Shuji Terai

JGH open : an open access journal of gastroenterology and hepatology 7 ( 6 ) 431 - 438 2023年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND AIM: Treatment response to ursodeoxycholic acid may predict the prognosis of patients with primary biliary cholangitis (PBC). Recent studies have suggested the benefits of using machine learning (ML) to forecast complex medical predictions. We aimed to predict treatment response in patients with PBC using ML and pretreatment data. METHODS: We conducted a single-center retrospective study and collected data from 194 patients with PBC who were followed up for at least 12 months after treatment initiation. Patient data were analyzed with five ML models, namely random forest, extreme gradient boosting (XGB), decision tree, naïve Bayes, or logistic regression, to predict treatment response using the Paris II criteria. The established models were assessed using an out-of-sample validation. The area under the curve (AUC) was used to evaluate the efficacy of each algorithm. Overall survival and liver-related deaths were analyzed using Kaplan-Meier analysis. RESULTS: Compared to logistic regression (AUC = 0.595, P = 0.0219, 0.031 models), ML analyses showed significantly high AUC in the random forest (AUC = 0.84) and XGB (AUC = 0.83) models; however, the AUC was not significantly high for decision tree (AUC = 0.633) or naïve Bayes (AUC = 0.584) models. Kaplan-Meier analysis showed significantly improved prognoses in patients predicted to achieve the Paris II criteria by XGB (log-rank = 0.005 and 0.007). CONCLUSION: ML algorithms could improve treatment response prediction using pretreatment data, which could lead to better prognoses. In addition, the ML model using XGB could predict the prognosis of patients before treatment initiation.

DOI： 10.1002/jgh3.12915

エクソソーム研究の最前線間葉系幹細胞由来エクソソームによる肝硬変線維化改善を目指した研究開発

阿部寛幸, 武田信峻, 水戸將貴, 土屋淳紀, 寺井崇二

The Journal of Toxicological Sciences 48 ( Suppl. ) S54 - S55 2023年6月

IgG4関連疾患における診断・治療困難例に対する取り組み自己免疫性膵炎のステロイド治療導入後再燃例における臨床経過の検証

小川光平, 名古屋拓郎, 五十嵐聡, 林和直, 寺井崇二

日本消化器病学会甲信越支部例会抄録集 72回 40 - 40 2023年6月

胆膵内視鏡検査・治療における工夫とトラブルシューティング当院における副乳頭アプローチカニュレーション

名古屋拓郎, 小川光平, 五十嵐聡, 林和直, 寺井崇二

日本消化器病学会甲信越支部例会抄録集 72回 48 - 48 2023年6月

ヘパプラスチンテストを取り入れた出血原因鑑別の検査戦略後天性第V因子欠乏症における経験

松田将門, 山田隆, 古山悠里, 柴崎康彦, 関義信, 星山良樹, 寺井崇二, 瀧澤淳, 曽根博仁, 増子正義

日本血栓止血学会誌 34 ( 2 ) 262 - 262 2023年5月

急性肝不全・ACLF診療の未来予想図(現状と課題) 肝線維化と老化細胞の出現から考えたAcute on chronic liver failureの病態解明

渡邉雄介, 土屋淳紀, 寺井崇二

肝臓 64 ( Suppl.1 ) A78 - A78 2023年4月

FDA,PMDAデータベース20年の副作用報告から報告形態による国際比較の解析

上村博輝, 酒井規裕, 木村成宏, 薛徹, 土屋淳紀, 寺井崇二

肝臓 64 ( Suppl.1 ) A412 - A412 2023年4月

NASHメダカモデルにおける老化細胞除去剤としてのダサチニブ及びケルセチンの有用性に関する検証

阿部寛幸, 弥久保俊太, 酒井規裕, 木村成宏, 坂牧僚, 土屋淳紀, 上村顕也, 寺井崇二

肝臓 64 ( Suppl.1 ) A364 - A364 2023年4月

急性腎障害を合併した消化器疾患における尿中NGAL測定による予後予測

小島雄一, 渡邉雄介, 土屋淳紀, 寺井崇二

日本消化器病学会雑誌 120 ( 臨増総会 ) A393 - A393 2023年3月

消化器疾患とビッグデータインターネット普及による薬物関連有害事象報告の変遷 FDAの20年の副作用報告からの解析

上村博輝, 土屋淳紀, 寺井崇二

日本消化器病学会雑誌 120 ( 臨増総会 ) A40 - A40 2023年3月

十全大補湯と間葉系幹細胞の併用療法は肝硬変・急性肝障害モデルマウスにおいて効果的な抗炎症・抗線維化効果を及ぼす

野尻俊介, 土屋淳紀, 佐藤毅昂, 熊谷優, 茂木聡子, 岩澤貴宏, 小川雅裕, 竹内卓, 寺井崇二

肝臓 64 ( 3 ) 172 - 172 2023年3月

臨床応用を目指した消化器領域の再生医療研究肝硬変のエクソソーム治療を目指した基礎的検討

武田信峻, 土屋淳紀, 寺井崇二

日本消化器病学会雑誌 120 ( 臨増総会 ) A166 - A166 2023年3月

消化器診療とliquid biopsy 肝硬変の線維化の新たなエクソソームマーカー開発

土屋淳紀, 寺井崇二

日本消化器病学会雑誌 120 ( 臨増総会 ) A159 - A159 2023年3月

肝線維化研究の最前線と治療への展開 HMGB1部分ペプチドを用いた肝線維化改善検証と医師主導治験

土屋淳紀, 渡邉雄介, 寺井崇二

日本消化器病学会雑誌 120 ( 臨増総会 ) A77 - A77 2023年3月

膵癌早期診断の最前線 cStage 0/I膵癌の臨床像膵癌病態解析に関する多施設後方視的観察研究の結果より

五十嵐聡, 林和直, 寺井崇二

日本消化器病学会雑誌 120 ( 臨増総会 ) A135 - A135 2023年3月

当院における膵小病変に対するEUS-FNA/Bの成績

林和直, 小川光平, 五十嵐聡, 寺井崇二

日本消化器病学会雑誌 120 ( 臨増総会 ) A375 - A375 2023年3月

肥満モデルマウスを用いた、脂肪細胞の機能に着目した肥満制御メカニズムの解明

坂牧僚, 阿部寛幸, 上村顕也, 寺井崇二

新潟県医師会報 ( 876 ) 12 - 13 2023年3月

肝疾患における血中セロトニン値のバイオマーカーとしての有用性の検討

薛徹, 上村顕也, 寺井崇二

肝臓 64 ( 3 ) 171 - 171 2023年3月

Escherichia coli-derived outer-membrane vesicles induce immune activation and progression of cirrhosis in mice and humans. 国際誌

Kazuki Natsui, Atsunori Tsuchiya, Risa Imamiya, Mayuko Osada-Oka, Yui Ishii, Yohei Koseki, Nobutaka Takeda, Kei Tomiyoshi, Fusako Yamazaki, Yuki Yoshida, Riuko Ohashi, Yiwei Ling, Koji Ueda, Nobuko Moritoki, Kazuhiro Sato, Takahiro Nakajima, Yoshinori Hasegawa, Shujiro Okuda, Shinsuke Shibata, Shuji Terai

Liver international : official journal of the International Association for the Study of the Liver 43 ( 5 ) 1126 - 1140 2023年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND & AIMS: Decompensated cirrhosis with fibrosis progression causes portal hypertension followed by an oedematous intestinal tract. These conditions weaken the barrier function against bacteria in the intestinal tract, a condition called leaky gut, resulting in invasion by bacteria and bacterial components. Here, we investigated the role of outer membrane vesicles (OMVs) of Escherichia coli which is the representative pathogenic gut-derived bacteria in patients with cirrhosis in the pathogenesis of cirrhosis. METHODS: We investigated the involvement of OMVs in humans using human serum and ascites samples and also investigated the involvement of OMVs from Escherichia coli in mice using mouse liver-derived cells and a mouse cirrhosis model. RESULTS: In vitro, OMVs induced inflammatory responses to macrophages and neutrophils, including the upregulation of C-type lectin domain family 4 member E (Clec4e), and induced the suppression of albumin production in hepatocytes but had a relatively little direct effect on hepatic stellate cells. In a mouse cirrhosis model, administration of OMVs led to increased liver inflammation, especially affecting the activation of macrophages, worsening fibrosis, and decreasing albumin production. Albumin administration weakened these inflammatory changes. In addition, multiple antibodies against bacterial components were increased with a progressing Child-Pugh grade, and OMVs were detected in ascites of patients with decompensated cirrhosis. CONCLUSIONS: In conclusion, OMVs induce inflammation, fibrosis and suppression of albumin production, affecting the pathogenesis of cirrhosis. We believe that our study paves the way for the future prevention and treatment of cirrhosis.

DOI： 10.1111/liv.15539

Performance characteristics of 5 numerical indexes in mixing test interpretation under coexistence of lupus anticoagulant and coagulation factor deficiency. 国際誌

Masato Matsuda, Yoshiki Hoshiyama, Kazuei Ogawa, Mari Emmi, Shuji Terai, Masato Moriyama

Research and practice in thrombosis and haemostasis 7 ( 2 ) 100065 - 100065 2023年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The mixing test is useful to investigate the cause of unexpectedly prolonged activated partial thromboplastin time (APTT). Several indexes are available for distinguishing correction from non-correction (ie, factor deficiency from inhibitors), but their performance characteristics may differ because of their different formulas. Furthermore, it is unclear how each index performs under the coexistence of factor deficiency and inhibitors. OBJECTIVES: The objective of this study was to examine the differences in indexes, depending on factor VIII activity (FVIII:C) levels and lupus anticoagulant (LA) titers in test samples. METHODS: APTT was measured in spiked samples with various FVIII:C levels and LA titers, normal pooled plasma (NPP), and their 4:1, 1:1, and 1:4 mixtures. The following 5 indexes were calculated: index of circulating anticoagulant, mixing test normalized ratio, 4:1 and 1:1 percent corrections, and an APTT difference between the 1:1 mixture and NPP. The samples with LA, showing correction, were measured for FVIII:C in a one-stage assay to check parallelism. RESULTS: All indexes showed correction under FVIII deficiency and non-correction under higher LA titers. However, under lower LA titers, some indexes showed non-correction but others showed correction because of dilution effects and variations in formulas and/or sample mix ratios. The differences among the indexes were more pronounced under coexistent FVIII deficiency and LA, even though LA titers were equal in the tested samples; samples with lower FVIII:C showed correction, whereas those with normal FVIII:C showed non-correction. The samples tested for FVIII:C showed non-parallelism. CONCLUSION: Each index had different performance characteristics to LA samples, which were pronounced under low FVIII:C levels in test samples.

DOI： 10.1016/j.rpth.2023.100065

急性肝不全に対する治療内科,外科の立場から新潟県での急性肝不全診療ネットワークの構築とOn line HD導入への取り組み

薛徹, 上村博輝, 坂牧僚, 横尾健, 上村顕也, 土屋淳紀, 高村昌明, 寺井崇二

肝臓 64 ( 2 ) 92 - 93 2023年2月

【高齢者の消化器疾患-最新の診断と治療-】肝硬変・肝細胞癌

坂牧僚, 寺井崇二

日本臨床 81 ( 2 ) 256 - 260 2023年2月

Analysis of Genetic Relatedness between Gastric and Oral Helicobacter pylori in Patients with Early Gastric Cancer Using Multilocus Sequence Typing

Ryoko Nagata, Hiroki Sato, Shoji Takenaka, Junji Yokoyama, Shuji Terai, Hitomi Mimuro, Yuichiro Noiri

International Journal of Molecular Sciences 24 ( 3 ) 2211 - 2211 2023年1月

掲載種別：研究論文（学術雑誌）出版者・発行元：MDPI AG

The oral cavity is the second most colonized site of Helicobacter pylori after the stomach. This study aimed to compare the genetic relatedness between gastric and oral H. pylori in Japanese patients with early gastric cancer through multilocus sequence typing (MLST) analysis using eight housekeeping genes. Gastric biopsy specimens and oral samples were collected from 21 patients with a fecal antigen test positive for H. pylori. The number of H. pylori allelic profiles ranged from zero to eight since the yield of DNA was small even when the nested PCR was performed. MLST analysis revealed that only one patient had a matching oral and gastric H. pylori genotype, suggesting that different genotypes of H. pylori inhabit the oral cavity and gastric mucosa. The phylogenetic analysis showed that oral H. pylori in six patients was similar to gastric H. pylori, implying that the two strains are related but not of the same origin, and those strains may be infected on separate occasions. It is necessary to establish a culture method for oral H. pylori to elucidate whether the oral cavity acts as the source of gastric infection, as our analysis was based on a limited number of allele sequences.

DOI： 10.3390/ijms24032211

Analysis of drug-induced liver-related adverse event trend reporting between 1997 and 2019. 国際誌

Hiroteru Kamimura, Toru Setsu, Naruhiro Kimura, Makoto Miyazawa, Shota Kaneko, Kenya Kamimura, Atsunori Tsuchiya, Yoshihiro Uesawa, Shuji Terai

Hepatology research : the official journal of the Japan Society of Hepatology 53 ( 6 ) 556 - 568 2023年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIM: This study aimed to analyze the current trends of drug-induced liver-related adverse events in the Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) databases. METHODS: The characteristics of implicated drugs were investigated by analyzing big data on drug-induced liver-related adverse events over the past 20 years in FAERS, comparing drug rankings between the JADER and FAERS databases, and calculating rankings of drugs inducing liver-related adverse events using the Medical Dictionary for Regulatory Activities Terminology. RESULTS: In the 452,272 cases registered in FAERS from 1997 to 2019, warfarin, paracetamol, and adalimumab were the drugs most related to DILI. In the 38,919 cases registered in the JADER from 2004 to 2019, sorafenib, nivolumab, and herbal extracts were the drugs most related to DILI. No associations were found between the top 30 drugs in either of the two databases. Notably, the number of drug-induced liver-related adverse event reports and total adverse events has sharply increased in recent years. CONCLUSIONS: Although liver-related adverse events are largely caused by host immunity and other constitutional factors, differences in primary diseases, countries, and historical backgrounds lead to differences in the number of reports. Securing an appropriate database and a mechanism to collect real-time information on the frequency of adverse drug reactions is warranted. This article is protected by copyright. All rights reserved.

DOI： 10.1111/hepr.13883

Navitoclax improves acute-on-chronic liver failure by eliminating senescent cells in mice. 国際誌

Yusuke Watanabe, Hiroyuki Abe, Naruhiro Kimura, Yoshihisa Arao, Natsuki Ishikawa, Maeda Yuichiro, Toru Setsu, Akira Sakamaki, Hiroteru Kamimura, Takeshi Yokoo, Kenya Kamimura, Atsunori Tsuchiya, Shuji Terai

Hepatology research : the official journal of the Japan Society of Hepatology 53 ( 5 ) 460 - 472 2023年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIM: Acute-on-chronic liver failure (ACLF), a disease with poor prognosis, is reportedly caused by cellular senescence due to mitochondrial dysfunction. In this study, we described and analyzed the underlying mechanism of a novel approach for ACLF using ABT263/navitoclax (Navi) that selectively eliminates senescent cells. METHODS: Irradiation-induced senescent hepatocytes were used for in vitro evaluation of the effects of Navi on ACLF (n = 6 for each group). Lipopolysaccharide- and carbon tetrachloride-induced ACLF mouse model was used for in vivo evaluation of the effects of Navi administration compared with the control using one-way or two-way analysis of variance, followed by Student's t-test or Kruskal-Wallis test. The effects on the senescence-associated secretory phenotype (n = 8 for each group) and mitochondrial functions, including adenosine triphosphate concentration and membrane potential (n = 8 for each group), were investigated using real-time polymerase chain reaction, immunohistochemistry, and enzyme analysis. RESULTS: Navi eliminated irradiation-induced senescent hepatocytes in vitro, leading to non-senescent hepatocyte proliferation. Navi eliminated senescent cells in the liver in vivo, resulting in downregulation of mRNA expression of senescence-associated secretory phenotype factors, a decrease of liver enzymes, and upregulated proliferation of non-senescent cells in the liver. Regarding mitochondrial functional assessment in the liver, adenosine triphosphate concentration and membrane potential were upregulated after Navi administration in vitro and in vivo. CONCLUSIONS: Navi may ameliorate ACLF damage by eliminating senescent cells in the liver, downregulating senescence-associated secretory phenotype factors, and upregulating mitochondrial functions. We believe that this novel approach using Navi will pave the way for ACLF treatment.

DOI： 10.1111/hepr.13879

Reducing relapse through maintenance steroid treatment can decrease the cancer risk in patients with IgG4-sclerosing cholangitis: Based on a Japanese nationwide study

Kubota, K., Kamisawa, T., Nakazawa, T., Tanaka, A., Naitoh, I., Kurita, Y., Takikawa, H., Unno, M., Kawa, S., Masamune, A., Nakamura, S., Okazaki, K., Furumatsu, K., Sawai, S., Goto, T., Okumura, T., Suzuki, D., Otsuka, M., Kobori, I., Tamano, M., Koizumi, M., Hiasa, Y., Kawabe, N., Hirooka, Y., Yamamoto, S., Asano, Y., Inui, K., Horiguchi, A., Watanabe, H., Toya, D., Hatayama, K., Ueki, T., Kinoshita, N., Sugimoto, M., Ohira, H., Mukai, T., Tomita, E., Iwata, K., Shimizu, S., Suetsugu, J., Shimizu, M., Tsuji, K., Ishida, R., Ito, M., Furukawa, R., Sakamoto, N., Araki, M., Tanno, S., Sakamoto, Y., Ito, T., Takai, S., Ikeya, S., Yamada, T., Kudara, N., Shimizu, A., Hanada, K., Ichiki, Y., Kitada, H., Hifumi, M., Kimura, H., Kurosaki, M., Izumi, N., Sumi, H., Haruta, J.-I., Hayashi, K., Harada, R., Inoue, M., Nakamura, S., Ito, T., Tomishima, K., Isayama, H., Oura, K., Masaki, T., Shimokawahara, N., Tanoue, S., Maemura, K., Ido, A., Mizushima, I., Kawano, M., Yoshida, K., Naganuma, M., Murata, M., Nishio, A., Fujita, Y., Teratani, T., Matsubara, S., Tamai, H., Yoshida, Y., Azemoto, R., Kamata, K., Watanabe, T., Kurosu, T., Koizumi, W., Fujita, J., Seki, H., Ueda, Y., Fukumoto, T., Kousaki, T., Uchida, K., Ochiai, T., Kawasaki, T., Tanaka, M., Ishida, E., Notohara, K., Mori, H., Mori, T., Kawabata, H., Miyata, M., Sakagami, J., Itoh, Y., Shiokawa, M., Seno, H., Watanabe, N., Kataoka, H., Aoki, T., Fujishiro, M., Niihara, T., Nishimata, H., Mitoro, A., Yoshiji, H., Yoshida, M., Ikeda, M., Tomita, K., Hokari, R., Hayasaka, K., Amano, Y., Shioji, K., Hayashi, K., Terai, S., Nakajima, M., Yamahana, J., Matsumoto, R., Kikuchi, H., Kanamori, A., Kiriyama, S., Iwatsu, S., Kato, Y., Horiguchi, S., Yagi, T., Okada, H., Ohkawa, K., Hirao, M., Hiramatsu, N., Oza, N., Imamura, H., Baba, T., Nakano, S., Shinobi, T., Ryozawa, S., Motoya, M., Nakase, H., Kinoshita, N., Ito, K., Miyake, T., Kohge, N., Tobita, H., Joshita, S., Umemura, T., Kawaguchi, S., Ohno, K., Sonobe, K., Satoh, A., Shimosegawa, T., Miura, F., Yagi, M., Sano, K., Kin, T., Katanuma, A., Koike, K., Miura, S., Kawashima, Y., Kagawa, T., Azuma, S., Watanabe, M., Honjyo, M., Itoi, T., Honda, A., Kobayashi, K., Asano, T., Mizuno, S., Koike, K., Nishino, T., Taniguchi, H., Tajiri, K., Yasuda, I., Tanaka, Y., Oe, S., Harada, M., Kurata, M., Fukasawa, M., Enomoto, N., Kawaji, Y., Kitano, M., Nishise, Y., Hirakawa, H., Ishizawa, T., Ueno, Y., Kaino, M., Fujimoto, Y., Sakaida, I.

Journal of Gastroenterology and Hepatology (Australia) 38 ( 4 ) 2023年

[Toward liver fibrosis amelioration and regenerative therapy using mesenchymal stem cells, extracellular vesicles, and peptides].

Atsunori Tsuchiya, Shuji Terai

Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology 120 ( 12 ) 973 - 979 2023年

Basic points to consider regarding the preparation of extracellular vesicles and their clinical applications in Japan

Tsuchiya, A., Terai, S., Horiguchi, I., Homma, Y., Saito, A., Nakamura, N., Sato, Y., Ochiya, T., Kino-oka, M.

Regenerative Therapy 21 19 - 24 2022年12月

Edwardsiella tardaによる大量膿瘍をきたした肝硬変患者の1例症例報告(Massive empyema with Edwardsiella tarda in a patient with liver cirrhosis: a case report)

水戸將貴, 木村成宏, 山崎華子, 神保遼, 小島雄一, 荒生祥尚, 林和直, 土屋淳紀, 寺井崇二

日本消化器病学会甲信越支部例会・日本消化器内視鏡学会甲信越支部例会抄録集 71回・93回 47 - 47 2022年12月

HBx and YAP expression could promote tumor development and progression in HBV-related hepatocellular carcinoma. 国際誌

Chiyumi Oda, Kenya Kamimura, Osamu Shibata, Shinichi Morita, Yuto Tanaka, Toru Setsu, Hiroyuki Abe, Takeshi Yokoo, Akira Sakamaki, Hiroteru Kamimura, Satoshi Kofuji, Toshifumi Wakai, Hiroshi Nishina, Shuji Terai

Biochemistry and biophysics reports 32 101352 - 101352 2022年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Background: Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) accounts for 10%-20% of the total HCC numbers. Its clinical features include the occurrence in the younger generation, large tumors, and poor prognosis. The contribution of hepatitis B virus X (HBx) protein in hepatocytes during activation of various oncogenic pathways has been reported. We aimed to assess the possible association between HBx and Yes-associated protein (YAP) expression in the liver tissue and the clinical features of HBV-related HCC. Methods: The relationship between HBx and YAP expression was examined in vivo using HCC tumor and peritumor tissues (n = 55). The clinical information including tumor size, marker, and the prognosis was assessed with protein expressions. The in vitro gene expression analyses were conducted using HBx- and YAP-overexpressing HCC cell lines. Results: Among 19 cases of HBV-related, 17 cases of hepatitis C virus (HCV)-related, and 19 cases of nonviral-related HCC, the HBV-related tumor showed the largest size. The HBx-stained area in the tumor and peritumor tissue showed a significant correlation with tumor size and serum α-fetoprotein level. YAP expression was higher in HBV-related tumor tissue than in the peritumor tissue and HCV-related tumor. Additionally, HBx and YAP protein expressions are correlated and both expressions in the tumor contributed to the poor prognosis. An in vitro study demonstrated that HBx and YAP overexpression in the hepatocytes activate the various oncogenic signaling pathways. Conclusions: Our study demonstrated that YAP expression in the liver of HBV-infected patients might be the key factor in HBV-related HCC development and control of tumor-related features.

DOI： 10.1016/j.bbrep.2022.101352

Gene panel testing detects important genetic alterations in ulcerative colitis-associated colorectal neoplasia. 国際誌

Yoshifumi Shimada, Mae Nakano, Ken-Ichi Mizuno, Junji Yokoyama, Akio Matsumoto, Kana Tanaka, Hidehito Oyanagi, Masato Nakano, Yuki Hirose, Hiroshi Ichikawa, Jun Sakata, Hitoshi Kameyama, Yasumasa Takii, Mika Sugai, Yiwei Ling, Shiho Takeuchi, Shujiro Okuda, Shuji Terai, Yoichi Ajioka, Toshifumi Wakai

Oncology letters 24 ( 6 ) 442 - 442 2022年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Ulcerative colitis-associated neoplasia (UCAN) harbors unique genetic alterations and mutational tendencies. The clinical application of gene panel testing enables precision medicine by tailoring treatment to individual gene alterations. We hypothesized that gene panel testing may detect clinically important genetic alterations in UCAN, with potential usefulness for the diagnosis and treatment of UCAN. In the present study, gene panel testing was used to identify genetic alterations in UCAN, and the possibility of clinical utility of gene panel testing in UCAN was investigated. The present study included 15 patients with UCAN, and gene panel testing was performed to identify genetic alterations associated with diagnosis and treatment. Genetic alterations of UCAN were compared with those of 203 patients with sporadic colorectal cancer (CRC). APC and PTEN mutations were less frequent, while RNF43 frameshift or nonsense mutations were more frequent in UCAN compared with sporadic CRC. TP53 mutations were identified in 13/15 patients (87%) with UCAN. Notably, 4/15 patients (27%) with UCAN had no genetic alterations other than TP53 mutation, while this occurred in 1/203 patients (0.5%) with sporadic CRC (P<0.001). Microsatellite instability-high was identified in 2/15 patients (13%) with UCAN. Mutational signature 3, which is associated with homologous recombination deficiency, was detected in 14/15 patients (93%) with UCAN, and enriched in UCAN compared with sporadic CRC (P=0.030). In conclusion, gene panel testing can detect important genetic alterations that can be useful for diagnosis and treatment in UCAN, and may provide clinicians with important information for tailored treatment strategies.

DOI： 10.3892/ol.2022.13562

術後再建腸管例の悪性胆道狭窄に対するバルーン内視鏡下胆道ドレナージの有用性

名古屋拓郎, 寺井崇二, 林和直, 五十嵐聡, 小川光平

ENDOSCOPIC FORUM for digestive disease 38 ( 2 ) 153 - 153 2022年12月

糖鎖欠損トランスフェリン値はγ-GTP値と相補的にアルコール性肝硬変の予後不良に関連する

坂牧僚, 小山究太郎, 酒井規裕, 阿部寛幸, 上村顕也, 寺井崇二

アルコールと医学生物学 41 71 - 73 2022年12月

記述言語：日本語出版者・発行元：梵天書房

アルコール性肝硬変症例67例(男性86.6%:年齢中央値65歳)を対象に、糖鎖欠損トランスフェリン(CDT)値とγ-GTP値と予後の関連について後方視的に検討した。経過観察期間は3年とした。Cox回帰分析の結果、%CDT値は単変量で有意な予後不良因子であったが多変量では抽出されず、γ-GTP高値が独立した予後不良因子であることが分かった。対象を%CDT値およびγ-GTP値ともに正常値であった12例(1群)、一方が高値であった34例(2群)、両方とも高値であった21例(3群)に分けて予後比較した。その結果、3年生存率は1群が100.0%で有意に予後良好であった。以上より、%CDTかγ-GTPの一方が高値であると予後不良に関連することが示された。

Two rare pancreatic parenchymal hemorrhagic lesions associated with acute pancreatitis in acute liver failure: a case report and literature review.

Ryo Jimbo, Yoshihisa Arao, Atsunori Tsuchiya, Hanako Yamazaki, Masaki Mito, Yuichi Kojima, Yuji Kobayashi, Naruhiro Kimura, Kazunao Hayashi, Shuji Terai

Clinical journal of gastroenterology 2022年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Acute pancreatitis is an uncommon occurrence in acute liver failure. Furthermore, such cases are rarely complicated by parenchymal hemorrhages. Herein, we report the case of a 69-year-old male patient with multiple pancreatic parenchymal hemorrhages concomitant with acute liver failure. The patient underwent conservative treatment for acute liver failure caused by hepatitis B virus infection. Plain computed tomography on the 30th day revealed two high-density mass lesions in the pancreatic body and tail, which were suspected to be multiple pancreatic parenchymal hemorrhages. Despite restarting gabexate mesylate, the patient died of multiple organ failure on the 49th day. The clinical information of the present case and our literature review of 61 similar cases in 43 case reports identified via a systematic keyword search of the PubMed database, which described acute pancreatitis concomitant with acute hepatitis and acute liver failure, will aid physicians in the diagnosis and treatment of this rare condition.

DOI： 10.1007/s12328-022-01738-x

Cell-free and concentrated ascites reinfusion therapy versus large-volume paracentesis for the treatment of cirrhotic patients with refractory ascites: A multicenter prospective observational study. 国際誌

Tatsunori Hanai, Hideto Kawaratani, Junji Nagano, Hirokazu Suii, Akira Sakamaki, Yoshitaka Arase, Hiroyuki Nakanishi, Tomomi Kogiso, Tomomi Okubo, Takao Miwa, Shogo Shimizu, Shuhei Hige, Masanori Atsukawa, Masahito Shimizu, Masayuki Kurosaki, Shuji Terai, Tatehiro Kagawa, Katsutoshi Tokushige, Hitoshi Yoshiji

Hepatology research : the official journal of the Japan Society of Hepatology 53 ( 3 ) 238 - 246 2022年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIM: Cell-free and concentrated ascites reinfusion therapy (CART) and large-volume paracentesis (LVP) with albumin infusion are useful for managing refractory ascites (RA). However, it remains unclear which therapy is more effective in patients with cirrhosis with RA. METHODS: From June 2018 to March 2022, 25 patients with RA treated with CART or LVP with albumin infusion were enrolled in this multicenter prospective observational study to investigate the number of abdominal paracenteses, albumin preparations used, and drainage volume during an 8-week observation period. RESULTS: Among all patients at entry (median age, 63 years; 52% men; 60% Child-Pugh B and 40% Child-Pugh C), 92% were treated with furosemide (median, 20 mg/day), 92% with spironolactone (25 mg/day), and all with tolvaptan (7.5 mg/day). Patients with RA had a poor health-related quality of life (HRQOL) and prominent ascites-related symptoms. Four of the 20 eligible patients were treated with CART, 11 with LVP with albumin infusion, and five with their combination. The median number of paracenteses, total drainage volume, and albumin infusions were 1.5, 7.4 L, and 0, respectively, in the CART group; 5.0, 22.0 L, and 5.0, respectively, in the LVP group; and 5.0, 30.0 L, and 5.0, respectively in their combination group. The treatment effects did not differ significantly among the three groups regarding weight loss, liver function, renal function, electrolytes, and HRQOL. However, patients treated with CART had fewer paracenteses and albumin infusions than those treated with LVP. CONCLUSIONS: CART and LVP have comparable therapeutic efficacy for RA in patients with cirrhosis.

DOI： 10.1111/hepr.13860

Weakly Supervised Multiple Instance Learning for Liver Cirrhosis Classification using Ultrasound Images

Yusuke Fujita, Kaito Ishihara, Kazuma Nakata, Yoshihiko Hamamoto, Makoto Segawa, Isao Sakaida, Yoshihiro Mitani, Shuji Terai

2022 7th International Conference on Intelligent Informatics and Biomedical Science (ICIIBMS) 2022年11月

Early‐phase prothrombin time‐international normalized ratio in acute liver injury indicates the timing of therapeutic intervention and predicts prognostic improvement

Kotaro Kumagai, Seiichi Mawatari, Akihiro Moriuchi, Kohei Oda, Yasuhiro Takikawa, Naoya Kato, Shigeto Oda, Kazuaki Inoue, Shuji Terai, Takuya Genda, Masahito Shimizu, Isao Sakaida, Satoshi Mochida, Akio Ido

Hepatology Research 53 ( 2 ) 160 - 171 2022年11月

【再生医療の現状と展望】間葉系幹細胞を用いた肝疾患の再生医療

土屋淳紀, 寺井崇二

BIO Clinica 37 ( 12 ) 1089 - 1093 2022年11月

記述言語：日本語出版者・発行元：(株)北隆館

肝硬変に対しては,本来自らが持つ線維化改善能力を促進させる薬剤の開発が行われている。間葉系幹細胞もその中で注目されているものの一つで生体内で"指揮細胞"として働き,肝内の"実働細胞"であるマクロファージに影響し,マクロファージを抗炎症性に変化させ肝硬変の改善に影響を及ぼすことを明らかにしてきた。更に,間葉系幹細胞のエクソソームは非常に重要で特にIFNγで間葉系幹細胞を刺激後に得られるエクソソームは肝硬変マウスに高い治療効果を発揮した。今後間葉系幹細胞,そしてそのエクソソームを用いた治療は高い治療効果を求めて次のステージへと動き始めている。(著者抄録)

小児NAFLD患者の背景疾患と移行医療への課題

上村博輝, 佐藤毅昂, 山崎文紗子, 坂牧僚, 土屋淳紀, 寺井崇二, 長崎啓祐, 齋藤昭彦

肥満研究 28 ( Suppl. ) 290 - 290 2022年11月

小児NAFLD患者の背景疾患と移行医療への課題

上村博輝, 佐藤毅昂, 山崎文紗子, 坂牧僚, 土屋淳紀, 寺井崇二, 長崎啓祐, 齋藤昭彦

肥満研究 28 ( Suppl. ) 290 - 290 2022年11月

Letrozole ameliorates liver fibrosis through the inhibition of the CTGF pathway and 17β-hydroxysteroid dehydrogenase 13 expression.

Norihiro Sakai, Kenya Kamimura, Hirotaka Miyamoto, Masayoshi Ko, Takuro Nagoya, Toru Setsu, Akira Sakamaki, Takeshi Yokoo, Hiroteru Kamimura, Hiroyuki Soki, Ayako Tokunaga, Tatsuo Inamine, Mikiro Nakashima, Hatsune Enomoto, Kazuki Kousaka, Hidehisa Tachiki, Kaname Ohyama, Shuji Terai

Journal of gastroenterology 58 ( 1 ) 53 - 68 2022年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: To establish a treatment option for liver fibrosis, the possibility of the drug repurposing theory was investigated, with a focus on the off-target effects of active pharmaceutical ingredients. METHODS: First, several active pharmaceutical ingredients were screened for their effects on the gene expression in the hepatocytes using chimeric mice with humanized hepatocytes. As per the gene expression-based screening assay for 36 medications, we assessed the mechanism of the antifibrotic effect of letrozole, a third-generation aromatase inhibitor, in mouse models of liver fibrosis induced by carbon tetrachloride (CCl4) and a methionine choline-deficient (MCD) diet. We assessed liver histology, serum biochemical markers, and fibrosis-related gene and protein expressions in the hepatocytes. RESULTS: A gene expression-based screening assay revealed that letrozole had a modifying effect on fibrosis-related gene expression in the hepatocytes, including YAP, CTGF, TGF-β, and CYP26A1. Letrozole was administered to mouse models of CCl4- and MCD-induced liver fibrosis and it ameliorated the liver fibrosis. The mechanisms involved the inhibition of the Yap-Ctgf profibrotic pathway following a decrease in retinoic acid levels in the hepatocytes caused by suppression of the hepatic retinol dehydrogenase, Hsd17b13 and activation of the retinoic acid hydrogenase, Cyp26a1. CONCLUSIONS: Letrozole slowed the progression of liver fibrosis by inhibiting the Yap-Ctgf pathway. The mechanisms involved the modification of the Hsd17b13 and Cyp26a1 expressions led to the suppression of retinoic acid in the hepatocytes, which contributed to the activation of Yap-Ctgf pathway. Because of its off-target effect, letrozole could be repurposed for the treatment of liver fibrosis. The third-generation aromatase inhibitor letrozole ameliorated liver fibrosis by suppressing the Yap-Ctgf pathway by partially modifying the Hsd17b13 and Cyp26a1 expressions, which reduced the retinoic acid level in the hepatocytes. The gene expression analysis using chimeric mice with humanized liver revealed that the mechanisms are letrozole specific and, therefore, may be repurposed for the treatment of liver fibrosis.

DOI： 10.1007/s00535-022-01929-w

肝再生・移植医療への新規トランスレーショナルリサーチ肝硬変に対するHMGB1部分ペプチドを用いた基礎研究から医師主導治験実施へ

土屋淳紀, 寺井崇二

肝臓 63 ( Suppl.3 ) A710 - A710 2022年10月

肝硬変,肝癌治療薬の薬物関連有害事象報告の国際比較把握とその解釈による今後のマネージメント

上村博輝, 土屋淳紀, 寺井崇二

肝臓 63 ( Suppl.3 ) A792 - A792 2022年10月

機械学習を用いた上部内視鏡施行時の咽頭老化の予測

上村博輝, 小島雄一, 高橋一也, 高綱将史, 平野正明, 政二文明, 水野研一, 横山純二, 寺井崇二

日本消化器病学会雑誌 119 ( 臨増大会 ) A812 - A812 2022年10月

門脈圧亢進症に対する診断・治療における新たな挑戦機械学習を用いた慢性心不全に続発した肝臓への障害(Cardiac Hepatopathy)の画像解析

三井田秀, 上村博輝, 寺井崇二

日本消化器病学会雑誌 119 ( 臨増大会 ) A640 - A640 2022年10月

ガイドライン改訂後の膵炎診療の現状と課題重症急性膵炎後Walled-off necrosisの経過における抗菌薬投与の影響

五十嵐聡, 林和直, 寺井崇二

日本消化器病学会雑誌 119 ( 臨増大会 ) A534 - A534 2022年10月

重症急性膵炎後Walled-off necrosisの内視鏡治療におけるLumen apposing metal stentの有効性

林和直, 五十嵐聡, 小川光平, 寺井崇二

Gastroenterological Endoscopy 64 ( Suppl.2 ) 2126 - 2126 2022年10月

Acute-on-chronic liver failure(ACLF):わが国の現状と今後の課題 ACLFの新規治療開発に向けた基盤研究

渡邉雄介, 土屋淳紀, 寺井崇二

肝臓 63 ( Suppl.2 ) A508 - A508 2022年9月

アテゾリズマブ+ベバシズマブ併用療法の非奏効例におけるLate line移行時期についての検討

横尾健, 酒井規裕, 渡邉雄介, 荒生祥尚, 木村成宏, 阿部寛幸, 薛徹, 上村博輝, 坂牧僚, 上村顕也, 土屋淳紀, 寺井崇二

肝臓 63 ( Suppl.2 ) A582 - A582 2022年9月

慢性肝疾患におけるTGFβ3の発現と肝予備能との関連性についての検討

阿部寛幸, 酒井規裕, 渡邉雄介, 荒生祥尚, 木村成宏, 上村博輝, 坂牧僚, 横尾健, 上村顕也, 土屋淳紀, 寺井崇二

肝臓 63 ( Suppl.2 ) A597 - A597 2022年9月

大腸菌の外膜小胞は肝硬変での更なる炎症・線維化増悪に寄与する

夏井一輝, 土屋淳紀, 寺井崇二

肝臓 63 ( Suppl.2 ) A593 - A593 2022年9月

ウイルス駆除時代における,院内非専門医での効果的なC型肝炎患者の拾い上げ

荒生祥尚, 酒井規裕, 寺井崇二

肝臓 63 ( Suppl.2 ) A557 - A557 2022年9月

アテゾリズマブ+ベバシズマブ併用療法の非奏効例におけるLate line移行時期についての検討

横尾健, 酒井規裕, 渡邉雄介, 荒生祥尚, 木村成宏, 阿部寛幸, 薛徹, 上村博輝, 坂牧僚, 上村顕也, 土屋淳紀, 寺井崇二

肝臓 63 ( Suppl.2 ) A582 - A582 2022年9月

慢性肝疾患におけるTGFβ3の発現と肝予備能との関連性についての検討

阿部寛幸, 酒井規裕, 渡邉雄介, 荒生祥尚, 木村成宏, 上村博輝, 坂牧僚, 横尾健, 上村顕也, 土屋淳紀, 寺井崇二

肝臓 63 ( Suppl.2 ) A597 - A597 2022年9月

Synthesized HMGB1 peptide prevents the progression of inflammation, steatosis, fibrosis, and tumor occurrence in a non-alcoholic steatohepatitis mouse model. 国際誌

Yui Ishii, Atsunori Tsuchiya, Kazuki Natsui, Youhei Koseki, Nobutaka Takeda, Kei Tomiyoshi, Fusako Yamazaki, Yuki Yoshida, Takashi Shimbo, Katsuto Tamai, Shuji Terai

Hepatology research : the official journal of the Japan Society of Hepatology 2022年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIM: Non-alcoholic steatohepatitis (NASH) with fibrosis eventually leads to cirrhosis and hepatocellular carcinoma. Thus, the development of therapies other than dietary restriction and exercise, particularly those that suppress steatosis and fibrosis of the liver and have a long-term beneficial effect, is necessary. We aimed to evaluate the therapeutic effects of the HMGB1 peptide synthesized from box A using the melanocortin-4 receptor-deficient (Mc4r-KO) NASH model mouse. METHODS: We performed short- and long-term administration of this peptide and evaluated the effects on steatosis, fibrosis, and carcinogenesis using Mc4r-KO mice. We also analyzed the direct effect of this peptide on macrophages and hepatic stellate cells in vitro and performed lipidomics and metabolomics techniques to evaluate the effect. RESULTS: Although this peptide did not show direct effects on macrophages and hepatic stellate cells in vitro, in the short-term administration model, we could confirm the reduction of liver damage, steatosis, and fibrosis progression. The results of lipidomics and metabolomics suggested that the peptide might ameliorate NASH by promoting lipolysis via the activation of fatty acid β-oxidation and improving insulin resistance. In the long-term administration model, this peptide prevented progression to cirrhosis but retained the steatosis state, that is, the peptide prevents the progression to "burnt-out NASH." This peptide inhibited carcinogenesis by about one-third. CONCLUSION: This HMGB1 peptide can reduce liver damage, improve fibrosis and steatosis, and inhibit carcinogenesis, suggesting that the peptide would be a new treatment candidate for NASH and can contribute to the long-term prognosis for patients with NASH.

DOI： 10.1111/hepr.13825

Effects of a selective PPARα modulator, sodium-glucose cotransporter 2 inhibitor, and statin on the myocardial morphology of medaka nonalcoholic fatty liver disease model. 国際誌

Marina Ohkoshi-Yamada, Kenya Kamimura, Atsushi Kimura, Yuto Tanaka, Itsuo Nagayama, Shunta Yakubo, Hiroyuki Abe, Takeshi Yokoo, Akira Sakamaki, Hiroteru Kamimura, Shuji Terai

Biochemical and biophysical research communications 625 116 - 121 2022年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic dysregulation and is linked with various cardiovascular complications, which often lead to poor prognostic outcomes. To develop a standard therapy for NAFLD and to urgently address its complications, the current study aimed to investigate the mechanisms of NAFLD-related heart disease and the therapeutic effects of drugs targeting various metabolic pathways. METHODS: To explore the mechanism of NAFLD-related heart disease, a medaka model of high-fat diet-induced NAFLD was utilized. The gross structural, histological, and inflammatory changes in the myocardium were evaluated in a time-dependent manner. In addition, the therapeutic effects of medicines used for NAFLD treatment including, selective peroxisome proliferator-activated receptor α modulator (SPPARMα, pemafibrate), sodium-glucose cotransporter 2 (SGLT2) inhibitor (tofogliflozin), and statin (pitavastatin), and their combinations on heart pathology were evaluated. To determine the mechanisms underlying the therapeutic effects, the expression of genes related to liver inflammation was assessed via whole transcriptome sequencing analysis. RESULTS: The fish with NAFLD-related heart injury presented with cardiomyocyte hypertrophy, which led to cardiac hypertrophy. This morphological change was caused by the infiltration of inflammatory cells, including macrophages and CD4- and CD8-positive lymphocytes, in the cardiac wall and the expression of transforming growth factor beta 1 in the cardiomyocytes. Further, the livers of the fish had upregulated expressions of senescence-associated secretory phenotype-related genes. Treatment with pemafibrate, tofogliflozin, and pitavastatin reduced these changes and, consequently, cardiomyopathy. CONCLUSION: Our results demonstrated that NAFLD-related heart disease was attributed to the senescence-associated secretory phenotype-induced inflammatory activity in the cardiac wall, which resulted in myocardial hypertrophy. Moreover, the effects of SPPARMα, SGLT2 inhibitor, and statin on NAFLD-related heart disease were evident in the medaka NAFLD model.

DOI： 10.1016/j.bbrc.2022.07.117

機械学習を用いた慢性心不全に続発した肝臓への障害(Cardiac Hepatopathy)の画像解析

三井田秀, 上村博輝, 山崎文紗子, 渡邉雄介, 荒生祥尚, 木村成宏, 薛徹, 横尾健, 坂牧僚, 土屋淳紀, 藤木伸也, 猪又孝元, 寺井崇二

日本門脈圧亢進症学会雑誌 28 ( 3 ) 152 - 152 2022年8月

Cumulative risk of developing a new symptom in patients with primary biliary cholangitis and its impact on prognosis. 国際誌

Naruhiro Kimura, Toru Setsu, Yoshihisa Arao, Norihiro Sakai, Yusuke Watanabe, Hiroyuki Abe, Hiroteru Kamimura, Akira Sakamaki, Takeshi Yokoo, Kenya Kamimura, Atsunori Tsuchiya, Akihiko Osaki, Kentarou Igarashi, Nobuo Waguri, Masahiko Yanagi, Toru Takahashi, Soichi Sugitani, Yuka Kobayashi, Masaaki Takamura, Akira Yoshikawa, Toru Ishikawa, Toshiaki Yoshida, Toshiaki Watanabe, Hitoshi Bannai, Tomoyuki Kubota, Kazuhiro Funakoshi, Hiroto Wakabayashi, So Kurita, Norio Ogata, Masashi Watanabe, Yuhsaku Mita, Shigeki Mori, Motoya Sugiyama, Toru Miyajima, Sumio Takahashi, Shuichi Sato, Kisei Ishizuka, Hironobu Ohta, Yutaka Aoyagi, Shuji Terai

JGH open : an open access journal of gastroenterology and hepatology 6 ( 8 ) 577 - 586 2022年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Background and Aim: Symptoms of primary biliary cholangitis (PBC) frequently impair one's quality of life (QOL). Nonetheless, with improved treatment, the prognosis of PBC also improves. QOL plays an important role in patients with PBC. In this study, we aimed to reevaluate the transition of new symptom development in PBC and its predictive factors. Methods: This retrospective multicenter study enrolled 382 patients with PBC for symptom analysis. The impact of a newly developed symptom on PBC prognosis was investigated by Kaplan-Meier analysis with propensity score matching and logistic progression analysis. Results: The cumulative risk of developing a new symptom after 10 and 20 years of follow-up was 7.6 and 28.2%, and specifically that of pruritus, which was the most common symptom, was 6.7 and 23.3%, respectively. In Cox hazard risk analysis, serum Alb level (hazard ratio [HR], 1.097; 95% confidence interval [CI], 1.033-1.165; P = 0.002), the serum D-Bil level (HR, 6.262; 95% CI, 2.522-15.553, P < 0.001), and Paris II criteria (HR, 0.435; 95% CI, 0.183-1.036; P = 0.037) were significant independent predictors of a new symptom. Kaplan-Meier analysis showed that the overall survival and liver-related death were not significant between patients with and without a new symptom. Conclusion: The cumulative risk of new symptom development is roughly 30% 20 years after diagnosis and could be predicted by factors including serum albumin levels, serum D-Bil level, and Paris II criteria.

DOI： 10.1002/jgh3.12789

機械学習を用いた慢性心不全に続発した肝臓への障害(Cardiac Hepatopathy)の画像解析

三井田秀, 上村博輝, 山崎文紗子, 渡邉雄介, 荒生祥尚, 木村成宏, 薛徹, 横尾健, 坂牧僚, 土屋淳紀, 藤木伸也, 猪又孝元, 寺井崇二

日本門脈圧亢進症学会雑誌 28 ( 3 ) 152 - 152 2022年8月

アルコール関連臓器障害における細胞間・臓器間ネットワークの新展開肝疾患における自律神経経路を介した臓器連関の関与

上村顕也, 永山逸夫, 大脇崇史, 高昌良, 名古屋拓郎, 井上良介, 坂牧僚, 寺井崇二

日本アルコール・薬物医学会雑誌 57 ( 4 ) 121 - 121 2022年8月

Allograft liver failure awaiting liver transplantation in Japan.

Takuya Genda, Takafumi Ichida, Eiji Tanaka, Satoshi Mochida, Yoshiyuki Ueno, Shuji Terai, Ayano Inui, Yoshihide Ueda, Hideki Ohdan, Hiroto Egawa, Koji Umeshita, Hiroyuki Furukawa, Yukihiro Inomata

Journal of gastroenterology 57 ( 7 ) 495 - 504 2022年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Following liver transplantation (LT), allograft liver failure can be developed by various causes and requires re-LT. Hence, this study aimed to clarify the characteristics and prognostic factors of patients with allograft liver failure awaiting deceased donor LT (DDLT) in Japan. METHODS: Of the 2686 DDLT candidates in Japan between 2007 and 2016, 192 adult patients listed for re-LT were retrospectively enrolled in this study. Factors associated with waitlist mortality were assessed using the Cox proportional hazards model. The transplant-free survival probabilities were evaluated using the Kaplan-Meier analysis and log-rank test. RESULTS: The median period from the previous LT to listing for re-LT was 1548 days (range, 4-8449 days). Primary sclerosing cholangitis (PSC), which was a primary indication, showed a higher listing probability for re-LT as compared with other primary etiologies. Recurrent liver disease was a leading cause of allograft failure and was more frequently observed in the primary indication of hepatitis C virus (HCV) infection and PSC in contrast with other etiologies. Multivariate analysis identified the following independent risk factors associated with waitlist mortality: age, Child-Turcotte-Pugh (CTP) score, mode for end-stage liver disease (MELD) score, alanine aminotransferase (ALT), and causes of allograft failure. CONCLUSIONS: Recurrent HCV and PSC were major causes of allograft liver failure in Japan. In addition to CTP and MELD scores, either serum ALT levels or causes of allograft failure should be considered as graft liver allocation measures.

DOI： 10.1007/s00535-022-01880-w

(II章)肝肝硬変に対する再生医療

寺井崇二, 土屋淳紀

消化器内科学レビュー 2022-'23 213 - 216 2022年7月

記述言語：日本語出版者・発行元：(株)総合医学社

＜最近の動向とガイドライン＞●現在までに、C型肝炎に対する有効な治療薬が開発され、またB型肝炎に対して核酸アナログ製剤を中心にコントロールが良好な症例が増え、なお制圧に向け薬剤開発が進んでいる状況である。●一方、アルコールや生活習慣を背景とした肝硬変は増えてきており、肝移植以外の肝硬変に対する治療法の開発は喫緊の課題である。●本項では肝臓再生医療で2019～2021年に著された臨床論文を解説すると同時にその背景や、現在行われている将来の治療の基盤となる基礎研究についても一部述べる。(著者抄録)

肝性腹水が腹部コンパートメント症候群を介して腎機能へ与える影響の検討

上村博輝, 酒井規裕, 小島雄一, 川田雄三, 渡邊雄介, 荒生祥尚, 木村成宏, 阿部寛幸, 薛徹, 横尾健, 坂牧僚, 土屋淳紀, 上村顕也, 横山純二, 寺井崇二

日本門脈圧亢進症学会雑誌 28 ( 2 ) 199 - 203 2022年7月

記述言語：日本語出版者・発行元：(一社)日本門脈圧亢進症学会

大量の肝性腹水が腹腔内圧の上昇をもたらし、腹部コンパートメント症候群を発症している状況を腹水前後の膀胱内圧測定、腎静脈流速測定を中心に検討した。対象症例は穿刺前後の膀胱内圧測定、腎静脈の流速測定等が可能であった腹水合併肝硬変8例。穿刺前後の膀胱内圧、尿潜血反応、腎機能、腎静脈流速等を経時的に観察した。末期肝硬変患者が肝腎症候群へ移行する過程で腹水による腹腔内圧の上昇が腎うっ血を併発させ、レニン-アンギオテンシン-アルドステロン系の亢進に関係する可能性が示唆された。(著者抄録)

『高齢者(75歳以上)の非アルコール性脂肪性肝疾患の現状と課題』非アルコール性脂肪性肝炎を背景とした高齢者肝硬変に対する非侵襲的スコアリングシステムの有用性の検討

坂牧僚, 酒井規裕, 阿部寛幸, 横尾健, 上村顕也, 寺井崇二

日本高齢消化器病学会誌 25 ( 1 ) 74 - 74 2022年7月

【肝性脳症の病態と治療】肝性脳症と腸内細菌病態と治療

坂牧僚, 上村顕也, 横山邦彦, 酒井規裕, 渡邉雄介, 荒生祥尚, 木村成宏, 薛徹, 阿部寛幸, 上村博輝, 横尾健, 土屋淳紀, 寺井崇二

消化器・肝臓内科 12 ( 1 ) 68 - 72 2022年7月

各都道府県における肝疾患対策取り組みの現状新潟県の肝炎対策について

荒生祥尚, 薛徹, 酒井規裕, 寺井崇二

肝臓クリニカルアップデート 8 ( 1 ) 82 - 85 2022年7月

肝性腹水が腹部コンパートメント症候群を介して腎機能へ与える影響の検討

上村博輝, 酒井規裕, 小島雄一, 川田雄三, 渡邊雄介, 荒生祥尚, 木村成宏, 阿部寛幸, 薛徹, 横尾健, 坂牧僚, 土屋淳紀, 上村顕也, 横山純二, 寺井崇二

日本門脈圧亢進症学会雑誌 28 ( 2 ) 199 - 203 2022年7月

記述言語：日本語出版者・発行元：(一社)日本門脈圧亢進症学会

大量の肝性腹水が腹腔内圧の上昇をもたらし、腹部コンパートメント症候群を発症している状況を腹水前後の膀胱内圧測定、腎静脈流速測定を中心に検討した。対象症例は穿刺前後の膀胱内圧測定、腎静脈の流速測定等が可能であった腹水合併肝硬変8例。穿刺前後の膀胱内圧、尿潜血反応、腎機能、腎静脈流速等を経時的に観察した。末期肝硬変患者が肝腎症候群へ移行する過程で腹水による腹腔内圧の上昇が腎うっ血を併発させ、レニン-アンギオテンシン-アルドステロン系の亢進に関係する可能性が示唆された。(著者抄録)

The liver-gut peripheral neural axis and nonalcoholic fatty liver disease pathologies via hepatic serotonin receptor 2A. 国際誌

Takashi Owaki, Kenya Kamimura, Masayoshi Ko, Itsuo Nagayama, Takuro Nagoya, Osamu Shibata, Chiyumi Oda, Shinichi Morita, Atsushi Kimura, Takeki Sato, Toru Setsu, Akira Sakamaki, Hiroteru Kamimura, Takeshi Yokoo, Shuji Terai

Disease models & mechanisms 15 ( 7 ) 2022年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Serotonin (5-HT) is one of the key bioamines of nonalcoholic fatty liver disease (NAFLD). Its mechanism via autonomic neural signal pathways remains unexplained; hence, we evaluated the involvement of 5-HT and related-signaling pathways via autonomic nerves in NAFLD. Diet-induced NAFLD animal models were developed using wild-type and melanocortin 4 receptor knockout (MC4RKO) mice, and the effects of autonomic neural axis on NAFLD physiology, 5-HT and its receptors (Htrs), and lipid metabolism-related genes were assessed applying hepatic nerve blockade. Hepatic neural blockade retarded the progression of NAFLD by reducing 5-HT in the small intestine, hepatic Htr2a, and hepatic lipogenic genes expression, and HTR2A antagonist reproduced these effects. The effects were milder in MC4RKO, and brain 5-HT and Htr2c expression did not correlate with peripheral neural blockade. Our study demonstrates that the autonomic liver-gut neural axis is involved in the etiology of diet-induced NAFLD and that 5-HT and HTR2A are key factors, implying that the modulation of the axis and use of HTR2A antagonists are potentially novel therapeutic strategies for NAFLD treatment.

DOI： 10.1242/dmm.049612

Involvement of DNA Damage Response via the Ccndbp1-Atm-Chk2 Pathway in Mice with Dextran-Sodium-Sulfate-Induced Colitis. 国際誌

Ryoko Horigome, Kenya Kamimura, Yusuke Niwa, Kohei Ogawa, Ken-Ichi Mizuno, Koichi Fujisawa, Naoki Yamamoto, Taro Takami, Tomoyuki Sugano, Akira Sakamaki, Hiroteru Kamimura, Masaaki Takamura, Shuji Terai

Journal of clinical medicine 11 ( 13 ) 2022年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

The dextran sodium sulfate (DSS)-induced colitis mouse model has been widely utilized for human colitis research. While its mechanism involves a response to double-strand deoxyribonucleic acid (DNA) damage, ataxia telangiectasia mutated (Atm)-checkpoint kinase 2 (Chk2) pathway activation related to such response remains unreported. Recently, we reported that cyclin D1-binding protein 1 (Ccndbp1) activates the pathway reflecting DNA damage in its knockout mice. Thus, this study aimed to examine the contribution of Ccndbp1 and the Atm-Chk2 pathway in DSS-induced colitis. We assessed the effect of DSS-induced colitis on colon length, disease activity index, and histological score and on the Atm-Chk2 pathway and the subsequent apoptosis in Ccndbp1-knockout mice. DSS-induced colitis showed distal colon-dominant Atm and Chk2 phosphorylation, increase in TdT-mediated dUTP-biotin nick end labeling and cleaved caspase 3-positive cells, and histological score increase, causing disease activity index elevation and colon length shortening. These changes were significantly ameliorated in Ccndbp1-knockout mice. In conclusion, Ccndbp1 contributed to Atm-Chk2 pathway activation in the DSS-induced colitis mouse model, causing inflammation and apoptosis of mucosal cells in the colon.

DOI： 10.3390/jcm11133674

Daisaikoto improves fatty liver and obesity in melanocortin-4 receptor gene-deficient mice via the activation of brown adipose tissue. 国際誌

Shinichi Morita, Akira Sakamaki, Kyutaro Koyama, Osamu Shibata, Takashi Owaki, Chiyumi Oda, Atsushi Kimura, Taiki Nakaya, Katsuya Ohbuchi, Miwa Nahata, Naoki Fujitsuka, Norihiro Sakai, Hiroyuki Abe, Kenya Kamimura, Shuji Terai

Scientific reports 12 ( 1 ) 10105 - 10105 2022年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Melanocortin 4 receptor gene-knockout (MC4R-KO) mice are known to develop obesity with a high-fat diet. Meanwhile, daisaikoto, one of Kampo medicines, is a drug that is expected to have therapeutic effects on obesity. Here, we report the efficacy of daisaikoto in MC4R-KO mice. Eight-week-old MC4R-KO male mice (n = 12) were divided into three groups as follows: the SD group, which is fed with a standard diet; the HFD group, fed a high-fat diet; and the DSK group, fed with a high-fat diet containing 10% of daisaikoto. After the four-week observation period, mice in each group were sacrificed and samples were collected. The body weights at 12 weeks were significantly higher in the HFD group than in the other groups, indicating that daisaikoto significantly reduced body weight gain and fat deposition of the liver. The metabolome analysis indicated that degradation of triglycerides and fatty acid oxidation in the liver were enhanced by daisaikoto administration. In MC4R-KO mice, the cytoplasm and uncoupling protein 1 expression of brown adipose tissue was decreased; however, it was reversed in the DSK group. In conclusion, daisaikoto has potentially improved fatty liver and obesity, making it a useful therapeutic agent for obesity and fatty liver.

DOI： 10.1038/s41598-022-14371-y

Establishment of a pancreatic cancer animal model using the pancreas-targeted hydrodynamic gene delivery method. 国際誌

Osamu Shibata, Kenya Kamimura, Yuto Tanaka, Kohei Ogawa, Takashi Owaki, Chiyumi Oda, Shinichi Morita, Atsushi Kimura, Hiroyuki Abe, Satoshi Ikarashi, Kazunao Hayashi, Takeshi Yokoo, Shuji Terai

Molecular therapy. Nucleic acids 28 342 - 352 2022年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

This research developed an easy-to-use, reproducible pancreatic cancer animal model utilizing pancreas-targeted hydrodynamic gene delivery to deliver human pancreatic cancer-related genes to the pancreas of wild-type rats. KRAS G12D -induced pancreatic intraepithelial neoplasia lesions showed malignant transformation in the main pancreatic duct at 4 weeks and developed acinar-to-ductal metaplasia, which led to pancreatic ductal adenocarcinoma within 5 weeks, and the gene combination of KRAS G12D and YAP enhanced these effects. The repeat hydrodynamic gene delivery of KRAS G12D + YAP combination at 4 weeks showed acinar-to-ductal metaplasia in all rats and pancreatic ductal adenocarcinoma in 80% of rats 1 week later. Metastatic tumors in the liver, lymph nodes, and subcutaneous lesions and nervous invasion were confirmed. KRAS G12D and YAP combined transfer contributes to the E- to N-cadherin switch in pancreatic ductal adenocarcinoma cells and to tumor metastases. This pancreatic cancer model will speed up pancreatic cancer research for novel treatments and biomarkers for early diagnosis.

DOI： 10.1016/j.omtn.2022.03.019

多発性出血性膵炎を伴う重度の急性肝不全の一例(A case of severe acute liver failure with multiple hemorrhagic pancreatitis)

神保遼, 荒生祥尚, 山崎華子, 水戸將貴, 小島雄一, 木村成宏, 小林雄司, 林和直, 土屋淳紀, 寺井崇二

日本消化器病学会甲信越支部例会抄録集 70回 np41 - np41 2022年6月

【肝臓と他臓器相関】脂肪性肝疾患における自律神経系を介した消化管ホルモンの関与

大脇崇史, 上村顕也, 永山逸夫, 高昌良, 名古屋拓郎, 井上良介, 薛徹, 寺井崇二

消化器・肝臓内科 11 ( 6 ) 709 - 713 2022年6月

多発性出血性膵炎を伴う重度の急性肝不全の一例(A case of severe acute liver failure with multiple hemorrhagic pancreatitis)

神保遼, 荒生祥尚, 山崎華子, 水戸將貴, 小島雄一, 木村成宏, 小林雄司, 林和直, 土屋淳紀, 寺井崇二

日本消化器病学会甲信越支部例会抄録集 70回 np41 - np41 2022年6月

悪性胆道狭窄に対する治療戦略術後再建腸管例の悪性胆道狭窄に対するバルーン内視鏡下胆道ドレナージの有用性

名古屋拓郎, 寺井崇二, 林和直, 五十嵐聡, 小川光平

日本消化器病学会甲信越支部例会抄録集 70回 np46 - np46 2022年6月

NAFLDにおける肝-脳-腸関連と自律神経の関係

永山逸夫, 上村顕也, 高昌良, 大脇崇史, 名古屋拓郎, 寺井崇二

自律神経 59 ( 2 ) 208 - 211 2022年6月

記述言語：日本語出版者・発行元：日本自律神経学会

肝臓の様々な病態で,肝臓,脳,消化管が種々の因子を介して密接に連関することが明らかになりつつある.我々は,非アルコール性脂肪性肝疾患(NAFLD)でも肝-脳-腸が自律神経を介して連関することを明らかとしてきた.そこで,本稿では,肝疾患と自律神経の関連,これまでの我々の研究結果を紹介したい.(著者抄録)

その他リンク： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00586&link_issn=&doc_id=20220725290008&doc_link_id=10.32272%2Fans.59.2_208&url=https%3A%2F%2Fdoi.org%2F10.32272%2Fans.59.2_208&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Diagnostic criteria for acute-on-chronic liver failure and related disease conditions in Japan. 国際誌

Satoshi Mochida, Nobuaki Nakayama, Shuji Terai, Hitoshi Yoshiji, Masahito Shimizu, Akio Ido, Kazuaki Inoue, Takuya Genda, Yasuhiro Takikawa, Taro Takami, Naoya Kato, Masanori Abe, Ryuzo Abe, Ayano Inui, Hiromasa Ohira, Mureo Kasahara, Kazuaki Chayama, Kiyoshi Hasegawa, Atsushi Tanaka

Hepatology research : the official journal of the Japan Society of Hepatology 52 ( 5 ) 417 - 421 2022年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

The Intractable Hepato-Biliary Disease Study Group of Japan, sponsored by the Ministry of Health, Labor and Wealth, proposed in 2018 that patients with cirrhosis and a Child-Pugh score of 5-9 should be diagnosed as having acute-on-chronic liver failure (ACLF) when a deterioration of liver function ("serum bilirubin level of 5.0 mg/dl or more" and "prothrombin time value of 40% or less of the standardized values and/or international normalization rates of 1.5 or more") caused by severe liver damage develops within 28 days after an acute insult, including alcohol abuse, bacterial infection, gastrointestinal bleeding, and the exacerbation of underlying liver diseases. Disease severity can be classified into 4 grades depending on the extent of the deterioration in organ functions, including liver, kidney, cerebral, blood coagulation, circulatory and respiratory functions. The Study Group has since performed an annual nationwide survey of patients with ACLF diagnosed according to the proposed diagnostic criteria as well as those with disease conditions related to ACLF. A total of 501 patients, including 183 patients diagnosed as having ACLF, seen between 2017 and 2019 were enrolled, and univariate and multivariate analyses revealed that the proposed diagnostic criteria were useful for identifying cirrhotic patients with an unfavorable outcome following an acute insult. Consequently, the Study Group determined that the proposed diagnostic criteria should be used in both clinical practice and clinical research as formal diagnostic criteria.

DOI： 10.1111/hepr.13763

Development of Dilated Esophagus, Sigmoid Esophagus, and Esophageal Diverticulum in Patients With Achalasia: Japan Achalasia Multicenter Study. 国際誌

Hiroki Sato, Yusuke Fujiyoshi, Hirofumi Abe, Hironari Shiwaku, Junya Shiota, Chiaki Sato, Hiroyuki Sakae, Masaki Ominami, Yoshitaka Hata, Hisashi Fukuda, Ryo Ogawa, Jun Nakamura, Tetsuya Tatsuta, Yuichiro Ikebuchi, Hiroshi Yokomichi, Shuji Terai, Haruhiro Inoue

Journal of neurogastroenterology and motility 28 ( 2 ) 222 - 230 2022年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Background/Aims: Patients with achalasia-related esophageal motility disorders (AEMDs) frequently present with dilated and sigmoid esophagus, and develop esophageal diverticulum (ED), although the prevalence and patients characteristics require further elucidation. Methods: We conducted a multicenter cohort study of 3707 patients with AEMDs from 14 facilities in Japan. Esophagography on 3682 patients were analyzed. Results: Straight (n = 2798), sigmoid (n = 684), and advanced sigmoid esophagus (n = 200) were diagnosed. Multivariate analysis revealed that long disease duration, advanced age, obesity, and type I achalasia correlate positively, whereas severe symptoms and integrated relaxation pressure correlate negatively with development of sigmoid esophagus. In contrast, Grade II dilation (3.5-6.0 cm) was the most common (52.9%), while grade III dilation (≥ 6 cm) was rare (5.0%). We found early onset, male, obesity, and type I achalasia correlated positively, while advanced age correlated negatively with esophageal dilation. Dilated and sigmoid esophagus were found mostly in types I and II achalasia, but typically not found in spastic disorders. The prevalence of ED was low (n = 63, 1.7%), and non-dilated esophagus and advanced age correlated with ED development. Patients with right-sided ED (n = 35) had a long disease duration (P = 0.005) with low integrated relaxation pressure values (P = 0.008) compared with patients with left-sided ED (n = 22). Patients with multiple EDs (n = 6) had lower symptom severity than patients with a single ED (P = 0.022). Conclusions: The etiologies of dilated esophagus, sigmoid esophagus, and ED are considered multifactorial and different. Early diagnosis and optimal treatment of AEMDs are necessary to prevent these conditions.

DOI： 10.5056/jnm21188

Effects of Atezolizumab and Bevacizumab on Adrenal Gland Metastasis of Hepatocellular Carcinoma: A Case Report and Review of Literature.

Natsuki Ishikawa, Kenya Kamimura, Saori Endo, Soichi Ishii, Kazuya Ogawa, Norihiro Sakai, Hiroyuki Abe, Masayoshi Ko, Osamu Shibata, Youhei Koseki, Junji Yokoyama, Akira Sakamaki, Shuji Terai

Internal medicine (Tokyo, Japan) 2022年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Regarding the prognosis of cases with advanced-stage hepatocellular carcinoma (HCC), a recent clinical study showed that the immune checkpoint inhibitors atezolizumab plus bevacizumab have superior efficacy to sorafenib. However, only a few reports have focused on their effects on extrahepatic metastases. We herein report a case of HCC in a 59-year-old man with intrahepatic lesions treated successfully by hepatic arterial chemoembolization, radiotherapy, and sorafenib; the extrahepatic lesion in the adrenal gland was treated by atezolizumab plus bevacizumab. The patient showed a tumor-free condition for one year. We have summarized the clinical course and reviewed the literature to underscore the efficacy of atezolizumab plus bevacizumab for treating extrahepatic lesions of HCC.

DOI： 10.2169/internalmedicine.9341-22

老化細胞除去治療のAcute on chronic liverfailureに対する効果の検証

渡邉雄介, 土屋淳紀, 寺井崇二

肝臓 63 ( Suppl.1 ) A371 - A371 2022年4月

肝硬変-合併症の管理(含む門脈圧亢進症) 水素型の小腸内細菌異常増殖は肝疾患の不顕性肝性脳症と筋肉量低下に関連する

坂牧僚, 土屋淳紀, 寺井崇二

肝臓 63 ( Suppl.1 ) A64 - A64 2022年4月

【革新的技術が変える肝疾患診療】間葉系幹細胞・エクソソームを用いた肝硬変治療

土屋淳紀, 寺井崇二

消化器・肝臓内科 11 ( 4 ) 494 - 499 2022年4月

Relative Dose Intensityに基づく高齢者レンバチニブ投与における全生存期間の検討

横尾健, 酒井規裕, 渡邉雄介, 荒生祥尚, 木村成宏, 阿部寛幸, 薛徹, 上村博輝, 坂牧僚, 上村顕也, 土屋淳紀, 寺井崇二

肝臓 63 ( Suppl.1 ) A302 - A302 2022年4月

Utility of autologous fecal microbiota transplantation and elucidation of microbiota in diversion colitis. 国際誌

Kentaro Tominaga, Atsunori Tsuchiya, Takeshi Mizusawa, Asami Matsumoto, Ayaka Minemura, Kentaro Oka, Motomichi Takahashi, Tomoaki Yoshida, Yuichi Kojima, Kohei Ogawa, Yuzo Kawata, Nao Nakajima, Naruhiro Kimura, Hiroyuki Abe, Toru Setsu, Kazuya Takahashi, Hiroki Sato, Satoshi Ikarashi, Kazunao Hayashi, Ken-Ichi Mizuno, Junji Yokoyama, Yosuke Tajima, Masato Nakano, Yoshifumi Shimada, Hitoshi Kameyama, Toshifumi Wakai, Shuji Terai

DEN open 2 ( 1 ) e63 2022年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Objectives: Diversion colitis (DC) is an inflammatory disorder caused by interruption of the fecal stream and subsequent nutrient deficiency from luminal bacteria. The utility of fecal microbiota transplantation (FMT) for DC was recently investigated; however, the precise pathogenesis of this condition remains unclear. This study aimed to evaluate the utility of autologous FMT in DC and to determine the related changes in the intestinal microbiota. Methods: Autologous FMT was performed to reestablish the intestinal microbiota in five patients (average age, 64.6 ± 8.3 years) with DC. They underwent double-ended colostomy. We assessed the diverted colon by endoscopy and evaluated the microbiota before and after FMT using the 16S rRNA gene sequencing method. Results: All five patients had mild inflammation (ulcerative colitis endoscopic index of severity [UCEIS] 2-3) in the diverted colon based on the colonoscopic findings. Three patients presented with symptoms, such as tenesmus, mucoid stool, and bloody stool. With FMT treatment, all patients achieved endoscopic remission (UCEIS score of 0 or 1) and symptomatic improvement. We observed a significantly decreased α-diversity in DC patients compared to healthy controls. The frequency of aerobic bacteria, such as Enterobacteriaceae, in the diverted colon decreased after autologous FMT. Conclusions: This study was the first to show that the microbiota in the diverted colon was significantly affected by autologous FMT. Since interruption of the fecal stream is central to the development of DC, FMT can be considered a promising treatment.

DOI： 10.1002/deo2.63

Intestinal duplication diagnosed preoperatively with double-balloon enteroscopy: an extremely rare case report and literature review.

Yusuke Niwa, Kentaro Tominaga, Yuzo Kawata, Takamasa Kobayashi, Takeshi Mizuwasa, Kazuya Takahashi, Hiroki Sato, Junji Kohisa, Satoshi Abe, Kenya Kamimura, Junji Yokoyama, Hirokazu Kawai, Hideaki Sugino, Hajime Umezu, Yumiko Hirai, Masato Nakano, Yoshifumi Shimada, Hitoshi Kameyama, Toshifumi Wakai, Shuji Terai

Clinical journal of gastroenterology 15 ( 2 ) 381 - 387 2022年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Gastrointestinal duplications are congenital malformations that are usually observed in pediatric patients. Diagnosis in adulthood is quite rare, and preoperative diagnosis of gastrointestinal duplication is difficult, particularly in the small intestine. We encountered an extremely rare adult case of duplication of the jejunum, which showed a stomach-like form diagnosed using double-balloon enteroscopy (DBE). The patient was an 18-year-old male who had been experiencing upper abdominal pain and vomiting repeatedly without any triggers for 3 years. Various examinations were performed, but no cause of symptoms was found. DBE revealed a narrow opening of the lumen at the upper jejunum, and the lumen was covered with mucosal folds similar to those of the stomach. Enteroclysis via DBE showed a tubular structure on the mesenteric side of the jejunum. We diagnosed a jejunal tubular duplication with ectopic gastric mucosa and underwent partial small bowel resection. The patient's abdominal symptoms resolved. From this, DBE can be a useful tool for diagnosing intestinal duplication in adults. We believe that this case and literature review will facilitate the accurate and prompt diagnosis of small intestinal duplication.

DOI： 10.1007/s12328-022-01596-7

Methotrexate-associated proliferative disorder in the lower esophagus extending to the gastroesophageal junction: A case report. 国際誌

Yuki Hojo, Masafumi Takatsuna, Satoshi Ikarashi, Hiroteru Kamimura, Rika Kimura, Masaki Mito, Yusuke Watanabe, Yusuke Tani, Junji Yokoyama, Shuji Terai

DEN open 2 ( 1 ) e14 2022年4月

記述言語：英語

A 64-year-old woman was receiving oral methotrexate (MTX) for rheumatoid arthritis (RA) for 15 years. She underwent esophagogastroduodenoscopy because of discomfort in the chest. Endoscopic findings revealed an ulcer in the lower esophagus extending to the gastroesophageal junction (EGJ). The ulcer occupied half of the esophageal lumen and had a sharp and clear margin. Magnifying narrow-band imaging endoscopy revealed the deposition of white plaque, and there were few microvessels in the edge and bottom of the ulcer. Histologic examination of the biopsy specimens from the oral edge of the lesion revealed proliferation of atypical lymphoid cells (immunophenotype results: CD20 [+], CD3 [partially +], CD5 [-], and BCL-2 [-]]. The patient was diagnosed with methotrexate-associated lymphoproliferative disorder (MTX-LPD) and was advised to stop MTX intake. After 2 months of stopping MTX, the ulcer was found to be almost regressed and showed signs of healing. MTX-LPD in the lower esophagus extending to the EGJ is extremely rare. This case can help in expanding the understanding of esophageal MTX-LPD.

DOI： 10.1002/deo2.14

肝線維化研究Revisited-肝臓学のBiologyからTranslationalへヒト肝細胞キメラマウスを用いた薬剤のスクリーニングドラッグリポジショニングによる肝線維化治療薬の探索・メカニズムの検証

酒井規裕, 上村顕也, 寺井崇二

肝臓 63 ( Suppl.1 ) A174 - A174 2022年4月

脂肪性肝疾患における自律神経系経路を介した脂質代謝制御の解明と治療薬スクリーニング

上村顕也, 大脇崇史, 寺井崇二

肝臓 63 ( Suppl.1 ) A254 - A254 2022年4月

Relative Dose Intensityに基づく高齢者レンバチニブ投与における全生存期間の検討

横尾健, 酒井規裕, 渡邉雄介, 荒生祥尚, 木村成宏, 阿部寛幸, 薛徹, 上村博輝, 坂牧僚, 上村顕也, 土屋淳紀, 寺井崇二

肝臓 63 ( Suppl.1 ) A302 - A302 2022年4月

肝疾患の小児・成人移行期医療の課題-全人的ケアの確立を目指して成人外来へ受診する可能性をもつ小児脂肪肝の特徴

上村博輝, 上村顕也, 寺井崇二

肝臓 63 ( Suppl.1 ) A169 - A169 2022年4月

医療機関連携急性肝不全ネットワークを円滑に行い生体肝移植にて救命できた急性肝不全昏睡型の1例

武田信峻, 土屋淳紀, 石井結唯, 夏井一輝, 荒生祥尚, 冨永顕太郎, 林和直, 寺井崇二

肝臓 63 ( Suppl.1 ) A265 - A265 2022年4月

本県での肝炎医療コーディネーター養成の現状と活動事例紹介

酒井規裕, 薛徹, 荒生祥尚, 澤栗裕美, 廣川光, 星田和哉, 是永匡紹, 寺井崇二, 新たな手法を用いた肝炎ウイルス検査受検率・陽性者受診率の向上に資する研究班

肝臓 63 ( Suppl.1 ) A243 - A243 2022年4月

【1ページでわかる内科疾患の診療ノート-"あたりまえ"のなかにある大事な視点】(第7章)肝・胆・膵非代償性肝硬変

上村博輝, 寺井崇二

内科 129 ( 4 ) 867 - 871 2022年4月

記述言語：日本語出版者・発行元：(株)南江堂

＜文献概要＞肝硬変は慢性肝疾患の終着点であり,「肝細胞がんに進行することはあっても肝硬変が戻ることはない」というのが従来の考え方であるが,原因とそれに伴う慢性炎症をきちんとコントロールできた場合には,肝硬変/肝線維化の少なくとも一部は可逆性であるという視点から,まず原因の治療,抗炎症療法が重要である.ただし,これらの治療が有効な症例においても肝線維化が改善するには年余の期間が必要である(新犬山分類の線維化の程度が1段階下降するには通常4～5年かかる).この期間,肝硬変患者は常に合併症や発がんのリスクにさらされている.したがって,これらの対策も並行して進める必要がある.さらに原因治療や抗炎症療法に不応性の症例では,肝不全対策や発がん対策(発がんスクリーニングを含む)がいっそう重要となる.詳細は文献1)を参照されたい.

その他リンク： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00974&link_issn=&doc_id=20220401100086&doc_link_id=issn%3D0022-1961%26volume%3D129%26issue%3D4%26spage%3D867&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0022-1961%26volume%3D129%26issue%3D4%26spage%3D867&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

肝疾患の小児・成人移行期医療の課題-全人的ケアの確立を目指して成人外来へ受診する可能性をもつ小児脂肪肝の特徴

上村博輝, 上村顕也, 寺井崇二

肝臓 63 ( Suppl.1 ) A169 - A169 2022年4月

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先天性心疾患術後の肝線維化進展に影響を及ぼす因子の解析

山崎文紗子, 上村博輝, 寺井崇二

肝臓 63 ( Suppl.1 ) A192 - A192 2022年4月

Effects of a novel selective PPARα modulator, statin, sodium-glucose cotransporter 2 inhibitor, and combinatorial therapy on the liver and vasculature of medaka nonalcoholic steatohepatitis model. 国際誌

Atsushi Kimura, Kenya Kamimura, Marina Ohkoshi-Yamada, Yoko Shinagawa-Kobayashi, Ryo Goto, Takashi Owaki, Chiyumi Oda, Osamu Shibata, Shinichi Morita, Norihiro Sakai, Hiroyuki Abe, Takeshi Yokoo, Akira Sakamaki, Hiroteru Kamimura, Shuji Terai

Biochemical and biophysical research communications 596 76 - 82 2022年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: Nonalcoholic steatohepatitis (NASH) is a disease entity with an increasing incidence, with involvement of several metabolic pathways. Various organs, including the liver, kidneys, and the vasculature, are damaged in NASH, indicating the urgent need to develop a standard therapy. Therefore, this study was conducted to investigate the effects of drugs targeting various metabolic pathways and their combinations on a high-fat diet (HFD)-induced NASH medaka model. METHODS: To investigate the effects of drugs on vascular structures, the NASH animal model was developed using the fli::GFP transgenic medaka fed with HFD at 20 mg/fish daily. The physiological changes, histological changes in the liver, vascular structures in the fin, and serum biochemical markers were evaluated in a time-dependent manner after treatment with selective peroxisome proliferator-activated receptor α modulator (pemafibrate), statin (pitavastatin), sodium-glucose cotransporter 2 inhibitor (tofogliflozin), and their combinations. Furthermore, to determine the mechanisms underlying the effects, whole transcriptome sequencing was conducted using medaka liver samples. RESULTS: Histological analyses revealed significant suppression of fat accumulation and fibrotic changes in the liver after treatment with drugs and their combinations. The expression levels of steatosis- and fibrosis-related genes were modified by the treatments. Moreover, the HFD-induced vascular damages in the fin exhibited milder changes after treatment with the drugs. CONCLUSION: The effects of treating various metabolic pathways on the medaka body, liver, and vascular structures of the NASH medaka model were evidenced. Moreover, to our knowledge, this study is the first to report whole genome sequence and gene expression evaluation of medaka livers, which could be helpful in clarifying the molecular mechanisms of drugs.

DOI： 10.1016/j.bbrc.2022.01.086

Long-Term Efficacy and Safety of Rifaximin in Japanese Patients with Hepatic Encephalopathy: A Multicenter Retrospective Study. 国際誌

Hideto Kawaratani, Yasuteru Kondo, Ryoji Tatsumi, Naoto Kawabe, Norikazu Tanabe, Akira Sakamaki, Kazuo Okumoto, Yoshihito Uchida, Kei Endo, Takumi Kawaguchi, Tsunekazu Oikawa, Yoji Ishizu, Shuhei Hige, Taro Takami, Shuji Terai, Yoshiyuki Ueno, Satoshi Mochida, Yasuhiro Takikawa, Takuji Torimura, Tomokazu Matsuura, Masatoshi Ishigami, Kazuhiko Koike, Hitoshi Yoshiji

Journal of clinical medicine 11 ( 6 ) 2022年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Rifaximin is commonly used for hepatic encephalopathy (HE). However, the effects of long-term treatment for Japanese people are limited. Therefore, this study aimed to investigate the effects and safety of long-term treatment with rifaximin on HE. METHODS: A total of 215 patients with cirrhosis administered with rifaximin developed overt or covert HE, which was diagnosed by an attending physician for >12 months. Laboratory data were extracted at pretreatment and 3, 6, and 12 months after rifaximin administration. The long-term effect of rifaximin was evaluated, and the incidence of overt HE during 12 months and adverse events was extracted. RESULTS: Ammonia levels were significantly improved after 3 months of rifaximin administration and were continued until 12 months. There were no serious adverse events after rifaximin administration. The number of overt HE incidents was 9, 14, and 27 patients within 3, 6, and 12 months, respectively. Liver enzymes, renal function, and electrolytes did not change after rifaximin administration. Prothrombin activity is a significant risk factor for the occurrence of overt HE. The serum albumin, prothrombin activity, and albumin-bilirubin (ALBI) scores were statistically improved after 3 and 6 months of rifaximin administration. Moreover, the same results were obtained in patients with Child-Pugh C. CONCLUSIONS: The long-term rifaximin treatment was effective and safe for patients with HE, including Child-Pugh C.

DOI： 10.3390/jcm11061571

消化器疾患に対する分化・老化・再生研究の展開 Acute on chronic liver failureに対する老化細胞除去治療の新規開発のための基盤研究

渡邉雄介, 土屋淳紀, 寺井崇二

日本消化器病学会雑誌 119 ( 臨増総会 ) A32 - A32 2022年3月

肝疾患の画像情報による病態解明と診療応用心不全患者が肝形態に及ぼす影響(Cardiac Hepatopathy)の画像による解析

上村博輝, 土屋淳紀, 寺井崇二

日本消化器病学会雑誌 119 ( 臨増総会 ) A223 - A223 2022年3月

消化器疾患診療に必要なバイオマーカー開発のための研究エクソソームタンパクEps8の膵癌バイオマーカーとしての検討

林和直, 土屋淳紀, 寺井崇二

日本消化器病学会雑誌 119 ( 臨増総会 ) A172 - A172 2022年3月

脂肪肝炎:今後の展開自律神経経路が制御する多臓器連関の解析と脂肪肝炎制御への展開

上村顕也, 大脇崇史, 寺井崇二

日本消化器病学会雑誌 119 ( 臨増総会 ) A60 - A60 2022年3月

肝線維化研究の進展と臨床応用肝線維化関連遺伝子発現変化にもとづく抗線維化作用を有するリパーパシングドラッグの探索

酒井規裕, 上村顕也, 寺井崇二

日本消化器病学会雑誌 119 ( 臨増総会 ) A138 - A138 2022年3月

老化と消化器がんの病態・診療 Relative Dose Intensityに注目した高齢者レンバチニブ治療の安全性と有効性

横尾健, 上村顕也, 寺井崇二

日本消化器病学会雑誌 119 ( 臨増総会 ) A186 - A186 2022年3月

肝移植適応疾患の病態解明と診療展開肝障害に伴う臓器連関による血中セロトニン濃度変化と病態の検討肝不全の病態変化を推測するマーカーの樹立へ

薛徹, 上村顕也, 寺井崇二

日本消化器病学会雑誌 119 ( 臨増総会 ) A219 - A219 2022年3月

脂肪肝炎:今後の展開自律神経経路が制御する多臓器連関の解析と脂肪肝炎制御への展開

上村顕也, 大脇崇史, 寺井崇二

日本消化器病学会雑誌 119 ( 臨増総会 ) A60 - A60 2022年3月

肝移植適応疾患の病態解明と診療展開肝障害に伴う臓器連関による血中セロトニン濃度変化と病態の検討肝不全の病態変化を推測するマーカーの樹立へ

薛徹, 上村顕也, 寺井崇二

日本消化器病学会雑誌 119 ( 臨増総会 ) A219 - A219 2022年3月

老化と消化器がんの病態・診療 Relative Dose Intensityに注目した高齢者レンバチニブ治療の安全性と有効性

横尾健, 上村顕也, 寺井崇二

日本消化器病学会雑誌 119 ( 臨増総会 ) A186 - A186 2022年3月

肝線維化研究の進展と臨床応用肝線維化関連遺伝子発現変化にもとづく抗線維化作用を有するリパーパシングドラッグの探索

酒井規裕, 上村顕也, 寺井崇二

日本消化器病学会雑誌 119 ( 臨増総会 ) A138 - A138 2022年3月

病態に基づく肝疾患医療連携の今後肝炎医療コーディネーターと連携した院内における肝炎ウイルス陽性者の拾い上げ

荒生祥尚, 薛徹, 寺井崇二

日本消化器病学会雑誌 119 ( 臨増総会 ) A229 - A229 2022年3月

重症急性膵炎後Walled-off necrosisの経過に対する抗菌薬投与の影響

五十嵐聡, 林和直, 寺井崇二, 小川光平

日本消化器病学会雑誌 119 ( 臨増総会 ) A344 - A344 2022年3月

栄養・代謝機能と消化器疾患の病態解明と治療膵臓癌における脂肪酸分画の臨床的意義についての検証

小川光平, 林和直, 寺井崇二

日本消化器病学会雑誌 119 ( 臨増総会 ) A174 - A174 2022年3月

Cyclin D1 Binding Protein 1 Responds to DNA Damage through the ATM-CHK2 Pathway. 国際誌

Yusuke Niwa, Kenya Kamimura, Kohei Ogawa, Chiyumi Oda, Yuto Tanaka, Ryoko Horigome, Masato Ohtsuka, Hiromi Miura, Koichi Fujisawa, Naoki Yamamoto, Taro Takami, Shujiro Okuda, Masayoshi Ko, Takashi Owaki, Atsushi Kimura, Osamu Shibata, Shinichi Morita, Norihiro Sakai, Hiroyuki Abe, Takeshi Yokoo, Akira Sakamaki, Hiroteru Kamimura, Shuji Terai

Journal of clinical medicine 11 ( 3 ) 2022年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Cyclin D1 binding protein 1 (CCNDBP1) is considered a tumor suppressor, and when expressed in tumor cells, CCNDBP1 can contribute to the viability of cancer cells by rescuing these cells from chemotherapy-induced DNA damage. Therefore, this study focused on investigating the function of CCNDBP1, which is directly related to the survival of cancer cells by escaping DNA damage and chemoresistance. Hepatocellular carcinoma (HCC) cells and tissues obtained from Ccndbp1 knockout mice were used for the in vitro and in vivo examination of the molecular mechanisms of CCNDBP1 associated with the recovery of cells from DNA damage. Subsequently, gene and protein expression changes associated with the upregulation, downregulation, and irradiation of CCNDBP1 were assessed. The overexpression of CCNDBP1 in HCC cells stimulated cell growth and showed resistance to X-ray-induced DNA damage. Gene expression analysis of CCNDBP1-overexpressed cells and Ccndbp1 knockout mice revealed that Ccndbp1 activated the Atm-Chk2 pathway through the inhibition of Ezh2 expression, accounting for resistance to DNA damage. Our study demonstrated that by inhibiting EZH2, CCNDBP1 contributed to the activation of the ATM-CHK2 pathway to alleviate DNA damage, leading to chemoresistance.

DOI： 10.3390/jcm11030851

A novel prostaglandin I2 agonist, ONO-1301, attenuates liver inflammation and suppresses fibrosis in non-alcoholic steatohepatitis model mice. 国際誌

Satoko Motegi, Atsunori Tsuchiya, Takahiro Iwasawa, Takeki Sato, Masaru Kumagai, Kazuki Natsui, Shunsuke Nojiri, Masahiro Ogawa, Suguru Takeuchi, Yosiki Sakai, Shigeru Miyagawa, Yoshiki Sawa, Shuji Terai

Inflammation and regeneration 42 ( 1 ) 3 - 3 2022年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: ONO-1301 is a novel long-lasting prostaglandin (PG) I2 mimetic with inhibitory activity on thromboxane (TX) A2 synthase. This drug can also induce endogenous prostaglandin (PG)I2 and PGE2 levels. Furthermore, ONO-1301 acts as a cytokine inducer and can initiate tissue repair in a variety of diseases, such as pulmonary hypertension, pulmonary fibrosis, cardiac infarction, and obstructive nephropathy. In this study, our aim was to evaluate the effect of ONO-1301 on liver inflammation and fibrosis in a mouse model of non-alcoholic steatohepatitis (NASH). METHODS: The therapeutic effects of ONO-1301 against liver damage, fibrosis, and occurrence of liver tumors were evaluated using melanocortin 4 receptor-deficient (Mc4r-KO) NASH model mice. The effects of ONO-1301 against macrophages, hepatic stellate cells, and endothelial cells were also evaluated in vitro. RESULTS: ONO-1301 ameliorated liver damage and fibrosis progression, was effective regardless of NASH status, and suppressed the occurrence of liver tumors in Mc4r-KO NASH model mice. In the in vitro study, ONO-1301 suppressed LPS-induced inflammatory responses in cultured macrophages, suppressed hepatic stellate cell (HSC) activation, upregulated vascular endothelial growth factor (VEGF) expression in HSCs, and upregulated hepatocyte growth factor (HGF) and VEGF expression in endothelial cells. CONCLUSIONS: The results of our study highlight the potential of ONO-1301 to reverse the progression and prevent the occurrence of liver tumors in NASH using in vivo and in vitro models. ONO-1301 is a multidirectional drug that can play a key role in various pathways and can be further analyzed for use as a new drug candidate against NASH.

DOI： 10.1186/s41232-021-00191-6

Simultaneous muscular hemorrhages in two regions three years after successfully controlling refractory ascites using transjugular intrahepatic portosystemic shunt treatment: a case report.

Hiroteru Kamimura, Michitaka Imai, Hiroyuki Abe, Aiko Yoshioka, Kanae Hirose, Noriko Ishihara, Toru Ishikawa, Shuji Terai

Clinical journal of gastroenterology 2022年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: Various therapies and drugs have been developed to extend the life expectancy of patients with liver cirrhosis. The prolonged prognosis of cirrhotic patients may change the final cause of death in the future. Deep bleeding into the muscle is an uncommon but potentially life-threatening complication of liver cirrhosis. CASE REPORT: A 53-year-old man had undergone transjugular intrahepatic portosystemic shunt treatment for refractory ascites, which successfully controlled it for three years. However, he had started drinking again and experienced acute-on-chronic liver failure. He also had severe back pain. Abdominal computed tomography showed hyperdensities in the retroperitoneum and right pleural cavity. Despite blood infusion, he died from acute-on-chronic liver failure. A pathological autopsy revealed bleeding from the iliopsoas and right diaphragmatic muscle simultaneously, evident from the presence of red blood cells located between the muscle sheaths. Disruption of the small vessels in the skeletal muscle fibers was inferred. CONCLUSION: This is a critical case that underscores the significance of improving available knowledge based on the cause of final death of the patients with cirrhosis, who now have a good long-term prognosis owing to the latest medical developments.

DOI： 10.1007/s12328-022-01591-y

Use of a Deep Learning Approach for the Sensitive Prediction of Hepatitis B Surface Antigen Levels in Inactive Carrier Patients. 国際誌

Hiroteru Kamimura, Hirofumi Nonaka, Masaya Mori, Taichi Kobayashi, Toru Setsu, Kenya Kamimura, Atsunori Tsuchiya, Shuji Terai

Journal of clinical medicine 11 ( 2 ) 2022年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Deep learning is a subset of machine learning that can be employed to accurately predict biological transitions. Eliminating hepatitis B surface antigens (HBsAgs) is the final therapeutic endpoint for chronic hepatitis B. Reliable predictors of the disappearance or reduction in HBsAg levels have not been established. Accurate predictions are vital to successful treatment, and corresponding efforts are ongoing worldwide. Therefore, this study aimed to identify an optimal deep learning model to predict the changes in HBsAg levels in daily clinical practice for inactive carrier patients. We identified patients whose HBsAg levels were evaluated over 10 years. The results of routine liver biochemical function tests, including serum HBsAg levels for 1, 2, 5, and 10 years, and biometric information were obtained. Data of 90 patients were included for adaptive training. The predictive models were built based on algorithms set up by SONY Neural Network Console, and their accuracy was compared using statistical analysis. Multiple regression analysis revealed a mean absolute percentage error of 58%, and deep learning revealed a mean absolute percentage error of 15%; thus, deep learning is an accurate predictive discriminant tool. This study demonstrated the potential of deep learning algorithms to predict clinical outcomes.

DOI： 10.3390/jcm11020387

患者まで届いている再生医療より効果のある肝硬変症に対する再生医療の実現を目指して

寺井崇二, 土屋淳紀, 渡邊雄介, 竹内卓, 野尻俊介, 酒井規裕, 木村成宏, 阿部寛幸

再生医療 21 ( 1 ) 20 - 23 2022年1月

記述言語：日本語出版者・発行元：(一社)日本再生医療学会

肝硬変症に対する治療として、2003年実施した臨床研究:自己骨髄細胞投与療法により、肝線維化改善とそれに引き続く肝再生の誘導、それに伴う肝機能の改善効果を確認してきた。その後、2017年より、肝硬変症に対する他家脂肪組織由来間葉系幹細胞投与療法の企業治験、現在軽症の肝硬変に対する他家脂肪組織由来間葉系幹細胞の医師主導治験を2021年より実施している。さらに2020年よりHMGB1ペプチドを用いた医師主導治験を実施しており、より効率のいい再生療法の開発を行っている。さらに次のステップとして間葉系幹細胞由来エクソソームを用いた治療の準備を行っている。本稿では、現時点における我々の肝硬変症に対するアプローチを紹介する。(著者抄録)

Diet-related changes of basal lamina fenestrations in the villous epithelium of the rat small intestine: Statistical analysis on scanning electron microscopy.

Masatoshi Sato, Keisuke Morita, Rie Azumi, Yusuke Mizutani, Manabu Hayatsu, Tatsuo Ushiki, Shuji Terai

Biomedical research (Tokyo, Japan) 43 ( 1 ) 11 - 22 2022年

記述言語：英語掲載種別：研究論文（学術雑誌）

The epithelial basal lamina of the small intestine has numerous fenestrations for intraepithelial migration of leukocytes. We have reported dynamic changes of fenestrations in dietary conditions. To investigate this phenomenon, we performed statistical analyses using scanning electron microscopy images of the epithelial basal lamina of rat intestinal villi after removal of the villous epithelium by osmium maceration. We examined structural changes in the number and size of fenestrations in the rat jejunum and ileum under fasted and fed states for 24 h. Our findings revealed that, in the jejunum, the number of free cells migrating into the epithelium through fenestrations increased from 2 h after feeding, resulting in an increase in the fenestration size of intestinal villi; the number of free cells then tended to decrease at 6 h after feeding, and the fenestration size also gradually decreased. By contrast, the increase in the fenestration size by feeding was not statistically significant in the ileum. These findings indicate that the number of migrating cells increases in the upper part of the small intestine under dietary conditions, which may influence the absorption efficiency of nutrients including lipids, as well as the induction of nutrient-induced inflammation.

DOI： 10.2220/biomedres.43.11

Longitudinal increase in albumin-bilirubin score is associated with non-malignancy-related mortality and quality of life in patients with liver cirrhosis. 国際誌

Akira Sakamaki, Masaaki Takamura, Norihiro Sakai, Yusuke Watanabe, Yoshihisa Arao, Naruhiro Kimura, Toru Setsu, Hiroyuki Abe, Takeshi Yokoo, Hiroteru Kamimura, Shunsuke Tsubata, Nobuo Waguri, Toru Ishikawa, Hirokazu Kawai, Soichi Sugitani, Tomomi Sato, Kazuhiro Funakoshi, Masashi Watanabe, Kentarou Igarashi, Kenya Kamimura, Atsunori Tsuchiya, Yutaka Aoyagi, Shuji Terai

PloS one 17 ( 2 ) e0263464 2022年

記述言語：英語掲載種別：研究論文（学術雑誌）

Due to the developments in the treatment for hepatitis, it is possible to prevent the progression of liver fibrosis and improve patients' prognosis even if it has already led to liver cirrhosis (LC). Consequently, a two-step study was conducted. To begin with, a retrospective study was conducted to identify the potential predictors of non-malignancy-related mortality from LC. Then, we prospectively analyzed the validity of these parameters as well as their association with patients' quality of life. In the retrospective study, 89 cases were included, and the multivariate Cox regression analysis indicated that age (P = 0.012), model for end-stage liver disease (MELD) score (P = 0.012), and annual rate of change of the albumin-bilirubin (ALBI) score (P < 0.001) were significantly associated with LC prognosis. In the prospective study, 70 patients were included, and the patients were divided into cirrhosis progression and non-progression groups. The univariate logistic regression analysis indicated the serum procollagen type III N-terminal peptide level (P = 0.040) and MELD score (P = 0.010) were significantly associated with the annual rate of change of the ALBI score. Furthermore, the mean Chronic Liver Disease Questionnaire score worsened from 5.3 to 4.9 in the cirrhosis progression group (P = 0.034). In conclusion, a longitudinal increase in the ALBI score is closely associated with non-malignancy-related mortality and quality of life.

DOI： 10.1371/journal.pone.0263464

Esophageal Diverticulum - Indications and Efficacy of Therapeutic Endoscopy.

Hiroki Sato, Manabu Takeuchi, Kazuya Takahashi, Ken-Ichi Mizuno, Koichi Furukawa, Akito Sato, Nao Nakajima, Junji Yokoyama, Shuji Terai

Internal medicine (Tokyo, Japan) 61 ( 7 ) 943 - 949 2022年

記述言語：英語掲載種別：研究論文（学術雑誌）

Objective Esophageal diverticulum is rare, and the concomitance of esophageal motility disorders (EMDs) and the efficacy of novel endoscopic treatment have not been investigated in Japan. Methods An examination including high-resolution manometry (HRM) was performed for patients with both EMDs and epiphrenic diverticulum. EMD-related epiphrenic diverticulum and Zenker's diverticulum were treated using salvage peroral endoscopic myotomy (s-POEM) and endoscopic diverticulotomy, respectively. Results Six cases of epiphrenic diverticulum were diagnosed in this study. Among 125 patients with achalasia and spastic disorders, concomitant epiphrenic diverticulum was observed in 4 (3.2%). Of these, three showed a normal lower esophageal sphincter pressure on HRM, although gastroscopy and esophagography revealed typical findings of an impaired lower esophageal sphincter relaxation. These four patients were successfully treated with s-POEM, and the Eckardt score improved from 6.3 to 0.25 at 32.5 (range: 13-56) months of follow-up, with equivalent treatment efficacy to that observed for achalasia and spastic disorders without epiphrenic diverticulum. In contrast, the two remaining cases of epiphrenic diverticulum had normal esophageal motility. Six cases of Zenker's diverticulum were diagnosed, and endoscopic diverticulotomy was successfully performed in all. The dysphagia score decreased from 2.8 to 0.17 at 14.8 (range: 2-36) months of follow-up. Overall, 12 endoscopic treatments were performed for esophageal diverticulum; no adverse events were observed. Conclusion In epiphrenic diverticulum patients, concomitant EMDs are not rare and should be carefully diagnosed. A normal lower esophageal sphincter pressure on HRM does not always mean a normal lower esophageal sphincter relaxation. S-POEM and endoscopic diverticulotomy are effective minimally invasive treatment options for EMD-related epiphrenic diverticulum and Zenker's diverticulum.

DOI： 10.2169/internalmedicine.8196-21

Endoscopic Submucosal Dissection for Gastric Tube Carcinoma after Esophagectomy Contributes to Long-Term Outcomes. 国際誌

Satoru Hashimoto, Hiroki Sato, Ken-Ichi Mizuno, Kazuya Takahashi, Masafumi Takatsuna, Junji Yokoyama, Hiroshi Ichikawa, Manabu Takeuchi, Masaaki Kobayashi, Shuji Terai

Canadian journal of gastroenterology & hepatology 2022 1631415 - 1631415 2022年

記述言語：英語掲載種別：研究論文（学術雑誌）

The incidence of gastric tube carcinoma (GTC) after esophagectomy for esophageal carcinoma has increased in recent years. Surgical removal of the reconstructed gastric tube is associated with high mortality, and endoscopic submucosal dissection (ESD) is a promising alternative. There are limited reports of ESD for GTC. This study investigated the efficacy and safety of ESD in GTC. This single-center retrospective study examined patients who underwent ESD for GTC after esophagectomy at our institution between 2003 and 2018. The curability of GTC with ESD was evaluated histologically according to the Japanese Gastric Cancer Treatment Guidelines. Patient characteristics and procedural and long-term outcomes were analyzed. Overall, 31 patients (29 men and 2 women; median age, 73 years) with 45 GTC lesions underwent ESD. The mean period between primary esophagectomy and the diagnosis of GTC was 10.6 years. Bleeding during ESD was noted in two patients (6.5%). No other adverse or fatal events such as perforation were noted. Complete resection and curative resection were documented in 80.6% and 48.4% of cases, respectively. The 3-year and 5-year overall survival rates were 67.6% and 47.7%, respectively. The 3-year and 5-year disease-specific survival rates were 100% and 92.9%, respectively. One patient died of GTC, and fourteen patients died of other diseases, including primary carcinoma in five cases. ESD was safe and provided good long-term outcomes in patients with GTC. Regular long-term gastroscopy is required for the early detection of GTC. Patients with GTC after esophagectomy for esophageal carcinoma have a high risk of other primary carcinomas or comorbidities after ESD.

DOI： 10.1155/2022/1631415

Hydrogen-producing small intestinal bacterial overgrowth is associated with hepatic encephalopathy and liver function. 国際誌

Kunihiko Yokoyama, Akira Sakamaki, Kazuya Takahashi, Takumi Naruse, Chihiro Sato, Yuzo Kawata, Kentaro Tominaga, Hiroyuki Abe, Hiroki Sato, Atsunori Tsuchiya, Kenya Kamimura, Masaaki Takamura, Junji Yokoyama, Shuji Terai

PloS one 17 ( 2 ) e0264459 2022年

記述言語：英語掲載種別：研究論文（学術雑誌）

Overt hepatic encephalopathy (HE) is one of the complications of liver cirrhosis (LC), which negatively affects the prognosis and quality of life of patients. Small intestinal bacterial overgrowth (SIBO) is significantly associated with LC and its complications, including HE. We investigated the relationship between SIBO and LC, and the difference between hydrogen-producing and methane-producing SIBO (H-SIBO and M-SIBO, respectively). This is a prospective cohort study of 107 cases. Breath measurements of hydrogen and methane concentrations were performed for the diagnosis of SIBO. The study cohort included 81 males with a median age of 70 (40-86) years, and SIBO was detected in 31 cases (29.0%). There were no significant differences between the SIBO positive and SIBO negative groups. Reclassification into H-SIBO (16 cases) and others (91 cases) was performed, and the Child-Pugh score was only derived in the multivariate logistic analysis (P = 0.028, odds ratio 1.39, 95% confidence interval 1.04-1.85). Furthermore, H-SIBO was significantly associated with covert HE in chi-square test (50.0% vs. 24.2%, P = 0.034). In addition, we evaluated the therapeutic response on SIBO of rifaximin in eight covert HE patients. 20% patients with M-SIBO and 67% patients with H-SIBO showed an improvement of the breath test. In conclusion, H-SIBO, but not M-SIBO, is significantly associated with liver function, and rifaximin might be more effective for covert HE with H-SIBO. Therefore, the diagnosis of SIBO, including the classification as H-SIBO and M-SIBO, might help to determine the choice of treatment for HE.

DOI： 10.1371/journal.pone.0264459

Liver-related events after direct-acting antiviral therapy in patients with hepatitis C virus-associated cirrhosis

Tahata, Y., Hikita, H., Mochida, S., Enomoto, N., Kawada, N., Kurosaki, M., Ido, A., Miki, D., Yoshiji, H., Takikawa, Y., Sakamori, R., Hiasa, Y., Nakao, K., Kato, N., Ueno, Y., Yatsuhashi, H., Itoh, Y., Tateishi, R., Suda, G., Takami, T., Nakamoto, Y., Asahina, Y., Matsuura, K., Yamashita, T., Kanto, T., Akuta, N., Terai, S., Shimizu, M., Sobue, S., Miyaki, T., Moriuchi, A., Yamada, R., Kodama, T., Tatsumi, T., Yamada, T., Takehara, T.

Journal of Gastroenterology 57 ( 2 ) 2022年

Tumor-to-tumor metastasis of colon cancer metastasizing to a pancreatic neuroendocrine tumor associated with von Hippel-Lindau disease: a case report

Natsui, H., Kohisa, J., Yoshikawa, S., Takeuchi, M., Yagi, R., Minagawa, M., Tani, T., Usuda, H., Terai, S.

Clinical Journal of Gastroenterology 15 ( 6 ) 2022年

Small extracellular vesicles and liver diseases: From diagnosis to therapy

Tsuchiya, A., Natsui, K., Ishii, Y., Koseki, Y., Takeda, N., Tomiyoshi, K., Yamazaki, F., Yoshida, Y., Terai, S.

World Journal of Hepatology 14 ( 7 ) 2022年

Prognostic study of acute-on-chronic liver failure patients Usefulness of the fibrosis-4 index

Watanabe, Y., Osaki, A., Waguri, N., Tsuchiya, A., Terai, S.

Medicine (United States) 101 ( 44 ) 2022年

Small G1 type III gastric neuroendocrine cell tumor showing scirrhous invasion and lymph node metastasis

Sato, A., Sato, Y., Oka, H., Honda, Y., Terai, S.

Gastrointestinal Endoscopy 95 ( 1 ) 2022年

Two cases of portal-systemic encephalopathy caused by multiple portosystemic shunts successfully treated with percutaneous transhepatic obliteration

Watanabe, Y., Osaki, A., Yamazaki, S., Yamazaki, H., Kimura, K., Takaku, K., Sato, M., Waguri, N., Terai, S.

Clinical Journal of Gastroenterology 15 ( 5 ) 2022年

Needle tract seeding after endoscopic ultrasound-guided tissue acquisition of pancreatic tumors: Nationwide survey in Japan

Kitano, M., Yoshida, M., Ashida, R., Kita, E., Katanuma, A., Itoi, T., Mikata, R., Nishikawa, K., Matsubayashi, H., Takayama, Y., Kato, H., Takenaka, M., Ueki, T., Kawashima, Y., Nakai, Y., Hashimoto, S., Shigekawa, M., Nebiki, H., Tsumura, H., Okabe, Y., Ryozawa, S., Harada, Y., Mitoro, A., Sasaki, T., Yasuda, H., Miura, N., Ikemoto, T., Ozawa, E., Shioji, K., Yamaguchi, A., Okuzono, T., Moriyama, I., Hisai, H., Fujita, K., Goto, T., Shirahata, N., Iwata, Y., Okabe, Y., Hara, K., Hashimoto, Y., Kuwatani, M., Isayama, H., Fujimori, N., Masamune, A., Hatamaru, K., Shimokawa, T., Okazaki, K., Takeyama, Y., Yamaue, H., Abue, M., Aiura, K., Akashi, T., Akiyama, T., Aoyagi, H., Araki, M., Arizumi, T., Aruga, Y., Asada, M., Asai, S., Baba, T., Ban, S., Chinen, K., Doi, S., Eguchi, T., Endo, M., Endo, S., Ezaki, T., Fujii, K., Fujii, M., Fujimori, M., Fujimoto, Y., Fujita, Y., Fujita, Y., Fukasawa, M., Fukuba, N., Fukuchi, S., Fukuda, K., Furukawa, M., Furumatsu, K., Hakamada, K., Hanada, K., Harada, K., Harano, M., Hashigo, S., Hashiguchi, K., Hayashi, K., Hayashi, N., Hayatsu, S., Hijioka, S., Hirano, A., Hirao, M., Hirooka, Y., Hirota, M., Horino, K., Hotta, Y., Ijima, M., Ikuta, Y., Imakiire, K., Imamura, T., Inatomi, O., Inoue, T., Irisawa, A., Ishida, E., Ishihara, K., Ishii, S., Ishii, T., Ito, H., Ito, J., Ito, T., Iwahashi, K., Iwano, H., Iwasaki, E., Iwashita, T., Iwata, K., Kakimoto, T., Kaku, T., Kamochi, J., Kanamori, A., Kaneto, H., Karasaki, H., Kato, Y., Kawaguchi, Y., Kawakami, H., Kawase, T., Kawashima, H., Kikuyama, M., Kimura, K., Kimura, T., Kitamura, K., Kobashigawa, K., Kobayashi, A., Kobayashi, K., Kobayashi, M., Kodama, R., Kodama, Y., Koike, Y., Komaki, T., Komura, T., Kondo, H., Kondo, H., Koshita, S., Koya, T., Ku, Y., Kuriyama, K., Kuroda, T., Kuroki, M., Kuroki, T., Kushiyama, Y., Maekawa, H., Makino, N., M, ai, K., Maruyama, H., Maruyama, M., Matsubara, S., Matsumoto, R., Matsunaga, K., Matsusaki, S., Matsushita, A., Mihara, M., Miyaike, J., Miyata, H., Miyoshi, H., Mizuno, S., Morita, T., Mouri, T., Mukai, T., Murakami, K., Nagano, H., Nakahara, K., Nakahara, O., Nakai, Y., Nakaji, S., Nakajima, J., Nakanishi, F., Nakano, Y., Nakashima, S., Naota, H., Nishida, N., Nishide, T., Nishikiori, H., Nomura, Y., Ochi, Y., Ochiai, T., Oe, S., Ogura, T., Ohata, A., Ohshima, T., Ohtsubo, K., Oka, H., Okazaki, A., Okochi, O., Onishi, Y., Otsuka, Y., Sagami, R., Sakakihara, I., Sakata, T., Sasahira, N., Sasaki, A., Sato, H., Sato, S., Sato, T., Satoh, A., Sekine, M., Sen-yo, M., Serikawa, M., Shibuya, H., Shimizu, S., Shinzato, M., Shitani, M., Suda, T., Sugimori, K., Sumi, H., Suzuki, N., Suzuki, R., Suzuki, Y., Tadauchi, A., Takahashi, K., Takahashi, K., Takaya, H., Takeda, Y., Takeda, O., Takihara, H., Tanaka, Y., Tanno, S., Tawada, K., Taya, Y., Terai, S., Terauchi, T., Togashi, J., Toki, M., Toyama, T., Tsuda, H., Tsugeno, H., Tsutsui, S., Uchida, K., Ueki, T., Usuba, T., Uza, N., Wakiyama, S., Watanabe, M., Yagi, Y., Yamada, R., Yamamoto, R., Yamazaki, M., Yasuda, I., Yawata, A., Yokota, T., Yokoyama, K., Yoshida, K., Yoshikawa, S., Yoshikawa, T.

Digestive Endoscopy 34 ( 7 ) 2022年

Gastric alarmin release: A warning signal in the development of gastric mucosal diseases

Wu, E., Zhu, J., Ma, Z., Tuo, B., Terai, S., Mizuno, K., Li, T., Liu, X.

Frontiers in Immunology 13 2022年

Steroid therapy still plays a crucial role and could serve as a bridge to the next promising treatments in patients with IgG4-related sclerosing cholangitis: Results of a Japanese nationwide study

Kubota, K., Kamisawa, T., Nakazawa, T., Tanaka, A., Naitoh, I., Takikawa, H., Unno, M., Kawa, S., Masamune, A., Nakamura, S., Okazaki, K., Furumatsu, K., Sawai, S., Goto, T., Okumura, T., Suzuki, D., Otsuka, M., Kobori, I., Tamano, M., Koizumi, M., Hiasa, Y., Kawabe, N., Hirooka, Y., Yamamoto, S., Asano, Y., Inui, K., Horiguchi, A., Watanabe, H., Toya, D., Hatayama, K., Ueki, T., Kinoshita, N., Sugimoto, M., Ohira, H., Mukai, T., Tomita, E., Iwata, K., Shimizu, S., Suetsugu, J., Shimizu, M., Tsuji, K., Ishida, R., Ito, M., Furukawa, R., Sakamoto, N., Araki, M., Tanno, S., Sakamoto, Y., Ito, T., Takai, S., Ikeya, S., Yamada, T., Kudara, N., Shimizu, A., Hanada, K., Ichiki, Y., Kitada, H., Hifumi, M., Kimura, H., Kurosaki, M., Izumi, N., Sumi, H., Haruta, Hayashi, K., Harada, R., Inoue, M., Nakamura, S., Ito, T., Tomishima, K., Isayama, H., Oura, K., Masaki, T., Shimokawahara, N., Tanoue, S., Maemura, K., Ido, A., Mizushima, I., Kawano, M., Yoshida, K., Naganuma, M., Murata, M., Nishio, A., Fujita, Y., Teratani, T., Matsubara, S., Tamai, H., Yoshida, Y., Azemoto, R., Kamata, K., Watanabe, T., Kurosu, T., Koizumi, W., Fujita, J., Seki, H., Ueda, Y., Fukumoto, T., Kousaki, T., Uchida, K., Ochiai, T., Kawasaki, T., Tanaka, M., Ishida, E., Notohara, K., Mori, H., Mori, T., Kawabata, H., Miyata, M., Sakagami, J., Itoh, Y., Shiokawa, M., Seno, H., Watanabe, N., Naitoh, I., Kataoka, H., Aoki, T., Fujishiro, M., Niihara, T., Nishimata, H., Mitoro, A., Yoshiji, H., Yoshida, M., Ikeda, M., Tomita, K., Hokari, R., Hayasaka, K., Amano, Y., Shioji, K., Hayashi, K., Terai, S., Nakajima, M., Yamahana, J., Matsumoto, R., Kikuchi, H., Kanamori, A., Kiriyama, S., Iwatsu, S., Kato, Y., Horiguchi, S., Yagi, T., Okada, H., Ohkawa, K., Hirao, M., Hiramatsu, N., Oza, N., Imamura, H., Baba, T., Nakano, S., Shinobi, T., Ryozawa, S., Motoya, M., Nakase, H., Kinoshita, N., Ito, K., Miyake, T., Kohge, N., Tobita, H., Joshita, S., Umemura, T., Kawaguchi, S., Ohno, K., Sonobe, K., Satoh, A., Shimosegawa, T., Miura, F., Yagi, M., Sano, K., Kin, T., Katanuma, A., Koike, K., Miura, S., Kawashima, Y., Kagawa, T., Azuma, S., Watanabe, M., Honjyo, M., Itoi, T., Honda, A., Kobayashi, K., Asano, T., Mizuno, S., Koike, K., Nishino, T., Taniguchi, H., Tajiri, K., Yasuda, I., Tanaka, Y., Oe, S., Harada, M., Kurata, M., Fukasawa, M., Enomoto, N., Kawaji, Y., Kitano, M., Nishise, Y., Hirakawa, H., Ishizawa, T., Ueno, Y., Kaino, M., Fujimoto, Y., Sakaida, I.

Journal of Hepato-Biliary-Pancreatic Sciences 29 ( 8 ) 2022年

Characteristics of colorectal neuroendocrine tumors in patients prospectively enrolled in a Japanese multicenter study: a first report from the C-NET STUDY

Sekiguchi, M., Hotta, K., Takeuchi, Y., Tanaka, S., Yamamoto, H., Shinmura, K., Harada, K., Uraoka, T., Hisabe, T., Sano, Y., Kondo, H., Horimatsu, T., Kikuchi, H., Kawamura, T., Nagata, S., Yamamoto, K., Tajika, M., Tsuji, S., Kusaka, T., Okuyama, Y., Yoshida, N., Moriyama, T., Hasebe, A., So, S., Kobara, H., Kashida, H., Miyanaga, R., Kato, S., Hayashi, Y., Sada, M., Fukuzawa, M., Kato, H., Takayama, T., Konishi, J., Matsushita, H.-O., Narasaka, T., Ohata, K., Togashi, K., Nakamura, H., Moriichi, K., Oda, Y., K, a, N., Kuwai, T., Terai, S., Sanomura, M., Kitamura, S., Miyamoto, H., Kiriyama, S., Mizuno, C., Saito, Y., Sekine, S., Ito, S., Nakahira, H., Oka, S., Hayashi, Y., Yoshimura, K., Ishikawa, H., Matsuda, T.

Journal of Gastroenterology 57 ( 8 ) 2022年

A difficult-to-diagnose case of Borrmann type IV gastric cancer with marked transverse colon stenosis

Natsui, K., Maruyama, M., Terai, S.

JGH Open 6 ( 11 ) 2022年

The Visceral-to-subcutaneous Adipose Tissue Area Ratio Is Associated with Retreatment in Chronic Pancreatitis Patients with Pancreatolithiasis after Extracorporeal Shock Wave Lithotripsy

Yokoyama, K., Takamura, M., Watanabe, J., Nakamura, A., Sato, Y., Sekine, A., Terai, S.

Internal Medicine 61 ( 24 ) 2022年

Environmental factors, medical and family history, and comorbidities associated with primary biliary cholangitis in Japan: a multicenter case–control study

Matsumoto, K., Ohfuji, S., Abe, M., Komori, A., Takahashi, A., Fujii, H., Kawata, K., Noritake, H., Tadokoro, T., Honda, A., Asami, M., Namisaki, T., Ueno, M., Sato, K., Kakisaka, K., Arakawa, M., Ito, T., Tanaka, K., Matsui, T., Setsu, T., Takamura, M., Yasuda, S., Katsumi, T., Itakura, J., Sano, T., Tamura, Y., Miura, R., Arizumi, T., Asaoka, Y., Uno, K., Nishitani, A., Ueno, Y., Terai, S., Takikawa, Y., Morimoto, Y., Yoshiji, H., Mochida, S., Ikegami, T., Masaki, T., Kawada, N., Ohira, H., Tanaka, A.

Journal of Gastroenterology 57 ( 1 ) 2022年

Delayed and Synchronous Recurrence of Breast Cancer Metastases in Multiple Organs

Owaki, T., Hashimoto, S., Umezu, H., Terai, S.

Internal Medicine 61 ( 22 ) 2022年

Intrahepatic Bile Duct Foreign Body With Cholangitis After Pylorus-preserving Pancreatoduodenectomy: Is It a Fish Bone?

Natsui, K., Maruyama, M., Terai, S.

Gastroenterology 163 ( 4 ) 2022年

Endoscopic Findings and Treatment of Gastric Neoplasms in Familial Adenomatous Polyposis

Sato, C., Takahashi, K., Sato, H., Naruse, T., Nakajima, N., Takatsuna, M., Mizuno, K.-I., Hashimoto, S., Takeuchi, M., Yokoyama, J., Kobayashi, M., Terai, S.

Journal of Gastric Cancer 22 ( 4 ) 2022年

Case report: New subtype of gastric adenocarcinoma arising from an H. pylori infection-negative stomach: Foveolar epithelium and mucous neck cell-mixed type adenocarcinoma

Liu, X., Wu, X., Zhu, J., Yagi, K., Ajioka, Y., Terai, S., Mizuno, K., Li, H., Tuo, B., Di, L.

Frontiers in Oncology 12 2022年

A rare case of duodenal variceal bleeding due to extrahepatic portal vein obstruction successfully treated with endoscopic injection sclerotherapy

Hori, A., Watanabe, Y., Takahashi, K., Tonouchi, T., Kimura, N., Setsu, T., Ikarashi, S., Kamimura, H., Yokoyama, J., Terai, S.

Clinical Journal of Gastroenterology 15 ( 3 ) 2022年

Benign Duodenal Stenosis Caused by Huge Mesenteric Hematoma Conservatively Improved with Long-term Use of Double Elementary Diet Tube

Setsu, T., Yokoo, T., Sato, T., Kumagai, M., Motegi, S., Kawata, Y., Ogawa, K., Mizuno, K.-I., Terai, S.

Internal Medicine 61 ( 13 ) 2022年

Gravity assistance enables liver stiffness measurements to detect liver fibrosis under congestive circumstances

Suda, T., Sugimoto, A., Kanefuji, T., Abe, A., Yokoo, T., Hoshi, T., Abe, S., Morita, S., Yagi, K., Takahashi, M., Terai, S.

World Journal of Hepatology 14 ( 4 ) 2022年

Combination therapy of Juzentaihoto and mesenchymal stem cells attenuates liver damage and regresses fibrosis in mice. 国際誌

Takahiro Iwasawa, Shunsuke Nojiri, Atsunori Tsuchiya, Suguru Takeuchi, Takayuki Watanabe, Masahiro Ogawa, Satoko Motegi, Takeki Sato, Masaru Kumagai, Taiki Nakaya, Katsuya Ohbuchi, Miwa Nahata, Naoki Fujitsuka, Masaaki Takamura, Shuji Terai

Regenerative therapy 18 231 - 241 2021年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Background: Liver cirrhosis is an end-stage multiple liver disease. Mesenchymal stem cells (MSCs) are an attractive cell source for reducing liver damage and regressing fibrosis; additional therapies accompanying MSCs can potentially enhance their therapeutic effects. Kampo medicines exhibit anti-inflammatory and anti-oxidative effects. Here, we investigated the therapeutic effect of MSCs combined with the Kampo medicine Juzentaihoto (JTT) as a combination therapy in a carbon tetrachloride (CCl4)-induced cirrhosis mouse model. Methods: C57BL/6 mice were administered JTT (orally) and/or MSCs (one time, intravenously). The levels of liver proteins were measured in the sera. Sirius Red staining and hydroxyproline quantitation of hepatic tissues and immune cells were conducted, and their associated properties were evaluated. Liver metabolomics of liver tissues was performed. Results: JTT monotherapy attenuated liver damage and increased serum albumin level, but it did not effectively induce fibrolysis. JTT rapidly reduced liver damage, in a dose-dependent manner, after a single-dose CCl4 administration. Furthermore, JTT-MSC combination therapy attenuated liver damage, improved liver function, and regressed liver fibrosis. The combination increased the CD4+/CD8+ ratio. JTT had stronger effects on NK and regulatory T cell induction, whereas MSCs more strongly induced anti-inflammatory macrophages. The combination therapy further induced anti-inflammatory macrophages. JTT normalized lipid mediators, and tricarboxylic acid cycle- and urea cycle-related mediators effectively. Conclusions: The addition of JTT enhanced the therapeutic effects of MSCs; this combination could be a potential treatment option for cirrhosis.

DOI： 10.1016/j.reth.2021.07.002

Nationwide survey for patients with acute-on-chronic liver failure occurring between 2017 and 2019 and diagnosed according to proposed Japanese criteria

Nobuaki Nakayama, Hayato Uemura, Yoshihito Uchida, Yukinori Imai, Tomoaki Tomiya, Shuji Terai, Hitoshi Yoshiji, Takuya Genda, Akio Ido, Kazuaki Inoue, Naoya Kato, Isao Sakaida, Masahito Shimizu, Yasuhiro Takikawa, Masanori Abe, Ryuzo Abe, Kazuaki Chayama, Kiyoshi Hasegawa, Ayano Inui, Mureo Kasahara, Hiromasa Ohira, Atsushi Tanaka, Hajime Takikawa, Satoshi Mochida

Journal of Gastroenterology 56 ( 12 ) 1092 - 1106 2021年12月

【再生医療への期待〜各疾患領域における現況と展望〜】肝臓領域における細胞を用いた再生医療の将来展望

寺井崇二, 渡邊雄介, 土屋淳紀

Pharma Medica 39 ( 12 ) 37 - 40 2021年12月

記述言語：日本語出版者・発行元：(株)メディカルレビュー社

＜文献概要＞本稿では,肝疾患領域の細胞を用いた再生医療の現状について概説する。2000年から基礎研究成果を基盤に,2003年から開始された肝硬変症に対する自己骨髄細胞投与療法,その後,血管内皮細胞投与療法,さらに自己脂肪組織細胞投与療法が実施されてきた。また,英国エジンバラ大学のForbesらは,肝硬変症に対して自己マクロファージ細胞投与療法を実施し,一方でSokalらは,代償性肝硬変症から急激に肝不全状態になるacute on chronic liver failure(ACLF)に対する,肝臓から採取した肝前駆細胞の投与療法を実施している。さらに,自己間葉系幹細胞を用いた治験も実施されてきた。日本では2017年より他家間葉系幹細胞投与療法の肝硬変症に対する治験を進めてきた(PhaseI,II)。また,2019年よりES細胞由来の肝臓様細胞を門脈より投与する先天性の尿素酵素欠損症に対する医師主導治験が進んでいる。本稿では,現在進んでいる細胞を用いた肝臓疾患に対する細胞を用いた再生療法を俯瞰し紹介する(図1)。

その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01750&link_issn=&doc_id=20211223100008&doc_link_id=issn%3D0289-5803%26volume%3D39%26issue%3D12%26spage%3D37&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0289-5803%26volume%3D39%26issue%3D12%26spage%3D37&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

アルコール性肝硬変におけるB型肝炎ウイルス感染の発癌と予後に対する関与についての検討

坂牧僚, 小山究太郎, 森田真一, 阿部寛幸, 上村顕也, 高村昌昭, 寺井崇二

アルコールと医学生物学 40 47 - 49 2021年12月

New cine magnetic resonance imaging parameters for the differential diagnosis of chronic intestinal pseudo-obstruction. 国際誌

Hiroki Sato, Hiroyuki Ogihara, Kazuya Takahashi, Yuzo Kawata, Yuichi Kojima, Kentaro Tominaga, Junji Yokoyama, Yoshihiko Hamamoto, Shuji Terai

Scientific reports 11 ( 1 ) 22974 - 22974 2021年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Chronic intestinal pseudo-obstruction (CIPO) is a severe and refractory intestinal motility disorder whose diagnosis currently relies on subjective imaging assessments. Cine magnetic resonance imaging (MRI) may potentially improve the quantitative analysis of gastrointestinal motility; however, suitable CIPO detection parameters should be determined. Cine MRI was performed in seven patients with CIPO and 11 healthy controls. The logarithm of the Mahalanobis distance (x1) and distance variation per time (x2) were used as the original parameters to determine CIPO diagnostic thresholds. Furthermore, the correlation between cine MRI findings and CIPO severity was investigated. Threshold values of α = 1.10 and β = 0.15 for x1 and x2, respectively, produced a CIPO diagnosis sensitivity of 1.00 (7/7) and specificity of 0.82 (9/11). The resulting error was 0.11 (2/18). The two parameters were correlated (Pearson's correlation coefficient: - 0.52). Any of the intestinal tracts of patients with severe CIPO requiring home parenteral nutrition belonged to the region defined by x1 ≥ 1.10 and x2 ≤ 0.15. Cine MRI is effective for the quantitative evaluation of small intestinal motility and CIPO diagnosis when using the abovementioned parameters and can be useful for treatment decision-making. However, these parameters have a wide distribution in healthy volunteers; this may complicate the detection of other disorders.

DOI： 10.1038/s41598-021-02268-1

The risk of cirrhosis and its complications based on PNPLA3 rs738409 G allele frequency. 国際誌

Xue Shao, Haruki Uojima, Taeang Arai, Yuji Ogawa, Toru Setsu, Masanori Atsukawa, Yoshihiro Furuichi, Yoshitaka Arase, Kazue Horio, Hisashi Hidaka, Takahide Nakazawa, Makoto Kako, Tatehiro Kagawa, Katsuhiko Iwakiri, Atsushi Nakajima, Shuji Terai, Yasuhito Tanaka, Wasaburo Koizumi

Digestive diseases (Basel, Switzerland) 40 ( 5 ) 625 - 634 2021年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Data regarding the influence of patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism for patients with liver cirrhosis (LC) are scarce. OBJECTIVE: This study assesses the role of the PNPLA3 polymorphism for the development of LC and its complications by the findings of genetic examinations. METHODS: Patients with LC caused by virus (n = 157), alcohol (n = 104), nonalcoholic fatty liver disease (NAFLD) (n = 106), or autoimmune disease (n = 33) and without LC (n = 128) were enrolled. LC were composed of the present and absent of complications, such as variceal bleeding, hepatic ascites, and/or hepatic encephalopathy. To assess the role of the PNPLA3 polymorphism, odds ratio (OR) for the rs738409 variant was calculated for the patients between (i) with LC and without LC in the entire cohort, and (ii) the present and absent of complications in the patients with LC. RESULTS: There was a significant difference among the patients without LC and those with alcohol, NAFLD related LC in the frequency of G alleles (p < 0.001, both). According to complications of LC, the OR for NAFLD related cirrhosis significantly increased in the presence of the two mutated alleles (OR = 3.165; p = 0.046) when the wild type was used as the reference. However, there were no significant risks for the complications in the virus and alcohol related cirrhosis unless there was a presence of G alleles. CONCLUSION: The PNPLA3 polymorphism was associated with the risk of NAFLD related LC and its complications.

DOI： 10.1159/000521062

Esophageal carcinoma in achalasia patients managed with endoscopic submucosal dissection and peroral endoscopic myotomy: Japan Achalasia Multicenter Study. 国際誌

Hiroki Sato, Yohei Nishikawa, Hirofumi Abe, Hironari Shiwaku, Junya Shiota, Chiaki Sato, Hiroyuki Sakae, Masaki Ominami, Yoshitaka Hata, Hisashi Fukuda, Ryo Ogawa, Jun Nakamura, Tetsuya Tatsuta, Yuichiro Ikebuchi, Hiroshi Yokomichi, Shuji Terai, Haruhiro Inoue

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 34 ( 5 ) 965 - 973 2021年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: Indications for peroral endoscopic myotomy (POEM) and endoscopic submucosal dissection (ESD) in patients with achalasia concomitant with esophageal carcinoma (EC) are unclear. This study aimed to clarify the role of POEM in cases of achalasia concomitant with EC and to elucidate the indications for ESD and efficient surveillance for EC. METHODS: We conducted a multicenter cohort study at 14 hospitals in Japan, including 3707 cases of achalasia-related esophageal motility disorders (EMDs). Factors contributing to EC risk, the characteristics of EC, and clinical outcomes of POEM/ESD were analyzed. RESULTS: In patients undergoing POEM, screening and surveillance endoscopy throughout a 1-year period resulted in diagnosis of 72.1% new EC cases. Of 62 patients with 123 ECs, 40.3% had multiple or metachronous lesions within 37.5 months. EC was predominantly observed in the middle thoracic esophagus (58.5%) and posteriorly (73.2%). POEM had comparable safety and efficacy in cases of concomitant EC even after ESD. Endoscopic en bloc resection was performed in 95.8% and 89.3% of ECs diagnosed before and after POEM, respectively (P = 0.351); however, ESD on the POEM-line was impaired by fibrosis. Multivariate analysis revealed risk factors for EC, including regular alcohol consumption, a history of smoking, advanced age, and extended disease duration. Alcohol intake and smoking had a synergistic effect on EC development. CONCLUSIONS: Screening and surveillance of POEM help in detecting EC. ESD is feasible in achalasia, although on the POEM-line is challenging. Surveillance endoscopy for EC is recommended for cases with specific risks and a history of ECs.

DOI： 10.1111/den.14197

脾動脈瘤破裂を契機にC型肝炎治療に至った肝硬変の1例

北條雄暉, 上村博輝, 大脇崇史, 木村莉菓, 岩澤貴宏, 渡邊雄介, 高綱将史, 五十嵐聡, 高村昌昭, 薛徹, 荒生祥尚, 堀井陽祐, 佐藤辰彦, 寺井崇二

肝臓 62 ( 11 ) 749 - 755 2021年11月

記述言語：日本語出版者・発行元：(一社)日本肝臓学会

症例は50代の女性.30代でC型肝炎ウイルスへの感染を指摘されていたが治療に至らず,継続的な受診も行っていなかった.腹痛と意識消失を主訴に救急搬送され,脾動脈瘤破裂による出血性ショックと診断された.当院で脾動脈瘤塞栓術を施行し,術後経過は良好であった.外来にて直接作用型抗ウイルス薬を導入し,ウイルス学的著効を達成した.CT検査の普及により,脾動脈瘤の偶然の発見も増加していると報告されていて,今後本例のように肝臓以外の疾患での受診を契機に,ウイルス性肝炎や肝硬変の診断から治療に至る症例もある.C型肝炎の未治療者や未受検者,非認識受検者は国内に未だ数多く存在しており,脾動脈瘤に関する文献的考察と,新潟県で実施している肝炎患者の拾い上げの試みについても併せて記載し報告する.(著者抄録)

その他リンク： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J00263&link_issn=&doc_id=20211111030008&doc_link_id=1390852945233297152&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1390852945233297152&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_3.gif

脾動脈瘤破裂を契機にC型肝炎治療に至った肝硬変の1例

北條雄暉, 上村博輝, 大脇崇史, 木村莉菓, 岩澤貴宏, 渡邊雄介, 高綱将史, 五十嵐聡, 高村昌昭, 薛徹, 荒生祥尚, 堀井陽祐, 佐藤辰彦, 寺井崇二

肝臓 62 ( 11 ) 749 - 755 2021年11月

【肝不全・肝硬変に対する再生療法-最先端の今】開発中の肝再生医療間葉系幹細胞,マクロファージ,エクソソームを用いた再生療法

土屋淳紀, 寺井崇二

臨床消化器内科 36 ( 13 ) 1647 - 1652 2021年11月

記述言語：日本語出版者・発行元：(株)日本メディカルセンター

＜文献概要＞肝臓は再生する臓器として知られているが,持続的な炎症の結果,肝細胞障害,それに伴う線維化形成で,再生力が低下した肝硬変に至る.進行した肝硬変に対して,肝移植は有効な治療であるが,ドナー不足などの問題もあり,新たな治療の選択肢として細胞治療や細胞を用いないセルフリー治療が期待されている.本稿ではとくに細胞治療として間葉系幹細胞,マクロファージを用いた治療,そしてセルフリー治療としてエクソソーム治療に関して紹介したい.

【肝不全・肝硬変に対する再生療法-最先端の今】基礎的知見の進歩自律神経経路を介した臓器連関と肝再生

上村顕也, 井上良介, 名古屋拓郎, 高昌良, 大脇崇史, 寺井崇二

臨床消化器内科 36 ( 13 ) 1623 - 1628 2021年11月

記述言語：日本語出版者・発行元：(株)日本メディカルセンター

＜文献概要＞生体臓器は,外界からのさまざまな刺激や病態に対し,臓器連関により恒常性を維持している.この臓器間を繋ぐ要諦の一つが自律神経経路である.これまで肝障害や肝疾患では,さまざまな細胞や液性因子,腸内細菌に焦点を当てた臓器連関の報告が中心であった.今回,自律神経経路を介した臓器連関が肝障害時の肝再生や,脂肪性肝疾患の病態に関与することが明らかとなった.このメカニズムの解明が,難治性疾患の新規治療法の開発にも結び付くと考える.

【肝硬変は治るか?組織改築改善・研究の最前線】トランスレーショナルリサーチ間葉系幹細胞、エクソソームを用いた肝硬変治療

土屋淳紀, 寺井崇二

医学のあゆみ 279 ( 8 ) 790 - 794 2021年11月

記述言語：日本語出版者・発行元：医歯薬出版(株)

肝臓は再生する臓器として知られているが、持続的な炎症の結果、肝細胞障害、それに伴う線維化形成で、再生力が低下して肝硬変に至る。黄疸や腹水がみられる程度まで進行した肝硬変は非代償性肝硬変といわれ、この病態に対して肝移植は有効な治療であるが、ドナー不足などの問題がある。また、本来このような非代償性肝硬変に至る前に積極的に治療が行えることが理想であるが、線維化の改善、再生促進に有効な治療法が乏しいのが現状である。本稿では肝硬変に対しての新たな治療の選択肢として細胞治療や細胞を用いない細胞フリー治療を間葉系幹細胞とそのエクソソームに絞って紹介をしたい。(著者抄録)

その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J00060&link_issn=&doc_id=20211122010006&doc_link_id=%2Faa7ayuma%2F2021%2F027908%2F007%2F0790b0794%26dl%3D3&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faa7ayuma%2F2021%2F027908%2F007%2F0790b0794%26dl%3D3&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_4.gif

Rapid progression of colonic mucinous adenocarcinoma with immunosuppressive condition: A case report and review of literature. 国際誌

Youhei Koseki, Kenya Kamimura, Yuto Tanaka, Marina Ohkoshi-Yamada, Qiliang Zhou, Yoshifumi Matsumoto, Takeshi Mizusawa, Hiroki Sato, Akira Sakamaki, Hajime Umezu, Junji Yokoyama, Shuji Terai

World journal of clinical cases 9 ( 30 ) 9182 - 9191 2021年10月

記述言語：英語

BACKGROUND: Colorectal mucinous adenocarcinoma is a rare subtype of colorectal cancer and is characterized by an abundance of mucin in the tumor. In addition, the colorectal mucinous adenocarcinoma often demonstrates poor differentiation in the histology of tumor cells and poor prognosis compared with those with adenocarcinoma. Here, we present the case of a young woman with colonic mucinous adenocarcinoma showing significantly rapid progression within four months of immunosuppressant therapy for Henoch-Schönlein purpura. CASE SUMMARY: Here we report a rare case of ascending colon mucinous adenocarcinoma with lymph node and liver metastases which developed and progressed rapidly within four months during the treatment of Henoch-Schönlein purpura using corticosteroids. The systemic screening examinations showed no tumors before the immunosuppressant therapy. Fortunately, the patient was successfully treated with chemotherapy. CONCLUSION: While no direct evidence that the immunosuppressants accelerated the tumor development, the case presenta tion and review of the literature demonstrated that surveillance for malignancies before and during treatment with immunosuppressive agents is essential.

DOI： 10.12998/wjcc.v9.i30.9182

胆管への浸潤を伴う胆管内乳頭状粘液性腺癌 1症例報告(Intraductal papillary mucinous adenocarcinoma with bile duct invasion: A case report)

水戸將貴, 戸田遼, 木村究, 小島雄一, 小川光平, 木村成宏, 荒生祥尚, 五十嵐聡, 林和直, 土屋淳紀, 寺井崇二, 加藤卓, 味岡洋一, 石川博補, 滝沢一泰, 若井俊文

日本消化器病学会甲信越支部例会・日本消化器内視鏡学会甲信越支部例会抄録集 69回・91回 53 - 53 2021年10月

Rare complication of hepatocellular carcinoma in Wilson's disease. 国際誌

Marina Ohkoshi-Yamada, Kenya Kamimura, Hiroteru Kamimura, Shuji Terai

JGH open : an open access journal of gastroenterology and hepatology 5 ( 10 ) 1220 - 1222 2021年10月

記述言語：英語

The complication of hepatocellular carcinoma (HCC) in Wilson's disease is rare. Wilson's disease treatment using D-penicillamine (DPA) is useful to prevent HCC occurrence; however, it also causes iron accumulation and synergistic radical formation in the liver, which may enhance carcinogenesis. Reported herein is a case of HCC in Wilson's disease treated with DPA for 36 years. The tumor was surgically resected and histologically diagnosed with moderately differentiated HCC surrounded by cirrhotic tissue with fatty infiltration. Rhodanine staining revealed a slight positively stained area in both tumor and surrounding tissues. Information obtained from this case and literature review highlight the feature of HCC in Wilson's disease.

DOI： 10.1002/jgh3.12648

自律神経経路を介した臓器連関と肝疾患

上村顕也, 大脇崇史, 高昌良, 永山逸夫, 名古屋拓郎, 井上良介, 上野将紀, 寺井崇二

日本自律神経学会総会プログラム・抄録集 74回 87 - 87 2021年10月

胆管への浸潤を伴う胆管内乳頭状粘液性腺癌 1症例報告(Intraductal papillary mucinous adenocarcinoma with bile duct invasion: A case report)

水戸將貴, 戸田遼, 木村究, 小島雄一, 小川光平, 木村成宏, 荒生祥尚, 五十嵐聡, 林和直, 土屋淳紀, 寺井崇二, 加藤卓, 味岡洋一, 石川博補, 滝沢一泰, 若井俊文

日本消化器病学会甲信越支部例会・日本消化器内視鏡学会甲信越支部例会抄録集 69回・91回 53 - 53 2021年10月

原発性胆汁性胆管炎患者の予後を最もよく予想する治療反応性判定Criteriaについて

木村成宏, 高村昌昭, 武田信峻, 荒生祥尚, 高綱将史, 渡邉雄介, 竹内卓, 阿部寛幸, 薛徹, 上村博輝, 坂牧僚, 上村顕也, 土屋淳紀, 寺井崇二

日本消化器病学会雑誌 118 ( 臨増大会 ) A698 - A698 2021年10月

消化器診療におけるサルコペニアの意義 1-kestoseが高齢サルコペニアの腸内細菌と筋肉量に与える影響

冨永顕太郎, 土屋淳紀, 寺井崇二

日本消化器病学会雑誌 118 ( 臨増大会 ) A461 - A461 2021年10月

有症化した症候性巨大肝嚢胞に対して、ミノサイクリン硬化療法が著効した一例

木南佳也, 小川和也, 石井壮一, 遠藤沙織, 石川夏生, 阿部寛幸, 佐藤裕樹, 坂牧僚, 上村顕也, 寺井崇二

日本消化器病学会甲信越支部例会・日本消化器内視鏡学会甲信越支部例会抄録集 69回・91回 93 - 93 2021年10月

消化器診療におけるサルコペニアの意義 1-kestoseが高齢サルコペニアの腸内細菌と筋肉量に与える影響

冨永顕太郎, 土屋淳紀, 寺井崇二

日本消化器病学会雑誌 118 ( 臨増大会 ) A461 - A461 2021年10月

原発性胆汁性胆管炎患者の予後を最もよく予想する治療反応性判定Criteriaについて

木村成宏, 高村昌昭, 武田信峻, 荒生祥尚, 高綱将史, 渡邉雄介, 竹内卓, 阿部寛幸, 薛徹, 上村博輝, 坂牧僚, 上村顕也, 土屋淳紀, 寺井崇二

日本消化器病学会雑誌 118 ( 臨増大会 ) A698 - A698 2021年10月

有症化した症候性巨大肝嚢胞に対して、ミノサイクリン硬化療法が著効した一例

木南佳也, 小川和也, 石井壮一, 遠藤沙織, 石川夏生, 阿部寛幸, 佐藤裕樹, 坂牧僚, 上村顕也, 寺井崇二

日本消化器病学会甲信越支部例会・日本消化器内視鏡学会甲信越支部例会抄録集 69回・91回 93 - 93 2021年10月

Interventional EUS超音波内視鏡下瘻孔形成術の現状と問題点(膵) 重症急性膵炎後Walled-off necrosisの自然軽快に関連する因子

五十嵐聡, 林和直, 寺井崇二

日本消化器病学会雑誌 118 ( 臨増大会 ) A550 - A550 2021年10月

大腸がん検診を受診しない理由に関するアンケート調査

水野研一, 川田雄三, 林和直, 寺井崇二, 中島尚

日本消化器病学会雑誌 118 ( 臨増大会 ) A706 - A706 2021年10月

超音波内視鏡システムにおける音速補正モードの膵癌診断における有用性の検討

林和直, 小川光平, 五十嵐聡, 寺井崇二

Gastroenterological Endoscopy 63 ( Suppl.2 ) 2046 - 2046 2021年10月

Synthesized HMGB1 peptide attenuates liver inflammation and suppresses fibrosis in mice. 国際誌

Shunsuke Nojiri, Atsunori Tsuchiya, Kazuki Natsui, Suguru Takeuchi, Takayuki Watanabe, Yuichi Kojima, Yusuke Watanabe, Hiroteru Kamimura, Masahiro Ogawa, Satoko Motegi, Takahiro Iwasawa, Takeki Sato, Masaru Kumagai, Yui Ishii, Tomomi Kitayama, Yu-Tung Li, Yuya Ouchi, Takashi Shimbo, Masaaki Takamura, Katsuto Tamai, Shuji Terai

Inflammation and regeneration 41 ( 1 ) 28 - 28 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

The liver has a high regenerative ability and can induce spontaneous regression of fibrosis when early liver damage occurs; however, these abilities are lost when chronic liver damage results in decompensated cirrhosis. Cell therapies, such as mesenchymal stem cell (MSC) and macrophage therapies, have attracted attention as potential strategies for mitigating liver fibrosis. Here, we evaluated the therapeutic effects of HMGB1 peptide synthesized from box A of high mobility group box 1 protein. Liver damage and fibrosis were evaluated using a carbon tetrachloride (CCl4)-induced cirrhosis mouse model. The effects of HMGB1 peptide against immune cells were evaluated by single-cell RNA-seq using liver tissues, and those against monocytes/macrophages were further evaluated by in vitro analyses. Administration of HMGB1 peptide did not elicit a rapid response within 36 h, but attenuated liver damage after 1 week and suppressed fibrosis after 2 weeks. Fibrosis regression developed over time, despite continuous liver damage, suggesting that administration of this peptide could induce fibrolysis. In vitro analyses could not confirm a direct effect of HMGB1 peptide against monocyte/macrophages. However, macrophages were the most affected immune cells in the liver, and the number of scar-associated macrophages (Trem2+Cd9+ cells) with anti-inflammatory markers increased in the liver following HMGB1 treatment, suggesting that indirect effects of monocytes/macrophages were important for therapeutic efficacy. Overall, we established a new concept for cell-free therapy using HMGB1 peptide for cirrhosis through the induction of anti-inflammatory macrophages.

DOI： 10.1186/s41232-021-00177-4

Transition of clinical and basic studies on liver cirrhosis treatment using cells to seek the best treatment. 国際誌

Shuji Terai, Atsunori Tsuchiya, Yusuke Watanabe, Suguru Takeuchi

Inflammation and regeneration 41 ( 1 ) 27 - 27 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

The liver is a highly regenerative organ; however, its regeneration potential is reduced by chronic inflammation with fibrosis accumulation, leading to cirrhosis. With an aim to tackle liver cirrhosis, a life-threatening disease, trials of autologous bone marrow cell infusion (ABMi) therapy started in 2003. Clinical studies revealed that ABMi attenuated liver fibrosis and improved liver function in some patients; however, this therapy has some limitations such as the need of general anesthesia. Following ABMi therapy, studies have focused on specific cells such as mesenchymal stromal cells (MSCs) from a variety of tissues such as bone marrow, adipose tissue, and umbilical cord tissues. Particularly, studies have focused on gaining mechanistic insights into MSC distribution and effects on immune cells, especially macrophages. Several basic studies have reported the use of MSCs for liver cirrhosis models, while a number of clinical studies have used autologous and allogeneic MSCs; however, there are only a few reports on the obvious substantial effect of MSCs in clinical studies. Since then, studies have analyzed and identified the important signals or components in MSCs that regulate immune cells, such as macrophages, under cirrhotic conditions and have revealed that MSC-derived exosomes are key regulators. Researchers are still seeking the best approach and filling the gap between basic and clinical studies to treat liver cirrhosis. This paper highlights the timeline of basic and clinical studies analyzing ABMi and MSC therapies for cirrhosis and the scope for future studies and therapy.

DOI： 10.1186/s41232-021-00178-3

Advances in the Treatment of Gastrointestinal Bleeding: Safety and Efficiency of Transnasal Endoscopy. 国際誌

Hiroyuki Abe, Kenya Kamimura, Yoshihisa Arao, Junji Kohisa, Shuji Terai

Medicines (Basel, Switzerland) 8 ( 9 ) 2021年9月

記述言語：英語

Acute upper gastrointestinal bleeding (UGIB) is a common disorder and a gastroenterological emergency. With the development of new techniques and devices, the survivability after gastrointestinal bleeding is improving. However, at the same time, we are facing the difficulty of severely complicated cases with various diseases. For example, while endoscopic examination with a normal diameter endoscope is essential for the diagnosis and treatment of UGIB, there are several cases in which it cannot be used. In these cases, transnasal endoscopy (TNE) may be a viable treatment option. This report reviews current hemostatic devices for endoscopic treatment and the safety and efficiency of using TNE in complicated cases. The latter will be demonstrated in a case report where TNE was employed in a patient with severe esophageal stenosis. This review summarizes the advances made in the devices used and will provide further ideas for the physician in terms of combining these devices and TNE.

DOI： 10.3390/medicines8090053

【肝疾患エキスパートブック栄養管理に活かすための最新情報】(Part 1)肝硬変肝硬変に対する運動療法について

上村博輝, 寺井崇二, 眞田菜緒, 小師優子

臨床栄養 139 ( 4 ) 445 - 451 2021年9月

記述言語：日本語出版者・発行元：医歯薬出版(株)

＜Key Point＞・これまで安静が基本とされていた肝硬変患者の運動については、サルコペニア対策からも最近はレジスタンス運動を含む、積極的な運動介入が推奨される傾向にある。・患者の状態(静脈瘤、腹水、肝肺症候群、サルコペニアなどの合併)に注意しながら、運動介入程度を決定していく。・"FITT"を構築して行うことが基本となるが、個人の状況に応じた継続可能な日常活動を、医師の外来診療、管理栄養士の栄養指導の際に医療機関側からアドバイスして背中を押してあげることも重要になってくる。(著者抄録)

急性肝障害からの回復の予測バイオマーカーとしての血中セロトニン測定の意義

薛徹, 上村顕也, 大脇崇史, 荒生祥尚, 横尾健, 坂牧僚, 上村博輝, 土屋淳紀, 高村昌昭, 寺井崇二

肝臓 62 ( Suppl.2 ) A536 - A536 2021年9月

消化器領域における再生医療の研究と新たな臨床応用肝硬変に対する間葉系幹細胞やそのエクソソームを用いた治療法開発を目指して

土屋淳紀, 高村昌昭, 寺井崇二

肝臓 62 ( Suppl.2 ) A533 - A533 2021年9月

肝硬変の近未来診療肝硬変の線維化改善を目指したHMGB1部分ペプチド療法の基礎検討と医師主導治験への展開

土屋淳紀, 高村昌昭, 寺井崇二

肝臓 62 ( Suppl.2 ) A511 - A511 2021年9月

【膵癌研究最前線】膵臓選択的ハイドロダイナミック遺伝子導入法

柴田理, 上村顕也, 田中裕登, 小川光平, 阿部寛幸, 五十嵐聡, 横尾健, 寺井崇二

消化器・肝臓内科 10 ( 3 ) 342 - 346 2021年9月

The prognosis and incidence of hepatic encephalopathy of patients with liver cirrhosis treated with proton pump inhibitors: A multicenter retrospective study in Japan. 国際誌

Akira Sakamaki, Kenya Kamimura, Takeshi Yokoo, Akihiko Osaki, Seiichi Yoshikawa, Yoshihisa Arao, Toru Setsu, Hiroteru Kamimura, Nobuo Waguri, Manabu Takeuchi, Kazuhiro Funakoshi, Shuji Terai

Medicine 100 ( 32 ) e26902 2021年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

ABSTRACT: Gastrointestinal bleeding, hepatic encephalopathy (HE), and hepatocarcinogenesis are associated with the prognosis of patients with liver cirrhosis (LC). Proton pump inhibitors (PPIs) have been used to prevent bleeding, however the effects of PPIs on overall survival have not yet been elucidated. Therefore, this multicenter retrospective study aimed to assess the effect of PPI on the prognosis and HE occurrence of the patients with liver cirrhosis in Japan.A total of 456 patients diagnosed with LC at the 4 institutes during the study period (2010-2014) were assessed. PPI-treated and non-treated patients were compared using propensity score matching analysis. Primary and secondary endpoints of the study were set as the occurrence of HE and overall survival, respectively.A comparison of all cases showed a significantly poorer hepatic reserve function in the PPI-treated patients. The propensity-score matching analysis was performed and 120 PPI-treated patients were 1:1 matched with non-treated patients. The analysis revealed a higher incidence of HE in the PPI-treated than in the non-treated patients (P = .032; hazard ratio [HR], 2.162; 95% confidence interval [CI], 1.066-4.176), but the prognosis of PPI-treated patients was no worse than that of non-treated patients (P = .676; HR, 1.101; 95% CI, 0.702-1.726).This retrospective study showed that PPI administration for the patients with liver cirrhosis may partly be related to the increased incidence of HE but not worsen the patient prognosis.

DOI： 10.1097/MD.0000000000026902

A Rare Case of Ulcerative Colitis with Severe Pneumocystis jirovecii Pneumonia and Cytomegalovirus Colitis: A Case Report and Literature Review.

Yusuke Watanabe, Kazunao Hayashi, Shuji Terai

Internal medicine (Tokyo, Japan) 2021年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Pneumocystis jirovecii pneumonia (PJP) and cytomegalovirus (CMV) colitis are opportunistic infections that occur during immunosuppressive treatments for ulcerative colitis (UC). The prognosis of PJP and CMV colitis is very poor. We herein report a rare case of a 74-year-old UC patient with PJP and CMV colitis that was successfully treated with intensive therapy. PJP progresses rapidly, so the timing and choice of treatment are critical. Furthermore, a literature review of similar cases suggested that prophylactic therapy for opportunistic infections might be important, especially in the elderly. This case will serve as a reference for successful treatment in future cases.

DOI： 10.2169/internalmedicine.7953-21

Risk of delayed bleeding after hot snare polypectomy and endoscopic mucosal resection in the colorectum with continuation of anticoagulants. 国際誌

Takamasa Kobayashi, Manabu Takeuchi, Yuki Hojo, Yui Ishii, Youhei Koseki, Yoko Kobayashi, Motoi Azumi, Yuji Kobayashi, Junji Kohisa, Seiichi Yoshikawa, Shuji Terai

Journal of gastrointestinal oncology 12 ( 4 ) 1518 - 1530 2021年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Background: Current guidelines recommend the temporary discontinuation of anticoagulants before colonoscopic polypectomy, but the effect of this practice on reducing the risk of delayed bleeding after hot snare polypectomy (HSP) and endoscopic mucosal resection (EMR) remains unclear. Our aim was to assess the impact of anticoagulants on the risk of colorectal delayed bleeding after HSP and EMR, and evaluate the necessity of drug withdrawal. Methods: We reviewed the clinical data of patients with colorectal polyps using antithrombotic drugs who underwent HSP and/or EMR between January 2016 and September 2020 at Nagaoka Red Cross Hospital. After excluding antiplatelet users, patients were classified into those who continued anticoagulants [continuation group: 50 patients (93 lesions)] and those who discontinued anticoagulants [discontinuation group: 87 patients (190 lesions)]. Results: Delayed bleeding occurred in 12 lesions, and there was no significant difference in the incidence rates between the continuation and the discontinuation groups (3.2% vs. 4.7%; P=0.756). Logistic regression analysis showed that continued use of anticoagulants was not a significant risk factor for delayed bleeding compared to anticoagulant discontinuation (odds ratio, 0.670; 95% CI, 0.177-2.537; P=0.556). There was no significant difference in the incidence rate and risk of delayed bleeding, regardless of the length of the anticoagulant withdrawal period. Conclusions: Continued use of anticoagulants, compared to their discontinuation, did not increase the risk of colorectal delayed bleeding after HSP and EMR. Our results suggest that current guideline recommendations for anticoagulant withdrawal before colonoscopic polypectomy may be reconsidered. Trial Registration: UMIN000040449.

DOI： 10.21037/jgo-21-3

The promise of radiotherapy for hepatocellular carcinoma. 国際誌

Kenya Kamimura, Shuji Terai

Hepatology research : the official journal of the Japan Society of Hepatology 51 ( 8 ) 837 - 838 2021年8月

Pyloric-gland metaplasia may be an origin of cancer and intestinal metaplasia with possible CDX2 expression. 国際誌

Kazuyoshi Yagi, Atsunori Tsuchiya, Satoru Hashimoto, Taisuke Kato, Osamu Onodera, Shuji Terai

Gastroenterology report 9 ( 4 ) 370 - 373 2021年8月

門脈圧亢進症と臓器相関心、肝、肺、腎、脾当院における心不全に伴う肝臓への影響(Cardiac Hepatopathy)の解析

上村博輝, 寺井崇二, 猪又孝文, 三井田秀, 山崎文紗子, 柏村健, 藤木信也, 渡邊雄介, 荒生祥尚, 木村成宏, 阿部寛幸, 薛徹, 坂牧僚, 横尾健

日本門脈圧亢進症学会雑誌 27 ( 3 ) 109 - 109 2021年8月

急性膵炎後の膵仮性嚢胞門脈瘻による広範な門脈血栓症を発症した2例

木村成宏, 林和直, 土屋淳紀, 寺井崇二

日本門脈圧亢進症学会雑誌 27 ( 3 ) 147 - 147 2021年8月

BRTO中に出血を来し、NBCAによるEISを併用し治療を完遂した十二指腸静脈瘤の1例

前田悠一郎, 荒生祥尚, 小島雄一, 川田雄三, 渡邉雄介, 薛徹, 阿部寛幸, 坂牧僚, 上村博輝, 横尾健, 土屋淳紀, 上村顕也, 横山純二, 寺井崇二

日本門脈圧亢進症学会雑誌 27 ( 3 ) 134 - 134 2021年8月

門脈圧亢進症を伴う肝硬変に対する薬物療法の進歩〜QOL、予後の改善を目指して〜肝硬変に伴うサルコペニアに対する難吸収性抗菌薬の有用性についての検討

坂牧僚, 土屋淳紀, 寺井崇二

日本門脈圧亢進症学会雑誌 27 ( 3 ) 106 - 106 2021年8月

潜在性肝性脳症は水素型SIBOに関連し、その治療にはリファキシミンが有効である

坂牧僚, 横山邦彦, 高橋一也, 成瀬匠, 冨永顕太郎, 佐藤裕樹, 上村顕也, 横山純二, 寺井崇二

日本門脈圧亢進症学会雑誌 27 ( 3 ) 176 - 176 2021年8月

Suppression of Noncoding RNAs as Shared Early Genetic Events in Multistep Hepatocarcinogenesis. 国際誌

Takeshi Suda, Seiichi Yoshikawa, Tsutomu Kanefuji, Satoshi Abe, Takahiro Hoshi, Shinichi Morita, Kazuyoshi Yagi, Shuji Terai

Hepatology (Baltimore, Md.) 2021年7月

A genome-wide association study identifying SVEP1 variant as a predictor of response to tolvaptan for cirrhotic ascites. 国際誌

Hideto Kawaratani, Hiromi Sawai, Masaya Onishi, Tomomi Kogiso, Noritomo Shimada, Haruki Uojima, Tomoaki Nakajima, Naoki Matsumoto, Kenichi Ikejima, Toru Ishikawa, Shuji Terai, Hiroyuki Motoyama, Atsumasa Komori, Noboru Hirashima, Satoru Saito, Yuichiro Eguchi, Masanori Nojima, Yosuke Kawai, Masakuni Tateyama, Hitoshi Yoshiji, Yasuhito Tanaka

Liver international : official journal of the International Association for the Study of the Liver 41 ( 12 ) 2944 - 2953 2021年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND & AIMS: Tolvaptan, vasopressin V2-receptor antagonist, has been used for patients with difficult-to-treat ascites in Japan. In this study, we conducted a genome-wide association study (GWAS) in the Japanese population to identify genetic variants associated with tolvaptan's efficacy for patients with hepatic ascites. METHODS: From 2014 through 2018, genomic DNA samples were obtained from 550 patients who were treated with tolvaptan. Of those, 80 cases (non-responder; increase of body weight [BW]) and 333 controls (responder; >1.5 kg decrease of BW) were included in the GWAS and replication study. RESULTS: Genome-wide association study showed 5 candidate SNPs around the miR818, KIAA1109, and SVEP1 genes. After validation and performing a replication study, an SNP (rs2991364) located in the SVEP1 gene was found to have a significant genome-wide association (OR = 3.55, P = 2.01 × 10-8 ). Multivariate analyses showed that serum sodium (Na), blood urea nitrogen (BUN) and SVEP1 SNP were significantly associated with the response (OR = 0.92, P = .003; OR = 1.02, P = .02 and OR = 3.98, P = .000008, respectively). Based on a prediction model of logistic regression analysis in a population with the rs2991364 risk allele, the failure probability (=exp (score: 22.234 + BUN*0.077 + Na*-0.179) (1 + exp (score)) was determined for the detection of non-responders. Assuming a cutoff of failure probability at 38.6%, sensitivity was 84.4%, specificity was 70% and AUC was 0.774. CONCLUSION: SVEP1 rs2991364 was identified as the specific SNP for the tolvaptan response. The prediction score (>38.6%) can identify tolvaptan non-responders and help to avoid a lengthy period of futile treatment.

DOI： 10.1111/liv.15022

Evidence-based clinical practice guidelines for Liver Cirrhosis 2020.

Hitoshi Yoshiji, Sumiko Nagoshi, Takemi Akahane, Yoshinari Asaoka, Yoshiyuki Ueno, Koji Ogawa, Takumi Kawaguchi, Masayuki Kurosaki, Isao Sakaida, Masahito Shimizu, Makiko Taniai, Shuji Terai, Hiroki Nishikawa, Yoichi Hiasa, Hisashi Hidaka, Hiroto Miwa, Kazuaki Chayama, Nobuyuki Enomoto, Tooru Shimosegawa, Tetsuo Takehara, Kazuhiko Koike

Journal of gastroenterology 56 ( 7 ) 593 - 619 2021年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japan Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.

DOI： 10.1007/s00535-021-01788-x

Evidence-based clinical practice guidelines for liver cirrhosis 2020. 国際誌

Hitoshi Yoshiji, Sumiko Nagoshi, Takemi Akahane, Yoshinari Asaoka, Yoshiyuki Ueno, Koji Ogawa, Takumi Kawaguchi, Masayuki Kurosaki, Isao Sakaida, Masahito Shimizu, Makiko Taniai, Shuji Terai, Hiroki Nishikawa, Yoichi Hiasa, Hisashi Hidaka, Hiroto Miwa, Kazuaki Chayama, Nobuyuki Enomoto, Tooru Shimosegawa, Tetsuo Takehara, Kazuhiko Koike

Hepatology research : the official journal of the Japan Society of Hepatology 51 ( 7 ) 725 - 749 2021年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japanese Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.

DOI： 10.1111/hepr.13678

Impact of continuous positive airway pressure therapy for nonalcoholic fatty liver disease in patients with obstructive sleep apnea. 国際誌

Haruka Hirono, Kazuhiko Watanabe, Katsuhiko Hasegawa, Masaki Kohno, Shuji Terai, Shogo Ohkoshi

World journal of clinical cases 9 ( 19 ) 5112 - 5125 2021年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Obstructive sleep apnea (OSA) has been suggested as an independent risk factor for nonalcoholic fatty liver disease (NAFLD), and continuous positive airway pressure (CPAP) is the first-line therapy for OSA. AIM: To clarify the efficacy of effective CPAP therapy on NAFLD of OSA patients by serum markers and transient elastography (TE) using FibroScan® (Echosens, Paris, France). METHODS: We prospectively enrolled 123 consecutive patients with OSA who met the indications for CPAP. Liver fibrosis and steatosis were assessed using TE. Before and after 6 mo of CPAP therapy, serum markers and TE were assessed for all patients. The mean usage rate of CPAP therapy for 6 mo was arbitrarily calculated in each patient and expressed as "mean compliance index" (m-CI). RESULTS: In 50 OSA patients with NAFLD, both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were significantly decreased after 6 mo of CPAP therapy. Univariate analysis showed that decreased body weight (BW), decreased body mass index (BMI), decreased AST level, decreased hemoglobin A1c, and high m-CI were significantly related with improved ALT level. In multivariate regression model adjusted for quantities of BW change during 6 mo of CPAP therapy, high m-CI tended to improve ALT level (P = 0.051). All 17 OSA patients with NAFLD, high m-CI and no BMI changes showed significant improvements in AST and ALT levels. Meanwhile, no significant changes in TE data or serum fibrosis markers were seen. CONCLUSION: Some NAFLD could be associated with chronic intermittent hypoxia due to OSA independent of BW changes. In those cases, adequate reoxygenation from effective CPAP therapy may improve NAFLD.

DOI： 10.12998/wjcc.v9.i19.5112

Biliary Obstruction Caused by B-Cell Lymphoma Associated With IgG4-Related Disease. 国際誌

Kazuya Ogawa, Hiroki Sato, Satoshi Ikarashi, Kazunao Hayashi, Shuji Terai

The American journal of gastroenterology 2021年7月

Tuberculous Spondylitis in a Woman without Pulmonary Lesions.

Shinichi Morita, Toshinori Takada, Kazumasa Ohashi, Shuji Terai

Internal medicine (Tokyo, Japan) 60 ( 13 ) 2157 - 2158 2021年7月

当院における腹腔鏡・内視鏡合同手術(LECS)の現状と課題

加納陽介, 羽入隆晃, 佐藤裕樹, 水野研一, 市川寛, 石川卓, 宗岡悠介, 茂木大輔, 須藤翔, 小柳英人, 三浦宏平, 滝沢一泰, 中野雅人, 島田能史, 永橋昌幸, 坂田純, 寺井崇二, 若井俊文

ENDOSCOPIC FORUM for digestive disease 37 ( 1 ) 36 - 36 2021年7月

Rapid decline in visceral adipose tissue over 1 month is associated with poor prognosis in patients with unresectable pancreatic cancer. 国際誌

Oki Nakano, Hirokazu Kawai, Takamasa Kobayashi, Junji Kohisa, Satoshi Ikarashi, Kazunao Hayashi, Junji Yokoyama, Shuji Terai

Cancer medicine 10 ( 13 ) 4291 - 4301 2021年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Involuntary weight loss related to cachexia is common in patients with advanced cancer, but the association between body composition changes and survival is still unclear in pancreatic cancer. METHODS: We retrospectively reviewed the clinical outcomes of 55 patients with advanced pancreatic cancer undergoing palliative therapy or best supportive care (BSC). The skeletal muscle index (SMI), visceral adipose tissue index (VATI), subcutaneous adipose tissue index (SATI), and visceral to subcutaneous adipose tissue area ratio (VSR) were calculated based on the cross-sectional area on two sets of computed tomography images obtained at cancer diagnosis and 1 month later before treatment. The prognostic value of body composition indexes at diagnosis and the changes in those indexes over 1 month was then evaluated. RESULTS: In total, 45 patients (81.8%) received chemotherapy, chemoradiation, or radiation therapy, whereas the remaining patients underwent BSC. There were 27 patients (49.1%) who had low SMI at cancer diagnosis. Univariate analysis showed no significant associations between the baseline body composition indexes including SMI, VATI, SATI, and VSR and survival. Meanwhile, male sex (HR, 2.79; 95% CI, 1.16-6.71, p = 0.022) and higher decrease in VATI over 1 month (HR, 2.41; 95% CI, 1.13-5.13, p = 0.023) were identified as independent risk factors for mortality in multivariate analysis. CONCLUSION: Rapid decline in VAT over 1 month is closely associated with poorer survival in unresectable advanced pancreatic cancer. A short-term assessment of body composition changes may be a rational approach to predict prognosis in these patients.

DOI： 10.1002/cam4.3964

Rapid Onset of Weight Gain and Liver Dysfunction Successfully Treated With Nutrition and Exercise. 国際誌

Hiroteru Kamimura, Masakazu Sano, Takanori Tsujimura, Yasunaga Takeda, Yuko Komoro, Junji Yokoyama, Shuji Terai

Cureus 13 ( 7 ) e16530 2021年7月

記述言語：英語

Physical inactivity is one of the causes of most metabolic syndromes. The incidence of metabolic syndrome is expected to increase in the near future because of the reduced opportunities for exercise caused by COVID-19. Non-alcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease. Changes in diet and lifestyle have led to a dramatic increase in the prevalence of NAFLD in the world. NAFLD is characterized by excessive triglyceride (TG) accumulation in the hepatocytes due to both increased inflow of free fatty acids and de novo hepatic lipogenesis. Thus far, no study quantitatively assessed the liver fat deposition after a rapid decline in physical activity. Herein, we describe a case of a 17-year-old Japanese boy with severe fat infiltration of the liver, due to a rapid decline in physical activity, treated at our facility. Our rehabilitation and nutritional support teams administered appropriate exercise and nutrition support to reduce weight and improve liver dysfunction. Our findings support dietary changes and exercise therapy to manage such cases.

DOI： 10.7759/cureus.16530

高齢者消化器がん化学療法〜高齢者のがん治療を安全・効果的に遂行するための取り組み高齢肝細胞癌症例における分子標的治療薬の生存期間延長効果と予測因子の検討

横尾健, 酒井規裕, 渡邉雄介, 荒生祥尚, 木村成宏, 阿部寛幸, 薛徹, 上村博輝, 坂牧僚, 上村顕也, 土屋淳紀, 寺井崇二

日本高齢消化器病学会誌 24 ( 1 ) 115 - 115 2021年7月

被包化膵壊死への真菌感染による敗血症性ショックをきたした一例

山田麻理奈[大越], 上村顕也, 石川夏生, 小関洋平, 田中裕登, 水澤健, 佐藤裕樹, 五十嵐聡, 林和直, 坂牧僚, 横山純二, 寺井崇二

ENDOSCOPIC FORUM for digestive disease 37 ( 1 ) 30 - 30 2021年7月

自己免疫性膵炎と膵癌との鑑別の現状と課題

小川光平, 林和直, 五十嵐聡, 寺井崇二

ENDOSCOPIC FORUM for digestive disease 37 ( 1 ) 32 - 32 2021年7月

Shrinkage of a Submucosal Tumor in the Rectum. 国際誌

Takamasa Kobayashi, Manabu Takeuchi, Shuji Terai

Journal of gastrointestinal and liver diseases : JGLD 30 ( 2 ) 183 - 184 2021年6月

Severe steatosis and mild colitis are important for the early occurrence of hepatocellular carcinoma. 国際誌

Takeki Sato, Atsunori Tsuchiya, Takashi Owaki, Masaru Kumagai, Satoko Motegi, Takahiro Iwasawa, Shunsuke Nojiri, Masahiro Ogawa, Suguru Takeuchi, Yusuke Watanabe, Yuzo Kawata, Hiroteru Kamimura, Shuji Terai

Biochemical and biophysical research communications 566 36 - 44 2021年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

The number of patients with non-alcoholic steatohepatitis (NASH) and inflammatory bowel disease (IBD) is increasing. This study elucidates the effect of both NASH and IBD on hepatocellular carcinoma (HCC) using a mouse model combining NASH and IBD. The melanocortin 4 receptor-deficient (Mc4r-KO) mice were divided into four groups with or without a high-fat diet (HFD) and with or without dextran sulfate sodium (DSS) to induce colitis, and the differences in liver damage and occurrence of HCC were analyzed. In the HFD + DSS group, the body weight, liver weight/body weight ratio, and serum levels of albumin and alanine aminotransferase were significantly lower than those in the HFD group. We further found that steatosis was significantly lower and lobular inflammation was significantly higher in the HFD + DSS group than those in the HFD group, and that individual steatosis and lobular inflammation state in the HFD + DSS mice varied. We detected HCC only in the HFD + DSS group, and mice with severe steatosis and mild colitis were found to be at high risk of HCC. Presently, the prediction of HCC is very difficult. In some cases, severe colitis reverses the fat accumulation due to appetite loss. Our findings clearly showed that severe steatohepatitis and mild colitis are simultaneously essential for the occurrence of HCC in patients with NASH and IBD.

DOI： 10.1016/j.bbrc.2021.05.097

Effect of Lenvatinib on a Hepatocellular Carcinoma with Fibroblast Growth Factor Receptor 4 Expression: A Case Report and Review of the Literature.

Osamu Shibata, Kenya Kamimura, Masayoshi Ko, Norihiro Sakai, Hiroyuki Abe, Shinichi Morita, Takeshi Mizusawa, Hiroki Sato, Akira Sakamaki, Shuji Terai

Internal medicine (Tokyo, Japan) 60 ( 11 ) 1709 - 1715 2021年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Basic and clinical research have shown that the expression of molecules involved in the hepatocellular carcinoma (HCC) cell signaling pathway is related to the sensitivity to molecular-targeted agents. We herein report a case of HCC that was effectively treated with lenvatinib after a poor response to sorafenib. The tumor showed a high expression of fibroblast growth factor receptor 4, which is reportedly related to the sensitivity to lenvatinib in vitro. The information obtained from this case and from our literature review highlights the importance of assessing the expression of the molecules involved in tumors for effective precision medicine.

DOI： 10.2169/internalmedicine.6580-20

A case of Helicobacter pylori -negative early gastric adenocarcinoma with gastrointestinal phenotype. 国際誌

Masafumi Takatsuna, Rie Azumi, Takeshi Mizusawa, Hiroki Sato, Ken-Ichi Mizuno, Takashi Kato, Junji Yokoyama, Yoichi Ajioka, Shuji Terai

Endoscopy international open 9 ( 6 ) E863-E866 2021年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

A 40-year-old man with slightly depressed (0-IIc) type gastric cancer of the pyloric anterior gastric area underwent pre-operative screening for tetralogy of Fallot and endoscopic submucosal dissection (ESD) and was tested for Helicobacter pylori antigens and antibodies. Both tests were negative. He did not have a history of eradication. Pathological diagnosis of ESD showed a well-differentiated adenocarcinoma. The tumor was CD10-positive, MUC5AC-negative, and MUC6-confocal positive; it showed differentiation with gastrointestinal phenotype. Moreover, the tumor cells were lysozyme-positive, resembling Paneth cells. Mucosal glands exhibited intestinal metaplasia on the anal side of the tumor lesion. On the oral side of the tumor, metaplasia was non-existent, with normal pyloric glands present in the mucosal layer. The patient was not infected with H. pylori ; however, intestinal metaplasia existed around the early gastric cancer. This suggested that the intestinal metaplasia occurred due to bile reflux, and the gastric neoplasia arose with the metaplasia without an H. pylori infection. This case may potentially help explain gastric cancer development in the absence of H. pylori infection.

DOI： 10.1055/a-1396-3854

Transoral surgery for superficial head and neck cancer: National Multi-Center Survey in Japan. 国際誌

Chikatoshi Katada, Manabu Muto, Satoshi Fujii, Tetsuji Yokoyama, Tomonori Yano, Akihito Watanabe, Toshiro Iizuka, Shigetaka Yoshinaga, Ichiro Tateya, Hiroki Mitani, Yuichi Shimizu, Akiko Takahashi, Tomoyuki Kamijo, Noboru Hanaoka, Makoto Abe, Akihiro Shiotani, Koichi Kano, Yukinori Asada, Tamotsu Matsuhashi, Hirohito Umeno, Kenji Okami, Kenichi Goda, Shinichiro Hori, Yoichiro Ono, Shuji Terai, Yasuaki Nagami, Kenichi Takemura, Kenro Kawada, Mizuo Ando, Naoto Shimeno, Akihito Arai, Yasutoshi Sakamoto, Masaaki Ichinoe, Tetsuo Nemoto, Masahiro Fujita, Hidenobu Watanabe, Tadakazu Shimoda, Atsushi Ochiai, Takakuni Kato, Ryuichi Hayashi

Cancer medicine 10 ( 12 ) 3848 - 3861 2021年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Head and neck cancers, especially in hypopharynx and oropharynx, are often detected at advanced stage with poor prognosis. Narrow band imaging enables detection of superficial cancers and transoral surgery is performed with curative intent. However, pathological evaluation and real-world safety and clinical outcomes have not been clearly understood. The aim of this nationwide multicenter study was to investigate the safety and efficacy of transoral surgery for superficial head and neck cancer. We collected the patients with superficial head and neck squamous cell carcinoma who were treated by transoral surgery from 27 hospitals in Japan. Central pathology review was undertaken on all of the resected specimens. The primary objective was effectiveness of transoral surgery, and the secondary objective was safety including incidence and severity of adverse events. Among the 568 patients, a total of 662 lesions were primarily treated by 575 sessions of transoral surgery. The median tumor diameter was 12 mm (range 1-75) endoscopically. Among the lesions, 57.4% were diagnosed as squamous cell carcinoma in situ. The median procedure time was 48 minutes (range 2-357). Adverse events occurred in 12.7%. Life-threatening complications occurred in 0.5%, but there were no treatment-related deaths. During a median follow-up period of 46.1 months (range 1-113), the 3-year overall survival rate, relapse-free survival rate, cause-specific survival rate, and larynx-preservation survival rate were 88.1%, 84.4%, 99.6%, and 87.5%, respectively. Transoral surgery for superficial head and neck cancer offers effective minimally invasive treatment. Clinical trials registry number: UMIN000008276.

DOI： 10.1002/cam4.3927

併存する疾患のあることが多い高齢者における上部消化管疾患のマネージメント地域病院における消化器サルコペニア疾患診療の有用性

上村博輝, 小島雄一, 高橋一也, 高綱将史, 平野正明, 政二文明, 藤田一, 辻村恭憲, 小林太一, 寺井崇二

日本消化器病学会甲信越支部例会抄録集 68回 52 - 52 2021年6月

感染性被包化と壊死門脈瘻を伴う膵仮性嚢胞の一例(A case of pancreatic pseudocyst-portal vein fistula with infected walled off necrosis)

前田悠一郎, 林和直, 戸田遼, 若林拓哉, 木村究, 水戸將貴, 小島雄一, 小川光平, 荒生祥尚, 木村成宏, 五十嵐聡, 土屋淳紀, 徳永麻美, 佐藤知巳, 寺井崇二

日本消化器病学会甲信越支部例会抄録集 68回 35 - 35 2021年6月

Effectiveness of EUS-Guided Fine-Needle Biopsy versus EUS-Guided Fine-Needle Aspiration: A Retrospective Analysis. 国際誌

Naosuke Kuraoka, Satoru Hashimoto, Shigeru Matsui, Shuji Terai

Diagnostics (Basel, Switzerland) 11 ( 6 ) 2021年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for pancreatic tumors and subepithelial lesions (SEL) of the gastrointestinal tract are effective for histological diagnosis. There are also reports that tissue sampling is possible with a smaller number of punctures by EUS-guided fine-needle biopsy (EUS-FNB). In this study, we retrospectively compared the diagnostic abilities of EUS-FNA and EUS-FNB. We examined 130 patients who underwent EUS-FNA/EUS-FNB for pancreatic tumors and SEL from July 2018 to January 2021. None of the cases underwent rapid on-site evaluation. There were 94 and 36 cases in the EUS-FNA and EUS-FNB groups, respectively. The median tumor size in the EUS-FNB group was 30 mm, which was significantly larger than the EUS-FNA group (p = 0.02). In addition, transgastric puncture was significantly more common in the EUS-FNB group (p = 0.01). The EUS-FNA and EUS-FNB groups had a sensitivity of 82.9% and 91.7% and an accuracy rate of 85.1% and 91.7%, respectively. However, both procedures had a comparable diagnostic ability.

DOI： 10.3390/diagnostics11060965

Long-term survival of 11 years with multidisciplinary therapy for hepatocellular carcinoma metastasis to the ovary and peritoneum: a case report.

Satoko Motegi, Takeshi Yokoo, Ryosuke Nozawa, Rie Azumi, Yuzo Kawata, Kohei Ogawa, Toru Setsu, Ken-Ichi Mizuno, Koji Nishino, Hajime Umezu, Hirokazu Kawai, Takeshi Suda, Shuji Terai

Clinical journal of gastroenterology 14 ( 4 ) 1211 - 1220 2021年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

We herein report a rare case of HCC metastases to the ovary and peritoneum in a 61-year-old female patient who has achieved 11-year survival with multidisciplinary therapy. The patient was diagnosed with HCC during balloon angioplasty performed for Budd-Chiari syndrome in 1994 and underwent partial hepatectomy twice. Five years after the second hepatectomy, allochronic recurrence of a single nodule detected in S8 was treated by radiofrequency ablation, followed by percutaneous ethanol injection therapy and stereotactic body radiotherapy. However, her α-fetoprotein level rose to 1862 ng/mL within one year and computed tomography revealed a large pelvic tumor suggesting HCC metastasis to the ovary. The subsequent laparotomy revealed one 11-cm left ovarian tumor, one small right ovarian nodule, and numerous peritoneal nodules. Bilateral salpingo-oophorectomy and peritoneal resection of as many nodules as possible were performed. Combination therapy with intravenous 5-fluorouracil plus cisplatin and ramucirumab monotherapy effectively suppressed tumor progression with maintenance of hepatic functional reserve, and she has achieved long-term survival of 11 years, illustrating that multidisciplinary therapy with favorable hepatic functional reserve maintenance can contribute to long-term survival in HCC with extrahepatic spread.

DOI： 10.1007/s12328-021-01434-2

Endoscopic retrieval of multiple sewing needles by using the tip of a magnetic tube. 国際誌

Shinichi Morita, Kazuyoshi Yagi, Takahiro Hoshi, Satoshi Abe, Shuji Terai

VideoGIE : an official video journal of the American Society for Gastrointestinal Endoscopy 6 ( 5 ) 228 - 230 2021年5月

Achalasia and esophageal cancer: a large database analysis in Japan.

Hiroki Sato, Shuji Terai, Yuto Shimamura, Shinwa Tanaka, Hironari Shiwaku, Hitomi Minami, Chiaki Sato, Ryo Ogawa, Hiroshi Yokomichi, Haruhiro Inoue

Journal of gastroenterology 56 ( 4 ) 360 - 370 2021年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Achalasia has been reported to be associated with esophageal cancers (ECs). However, owing to the rarity of achalasia, details of achalasia-related ECs are not well investigated. METHOD: The incidence of ECs in Japanese patients with achalasia and achalasia-related esophageal motility disorders (EMDs) was estimated, and risk factors for achalasia-related ECs were determined. Characteristics of ECs and treatment courses were also analyzed. RESULTS: Between 2010 and 2019, 2714 Japanese patients with achalasia and achalasia-related EMDs were recorded in 7 high-volume centers; 24 patients (21 men, 3 women) developed ECs. The incidence of ECs was estimated at 0.078 and 0.28 per 100 person-years from the onset and the diagnosis of disease, respectively. Kaplan-Meier estimate suggested that, in addition to a long history of achalasia, advanced age, male sex, and regular alcohol consumption were statistically significant risk factors for EC development. A prevalence of 40 ECs (12.5% multiple lesions, and 22.7% metachronal lesions) was also noted, predominantly distributed over the thoracic esophagus. All were histologically diagnosed as squamous cell carcinoma. Superficial ECs were successfully treated with endoscopic treatment in all cases, except one. Achalasia-related Barret esophagus was extremely rare, and Barret adenocarcinoma was not detected in our cohort. CONCLUSION: The high relative risk of ECs was clarified in Japanese achalasia patients, although the absolute risk remained low. Therefore, surveillance endoscopy may be recommended in limited patients with several aforementioned risk factors determined. Superficial cancer can be treated with endoscopic treatment. Multiple and metachronal ECs should be screened.

DOI： 10.1007/s00535-021-01763-6

The first case of balloon-occluded retrograde transvenous obliteration and partial splenic embolization for gastric varices in situs inversus abdominus.

Yusuke Watanabe, Akihiko Osaki, Nobuo Waguri, Shuji Terai

Clinical journal of gastroenterology 14 ( 2 ) 656 - 661 2021年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Situs inversus abdominus is a congenital abnormality characterized by the mirror image positioning of the abdominal organs, making it difficult to diagnosis and treatment of many diseases. Here, we report a rare case of gastric varices in situs inversus abdominus patient. A 55-year-old man was diagnosed with F2-shaped gastric varices associated with alcoholic cirrhosis. Abdominal dynamic computed tomography showed situs inversus abdominus, and gastric varices with a gastrorenal shunt. Due to the complex anatomy, emergency interventional radiology during bleeding was extremely difficult. Therefore, after thorough consultation, we decided to treat gastric varices prophylactically by balloon-occluded retrograde transvenous obliteration. After treatment, the patient's clinical course was generally good, with no adverse events, and the gastric varices disappeared. It is important to assess anatomical positioning using three-dimensional reconstruction computed tomography images before treatment, to adequately prepare, including selecting appropriate devices (i.e., catheters and sheath). Although preventive treatment of gastric varices is controversial, in cases with anatomical complexity, preventive treatment with sufficient preparation would be recommended. To the best of our knowledge, there are no reports of treatment for gastric varices in situs inversus abdominus patient. This case will serve as a reference for successful treatment in future cases.

DOI： 10.1007/s12328-020-01332-z

Paris II and Rotterdam criteria are the best predictors of outcomes in patients with primary biliary cholangitis in Japan. 国際誌

Naruhiro Kimura, Masaaki Takamura, Nobutaka Takeda, Yusuke Watanabe, Yoshihisa Arao, Masahumi Takatsuna, Suguru Takeuchi, Hiroyuki Abe, Toru Setsu, Hiroteru Kamimura, Akira Sakamaki, Kenya Kamimura, Atsunori Tsuchiya, Shuji Terai

Hepatology international 15 ( 2 ) 437 - 443 2021年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Biochemical response to treatment in patients with primary biliary cholangitis (PBC) reflects prognosis. However, the best predictive criteria to detect biochemical response remain undetermined. In addition, because these criteria need > 6 months until definition, parameters that can estimate its results before initiating treatment are needed. METHODS: We conducted a single-center retrospective study on 196 patients with PBC, followed up for at least 12 months after initiating treatment. RESULTS: Kaplan-Meier analysis showed that Paris II (p = 0.002) and Rotterdam criteria (p = 0.001) could estimate the overall survival of PBC patients, whereas Paris II (p = 0.001), Rotterdam (p = 0.001), and Rochester criteria (p= 0.025) could estimate liver-related deaths. Cox hazard analysis revealed Paris II and Rotterdam criteria as significantly independent predictors of overall survival (hazard ratio (HR) 3.948, 95% CI 1.293-12.054, p = 0.016 and HR 6.040, 95% CI 1.969-18.527, p = 0.002, respectively) and liver-related deaths (HR 10.461, 95% CI 1.231-88.936, p = 0.032 and HR 10.824, 95% CI 1.252-93.572, p = 0.032, respectively). The results of Paris II criteria could be estimated by serum prothrombin time (Odds ratio (OR) 1.052, 95% CI 1.008-1.098, p = 0.021) and alanine transaminase level (OR 0.954, 95% CI 0.919-0.991, p = 0.014) whereas, those of Rotterdam criteria could be estimated by serum albumin level (OR 3.649, 95% CI 1.098-12.128, p = 0.035) at the time of diagnosis. CONCLUSIONS: This study highlights the best prediction criteria and pre-treatment parameters that facilitate the prognosis of PBC patients.

DOI： 10.1007/s12072-021-10163-0

Analysis of the safety of pretransplant corticosteroid therapy in patients with acute liver failure and late-onset hepatic failure in Japan. 国際誌

Takuro Hisanaga, Isao Hidaka, Isao Sakaida, Nobuaki Nakayama, Akio Ido, Naoya Kato, Yasuhiro Takikawa, Kazuaki Inoue, Masahito Shimizu, Takuya Genda, Shuji Terai, Hirohito Tsubouchi, Hajime Takikawa, Satoshi Mochida, Intractable Hepato-Biliary Disease Study Group Of Japan

JGH open : an open access journal of gastroenterology and hepatology 5 ( 4 ) 428 - 433 2021年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Background and Aim: In Japan, corticosteroids have been commonly used as a part of multidisciplinary therapy for patients with acute liver failure and late-onset hepatic failure. However, there is controversy regarding the development of infections and other complications. In this study, the influence of corticosteroids on patient outcomes after liver transplantation was investigated. Methods: This study included 167 patients with acute liver failure and late-onset hepatic failure who underwent liver transplantation between 2010 and 2015. The effects of pretransplant corticosteroid therapy on patient outcomes were evaluated using a database constructed by the subcommittee for fulminant hepatitis in the Intractable Hepato-Biliary Diseases Study Group of Japan. Results: The subacute type and the median total bilirubin levels were higher in those receiving corticosteroids than in those not receiving corticosteroids. Although infections tended to be higher in patients receiving corticosteroids, pretransplant corticosteroid administration did not affect the survival rates. The duration from corticosteroid initiation to liver transplantation was longer in patients who developed infections. The survival rates, however, did not differ between patients with and without infections. Conclusions: Corticosteroids were administered to patients with poor prognoses. Otherwise, the overall outcome in those administered corticosteroids was not significantly different from that in those administered without corticosteroids. Although infectious complications tended to occur, they were generally controllable and nonfatal. Pretransplant corticosteroid therapy may be permissible, with regarding for infections and performed within the minimum duration.

DOI： 10.1002/jgh3.12508

当センターでの肝炎医療コーディネーター養成の現状と院内非専門医対策について

薛徹, 荒生祥尚, 廣川光, 寺井崇二

肝臓 62 ( Suppl.1 ) A242 - A242 2021年4月

新潟県における自治体肝炎ウイルス検診の現状

薛徹, 菊田玲, 中島徹, 荒生祥尚, 中山均, 寺井崇二

肝臓 62 ( Suppl.1 ) A230 - A230 2021年4月

臨床応用を目指したバイオマーカー研究の最前線急性肝障害条件下での血中セロトニン量の病態・予後予測バイオマーカーとしての有用性の検討

薛徹, 上村顕也, 寺井崇二

肝臓 62 ( Suppl.1 ) A170 - A170 2021年4月

肝移植の現状と課題当県での肝障害症例を対象としたネットワークの運用と、アンケート調査からみた県内の肝障害診療の現状と今後の啓発の必要性

薛徹, 寺井崇二

肝臓 62 ( Suppl.1 ) A113 - A113 2021年4月

新潟県における自治体肝炎ウイルス検診の現状

薛徹, 菊田玲, 中島徹, 荒生祥尚, 中山均, 寺井崇二

肝臓 62 ( Suppl.1 ) A230 - A230 2021年4月

当センターでの肝炎医療コーディネーター養成の現状と院内非専門医対策について

薛徹, 荒生祥尚, 廣川光, 寺井崇二

肝臓 62 ( Suppl.1 ) A242 - A242 2021年4月

肝疾患におけるビックデータとAI(人工知能)の臨床応用ディープラーニングを活用したPBC多施設データから予測する高齢者PBCの介入の必要性の検討

上村博輝, 高村昌昭, 寺井崇二

肝臓 62 ( Suppl.1 ) A208 - A208 2021年4月

肝疾患移行期医療の現状と問題点先天性心疾患術後に肝線維化悪化に影響を及ぼす因子の解析

山崎文紗子, 上村博輝, 寺井崇二

肝臓 62 ( Suppl.1 ) A167 - A167 2021年4月

多発肝転移、リンパ節転移を伴う直腸原発神経内分泌腫瘍に対して集学的治療が有効であった一例当院での症例群の検討と共に

小川和也, 阿部寛幸, 上村顕也, 寺井崇二

肝臓 62 ( Suppl.1 ) A266 - A266 2021年4月

point shear wave elastographyを利用した肝線維化のheterogeneityの検証

横尾健, 杉田萌乃, 荒生祥尚, 薛徹, 上村博輝, 坂牧僚, 上村顕也, 土屋淳紀, 高村昌昭, 寺井崇二

超音波医学 48 ( Suppl. ) S713 - S713 2021年4月

肝再生の可能性と障壁 HMGB1の部分ペプチドを用いた慢性肝疾患に対するセルフリー治療の開発

土屋淳紀, 野尻俊介, 寺井崇二

肝臓 62 ( Suppl.1 ) A69 - A69 2021年4月

【肝類洞壁細胞研究における新知見】肝の炎症、線維化と類洞壁細胞間葉系幹細胞を用いた新規治療法の開発

渡邉雄介, 土屋淳紀, 寺井崇二

肝胆膵 82 ( 4 ) 525 - 529 2021年4月

肝癌に対する局所療法としての放射線療法の安全性と有効性の検証

山田麻理奈, 上村顕也, 柴田理, 森田真一, 寺井崇二

肝臓 62 ( Suppl.1 ) A338 - A338 2021年4月

Small extracellular vesicles derived from interferon-γ pre-conditioned mesenchymal stromal cells effectively treat liver fibrosis. 国際誌

Suguru Takeuchi, Atsunori Tsuchiya, Takahiro Iwasawa, Shunsuke Nojiri, Takayuki Watanabe, Masahiro Ogawa, Tomoaki Yoshida, Katsunori Fujiki, Yuta Koui, Taketomo Kido, Yusuke Yoshioka, Mayu Fujita, Junichi Kikuta, Tohru Itoh, Masaaki Takamura, Katsuhiko Shirahige, Masaru Ishii, Takahiro Ochiya, Atsushi Miyajima, Shuji Terai

NPJ Regenerative medicine 6 ( 1 ) 19 - 19 2021年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Mesenchymal stromal cells (MSCs) are used for ameliorating liver fibrosis and aiding liver regeneration after cirrhosis; Here, we analyzed the therapeutic potential of small extracellular vesicles (sEVs) derived from interferon-γ (IFN-γ) pre-conditioned MSCs (γ-sEVs). γ-sEVs effectively induced anti-inflammatory macrophages with high motility and phagocytic abilities in vitro, while not preventing hepatic stellate cell (HSC; the major source of collagen fiber) activation in vitro. The proteome analysis of MSC-derived sEVs revealed anti-inflammatory macrophage inducible proteins (e.g., annexin-A1, lactotransferrin, and aminopeptidase N) upon IFN-γ stimulation. Furthermore, by enabling CX3CR1+ macrophage accumulation in the damaged area, γ-sEVs ameliorated inflammation and fibrosis in the cirrhosis mouse model more effectively than sEVs. Single cell RNA-Seq analysis revealed diverse effects, such as induction of anti-inflammatory macrophages and regulatory T cells, in the cirrhotic liver after γ-sEV administration. Overall, IFN-γ pre-conditioning altered sEVs resulted in efficient tissue repair indicating a new therapeutic strategy.

DOI： 10.1038/s41536-021-00132-4

Modulation of serotonin in the gut-liver neural axis ameliorates the fatty and fibrotic changes in non-alcoholic fatty liver. 国際誌

Masayoshi Ko, Kenya Kamimura, Takashi Owaki, Takuro Nagoya, Norihiro Sakai, Itsuo Nagayama, Yusuke Niwa, Osamu Shibata, Chiyumi Oda, Shinichi Morita, Atsushi Kimura, Ryosuke Inoue, Toru Setsu, Akira Sakamaki, Takeshi Yokoo, Shuji Terai

Disease models & mechanisms 14 ( 3 ) 2021年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

The etiology of non-alcoholic fatty liver disease (NAFLD) consists of various factors, including neural signal pathways. However, the molecular mechanisms of the autonomic neural signals influencing NAFLD progression have not been elucidated. Therefore, we examined the involvement of the gut-liver neural axis in NAFLD development and tested the therapeutic effect of modulation of this axis in this study. To test the contribution of the gut-liver neural axis, we examined NAFLD progression with respect to body weight, hepatic steatosis, fibrosis, intestinal tight junction, microbiota and short-chain fatty acids in NAFLD models of choline-deficient defined L-amino-acid and high-fat diet-fed mice with or without blockades of autonomic nerves from the liver. Blockade of the neural signal from the liver to the gut in these NAFLD mice models ameliorated the progression of liver weight, hepatic steatosis and fibrosis by modulating serotonin expression in the small intestine. It was related to the severity of the liver pathology, the tight junction protein expression, microbiota diversity and short-chain fatty acids. These effects were reproduced by administrating serotonin antagonist, which ameliorated the NAFLD progression in the NAFLD mice models. Our study demonstrated that the gut-liver neural axis is involved in the etiologies of NAFLD progression and that serotonin expression through this signaling network is the key factor of this axis. Therefore, modulation of the gut-liver neural axis and serotonin antagonist ameliorates fatty and fibrotic changes in non-alcoholic fatty liver, and can be a potential therapeutic target of NAFLD.This article has an associated First Person interview with the first author of the paper.

DOI： 10.1242/dmm.048922

Successful treatment of positive-sense RNA virus coinfection with autoimmune hepatitis using double filtration plasmapheresis. 国際誌

Hiroteru Kamimura, Kenya Kamimura, Atsunori Tsuchiya, Shuji Terai

BMJ case reports 14 ( 3 ) 2021年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Double filtration plasmapheresis (DFPP) is an apheretic technique that selectively removes high molecular weight substances using a plasma component filter. DFPP has been used to treat positive-sense RNA virus infections, mainly chronic hepatitis C virus (HCV) infection, because of its ability to directly eliminate viral particles from blood plasma from 2008 to about 2015, before direct-acting antiviral agents was marketed. This effect has been termed virus removal and eradication by DFPP. HCV is a positive-sense RNA virus similar to West Nile virus, dengue virus and the SARS and Middle East respiratory syndrome coronaviruses. SARS-CoV-2 is classified same viral species. These viruses are all classified in Family Flaviviridae which are family of single-stranded plus-stranded RNA viruses. Viral particles are 40-60 nm in diameter, enveloped and spherical in shape. We present a rare case of HCV removal where an RNA virus infection that copresented with virus-associated autoimmune hepatitis was eliminated using DFPP. Our results indicate that DFPP may facilitate prompt viraemia reduction and may have novel treatment applications for SARS-CoV-2, that is, use of therapeutic plasma exchange for fulminant COVID-19.

DOI： 10.1136/bcr-2020-236984

Adipose most abundant 2 protein is a predictive marker for cisplatin sensitivity in cancers. 国際誌

Kenya Kamimura, Takeshi Suda, Yasuo Fukuhara, Shujiro Okuda, Yu Watanabe, Takeshi Yokoo, Akihiko Osaki, Nobuo Waguri, Toru Ishikawa, Toshihiro Sato, Yutaka Aoyagi, Masaaki Takamura, Toshifumi Wakai, Shuji Terai

Scientific reports 11 ( 1 ) 6255 - 6255 2021年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Cisplatin (CDDP) is one of the chemotherapeutic drugs being used to treat various cancers. Although effective in many cases, as high doses of CDDP cause cytotoxic effects that may worsen patients' condition, therefore, a marker of sensitivity to CDDP is necessary to enhance the safety and efficiency of CDDP administration. This study focused on adipose most abundant 2 (APM2) to examine its potential as a marker of CDDP sensitivity. The relationship of APM2 expression with the mechanisms of CDDP resistance was examined in vitro and in vivo using hepatocellular carcinoma (HCC) cells, tissues and serum of HCC patients (n = 71) treated initially with intrahepatic arterial infusion of CDDP followed by surgical resection. The predictability of serum APM2 for CDDP sensitivity was assessed in additional 54 HCC patients and 14 gastric cancer (GC) patients. APM2 expression in CDDP-resistant HCC was significantly higher both in serum and the tissue. Bioinformatic analyses and histological analyses demonstrated upregulation of ERCC6L (DNA excision repair protein ERCC6-like) by APM2, which accounts for the degree of APM2 expression. The serum APM2 level and chemosensitivity for CDDP were assessed and cut-off value of serum APM2 for predicting the sensitivity to CDDP was determined to be 18.7 µg/mL. The value was assessed in HCC (n = 54) and GC (n = 14) patients for its predictability of CDDP sensitivity, resulted in predictive value of 77.3% and 100%, respectively. Our study demonstrated that APM2 expression is related to CDDP sensitivity and serum APM2 can be an effective biomarker of HCC and GC for determining the sensitivity to CDDP.Trial registration: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000028487).

DOI： 10.1038/s41598-021-85498-7

Relationship between detection of hepatitis B virus in saliva and periodontal disease in hepatitis B virus carriers in Japan. 国際誌

Hiroteru Kamimura, Jun Watanabe, Tomoyuki Sugano, Junji Kohisa, Hiroyuki Abe, Kenya Kamimura, Atsunori Tsuchiya, Masaaki Takamura, Shogo Okoshi, Yoshinari Tanabe, Ritsuo Takagi, Hirofumi Nonaka, Shuji Terai

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 27 ( 3 ) 492 - 496 2021年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: Although hepatitis B virus infection is well-described, the additional risk posed by oral bleeding in individuals with chronic hepatitis B virus infection has not been determined. This study aimed to determine the quantity of hepatitis B virus in the saliva of carriers in Japan, as a means of understanding the potential risk for horizontal transmission. METHODS: Saliva samples from 48 confirmed hepatitis B virus carriers were included in the analysis. Hepatitis B virus concentrations and the presence of occult blood as periodontal disease were evaluated in each sample. RESULTS: Hepatitis B surface antigen was identified in 46 of the 48 samples (98%), with hepatitis B virus DNA identified in 19 of the 48 saliva samples (40%). Occult blood was detected in 32 (67%) samples with the prevalence increasing as a function of age (r = 0.413; P = 0.003). There was a significantly positive correlation between hepatitis B virus DNA levels in the serum and saliva specimens (r = 0.895; P < 0.001). CONCLUSIONS: Occult blood in saliva was detected in most participants. The detection of hepatitis B virus DNA correlated positively with hepatitis B virus in the serum and occult blood in the saliva. Therefore, improved care of periodontal disease among older people is important for preventing horizontal transmission of hepatitis B virus.

DOI： 10.1016/j.jiac.2020.10.028

Evaluation of intestinal microbiota, short-chain fatty acids, and immunoglobulin a in diversion colitis. 国際誌

Kentaro Tominaga, Atsunori Tsuchiya, Takeshi Mizusawa, Asami Matsumoto, Ayaka Minemura, Kentaro Oka, Motomichi Takahashi, Tomoaki Yosida, Yuzo Kawata, Kazuya Takahashi, Hiroki Sato, Satoshi Ikarashi, Kazunao Hayashi, Ken-Ichi Mizuno, Yosuke Tajima, Masato Nakano, Yoshifumi Shimada, Hitoshi Kameyama, Junji Yokoyama, Toshifumi Wakai, Shuji Terai

Biochemistry and biophysics reports 25 100892 - 100892 2021年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

It is reported that an increase in aerobic bacteria, a lack of short-chain fatty acids (SCFAs), and immune disorders in the diverted colon are major causes of diversion colitis. However, the precise pathogenesis of this condition remains unclear. The aim of the present study was to examine the microbiota, intestinal SCFAs, and immunoglobulin A (IgA) in the diverted colon. Eight patients underwent operative procedures for colostomies. We assessed the diverted colon using endoscopy and obtained intestinal samples from the diverted colon and oral colon in these patients. We analyzed the microbiota and SCFAs of the intestinal samples. The bacterial communities were investigated using a 16S rRNA gene sequencing method. The microbiota demonstrated a change in the proportion of some species, especially Lactobacillus, which significantly decreased in the diverted colon at the genus level. We also showed that intestinal SCFA values were significantly decreased in the diverted colon. Furthermore, intestinal IgA levels were significantly increased in the diverted colon. This study was the first to show that intestinal SCFAs were significantly decreased and intestinal IgA was significantly increased in the diverted colon. Our data suggest that SCFAs affect the microbiota and may play an immunological role in diversion colitis.

DOI： 10.1016/j.bbrep.2020.100892

Comorbidities and healthcare costs and resource use of patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) in the Japan medical data vision database.

Shuji Terai, Amy Buchanan-Hughes, Alvin Ng, I-Heng Lee, Ken Hasegawa

Journal of gastroenterology 56 ( 3 ) 274 - 284 2021年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: This study examined demographics, comorbidities and healthcare resource use (HCRU) and costs among Japanese patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). METHODS: We conducted a repeated cross-sectional analysis of the Medical Data Vision (MDV) claims database, from January 2011 to March 2018. Demographics were described at index date and by calendar year; a "NASH" subpopulation included patients with ≥ 1 claim for NASH at any time. Prevalence of pre-specified comorbidities of interest and data-emergent top comorbidities were estimated. All-cause HCRU and costs were quantified by calendar year. Outcomes were compared between 2011 and 2017 using partially overlapping t tests. RESULTS: 58,958 patients (mean age 61.6 years; 55.5% male) were included. 1139 patients (2%) were in the NASH subpopulation. At baseline, comorbid cardiovascular disease (69.4%), diabetes (62.1%) and hyperlipidaemia (54.4%) were most prevalent; comorbidity prevalence increased with age. Mean outpatient visits decreased from 9.36 per patient in 2011 to 7.80 in 2017; mean inpatient admissions increased (both p < 0.001 for 2011 vs 2017). Mean total all-cause healthcare costs ranged from \322,206 to \340,399 per patient per year between 2011 and 2017. Although total all-cause healthcare costs did not change significantly (p = 0.552), cost burden shifted from the outpatient to inpatient setting between 2011 and 2017. All-cause healthcare resource use/costs were generally higher for the NASH subgroup compared with the overall population. CONCLUSIONS: There is a high burden of disease among Japanese NAFLD/NASH patients, including a high prevalence of comorbidities which generally increase with age. Accordingly, substantial all-cause HCRU and costs were incurred.

DOI： 10.1007/s00535-021-01759-2

当院における肝炎医療コーディネーターの取り組み・課題と今後の展望

廣川光, 荒生祥尚, 薛徹, 寺井崇二

日本消化器病学会雑誌 118 ( 臨増総会 ) A266 - A266 2021年3月

Hepatocellular carcinoma development in diabetic patients: a nationwide survey in Japan

Ryosuke Tateishi, Takeshi Matsumura, Takeshi Okanoue, Toshihide Shima, Koji Uchino, Naoto Fujiwara, Takafumi Senokuchi, Kazuyoshi Kon, Takayoshi Sasako, Makiko Taniai, Takumi Kawaguchi, Hiroshi Inoue, Hirotaka Watada, Naoto Kubota, Hitoshi Shimano, Shuichi Kaneko, Etsuko Hashimoto, Sumio Watanabe, Goshi Shiota, Kohjiro Ueki, Kosuke Kashiwabara, Yutaka Matsuyama, Hideo Tanaka, Masato Kasuga, Eiichi Araki, Kazuhiko Koike, Yoshiyasu Karino, Shuhei Hige, Masatomo Sekiguchi, Koji Ogawa, Hideaki Miyoshi, Kyu Yong Cho, Masaru Baba, Atsushi Inoue, Kazuobu Aso, Mitsuyoshi Okada, Yasuhiro Takikawa, Kei Endo, Yasushi Ishigaki, Hirobumi Togashi, Michiaki Unno, Takanori Morikawa, Hideki Katagiri, Shojiro Sawada, Hiromasa Ohira, Atsushi Takahashi, Michio Shimabukuro, Akihiro Kudo, Naomi Tanaka, Junko Mitsuhashi, Toshifumi Tokai, Yasushi Matsuzaki, Tadashi Ikegami, Masato Imai, Kou Nishikawa, Sadao Takahashi, Sumiko Nagoshi, Kosuke Maezawa, Masafumi Matsuda, Tetsuhiro Chiba, Masayuki Yokoyama, Koutaro Yokote, Yoko Hidetaka, Mitsuhiko Moriyama, Hitomi Nakamura, Midori Fujishiro, Tadakazu Hisamatsu, Kaori Nishikawa, Toshihiko Nouchi, Yuki Sakurai, Harumi Daikoku, Michinori Murayama, Yoshinori Saigusa, Takashi Matsui, Ryosuke Tateishi, Hidenari Nagai, Takanori Mukozu, Takahisa Hirose, Masahiko Miyagi, Hiroaki Sato, Akira Mizuki, Masanori Miura, Yuzuru Sato, Rena Kaneko, Kumiko Hamano, Hiroko Kato, Kentaro Kikuchi, Yusuke Kajiyama, Makoto Chuma, Hiroko Ito, Hiroshi Yasuda, Nobuyuki Matsumoto, Yasushi Tanaka, Yoshio Nagai, Kento Imajo, Yasuo Terauchi, Yuzuru Ito, Shuji Terai, Hirohito Sone, Satoshi Matsunaga

Journal of Gastroenterology 56 ( 3 ) 261 - 273 2021年3月

掲載種別：研究論文（学術雑誌）

Background: Although type 2 diabetes mellitus (T2DM) is a known risk factor for hepatocellular carcinoma (HCC) development, the annual incidence in diabetes patients is far below the threshold of efficient surveillance. This study aimed to elucidate the risk factors for HCC in diabetic patients and to determine the best criteria to identify surveillance candidates. Methods: The study included 239 patients with T2DM who were diagnosed with non-viral HCC between 2010 and 2015, with ≥ 5 years of follow-up at diabetes clinics of 81 teaching hospitals in Japan before HCC diagnosis, and 3277 non-HCC T2DM patients from a prospective cohort study, as controls. Clinical data at the time of and 5 years before HCC diagnosis were collected. Results: The mean patient age at HCC diagnosis was approximately 73 years, and 80% of the patients were male. The proportion of patients with insulin use increased, whereas the body mass index (BMI), proportion of patients with fatty liver, fasting glucose levels, and hemoglobin A1c (HbA1c) levels decreased significantly in 5 years. In the cohort study, 18 patients developed HCC during the mean follow-up period of 4.7 years with an annual incidence of 0.11%. Multivariate logistic regression analyses showed that the FIB-4 index was an outstanding predictor of HCC development along with male sex, presence of hypertension, lower HbA1c and albumin levels, and higher BMI and gamma-glutamyl transpeptidase levels. Receiver-operating characteristic analyses showed that a FIB-4 cut-off value of 3.61 could help identify high-risk patients, with a corresponding annual HCC incidence rate of 1.1%. Conclusion: A simple calculation of the FIB-4 index in diabetes clinics can be the first step toward surveillance of HCC with a non-viral etiology.

DOI： 10.1007/s00535-020-01754-z

門脈圧亢進症:診断と治療の最前線傍食道静脈の発達の有無を指標としたEVL/EISの選択による治療成績

薛徹, 横山純二, 寺井崇二

日本消化器病学会雑誌 118 ( 臨増総会 ) A201 - A201 2021年3月

地域病院健診時の消化器サルコペニア疾患診療の有用性

上村博輝, 小島雄一, 寺井崇二

日本消化器病学会雑誌 118 ( 臨増総会 ) A345 - A345 2021年3月

【小児期発症慢性肝疾患における移行期医療の現状と課題-小児と成人のダイアログ-】NAFLD Pediatric fatty liver disease(PeFLD)における概説と成人との比較(肝組織学的検討を含めて) 小児と成人の相違

上村博輝, 山崎文紗子, 佐藤毅昂, 薛徹, 土屋淳紀, 上村顕也, 高村昌昭, 寺井崇二, 長崎啓祐, 斎藤昭彦, 梅津哉

肝胆膵 82 ( 3 ) 425 - 440 2021年3月

消化器疾患診療におけるディープラーニングの有用性の検証

上村博輝, 野中尋史, 寺井崇二

日本消化器病学会雑誌 118 ( 臨増総会 ) A354 - A354 2021年3月

消化器疾患と神経系の臓器相関脂肪性肝疾患における自律神経系ネットワークを介したセロトニンの関与

大脇崇史, 上村顕也, 寺井崇二

日本消化器病学会雑誌 118 ( 臨増総会 ) A144 - A144 2021年3月

肝発癌抑制を目指したB型肝炎の最新治療肝細胞癌におけるYAPとHBx蛋白の臨床的有用性の検討

小田知友美, 上村顕也, 寺井崇二

日本消化器病学会雑誌 118 ( 臨増総会 ) A73 - A73 2021年3月

消化器領域におけるバイオマーカーの新展開エクソソームタンパクEps8の膵癌バイオマーカーとしての検討

林和直, 土屋淳紀, 寺井崇二

日本消化器病学会雑誌 118 ( 臨増総会 ) A151 - A151 2021年3月

消化器領域における再生医療:基礎的研究の最前線 HMGB1の部分ペプチドを用いた新たな肝硬変治療開発

土屋淳紀, 野尻俊介, 寺井崇二

日本消化器病学会雑誌 118 ( 臨増総会 ) A132 - A132 2021年3月

ACLF:欧米、アジアと我が国での差異 Acute on chronic liver failureに対する肝細胞老化改善の検証

渡邉雄介, 土屋淳紀, 寺井崇二

日本消化器病学会雑誌 118 ( 臨増総会 ) A110 - A110 2021年3月

胆膵疾患研究の最前線〜from bench to bedside, from bedside to bench〜膵臓選択的ハイドロダイナミック遺伝子導入法による新規膵癌モデル動物の確立

柴田理, 上村顕也, 寺井崇二

日本消化器病学会雑誌 118 ( 臨増総会 ) A232 - A232 2021年3月

脂肪性肝疾患:新規治療法を目指した基礎研究とトランスレーショナルリサーチ ONO-1301を用いた肝硬変に対するセルフリー治療の開発

茂木聡子, 土屋淳紀, 寺井崇二

日本消化器病学会雑誌 118 ( 臨増総会 ) A223 - A223 2021年3月

消化器領域の救急医療、集中治療:急性膵炎予後因子・CT gradeを用いた重症急性膵炎の予後・感染性被包化膵壊死合併の予測

林和直, 五十嵐聡, 寺井崇二

日本消化器病学会雑誌 118 ( 臨増総会 ) A251 - A251 2021年3月

高齢者膵癌に対する治療の適応と限界県全域における高齢者膵癌診療の現状多施設後方視的研究の結果より

五十嵐聡, 林和直, 寺井崇二

日本消化器病学会雑誌 118 ( 臨増総会 ) A237 - A237 2021年3月

Potential Effect of a Selective Peroxisome Proliferator-activated Receptor Alpha Modulator on Metabolic Dysfunction-associated Fatty Liver Disease.

Hiroteru Kamimura, Atsushi Kimura, Shuji Terai

Internal medicine (Tokyo, Japan) 60 ( 14 ) 2165 - 2166 2021年2月

Rare paraneoplastic syndromes in digestive systems caused by lung cancer. 国際誌

Hiroteru Kamimura, Tomohiro Iwasaki, Kazunao Hayashi, Shuji Terai

BMJ case reports 14 ( 2 ) 2021年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

We observed a rare case of two different digestive paraneoplastic syndromes that improved with the treatment of the neoplasms. The first syndrome was chronic intestinal pseudo-obstruction (CIPO), which is a subtype of paraneoplastic syndromes called a paraneoplastic neurological syndrome (PNS). The second was Stauffer's syndrome, which is a unique paraneoplastic syndrome characterised by non-metastatic intrahepatic cholestasis associated with neoplasms. Here, we report the case of a 55-year-old man who presented with two concurrent paraneoplastic syndromes in the digestive system. The intestinal pseudo-obstruction and elevated biliary enzyme levels improved as the lung cancer responded to chemotherapy. In this case, CIPO as a PNS led to the detection of lung cancer. To our knowledge, this is the first report of Stauffer's syndrome caused by lung adenocarcinoma.

DOI： 10.1136/bcr-2020-240161

Immunoglobulin therapy for successful management of prolonged, recurrent jaundice in a young adult male with combined immunodeficiency.

Chiyumi Oda, Atsunori Tsuchiya, Atsushi Kimura, Kentaro Tominaga, Kazunao Hayashi, Takashi Ushiki, Hajime Umezu, Shuji Terai

Clinical journal of gastroenterology 14 ( 4 ) 1197 - 1201 2021年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Jaundice may be persistent in drug-induced liver injury associated with vanishing bile duct syndrome. However, recurrent jaundice is atypical, following bile flow restoration. Here, we report a 28-year-old man with prolonged, recurrent jaundice (more than 300 days) and combined immunodeficiency (CID) of B-cells, T-cells, and natural killer (NK) cells. Hypogammaglobulinemia was observed throughout his hospitalization, and peripheral blood flow cytometry detected a few B-cells (2% of CD19 + cells and 2% of CD20 + cells). We further detected the dysfunction of T-cells and NK cells. Based on these findings, CID was diagnosed. We presumed that hypogammaglobulinemia was related to the jaundice. After regular injections of intravenous immunoglobulin (IVIG), the stool color gradually turned brown. However, the color returned to white as IgG levels decreased. The brown-to-white stool pattern was repeated with another IVIG administration, suggesting that the patient's serum immunoglobulin levels were related to the jaundice. On follow-up, IVIG was performed every two to three weeks, and his total bilirubin improved gradually. Immunoglobulin replacement therapy could be one of the treatment choices for jaundice with CID.

DOI： 10.1007/s12328-021-01347-0

Multiple Tumor-Like Fatty Changes in the Liver Disappeared After Hepatitis C Virus Eradication With Direct-Acting Antiviral Treatment. 査読国際誌

Norihiro Sakai, Kenya Kamimura, Shuji Terai

The American journal of gastroenterology 116 ( 2 ) 237 - 237 2021年2月

Changes in disease characteristics of primary biliary cholangitis: An observational retrospective study from 1982 to 2016. 国際誌

Masaaki Takamura, Yasunobu Matsuda, Naruhiro Kimura, Masafumi Takatsuna, Toru Setsu, Atsunori Tsuchiya, Akihiko Osaki, Nobuo Waguri, Masahiko Yanagi, Toru Takahashi, Soichi Sugitani, Yuka Kobayashi, Akira Yoshikawa, Toru Ishikawa, Toshiaki Yoshida, Toshiaki Watanabe, Hitoshi Bannai, Tomoyuki Kubota, Kazuhiro Funakoshi, Hiroto Wakabayashi, So Kurita, Norio Ogata, Masashi Watanabe, Yuhsaku Mita, Shigeki Mori, Motoya Sugiyama, Toru Miyajima, Sumio Takahashi, Shuichi Sato, Kisei Ishizuka, Hironobu Ohta, Yutaka Aoyagi, Shuji Terai

Hepatology research : the official journal of the Japan Society of Hepatology 51 ( 2 ) 166 - 175 2021年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIM: Disease characteristics of primary biliary cholangitis have changed recently. However, detailed studies on the subject have been limited. Therefore, we aimed to clarify disease characteristics of patients with recent primary biliary cholangitis using the cohort from Niigata University and 21 affiliated hospitals. METHODS: Overall, 508 patients were enrolled in this study from 1982 to 2016, divided into three cohorts according to their year of diagnosis: ≤1999, 2000-2009 and ≥2010. We compared differences in clinical characteristics, response to ursodeoxycholic acid and prognosis. RESULTS: The male-to-female ratio increased incrementally from 1:16.4 (≤1999) to 1:3.8 (≥2010) (P < 0.001). In women, the median age at diagnosis increased incrementally from 54.0 years (≤1999) to 60.5 years (≥2010) (P < 0.001) and serum albumin decreased gradually (P = 0.001), which might have affected the increase in the Fibrosis-4 Index and albumin-bilirubin score. The ursodeoxycholic acid response rate according to the Barcelona criteria increased incrementally from 26.7% (≤1999) to 78.4% (≥2010) (P < 0.010), and those according to other criteria (Paris-I, Rotterdam and Toronto) were approximately ≥80% in all cohorts. Ten-year survival rate in the ≤1999 and 2000-2009 cohorts were 98.6% and 95.6%, respectively. These earlier cohorts were also characterized by a higher rate of asymptomatic state and mild histology (83.5% [≤1999] and 84.7% [2000-2009], and 93.6% [≤1999] and 91.1% [2000-2009]). CONCLUSIONS: Patients with primary biliary cholangitis were characterized by older age at diagnosis and an increase in male to female ratio as well as higher response rates of ursodeoxycholic acid and longer survival, resulting from the early recognition of primary biliary cholangitis.

DOI： 10.1111/hepr.13586

【肝硬変診療ガイドラインの改正をめぐって】肝腎症候群

坂牧僚, 薛徹, 阿部寛幸, 上村顕也, 高村昌昭, 寺井崇二

消化器・肝臓内科 9 ( 2 ) 155 - 159 2021年2月

Acute on chronicの新展開当科における我が国の新診断基準でのAcute On Chronic Liver Failure症例の検討

野尻俊介, 土屋淳紀, 阿部聡司, 坂牧僚, 上村博輝, 上村顕也, 高村昌昭, 寺井崇二

肝臓 62 ( 2 ) 107 - 107 2021年2月

Molecular Mechanisms and Treatment of Sarcopenia in Liver Disease: A Review of Current Knowledge. 国際誌

Hiroteru Kamimura, Takeki Sato, Kazuki Natsui, Takamasa Kobayashi, Tomoaki Yoshida, Kenya Kamimura, Atsunori Tsuchiya, Toshiko Murayama, Junji Yokoyama, Hirokazu Kawai, Masaaki Takamura, Shuji Terai

International journal of molecular sciences 22 ( 3 ) 2021年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Sarcopenia is characterized by progressive and generalized loss of skeletal muscle mass and strength that occurs with aging or in association with various diseases. The condition is prevalent worldwide and occurs more frequently in patients with chronic diseases owing to the intrinsic relationship of muscles with glucose, lipid, and protein metabolism. Liver cirrhosis is characterized by the progression of necro-inflammatory liver diseases, which leads to fibrosis, portal hypertension, and a catabolic state, which causes loss of muscle tissue. Sarcopenia is of significant concern in the state of liver cirrhosis because sarcopenia has been associated with higher mortality, increased hospital admissions, worse post-liver transplant outcomes, decreased quality of life, and increased risk for other complications associated with cirrhosis. Therefore, sarcopenia is also an important feature of liver cirrhosis, representing a negative prognostic factor and influencing mortality. An increased understanding of sarcopenia could lead to the development of novel therapeutic approaches that could help improve the cognitive impairment of cirrhotic patients; therefore, we present a review of the mechanisms and diagnosis of sarcopenia in liver disease and existing therapeutic approaches.

DOI： 10.3390/ijms22031425

Usefulness of an artificial intelligence system for the detection of esophageal squamous cell carcinoma evaluated with videos simulating overlooking situation. 国際誌

Kotaro Waki, Ryu Ishihara, Yusuke Kato, Ayaka Shoji, Takahiro Inoue, Katsunori Matsueda, Muneaki Miyake, Yusaku Shimamoto, Hiromu Fukuda, Noriko Matsuura, Yoichiro Ono, Kenshi Yao, Satoru Hashimoto, Shuji Terai, Masayasu Ohmori, Kyosuke Tanaka, Motohiko Kato, Takashi Shono, Hideaki Miyamoto, Yasuhito Tanaka, Tomohiro Tada

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 33 ( 7 ) 1101 - 1109 2021年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: Artificial intelligence (AI) systems have shown favorable performance in the detection of esophageal squamous cell carcinoma (ESCC). However, previous studies were limited by the quality of their validation methods. In this study, we evaluated the performance of an AI system with videos simulating situations in which ESCC has been overlooked. METHODS: We used 17,336 images from 1376 superficial ESCCs and 1461 images from 196 noncancerous and normal esophagi to construct the AI system. To record validation videos, the endoscope was passed through the esophagus at a constant speed without focusing on the lesion to simulate situations in which ESCC has been missed. Validation videos were evaluated by the AI system and 21 endoscopists. RESULTS: We prepared 100 video datasets, including 50 superficial ESCCs, 22 noncancerous lesions, and 28 normal esophagi. The AI system had sensitivity of 85.7% (54 of 63 ESCCs) and specificity of 40%. Initial evaluation by endoscopists conducted with plain video (without AI support) had average sensitivity of 75.0% (47.3 of 63 ESCC) and specificity of 91.4%. Subsequent evaluation by endoscopists was conducted with AI assistance, which improved their sensitivity to 77.7% (P = 0.00696) without changing their specificity (91.6%, P = 0.756). CONCLUSIONS: Our AI system had high sensitivity for the detection of ESCC. As a support tool, the system has the potential to enhance detection of ESCC without reducing specificity. (UMIN000039645).

DOI： 10.1111/den.13934

Transcatheter Arterial Embolization Using Microspheres for Palliating Pain from Bone Metastasis in a Patient with Cholangiocellular Carcinoma.

Shinichi Morita, Shunsuke Sugawara, Takeshi Suda, Didik Prasetyo, Takahiro Hoshi, Satoshi Abe, Kazuyoshi Yagi, Shuji Terai

Internal medicine (Tokyo, Japan) 60 ( 2 ) 241 - 246 2021年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

A 72-year-old man with intractable left shoulder pain due to bone metastasis from cholangiocellular carcinoma was admitted to our hospital. Computed tomography showed an osteoblastic metastatic lesion of the left scapula. Since the pain persisted even after the administration of opioids and external irradiation, microspheres were injected through a catheter; the catheter tip was placed at the arteries feeding the metastatic lesion. After the intervention, the shoulder pain was alleviated without any procedure-related complications, leading to a reduction in the opioid dose. This case suggests the efficacy of transcatheter arterial embolization using microspheres for palliating pain from bone metastasis.

DOI： 10.2169/internalmedicine.5351-20

Comparison of Oral and Esophageal Microbiota in Patients with Achalasia Before and After Peroral Endoscopic Myotomy. 国際誌

Kazuya Takahashi, Hiroki Sato, Takeshi Mizusawa, Kentaro Tominaga, Satoshi Ikarashi, Kazunao Hayashi, Ken-Ichi Mizuno, Satoru Hashimoto, Junji Yokoyama, Shuji Terai

The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology 32 ( 1 ) 42 - 52 2021年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND/AIMS: Patients with achalasia have a high incidence of esophageal squamous cell carcinoma (ESCC), which may be associated with alterations in oral and esophageal microbiota caused by food stasis. This study compared the oral and esophageal microbiota of patients with achalasia before and after peroral endoscopic myotomy (POEM). It also compared patients with achalasia to those with ESCC. MATERIALS AND METHODS: The study prospectively examined 6 patients with achalasia and 14 with superficial ESCC. Oral samples obtained from the buccal mucosa using a swab and esophageal samples obtained from the mid-esophagus using a brush via endoscopy were analyzed by 16S rRNA metagenome sequencing. Additionally, endoscopic and histological findings of patients with achalasia before and after POEM were prospectively compared. RESULTS: In patients with achalasia, Streptococcus was most abundant in both the oral and the esophageal microbiota, and these microbiota were significantly different. Although the overall structure of the oral and esophageal microbiota did not change after POEM, the relative abundance rate of Haemophilus and Neisseria increased in the esophagus, and endoscopic findings of inflammation improved after POEM (P = .04). The relative abundance of microbiota was not different among patients with achalasia from those with ESCC. CONCLUSIONS: The oral and esophageal microbiota were significantly different in patients with achalasia, and some of the composition of the esophageal microbiota changed after POEM. However, these findings and disease-specific microbiota should be further evaluated in large-scale studies.

DOI： 10.5152/tjg.2020.19995

The development of mesenchymal stem cell therapy in the present, and the perspective of cell-free therapy in the future. 国際誌

Yusuke Watanabe, Atsunori Tsuchiya, Shuji Terai

Clinical and molecular hepatology 27 ( 1 ) 70 - 80 2021年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Cirrhosis is a chronic condition that can lead to liver failure. Currently, the viable option for decreasing mortality is liver transplantation. However, transplant surgery is highly invasive. Therefore, cell-based therapy has been developed as an alternative. Based on promising findings from preclinical research, some new trials have been registered. One of them was autologous bone marrow cell infusion therapy and found that ameliorating liver fibrosis activated liver regeneration. Now, majority of trials focus on low-immunogenicity mesenchymal stem cells (MSCs) appropriate for allogeneic administration. However, despite about 20 years of research, only a limited number of cell-based therapies have entered routine practice. Furthermore, potential shortcomings of cell-based therapy include a limit on the number of cells, which may be administered, as well as their failure to infiltrate target organs. On the other hand, these research show that MSCs act as "conducting cells" and regulate host cells including macrophages via extracellular vesicles (EVs) or exosome signals, leading to ameliorate liver fibrosis and promote regeneration. Therefore, the concept of cell-free therapy, which makes use of cell-derived EVs or exosomes, is attracting attention. Cell-free therapies may be safely administered in large doses and are able to infiltrate target organs. However, development of cell-free therapy exhibits its own set of challenges and such therapy may not be completely curative in the context of liver disease. This review describes the history of cell-based therapy research and recent advances in cell-free therapy, as well as discussing the need for more effective therapies.

DOI： 10.3350/cmh.2020.0194

Sofosbuvir plus velpatasvir treatment for hepatitis C virus in patients with decompensated cirrhosis: a Japanese real-world multicenter study.

Yuki Tahata, Hayato Hikita, Satoshi Mochida, Norifumi Kawada, Nobuyuki Enomoto, Akio Ido, Hitoshi Yoshiji, Daiki Miki, Yoichi Hiasa, Yasuhiro Takikawa, Ryotaro Sakamori, Masayuki Kurosaki, Hiroshi Yatsuhashi, Ryosuke Tateishi, Yoshiyuki Ueno, Yoshito Itoh, Taro Yamashita, Tatsuya Kanto, Goki Suda, Yasunari Nakamoto, Naoya Kato, Yasuhiro Asahina, Kentaro Matsuura, Shuji Terai, Kazuhiko Nakao, Masahito Shimizu, Taro Takami, Norio Akuta, Ryoko Yamada, Takahiro Kodama, Tomohide Tatsumi, Tomomi Yamada, Tetsuo Takehara

Journal of gastroenterology 56 ( 1 ) 67 - 77 2021年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Real-world data on the efficacy and safety of sofosbuvir plus velpatasvir (SOF/VEL) treatment for patients with hepatitis C virus (HCV)-related decompensated cirrhosis are limited in Japan. METHODS: A total of 190 patients with compensated (108) or decompensated (82) cirrhosis who initiated direct-acting antiviral (DAA) treatment between February 2019 and August 2019 were enrolled. Sustained virologic response (SVR) was defined as undetectable serum HCV-RNA at 12 weeks after the end of treatment (EOT). RESULTS: The SVR12 rates were 92.6% in patients with compensated cirrhosis and 90.2% in patients with decompensated cirrhosis (p = 0.564), and the treatment completion rates were 98.1% and 96.3%, respectively (p = 0.372). In patients with decompensated cirrhosis, 3 patients discontinued treatment and 2 patients died because of liver-related events. In patients with decompensated cirrhosis with SVR12, 50% of patients with Child-Pugh class B at baseline showed improvement to class A at SVR12, and 27% and 9% of patients with Child-Pugh class C at baseline showed improvement to class B and class A at SVR12, respectively. Patients who achieved SVR12 showed elevated serum albumin levels at the EOT, which were further elevated at SVR12, but no elevated serum albumin levels after the EOT were observed in patients with baseline serum albumin levels less than 2.8 g/dl. CONCLUSIONS: Real-world efficacy of SOF/VEL treatment for patients with decompensated cirrhosis was similar to Japanese phase 3 study, although treatment discontinuation and death related to liver disease occurred. In patients with poor hepatic reserve, whether it improves continuously after viral clearance requires further evaluation.

DOI： 10.1007/s00535-020-01733-4

【新しい肝硬変診療〜ガイドライン2020を紐解く〜】肝硬変診療の課題と今後の展望

寺井崇二, 坂牧僚

日本消化器病学会雑誌 118 ( 1 ) 41 - 45 2021年1月

記述言語：日本語出版者・発行元：(一財)日本消化器病学会

肝硬変診療ガイドライン2020では、11項目のfuture research questionが挙げられており、これらが特に重点的な今後の課題である。非ウイルス性肝硬変の治療では、アルコール性では減酒によるハームリダクションという概念が提唱されている。非アルコール性では、現時点では肝硬変の線維化を改善する薬物療法はなく、今後のさらなる新薬の開発が期待される。加えてトルバプタンやアルブミンの最適な使用法や、新たに追加されたacute-on-chronic liver failure(ACLF)、肝肺症候群と門脈圧亢進に関連した肺動脈性肺高血圧症の項目の病態について記述する。(著者抄録)

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01118&link_issn=&doc_id=20210122320006&doc_link_id=%2Fck8syokb%2F2021%2F011801%2F006%2F0041-0045%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fck8syokb%2F2021%2F011801%2F006%2F0041-0045%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Visceral Adipose Tissue Index and Hepatocellular Carcinoma Are Independent Predictors of Outcome in Patients with Cirrhosis Having Endoscopic Treatment for Esophageal Varices. 査読国際誌

Naruhiro Kimura, Atsunori Tsuchiya, Chiyumi Oda, Atsushi Kimura, Kazunori Hosaka, Kentaro Tominaga, Kazunao Hayashi, Junji Yokoyama, Shuji Terai

Digestive diseases (Basel, Switzerland) 39 ( 1 ) 58 - 65 2021年

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The relationship between the amount of adipose tissue and advanced-stage liver cirrhosis with esophageal varices (EV) is unknown. We aimed to reveal the prognostic significance of adipose tissues in patients with liver cirrhosis. METHODS: We enrolled 87 patients with EV who received initial endoscopic treatment and underwent scheduled treatments in our hospital. Computed tomography (CT) images were obtained of a 5-mm slice at the umbilical level. We evaluated the effect of mortality based on the visceral adipose tissue index (VATI), subcutaneous adipose tissue index (SATI), and visceral to subcutaneous adipose tissue ratio (VSR). RESULTS: Cox hazard multivariate analysis showed that the presence of hepatocellular carcinoma (HCC; hazard ratio [HR]: 4.650, 95% confidence interval [CI]: 1.750-12.353, p = 0.002), γ-GTP (HR: 1.003, 95% CI: 1.001-1.006, p = 0.026), and VATI (HR: 1.057, 95% CI: 1.030-1.085, p < 0.001) significantly affected mortality. Cox hazard multivariate analysis for liver-related death was also significantly affected by HCC (HR: 1.057, 95% CI: 1.030-1.085, p < 0.001) and VATI (HR: 1.052, 95% CI: 1.019-1.086, p = 0.002). The difference between the Child-Pugh scores 12 months after treatment and that during initial treatment were significantly positively correlated with VATI (r = 0.326, p = 0.027). Patients with high VATI had a significantly higher frequency of HCC after EV treatment by Kaplan-Meier analysis (p = 0.044). CONCLUSION: Our findings suggest that VATI measured by CT could significantly predict mortality in cirrhosis patients through decreasing liver function and increasing HCC frequency, and appropriately controlling VATI could improve their prognosis.

DOI： 10.1159/000508867

[Problems and future questions in the clinical practice of liver cirrhosis].

Shuji Terai, Akira Sakamaki

Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology 118 ( 1 ) 41 - 45 2021年

Increase in muscle mass associated with the prebiotic effects of 1-kestose in super-elderly patients with sarcopenia.

Kentaro Tominaga, Atsunori Tsuchiya, Oki Nakano, Yasutoshi Kuroki, Kentaro Oka, Ayaka Minemura, Asami Matsumoto, Motomichi Takahashi, Yoshihiro Kadota, Takumi Tochio, Yusuke Niwa, Tomoaki Yoshida, Masatoshi Sato, Takeshi Yokoo, Satoru Hashimoto, Junji Yokoyama, Jun Matsuzawa, Katsuya Fujimori, Shuji Terai

Bioscience of microbiota, food and health 40 ( 3 ) 150 - 155 2021年

記述言語：英語掲載種別：研究論文（学術雑誌）

Sarcopenia causes functional disorders and decreases the quality of life. Thus, it has attracted substantial attention in the aging modern world. Dysbiosis of the intestinal microbiota is associated with sarcopenia; however, it remains unclear whether prebiotics change the microbiota composition and result in the subsequent recovery of muscle atrophy in elderly patients with sarcopenia. This study aimed to assess the effects of prebiotics in super-elderly patients with sarcopenia. We analyzed the effects of 1-kestose on the changes in the intestinal microbiota and body composition using a next-generation sequencer and a multi-frequency bioimpedance analysis device. The Bifidobacterium longum population was significantly increased in the intestine after 1-kestose administration. In addition, in all six patients after 12 weeks of 1-kestose administration, the skeletal muscle mass index was greater, and the body fat percentage was lower. This is the first study to show that administration of a prebiotic increased the population of B. longum in the intestinal microbiota and caused recovery of muscle atrophy in super-elderly patients with sarcopenia.

DOI： 10.12938/bmfh.2020-063

Novel Strategy for Diagnosis of Focal Nodular Hyperplasia Using Gadolinium Ethoxybenzyl Diethylenetriaminepentaacetic Acid: Enhanced Magnetic Resonance Imaging and Magnetic Resonance Elastography

Nobutaka Takeda, Atsunori Tsuchiya, Kazuki Natsui, Yui Ishii, Yoshihisa Arao, Naruhiro Kimura, Kentaro Tominaga, Suguru Takeuchi, Kazunao Hayashi, Masaaki Takamura, Shuji Terai

CASE REPORTS IN GASTROENTEROLOGY 15 ( 2 ) 507 - 512 2021年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：KARGER

Focal nodular hyperplasia (FNH) is the second most frequent benign liver tumor, and it is a fiber-rich stiff lesion. Typically, FNH can be diagnosed by imaging without biopsy. However, liver biopsy and diagnostic resection may be required to differentiate atypical FNH from other liver tumors, such as hepatocellular adenoma (HCA). Therefore, improved noninvasive diagnostic methods are needed. We experienced 2 cases where combination of magnetic resonance elastography (MRE) and gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) helped diagnose FNH. A 36-year-old woman and 17-year-old boy with liver tumors measuring 40 mm in diameter each showed hypointense nodule centers, indicating a central scar, surrounded by hyperintense signals during the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI. To rule out HCA, we performed MRE and liver biopsy. On MRE, the mean stiffness of the mass was 11.6 kPa (mean stiffness of the background liver was 1.7 kPa) and 11.1 kPa (mean stiffness of the background liver was 2.4 kPa) in the first and second patients, respectively. Histological examination of both specimens showed CK7-positive bile-ductular proliferations, abundant fibrous tissue, and few Ki-67-positive cells. Based on these results, we diagnosed these tumors as FNH. Combination of Gd-EOB-DTPA-enhanced MRI and MRE can evaluate the character and stiffness of lesion and help in the diagnosis of FNH.

DOI： 10.1159/000516552

Clinical characteristics of immunoglobulin IgG4-related sclerosing cholangitis: Comparison of cases with and without autoimmune pancreatitis in a large cohort

Naitoh, I., Kamisawa, T., Tanaka, A., Nakazawa, T., Kubota, K., Takikawa, H., Unno, M., Masamune, A., Kawa, S., Nakamura, S., Okazaki, K., Furumatsu, K., Sawai, S., Goto, T., Okumura, T., Suzuki, D., Otsuka, M., Kobori, I., Tamano, M., Koizumi, M., Hiasa, Y., Kawabe, N., Hirooka, Y., Yamamoto, S., Asano, Y., Inui, K., Horiguchi, A., Watanabe, H., Toya, D., Hatayama, K., Ueki, T., Kinoshita, N., Sugimoto, M., Ohira, H., Mukai, T., Tomita, E., Iwata, K., Shimizu, S., Suetsugu, J., Shimizu, M., Tsuji, K., Ishida, R., Ito, M., Furukawa, R., Sakamoto, N., Araki, M., Tanno, S., Sakamoto, Y., Ito, T., Takai, S., Ikeya, S., Yamada, T., Kudara, N., Shimizu, A., Hanada, K., Ichiki, Y., Kitada, H., Hifumi, M., Kimura, H., Kurosaki, M., Izumi, N., Sumi, H., Haruta, J.-I., Hayashi, K., Harada, R., Inoue, M., Nakamura, S., Ito, T., Tomishima, K., Isayama, H., Oura, K., Masaki, T., Shimokawahara, N., Tanoue, S., Maemura, K., Ido, A., Mizushima, I., Kawano, M., Yoshida, K., Naganuma, M., Murata, M., Nishio, A., Fujita, Y., Teratani, T., Matsubara, S., Tamai, H., Yoshida, Y., Azemoto, R., Kamata, K., Watanabe, T., Kurosu, T., Koizumi, W., Fujita, J., Seki, H., Ueda, Y., Fukumoto, T., Kousaki, T., Uchida, K., Ochiai, T., Kawasaki, T., Tanaka, M., Ishida, E., Notohara, K., Mori, H., Mori, T., Kawabata, H., Miyata, M., Sakagami, J., Itoh, Y., Shiokawa, M., Seno, H., Watanabe, N., Kataoka, H., Aoki, T., Fujishiro, M., Niihara, T., Nishimata, H., Mitoro, A., Yoshiji, H., Yoshida, M., Ikeda, M., Tomita, K., Hokari, R., Hayasaka, K., Amano, Y., Shioji, K., Hayashi, K., Terai, S., Nakajima, M., Yamahana, J., Matsumoto, R., Kikuchi, H., Kanamori, A., Kiriyama, S., Iwatsu, S., Kato, Y., Horiguchi, S., Yagi, T., Okada, H., Ohkawa, K., Hirao, M., Hiramatsu, N., Oza, N., Imamura, H., Baba, T., Nakano, S., Shinobi, T., Ryozawa, S., Motoya, M., Nakase, H., Kinoshita, N., Ito, K., Miyake, T., Kohge, N., Tobita, H., Joshita, S., Umemura, T., Kawaguchi, S., Ohno, K., Sonobe, K., Satoh, A., Shimosegawa, T., Miura, F., Yagi, M., Sano, K., Kin, T., Katanuma, A., Koike, K., Miura, S., Kawashima, Y., Kagawa, T., Azuma, S., Watanabe, M., Honjyo, M., Itoi, T., Honda, A., Kobayashi, K., Asano, T., Mizuno, S., Nishino, T., Taniguchi, H., Tajiri, K., Yasuda, I., Tanaka, Y., Oe, S., Harada, M., Kurata, M., Fukasawa, M., Enomoto, N., Kawaji, Y., Kitano, M., Nishise, Y., Hirakawa, H., Ishizawa, T., Ueno, Y., Kaino, M., Fujimoto, Y., Sakaida, I.

Digestive and Liver Disease 53 ( 10 ) 2021年

Liver cirrhosis with ruptured splenic artery aneurysm leading to hepatitis c treatment: A case report

Hojo, Y., Kamimura, H., Owaki, T., Kimura, R., Iwasawa, T., Watanabe, Y., Takatsuna, M., Ikarashi, S., Takamura, M., Setsu, T., Arao, Y., Horii, Y., Sato, T., Terai, S.

Kanzo/Acta Hepatologica Japonica 62 ( 11 ) 2021年

Predicting Cervical Lymph Node Metastasis Following Endoscopic Surgery in Superficial Head and Neck Carcinoma. 国際誌

Ryuichi Okabe, Yushi Ueki, Riuko Ohashi, Manabu Takeuchi, Satoru Hashimoto, Takeshi Takahashi, Ryusuke Shodo, Keisuke Yamazaki, Hiroshi Matsuyama, Hajime Umezu, Shuji Terai, Yoichi Ajioka, Arata Horii

Frontiers in surgery 8 813260 - 813260 2021年

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Early detection of head and neck carcinoma (HNC) as superficial HNC (SHNC) identified using recently developed optical techniques, such as magnifying endoscopy and narrow-band imaging (NBI), in combination with endoscopic surgeries enables minimally invasive treatment with favorable outcomes for HNC. This study aimed to identify the predictive factors for the rare but important clinical issue of SHNC, namely cervical lymph node metastasis (CLNM), following endoscopic resection. METHODS: Sixty-nine patients with SHNC who underwent endoscopic resection were enrolled in the study. Clinical data, preoperative endoscopic findings, pathological findings, and treatment outcomes were retrospectively reviewed. Because the pharyngeal mucosa lacks the muscularis mucosa, we measured tumor thickness in permanent pathology as an alternative to the depth of invasion. Correlations with the occurrence of CLNM were statistically examined. RESULTS: The 5-year disease-specific survival rate was 100%. Of 69 patients, 3 (4.3%) developed CLNM. All had subepithelial but not epithelial tumors. The 0-IIa type in the macroscopic findings, type B2/B3 vessels in narrow-band imaging, tumors ≥ pathological stage T2, lymphatic invasion, positive surgical margins, and tumor thickness >1,000 μm showed significant correlations with CLNM following endoscopic resection. Furthermore, the classification of type B vessels was significantly associated with tumor thickness. CONCLUSION: The treatment outcomes following endoscopic resection for SHNC were favorable. The risk of CLNM following endoscopic resection in SHNC can be predicted by several preoperative endoscopic and postoperative pathological findings. Among them, the classification of type B vessels, which correlated with both tumor thickness and CLNM, might be a useful predictive factor.

DOI： 10.3389/fsurg.2021.813260

Outcomes of endoscopic ultrasound-guided biliary drainage in a general hospital for patients with endoscopic retrograde cholangiopancreatography-difficult transpapillary biliary drainage

Kuraoka, N., Hashimoto, S., Matsui, S., Terai, S.

Journal of Clinical Medicine 10 ( 18 ) 2021年

Unresectable primary hepatic adenosquamous carcinoma successfully treated with systemic and transcatheter hepatic arterial injection chemotherapies followed by conversion surgery: a case report and literature review

Watanabe, Y., Osaki, A., Kimura, K., Yakubo, S., Takaku, K., Sato, M., Hashidate, H., Waguri, N., Terai, S.

BMC Gastroenterology 21 ( 1 ) 2021年

Choledochocele observed on direct peroral cholangioscopy using an ultra-slim endoscope.

Satoshi Ikarashi, Kazunao Hayashi, Shuji Terai

Journal of hepato-biliary-pancreatic sciences 2020年12月

Monitoring chronological change by liver-to-spleen attenuation ratio for secondary hepatic steatosis for a short term. 査読

Hiroteru Kamimura, Kunihiko Yokoyama, Shunsuke Nojiri, Yuko Komoro, Toshiko Murayama, Yu Koyama, Kenya Kamimura, Masaaki Takamura, Junji Yokoyama, Shuji Terai

Clinical journal of gastroenterology 13 ( 6 ) 1219 - 1224 2020年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Parenteral nutrition-associated liver disease (PNALD) causes hepatic steatosis and moderate liver enzyme elevation due to lack of enteral nutrition and deficiency of some nutrients. However, the period for recovery from PNALD after a nutritional intervention is unknown with no report. Herein, we report a case of a 44-year-old Japanese woman with severe fatty infiltration of the liver due to malnutrition. Our nutritional support team administered appropriate total parenteral, especially fat and carnitine, nutrition to improve her malnutrition. Chronological changes in liver-to-spleen attenuation ratio were also considered because of her disease state. Computed tomography demonstrated improved attenuation of the liver, and the liver enzymes level normalized after 5 weeks from appropriate nutrition. Understanding the nutritional condition of a patient may help in elucidating an appropriate treatment strategy.

DOI： 10.1007/s12328-020-01165-w

Rare case of gastric perforation due to ischemic gastropathy. 国際誌

Yui Ishii, Hiroki Sato, Shuji Terai

Gastrointestinal endoscopy 92 ( 6 ) 1266 - 1268 2020年12月

Daily Monitoring of Serum Wisteria floribunda Agglutinin-Positive Mac-2 Binding Protein Is Useful for Predicting Therapeutic Effect of Tolvaptan in Cirrhotic Ascites.

Masaaki Takamura, Akira Sakamaki, Yoshihisa Arao, Toru Setsu, Hiroteru Kamimura, Takeshi Yokoo, Kenya Kamimura, Atsunori Tsuchiya, Shuji Terai

The Tohoku journal of experimental medicine 252 ( 4 ) 287 - 296 2020年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Wisteria floribunda agglutinin (WFA) is a lectin that binds to the sugar chain of Mac-2 binding protein (M2BP), and WFA-positive M2BP (WFA+-M2BP) has been reported as a useful marker for assessing liver fibrosis in chronic liver disease. Tolvaptan (TLV), a selective vasopressin V2 receptor antagonist, is used for cirrhotic ascites in Japan, but good predictors of treatment efficacy remain to be established. Our aim was to investigate whether WFA+-M2BP monitoring before and after TLV administration can predict treatment efficacy in patients with cirrhotic ascites. Twenty patients (10 men), with a median age of 72 years, were enrolled. Cirrhosis was caused by hepatitis B virus (n = 3), hepatitis C virus (n = 4), alcohol (n = 8), and others (n = 5). Responders were defined as having a body weight loss of ≥ 1.5 kg/week after TLV administration. Serum WFA+-M2BP levels were measured at baseline and days 1, 3, and 7 after TLV treatment. Twelve patients (60%) were responders. Baseline WFA+-M2BP levels were correlated with serum albumin levels (r = -0.544, P = 0.013). The baseline furosemide dose was lower and platelet count was higher in responders than in non-responders (P < 0.05). The ratio of WFA+-M2BP levels on day 1 after TLV administration to baseline was lower in responders than in non-responders (P < 0.05). The decrease in the ratio discriminated responders from non-responders (AUC = 0.844, P < 0.05). In conclusion, monitoring serum WFA+-M2BP is helpful for predicting the efficacy of TLV treatment in patients with cirrhotic ascites.

DOI： 10.1620/tjem.252.287

アルコール性肝硬変におけるALD/NAFLD Index低値例の臨床的特徴

坂牧僚, 横山邦彦, 森田真一, 上村顕也, 高村昌昭, 寺井崇二

アルコールと医学生物学 39 96 - 97 2020年12月

急性肝炎後再生不良性貧血の1例

阿部聡司, 名古屋拓郎, 土屋淳紀, 川合弘一, 山際訓, 寺井崇二

肝臓 61 ( 12 ) 753 - 753 2020年12月

キーワード(No.39) Leaky GUT

夏井一輝, 土屋淳紀, 寺井崇二

消化器病学サイエンス 4 ( 4 ) 227 - 227 2020年12月

Usefulness of ultrasonography to assess the response to steroidal therapy for the rare case of type 2b immunoglobulin G4-related sclerosing cholangitis without pancreatitis: A case report. 国際誌

Yuto Tanaka, Kenya Kamimura, Ryota Nakamura, Marina Ohkoshi-Yamada, Yohei Koseki, Takeshi Mizusawa, Satoshi Ikarashi, Kazunao Hayashi, Hiroki Sato, Akira Sakamaki, Junji Yokoyama, Shuji Terai

World journal of clinical cases 8 ( 22 ) 5821 - 5830 2020年11月

記述言語：英語

BACKGROUND: A type 2b immunoglobulin G4 (IgG4)-related sclerosing cholangitis (SC) without autoimmune pancreatitis is a rare condition with IgG4-SC. While the variety of the imaging modalities have tested its usefulness in diagnosing the IgG4-SC, however, the usage of ultrasonography for the assessment of the response to steroidal therapy on the changes of bile duct wall thickness have not been reported in the condition. Therefore, the information of our recent case and reported cases have been summarized. CASE SUMMARY: We report the case of an 82-year-old Japanese man diagnosed with isolated IgG4-related SC based on the increase of serum IgG4, narrowing of the bile duct, its wall thickness, no complication of autoimmune pancreatitis, and IgG4 positive inflammatory cell infiltration to the wall with the fibrotic changes. The cholangiogram revealed type 2b according to the classification. Corticosteroid treatment showed a favorable effect, with the smooth decrease in serum IgG4 and the improvement of the bile duct wall thickness. CONCLUSION: As isolated type 2b, IgG4-SC is rare, the images, histological findings, and clinical course of our case will be helpful for physicians to diagnose and treat the new cases appropriately.

DOI： 10.12998/wjcc.v8.i22.5821

Stent Placement for Malignant Inferior Vena Cava Syndrome in a Patient with Recurrent Colon Cancer.

Shinichi Morita, Shunsuke Sugawara, Takeshi Suda, Didik Prasetyo, Yuka Kobayashi, Takahiro Hoshi, Satoshi Abe, Kazuyoshi Yagi, Shuji Terai

Internal medicine (Tokyo, Japan) 59 ( 22 ) 2885 - 2890 2020年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

A 70-year-old man was admitted to our hospital with gait disturbance due to marked edema of the lower limbs for more than 6 months. He had been receiving systemic chemotherapy over two years for multiple recurrence after sigmoid colon cancer resection. Contrast-enhanced computed tomography demonstrated severe inferior vena cava (IVC) stenosis due to compression by lymph node metastases, i.e. IVC syndrome. As increased doses of diuretic agents failed to improve the edema, IVC stent placement was performed. This led to significant improvement of the edema and complete gait normalization. This case demonstrates the efficacy of IVC stent placement for IVC syndrome.

DOI： 10.2169/internalmedicine.5033-20

Pancreas Gas Gangrene Caused by Klebsiella pneumoniae.

Yui Ishii, Atsunori Tsuchiya, Kazunao Hayashi, Shuji Terai

Internal medicine (Tokyo, Japan) 59 ( 22 ) 2963 - 2964 2020年11月

Esophageal High-Resolution Manometry for Diagnosing the Severity of the Chronic Intestinal Pseudo-Obstruction: A Case Series. 国際誌

Hiroki Sato, Kenya Kamimura, Hideaki Matsui, Takashi Owaki, Shinichi Morita, Yuto Tanaka, Natsuki Ishikawa, Yoshifumi Shimada, Junji Yokoyama, Toshifumi Wakai, Shuji Terai

Digestive diseases and sciences 66 ( 11 ) 3960 - 3967 2020年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Chronic intestinal pseudo-obstruction (CIPO) is a severe and refractory intestinal motility disorder. However, due to its rarity and difficult histological investigation, its pathophysiology has not been characterized. AIM: Therefore, in this study, we aimed to determine the role of esophageal high-resolution manometry (HRM) in CIPO and the histological and clinical characteristics of the disease. METHODS: Patients with CIPO were analyzed for clinical characteristics; histological findings; and clinical courses after therapeutic intervention. In addition, HRM was performed to determine the esophageal involvement. RESULTS: Eleven patients were diagnosed with CIPO, and five required the long period of parenteral nutrition showing impaired esophageal motility including achalasia and absent contractility diagnosed with HRM. The four of these five cases showed acute onset of the CIPO following the triggering events of pregnancy, appendicitis, and surgery. In contrast, other six patients with normal or Jackhammer esophagus on HRM had moderate severity of CIPO with gradual onset. The histological analyses revealed that the loss of the intestinal neural ganglion cells and layers by inflammation, destruction, and atrophy are related to the severity of the clinical course of the disease and esophageal HRM findings of achalasia and absent contractility. CONCLUSIONS: HRM may be useful to diagnose the severity of the clinical course and to determine the therapeutic options for CIPO.

DOI： 10.1007/s10620-020-06701-9

消化管疾患に対する低侵襲治療の現状と今後の展開-内科、外科の立場から- 当院における腹腔鏡・内視鏡合同手術(LECS)の現状と課題

加納陽介, 羽入隆晃, 佐藤裕樹, 水野研一, 市川寛, 石川卓, 宗岡悠介, 茂木大輔, 須藤翔, 小柳英人, 三浦宏平, 滝沢一泰, 中野雅人, 島田能史, 永橋昌幸, 坂田純, 寺井崇二, 若井俊文

日本消化器病学会甲信越支部例会抄録集 67回 69 - 69 2020年11月

Risk factors for walled-off necrosis associated with severe acute pancreatitis: A multicenter retrospective observational study.

Satoshi Ikarashi, Hirokazu Kawai, Kazunao Hayashi, Junji Kohisa, Toshifumi Sato, Yujiro Nozawa, Shinichi Morita, Hiromitsu Oka, Munehiro Sato, Yukio Aruga, Seiichi Yoshikawa, Shuji Terai

Journal of hepato-biliary-pancreatic sciences 27 ( 11 ) 887 - 895 2020年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: This study aimed to identify the risk factors for walled-off necrosis (WON) associated with severe acute pancreatitis (SAP). METHODS: This retrospective study was conducted in eight institutions in Japan between 2014 and 2017. We analyzed WON incidence, patient characteristics, and risk factors for WON in patients with SAP who were observed for >28 days. RESULTS: Of 134 patients with SAP, WON occurred in 40 (29.9%). Male sex (P = .045), body mass index (BMI) ≥25 (P < .001), post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (P = .020), and disseminated intravascular coagulation (DIC) (P = .001) were more frequent in the WON group than in the non-WON group. On admission, the frequency of white blood cell counts ≥ 12 000/µL (P = .037) and hypoenhanced pancreatic lesion on computed tomography (P = .047) were significantly higher in the WON group. In multivariate analysis, BMI ≥ 25 (odds ratio [OR] 5.73, 95% confidence interval [CI] 1.95-16.8; P = .002), post-ERCP (OR 8.08, 95% CI 1.57-41.7; P = .013), and DIC (OR 3.52, 95% CI 1.20-10.4; P = .022) were independent risk factors for WON. CONCLUSIONS: High BMI, post-ERCP pancreatitis, and DIC are risk factors for the development of WON associated with SAP.

DOI： 10.1002/jhbp.787

ステロイド治療前後で肝硬度と病理像を評価し得た肝サルコイドーシスの一例

水戸將貴, 荒生祥尚, 夏井一輝, 前田悠一郎, 小島雄一, 林和直, 土屋敦紀, 梅津哉, 寺井崇二

日本消化器病学会甲信越支部例会抄録集 67回 95 - 95 2020年11月

被包化膵壊死への真菌感染による敗血症性ショックをきたした一例

山田麻理奈[大越], 上村顕也, 石川夏生, 小関洋平, 田中裕登, 水澤健, 佐藤裕樹, 五十嵐聡, 林和直, 坂牧僚, 横山純二, 寺井崇二

日本消化器病学会甲信越支部例会抄録集 67回 26 - 26 2020年11月

良悪性鑑別困難な胆膵疾患の診断と治療の最前線-内科、外科の立場から- 自己免疫性膵炎と膵癌との鑑別の現状と課題

小川光平, 林和直, 五十嵐聡, 寺井崇二

日本消化器病学会甲信越支部例会抄録集 67回 32 - 32 2020年11月

急性腹症を契機にC型慢性肝炎が発見された1例

北條雄暉, 上村博輝, 木村莉菓, 大脇崇史, 岩澤貴宏, 渡邉雄介, 高綱将史, 荒生祥尚, 薛徹, 五十嵐聡, 高村昌昭, 寺井崇二

日本消化器病学会甲信越支部例会抄録集 67回 96 - 96 2020年11月

ウイルス肝炎診療:新旧の課題と解決への戦略当院・関連施設におけるソホスブビル/ベルパタスビル11症例での治療効果と安全性の検討

荒生祥尚, 薛徹, 寺井崇二

肝臓 61 ( Suppl.3 ) A775 - A775 2020年11月

よりよい肝移植医療のあり方を探る当県での移植へのゲートウェイとしてのネットワークシステムの取り組み

薛徹, 高村昌昭, 寺井崇二

肝臓 61 ( Suppl.3 ) A800 - A800 2020年11月

肝疾患に対するPrecision Medicineの実現可能性を探る:新規バイオマーカーを含めて肝障害の程度、機能回復の指標としての血中セロトニンの検証

薛徹, 上村顕也, 寺井崇二

肝臓 61 ( Suppl.3 ) A832 - A832 2020年11月

短期間に急速な肝脂肪沈着と栄養・運動介入による肝機能の改善を確認できたアスリートの一例

上村博輝, 木村莉菓, 北條雄暉, 渡邊雄介, 高綱将史, 五十嵐聡, 佐野正和, 真田奈緒, 武田安永, 小師優子, 高村昌昭, 寺井崇二

日本消化器病学会甲信越支部例会抄録集 67回 97 - 97 2020年11月

令和の時代に求められる肝硬変の多角的治療戦略十全大補湯と間葉系幹細胞の併用療法はCC14投与肝硬変モデルマウスにおいて効果的な抗炎症・抗線維化効果を及ぼす

野尻俊介, 土屋淳紀, 寺井崇二

肝臓 61 ( Suppl.3 ) A853 - A853 2020年11月

臨床応用を見据えた肝の臓器再生研究の展望肝硬変に対する間葉系細胞治療とそのエクソソーム治療の可能性

土屋淳紀, 竹内卓, 寺井崇二

肝臓 61 ( Suppl.3 ) A827 - A827 2020年11月

【肝硬変診療の新時代】肝再生治療開発の現況

竹内卓, 渡邉雄介, 土屋淳紀, 寺井崇二

臨床消化器内科 35 ( 13 ) 1601 - 1605 2020年11月

記述言語：日本語出版者・発行元：(株)日本メディカルセンター

＜文献概要＞近年開発された抗ウイルス薬によりウイルス性肝炎の治療法は確立されつつあるが,依然として肝硬変患者は世界中に多く存在している.肝硬変に対する根治治療は肝移植が唯一の治療法であるが,実施できるのは一部の患者に限られるため再生医療による低侵襲な新規治療法が嘱望されている.ここ数年で肝臓の分野で再生医療は著しく進歩しており,今回はおもに最近の研究成果を中心に細胞や細胞外小胞による有望な肝再生治療の現状について述べる.これらの研究は使用する細胞や小胞の安全性の確保,大量生産における均一性や品質保持など一般化に向けてクリアすべき課題も存在するが,新たな肝再生治療開発に向けて努力を継続していく必要がある.

Shear wave elastographyを用いたNAFLDにおける肝線維化の左右差の検討

横尾健, 杉田萌乃, 荒生祥尚, 薛徹, 上村博輝, 坂牧僚, 上村顕也, 土屋淳紀, 高村昌昭, 寺井崇二

超音波医学 47 ( Suppl. ) S349 - S349 2020年11月

脂肪性肝疾患:治療のターゲットとゴール脂肪性疾患の病態進行と自律神経ネットワークを介する臓器連関の関与

上村顕也, 大脇崇史, 寺井崇二

肝臓 61 ( Suppl.3 ) A758 - A758 2020年11月

進行肝細胞癌に対する集学的治療:エビデンスとコンセンサス肝癌に対する放射線治療の安全性と有用性の検討

上村顕也, 大越麻理奈, 寺井崇二

肝臓 61 ( Suppl.3 ) A811 - A811 2020年11月

MC4R遺伝子及びMaid遺伝子両欠損マウスを用いた新規脂肪肝モデルマウスの検討

森田真一, 坂牧僚, 永山逸夫, 大越麻理奈, 小山究太郎, 田中裕登, 大脇崇史, 小田知友美, 柴田理, 木村淳史, 阿部寛幸, 上村顕也, 寺井崇二

肝臓 61 ( Suppl.3 ) A876 - A876 2020年11月

Efficacy and Safety of the Radiotherapy for Liver Cancer: Assessment of Local Controllability and its Role in Multidisciplinary Therapy. 国際誌

Marina Ohkoshi-Yamada, Kenya Kamimura, Osamu Shibata, Shinichi Morita, Motoki Kaidu, Toshimichi Nakano, Katsuya Maruyama, Atsushi Ota, Hirotake Saito, Nobuko Yamana, Tomoya Oshikane, Yukiyo Goto, Natsumi Yoshimura, Satoshi Tanabe, Hisashi Nakano, Madoka Sakai, Yuto Tanaka, Yohei Koseki, Yoshihisa Arao, Hiroyuki Abe, Toru Setsu, Akira Sakamaki, Takeshi Yokoo, Hiroteru Kamimura, Hidefumi Aoyama, Shuji Terai

Cancers 12 ( 10 ) 2020年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

This study investigated the efficacy and safety of radiotherapy as part of multidisciplinary therapy for advanced hepatocellular carcinoma (HCC). Clinical data of 49 HCC patients treated with radiotherapy were assessed retrospectively. The efficacy of radiotherapy was assessed by progression-free survival, disease control rate, and overall survival. Safety was assessed by symptoms and hematological assay, and changes in hepatic reserve function were determined by Child-Pugh score and albumin-bilirubin (ALBI) score. Forty patients underwent curative radiotherapy, and nine patients with portal vein tumor thrombus (PVTT) underwent palliative radiotherapy as part of multidisciplinary therapy. Local disease control for curative therapy was 80.0% and stereotactic body radiotherapy was 86.7% which was greater than that of conventional radiotherapy (60.0%). Patients with PVTT had a median observation period of 651 days and 75% three-year survival when treated with multitherapy, including radiotherapy for palliative intent, transcatheter arterial chemoembolization, and administration of molecular targeted agents. No adverse events higher than grade 3 and no changes in the Child-Pugh score and ALBI score were seen. Radiotherapy is safe and effective for HCC treatment and can be a part of multidisciplinary therapy.

DOI： 10.3390/cancers12102955

Blocking sphingosine 1-phosphate receptor 2 accelerates hepatocellular carcinoma progression in a mouse model of NASH. 査読国際誌

Tomoaki Yoshida, Atsunori Tsuchiya, Masaru Kumagai, Suguru Takeuchi, Shunsuke Nojiri, Takayuki Watanabe, Masahiro Ogawa, Michiko Itoh, Masaaki Takamura, Takayoshi Suganami, Yoshihiro Ogawa, Shuji Terai

Biochemical and biophysical research communications 530 ( 4 ) 665 - 672 2020年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

The role of sphingosine 1-phosphate (S1P) and its sphingosine-1-phosphate receptors (S1PRs) in non-alcoholic steatohepatitis (NASH) is unclear. We aimed to analyze the role of S1P/S1PRs in a Melanocortin-4 receptor (Mc4r)-deficient NASH murine model using FTY720, the functional antagonist of S1PR1, S1PR3, S1PR4, and S1PR5, and JTE-013, the antagonist of S1PR2. We observed that, compared to that in the control, the mRNA of S1pr1 tended to decrease, whereas those of S1pr2 and S1pr3 significantly increased in Mc4r-knockout (KO) mice subjected to a Western diet (WD). While the fat area did not differ, fibrosis progression differed significantly between control mice and mice in which liver S1PRs were blocked. Lipidomic and metabolomic analysis of liver tissues showed that JTE-013-administered mice showed elevation of S-adenosyl-l-methionine level, which can induce aberrant methylation due to reduction in glycine N-methyltransferase (GNMT) and elevation in diacylglycerol (DG) and triacylglycerol (TG) levels, leading to increased susceptibility to hepatocellular carcinoma (HCC). These phenotypes are similar to those of Gnmt-KO mice, suggesting that blocking the S1P/S1PR2 axis triggers aberrant methylation, which may increase DG and TG, and hepatocarcinogenesis. Our observations that the S1P/S1PR2 axis averts HCC occurrence may assist in HCC prevention in NASH.

DOI： 10.1016/j.bbrc.2020.07.099

Screening and follow-up of chronic liver diseases with understanding their etiology in clinics and hospitals. 国際誌

Masahiro Ogawa, Atsunori Tsuchiya, Takayuki Watanabe, Toru Setsu, Naruhiro Kimura, Masato Matsuda, Yoshiki Hoshiyama, Hiroaki Saito, Tsutomu Kanazawa, Motoi Shiotani, Tatsuhiko Sato, Takuya Yagi, Koji Igarashi, Norihiko Yoshimura, Masaaki Takamura, Hidefumi Aoyama, Shuji Terai

JGH open : an open access journal of gastroenterology and hepatology 4 ( 5 ) 827 - 837 2020年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Background and Aim: Considering the increasing prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH), the development of an effective screening and follow-up system that enables the recognition of etiological changes by primary physicians in clinics and specialists in hospitals is required. Methods: Chronic hepatitis B (HBV) and C (HCV), NASH, and alcoholic steatohepatitis (ASH) patients who were assayed for Mac-2-binding protein glycosylation isomer (M2BPGi) (n = 272) and underwent magnetic resonance elastography (MRE) (n = 119) were enrolled. Patients who underwent MRE were also tested by ultrasound elastography (USE) (n = 80) and for M2BPGi (n = 97), autotaxin (ATX) (n = 62), and platelet count (n = 119), and their fibrosis-4 (FIB-4) index was calculated (n = 119). Results: FIB-4 index >2, excluding HBV-infected patients, M2BPGi >0.5, ATX >0.5, and platelet count <20 × 104/μL were the benchmark indices, and we took into consideration other risk factors, such as diabetes mellitus and age, to recommend further examinations, such as USE, based on the local situation to avoid overlooking hepatocellular carcinoma (HCC) in the clinic. During specialty care in the hospital, MRE exhibited high diagnostic ability for fibrosis stages >F3 or F4; it could efficiently predict collateral circulation with high sensitivity, which can replace USE. We also identified etiological features and found that collateral circulation in NASH/ASH patients tended to exceed high-risk levels; moreover, these patients exhibited more variation in HCC-associated liver stiffness than the HBV and HCV patients. Conclusions: Using appropriate markers and tools, we can establish a stepwise, practical, noninvasive, and etiology-based screening and follow-up system in primary and specialty care.

DOI： 10.1002/jgh3.12406

Refractory hemorrhagic esophageal ulcers by Candida esophagitis with advanced systemic sclerosis. 国際誌

Kazuki Natsui, Atsunori Tsuchiya, Shuji Terai

JGH open : an open access journal of gastroenterology and hepatology 4 ( 5 ) 1007 - 1008 2020年10月

記述言語：英語

A 64-year-old woman diagnosed with rheumatoid arthritis (RA) and systemic sclerosis (SSc) was admitted to our hospital with chief complaints of uncontrolled bleeding from esophageal ulcers and an inability to consume meals. For RA and SSc, she was treated with prednisolone and abatacept and was taking vonoprazan as prophylaxis for steroid-induced gastric ulcers. She was diagnosed with severe Candida esophagitis, with multiple large and small ulcers with bleeding, based on esophagogastroduodenoscopy and pathological findings. We performed comprehensive treatment; abatacept was discontinued, and total parenteral nutrition was initiated along with antifungal therapy. Improvement in the esophageal ulcers was observed. Although severe Candida esophagitis is a rare condition, we should keep in mind that severe Candida esophagitis can occur in patients with an immunosuppressive compromised host and esophageal movement disorders such as SSc. Regular follow up by endoscopy and prophylactic treatment to prevent severe esophagitis may be necessary.

DOI： 10.1002/jgh3.12353

重症急性膵炎後Walled-off necrosisの内視鏡治療におけるLumen apposing metal stentの有効性

五十嵐聡, 林和直, 寺井崇二

Gastroenterological Endoscopy 62 ( Suppl.2 ) 2162 - 2162 2020年10月

急性膵炎およびその合併症治療の最前線新潟県における重症急性膵炎の予後改善を目指して Niigata SAP network

林和直, 五十嵐聡, 寺井崇二

日本消化器病学会雑誌 117 ( 臨増大会 ) A624 - A624 2020年10月

【肝硬変のトータルマネジメント】肝腎症候群に対する治療海外での動向

坂牧僚, 薛徹, 阿部寛幸, 上村顕也, 高村昌昭, 寺井崇二

肝臓クリニカルアップデート 6 ( 2 ) 205 - 211 2020年10月

記述言語：日本語出版者・発行元：医学図書出版(株)

肝腎症候群は肝硬変や末期肝疾患患者に発症した可逆的な腎機能障害である。薬物治療の基本は、アルブミン製剤投与下に血管収縮薬を投与することであり、欧米ではテルリプレシンが最も一般的に使用されている。また、経頸静脈的肝内門脈大循環短絡術や血液透析も考慮されるが、肝移植が根治的な治療として位置付けられている。治療方針の決定においては、個々の症例の状況を慎重に検討のうえ、最新のガイドラインなどを参考にしつつ行う必要がある。(著者抄録)

食道・胃静脈瘤治療の現状と今後の展望門亢症の病態から考えたEIS/EVLの長期予後

薛徹, 横山純二, 寺井崇二

日本門脈圧亢進症学会雑誌 26 ( 3 ) 68 - 68 2020年10月

Translational researchを目指した下部消化管研究炎症性腸疾患に対する間葉系幹細胞(MSC)、エクソソーム療法の可能性の検討

川田雄三, 土屋淳紀, 寺井崇二

日本消化器病学会雑誌 117 ( 臨増大会 ) A602 - A602 2020年10月

再生医療はどこまで進んだか(vol.17) 間葉系幹細胞投与による肝線維化改善、再生誘導効果基礎研究成果の臨床応用

寺井崇二, 土屋淳紀

医学のあゆみ 275 ( 4 ) 367 - 370 2020年10月

記述言語：日本語出版者・発行元：医歯薬出版(株)

肝臓は再生する臓器として知られているが、持続的な炎症の結果、肝細胞障害、それに伴う線維化形成で、再生力が低下した肝硬変に至る。2003年より、肝硬変症に対する自己骨髄細胞の臨床研究を開始、その後局所麻酔で少量の骨髄液を回収し間葉系幹細胞に培養し投与する方法を開発した。さらに、より多くの患者に対し治療を実行するため"他家脂肪組織由来間葉系幹細胞投与療法"の治験を行ってきた。臨床研究からは、肝線維化改善に伴う肝再生の誘導が肝機能の改善に重要であることが臨床的に明らかになった。一方で、なぜ骨髄細胞は肝硬変に効果があるのか?という疑問に関しての基礎研究は、2000年代の技術を用いた解析では、骨髄由来細胞が肝硬変部にいきコラゲナーゼなどを出すことで線維化改善、再生誘導するという結果であった。しかし現在の二光子励起顕微鏡などを用いた解析では、投与した間葉系幹細胞は主に肺に遊走され、そこで"指揮細胞"としてエクソソームを出すことで硬変部に実働細胞として働くマクロファージなどの細胞に影響を与えて、抗炎症性マクロファージに極性変化を促したり遊走させたりして組織修復に関わっている可能性が出てきた。今になってあらためて過去のデータを見直すと、全骨髄細胞を投与した場合、肝硬変部の肝臓に定着していた細胞は主にマクロファージであった。基礎、臨床研究・治験を推進してきた現在までの結果について総括する。(著者抄録)

その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J00060&link_issn=&doc_id=20201023020012&doc_link_id=%2Faa7ayuma%2F2020%2F027504%2F013%2F0367-0370%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faa7ayuma%2F2020%2F027504%2F013%2F0367-0370%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

肝性脳症〜わが国における現状と課題〜潜在性肝性脳症患者における呼気中水素・メタン分析の有用性の検討

坂牧僚, 横山邦彦, 小山究太郎, 森田真一, 阿部寛幸, 上村顕也, 高村昌昭, 横山純二, 寺井崇二

日本門脈圧亢進症学会雑誌 26 ( 3 ) 76 - 76 2020年10月

急性膵炎およびその合併症治療の最前線新潟県における重症急性膵炎の予後改善を目指して Niigata SAP network

林和直, 五十嵐聡, 寺井崇二

日本消化器病学会雑誌 117 ( 臨増大会 ) A624 - A624 2020年10月

Synchronous Double Bile Duct Cancers with Distinct Genetic Features.

Shinichi Morita, Takeshi Suda, Yoji Kishi, Toshimitsu Iwasaki, Nobuyoshi Hiraoka, Itsuo Nagayama, Takahiro Hoshi, Satoshi Abe, Kazuyoshi Yagi, Go Hasegawa, Toshihiko Ikarashi, Shuji Terai

Internal medicine (Tokyo, Japan) 59 ( 17 ) 2129 - 2134 2020年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

A 69-year-old man was referred to our hospital because of appetite loss. Imaging showed a nodular tumor in the perihilar bile duct and a second flat lesion in the distal bile duct. Right hepatopancreaticoduodenectomy was performed, and the histopathological findings demonstrated that the perihilar and distal lesions were moderately and poorly differentiated adenocarcinoma, respectively, and anatomically separated. Furthermore, the resected specimens showed no pancreaticobiliary maljunction. Histological and TP53 gene analyses in a rare case of synchronous double bile duct cancers suggest that there are various genetic pathways through which bile duct cancer develops, highlighting the complexity of its pathogenesis.

DOI： 10.2169/internalmedicine.4613-20

Transcriptomic Dissection of Hepatocyte Heterogeneity: Linking Ploidy, Zonation, and Stem/Progenitor Cell Characteristics 査読

Takeshi Katsuda, Kazunori Hosaka, Juntaro Matsuzaki, Wataru Usuba, Marta Prieto-Vila, Tomoko Yamaguchi, Atsunori Tsuchiya, Shuji Terai, Takahiro Ochiya

Cellular and Molecular Gastroenterology and Hepatology 9 ( 1 ) 161 - 183 2020年9月

2D-Shear Wave ElastographyとTransient Elastographyの乖離症例の特徴

杉田萌乃, 横尾健, 荒生祥尚, 薛徹, 上村博輝, 坂牧僚, 上村顕也, 土屋淳紀, 高村昌昭, 寺井崇二

肝臓 61 ( Suppl.2 ) A695 - A695 2020年9月

健診受検者における年齢層別NAFLDの解析と高齢者の意識変化

横尾健, 佐藤公俊, 丹羽佑輔, 荒生祥尚, 薛徹, 上村博輝, 坂牧僚, 上村顕也, 土屋淳紀, 高村昌昭, 寺井崇二

肝臓 61 ( Suppl.2 ) A671 - A671 2020年9月

mALBI score/gradeからみたNASH薬物治療に対する肝予備能への影響

高村昌昭, 横尾健, 荒生祥尚, 薛徹, 上村博輝, 坂牧僚, 上村顕也, 土屋淳紀, 寺井崇二

肝臓 61 ( Suppl.2 ) A691 - A691 2020年9月

2D-Shear Wave ElastographyとTransient Elastographyの乖離症例の特徴

杉田萌乃, 横尾健, 荒生祥尚, 薛徹, 上村博輝, 坂牧僚, 上村顕也, 土屋淳紀, 高村昌昭, 寺井崇二

肝臓 61 ( Suppl.2 ) A695 - A695 2020年9月

mALBI score/gradeからみたNASH薬物治療に対する肝予備能への影響

高村昌昭, 横尾健, 荒生祥尚, 薛徹, 上村博輝, 坂牧僚, 上村顕也, 土屋淳紀, 寺井崇二

肝臓 61 ( Suppl.2 ) A691 - A691 2020年9月

健診受検者における年齢層別NAFLDの解析と高齢者の意識変化

横尾健, 佐藤公俊, 丹羽佑輔, 荒生祥尚, 薛徹, 上村博輝, 坂牧僚, 上村顕也, 土屋淳紀, 高村昌昭, 寺井崇二

肝臓 61 ( Suppl.2 ) A671 - A671 2020年9月

消化器疾患に対する再生医療の応用間葉系幹細胞の治療効果メカニズム検証に基づく肝硬変に対するより効果的な治療法開発

土屋淳紀, 高村昌昭, 寺井崇二

肝臓 61 ( Suppl.2 ) A583 - A583 2020年9月

Effectiveness of Endoscopic Pancreatic Stenting for Pancreatic Pseudocyst-Portal Vein Fistula

Atsushi Kimura, Kazunao Hayashi, Chiyumi Oda, Kazunori Hosaka, Naruhiro Kimura, Kentaro Tominaga, Satoshi Ikarashi, Atsunori Tsuchiya, Shuji Terai

CASE REPORTS IN GASTROENTEROLOGY 14 ( 3 ) 570 - 576 2020年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：KARGER

Pancreatic pseudocyst-portal vein (PP-PV) fistula, mostly occurring after pseudocyst formation following acute/chronic pancreatitis, is a rare but life-threatening condition. The majority of treatments are based on conservative or surgical interventions. We report the case of a 70-year-old man with a PP-PV fistula and PV thrombosis. We adopted conservative treatment at first due to his mild symptoms. However, after resuming food intake, the patient had severe abdominal pain. Following endoscopic retrograde cholangiopancreatography, we found that the pseudocyst was connected with the PV through the fistula. Subsequently, an endoscopic nasopancreatic drainage (ENPD) catheter was inserted into the main pancreatic duct to establish pancreatic drainage, which resulted in a decrease in the abdominal pain. After the ENPD tube had been exchanged for endoscopic pancreatic stenting, his abdominal pain did not recur. Therefore, this case demonstrated endoscopic treatment as an effective treatment option for PP-PV fistula.

DOI： 10.1159/000510331

脂肪性肝疾患における自律神経系ネットワークを介したセロトニンの関与

大脇崇史, 上村顕也, 高昌良, 名古屋拓郎, 永山逸夫, 大越麻理奈, 薛徹, 寺井崇二

肝臓 61 ( Suppl.2 ) A670 - A670 2020年9月

肝臓を基軸とした臓器連関肝臓を基軸とし自律神経系経路を介する多臓器連関の肝病態への関与の解明

上村顕也, 大脇崇史, 寺井崇二

肝臓 61 ( Suppl.2 ) A613 - A613 2020年9月

Portal Vein Thrombosis Associated with Trousseau Syndrome due to Urinary Bladder Squamous Cell Carcinoma in a Liver Cirrhosis Patient. 査読

Naruhiro Kimura, Atsunori Tsuchiya, Chiyumi Oda, Atsushi Kimura, Kazunori Hosaka, Kentaro Tominaga, Kazunao Hayashi, Tatsuya Abé, Hajime Umezu, Shuji Terai

Internal medicine (Tokyo, Japan) 59 ( 16 ) 1971 - 1975 2020年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

A 75-year-old woman with liver cirrhosis was admitted for treatment of portal vein thrombosis (PVT). Computed tomography (CT) showed PVT, massive ascites, and multiple abdominal organ embolism. Blood tests revealed a decreased liver function (Child-Pugh grade C). Language impairment followed by progressive left hemi-paralysis was subsequently detected. Magnetic resonance imaging revealed multiple small acute cerebral infarctions and, on CT, a 30-mm bladder tumour; a biopsy specimen examination showed squamous cell carcinoma. Her general condition worsened rapidly, and the best supportive care was chosen. Our findings suggest that, in patients with PVT, Trousseau syndrome should be considered, even in cases of liver cirrhosis.

DOI： 10.2169/internalmedicine.4112-19

Esophageal Ulcers Associated with Ulcerative Colitis: A Case Series and Literature Review. 査読

Kentaro Tominaga, Atsunori Tsuchiya, Hiroki Sato, Takeshi Mizusawa, Shinichi Morita, Yui Ishii, Nobutaka Takeda, Kazuki Natsui, Yuzo Kawata, Naruhiro Kimura, Yoshihisa Arao, Kazuya Takahashi, Kazunao Hayashi, Junji Yokoyama, Shuji Terai

Internal medicine (Tokyo, Japan) 59 ( 16 ) 1983 - 1989 2020年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Ulcerative colitis, a chronic and recurrent inflammatory disease, is localized to the colonic mucosa but can affect other organs and lead to various complications. Gastroduodenitis associated with ulcerative colitis has been reported. However, little is known about esophageal ulcers. We herein report two rare cases of esophageal ulcers associated with ulcerative colitis. Furthermore, the clinical and histological characteristics of 18 previously reported cases are summarized. This case series and literature review will encourage the accurate diagnosis and treatment of esophageal ulcers associated with ulcerative colitis.

DOI： 10.2169/internalmedicine.4437-20

Advanced squamous cell carcinoma in an asymptomatic, large, epiphrenic esophageal diverticulum.

Tomoaki Yoshida, Satoru Hashimoto, Ken-Ichi Mizuno, Hiroshi Ichikawa, Junji Yokoyama, Hajime Umezu, Shuji Terai

Clinical journal of gastroenterology 13 ( 4 ) 477 - 482 2020年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

An asymptomatic epiphrenic diverticulum (ED) was diagnosed in a man undergoing annual esophagogastroduodenoscopy (EGD) at another hospital 40 years before he presented to our hospital at age 63 years for his annual EGD. However, because substantial food retention was found in the ED, we could not confirm a lesion. After the retained food was removed endoscopically, a second EGD showed a reddish, flat lesion with an elevated mass within the ED. Endoscopic ultrasonography indicated that the elevated mass was deep in the submucosal layer. An esophagram showed that the ED was approximately 80 mm in diameter, which is considered large. An endoscopic biopsy of the lesion confirmed squamous cell carcinoma. Total esophagectomy was performed. Microscopic examination revealed well-differentiated to moderately differentiated squamous cell carcinoma invading the adventitia at the elevated lesion. The final pathological stage was pT3N0M0. There was no evidence of recurrence for 3 years during the quarterly follow-up examinations. To our knowledge, this case involved the longest asymptomatic term (40 years) since the ED was detected. A review of 18 reported cases of carcinoma in an ED indicated that advanced cancer has a poor prognosis. Periodic follow-up of ED patients is essential for early diagnosis.

DOI： 10.1007/s12328-020-01098-4

Real-world effectiveness and safety of tolvaptan in liver cirrhosis patients with hepatic edema: results from a post-marketing surveillance study (START study).

Isao Sakaida, Shuji Terai, Masayuki Kurosaki, Mitsuru Okada, Takahiro Hirano, Yasuhiko Fukuta

Journal of gastroenterology 55 ( 8 ) 800 - 810 2020年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: This large-scale post-marketing surveillance study (START study) evaluated the effectiveness and safety of tolvaptan in Japanese liver cirrhosis patients with hepatic edema in real-world clinical settings. Here, we present the final analysis outcomes. METHODS: A prospective, multicenter, non-interventional study involving patients who received tolvaptan for the treatment of liver cirrhosis with hepatic edema with an insufficient response to conventional diuretics. The observation period was up to 6 months. Effectiveness evaluation included changes in body weight and clinical symptoms. Safety analysis included evaluation of adverse drug reactions (ADRs). RESULTS: Case reports of 1111 patients were collected. Of these, 1109 were included in the safety analysis and 1098 in the effectiveness analysis. The mean age was 69.4 ± 11.5 years and 695 (62.7%) patients were male. After tolvaptan treatment, a decrease in body weight from baseline was - 2.6 ± 2.7 kg on day 7 and - 3.8 ± 4.1 kg on day 14. Moreover, clinical symptoms significantly improved over the 14-day treatment. Frequently reported ADRs were thirst (6.6%), hepatic encephalopathy (2.3%), dehydration (1.5%), and hypernatremia (1.2%). A serum sodium level of ≥ 150 mEq/L was reported in five patients (0.5%). Multivariate analyses showed that the baseline blood urea nitrogen (BUN) level (cut-off value: 22.4 mg/dL) was the predictive factor for tolvaptan treatment response. CONCLUSIONS: The results suggest that tolvaptan was effective and well-tolerated in liver cirrhosis patients with hepatic edema. In the real-world clinical setting, tolvaptan provides a useful option for the treatment of hepatic edema.

DOI： 10.1007/s00535-020-01691-x

側方発育型大腸腫瘍と肥満ならびに代謝指数に関する検討

高綱将史, 水野研一, 川田雄三, 冨永顕太郎, 水澤健, 佐藤裕樹, 五十嵐聡, 林和直, 横山純二, 橋本哲, 寺井崇二

Gastroenterological Endoscopy 62 ( Suppl.1 ) 1332 - 1332 2020年8月

【線維化慢性疾患のキープロセス多彩な間質細胞が織りなす組織リモデリング"fibrosis"の理解】(第3章)各臓器疾患における線維化間葉系幹細胞投与による肝線維化改善、再生誘導効果

寺井崇二, 土屋淳紀

実験医学 38 ( 12 ) 2059 - 2062 2020年8月

記述言語：日本語出版者・発行元：(株)羊土社

われわれは2003年より、肝硬変症に対する自己骨髄細胞の臨床研究を開始、その後局所麻酔で少量の骨髄液を回収し間葉系幹細胞に培養し投与する方法を開発した。さらに、より多くの患者に対し治療を実行するため"他家脂肪組織由来間葉系幹細胞投与療法"の治験を行ってきた。一方で、なぜ骨髄細胞は肝硬変に効果があるか?についての基礎研究は、現在の二光子励起顕微鏡等を用いた解析では、投与した間葉系幹細胞は主に肺に遊走され、そこで"指揮細胞"としてエクソソームを出すことで、硬変部に、実働細胞としてマクロファージ等の細胞を遊走させ、マクロファージがM2表現型になることで線維化改善、さらにオンコスタチンMあるいはVEGF等を出すことで、肝線維化改善、再生誘導することが明らかになった。今になってあらためて過去のデータを見直すと、肝臓に定着していた細胞は主にマクロファージであった。基礎、臨床研究・治験を推進してきた現在までの結果について総括する。(著者抄録)

当院におけるクローン病の患者に対する内視鏡的小腸結腸拡張術の臨床的検討

富吉圭, 川田雄三, 冨永顕太郎, 橋本哲, 横山純二, 寺井崇二

Gastroenterological Endoscopy 62 ( Suppl.1 ) 1332 - 1332 2020年8月

Changes in Magnetic Resonance Imaging Findings in a Malignant Melanoma Patient.

Toru Setsu, Atsunori Tsuchiya, Shuji Terai

Internal medicine (Tokyo, Japan) 59 ( 13 ) 1671 - 1672 2020年7月

三次リンパ組織の臓器普遍性の解明

鳥生直哉, 佐藤有紀, 上村博輝, 田中真生, 寺井崇二, 柳田素子

日本腎臓学会誌 62 ( 4 ) 262 - 262 2020年7月

Rare case of circumferential esophageal peeling. 査読国際誌

Kentaro Tominaga, Atsunori Tsuchiya, Hiroki Sato, Yui Ishii, Nobutaka Takeda, Kazuki Natsui, Yuzo Kawata, Naruhiro Kimura, Yoshihisa Arao, Suguru Takeuchi, Kazunao Hayashi, Junji Yokoyama, Shuji Terai

Clinical case reports 8 ( 7 ) 1306 - 1308 2020年7月

Outcomes of EUS-guided choledochoduodenostomy as primary drainage for distal biliary obstruction with covered self-expandable metallic stents. 国際誌

Naosuke Kuraoka, Kazuo Hara, Nozomi Okuno, Takamichi Kuwahara, Nobumasa Mizuno, Yasuhiro Shimizu, Yasumasa Niwa, Shuji Terai

Endoscopy international open 8 ( 7 ) E861-E868 2020年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Background and study aims Endoscopic ultrasonography-guided choledochoduodenostomy (EUS-CDS) is an alternative therapy for percutaneous transhepatic biliary drainage. Outcomes of EUS-CDS for distal biliary tract obstruction with a covered self-expandable metallic stent (SEMS) as a primary drainage technique are unclear because there are few relevant reports. This study aimed to determine outcomes in patients undergoing EUS-CDS using SEMS as the primary drainage technique for malignant distal biliary duct obstruction. Patients and methods This retrospective study was conducted at Aichi Cancer Center Hospital, from January 2010 to July 2018, using data from our database. Results EUS-CDS was performed as a primary drainage technique for 92 patients. The technical success rate was 92.8 %, and the clinical success rate was 91.6 %. The overall incidence of adverse events was 15.7 %. The median stent patency time for the EUS-CDS was 396 days. Nineteen patients required re-intervention because of cholangitis or jaundice. Conclusion EUS-CDS as a primary drainage technique using SEMS has high technical and clinical success rates. It should be considered an effective drainage method with respect to long-term stent patency, low re-intervention rates, and absence of severe complications.

DOI： 10.1055/a-1161-8488

三次リンパ組織の臓器普遍性の解明

鳥生直哉, 佐藤有紀, 上村博輝, 田中真生, 寺井崇二, 柳田素子

日本腎臓学会誌 62 ( 4 ) 262 - 262 2020年7月

当院における心疾患に合併する遠隔期肝合併症における右心負荷系因子の重要性

上村博輝, 高村昌昭, 寺井崇二

日本消化器病学会雑誌 117 ( 臨増総会 ) A252 - A252 2020年7月

EUS-FNAが術前診断に有用であった十二指腸Brunner腺過誤腫出血の1切除例

荒生祥尚, 小林正明, 池見雅俊, 塩路和彦, 清野智, 阿部寛幸, 岩城孝和, 田口貴博, 谷優佑, 寺井崇二

Gastroenterological Endoscopy 62 ( 7 ) 778 - 784 2020年7月

肝胆膵疾患における血清DPPIV解析

林和直, 五十嵐聡, 土屋淳紀, 寺井崇二

日本消化器病学会雑誌 117 ( 臨増総会 ) A387 - A387 2020年7月

オステオポンチン・脂肪酸・高トリグリセライド血症による膵癌高リスク患者の同定

五十嵐聡, 林和直, 寺井崇二

膵臓 35 ( 3 ) A305 - A305 2020年7月

膵癌早期発見を目指した新潟県膵癌ネットワーク(Phoenix Study)の構築と膵癌病態解析に関する多施設後方視的観察研究

五十嵐聡, 林和直, 寺井崇二

日本消化器病学会雑誌 117 ( 臨増総会 ) A258 - A258 2020年7月

当院におけるIgG4関連硬化性胆管炎の診断の現状と課題

田中裕登, 林和直, 五十嵐聡, 寺井崇二

日本消化器病学会雑誌 117 ( 臨増総会 ) A298 - A298 2020年7月

EUS-FNAが術前診断に有用であった十二指腸Brunner腺過誤腫出血の1切除例

荒生祥尚, 小林正明, 池見雅俊, 塩路和彦, 清野智, 阿部寛幸, 岩城孝和, 田口貴博, 谷優佑, 寺井崇二

Gastroenterological Endoscopy 62 ( 7 ) 778 - 784 2020年7月

記述言語：日本語出版者・発行元：(一社)日本消化器内視鏡学会

症例は75歳男性.黒色便を認め,内視鏡検査で十二指腸球部後面に無茎性腫瘤性病変(25mm)を認め,頂部に微小な露出血管を伴ったびらんがあり止血処置を行った.EUS-FNAを施行しBrunner腺の過形成を認め悪性の可能性は極めて低いと判断したが,出血を繰り返し治療適応と判断した.局在や大きさ,形態から内視鏡的切除困難なため外科的局所切除を施行した.病理はBrunner腺の他に導管や平滑筋の増生も認めBrunner腺過誤腫と診断した.Brunner腺過誤腫が内視鏡切除できない場合,病変の局在によっては膵頭十二指腸切除など侵襲的な手術が選択された報告もあるが,EUS-FNAは診断に有用であった.(著者抄録)

消化器疾患における移植医療の現状と問題点本県の急性肝不全診療におけるネットワーク構築の取り組み

薛徹, 土屋淳紀, 寺井崇二

日本消化器病学会雑誌 117 ( 臨増総会 ) A73 - A73 2020年7月

肝硬変に対する間葉系幹細胞由来エクソソーム治療のライブイメージング技術、Single cell RNA-seqを用いたメカニズム解析

土屋淳紀, 竹内卓, 寺井崇二

日本消化器病学会雑誌 117 ( 臨増総会 ) A238 - A238 2020年7月

肝硬変患者のQOL・予後の改善と基盤研究の最前線 IFN-γ刺激下間葉系幹細胞由来エクソソームの肝線維化改善における効果・メカニズムの検証

土屋淳紀, 竹内卓, 寺井崇二

日本消化器病学会雑誌 117 ( 臨増総会 ) A97 - A97 2020年7月

胃瘻造設によりS状結腸間膜穿孔をきたした一例

吉田悠紀, 川田雄三, 永山逸夫, 野澤良祐, 冨永顕太郎, 薛徹, 横尾健, 水野研一, 寺井崇二

ENDOSCOPIC FORUM for digestive disease 36 ( 1 ) 46 - 46 2020年7月

肝癌治療に対する内科外科のすみわけと連携における放射線治療の役割

上村顕也, 柴田理, 大越麻理奈, 寺井崇二

日本消化器病学会雑誌 117 ( 臨増総会 ) A292 - A292 2020年7月

非アルコール性脂肪性肝疾患(NAFLD)の病態進行における自律神経を介した臓器間ネットワークの関与

高昌良, 上村顕也, 名古屋拓郎, 酒井規裕, 坂牧僚, 横尾健, 寺井崇二

日本門脈圧亢進症学会雑誌 26 ( 2 ) 143 - 146 2020年7月

記述言語：日本語出版者・発行元：(一社)日本門脈圧亢進症学会

【目的】非アルコール性脂肪性肝疾患(non-alcoholic fatty liver disease、NAFLD)は肝不全の一病態として重要な治療対象である。これまでに我々は肝障害時の肝再生に自律神経を介した消化管ホルモンの活性化の重要性を明らかにした。本研究では、NAFLDモデルマウスを対象として、その病態への神経ネットワークの関与および治療対象としての可能性を検討することを目的とした。【方法】NAFLDモデルマウスとして、コリン欠乏・メチオニン減量(CDAA)食給餌モデルと高脂肪食(HFD)給餌モデルを対象として、肝臓からの求心性内臓神経、迷走神経肝臓枝の遮断を行い、消化管ホルモン、腸内細菌叢への影響を評価した。【成績】CDAA食給餌モデルで彼からのグレリン分泌の活性化を認めたが、神経遮断により抑制され、NAFLDの進行抑制効果を認めた。また、両モデルで神経遮断により腸内細菌叢の構成が変化した。【結語】神経ネットワークへの介入が消化管ホルモン、腸内細菌叢に影響を与え、NAFLDの進行を抑制することが明らかとなった。(著者抄録)

消化器疾患における共生微生物叢研究の新たな知見 NAFLDの病態における自律神経ネットワークを介した腸内細菌叢の関与

高昌良, 上村顕也, 寺井崇二

日本消化器病学会雑誌 117 ( 臨増総会 ) A78 - A78 2020年7月

肝癌分子標的薬治療時の鰹だし併用による肝予備能維持効果

小関洋平, 上村顕也, 坂牧僚, 大越麻理奈, 田中裕登, 寺井崇二

日本消化器病学会雑誌 117 ( 臨増総会 ) A296 - A296 2020年7月

臨床応用に向けた肝癌の病態解明放射線照射によるDNA損傷時のHHMの役割

丹羽佑輔, 上村顕也, 寺井崇二

日本消化器病学会雑誌 117 ( 臨増総会 ) A161 - A161 2020年7月

Cytapheresis for pyoderma gangrenosum associated with inflammatory bowel disease: A review of current status. 査読国際誌

Kentaro Tominaga, Kenya Kamimura, Hiroki Sato, Masayoshi Ko, Yuzo Kawata, Takeshi Mizusawa, Junji Yokoyama, Shuji Terai

World journal of clinical cases 8 ( 11 ) 2092 - 2101 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis clinically characterized by the presence of painful skin ulcerations with erythematous. As it is frequently associated with inflammatory bowel diseases, including ulcerative colitis, gastroenterologists should be familiar with the disease including therapeutic options. Therefore, we have conducted a review focusing on the cytapheresis for PG in cases of inflammatory bowel diseases. A literature search was conducted to extract studies published in the last 20 years, with information on demographics, clinical symptoms, treatment, and the clinical course from a total of 22 cases reported and our recent case. In most patients, cytapheresis was associated with improvement or resolution of PG after failure of conventional therapeutic options such as corticosteroids, antibiotics, immunosuppressive agents and immunoglobulin. Based on the information summarized, cytapheresis is helpful in the majority of patients with PG refractory to medical treatment associated with inflammatory bowel diseases and could be further studied in a multicenter, randomized trial.

DOI： 10.12998/wjcc.v8.i11.2092

Development of a non-alcoholic steatohepatitis model with rapid accumulation of fibrosis, and its treatment using mesenchymal stem cells and their small extracellular vesicles. 査読国際誌

Takayuki Watanabe, Atsunori Tsuchiya, Suguru Takeuchi, Shunsuke Nojiri, Tomoaki Yoshida, Masahiro Ogawa, Michiko Itoh, Masaaki Takamura, Takayoshi Suganami, Yoshihiro Ogawa, Shuji Terai

Regenerative therapy 14 252 - 261 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Introduction: Currently, there are no approved drugs for treating non-alcoholic steatohepatitis (NASH); however, mesenchymal stem cells (MSCs) and their small extracellular vesicles (sEVs), which possess immunomodulatory activities, are potential candidates. This study aimed to develop a mouse model of NASH with rapid accumulation of fibrosis using the pre-established melanocortin type-4 receptor knockout (Mc4r-KO) NASH mouse model and lipopolysaccharide (LPS), and to evaluate the therapeutic effect of MSCs and their sEVs. Methods: Mc4r-KO mice (8 weeks old, male) were fed a western diet (WD) for 8 weeks. Next, the mice were intraperitoneally injected with lipopolysaccharide (LPS) twice a week for 4 weeks while continuing the WD. To confirm the therapeutic effect of MSCs and sEVs, human adipose tissue-derived MSCs or their sEVs were administered 12 weeks after initiation of the WD, and serum testing, quantitative analysis of fibrosis, and quantitative reverse transcription-polymerase chain reaction qRT-PCR were performed. Results: By providing a WD combined with LPS treatment, we successfully developed a NASH model with rapid accumulation of fibrosis. Both human MSCs and their sEVs decreased serum alanine transaminase levels and inflammatory markers based on qRT-PCR. Histological analysis showed that MSC or sEV treatment did not affect fat accumulation. However, an improvement in fibrosis in the groups treated with MSCs and their sEVs was observed. Furthermore, after administering MSCs and sEVs, there was a significant increase in anti-inflammatory macrophages in the liver. Conclusion: We successfully developed a NASH model with rapid accumulation of fibrosis and confirmed the anti-inflammatory and anti-fibrotic effects of MSCs and their sEVs, which may be options for future therapy.

DOI： 10.1016/j.reth.2020.03.012

A rare case of peliosis hepatis in a patient with chronic renal failure and renal cell carcinoma.

Hiroki Maruyama, Kazuya Takahashi, Natsuki Ishikawa, Kazunori Hosaka, Daisuke Kumaki, Yukio Aruga, Masashi Yamakawa, Masaaki Hirano, Kazuhiro Funakoshi, Shuji Terai

Clinical journal of gastroenterology 13 ( 3 ) 403 - 407 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Peliosis hepatis (PH) is a rare disease characterized by the presence of sinusoidal dilation and blood-filled cysts throughout the hepatic parenchyma. We report a case of PH in a 49-year-old woman with chronic renal failure (CRF) on hemodialysis and with renal cell carcinoma (RCC). Dynamic contrast-enhanced computed tomography (CT) showed a 35-mm-diameter, hypervascular tumor in the liver and RCC in the right renal cyst. Ultrasound and superparamagnetic iron oxide-enhanced magnetic resonance imaging were also performed; however, the liver tumor could not be distinguished from the metastasis of RCC. Therefore, echo-guided biopsy of the liver tumor using an 18-G Majima needle was performed. Histological evaluation of the specimen showed irregular sinusoidal dilatation and blood-filled cavities without malignant cells. She was ultimately diagnosed with PH. Subsequently, she underwent total right nephrectomy for RCC and was diagnosed with RCC stage 1 (pT1N0M0). A follow-up CT performed 4 months after nephrectomy showed no growth of PH. Although the development of PH in patients with CRF or RCC who do not undergo renal transplantation is extremely rare, it should be considered in the differential diagnosis to distinguish PH from the metastasis of RCC.

DOI： 10.1007/s12328-019-01068-5

【幹細胞治療と疾患】間葉系幹細胞は"指揮細胞"としてマクロファージに作用し肝硬変の肝線維化改善、再生を誘導する自己骨髄細胞投与療法から他家脂肪組織由来間葉系幹細胞投与へ

寺井崇二, 土屋淳紀

BIO Clinica 35 ( 5 ) 406 - 410 2020年5月

記述言語：日本語出版者・発行元：(株)北隆館

肝臓は再生能力の高い臓器として知られているが、肝障害が遷延し進行した肝硬変に進展するとその再生能力は落ち、現在根本的に改善する治療は肝移植である。しかし肝移植はドナーの不足という深刻な状態に直面している。現在、肝硬変の線維化改善、再生促進を目指した新規治療が世界中で開発を目指して展開されているが、細胞治療もその一つである。我々は2003年に肝硬変症に対する自己骨髄細胞投与療法の臨床研究を開始し、その過程において、肝線維化改善に伴う肝再生、肝機能の改善を明らかにしてきた。一方でさらに再生医療として考えた場合、今後は自己から他家細胞投与が必要と考えられた。基礎研究を踏まえ、2017年よりロート製薬と肝硬変症に対する他家脂肪由来間葉系幹細胞投与の治験を開始した。一方で、基礎研究の解析では間葉系幹細胞投与療法において、間葉系幹細胞は指揮細胞として作用し、マクロファージをM2型に変化させ、肝線維化改善、肝再生を誘導することも明らかになってきた。本稿では我々が現在までの他家間葉系幹細胞の臨床展開までの道のりを概説する。(著者抄録)

Small Intestinal Bacterial Overgrowth Diagnosed by a Breath Test and Improved by Rifaximin in a Patient with Hepatic Encephalopathy and Alcoholic Liver Cirrhosis: A Case Report. 査読

Akira Sakamaki, Kunihiko Yokoyama, Fusako Yamazaki, Hiroteru Kamimura, Kenya Kamimura, Masaaki Takamura, Junji Yokoyama, Shuji Terai

Internal medicine (Tokyo, Japan) 59 ( 15 ) 1849 - 1853 2020年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

A 66-year-old Japanese man was admitted to our hospital with grade 2 hepatic encephalopathy (HE). Abdominal computed tomography and laboratory examinations revealed decompensated liver cirrhosis. Intravenous administration of branched-chain amino acids immediately ameliorated the HE, and lactulose was initiated. However, a breath test revealed small intestinal bacterial overgrowth (SIBO); therefore, rifaximin was additionally initiated. The breath test was repeated after discharge, when no evidence of SIBO or overt HE was identified. This case suggested that a breath test is effective for the identification of SIBO and that the administration of a poorly absorbed antibiotic should be considered in SIBO-positive HE patients taking lactulose.

DOI： 10.2169/internalmedicine.4593-20

Effect of methionine/choline-deficient diet and high-fat diet-induced steatohepatitis on mitochondrial homeostasis in mice. 査読国際誌

Yoshihisa Arao, Hirokazu Kawai, Kenya Kamimura, Takamasa Kobayashi, Oki Nakano, Manabu Hayatsu, Tatsuo Ushiki, Shuji Terai

Biochemical and biophysical research communications 527 ( 2 ) 365 - 371 2020年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Considering the increase in cases of non-alcoholic steatohepatitis (NASH), the use of appropriate animal model of NASH is essential to understand the underlying pathogenesis mechanism. To date, several mice models have been used; however, significant differences in the etiologies and food administered affected the results, with inconsistent conclusions. Therefore, it is necessary to understand these models and their differences to be able to choose appropriate models. Inspired by the fact that mitochondrial (mt)DNA content is changed in non-alcoholic fatty liver disease in humans, we investigated the mtDNA copy number in the NASH mice models induced by high-fat diet (HFD) and methionine/choline-deficient diet (MCD) to understand the differences between these models. Megamitochondria were observed in both MCD and HFD groups. However, the MCD group showed significant decrease in liver mtDNA content compared with that in the HFD group. These changes were associated with significant upregulation of mitochondrial biogenesis- and degradation-related genes in MCD model than in HFD model. Thus, stability of mtDNA is associated with the differences between MCD and HFD-induced NASH models often used in studies; these findings could help in choosing appropriate models for studies on NASH.

DOI： 10.1016/j.bbrc.2020.03.180

Rare Genotype of His/His in NUDT15 Codon 139 and Thiopurine-associated Adverse Events in a Case of Ulcerative Colitis. 査読

Kei Tomiyoshi, Hiroki Sato, Kentaro Tominaga, Yuzo Kawata, Daisuke Okamoto, Yoichi Kakuta, Junji Yokoyama, Shuji Terai

Internal medicine (Tokyo, Japan) 59 ( 13 ) 1611 - 1613 2020年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Thiopurine drugs are commonly used to treat immunologic diseases. However, the narrow therapeutic safety margin demands evidence-based precision medicine approaches. NUDT15 variants are associated with thiopurine-induced adverse events, particularly in Asians. We herein report a rare genotype of His/His in NUDT15 codon 139 in a case of ulcerative colitis and review the relevant literature. The patient experienced severe thiopurine-associated adverse events, including leukopenia and alopecia. There is no literature on the His/His genotype in NUDT15 codon 139, and our case suggests cautious use or the contraindication of thiopurines for patients with this genotype.

DOI： 10.2169/internalmedicine.4261-19

新潟県における肝炎対策査読

荒生祥尚, 菊田玲, 渡辺和仁, 中山均, 田村務, 薛徹, 寺井崇二

肝臓 61 ( Suppl.1 ) A263 - A263 2020年4月

当院における肝炎医療コーディネーターの取り組みと今後の課題査読

廣川光, 薛徹, 荒生祥尚, 澤栗裕美, 寺井崇二

肝臓 61 ( Suppl.1 ) A246 - A246 2020年4月

Huge liver tumor in young man. 査読国際誌

Osamu Shibata, Kenya Kamimura, Rie Azumi, Kei Shibuya, Shintaro Shiba, Tatsuya Ohno, Shuji Terai

JGH open : an open access journal of gastroenterology and hepatology 4 ( 2 ) 301 - 302 2020年4月

記述言語：英語

Intrahepatic cholangiocarcinoma is the second leading primary hepatic tumors, accounting for 5% of all hepatic tumors. The curability depends on the operability; however, the difficulty of early diagnosis and late clinical presentation account for the poor prognosis. Therefore, development of a novel therapeutic option and a method to determine the viability of the primary tumor, which hinder the assessment of the impact of other therapies, including chemotherapy and radiotherapy are needed. Although FDG-PET has been used to detect distant metastases of ICC, which are present in 20% of patients at the initial diagnosis, little is known about the efficacy of FDG-PET of the primary lesion of ICC. Here, we present the case of a 31-year-old male diagnosed with unresectable ICC and successfully treated with carbon-ion radiation, and present the usefulness of fluorodeoxyglucose-positron emission tomography in the determination of the viability of the tumor.

DOI： 10.1002/jgh3.12234

Hypereosinophilia-related liver pseudotumor with elevated interleukin-5 levels preceding T-cell lymphoma. 国際誌

Atsunori Tsuchiya, Tomoyuki Tanaka, Yasuhiko Shibasaki, Shuji Terai

JGH open : an open access journal of gastroenterology and hepatology 4 ( 2 ) 312 - 314 2020年4月

記述言語：英語

A 61-year-old woman with hypereosinophilia and elevated interleukin (IL)-5 level was admitted to our hospital after detection of multiple liver tumors. Liver biopsy demonstrated that the tumor consisted of scar tissue with remnants of eosinophilic infiltration, suggesting that it had formed by massive eosinophilic infiltration. The hypereosinophilia was treated mainly by prednisolone, and thereafter, the liver tumors disappeared. However, 10 months postadmission, CD4+ T-cell lymphoma, which can produce IL-5, was detected in the nasopharynx and oropharynx. Therefore, we believe that this is a rare case of hypereosinophilia-related liver pseudotumor induced by presumed by IL-5 elevation.

DOI： 10.1002/jgh3.12253

自己免疫性肝炎における赤血球容量粒度分布幅変動係数の臨床的意義

高村昌昭, 高綱将史, 薛徹, 上村博輝, 土屋淳紀, 寺井崇二

肝臓 61 ( Suppl.1 ) A433 - A433 2020年4月

肝疾患における移行期医療小児NAFLD患者の背景疾患と移行医療への課題

上村博輝, 上村顕也, 寺井崇二

肝臓 61 ( Suppl.1 ) A142 - A142 2020年4月

肝移植医療における内科・外科連携の現状と問題点本県における急性肝不全に対する肝移植再開に向けた診療ネットワーク運用の検討

薛徹, 寺井崇二

肝臓 61 ( Suppl.1 ) A125 - A125 2020年4月

門脈圧亢進症の診断と治療原発性胆汁性胆管炎における食道静脈瘤発生の検討

薛徹, 横山純二, 寺井崇二

肝臓 61 ( Suppl.1 ) A151 - A151 2020年4月

NAFLDの病態解明及び新規治療法の探索非アルコール性脂肪性肝炎(NASH)モデルマウスを用いたスフィンゴシン1リン酸受容体ブロックによる脂質構成の変化と発癌機構の解明

吉田智彰, 土屋淳紀, 寺井崇二

肝臓 61 ( Suppl.1 ) A215 - A215 2020年4月

肝硬変の予後改善を目指した治療戦略肝硬変に対する間葉系幹細胞由来のエクソソーム療法の開発に向けて

土屋淳紀, 竹内卓, 寺井崇二

肝臓 61 ( Suppl.1 ) A92 - A92 2020年4月

生体試料を用いた研究の最前線間葉系幹細胞のエクソソームによる肝線維化改善抗炎症性マクロファージ誘導法の開発

竹内卓, 土屋淳紀, 寺井崇二

肝臓 61 ( Suppl.1 ) A33 - A33 2020年4月

健診での生活歴から考察したNAFLD症例に対する新しい生活指導法の提案

横尾健, 中野応央樹, 佐藤公俊, 冨永顕太郎, 橋本哲, 高村昌昭, 寺井崇二

肝臓 61 ( Suppl.1 ) A454 - A454 2020年4月

肝発癌進展研究の最前線肝発癌,治療抵抗性にかかわるHHM遺伝子のDNA損傷応答メカニズムの解析

上村顕也, 丹羽佑輔, 寺井崇二

肝臓 61 ( Suppl.1 ) A44 - A44 2020年4月

臓器間ネットワークと肝疾患自律神経経路を介する肝-脳-消化管軸の非アルコール性脂肪肝炎の病態への関与

上村顕也, 大脇崇史, 寺井崇二

肝臓 61 ( Suppl.1 ) A182 - A182 2020年4月

An unusual case of esophageal motility disorder. 査読国際誌

Youhei Koseki, Hiroki Sato, Shuji Terai

Gastroenterology 159 ( 3 ) 838 - 841 2020年3月

Secondary Achalasia in Myotonic Dystrophy May Have a Different Pathology and Management. 査読

Hiroki Sato, Ken-Ichi Mizuno, Satoru Hashimoto, Masafumi Takatsuna, Shuji Terai

Internal medicine (Tokyo, Japan) 59 ( 6 ) 875 - 875 2020年3月

Variations of small bowel transit time on capsule endoscopy 査読国際誌

Tominaga K, Sato H, Yokomichi H, Tsuchiya A, Yoshida T, Kawata Y, Yokoyama J, Terai S

Annals of Translational Medicine in Press ( 6 ) 348 - 348 2020年3月

Rare gastric outlet obstruction owing to ectopic pancreas: a case report and literature review. 国際誌

Kunihiko Yokoyama, Hiroki Sato, Yuichi Sato, Jun Watanabe, Atsuo Nakamura, Shuji Terai

Annals of translational medicine 8 ( 5 ) 252 - 252 2020年3月

記述言語：英語

The ectopic pancreas is often observed in the gastrointestinal tract, and is typically asymptomatic. A 28-year-old woman was referred to our hospital following repeated vomiting after every meal. Following gastroscopy, contrast-enhanced computed tomography (CE-CT), and endoscopic ultrasonography (EUS), she was diagnosed with gastric outlet obstruction, also known as pyloric obstruction, caused by a giant submucosal cystic tumor. The condition was successfully treated with EUS-guided cystic drainage, and she was diagnosed with a cystic tumor originating from the ectopic pancreas. The tumor shrank following EUS-guided cystic drainage, and her obstructive symptoms resolved. In cases with overgrowth of the ectopic pancreas, the differential diagnosis of malignancy is important but challenging. Herein, we report a unique final pathology of this rare case and discuss the findings with a literature review.

DOI： 10.21037/atm.2020.01.64

Percutaneous Gastrojejunostomy Catheter Placement Using a Slow-Leak Balloon through the Reconstructed Gastric Tube after Esophagectomy. 国際誌

Shinichi Morita, Yasuaki Arai, Shunsuke Sugawara, Miyuki Sone, Koji Tomita, Hiroaki Ishii, Shuji Terai

Journal of vascular and interventional radiology : JVIR 31 ( 3 ) 478 - 481 2020年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Twelve patients who had undergone esophageal reconstruction because of cancer and in whom conventional percutaneous radiologic or endoscopic gastrostomy was considered difficult are reported. These patients underwent placement of a percutaneous gastrojejunostomy catheter through the reconstructed gastric tube using a slow-leak balloon that had been developed for percutaneous transesophageal gastrotubing. Retrospective evaluation showed successful outcomes without severe complications in all patients. Eight (66.6%) were able to resume oral intake, which allowed gastrojejunostomy catheter withdrawal in 3 (25%). This technique is feasible with acceptable clinical outcomes for patients who have undergone gastric tube reconstruction after esophagectomy.

DOI： 10.1016/j.jvir.2019.09.009

肝悪性腫瘍との鑑別に苦慮した原発性肝放線菌症の1例

本田博樹, 野澤優次郎, 高村昌昭, 上村博輝, 土屋淳紀, 寺井崇二

肝臓 61 ( 3 ) 109 - 115 2020年3月

記述言語：日本語出版者・発行元：(一社)日本肝臓学会

症例は71歳男性。近医で胆道系酵素の上昇を指摘され、2011年6月に新潟大学医歯学総合病院消化器内科を紹介受診した。腹部CTでは、肝右葉に10cm大の嚢胞成分と充実成分からなる腫瘤が指摘され、末梢の肝内胆管拡張を伴っていた。また肝門部から大動脈周囲に多発するリンパ節腫大がみられた。肝膿瘍を併発した肝内胆管癌を考えたが、外科的切除の適応外であり、化学療法導入前の組織学的診断のため、2011年8月経皮経肝的肝生検を施行したが腫瘍細胞は認められなかった。その後肝膿瘍に対する抗生剤治療および経皮経肝的ドレナージ術を行ったが、膿瘍腔の十分な縮小には至らなかった。後日、肝病理組織から放線菌を確認し、肝放線菌症と診断して抗生剤をペニシリンに変更したところ、病変の著明な縮小を認めた。肝悪性腫瘍と鑑別を要した肝放線菌症の一例を経験したので報告する。(著者抄録)

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J00263&link_issn=&doc_id=20200310120008&doc_link_id=10.2957%2Fkanzo.61.109&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.61.109&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

【間葉系幹細胞の基礎と臨床応用】疾患治療他家脂肪組織由来間葉系幹細胞投与療法の開発

寺井崇二, 土屋淳紀

医学のあゆみ 272 ( 10 ) 1032 - 1039 2020年3月

記述言語：日本語出版者・発行元：医歯薬出版(株)

肝は再生能力の高い臓器として知られているが、肝障害が遷延し進行した肝硬変に進展すると、その再生能力は落ち、現在、根本的な治療は肝移植のみである。しかし、肝移植はドナーの不足という深刻な状態に直面している。現在、肝硬変の線維化改善、再生促進をめざした新規治療の開発が世界中で展開されているが、細胞治療もそのひとつである。本稿では、著者らが現在まで開発してきた間葉系幹細胞(MSC)の臨床展開(自己骨髄細胞投与療法の開発、自己・他家間葉系幹細胞投与療法)の開発までの道のり、また明らかにしてきた幹細胞の"指揮細胞"としての機能を概説する。(著者抄録)

その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J00060&link_issn=&doc_id=20200309030011&doc_link_id=%2Faa7ayuma%2F2020%2F027210%2F012%2F1032-1039%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faa7ayuma%2F2020%2F027210%2F012%2F1032-1039%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Effect of Diphtheria Toxin-Based Gene Therapy for Hepatocellular Carcinoma. 査読国際誌

Kenya Kamimura, Takeshi Yokoo, Hiroyuki Abe, Norihiro Sakai, Takuro Nagoya, Yuji Kobayashi, Masato Ohtsuka, Hiromi Miura, Akira Sakamaki, Hiroteru Kamimura, Norio Miyamura, Hiroshi Nishina, Shuji Terai

Cancers 12 ( 2 ) 2020年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Hepatocellular carcinoma (HCC) is a major global malignancy, responsible for >90% of primary liver cancers. Currently available therapeutic options have poor performances due to the highly heterogeneous nature of the tumor cells; recurrence is highly probable, and some patients develop resistances to the therapies. Accordingly, the development of a novel therapy is essential. We assessed gene therapy for HCC using a diphtheria toxin fragment A (DTA) gene-expressing plasmid, utilizing a non-viral hydrodynamics-based procedure. The antitumor effect of DTA expression in HCC cell lines (and alpha-fetoprotein (AFP) promoter selectivity) is assessed in vitro by examining HCC cell growth. Moreover, the effect and safety of the AFP promoter-selective DTA expression was examined in vivo using an HCC mice model established by the hydrodynamic gene delivery of the yes-associated protein (YAP)-expressing plasmid. The protein synthesis in DTA transfected cells is inhibited by the disappearance of tdTomato and GFP expression co-transfected upon the delivery of the DTA plasmid; the HCC cell growth is inhibited by the expression of DTA in HCC cells in an AFP promoter-selective manner. A significant inhibition of HCC occurrence and the suppression of the tumor marker of AFP and des-gamma-carboxy prothrombin can be seen in mice groups treated with hydrodynamic gene delivery of DTA, both 0 and 2 months after the YAP gene delivery. These results suggest that DTA gene therapy is effective for HCC.

DOI： 10.3390/cancers12020472

On-line HDFを急性肝不全の患者に施行する際の診療ガイド

井上和明, 織田成人, 安部隆三, 滝川康裕, 中山伸朗, 加藤直也, 藤原慶一, 安井伸, 寺井崇二, 井戸章雄, 坂井田功, 玄田拓哉, 清水雅仁, 持田智, 滝川一

肝臓 61 ( 2 ) 47 - 60 2020年2月

Septicemic listeriosis during adalimumab- and golimumab-based treatment for ulcerative colitis: case presentation and literature review. 査読

Ryoko Horigome, Hiroki Sato, Terasu Honma, Shuji Terai

Clinical journal of gastroenterology 13 ( 1 ) 22 - 25 2020年2月

記述言語：英語

Listeria monocytogenes is a common bacterium that can trigger an episode of amphixenosis from the consumption of contaminated food. It survives in the host as an intracellular parasite and can get reactivated when the host's immune system is compromised. The use of anti-tumor necrosis factor-α (TNF-α) blockers is reported to increase the risk of L. monocytogenes infections. In the field of gastroenterology, the use of TNF-α blockers is on the rise due to remarkable efficacy in select patients with inflammatory bowel diseases (IBDs) such as ulcerative colitis and Crohn's disease and the rise in the incidence and prevalence of IBDs. There are few case reports on this topic, despite the rapid development of novel TNF-α blockers. Here, we report two cases of septicemic listeriosis encountered during treatment with the more recent TNF-α blockers, namely, adalimumab and golimumab, in ulcerative colitis and review the published literature on the topic.

DOI： 10.1007/s12328-019-01005-6

Rare paradoxical adverse event in Crohn's disease: a case report. 査読国際誌

Marina Okoshi, Hiroki Sato, Terasu Honma, Shuji Terai

Annals of translational medicine 8 ( 4 ) 133 - 133 2020年2月

記述言語：英語

An 18-year-old male adolescent diagnosed with ileocolitis-type Crohn's disease received therapy involving an anti-tumor necrosis factor-α (TNF-α) blocker, which resulted in remission for 2 years. The patient presented with fever, stomatitis, and cough with respiratory distress. Chest radiography revealed bilateral hilar lymphadenopathy; bronchoalveolar lavage showed high lymphocyte level: 40.8% and CD4/8 value: 3.9. Transbronchial lung biopsy identified multiple non-caseating granulomas fused to each other with connective tissue septa, leading to the diagnosis of sarcoidosis. The sarcoidosis was defined as a paradoxical adverse event (PAE) due to the use of TNF-α blocker; therefore, cessation of TNF-α blocker administration was sufficient to induce remission. We report a rare case of PAE on Crohn's disease. The characteristics and distinguishing histologies of PAE and Crohn's disease are described. Biological agent therapy has been reported to cause several PAEs during the treatment of immune-mediated inflammatory disorders. PAEs are defined as pathological conditions that occur during biological agent therapy usually effective in treatment. The laboratory, radiography, and histological findings shown in this case are useful for differential diagnosis and management of PAE.

DOI： 10.21037/atm.2019.12.122

肝癌に対する局所療法としての放射線療法の安全性と有効性の検証

大越麻理奈, 上村顕也, 柴田修, 森田慎一, 坂牧僚, 田中裕登, 小関洋平, 寺井崇二

日本内科学会雑誌 109 ( Suppl. ) 155 - 155 2020年2月

Ghrelin-insulin-like growth factor-1 axis is activated via autonomic neural circuits in the non-alcoholic fatty liver disease. 査読国際誌

Takuro Nagoya, Kenya Kamimura, Ryosuke Inoue, Masayoshi Ko, Takashi Owaki, Yusuke Niwa, Norihiro Sakai, Toru Setsu, Akira Sakamaki, Takeshi Yokoo, Hiroteru Kamimura, Yuka Nakamura, Masaki Ueno, Shuji Terai

Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society 32 ( 5 ) e13799 2020年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The correlation of the growth hormone (GH) and insulin-like growth factor-1 (IGF-1) with non-alcoholic fatty liver disease (NAFLD) has been reported in epidemiological studies. However, the mechanisms of molecular and inter-organ systems that render these factors to influence on NAFLD have not been elucidated. In this study, we examined the induction of ghrelin which is the GH-releasing hormone and IGF-1, and involvement of autonomic neural circuits, in the pathogenesis of NAFLD. METHODS: The expression of gastric and hypothalamic ghrelin, neural activation in the brain, and serum IGF-1 were examined in NAFLD models of choline-deficient defined l-amino-acid diet-fed, melanocortin 4 receptor knockout mice, and partial hepatectomy mice with or without the blockades of autonomic nerves to test the contribution of neural circuits connecting the brain, liver, and stomach. KEY RESULTS: The fatty changes in the liver increased the expression of gastric ghrelin through the autonomic pathways which sends the neural signals to the arcuate nucleus in the hypothalamus through the afferent vagal nerve which reached the pituitary gland to release GH and then stimulate the IGF-1 release from the liver. In addition, high levels of ghrelin expression in the arcuate nucleus were correlated with NAFLD progression regardless of the circuits. CONCLUSIONS: Our study demonstrated that the fatty liver stimulates the autonomic nervous signal circuits which suppress the progression of the disease by activating the gastric ghrelin expression, the neural signal transduction in the brain, and the release of IGF-1 from the liver.

DOI： 10.1111/nmo.13799

Prostaglandin E2 and its receptor EP2 trigger signaling that contributes to YAP-mediated cell competition. 査読国際誌

Erika Ishihara, Yuya Nagaoka, Toshiaki Okuno, Satoshi Kofuji, Mari Ishigami-Yuasa, Hiroyuki Kagechika, Kenya Kamimura, Shuji Terai, Takehiko Yokomizo, Yukihiko Sugimoto, Yasuyuki Fujita, Akira Suzuki, Hiroshi Nishina

Genes to cells : devoted to molecular & cellular mechanisms 25 ( 3 ) 197 - 214 2020年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Cell competition is a biological process by which unfit cells are eliminated from "cell society." We previously showed that cultured mammalian epithelial Madin-Darby canine kidney (MDCK) cells expressing constitutively active YAP were eliminated by apical extrusion when surrounded by "normal" MDCK cells. However, the molecular mechanism underlying the elimination of active YAP-expressing cells was unknown. Here, we used high-throughput chemical compound screening to identify cyclooxygenase-2 (COX-2) as a key molecule triggering cell competition. Our work shows that COX-2-mediated PGE2 secretion engages its receptor EP2 on abnormal and nearby normal cells. This engagement of EP2 triggers downstream signaling via an adenylyl cyclase-cyclic AMP-PKA pathway that, in the presence of active YAP, induces E-cadherin internalization leading to apical extrusion. Thus, COX-2-induced PGE2 appears a warning signal to both abnormal and surrounding normal cells to drive cell competition.

DOI： 10.1111/gtc.12750

Usefulness of autotaxin for the complications of liver cirrhosis. 国際誌

Xue Shao, Haruki Uojima, Toru Setsu, Tomomi Okubo, Masanori Atsukawa, Yoshihiro Furuichi, Yoshitaka Arase, Hisashi Hidaka, Yoshiaki Tanaka, Takahide Nakazawa, Makoto Kako, Tatehiro Kagawa, Katsuhiko Iwakiri, Shuji Terai, Wasaburo Koizumi

World journal of gastroenterology 26 ( 1 ) 97 - 108 2020年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Autotaxin (ATX) has been reported as a direct biomarker for estimating the evaluation of liver fibrosis. But available data on ATX as a useful biomarker for the complications of liver cirrhosis (LC) are scant. AIM: To assess the clinical usefulness of ATX for assessing the complications of LC. METHODS: This multicenter, retrospective study was conducted at six locations in Japan. We include patients with LC, n = 400. The ATX level was evaluated separately in men and women because of its high level in female patients. To assess the clinical usefulness of ATX for the complications of LC, the area under the curve (AUC) of ATX assessing for the severe complications was analyzed in comparison with the model for end-stage liver disease score, albumin-bilirubin (ALBI) score, fibrosis-4 index, and aspartate aminotransferase-to-platelet ratio index. RESULTS: The mean age was 68.4 ± 11.4 years, 240 patients (60.0%) were male. A total of 213 (53.3%) and 187 (46.8%) patients were compensated and decompensated, respectively. The numbers of patients with varix rupture, hepatic ascites, and hepatic encephalopathy were 35 (8.8%), 131 (32.8%), and 103 (25.8%), respectively. The AUCs of ATX in men for hepatic encephalopathy, hepatic ascites, and varix ruptures were 0.853, 0.816, and 0.706, respectively. The AUCs of ATX in women for hepatic encephalopathy, hepatic ascites, and varix rupture were 0.759, 0.717, and 0.697, respectively. The AUCs of ATX in men were higher than those in women, as were all the other biomarkers used to detect encephalopathy and varix ruptures. However, for detecting ascites, the AUC of ALBI in men was more effective than using ATX. CONCLUSION: ATX in men was more effective than any other biomarkers for detecting hepatic encephalopathy and varix ruptures.

DOI： 10.3748/wjg.v26.i1.97

Achalasia in a Patient with Myotonic Dystrophy. 査読

Hiroki Sato, Ken-Ichi Mizuno, Satoru Hashimoto, Masafumi Takatsuna, Shuji Terai

Internal medicine (Tokyo, Japan) 59 ( 1 ) 67 - 68 2020年1月

記述言語：英語

Myotonic dystrophy is a progressive disorder mainly affecting the voluntary muscles. We herein report a rare case of myotonic dystrophy complicated with high-resolution manometry-defined achalasia, the pathology of which is absent relaxation of the smooth muscles of lower esophageal sphincter (LES). In the present case, achalasia was considered a complication of myotonic dystrophy instead of sporadic achalasia, as on performing high-resolution manometry, the finding of an impaired LES relaxation (myotonic phase) changed to a totally emaciated LES function (muscle weakness phase) as myotonic dystrophy progressed.

DOI： 10.2169/internalmedicine.3360-19

Rare Brain Metastasis From a Pancreatobiliary Subtype of Intraductal Papillary Mucinous Neoplasm. 査読国際誌

Arao Y, Kamimura K, Ikemi M, Hayashi K, Takaki M, Takahashi S, Seino S, Abe H, Tsuboguchi S, Otsu Y, Sanpei K, Kohisa J, Kondo S, Tani Y, Ito J, Toyoshima Y, Kakita A, Ajioka Y, Terai S

Pancreas 49 ( 1 ) e8 - e11 2020年1月

Endoscopic diverticulectomy for Zenker's diverticulum with heterotopic gastric mucosa. 査読国際誌

Hiroki Sato, Manabu Takeuchi, Shuji Terai

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 32 ( 1 ) 145 - 145 2020年1月

Loss of autophagy impairs physiological steatosis by accumulation of NCoR1. 国際誌

Shun-Saku Takahashi, Yu-Shin Sou, Tetsuya Saito, Akiko Kuma, Takayuki Yabe, Yuki Sugiura, Hyeon-Cheol Lee, Makoto Suematsu, Takehiko Yokomizo, Masato Koike, Shuji Terai, Noboru Mizushima, Satoshi Waguri, Masaaki Komatsu

Life science alliance 3 ( 1 ) 2020年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Lipid droplets (LDs) are dynamic organelles that store neutral lipids during times of energy excess, such as after a meal. LDs serve as an energy reservoir during fasting and have a buffering capacity that prevents lipotoxicity. Autophagy and the autophagic machinery have been proposed to play a role in LD biogenesis, but the underlying molecular mechanism remains unclear. Here, we show that when nuclear receptor co-repressor 1 (NCoR1), which inhibits the transactivation of nuclear receptors, accumulates because of autophagy suppression, LDs decrease in size and number. Ablation of ATG7, a gene essential for autophagy, suppressed the expression of gene targets of liver X receptor α, a nuclear receptor responsible for fatty acid and triglyceride synthesis in an NCoR1-dependent manner. LD accumulation in response to fasting and after hepatectomy was hampered by the suppression of autophagy. These results suggest that autophagy controls physiological hepatosteatosis by fine-tuning NCoR1 protein levels.

DOI： 10.26508/lsa.201900513

Therapeutic potential of mesenchymal stem cells and their exosomes in severe novel coronavirus disease 2019 (COVID-19) cases. 査読国際誌

Atsunori Tsuchiya, Suguru Takeuchi, Takahiro Iwasawa, Masaru Kumagai, Takeki Sato, Satoko Motegi, Yui Ishii, Youhei Koseki, Kei Tomiyoshi, Kazuki Natsui, Nobutaka Takeda, Yuki Yoshida, Fusako Yamazaki, Yuichi Kojima, Yusuke Watanabe, Naruhiro Kimura, Kentaro Tominaga, Hiroteru Kamimura, Masaaki Takamura, Shuji Terai

Inflammation and regeneration 40 14 - 14 2020年

記述言語：英語掲載種別：研究論文（学術雑誌）

The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19) and the ensuing worldwide pandemic. The spread of the virus has had global effects such as activity restriction, economic stagnation, and collapse of healthcare infrastructure. Severe SARS-CoV-2 infection induces a cytokine storm, leading to acute respiratory distress syndrome (ARDS) and multiple organ failure, which are very serious health conditions and must be mitigated or resolved as soon as possible. Mesenchymal stem cells (MSCs) and their exosomes can affect immune cells by inducing anti-inflammatory macrophages, regulatory T and B cells, and regulatory dendritic cells, and can inactivate T cells. Hence, they are potential candidate agents for treatment of severe cases of COVID-19. In this review, we report the background of severe cases of COVID-19, basic aspects and mechanisms of action of MSCs and their exosomes, and discuss basic and clinical studies based on MSCs and exosomes for influenza-induced ARDS. Finally, we report the potential of MSC and exosome therapy in severe cases of COVID-19 in recently initiated or planned clinical trials of MSCs (33 trials) and exosomes (1 trial) registered in 13 countries on ClinicalTrials.gov.

DOI： 10.1186/s41232-020-00121-y

10年目を迎えた新潟県肝疾患相談センターの現況査読

上村博輝, 高村昌昭, 五十嵐正人, 青栁豊, 菊田玲, 渡辺和仁, 中山均, 田村務, 寺井崇二, 薛徹, 荒生祥尚, 廣川光, 澤栗裕美, 渡邊文子, 小師優子, 坂牧僚, 土屋淳紀

肝臓 61 ( 5 ) 245 - 254 2020年

記述言語：日本語出版者・発行元：一般社団法人日本肝臓学会

<p>平成21年に設立された新潟大学医歯学総合病院肝疾患相談センターは令和元年に10年目を迎え，236万人の新潟県民や医療従事者に対するウイルス性肝炎の情報の提供，啓発活動，助成制度のサポート等を新潟県健康対策課，厚生労働省健康局がん・疾病対策課肝炎対策室，国立国際医療センター肝炎情報センターとともに行ってきた．新潟県内の各種肝炎ウイルスの発生動向の報告，助成対象人数の把握や非受検者に対する啓発活動を各年度で行ってきた．C型肝炎については他県と同じく新規治療者数については減少段階にある．しかし，肝炎ウイルスは世界最大級の感染症であることにかわりなく，A型肝炎のエンデミック，B型肝炎ウイルスに対する耐性ウイルス発生や核酸アナログ製剤の長期利用による諸問題，E型肝炎の報告例の増加などについては今後も監視が必要である．また肝炎検査未受検者も多く，啓発活動を行う肝疾患相談センターの存在意義は今後も重要である．</p>

DOI： 10.2957/kanzo.61.245

Obesity and accumulation of subcutaneous adipose tissue are poor prognostic factors in patients with alcoholic liver cirrhosis. 国際誌

Akira Sakamaki, Kunihiko Yokoyama, Kyutaro Koyama, Shinichi Morita, Hiroyuki Abe, Kenya Kamimura, Masaaki Takamura, Shuji Terai

PloS one 15 ( 11 ) e0242582 2020年

記述言語：英語掲載種別：研究論文（学術雑誌）

In alcoholic liver cirrhosis (LC) patients, obesity has become a problem that progresses into liver dysfunction. Herein, we investigated the relationship between the prognosis of steatohepatitis and body weight, along with fat accumulation in patients with alcoholic LC. We conducted a single-center retrospective study, enrolled 104 alcoholic LC patients without hepatocellular carcinoma (HCC) based on histological and clinical evidence, and investigated factors related to poor prognosis using multivariate Cox regression and cluster analyses. Cox regression analysis revealed three independent relevant factors: subcutaneous adipose tissue (SAT) index (median 34.8 cm2/m2, P = 0.009, hazard ratio [HR] 1.017, 95% confidence interval [CI] 1.004-1.030), total bilirubin level (median 1.7 mg/dL, P = 0.003, HR 1.129, 95% CI 1.042-1.223), and prothrombin time value (median 64%, P = 0.007, HR 0.967, 95% CI 0.943-0.991). In the cluster analysis, we categorized the patients into three groups: no adipose tissue accumulation (NAT group), SAT prior accumulation (SAT group), and visceral adipose tissue prior accumulation (VAT group). The results of the three groups revealed that the SAT group displayed a significantly poor prognosis of the Kaplan-Meier curve (67.1 vs 21.2 vs 65.3, P<0.001) of a 5-year survival rate. Propensity score matching analysis of the SAT and VAT groups was performed to adjust the patient's background, but no significant differences were found between them; however, the prognosis was poorer (21.2 vs 66.3, P<0.001), and hemostatic factors were still at a lower level in the SAT group. These findings suggest that SAT accumulation type of obesity is a poor prognostic factor in alcoholic LC patients without HCC, and the hemorrhagic tendency might worsen the poor prognosis in such cases.

DOI： 10.1371/journal.pone.0242582

Nationwide epidemiological survey of autoimmune pancreatitis in Japan in 2016

Masamune, A., Kikuta, K., Hamada, S., Tsuji, I., Takeyama, Y., Shimosegawa, T., Okazaki, K., Kanno, A., Sano, T., Uchida, K., Ikeura, T., Fujimori, N., Nakai, Y., Kamisawa, T., Kubota, K., Motoya, M., Shimizu, K., Ushijima, T., Fukasawa, M., Naitoh, I., Ueno, M., Okuwaki, K., Uza, N., Asada, M., Mukai, T., Kudo, Y., Uetsuki, K., Mitoro, A., Watanabe, H., Terai, S., Hayashi, K., Imamura, Y., Haba, S., Hara, K., Fujisawa, T., Iwasaki, E., Okumura, F., Kawaji, Y., Kitano, M., Nishino, T., Nagahama, M., Hirano, A., Aruga, Y., Yamamoto, S., Inui, K., Kubota, Y., Takahashi, K., Sakagami, J., Kobayashi, T., Miraki, T., Watanabe, T., Sato, H., Takeda, Y., Satoh, M., Kobashigawa, K., Chiba, M., Tamura, T., Sawada, N., Mizukami, K., Sekine, M., Unno, J., Ishizawa, T., Funayama, H., Hatayama, K., Miyakawa, H., Sakai, T., Kuwatani, M., Toki, M., Toyokawa, T., Hashimoto, S., Itoi, T., Iwashita, Y., Sato, A., Kato, H., Takatori, H., Iizawa, Y., Iwashita, T., Kondo, H., Sato, Y., Tanabe, M., Ogura, T., Yamamoto, K., Masaka, T., Setsuda, M., Sano, T., Matsubara, S., Kitamura, K., Iwata, K., Shirahata, N., Hagiwara, H., Yoshida, M., Yokota, T., Shigoka, H., Kaneko, N., Abue, M., Tsuruoka, N.

Journal of Gastroenterology 55 ( 4 ) 2020年

Nationwide epidemiological survey of chronic pancreatitis in Japan: introduction and validation of the new Japanese diagnostic criteria 2019

Masamune, A., Kikuta, K., Kume, K., Hamada, S., Tsuji, I., Takeyama, Y., Shimosegawa, T., Okazaki, K., Miura, S., Takikawa, T., Hongo, S., Nakano, E., Nabeshima, T., Matsumoto, R., Tanaka, Y., Ueno, M., Mukai, T., Matsumoto, M., Kudo, Y., Azuma, S., Okuwaki, K., Yamamoto, S., Inui, K., Kobashigawa, K., Unno, J., Fujimori, N., Kitamura, K., Miyakawa, H., Takahashi, K., Ikeura, T., Takenaka, M., Fukasawa, M., Funayama, H., Mitoro, A., Takagi, T., Sekine, M., Suwa, K., Sakagami, J., Ishida, M., Ohtsuka, M., Kagawa, S., Muraki, T., Watanabe, T., Watanabe, T., Yamamoto, K., Masaka, T., Nagahama, M., Sato, A., Aruga, Y., Nakai, Y., Iwasaki, E., Itoi, T., Kawaji, Y., Kitano, M., Mizukami, K., Iwasaki, S., Mori, M., Kaneko, N., Kodama, Y., Sato, H., Yoshida, N., Hatayama, K., Kobayashi, T., Hirano, A., Kaino, M., Fujisawa, T., Ushijima, T., Chiba, M., Shimizu, K., Ota, H., Toki, M., Nishikawa, T., Yoshida, Y., Tanaka, K., Uetsuki, K., Motoya, D., Muro, S., Watanabe, H., Imamura, Y., Ishizawa, T., Kamisawa, T., Tsuruoka, M., Hayashi, K., Terai, S., Iwatsuka, K., Iwata, K., Yoshida, M., Takagi, T., Goto, M., Oza, N., Takeda, Y., Hagiwara, H., Tadano, T., Sakai, T., Sumimoto, K., Nishimura, N., Irisawa, A., Kuwatani, M., Shirahata, N., Satoh, M., Fujikawa, T., Iizawa, Y., Watanabe, N., Ishiguro, H., Sawada, N., Katada, K., Kondo, H., Sakakihara, I., Nishida, J., Tamura, T., Dairaku, N., Kamezaki, H., Okano, H., Suzuki, S., Okamoto, T., Matsugu, Y., Imamura, M., Honjo, M., Sugiyama, G., Ohta, H., Higashide, S., Ishii, S., Hoshi, T., Takagi, Y., Satoh, A., Yamaji, N., Nishimura, N., Shibasaki, M., Tamura, H., Iwashita, T., Motoya, M., Tanisaka, Y., Ryozawa, S., Takatori, H., Tsuruoka, N., Hashimoto, S., Suzuki, N., Sato, Y., Tamai, H., Hara, K., Ashida, K., Yokota, T., Tsuji, T., Abue, M., Tomaki, H., Fukunishi, M., Koga, H., Takehara, Y., Kawamura, H., Shimokawahara, N., Otsu, N., Kimura, Y., Ishido, K., Kofunato, Y., Shiihara, M., Sakaguchi, T., Masui, T., Eguchi, H., Suzumura, K., Ide, T., Inomata, M., Maemura, K., Iizawa, H., Nakajima, A., Uyama, S., Shiozaki, S., Yokoyama, S., Wakabayashi, T., Furuuchi, T., Gushima, T., Satoh, S., Shioya, T., Nakazawa, K., Takahashi, Y., Fukuba, N., Matsubara, S.

Journal of Gastroenterology 55 ( 11 ) 2020年

Usefulness of endoscopic ultrasound (EUS)-fine needle aspiration (FNA) for local excision of brunner's gland hamartoma with hemorrhage: A case report and literature review,EUS-FNA が術前診断に有用であった十二指腸 Brunner 腺過誤腫出血の <sub>1</sub> 切除例

Arao, Y., Kobayashi, M., Ikemi, M., Shioji, K., Seino, S., Abe, H., Iwaki, T., Taguchi, T., Tani, Y., Terai, S.

Gastroenterological Endoscopy 62 ( 7 ) 2020年

Practical guide on on-line hemodiafiltration for acute liver failure

Inoue, K., Oda, S., Abe, R., Takikawa, Y., Nakayama, N., Kato, N., Fujiwara, K., Yasui, S., Terai, S., Ido, A., Sakaida, I., Genda, T., Shimizu, M., Mochida, S., Takikawa, H.

Kanzo/Acta Hepatologica Japonica 61 ( 2 ) 2020年

Clinical practice of acute pancreatitis in Japan: An analysis of nationwide epidemiological survey in 2016

Masamune, A., Kikuta, K., Hamada, S., Tsuji, I., Takeyama, Y., Shimosegawa, T., Okazaki, K., Matsumoto, R., Kume, K., Miura, S., Takikawa, T., Hongo, S., Tanaka, Y., Sakai, T., Ueno, M., Unno, J., Toki, M., Nishimura, M., Kitamura, K., Kobashigawa, K., Ashida, K., Takahashi, K., Watanabe, T., Sato, Y., Satoh, A., Yoshida, N., Tanaka, K., Kondo, H., Suzuki, N., Sato, H., Mitoro, A., Minami, K., Iwasaki, E., Okuwaki, K., Mukai, T., Kudo, Y., Azuma, S., Takeda, Y., Setsuda, M., Tsuchida, K., Irisawa, A., Motoya, D., Shirahata, N., Iwata, K., Oza, N., Kawaguchi, Y., Hoshino, A., Hirano, A., Sakakihara, I., Watanabe, N., Funayama, H., Nakamura, Y., Yamamoto, T., Uchida, H.H., Iizawa, Y., Imamura, M., Sekine, M., Inui, K., Yamamoto, S., Sato, S., Ishii, S., Yakushijin, T., Yamamoto, K., Masaka, T., Yoshida, M., Arizumi, T., Goto, M., Takenaka, M., Miyakawa, H., Otsuka, Y., Nishi, M., Suwa, K., Sakagami, J., Satoh, M., Koga, H., Takagi, T., Nagahama, M., Hatayama, K., Kaneko, N., Mori, M., Nakai, Y., Iwashita, Y., Iwatsuka, K., Hayashi, K., Terai, S., Kaneto, H., Nishikawa, T., Uchi, M., Honjo, M., Takagi, T., Mizukami, K., Tamura, T., Gushima, T., Sato, A., Shimizu, K., Aruga, Y., Nonogaki, K., Kaino, M., Iwashita, T., Tsuruoka, M., Miura, M., Hasegawa, H., Takai, T., Yokota, H., Fujisawa, T., Uetsuki, K., Kobayashi, T., yamaji, N., Itoi, T., Muraki, T., Watanabe, T., Inatomi, O., Ushijima, T., Takehara, Y., Kawamura, H., Fukasawa, M., Hagiwara, H., Tamura, H., Moriya, T., Kuwatani, M., Kawaji, Y., Kamisawa, T., Abue, M., Fukunishi, M., Onoyama, H., Mochizuki, S., Sumimoto, K., Koyabu, M., Nishio, A., Sakao, M., Imamura, Y., Ohta, H., Nishimura, N., Shiihara, M., Anan, H., Motoya, M., Chiba, M., Deguchi, T., Kofunato, Y., Sawada, N., Katada, K., Matsumoto, S., Higashide, S., Okano, H., Ishida, M., Yamazaki, M., Tamura, N., Muraoka, T., Uza, N., Kodama, Y., Muro, S., Fujimori, N., Ikeda, T., Shimokawahara, N., Otsu, N., Yano, Y., Sugawara, S., Takaura, K., Ogura, Y., Furuuchi, T., Shibasaki, M., Kishimoto, M.

Pancreatology 20 ( 4 ) 2020年

A case of primary hepatic actinomycosis difficult to distinguish from malignant hepatic tumors

Honda, H., Nozawa, Y., Takamura, M., Kamimura, H., Tsuchiya, A., Terai, S.

Kanzo/Acta Hepatologica Japonica 61 ( 3 ) 2020年

Rare Mesenteric Arterial Diseases: Fibromuscular Dysplasia and Segmental Arterial Mediolysis and Literature Review. 査読

Masayoshi Ko, Kenya Kamimura, Akira Sakamaki, Yusuke Niwa, Kentaro Tominaga, Kenichi Mizuno, Shuji Terai

Internal medicine (Tokyo, Japan) 58 ( 23 ) 3393 - 3400 2019年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Fibromuscular dysplasia (FMD) and segmental arterial mediolysis (SAM) are noninflammatory, nonatherosclerotic arterial diseases that cause aneurysm, occlusion, and thromboses. These diseases are rarely seen in mesenteric arterial lesions; however, as they can be lethal if appropriate management is not provided, the accumulation of clinical information from cases is essential. We herein report the cases of a 57-year-old man diagnosed with FMD and a 63-year-old man diagnosed with SAM. We conclude that an early diagnosis with imaging modalities and clinical information followed by the appropriate treatment improves the prognosis of these arterial diseases.

DOI： 10.2169/internalmedicine.3094-19

Pulmonary tumor thrombotic microangiopathy of hepatocellular carcinoma: A case report and review of literature. 査読国際誌

Morita S, Kamimura K, Abe H, Watanabe-Mori Y, Oda C, Kobayashi T, Arao Y, Tani Y, Ohashi R, Ajioka Y, Terai S

World journal of gastroenterology 25 ( 48 ) 6949 - 6958 2019年12月

Efficacy of gelatin hydrogels incorporating triamcinolone acetonide for prevention of fibrosis in a mouse model. 査読国際誌

Nao Nakajima, Satoru Hashimoto, Hiroki Sato, Kazuya Takahashi, Takuro Nagoya, Kenya Kamimura, Atsunori Tsuchiya, Junji Yokoyama, Yuichi Sato, Hanako Wakatsuki, Masayuki Miyata, Yusuke Akashi, Ryusuke Tanaka, Ken Matsuda, Yasuhiko Tabata, Shuji Terai

Regenerative therapy 11 41 - 46 2019年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Introduction: Triamcinolone acetonide (TA), a steroid, is often used clinically to prevent dysfunctions associated with fibrosis. The objective of this study was to examine whether TA can be suspended in a gelatin sheet for tissue engineering using a mouse skin wound model. Methods: TA was suspended in biodegradable gelatin and freeze-dried in a sheet form. The sheet was analyzed for homogeneity and controlled release of TA by high-performance liquid chromatography. We made two skin wounds on the dorsal side of mice. Gelatin sheets with TA (TA sheet) and without TA (control sheet) were attached to each skin wound. To determine the efficacy of the prepared TA sheet on the skin wounds, TA-sheet versus TA-injection experiments were conducted. Hematoxylin and eosin staining was performed to assess the grade of epithelialization and alpha smooth muscle actin (α-SMA) immunohistochemical staining was conducted to evaluate myofibroblast infiltration. Results: In the TA-release test in vitro, 7.7 ± 2.3% of TA was released from the sheet by 24 h. After replacing the initial phosphate-buffered saline (PBS) with collagenase PBS, the amount of released TA increased over time. The wound area/original skin wound area after 15 days with the TA sheet was significantly larger than that with the control sheet (26.9 ± 5.5% vs 10.7 ± 2.6%, p = 0.023). The α-SMA positive area/whole area with the TA sheet was significantly lower than that with the control sheet (4.65 ± 0.66% vs 7.24 ± 0.7%, p = 0.023). Furthermore, the α-SMA positive area/whole area with the TA sheet was significantly lower than that with TA injection (5.32 ± 0.45% vs 7.93 ± 0.75%, p = 0.013). Conclusions: We developed a TA sheet and confirmed both the homogeneity of the suspended TA and controlled-release of the TA in the presence of collagenase in vitro. The TA sheet caused less myofibroblast infiltration into the tissue than the control sheet or TA injection did.

DOI： 10.1016/j.reth.2019.04.001

Rare case of systemic scleroderma showing full-layer histologic features of an ileal lesion. 査読国際誌

Hiroki Sato, Terasu Honma, Saki Yamada, Takashi Owaki, Shuji Terai

Gastrointestinal endoscopy 90 ( 6 ) 991 - 993 2019年12月

表在型食道癌患者における禁酒後の体組成変化の検討

水澤健, 橋本哲, 上村博輝, 高村昌昭, 寺井崇二

アルコールと医学生物学 38 54 - 54 2019年12月

心窩部痛、肝障害を契機に発見されたcholedochoceleの一例

岩澤貴宏, 五十嵐聡, 林和直, 大脇崇史, 上村博輝, 橋本哲, 寺井崇二

ENDOSCOPIC FORUM for digestive disease 35 ( 2 ) 152 - 152 2019年12月

A case of pancreatic pseudocysts accompanied by infection, pseudoaneurysm ruptures, and pseudocystocolonic fistulae.

Kosuke Sato, Kazuya Takahashi, Yukio Aruga, Fusako Yamazaki, Daisuke Kumaki, Masashi Yamakawa, Masaaki Hirano, Kazuhiro Funakoshi, Shuji Terai

Clinical journal of gastroenterology 12 ( 6 ) 615 - 620 2019年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Pancreatic pseudocysts (PPs) can be accompanied by infection, pseudoaneurysm ruptures, and fistulae to other organs, which can be fatal without appropriate treatment. Herein, we present the case of an 82-year-old man with PPs accompanied by infection, pseudoaneurysm rupture, and pseudocystocolonic fistula that were managed via multidisciplinary treatment. Computed tomography (CT) revealed two inflamed PPs, one each in the pancreatic head and tail. He was, therefore, diagnosed with infectious PPs. The pancreatic head PP shrunk on endoscopic nasopancreatic drainage (ENPD), but the pancreatic tail PP did not. Endoscopic ultrasound (EUS)-guided transluminal drainage was performed to treat the pancreatic tail PP; his symptoms improved. However, he vomited blood at 14 day post-drainage. Angiography revealed pseudoaneurysm rupture in a left gastric artery branch. After successful angioembolization, he developed hematochezia 2 days later. We suspected re-bleeding of the pseudoaneurysm. The bleeding stopped spontaneously, but CT and radiography revealed the presence of a pseudocystocolonic fistula. Careful follow-up was performed, and he has not had any symptoms at 9 month post-discharge. We managed PP-related complications via ENPD, EUS-guided transluminal drainage, angioembolization, and careful follow-up. Infection, pseudoaneurysm rupture, and pseudocystocolonic fistula are rare, but can occur simultaneously. Therefore, clinicians should consider these complications when treating patients with PPs.

DOI： 10.1007/s12328-019-00986-8

Gene Therapy for Liver Cancers: Current Status from Basic to Clinics. 査読国際誌

Kamimura K, Yokoo T, Abe H, Terai AS

Cancers 11 ( 12 ) 2019年11月

Methotrexate-related lymphoproliferative disorders in the liver: Case presentation and mini-review. 査読国際誌

Takeshi Mizusawa, Kenya Kamimura, Hiroki Sato, Takeshi Suda, Hiroyuki Fukunari, Go Hasegawa, Osamu Shibata, Shinichi Morita, Akira Sakamaki, Junji Yokoyama, Yu Saito, Yoshihisa Hori, Yuduru Maruyama, Fumitoshi Yoshimine, Takahiro Hoshi, Shinichi Morita, Tsutomu Kanefuji, Masaaki Kobayashi, Shuji Terai

World journal of clinical cases 7 ( 21 ) 3553 - 3561 2019年11月

記述言語：英語

BACKGROUND: Immunosuppression is effective in treating a number of diseases, but adverse effects such as bone marrow suppression, infection, and oncogenesis are of concern. Methotrexate is a key immunosuppressant used to treat rheumatoid arthritis. Although it is effective for many patients, various side effects have been reported, one of the most serious being methotrexate-related lymphoproliferative disorder. While this may occur in various organs, liver involvement is rare. Information on these liver lesions, including clinical characteristics, course, and imaging studies, has not been summarized to date. CASE SUMMARY: We present a case of 70-year-old woman presented with a 2-wk history of fever and abdominal pain. She had had rheumatoid arthritis for 5 years and was being treated with medication including methotrexate. Contrast-enhanced computed tomography revealed multiple low density tumors in the liver and the histological analyses showed significant proliferation of lymphocytes in masses that were positive on immunohistochemical staining for CD3, CD4, CD8, and CD79a but negative for CD20 and CD56. Staining for Epstein-Barr virus-encoded RNA was negative. And based on these findings, the liver tumors were diagnosed as Methotrexate-related lymphoproliferative disorders. A time-dependent disappearance of the liver tumors after stopping methotrexate supported the diagnoses. CONCLUSION: The information obtained from our case and a review of 9 additional cases reported thus far assist physicians who may face the challenge of diagnosing and managing this disorder.

DOI： 10.12998/wjcc.v7.i21.3553

肝硬度測定を用いたICG検査の代替の試み

熊谷優, 横尾健, 佐藤毅昂, 茂木聡子, 川田雄三, 薛徹, 水野研一, 木村成宏, 上村博輝, 坂牧僚, 上村顕也, 土屋淳紀, 高村昌昭, 寺井崇二

日本消化器病学会雑誌 116 ( 臨増大会 ) A849 - A849 2019年11月

高齢者表在型食道癌患者における内視鏡的粘膜下層剥離術後の体組成変化の検討

水澤健, 橋本哲, 上村博輝, 寺井崇二

日本消化器病学会雑誌 116 ( 臨増大会 ) A811 - A811 2019年11月

IgG4関連硬化性胆管炎の一例

中村涼太, 田中裕登, 大越麻里奈, 小関洋平, 水澤健, 五十嵐聡, 林和直, 佐藤裕樹, 坂牧僚, 上村顕也, 横山純二, 寺井崇二

日本消化器病学会甲信越支部例会抄録集 65回 81 - 81 2019年11月

複合型免疫不全症を合併する遷延性黄疸が免疫グロブリン療法により改善した一例

小田知友美, 土屋淳紀, 木村淳史, 冨永顕太郎, 林和直, 寺井崇二

肝臓 60 ( Suppl.3 ) A1000 - A1000 2019年11月

胃瘻造設によりS状結腸間膜穿孔をきたした一例

吉田悠紀, 川田雄三, 永山逸夫, 野澤良祐, 冨永顕太郎, 薛徹, 横尾健, 水野研一, 寺井崇二

日本消化器病学会甲信越支部例会・日本消化器内視鏡学会甲信越支部例会抄録集 65回・87回 47 - 47 2019年11月

肝癌の局所制御及び集学的治療法としての放射線治療の検討

上村顕也, 柴田理, 寺井崇二

肝臓 60 ( Suppl.3 ) A875 - A875 2019年11月

有腹水肝硬変症例に対するtolvaptan投与前後のM2BPGiの経時的変化とその臨床的意義

高村昌昭, 坂牧僚, 寺井崇二, 上村博輝, 土屋淳紀, 薛徹, 上村顕也, 横尾健

肝臓 60 ( Suppl.3 ) A936 - A936 2019年11月

NASHの病態への臓器間ネットワークの関与

高昌良, 上村顕也, 名古屋拓郎, 井上良介, 酒井規裕, 丹羽祐輔, 坂牧僚, 寺井崇二

日本消化器病学会雑誌 116 ( 臨増大会 ) A846 - A846 2019年11月

Eosinophilic esophagitis after total gastrectomy treated with proton pump inhibitors: a case report. 査読

Takashi Owaki, Hiroki Sato, Ryoko Horigome, Satoru Hashimoto, Terasu Honma, Shuji Terai

Clinical journal of gastroenterology 12 ( 5 ) 420 - 423 2019年10月

記述言語：英語

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disorder in the esophagus characterized by symptoms related to esophageal dysfunction and eosinophil-predominant inflammation. EoE and Gastro Esophageal Reflux Disease (GERD) are known not to be mutually exclusive and share a complex relationship. Proton pump inhibitors (PPIs), which are generally used in the treatment of GERD, could be used to treat esophageal eosinophilia in suspected EoE. We report a rare case of EoE after total gastrectomy that responded to PPIs. Our case indicates that the onset of EoE does not necessarily require an acid reflux-induced antigen-mediated drive, and the action of PPIs in patients with active EoE is unrelated to gastric acid suppression.

DOI： 10.1007/s12328-019-00960-4

A rare case of Paneth cell-rich depressed adenoma in the terminal ileum. 査読国際誌

Kentaro Tominaga, Atsunori Tsuchiya, Hiroki Sato, Shuji Terai

Gastrointestinal endoscopy 90 ( 4 ) 694 - 695 2019年10月

Endoscopic retrieval of a button battery using the tip of a magnetic tube. 査読国際誌

Morita S, Yagi K, Terai S

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 31 ( 6 ) e116-e117 2019年10月

肝臓病理の臨床への貢献と次世代への飛躍を目指して小児NAFLD患者の臨床スコアの動態とSerial Biopsyによる知見

上村博輝, 上村顕也, 寺井崇二

肝臓 60 ( Suppl.2 ) A607 - A607 2019年10月

さあ、どうする?治療内視鏡におけるトラブルシューティング(胆膵編) 当科における副乳頭アプローチカニュレーションの工夫

林和直, 五十嵐聡, 寺井崇二

Gastroenterological Endoscopy 61 ( Suppl.2 ) 2055 - 2055 2019年10月

急性膵炎後の諸問題に対する内視鏡の役割重症急性膵炎後Walled-off necrosisに対するLumen apposing metal stentの有効性

五十嵐聡, 林和直, 寺井崇二

Gastroenterological Endoscopy 61 ( Suppl.2 ) 2066 - 2066 2019年10月

IFN-γ刺激下採取エクソソームは抗炎症マクロファージを誘導し、肝線維化改善に寄与する

竹内卓, 土屋淳紀, 寺井崇二

肝臓 60 ( Suppl.2 ) A681 - A681 2019年10月

消化器疾患での間葉系幹細胞を用いた治療法開発

土屋淳紀, 高村昌昭, 寺井崇二

肝臓 60 ( Suppl.2 ) A570 - A570 2019年10月

間葉系幹細胞を"指揮細胞"として用いた肝硬変に対する再生医療の治療戦略

寺井崇二, 土屋淳紀, 竹内卓

肝臓 60 ( Suppl.2 ) A561 - A561 2019年10月

非ウイルス性肝炎・肝硬変増加時代の効果的な肝細胞癌リスク患者の拾い上げと専門医による評価

土屋淳紀, 高村昌昭, 寺井崇二

肝臓 60 ( Suppl.2 ) A696 - A696 2019年10月

高齢者におけるFIB-4 indexの特徴

横尾健, 薛徹, 上村博輝, 坂牧僚, 上村顕也, 土屋淳紀, 高村昌昭, 寺井崇二

肝臓 60 ( Suppl.2 ) A696 - A696 2019年10月

肝癌に対する分子標的治療中のヒスチジンによる肝予備能維持効果と副作用予防

上村顕也, 寺井崇二

肝臓 60 ( Suppl.2 ) A674 - A674 2019年10月

アルコール性肝硬変の予後における、るいそうおよび肥満の影響

坂牧僚, 横山邦彦, 上村顕也, 高村昌昭, 寺井崇二

肥満研究 25 ( Suppl. ) 304 - 304 2019年10月

マウス肝線維化進展予防薬の探索及びレトロゾールによる線維化進展予防効果の検証

酒井規裕, 上村顕也, 名古屋拓郎, 丹羽佑輔, 高昌良, 薛徹, 横尾健, 坂牧僚, 榎本初音, 立木秀尚, 寺井崇二

肝臓 60 ( Suppl.2 ) A680 - A680 2019年10月

NASHモデルマウスにおける自律神経系を介したグレリンの関与

名古屋拓郎, 上村顕也, 井上良介, 酒井規裕, 後藤諒, 高昌良, 丹羽佑輔, 坂牧僚, 寺井崇二

肝臓 60 ( Suppl.2 ) A682 - A682 2019年10月

Wavy mucosal tear in the sigmoid colon. 査読国際誌

Kentaro Tominaga, Junji Yokoyama, Kazunao Hayashi, Atsunori Tsuchiya, Shuji Terai

Clinical case reports 7 ( 9 ) 1825 - 1826 2019年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Although linear mucosal tears have been reported, we found a relatively rare case of wavy mucosal tear in collagenous colitis. This may be related to the mutual weak adhesiveness between the epithelium and collagen band. This complication necessitates great care to be taken while performing colonoscopy in patients suspected of collagenous colitis.

DOI： 10.1002/ccr3.2275

Inhibition of sodium-glucose cotransporter 2 ameliorated renal injury in a novel medaka model of nonalcoholic steatohepatitis-related kidney disease. 査読国際誌

Nagoya T, Kamimura K, Goto R, Shinagawa-Kobayashi Y, Niwa Y, Kimura A, Sakai N, Ko M, Nishina H, Terai S

FEBS open bio 9 ( 12 ) 2016 - 2024 2019年9月

NSTによる消化器内科病変の発見により自宅退院まで改善した症例

小師優子, 村山稔子, 上村博輝, 小山諭, 寺井崇二

学会誌JSPEN 1 ( Suppl. ) 1331 - 1331 2019年9月

非ウイルス性肝硬変時代の門亢症〜ウイルス性との共通点・相違点を中心に〜原発性胆汁性胆管炎における食道・胃静脈瘤の検討

薛徹, 横山純二, 高綱将史, 荒生祥尚, 上村輝博, 坂牧僚, 横尾健, 上村顕也, 土屋淳紀, 高村昌昭, 寺井崇二

日本門脈圧亢進症学会雑誌 25 ( 3 ) 110 - 110 2019年9月

門亢症に伴う慢性肝不全の臓器関連〜脳・腎・腸〜 NASHの病態進行との自律神経を介した臓器間ネットワークの関与

高昌良, 上村顕也, 名古屋拓郎, 大脇崇史, 井上良介, 酒井規裕, 丹羽祐輔, 坂牧僚, 横尾健, 寺井崇二

日本門脈圧亢進症学会雑誌 25 ( 3 ) 77 - 77 2019年9月

Change in body composition in patients with achalasia before and after peroral endoscopic myotomy. 査読国際誌

Takeshi Mizusawa, Hiroki Sato, Kenya Kamimura, Satoru Hashimoto, Ken-Ichi Mizuno, Hiroteru Kamimura, Satoshi Ikarashi, Kazunao Hayashi, Masaaki Takamura, Junji Yokoyama, Shuji Terai

Journal of gastroenterology and hepatology 35 ( 4 ) 601 - 608 2019年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND AIM: Patients with achalasia experience weight loss because of dysphagia caused by impaired relaxation of the lower esophageal sphincter. This study aimed to use dual bioelectrical impedance analysis (BIA) to determine the change in bodyweight and body composition in patients with achalasia before and after peroral endoscopic myotomy (POEM). METHODS: Patients with achalasia who underwent POEM from 2013 to 2018 (n = 72) were retrospectively analyzed for change in bodyweight before and after 3 months. Additionally, change in body composition was prospectively investigated in the final 10 of 72 patients using non-radiation dual BIA. RESULTS: Twenty patients (27.8%) were underweight (body mass index < 18.5) before undergoing POEM. No clinical parameters were identified to be associated with the underweight condition before POEM and be predictive of an increase in bodyweight after POEM. Low visceral fat volume observed on dual BIA correlated closely with the result obtained using computed tomography (Pearson correlation coefficient: r = 0.850, P < 0.01). Patients with achalasia had a statistically significant increase in visceral (P < 0.01) and subcutaneous fat volumes (P < 0.01) after POEM. Skeletal muscle mass index slightly increased (P = 0.02), although the value after POEM was still low. No blood biomarkers were indicators for low bodyweight or low visceral fat volume. CONCLUSIONS: Dual BIA is an effective non-invasive tool to evaluate the change in body composition of underweight patients with achalasia. Skeletal muscle volume was not enough after POEM, although a rapid increase in the intra-abdominal fat volume was observed. Additional studies are warranted to understand the pathological implications.

DOI： 10.1111/jgh.14847

Methotrexate-Associated Lymphoproliferative Disorder: A Rare Case of Large Liver Tumors. 国際誌

Saori Watanabe, Kazuya Takahashi, Kazuhiro Funakoshi, Shuji Terai

Hepatology (Baltimore, Md.) 70 ( 2 ) 748 - 750 2019年8月

Epidemiological analysis of achalasia in Japan using a large-scale claims database 査読

Sato, H., Yokomichi, H., Takahashi, K., Tominaga, K., Mizusawa, T., Kimura, N., Kawata, Y., Terai, S.

Journal of Gastroenterology 54 ( 7 ) 621 - 627 2019年7月

Case of early-stage gastric cancer identified in the gastric mucosa with lanthanum phosphate deposition. 査読

Takatsuna M, Takeuchi M, Usuda H, Terai S

Endoscopy international open 7 ( 7 ) E893 - E895 2019年7月

Colorectal neuroendocrine carcinoma: A case report and review of the literature. 査読国際誌

Yoshida T, Kamimura K, Hosaka K, Doumori K, Oka H, Sato A, Fukuhara Y, Watanabe S, Sato T, Yoshikawa A, Tomidokoro T, Terai S

World journal of clinical cases 7 ( 14 ) 1865 - 1875 2019年7月

Delayed pancreatic ductal leakage after EUS-FNA for autoimmune pancreatitis. 査読

Ikarashi S, Tsuchiya A, Hayashi K, Terai S

Endoscopic ultrasound 8 ( 4 ) 277 - 278 2019年7月

肝癌薬剤耐性におけるエクソソームの有用性および課題

松田康伸, 寺井崇二

BIO Clinica 34 ( 7 ) 737 - 740 2019年7月

記述言語：日本語出版者・発行元：(株)北隆館

エクソソームは、細胞-細胞間コミュニケーションを司る機能をもつ不溶性粒子である。近年ではエクソソームががん診断・治療に有用な生体ツールであることが明らかにされて以降、その実用性に関する注目が集まっている。肝がんは化学療法耐性を伴う、予後不良な悪性疾患であり、エクソソームを用いた治療への期待は高い。肝がん由来のエクソソームはがん進展や転移能を促進し、薬剤耐性獲得にも関与しているため、今後はエクソソーム分泌阻害剤による肝がん治療法の開発が待たれている。(著者抄録)

A case report of psychiatric symptoms following direct-acting antiviral and ribavirin combination therapy for chronic hepatitis C in a patient with innate anxiety. 査読国際誌

Akira Sakamaki, Kenya Kamimura, Naoki Fukui, Haruka Watanabe, Norihiro Sakai, Kentaro Tominaga, Kenichi Mizuno, Masaaki Takamura, Hirokazu Kawai, Takuro Sugai, Satoshi Yamagiwa, Toshiyuki Someya, Shuji Terai

BMC gastroenterology 19 ( 1 ) 85 - 85 2019年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Direct-acting antivirals (DAAs) result in a highly sustained virological response rate and better patient tolerance. However, this therapeutic approach may, on rare occasions, give rise to psychiatric symptoms. We describe a case requiring discontinuation of DAA and ribavirin combination therapy due to psychiatric symptoms in a patient with congenital anxious personality traits. The information summarized here will be helpful to physicians treating chronic hepatitis C virus (HCV) infection in patients with underlying psychiatric problems. CASE PRESENTATION: A 57-year-old Japanese woman diagnosed with chronic HCV infection was prescribed DAA and ribavirin combination therapy. She had a history of mild innate anxiety and development of psychiatric symptoms due to interferon (IFN) therapy 8 years prior, which subsided with discontinuation of the therapy. Similar psychiatric symptoms such as enervation, palpitations, an episode of hyperventilation, and consciousness disturbances with myotonia were observed after the administration of the antiviral agents. No abnormal findings related to her symptoms were observed on laboratory or imaging results. Psychiatrists diagnosed the patient as having a somatization disorder induced by the antiviral agents on the basis of innate anxiety. After the discontinuation of therapy, her symptoms gradually improved. CONCLUSIONS: Although DAAs were not causative factors for psychiatric symptoms in phase 3 studies, a post-marketing study reported psychiatric symptoms such as depression in patients with underlying psychiatric problems. Our case suggests psychiatric symptoms might worsen after DAA and ribavirin administration in patients with underlying psychiatric disorders, and therefore, close monitoring is necessary for these patients, especially if they have a history of psychiatric symptoms after IFN.

DOI： 10.1186/s12876-019-1013-1

Evaluating the effect of injecting triamcinolone acetonide in two sessions for preventing esophageal stricture after endoscopic submucosal dissection. 査読国際誌

Satoru Hashimoto, Ken-Ichi Mizuno, Kazuya Takahashi, Hiroki Sato, Junji Yokoyama, Manabu Takeuchi, Yuichi Sato, Masaaki Kobayashi, Shuji Terai

Endoscopy international open 7 ( 6 ) E764-E770 - E770 2019年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Background and study aims Several previous reports indicate that endoscopic injection of triamcinolone acetonide (TA) after widespread endoscopic submucosal dissection (ESD) is effective for preventing esophageal stricture. We investigated the efficacy of injecting TA in two sessions for preventing stricture formation post-ESD. Patients and methods Sixty-six consecutive patients with widespread mucosal defects that affected more than three-fourths of the circumference of the esophagus were included. The study group (n = 40) received TA injections over two sessions: immediately after and 14 days after ESD. The control group (n = 26) did not receive a TA injection. This study was performed retrospectively against historical controls. The primary endpoint of this study was frequency of stricture after TA injection. The secondary endpoint was number of required endoscopic balloon dilations (EBDs) after TA injection. Results The post-ESD stricture rate among patients who had subcircumferential mucosal defects was 45.7 % in the study group (16/35 patients), which was significantly lower than the rate of 73.9 % in the control group (17/23 patients; P = 0.031). The number of EBD procedures required was significantly lower in the study group (median 0, range 0 - 7) than in the control group (median 4, range 0 - 20; P < 0.001). There was no significant difference between the study and control groups among the patients who had full circumferential mucosal defects. Conclusion This study showed that performing two sessions of TA injection is an effective and safe treatment for prevention of esophageal stricture following subcircumferential ESD.

DOI： 10.1055/a-0894-4374

医学・医療におけるシミュレータの進歩と普及(Vol.23) 消化器領域超音波のシミュレータ腹部超音波/超音波内視鏡

林和直, 五十嵐聡, 寺井崇二

医学のあゆみ 269 ( 12 ) 945 - 948 2019年6月

記述言語：日本語出版者・発行元：医歯薬出版(株)

腹部超音波はその非侵襲性と簡便性のため、検診的なスクリーニングから緊急時のスクリーニング、造影超音波や穿刺治療など、幅広い場面で日常診療において使用されている。したがって、腹部超音波の技術の習得は実臨床において非常に重要である。腹部超音波診断ファントムは、生体と同じようにプローベを当てることができ、腹部臓器の基本描出の習得に有用である。また、バーチャル技術を用いたシミュレータでは超音波画像と周囲臓器の超音波の断面を同時に見ることができ、超音波検査における臓器の解剖学的位置関係の理解や技術習得の助けとなる。また、近年では腹部消化器領域、とくに胆膵領域の診断と治療において超音波内視鏡が必須となってきている。超音波内視鏡の画像読影と技術の習得には修練を要するが、専用のファントムやバーチャル技術を用いたシミュレータが使用可能となってきており、技術の習得が、より容易になることが期待される。(著者抄録)

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00060&link_issn=&doc_id=20190624030012&doc_link_id=%2Faa7ayuma%2F2019%2F026912%2F013%2F0945-0948%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faa7ayuma%2F2019%2F026912%2F013%2F0945-0948%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

ダブルバルーン内視鏡で診断に至った消化管重複症の成人例

丹羽佑輔, 上村顕也, 小林隆昌, 高橋一也, 冨永顕太郎, 河久順志, 阿部聡司, 川合弘一, 横山純二, 杉野英明, 梅津哉, 寺井崇二

ENDOSCOPIC FORUM for digestive disease 35 ( 1 ) 44 - 44 2019年6月

FDG-PETが重粒子線治療の効果判定に有用であった、若年者切除不能肝内胆管癌の1例

渡邉緑, 柴田理, 上村顕也, 安住里映, 渋谷圭, 大野達也, 寺井崇二

日本消化器病学会甲信越支部例会抄録集 64回 34 - 34 2019年6月

Rational arrangement of measuring shear wave speed in the liver. 査読国際誌

Takeshi Yokoo, Tsutomu Kanefuji, Takeshi Suda, Itsuo Nagayama, Takahiro Hoshi, Satoshi Abe, Shinichi Morita, Hiroteru Kamimura, Kenya Kamimura, Atsunori Tsuchiya, Masaaki Takamura, Kazuyoshi Yagi, Shuji Terai

World journal of gastroenterology 25 ( 20 ) 2503 - 2513 2019年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Shear wave speed has been widely applied to quantify a degree of liver fibrosis. However, there is no standardized procedure, which makes it difficult to utilize the speed universally. AIM: To provide procedural standardization of shear wave speed measurement. METHODS: Point shear wave elastography (pSWE) was measured in 781 patients, and two-dimensional shear wave elastography (2dSWE) was measured on the same day in 18 cases. Regions-of-interest were placed at 12 sites, and the median and robust coefficient-of-variation (CVR) were calculated. A residual sum-of-square (Σdi2) was computed for bootstrap values of 1000 iterations in 18 cases with each assumption of 1 to 12 measurements. The proportion of the Σdi2 (%Σdi2) was calculated as the ratio of Σdi2 to pSWE after converting it based on the correlation between pSWE and 2dSWE. RESULTS: The CVR showed a significantly broader distribution in the left lobe (P < 0.0001), and the smallest CVR in the right anterior segment that covered 95% cases was 40.4%. pSWE was significantly higher in the left lobe than in the right lobe (1.63 ± 0.78 m/s vs 1.61 ± 0.78 m/s, P = 0.0004), and the difference between the lobes became further discrete when the subjects were limited to the cases with a CVR less than 40.4% in any segment (1.76 ± 0.80 m/s vs 1.70 ± 0.82 m/s, P < 0.0001). The highest values of the CVR in every 0.1 m/s interval were plotted in convex upward along pSWE and peaked at 1.93 m/s. pSWE and 2dSWE were significantly correlated (P < 0.0001, r = 0.95). In 216000 resamples from 18 cases, the %Σdi2 of 12 sites was 8.0% and gradually increased as the acquisition sites decreased to reach a significant difference with a %Σdi2 of 7 sites (P = 0.027). CONCLUSION: These data suggest that shear wave speed should be measured at 8 or more sites of spreading in both lobes.

DOI： 10.3748/wjg.v25.i20.2503

Utility of measuring paraesophageal varices using computed tomography to select endoscopic treatment for patients with esophageal varices 査読

Kimura, N., Yokoyama, J., Terai, S.

Digestive Endoscopy 31 ( 3 ) 335 - 335 2019年5月

Efficacy and safety of ribavirin therapy for chronic hepatitis E after kidney transplantation. 査読国際誌

Yoshida T, Takamura M, Goto R, Takeuchi S, Tsuchiya A, Kamimura K, Tasaki M, Nakagawa Y, Saito K, Tomita Y, Terai S

Hepatology research : the official journal of the Japan Society of Hepatology 49 ( 10 ) 1244 - 1248 2019年5月

Multiple Endocrine Neoplasia Type 1-Related Acute Pancreatitis. 査読

Takahashi S, Kamimura K, Abe H, Watanabe Y, Hayashi K, Mizuno K, Yamamoto T, Takeuchi M, Natsui M, Terai S

Pancreas 48 ( 5 ) e35 - e38 2019年5月

A rare duodenal carcinosarcoma: A case report and literature review 査読

Arao, Y., Kamimura, K., Ikemi, M., Takaki, M., Takahashi, S., Seino, S., Abe, H., Kohisa, J., Kato, T., Ajioka, Y., Terai, S.

Internal Medicine 58 ( 9 ) 1273 - 1278 2019年5月

Endoscopic ultrasound-guided hepaticogastrostomy using a novel covered metallic stent with a fine-diameter delivery system 査読

Morita, S., Yagi, K., Terai, S.

Digestive Endoscopy 31 ( 3 ) e60 - e61 2019年5月

Submucosal painting for gastroduodenal stent placement. 査読国際誌

Morita S, Suda T, Terai S

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 31 ( 3 ) e64 - e65 2019年5月

膵癌術前胆道ドレナージにおける大口径プラスチックステントの役割

五十嵐聡, 林和直, 寺井崇二, 水澤健, 川田雄三, 冨永顕太郎, 佐藤裕樹, 水野研一, 橋本哲, 横山純二, 高村昌昭

Gastroenterological Endoscopy 61 ( Suppl.1 ) 981 - 981 2019年5月

慢性膵炎による膵管狭窄に対するステント治療の現状と課題

林和直, 五十嵐聡, 寺井崇二, 水澤健, 冨永顕太郎, 佐藤裕樹, 水野研一, 橋本哲, 横山純二

Gastroenterological Endoscopy 61 ( Suppl.1 ) 1000 - 1000 2019年5月

当院における小腸カルチノイド7例の臨床的検討

冨永顕太郎, 川田雄三, 本田穣, 上村顕也, 横山純二, 寺井崇二, 田島陽介, 中野雅人, 島田能史, 亀山仁史, 若井俊文, アネコフ・アレクセイ, 味岡洋一, 阿部達也, 梅津哉, 岩渕三哉

日本大腸肛門病学会雑誌 72 ( 5 ) 348 - 348 2019年5月

A Rare Case Involving the Inability to Belch. 査読

Hiroki Sato, Shunzo Ikarashi, Shuji Terai

Internal medicine (Tokyo, Japan) 58 ( 7 ) 929 - 931 2019年4月

記述言語：英語

A 17-year-old girl was referred to our hospital with an inability to belch, while experiencing chest gurgling noises, and severe abdominal bloating. She reported having these symptoms all her life. A timed barium esophagogram revealed a moderate amount of bubbles in the esophagus and gastric fundus, which significantly increased after the examination. High resolution manometry revealed that the basal upper esophageal sphincter pressure increased with a rise in the cervical esophageal pressure. A pathological inability to belch is rare; at present, no specific name exists to describe the disorder. Further research is needed in this unexplored field.

DOI： 10.2169/internalmedicine.1908-18

Overlap in disease concept of functional esophageal disorders and minor esophageal motility disorders. 査読

Sato H, Takahashi K, Mizuno KI, Hashimoto S, Kawata Y, Mizusawa T, Tominaga K, Yokoyama J, Terai S

Journal of gastroenterology and hepatology 34 ( 11 ) 1940 - 1945 2019年4月

Considerations of elderly factors to manage the complication of liver cirrhosis in elderly patients. 査読国際誌

Kamimura K, Sakamaki A, Kamimura H, Setsu T, Yokoo T, Takamura M, Terai S

World journal of gastroenterology 25 ( 15 ) 1817 - 1827 2019年4月

Inhibition of sodium glucose cotransporter 2 (SGLT2) delays liver fibrosis in a medaka model of nonalcoholic steatohepatitis (NASH). 査読国際誌

Goto R, Kamimura K, Shinagawa-Kobayashi Y, Sakai N, Nagoya T, Niwa Y, Ko M, Ogawa K, Inoue R, Yokoo T, Sakamaki A, Kamimura H, Abe S, Nishina H, Terai S

FEBS open bio 9 ( 4 ) 643 - 652 2019年4月

Esophageal Stenosis by Prostate Cancer Metastasis 査読

Kamimura, K., Shinagawa-Kobayashi, Y., Mizuno, K., Terai, S.

American Journal of Gastroenterology 114 ( 4 ) 685 - 687 2019年4月

Duodenal lymphangiectasia distinguished from follicular lymphoma by narrow-band imaging magnification endoscopy 査読

Tominaga, K., Tsuchiya, A., Mizuno, K.-I., Terai, S.

Gastrointestinal Endoscopy 90 ( 3 ) 2019年4月

Usefulness of CCR7<sup>-</sup> PD-1<sup>+</sup> follicular helper T cell subset frequencies in the diagnosis of autoimmune hepatitis. 査読

Kimura N, Yamagiwa S, Sugano T, Horigome R, Setsu T, Tominaga K, Kamimura H, Takamura M, Terai S

Hepatology research : the official journal of the Japan Society of Hepatology 49 ( 9 ) 1026 - 1033 2019年4月

Management of endoscopic submucosal dissection for ulcerative colitis‐associated neoplasia: Tips and pitfalls

Ken‐ichi Mizuno, Junji Yokoyama, Shuji Terai

Digestive Endoscopy 31 ( S1 ) 44 - 45 2019年4月

当院における高齢発症原発性胆汁性胆管炎患者の予後予測マーカーについて

高村昌昭, 木村成宏, 薛徹, 上村博輝, 坂牧僚, 横尾健, 土屋淳紀, 上村顕也, 松田康伸, 寺井崇二

肝臓 60 ( Suppl.1 ) A407 - A407 2019年4月

急性肝不全:救命率の向上を目指した取り組み本県における急性肝不全診療ネットワーク構築の取り組み

薛徹, 高村昌昭, 寺井崇二

肝臓 60 ( Suppl.1 ) A211 - A211 2019年4月

肝癌診療ガイドライン2017を再検証する肝癌に対する放射線治療の検討

上村顕也, 柴田理, 寺井崇二

肝臓 60 ( Suppl.1 ) A132 - A132 2019年4月

NASH/NAFLDの病態解明に向けた基礎的検討 NASH/NAFLDの病態における自律神経を介した消化管ホルモンの関与

上村顕也, 名古屋拓郎, 寺井崇二

肝臓 60 ( Suppl.1 ) A146 - A146 2019年4月

肝癌に対する分子標的薬の有害事象の発症予測

上村顕也, 寺井崇二

肝臓 60 ( Suppl.1 ) A487 - A487 2019年4月

免疫チェックポイント阻害薬による免疫関連有害事象と考えられる肝障害を呈した2例

坂牧僚, 上村顕也, 寺井崇二

肝臓 60 ( Suppl.1 ) A488 - A488 2019年4月

メダカを用いた食品・医薬品の機能性評価基盤の構築メダカモデルを用いた薬物スクリーニングと医学研究応用

寺井崇二, 上村顕也

日本栄養・食糧学会大会講演要旨集 73回 174 - 174 2019年4月

Esophageal diverticulum: New perspectives in the era of minimally invasive endoscopic treatment. 査読国際誌

Hiroki Sato, Manabu Takeuchi, Satoru Hashimoto, Ken-Ichi Mizuno, Koichi Furukawa, Akito Sato, Junji Yokoyama, Shuji Terai

World journal of gastroenterology 25 ( 12 ) 1457 - 1464 2019年3月

記述言語：英語

Esophageal diverticula are rare conditions that cause esophageal symptoms, such as dysphagia, regurgitation, and chest pain. They are classified according to their location and characteristic pathophysiology into three types: epiphrenic diverticulum, Zenker's diverticulum, and Rokitansky diverticulum. The former two disorders take the form of protrusions, and symptomatic cases require interventional treatment. However, the esophageal anatomy presents distinct challenges to surgical resection of the diverticulum, particularly when it is located closer to the oral orifice. Since the condition itself is not malignant, minimally invasive endoscopic approaches have been developed with a focus on alleviation of symptoms. Several types of endoscopic devices and techniques are currently employed, including peroral endoscopic myotomy (POEM). However, the use of minimally invasive endoscopic approaches, like POEM, has allowed the development of new disorder called iatrogenic esophageal diverticula. In this paper, we review the pathophysiology of each type of diverticulum and the current state-of-the-art treatment based on our experience.

DOI： 10.3748/wjg.v25.i12.1457

M2-polarized macrophages relate the clearance of gastric lanthanum deposition 査読

Nakamura, T., Tsuchiya, A., Kobayashi, M., Naito, M., Terai, S.

Clinical Case Reports 7 ( 3 ) 570 - 572 2019年3月

Diverse perspectives to address for the future treatment of heterogeneous hepatocellular carcinoma. 査読国際誌

Tsuchiya A, Ogawa M, Watanabe T, Takeuchi S, Kojima Y, Watanabe Y, Kimura N, Hayashi K, Yokoyama J, Terai S

Heliyon 5 ( 3 ) e01325 2019年3月

当院における切除不能局所進行膵癌の治療の現況

林和直, 五十嵐聡, 水澤健, 川田雄三, 冨永顕太郎, 佐藤裕樹, 水野研一, 橋本哲, 横山純二, 寺井崇二

日本消化器病学会雑誌 116 ( 臨増総会 ) A468 - A468 2019年3月

術後再建腸管例におけるEUS-FNAの現状と工夫

五十嵐聡, 林和直, 水澤健, 川田雄三, 冨永顕太郎, 佐藤裕樹, 水野研一, 橋本哲, 横山純二, 高村昌昭, 寺井崇二

日本消化器病学会雑誌 116 ( 臨増総会 ) A299 - A299 2019年3月

当院における肝癌に対する放射線治療の検討

柴田理, 上村顕也, 木村成宏, 薛徹, 横尾健, 坂牧僚, 上村博輝, 土屋淳紀, 高村昌昭, 丸山克也, 太田篤, 海津元樹, 青山英史, 寺井崇二

日本消化器病学会雑誌 116 ( 臨増総会 ) A456 - A456 2019年3月

難治性潰瘍性大腸炎の治療戦略における外科と内科のコラボレーション難治性潰瘍性大腸炎に対する治療と今後の課題

横山純二, 冨永顕太郎, 寺井崇二

日本消化器病学会雑誌 116 ( 臨増総会 ) A53 - A53 2019年3月

消化器領域における腸内細菌研究と臨床応用空置腸炎に対宇る自家糞便移植の有用性と腸内細菌叢への影響の解明

冨永顕太郎, 横山純二, 寺井崇二

日本消化器病学会雑誌 116 ( 臨増総会 ) A161 - A161 2019年3月

メタボリックシンドロームとしての脂肪肝 SGLT2阻害薬によるNASH進展抑制効果の検証メダカNASHモデルを用いて

上村顕也, 後藤諒, 寺井崇二

日本消化器病学会雑誌 116 ( 臨増総会 ) A142 - A142 2019年3月

Radial incision and cutting for refractory benign esophageal stricture. 国際誌

Takeshi Mizusawa, Masaaki Kobayashi, Shuji Terai

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 31 ( 2 ) e46-e47 2019年3月

肝線維化研究の展開と臨床応用マウス肝線維化進展予防薬の探索及びレトロゾールによる線維化進展予防効果の検証

酒井規裕, 上村顕也, 寺井崇二

日本消化器病学会雑誌 116 ( 臨増総会 ) A214 - A214 2019年3月

高齢肝癌症例におけるソラフェニブの効果と有用性

横尾健, 森田真一, 木村成宏, 薛徹, 坂牧僚, 上村博輝, 上村顕也, 土屋淳紀, 高村昌昭, 寺井崇二

日本消化器病学会雑誌 116 ( 臨増総会 ) A413 - A413 2019年3月

Co-existent ulcerative colitis and Guillain-Barré syndrome: a case report and literature review. 査読

Tominaga K, Tsuchiya A, Sato H, Kimura A, Oda C, Hosaka K, Kawata Y, Kimura N, Hayashi K, Yokoyama J, Terai S

Clinical journal of gastroenterology 12 ( 3 ) 243 - 246 2019年2月

Clinical and pathological profile of eosinophilic gastroenteritis. 査読国際誌

Hiroki Sato, Terasu Honma, Takashi Owaki, Kentaro Tominaga, Junji Yokoyama, Shuji Terai

European journal of gastroenterology & hepatology 31 ( 2 ) 157 - 162 2019年2月

記述言語：英語

BACKGROUND: Eosinophilic gastroenteritis (EoGE) can be diagnosed on the basis of histologic criteria; however, the pathology is considered to be heterogeneous. There is no consensus on the management of this enigmatic disorder with an unknown etiology. PATIENTS AND METHODS: Data for patients diagnosed with EoGE and followed up over a 1-year period were analyzed. Their symptoms, patterns of flares, and type of treatment were documented. The shift in peripheral blood eosinophil levels was also examined. RESULTS: A total of 10 (mean age, 44 years; range: 31-70 years; women, 5) patients were diagnosed with EoGE. The most frequent presenting symptom was abdominal pain, and eight patients were classified with mucosal type of EoGE. Chronic disease or multiple flares were observed in seven out of 10 (70.0%) patients, and all of them had a history of allergy. Four were corticosteroid dependent (three relapsed during corticosteroid tapering and one following corticosteroid withdrawal). One of them received anti-IL5 monoclonal antibody that enabled corticosteroid dose tapering. In four patients with highly elevated initial eosinophil levels at diagnosis, the peripheral eosinophil level correlated with the amelioration and deterioration of their symptoms. The remaining three patients had a single flare without relapse. Two had no history of allergy. CONCLUSION: EoGE is a unique disorder with a variable clinical course. Although further studies are required to confirm our observations, the presence of other allergic disorders is associated with chronicity or multiple flares. Peripheral eosinophil level may be an effective biomarker for recurrence in patients with severe systemic disorders at diagnosis.

DOI： 10.1097/MEG.0000000000001241

A cut-off value of shear wave speed to distinguish nonalcoholic steatohepatitis candidates 査読

Suda, T., Kanefuji, T., Abe, A., Nagayama, I., Hoshi, T., Morita, S., Yagi, K., Hatakeyama, S., Hayatsu, M., Hasegawa, N., Terai, S.

Medicine (United States) 98 ( 2 ) e13958 2019年1月

Early injection of human adipose tissue-derived mesenchymal stem cell after inflammation ameliorates dextran sulfate sodium-induced colitis in mice through the induction of M2 macrophages and regulatory T cells. 査読

Kawata Y, Tsuchiya A, Seino S, Watanabe Y, Kojima Y, Ikarashi S, Tominaga K, Yokoyama J, Yamagiwa S, Terai S

Cell and tissue research 376 ( 2 ) 257 - 271 2019年1月

EpCAM- and/or NCAM-Expressing Hepatocellular Carcinoma in Which Behavior of Hepatic Progenitor Cell Marker-Positive Cells Are Followed. 査読

Tsuchiya A, Suda T, Oda C, Kimura A, Hosaka K, Kimura N, Tominaga K, Hayashi K, Takamura M, Terai S

Case reports in gastroenterology 13 ( 1 ) 118 - 124 2019年1月

Re-examination using newly proposed diagnostic criteria of acute-on-chronic liver failure in Japan 査読

Nojiri, S., Tsuchiya, A., Terai, S.

Hepatology Research 49 ( 1 ) 2019年

Effective prevention of sorafenib-related vascular damage induced adverse events and maintenance of hepatic function by dried bonito broth and histidine. 査読国際誌

Sakai N, Kamimura K, Shinagawa-Kobayashi Y, Nagoya T, Niwa Y, Ko M, Setsu T, Sakamaki A, Yokoo T, Abe S, Kamimura H, Sugitani S, Yanagi M, Terai S

Cancer management and research 11 4437 - 4448 2019年

A First Ileus Event in an Elderly Man With Malrotation 査読

Tominaga, K., Tsuchiya, A., Terai, S.

Gastroenterology 156 ( 3 ) 35026 - 1 2019年

Dynamic changes in basal lamina fenestrations in rat intestinal villous epithelium under high-fat diet condition 査読

Morita Keisuke, Azumi Rie, Sato Masatoshi, Mizutani Yusuke, Hayatsu Manabu, Terai Shuji, Ushiki Tatsuo

BIOMEDICAL RESEARCH-TOKYO 40 ( 2 ) 57 - 66 2019年

Different distribution of mucosal-associated invariant T cells within the human cecum and colon. 査読

Hama I, Tominaga K, Yamagiwa S, Setsu T, Kimura N, Kamimura H, Wakai T, Terai S

Central-European journal of immunology 44 ( 1 ) 75 - 83 2019年

A case of early<sup>-</sup>stage gastric mixed adenoneuroendocrine carcinoma (MANEC),早期胃 mixed adenoneuroendocrine carcinoma（MANEC）の例

Koseki, Y., Takatsuna, M., Kumagai, M., Kobayashi, Y., Azumi, M., Yoshioka, A., Yoshikawa, S., Usuda, H., Takeuchi, M., Terai, S.

Gastroenterological Endoscopy 61 ( 12 ) 2019年

Gastrointestinal: Endoscopic diverticulectomy for the treatment of Zenker's diverticulum with a unique “tip”: A first case report in Japan

Sato, H., Takeuchi, M., Terai, S.

Journal of Gastroenterology and Hepatology (Australia) 34 ( 8 ) 1272 - 1272 2019年

The search, coagulation, and clipping (SCC) method prevents delayed bleeding after gastric endoscopic submucosal dissection

Azumi, M., Takeuchi, M., Koseki, Y., Kumagai, M., Kobayashi, Y., Takatsuna, M., Yoshioka, A., Yoshikawa, S., Miura, T., Terai, S.

Gastric Cancer 22 ( 3 ) 2019年

Correction to: The search, coagulation, and clipping (SCC) method prevents delayed bleeding after gastric endoscopic submucosal dissection (Gastric Cancer, (2019), 22, 3, (567-575), 10.1007/s10120-018-0878-y)

Azumi, M., Takeuchi, M., Koseki, Y., Kumagai, M., Kobayashi, Y., Takatsuna, M., Yoshioka, A., Yoshikawa, S., Miura, T., Terai, S.

Gastric Cancer 22 ( 3 ) 576 - 576 2019年

Microbiome in Liver Cirrhosis

Sakamaki, A., Takamura, M., Terai, S.

The Evolving Landscape of Liver Cirrhosis Management 2019年

Long-Term Culture of Mouse Fetal Hepatic Stem/Progenitor Cells

Tsuchiya, A., Terai, S.

Methods in molecular biology (Clifton, N.J.) 1905 2019年

Mesenchymal stem cell therapies for liver cirrhosis: MSCs as "conducting cells" for improvement of liver fibrosis and regeneration

Tsuchiya, A., Takeuchi, S., Watanabe, T., Yoshida, T., Nojiri, S., Ogawa, M., Terai, S.

Inflammation and Regeneration 39 ( 1 ) 2019年

Hepatobiliary and Pancreatic: AL amyloidosis presented as a hematoma in the hepatoduodenal ligament

Kobayashi, T., Yoshikawa, S., Takeuchi, M., Terai, S.

Journal of Gastroenterology and Hepatology (Australia) 34 ( 11 ) 1897 - 1897 2019年

肝胆膵疾患に対する低侵襲治療の工夫当院におけるWalled-off necrosis(WON)に対する内視鏡治療成績の検討

林和直, 五十嵐聡, 河久順志, 横山純二, 寺井崇二

ENDOSCOPIC FORUM for digestive disease 34 ( 2 ) 189 - 189 2018年12月

Gastrointestinal: A case of hypereosinophilic syndrome with esophageal involvement 査読

Takahashi, K., Sato, H., Tominaga, K., Kohisa, J., Ikarashi, S., Hayashi, K., Miuzno, K., Hashimoto, S., Yokoyama, J., Terai, S.

Journal of Gastroenterology and Hepatology (Australia) 33 ( 11 ) 1817 - 1817 2018年11月

Novel Magnified Single-Balloon Enteroscopy Enables Observation of Jejunal White Spots Associated with Lymphangiectasia. 査読

Tominaga K, Tsuchiya A, Kawata Y, Yokoyama J, Terai S

Digestive diseases (Basel, Switzerland) 37 ( 2 ) 1 - 5 2018年11月

Mesenchymal Stem Cells and Induced Bone Marrow-Derived Macrophages Synergistically Improve Liver Fibrosis in Mice. 査読国際誌

Watanabe Y, Tsuchiya A, Seino S, Kawata Y, Kojima Y, Ikarashi S, Starkey Lewis PJ, Lu WY, Kikuta J, Kawai H, Yamagiwa S, Forbes SJ, Ishii M, Terai S

Stem cells translational medicine 8 ( 3 ) 271 - 284 2018年11月

高齢者消化器疾患に対する治療方針高齢者の術後再建腸管に対するERCPの検討

水澤健, 五十嵐聡, 林和直, 寺井崇二

日本消化器病学会甲信越支部例会抄録集 63回 47 - 47 2018年11月

腹部大動脈瘤増大により初めての腸閉塞をきたした腸回転異常症の高齢者の1例

村松夏季, 土屋敦紀, 小田知友美, 木村淳史, 保坂和徳, 木村成宏, 冨永顕太郎, 林和直, 寺井崇二

日本消化器病学会甲信越支部例会抄録集 63回 74 - 74 2018年11月

画像診断の新しいモダリティを用いた診断 MRエラストグラフィーを用いたリスクに応じた肝細胞癌及び門脈大循環シャントのマネージメントの確立に向けて

薛徹, 土屋淳紀, 寺井崇二

肝臓 59 ( Suppl.3 ) A850 - A850 2018年11月

原発巣とは真逆なMRI T2所見を呈したぶどう膜悪性黒色腫の多発肝転移の1例

薛徹, 土屋淳紀, 寺井崇二

肝臓 59 ( Suppl.3 ) A893 - A893 2018年11月

ダブルバルーン内視鏡で診断に至った消化管重複症の成人例

丹羽佑輔, 上村顕也, 小林隆昌, 高橋一也, 冨永顕太郎, 河久順志, 阿部聡司, 川合弘一, 横山純二, 杉野英明, 梅津哉, 寺井崇二

日本消化器病学会甲信越支部例会・日本消化器内視鏡学会甲信越支部例会抄録集 63回・85回 59 - 59 2018年11月

肝疾患と臓器相関肝疾患における自律神経による臓器間ネットワークの関与

上村顕也, 名古屋拓郎, 寺井崇二

肝臓 59 ( Suppl.3 ) A862 - A862 2018年11月

Green epithelium revealed by narrow-band imaging (NBI): a feature for practical assessment of extent of gastric cancer after <i>H. pylori</i> eradication. 査読

Yagi K, Nagayama I, Hoshi T, Abe S, Morita SI, Suda T, Hasegawa G, Sato YI, Terai S

Endoscopy international open 6 ( 11 ) E1289 - E1295 2018年11月

Usefulness of Capsule Endoscopy and Double-balloon Enteroscopy for the Diagnosis of Multiple Carcinoid Tumors in the Small Intestine: Case Reports and a Literature Review. 査読

Tominaga K, Kamimura K, Yokoyama J, Terai S

Internal medicine (Tokyo, Japan) 58 ( 5 ) 655 - 659 2018年10月

Gene therapy for pancreatic diseases: Current status 査読

Kamimura, K., Yokoo, T., Terai, S.

International Journal of Molecular Sciences 19 ( 11 ) 2018年10月

超高齢者における肝硬変診療査読

上村顕也, 坂牧僚, 木村成広, 薛徹, 上村博輝, 横尾健, 阿部聡司, 寺井崇二

消化器・肝臓内科 4 ( 4 ) 344 - 347 2018年10月

フレイルとサルコペニアについて進行消化器癌における体組成と予後との関連

川合弘一, 小林隆昌, 中野応央樹, 五十嵐聡, 河久順志, 阿部聡司, 上村博輝, 坂牧僚, 林和直, 上村顕也, 土屋淳紀, 高村昌昭, 寺井崇二

新潟医学会雑誌 132 ( 10 ) 350 - 352 2018年10月

記述言語：日本語出版者・発行元：新潟医学会

近年、様々な疾患で体組成が病態や予後と関連していることが報告されている。我々の検討で、経動脈的治療を行った進行肝細胞癌症例のうち、骨格筋の6ヵ月間変化率が-4.6%未満の症例は予後不良であることが明らかとなった。また低皮下脂肪量も予後不良因子の一つであることを見出した。膵癌非切除例においては、内臓脂肪量が1ヵ月間で大きく減少した群で予後不良だった。進行消化器癌においては体組成、特にその変化率と予後が密接に関連していることが示唆された。(著者抄録)

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J00990&link_issn=&doc_id=20200305060005&doc_link_id=%2Fdg3nigta%2F2018%2F013210%2F005%2F0350-0352%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2018%2F013210%2F005%2F0350-0352%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

ステロイド使用例における胆管結石治療の現状

五十嵐聡, 林和直, 河久順志, 冨永顕太郎, 高橋一也, 水野研一, 橋本哲, 横山純二, 山際訓, 寺井崇二

Gastroenterological Endoscopy 60 ( Suppl.2 ) 2086 - 2086 2018年10月

超音波内視鏡における音速補正モードの有用性

林和直, 五十嵐聡, 河久順志, 高橋一也, 冨永顕太郎, 水野研一, 橋本哲, 横山純二, 山際訓, 寺井崇二

Gastroenterological Endoscopy 60 ( Suppl.2 ) 2110 - 2110 2018年10月

重篤な基礎疾患を持たないサイトメガロウイルス小腸炎の特徴と小腸内視鏡の有用性

横山純二, 冨永顕太郎, 寺井崇二

日本消化器病学会雑誌 115 ( 臨増大会 ) A760 - A760 2018年10月

炎症性腸疾患患者における血清IgAの検討

冨永顕太郎, 横山純二, 寺井崇二

Gastroenterological Endoscopy 60 ( Suppl.2 ) 2121 - 2121 2018年10月

NASHモデルマウスにおける自律神経系を介した消化管ホルモンの関与

名古屋拓郎, 上村顕也, 井上良介, 酒井規裕, 後藤諒, 高昌良, 丹羽佑輔, 坂牧僚, 中村由香, 上野将紀, 寺井崇二

日本消化器病学会雑誌 115 ( 臨増大会 ) A732 - A732 2018年10月

Peroral cholangioscopy of nivolumab-related (induced) ulcerative cholangitis in a patient with non-small cell lung cancer 査読

Kuraoka, N., Hara, K., Terai, S., Yatabe, Y., Horio, Y.

Endoscopy 50 ( 9 ) E259 - E261 2018年9月

Listeria meningitis during infliximab-based treatment for ulcerative colitis 査読

Tsuchiya, A., Terai, S.

Internal Medicine 57 ( 17 ) 2603 - 2603 2018年9月

Disappearance of multiple pancreatic cysts after prednisolone treatment in a patient with autoimmune pancreatitis 査読

Kohisa, J., Tsuchiya, A., Ikemi, M., Terai, S.

Clinical Case Reports 6 ( 9 ) 1898 - 1900 2018年9月

マウス肝線維化進展予防薬の探索及び効果の検証

酒井規裕, 上村顕也, 後藤諒, 小川光平, 坂牧僚, 阿部聡司, 榎本初音, 立木秀尚, 寺井崇二

肝臓 59 ( Suppl.2 ) A723 - A723 2018年9月

消化管疾患と肝疾患の関連-消化管・肝臓間の相互の影響- 自律神経線維による肝,脳,腸の臓器間ネットワークを介した肝切除後の肝再生メカニズムの検討

上村顕也, 寺井崇二

肝臓 59 ( Suppl.2 ) A609 - A609 2018年9月

Diagnosis and management of fibromuscular dysplasia and segmental arterial mediolysis in gastroenterology field: A mini-review. 査読国際誌

Ko M, Kamimura K, Ogawa K, Tominaga K, Sakamaki A, Kamimura H, Abe S, Mizuno K, Terai S

World journal of gastroenterology 24 ( 32 ) 3637 - 3649 2018年8月

Potential role of extracellular vesicle-mediated antigen presentation in Helicobacter pylori hypersensitivity during eradication therapy. 査読国際誌

Takamasa Ito, Takashi Shiromizu, Shunsuke Ohnishi, Shotaro Suzuki, Katsuhiro Mabe, Akito Hasegawa, Hideyuki Ujiie, Yasuyuki Fujita, Yuichi Sato, Shuji Terai, Mototsugu Kato, Masahiro Asaka, Takeshi Tomonaga, Hiroshi Shimizu, Riichiro Abe

The Journal of allergy and clinical immunology 142 ( 2 ) 672 - 676 2018年8月

Gastric Cavernous Hemangioma Resected by Endoscopic Submucosal Dissection. 査読

Watanabe Y, Takahashi K, Yokoyama J, Terai S

Internal medicine (Tokyo, Japan) 57 ( 15 ) 2269 - 2270 2018年8月

The Value of <sup>18</sup>F-FDG PET in the Diagnosis of Intertrabecular Vertebral Metastasis in a Small Cell Lung Cancer Patient with a High Serum CEA Level. 査読

Morita S, Suda T, Oda C, Kobayashi M, Hoshi T, Kanefuji T, Yagi K, Hasegawa G, Terai S

Internal medicine (Tokyo, Japan) 58 ( 3 ) 415 - 418 2018年8月

Successful treatment of aortic dissection during sorafenib therapy for hepatocellular carcinoma. 査読国際誌

Tsuchiya A, Ogawa M, Watanabe Y, Kimura N, Hayashi K, Suda T, Terai S

Clinical case reports 6 ( 8 ) 1643 - 1644 2018年8月

Rapidly declining skeletal muscle mass predicts poor prognosis of hepatocellular carcinoma treated with transcatheter intra-arterial therapies. 査読国際誌

Takamasa Kobayashi, Hirokazu Kawai, Oki Nakano, Satoshi Abe, Hiroteru Kamimura, Akira Sakamaki, Kenya Kamimura, Atsunori Tsuchiya, Masaaki Takamura, Satoshi Yamagiwa, Shuji Terai

BMC cancer 18 ( 1 ) 756 - 756 2018年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The impact of sarcopenia on the prognosis of patients with hepatocellular carcinoma (HCC) who receive transcatheter intra-arterial therapies, including transcatheter arterial chemoembolization and transcatheter arterial infusion chemotherapy, remains unclear. We investigated the prognostic value of skeletal muscle loss (SML) stratified by cutoffs for sarcopenia and rate of change in skeletal muscle mass over 6 months. METHODS: We retrospectively evaluated 102 patients with HCC treated with transcatheter intra-arterial therapies between 2005 and 2015. Computed tomography images of the third lumbar vertebra (L3) were analyzed to obtain the skeletal muscle area normalized for the height squared, defined as the skeletal muscle index at L3 (L3 SMI), before and 6 months after treatment. Low or high SMI was defined using cutoff values of 42 cm2/m2 in men and 38 cm2/m2 in women. The rate of change in skeletal muscle mass (ΔL3 SMI) over 6 months was calculated. Overall survival (OS) was compared in groups classified by baseline L3 SMI and ΔL3 SMI; prognostic significance was assessed with univariate and multivariate analyses, using Cox proportional hazards models. RESULTS: OS did not differ significantly between groups with low (n = 31) and high (n = 71) SMI at baseline (P = 0.172), but OS was significantly poorer in patients with SML (n = 41), defined as ΔL3 SMI < - 4.6% over 6 months than in those without SML (n = 61, P = 0.018). On multivariate analysis, SML (hazard ratio [HR], 1.675; 95% confidence interval [CI], 1.031-2.721; P = 0.037), serum alpha-fetoprotein ≥20 ng/mL (HR, 2.550; 95% CI, 1.440-4.515; P = 0.001), and maximum tumor diameter ≥ 30 mm (HR, 1.925; 95% CI, 1.166-3.179; P = 0.010) were independent predictors of poor OS. Baseline L3 SMI was not significantly associated with OS (HR, 1.405; 95% CI, 0.861-2.293; P = 0.174). CONCLUSIONS: ΔL3 SMI was an independent prognostic factor in patients with HCC treated with transcatheter intra-arterial therapies. Further study is required to reveal whether prevention of skeletal muscle depletion might be a new therapeutic strategy to contribute to improved clinical outcomes in patients with HCC.

DOI： 10.1186/s12885-018-4673-2

Management decision based on lymphovascular involvement leads to favorable outcomes after endoscopic treatment of esophageal squamous cell carcinoma 査読

Kazuya Takahashi, Satoru Hashimoto, Ken-Ichi Mizuno, Takamasa Kobayashi, Kentaro Tominaga, Hiroki Sato, Junji Kohisa, Satoshi Ikarashi, Kazunao Hayashi, Manabu Takeuchi, Junji Yokoyama, Hirokazu Kawai, Yuichi Sato, Masaaki Kobayashi, Shuji Terai

Endoscopy 50 ( 7 ) 662 - 670 2018年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Georg Thieme Verlag

Background Esophageal squamous cell carcinoma (ESCC) invading the muscularis mucosae (MM) and submucosa up to 200μm (SM1) has a risk of metastasis. The aims of this study were to investigate the long-term outcome of endoscopic submucosal dissection (ESD) for MM/SM1 ESCC and to assess the management after ESD in our hospital. Methods This was a retrospective cohort study conducted at a single institution. Patients with MM or SM1 ESCC who were treated with ESD were included. Additional prophylactic therapy was added if lymphovascular involvement (LVI) was noted in the ESD specimens. Results A total of 102 patients were analyzed. The median length of follow-up was 71.5 months (range 9-144 months) and the median number of CTs was 6 (range 0-24). LVI was found in 21 patients (20.6%), and 12 patients underwent additional prophylactic therapy. The 5-year overall survival, disease-specific survival, and tumor-free survival rates were 84.1%, 97.5%, and 82.1%, respectively. A total of 26 patients died, but only 2 of them died from ESCC. The cumulative metastasis rate was 11.8%, and LVI was a significant predictor of metastasis (hazard ratio 5.42, 95% confidence interval 1.39-21.18
P =0.02). There were no differences between patients with MM ESCC and those with SM1 ESCC. Conclusions The long-term outcome after ESD for MM/SM1 ESCC was favorable with additional prophylactic therapy and strict adherence to follow-up.These results indicate that our management decision based on LVI is a valid approach and that ESD can be offered as a therapeutic option to MM/SM1 ESCCs.

DOI： 10.1055/s-0043-124433

A case of inferior vena cava thrombosis caused by compression due to growing giant liver cyst. 査読

Kimura N, Tsuchiya A, Ogawa M, Watanabe Y, Hayashi K, Yokoyama J, Umezu H, Terai S

Clinical journal of gastroenterology 12 ( 1 ) 71 - 75 2018年7月

Anti-Programmed Cell Death-1 Immunotherapy-Related Secondary Sclerosing Cholangitis. 査読国際誌

Ogawa K, Kamimura K, Terai S

Hepatology (Baltimore, Md.) 69 ( 2 ) 914 - 916 2018年7月

Renal Impairment in Chronic Hepatitis B: A Review. 査読国際誌

Hiroteru Kamimura, Toru Setsu, Naruhiro Kimura, Takeshi Yokoo, Akira Sakamaki, Kenya Kamimura, Atsunori Tsuchiya, Masaaki Takamura, Satoshi Yamagiwa, Shuji Terai

Diseases (Basel, Switzerland) 6 ( 2 ) 2018年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

The liver plays a key role in the metabolism of proteins. Liver dysfunction affects many organs because it communicates with the spleen and all digestive organs through the portal vein. Additionally, the kidney is an organ that is closely related to the liver and is involved in liver diseases. Glomerulonephritis is an important extrahepatic manifestation of chronic hepatitis B virus (HBV) infection. Nucleos(t)ide analog (NA) therapy effectively suppresses HBV replication by inhibiting HBV polymerase, thus decreasing the levels of serum HBV-DNA and delaying the progression of cirrhosis. Although NA therapy is recommended for all patients with chronic HBV infection, regardless of the level of renal dysfunction, there is limited information on NA use in patients with chronic kidney disease. In addition, in patients with end-stage liver cirrhosis, hepatorenal syndrome can be fatal. Hence, we should take into account the stage of impaired renal function in patients with cirrhosis. The aims of this article are to review the epidemiology, clinical presentation, treatment, and prevention of HBV-associated nephropathy.

DOI： 10.3390/diseases6020052

Eosinophilic Esophageal Myositis (EoEM) Causes Jackhammer Esophagus, Rarely Posing a Problem in the Differential Diagnosis of Eosinophilic Esophagitis 査読

Hiroki Sato, Shuji Terai

American Journal of Gastroenterology 113 ( 8 ) 1 - 2 2018年6月

Reply to the letter to the editor: Lymph node metastasis of adenocarcinoma and different definitions of sm1 cancer in the esophagus 査読

Ryu Ishihara, Tsuneo Oyama, Seiichiro Abe, Hiroaki Takahashi, Hiroyuki Ono, Junko Fujisaki, Mitsuru Kaise, Kenichi Goda, Kenro Kawada, Tomoyuki Koike, Manabu Takeuchi, Rie Matsuda, Dai Hirasawa, Masayoshi Yamada, Junichi Kodaira, Masaki Tanaka, Masami Omae, Akira Matsui, Takashi Kanesaka, Akiko Takahashi, Shinichi Hirooka, Masahiro Saito, Yosuke Tsuji, Yuki Maeda, Hiroharu Yamashita, Ichiro Oda, Yasuhiko Tomita, Takashi Matsunaga, Shuji Terai, Soji Ozawa, Tatsuyuki Kawano, Yasuyuki Seto

Journal of Gastroenterology 53 ( 6 ) 804 - 805 2018年6月

Nationwide survey for acute liver failure and late-onset hepatic failure in Japan 査読

Masamitsu Nakao, Nobuaki Nakayama, Yoshihito Uchida, Tomoaki Tomiya, Akio Ido, Isao Sakaida, Osamu Yokosuka, Yasuhiro Takikawa, Kazuaki Inoue, Takuya Genda, Masahito Shimizu, Shuji Terai, Hirohito Tsubouchi, Hajime Takikawa, Satoshi Mochida

Journal of Gastroenterology 53 ( 6 ) 752 - 769 2018年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Tokyo

Background: A nationwide survey was performed to clarify the recent status of acute liver failure (ALF) and late-onset hepatic failure (LOHF) in Japan. Methods: Two-step surveys for patients with ALF and LOHF meeting the Japanese diagnostic criteria were performed annually in 782 hospitals. The clinical features of the patients were then compared to those reported in previous surveys. Results: In total, 1554 and 49 patients with ALF and LOHF, respectively, who were seen between 2010 and 2015 were enrolled. The subjects were classified into 1280 patients with hepatitis (642 non-comatose and 638 comatose) and 323 patients without hepatitis (190 non-comatose and 133 comatose). Compared with patients seen between 1998 and 2009, an older patient age and a higher percentage of underlying extrahepatic disease were observed. Although hepatitis virus infection was the most frequent etiology, the percentage of patients with this etiology had decreased, compared with previous cohorts, while the percentages of patients with drug-induced liver injuries, autoimmune hepatitis, and an indeterminate etiology had increased. Liver transplantation was performed in 170 patients (10.6%), whereas artificial liver support with plasmapheresis and/or hemodiafiltration were performed for most of the comatose patients. The outcomes of comatose patients were unfavorable, similar to previous surveys, especially the outcomes of hepatitis B virus carriers, including those with de novo hepatitis B (survival rate of 5.4% without liver transplantation). Conclusion: Although the clinical features, including the etiologies, of patients with ALF and LOHF have changed, the outcomes of patients have not improved in recent years.

DOI： 10.1007/s00535-017-1394-2

IS ENDOSCOPIC SUBMUCOSAL DISSECTION VALUABLE FOR ELDERLY PATIENTS WITH SUPERFICIAL ESOPHAGEAL SQUAMOUS CELL CARCINOMA? 査読

Hashimoto Satoru, Mizuno Kenichi, Takahashi Kazuya, Sato Hiroki, Tominaga Kentaro, Kohisa Junji, Ikarashi Satoshi, Hayashi Kazunao, Yokoyama Junji, Terai Shuji

GASTROINTESTINAL ENDOSCOPY 87 ( 6 ) AB287 - AB287 2018年6月

Persistent reduction of mucosal-associated invariant T cells in primary biliary cholangitis. 査読国際誌

Toru Setsu, Satoshi Yamagiwa, Kentaro Tominaga, Naruhiro Kimura, Hiroki Honda, Hiroteru Kamimura, Atsunori Tsuchiya, Masaaki Takamura, Shuji Terai

Journal of gastroenterology and hepatology 33 ( 6 ) 1286 - 1294 2018年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND AIM: Mucosal-associated invariant T (MAIT) cells constitute a novel subset of innate-like T lymphocytes characterized by a semi-invariant T-cell receptor repertoire capable of recognizing bacterial products. Considering the abundance of MAIT cells in the liver and the possible association between bacterial infections and primary biliary cholangitis (PBC), we aimed to analyze the involvement of MAIT cells in the immunopathogenesis of PBC. METHODS: Peripheral blood and liver biopsy specimens were collected from 25 patients with PBC and 19 patients with chronic viral hepatitis. Surgically removed liver tissues distant from tumors in patients with metastatic liver tumors were used as controls. Mononuclear cells were separated using Ficoll gradient, and the expression of various markers was investigated by flow cytometry. Cytokine production was investigated using blood MAIT cells after stimulation by anti-CD3/CD28-coupled beads with/without interleukin-7 (IL-7). RESULTS: Mucosal-associated invariant T cells were significantly reduced in both the blood and liver of PBC patients compared with those in controls. MAIT cells in the blood of PBC patients expressed significantly lower levels of activation markers and IL-7 receptor. Moreover, MAIT cells in the blood of PBC patients showed impaired production of cytokines, especially tumor necrosis factor alpha, after in vitro stimulation with IL-7. Interestingly, even after biochemical responses were achieved by ursodeoxycholic acid treatment, the frequencies of MAIT cells did not fully recover to normal levels. CONCLUSIONS: These findings suggested that MAIT cells were activated, exhausted, and persistently depleted in PBC patients even after ursodeoxycholic acid treatment, possibly as a consequence of persistent liver inflammation.

DOI： 10.1111/jgh.14076

ENDOSCOPIC MANAGEMENT OF UNRESECTABLE MALIGNANT HILAR STRICTURES USING THREADED INSIDE STENTS VERSUS METALLIC STENTS 査読

Hayashi Kazunao, Ikarashi Satoshi, Kohisa Junji, Takahashi Kazuya, Tominaga Kentaro, Mizuno Ken-ichi, Hashimoto Satoru, Yokoyama Junji, Yamagiwa Satoshi, Terai Shuji

GASTROINTESTINAL ENDOSCOPY 87 ( 6 ) AB208 - AB208 2018年6月

IS ENDOSCOPIC SUBMUCOSAL DISSECTION A FEASIBLE TREATMENT FOR ESOPHAGOGASTRIC JUNCTION CANCER? 査読

Takahashi Kazuya, Hashimoto Satoru, Mizuno Kenichi, Sato Hiroki, Tominaga Kentaro, Kohisa Junji, Ikarashi Satoshi, Hayashi Kazunao, Yokoyama Junji, Terai Shuji

GASTROINTESTINAL ENDOSCOPY 87 ( 6 ) AB396 - AB397 2018年6月

SAFETY AND EFFICACY OF PROPOFOL-BASED SEDATION FOR BALLOON ENTEROSCOPE-ASSISTED ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY IN ELDERLY PATIENTS 査読

Kohisa Junji, Ikarashi Satoshi, Hayashi Kazunao, Takahashi Kazuya, Tominaga Kentaro, Mizuno Kenichi, Hashimoto Satoru, Yokoyama Junji, Yamagiwa Satoshi, Terai Shuji

GASTROINTESTINAL ENDOSCOPY 87 ( 6 ) AB229 - AB229 2018年6月

フランシーン形状針を用いたEUS-FNAの有用性についての検討

河久順志, 林和直, 寺井崇二

ENDOSCOPIC FORUM for digestive disease 34 ( 1 ) 73 - 73 2018年6月

How do you treat this diversion ileitis and pouchitis? 査読

Kentaro Tominaga, Atsunori Tsuchiya, Junji Yokoyama, Shuji Terai

Gut 2018年5月

Efficacy and safety of rifaximin in Japanese patients with hepatic encephalopathy: A phase II/III, multicenter, randomized, evaluator-blinded, active-controlled trial and a phase III, multicenter, open trial 査読

Kazuyuki Suzuki, Ryujin Endo, Yasuhiro Takikawa, Fuminori Moriyasu, Yutaka Aoyagi, Hisataka Moriwaki, Shuji Terai, Isao Sakaida, Yoshiyuki Sakai, Shuhei Nishiguchi, Toru Ishikawa, Hitoshi Takagi, Atsushi Naganuma, Takuya Genda, Takafumi Ichida, Koichi Takaguchi, Katsuhiko Miyazawa, Kiwamu Okita

Hepatology Research 48 ( 6 ) 411 - 423 2018年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Blackwell Publishing Ltd

Aim: The efficacy and safety of rifaximin in the treatment of hepatic encephalopathy (HE) are widely known, but they have not been confirmed in Japanese patients with HE. Thus, two prospective, randomized studies (a phase II/III study and a phase III study) were carried out. Methods: Subjects with grade I or II HE and hyperammonemia were enrolled. The phase II/III study, which was a randomized, evaluator-blinded, active-comparator, parallel-group study, was undertaken at 37 institutions in Japan. Treatment periods were 14 days. Eligible patients were randomized to the rifaximin group (1200 mg/day) or the lactitol group (18–36 g/day). The phase III study was carried out in the same patients previously enrolled in the phase II/III study, and they were all treated with rifaximin (1200 mg/day) for 10 weeks. Results: In the phase II/III study, 172 patients were enrolled. Blood ammonia (B-NH3) concentration was significantly improved in the rifaximin group, but the difference between the two groups was not significant. The portal systemic encephalopathy index (PSE index), including HE grade, was significantly improved in both groups. In the phase III study, 87.3% of enrolled patients completed the treatment. The improved B-NH3 concentration and PSE index were well maintained from the phase II/III study during the treatment period of the phase III study. Adverse drug reactions (ADRs) were seen in 13.4% of patients who received rifaximin, but there were no severe ADRs leading to death. Conclusion: The efficacy of rifaximin is sufficient and treatment is well tolerated in Japanese patients with HE and hyperammonemia.

DOI： 10.1111/hepr.13045

Cost-effectiveness of combined serum anti-Helicobacter pylori IgG antibody and serum pepsinogen concentrations for screening for gastric cancer risk in Japan 査読

Shota Saito, Motoi Azumi, Yusuke Muneoka, Katsuhiko Nishino, Takashi Ishikawa, Yuichi Sato, Shuji Terai, Kouhei Akazawa

European Journal of Health Economics 19 ( 4 ) 545 - 555 2018年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Verlag

Background: A combination of assays for the presence of serum anti-Helicobacter pylori IgG antibody (HPA) and serum pepsinogen (PG) concentrations can be used to screen for gastric cancer risk. In Japan, this “ABC method” is considered an effective means of stratifying gastric cancer risk. This study aimed to ascertain its cost-effectiveness for assessing gastric cancer risk. Methods: A Markov model was constructed to compare the cost-effectiveness of two strategies for gastric cancer-risk screening over a 30-year period: the ABC method, which uses a combination of assessing the presence of HPA and measuring serum PG concentrations and scheduling endoscopies accordingly, and annual endoscopic screening. Clinical and epidemiological data on variables in the model were obtained from published reports. Analyses were made from the perspective of the Japanese health care payer. Results: According to base-case analysis, the ABC method cost less than annual endoscopic screening (64,489 vs. 64,074 USD) and saved more lives (18.16 vs. 18.30 quality-adjusted life years). One-way analyses confirmed the robustness of the cost-effectiveness results. The probability that the ABC method is cost-effective in Japanese individuals aged 50 years was 0.997. Conclusions: A combination of HPA and serum PG assays, plus scheduling endoscopy accordingly, is a cost-effective method of screening for gastric cancer risk in Japan.

DOI： 10.1007/s10198-017-0901-y

Diversion colitis and pouchitis: A mini-review 査読

Kentaro Tominaga, Kenya Kamimura, Kazuya Takahashi, Junji Yokoyama, Satoshi Yamagiwa, Shuji Terai

World Journal of Gastroenterology 24 ( 16 ) 1734 - 1747 2018年4月

記述言語：英語出版者・発行元：Baishideng Publishing Group Co., Limited

Diversion colitis is characterized by inflammation of the mucosa in the defunctioned segment of the colon after colostomy or ileostomy. Similar to diversion colitis, diversion pouchitis is an inflammatory disorder occurring in the ileal pouch, resulting from the exclusion of the fecal stream and a subsequent lack of nutrients from luminal bacteria. Although the vast majority of patients with surgically-diverted gastrointestinal tracts remain asymptomatic, it has been reported that diversion colitis and pouchitis might occur in almost all patients with diversion. Surgical closure of the stoma, with reestablishment of gut continuity, is the only curative intervention available for patients with diversion disease. Pharmacologic treatments using short-chain fatty acids, mesalamine, or corticosteroids are reportedly effective for those who are not candidates for surgical reestablishment
however, there are no established assessment criteria for determining the severity of diversion colitis, and no management strategies to date. Therefore, in this mini-review, we summarize and review various recently-reported treatments for diversion disease. We are hopeful that the information summarized here will assist physicians who treat patients with diversion colitis and pouchitis, leading to better case management.

DOI： 10.3748/wjg.v24.i16.1734

Endoscopic ultrasound-guided transmural drainage for subphrenic abscess: Report of two cases and a literature review 査読

Shinichi Morita, Kenya Kamimura, Takeshi Suda, Chiyumi Oda, Takahiro Hoshi, Tsutomu Kanefuji, Kazuyoshi Yagi, Shuji Terai

BMC Gastroenterology 18 ( 1 ) 55 2018年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BioMed Central Ltd.

Background: An intra-abdominal abscess can sometimes become serious and difficult to treat. The current standard treatment strategy for intra-abdominal abscess is percutaneous imaging-guided drainage. However, in cases of subphrenic abscess, it is important to avoid passing the drainage route through the thoracic cavity, as this can lead to respiratory complications. The spread of intervention techniques involving endoscopic ultrasonography (EUS) has made it possible to perform drainage via the transmural route. Case presentation: We describe two cases of subphrenic abscess that occurred after intra-abdominal surgery. Both were treated successfully by EUS-guided transmural drainage (EUS-TD) without severe complications. Our experience of these cases and a review of the literature suggest that the drainage catheters should be placed both internally and externally together into the abscess cavity. In previous cases there were no adverse events except for one case of mediastinitis and pneumothorax resulting from transesophageal drainage. Therefore, we consider that the transesophageal route should be avoided if possible. Conclusions: Although further studies are necessary, our present two cases and a literature review suggest that EUS-TD is feasible and effective for subphrenic abscess, and not inferior to other treatments. We anticipate that this report will be of help to physicians when considering the drainage procedure for this condition. As there have been no comparative studies to date, a prospective study involving a large number of patients will be necessary to determine the therapeutic options for such cases.

DOI： 10.1186/s12876-018-0782-2

Clinical outcome of hepatocellular carcinoma can be predicted by the expression of hepatic progenitor cell markers and serum tumour markers. 査読国際誌

Satoshi Seino, Atsunori Tsuchiya, Yusuke Watanabe, Yuzo Kawata, Yuichi Kojima, Shunzo Ikarashi, Hiroyuki Yanai, Koji Nakamura, Daisuke Kumaki, Masaaki Hirano, Kazuhiro Funakoshi, Takashi Aono, Takeshi Sakai, Jun Sakata, Masaaki Takamura, Hirokazu Kawai, Satoshi Yamagiwa, Toshifumi Wakai, Shuji Terai

Oncotarget 9 ( 31 ) 21844 - 21860 2018年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

The high heterogeneity of hepatocellular carcinomas (HCCs) complicates stratification of HCC patients for treatment. Therefore, it is necessary to establish a comprehensive panel of HCC biomarkers related to tumour behaviour and cancer prognosis. Resected HCCs from 251 patients were stained for hepatic progenitor cell (HPC) markers epithelial cell adhesion molecule (EpCAM), neural cell adhesion molecule (NCAM), delta-like 1 homolog (DLK1), and cytokeratin 19 (CK19). Staining patterns were analysed for their prognostic association with relapse-free survival and overall survival. α-Fetoprotein (AFP), lectin-reactive α-fetoprotein (AFP-L3), and des-γ-carboxy prothrombin (DCP) were assessed as indicators of HPC protein expression. Expression pattern of HPC markers correlated with tumour malignancy indicated by high AFP/AFP-L3 serum levels, more frequent vascular invasion, and poorer tumour differentiation. EpCAM expression, DCP ≥300 mAU/ml, age ≥60, and Child-Pugh score grade B or C were independent prognostic factors of poor outcome and were used in a new scoring system for HCC prognosis after operation. Expression of two or more HPC markers was a significant predictor of poor HCC outcome and serum levels of AFP/AFP-L3 correlated with the expression of HPC proteins. Our study paved the way for further elucidation of the association among HPC markers, serum tumour markers, and HCC clinical outcome for precision medicine.

DOI： 10.18632/oncotarget.25074

Autonomic nervous system network and liver regeneration 査読

Kenya Kamimura, Ryosuke Inoue, Takuro Nagoya, Norihiro Sakai, Ryo Goto, Masayoshi Ko, Yusuke Niwa, Shuji Terai

World Journal of Gastroenterology 24 ( 15 ) 1616 - 1621 2018年4月

記述言語：英語出版者・発行元：Baishideng Publishing Group Co., Limited

To date, various signal transducers, cytokines, growth factors, and hormones have been reported to play an important role in homeostasis of various organs. Various cells and organs are involved in the hepatic regeneration process, which proceeds as a result of the coordination of many factors. While these factors are well known to be involved in the liver regeneration after the liver injury, however, as the details of such mechanisms have not been sufficiently elucidated, the practical applicability of hepatic regeneration based on the action of these and cytokines growth factors is still unclear. In terms of the involvement of the autonomic nervous system in hepatic regeneration, cell proliferation resulting from direct signal transduction to the liver has also been reported and recent studies focusing on the inter-organ communication via neural network opened a novel aspect of this field for therapeutic applicability. Therefore, the appropriate understanding of the relationship between autonomic neural network and liver regeneration through various organs including brain, afferent nerve, efferent nerve, etc . is essential. This mini-review explains the principle of neural system involved in the inter-organ communication and its contribution on the liver regeneration upon the liver injury reviewing recent progress in this field.

DOI： 10.3748/wjg.v24.i15.1616

A case of Behçet's disease with various gastrointestinal findings. 査読

Tominaga K, Kamimura K, Takahashi K, Yokoyama J, Terai S

Clinical journal of gastroenterology 11 ( 5 ) 1 - 5 2018年4月

Efficacy of EUS for detection of a buried fish bone in the esophagus. 査読

Kohisa J, Mizuno KI, Takahashi K, Yokoyama J, Terai S

VideoGIE : an official video journal of the American Society for Gastrointestinal Endoscopy 3 ( 4 ) 125 - 126 2018年4月

A clinical study of peroral endoscopic myotomy reveals that impaired lower esophageal sphincter relaxation in Achalasia is not only defined by high-resolution manometry 査読

Hiroki Sato, Kazuya Takahashi, Ken-Ichi Mizuno, Satoru Hashimoto, Junji Yokoyama, Shuji Terai

PLoS ONE 13 ( 4 ) e0195423 2018年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Public Library of Science

Background and aim Achalasia is an esophageal motility disorder characterized by impaired lower esophageal sphincter (LES) relaxation. On high-resolution manometry (HRM), impaired LES relaxation is defined by elevated integrated relaxation pressure (IRP). However, a new category of Achalasia within the normal IRP range has been suggested. Methods HRM was performed using a Starlet device and an IRP threshold of 26 mmHg. Peroral endoscopic myotomy (POEM) was performed for cases of Achalasia diagnosed using established methods. During POEM, the histology of the LES was assessed. Follow-up was performed 2 months post-operatively. Results Forty-one patients with Achalasia (18 women, mean age 53 ± 18.6 years) were included. Among them, 27 were placed in the IRP &gt
26 mmHg subgroup (impaired LES relaxation on HRM) and 14 in the IRP ≤ 26 mmHg subgroup (normal LES relaxation on HRM). In the IRP ≤ 26 mmHg subgroup, patients were older, had longer symptom duration, and had more esophageal dilation. The IRP ≤ 26 mmHg subgroup had the same symptom severity as the higher IRP subgroup and POEM significantly improved symptoms and IRP, although four patients still had severe LES fibrosis. Conclusions The clinical presentation of Achalasia has a gap between a HRM-defined impaired LES relaxation, with aging or disease progression considered reasons for a lowered LES pressure. POEM can be a feasible treatment option, even for cases of Achalasia with a normal IRP. However, patients with severe LES fibrosis need more attention for the therapeutic indication.

DOI： 10.1371/journal.pone.0195423

Esophageal motility disorders: new perspectives from high-resolution manometry and histopathology 査読

Hiroki Sato, Kazuya Takahashi, Ken-ichi Mizuno, Satoru Hashimoto, Junji Yokoyama, Go Hasegawa, Shuji Terai

Journal of Gastroenterology 53 ( 4 ) 484 - 493 2018年4月

記述言語：英語出版者・発行元：Springer Tokyo

High-resolution manometry (HRM) and peroral endoscopic myotomy (POEM) have contributed significantly to the field of esophageal motility disorders in recent years. The development of HRM has categorized various esophageal motility disorders with a focus on a diverse range of manometric anomalies. Additionally, the Chicago classification criteria is widely used for manometric diagnosis. Moreover, POEM was introduced as a minimally invasive radical therapy for achalasia and shows promise for other spastic esophageal motility disorders as well. POEM has also enabled a transluminal endoscopic approach for determining the histology of the esophageal muscle layer, which is expected to assist in elucidating the etiology of disorders associated with esophageal motility. The purpose of this review is to update the diagnosis, pathology, and treatment of esophageal motility disorders, with a focus on the recent advances in this field.

DOI： 10.1007/s00535-017-1413-3

Ombitasvir–Paritaprevir–Ritonavir Therapy in a Kidney Transplant Recipient With Chronic Hepatitis C Virus Genotype 1 Infection: A Case Report on the Importance of Considering Drug–Drug Interactions and Monitoring Cyclosporine Levels 査読

S. Takeuchi, M. Takamura, T. Yoshida, K. Takahashi, K. Hayashi, S. Hashimoto, S. Yamagiwa, M. Tasaki, Y. Nakagawa, K. Saito, Y. Tanabe, Y. Tomita, S. Terai

Transplantation Proceedings 50 ( 3 ) 884 - 886 2018年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Elsevier USA

A 74-year-old Japanese man with a history of chronic hepatitis C and kidney transplant (KT) was administered pegylated-interferon plus ribavirin therapy. However, this therapy was ineffective. The patient was then hospitalized to receive ombitasvir (OBV) plus paritaprevir (PTV) plus ritonavir (r) antiviral combination therapy. He tested negative for the virus after 4 weeks, and completed 12 weeks of treatment. The patient ultimately achieved a sustained virological response after the 12 weeks of treatment. Cyclosporine (CyA) trough levels, during the OBV-PTV-r therapy, reached a peak within 5 days of initiating therapy, and increases in serum creatinine and total bilirubin were also observed. However, onset of irreversible nephropathy and hepatopathy were avoided by reducing the CyA dosage. The OBV-PTV-r therapy demonstrated a sufficient antiviral effect and could be safely administered postoperatively to patients having undergone KT. When a combination therapy with interferon-free, direct-acting antivirals is used in patients post-transplantation, consideration of drug-drug interactions with and monitoring CyA are of vital importance.

DOI： 10.1016/j.transproceed.2018.01.006

当院における非切除悪性肝門部胆管狭窄に対する内視鏡的ステント留置術の現状と課題

林和直, 五十嵐聡, 河久順志, 水野研一, 橋本哲, 横山純二, 山際訓, 寺井崇二

Gastroenterological Endoscopy 60 ( Suppl.1 ) 797 - 797 2018年4月

Bleeding from a Small-Intestinal Ulcer Associated with Chronic Hepatitis C. 査読国際誌

Hiroteru Kamimura, Satoshi Yamagiwa, Iwasaki Tomohiro, Wataru Higuchi, Norio Ogata, Atsunori Tsuchiya, Kenya Kamimura, Masaaki Takamura, Hirokazu Kawai, Shuji Terai

The American journal of case reports 19 234 - 237 2018年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND Hepatitis C virus infection is probably the most common chronic viral infection and affects an estimated 180 million people worldwide. Extrahepatic manifestations are well recognized among patients with chronic HCV infection. CASE REPORT We report a case of melena occurring in a 69-year-old Japanese man who had been diagnosed with CHC and who was treated with antiviral therapy. CONCLUSIONS Finally, he was diagnosed with multiple small intestine ulcers in a short time. We herein report the case of HCV with rapidly developing small intestine ulcers.

Proposed diagnostic criteria for acute-on-chronic liver failure in Japan 査読

Satoshi Mochida, Nobuaki Nakayama, Akio Ido, Kazuaki Inoue, Takuya Genda, Yasuhiro Takikawa, Isao Sakaida, Shuji Terai, Osamu Yokosuka, Masahito Shimizu, Hajime Takikawa

Hepatology Research 48 ( 4 ) 219 - 224 2018年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Blackwell Publishing Ltd

To establish diagnostic criteria for acute-on-chronic liver failure (ACLF) in Japan, the Intractable Hepato-Biliary Disease Study Group of Japan undertook a multicenter pilot survey for patients fulfilling the Asian Pacific Association for the Study of the Liver (APASL), Association for the Study of the Liver–Chronic Liver Failure (EASL-Clif) Consortium, or Chinese Medical Association (CMA) diagnostic criteria for ACLF. The APASL criteria were suitable for screening Japanese patients with ACLF when patients whose conditions were triggered by gastrointestinal bleeding were included within the disease entity, and the EASL-Clif Consortium criteria were useful for classifying the severity of the patients’ conditions. Based on these observations, the Study Group proposed the following diagnostic criteria for ACLF in Japan: patients with cirrhosis and a Child–Pugh score of 5–9 should be diagnosed as having ACLF when a deterioration of liver function (serum bilirubin level ≥5.0 mg/dL and prothrombin time value ≤40% of the standardized values and/or international normalization rate ≥1.5) caused by severe liver damage develops within 28 days after acute insults, such as alcohol abuse, bacterial infection, gastrointestinal bleeding, or the exacerbation of underlying liver diseases. The severities of the patients can be classified into four grades depending on the extent of the deterioration in organ functions, including kidney, cerebral, blood coagulation, circulatory and respiratory functions, as well as liver function. The usefulness of these novel criteria should be validated prospectively in a large-scale cohort in the future.

DOI： 10.1111/hepr.13066

Effect of a neural relay on liver regeneration in mice: activation of serotonin release from the gastrointestinal tract 査読

Ryosuke Inoue, Kenya Kamimura, Takuro Nagoya, Norihiro Sakai, Takeshi Yokoo, Ryo Goto, Kohei Ogawa, Yoko Shinagawa-Kobayashi, Yukari Watanabe-Mori, Akira Sakamaki, Satoshi Abe, Hiroteru Kamimura, Norio Miyamura, Hiroshi Nishina, Shuji Terai

FEBS Open Bio 8 ( 3 ) 449 - 460 2018年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Wiley Blackwell

The development of therapeutic options to promote hepatic regeneration following severe liver injury is essential. While humoral factors have been reported as mechanisms of liver regeneration, the contributions of interorgan communication to liver regeneration have not been reported. In this study, we examined the effect of a neural relay on liver regeneration via activation of serotonin release from the gastrointestinal (GI) tract. Our results demonstrated that the afferent visceral nerve from the liver activates the efferent vagus nerve from the brain, leading to activation of serotonin release from the GI tract and contributing to liver regeneration. While it is difficult to apply these results directly to human health, we believe that this study may represent a step toward developing essential therapeutics to promote liver regeneration.

DOI： 10.1002/2211-5463.12382

A multicenter pilot survey to clarify the clinical features of patients with acute-on-chronic liver failure in Japan 査読

Nobuaki Nakayama, Hayato Uemura, Yoshihito Uchida, Tomoaki Tomiya, Akio Ido, Kazuaki Inoue, Takuya Genda, Yasuhiro Takikawa, Isao Sakaida, Shuji Terai, Osamu Yokosuka, Masahito Shimizu, Hajime Takikawa, Satoshi Mochida

Hepatology Research 48 ( 4 ) 303 - 312 2018年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Blackwell Publishing Ltd

Aim: To establish diagnostic criteria for acute-on-chronic liver failure (ACLF) in Japan, a multicenter pilot survey was carried out to examine the usefulness of overseas criteria in patients with chronic liver diseases manifesting acute decompensation. Methods: Patients fulfilling the Asian-Pacific Association for the Study of the Liver (APASL), European Association for the Study of the Liver (EASL), or Chinese Medical Association (CMA) criteria for decompensation were enrolled from eight institutions in Japan, and the clinical features were evaluated. Results: Among 112 patients, 109 patients (97.3%) fulfilled the APASL criteria for decompensation
7 patients were excluded because the decompensation had been provoked by gastrointestinal bleeding. Consequently, 102 patients (91.1%) were diagnosed as having ACLF according to the APASL definition. Among the patients who fulfilled the APASL criteria for decompensation, the etiologies of the underlying liver diseases were alcohol abuse in 59 cases (54.1%) and hepatitis B or hepatitis C virus infection in 24 (22.0%). The acute insults were alcohol abuse in 50 (45.9%), bacterial infection in 26 (23.9%), and exacerbation of underlying liver disease in 14 (12.8%). Fifty-four patients (49.5%) satisfied the CMA criteria, but the survival rates were similar between patients who did and those who did not meet the criteria. When 84 patients with underlying cirrhosis were classified according to the EASL–Chronic Liver Failure (Clif) Consortium criteria, the survival rates differed according to grade: 67.6% (23/34) for patients without ACLF, and 41.2% (14/34) and 18.8% (3/16) for those with grade 1/2 and grade 3 ACLF, respectively. Conclusion: The APASL definition was suitable for screening Japanese patients with ACLF, including those whose conditions were triggered by gastrointestinal bleeding, and the EASL-Clif Consortium criteria were useful for predicting outcome.

DOI： 10.1111/hepr.13064

Gastric Metastasis From Uveal Melanoma. 査読国際誌

Morita S, Suda T, Terai S

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 17 ( 7 ) A20 2018年3月

急性膵炎診療Up-to-date 重症急性膵炎におけるwalled-off necrosis合併のリスク因子に関する多施設共同後方視的研究

五十嵐聡, 林和直, 寺井崇二

日本消化器病学会雑誌 115 ( 臨増総会 ) A176 - A176 2018年3月

切除不能膵癌における好中球リンパ球比と他の炎症・栄養指標による予後予測能の比較検討

中野応央樹, 川合弘一, 小林隆昌, 河久順志, 五十嵐聡, 林和直, 横山順二, 寺井崇二

日本消化器病学会雑誌 115 ( 臨増総会 ) A373 - A373 2018年3月

Effect of histidine on sorafenib-induced vascular damage: Analysis using novel medaka fish model 査読

Yoko Shinagawa-Kobayashi, Kenya Kamimura, Ryo Goto, Kohei Ogawa, Ryosuke Inoue, Takeshi Yokoo, Norihiro Sakai, Takuro Nagoya, Akira Sakamaki, Satoshi Abe, Soichi Sugitani, Masahiko Yanagi, Koichi Fujisawa, Yoshizu Nozawa, Naoto Koyama, Hiroshi Nishina, Makoto Furutani-Seiki, Isao Sakaida, Shuji Terai

Biochemical and Biophysical Research Communications 496 ( 2 ) 556 - 561 2018年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Elsevier B.V.

Background Sorafenib (SFN) is an anti-angiogenic chemotherapeutic that prolongs survival of patients with hepatocellular carcinoma (HCC)
its side effects, including vascular damages such as hand-foot syndrome (HFS), are a major cause of therapy discontinuation. We previously reported that maintenance of peripheral blood flow by intake of dried bonito broth (DBB) significantly prevented HFS and prolonged the administration period. The amino acids contained in DBB probably contribute to its effects, but the mechanism has not been clarified. We hypothesized that histidine, the largest component among the amino acids contained in DBB, has effects on SFN-induced vascular damage, and evaluated this possibility using a novel medaka fish model. Methods The fli::GFP transgenic medaka fish model has a fluorescently visible systemic vasculature. We fed the fish with SFN with and without histidine to compare blood flow and vascular structure among the differently fed models. The vascular cross-sectional area of each fish was measured to determine vascular diameter changes. Results Our results demonstrated that SFN-fed medaka developed a narrower vascular diameter. In addition, this narrowing was counteracted by addition of histidine to the medaka diet. We observed no positive effect of histidine on regeneration of cut vessels or on cell growth of endothelial cells and HCC cell lines. Conclusion We proved the efficacy of the medaka model to assess vascular changes after administration of specific chemicals. And our results suggest that SFN causes vascular damage by narrowing peripheral vessel diameter, and that histidine effectively counteracts these changes to maintain blood flow.

DOI： 10.1016/j.bbrc.2018.01.057

A case of panenteritis with massive IgG4-positive plasma cell infiltration developed 26 years after total proctocolectomy for ulcerative colitis 査読

Kentaro Tominaga, Atsunori Tsuchiya, Yutaka Honda, Tatsuya Abe, Junji Yokoyama, Hajime Umezu, Shuji Terai

American Journal of Gastroenterology 113 ( 2 ) 173 2018年2月

Response criteria of tolvaptan for the treatment of hepatic edema 査読

Yasunari Hiramine, Haruki Uojima, Hiroyuki Nakanishi, Akira Hiramatsu, Takuya Iwamoto, Mutsuumi Kimura, Hideto Kawaratani, Shuji Terai, Hitoshi Yoshiji, Hirofumi Uto, Isao Sakaida, Namiki Izumi, Kiwamu Okita, Kazuhiko Koike

Journal of Gastroenterology 53 ( 2 ) 258 - 268 2018年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Tokyo

Background: Although tolvaptan is an effective treatment for hepatic edema, there are no established criteria for assessment of the therapeutic effect. The present study evaluates the association between body weight change and clinical symptoms to identify an effective indicator of tolvaptan response. Methods: The study comprised 460 patients. The first data set contained 147 patients with hepatic edema who received tolvaptan in Kagoshima Kouseiren Hospital, a representative institution of this study. From these data, an optimal cutoff value of body weight change, which accurately indicated symptom reduction, was identified. The response rates obtained based on the cutoff value were evaluated by receiver-operating characteristic (ROC) analysis and kappa coefficients. The kappa coefficient was then validated internally using the bootstrap method and externally using the validation data set of 313 patients from four other hospitals. Results: A cutoff value for body weight loss of 1.5 kg/week produced the largest area under the ROC curve (0.961
sensitivity, 89.8%
specificity, 92.0%) and a high kappa coefficient (0.831). The correlation between symptom reduction and body weight loss of 1.5 kg/week was evaluated internally and externally, and the cutoff value was validated. Conclusions: The cutoff value of body weight change that most accurately reflected symptom reduction was 1.5 kg/week
this value is expected to be an effective indicator of response to tolvaptan in clinical practice.

DOI： 10.1007/s00535-017-1366-6

The factors influencing long-term outcomes of stenting for malignant colorectal obstruction in elderly group in community medicine 査読

Michitaka Imai, Kenya Kamimura, Yoshifumi Takahashi, Toshihiro Sato, Osamu Isokawa, Masaki Maruyama, Takamasa Kobayashi, Kazunao Hayashi, Shuji Terai

International Journal of Colorectal Disease 33 ( 2 ) 189 - 197 2018年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Verlag

Purpose: Malignant bowel obstruction is a complication of colorectal carcinoma or metastasis from other carcinoma, and it causes significant damage on the condition of elderly patients
however, the self-expandable metallic stents (SEMSs) have been effectively used either for palliation or for bridging to the surgical procedure for this condition. The aim of this study was to investigate the factors influencing long-term outcomes of old-aged patients with SEMS for large bowel obstruction to develop the strategy for those patients in the community medicine. Methods: We performed a retrospective review of 42 patients with a median age of 83.0 years (range, 65–99 years), who underwent SEMS placement for malignant colorectal obstruction between 2006 and 2015 in our hospital. Univariate and multivariate logistic regressions were performed on data from the patients to assess the factors affecting 6-month survival without stent dysfunction. Results: The study population comprised 24 females (57.1%) and 18 males (42.9%). Of these, 38 patients (90.5%) received SEMS as palliation, whereas 4 patients (9.5%) underwent subsequent surgery. SEMSs were successfully inserted in 97.6% of patients. The median duration of follow-up was 205.0 days (range, 20–1377 days). On multivariate analysis, shorter stents (&lt
10 cm) yielded better outcomes than longer stents (≥ 10 cm) (P = 0.041), and the Cox proportional hazard model also indicated that shorter stents (P = 0.036) predicted longer event-free survival. Conclusions: Elderly patients with malignant bowel obstruction receiving shorter stents had longer event-free survival after stenting with better general condition.

DOI： 10.1007/s00384-017-2946-x

Possible involvement of chemokine C-C receptor 7−programmed cell death-1+ follicular helper T-cell subset in the pathogenesis of autoimmune hepatitis 査読

Naruhiro Kimura, Satoshi Yamagiwa, Tomoyuki Sugano, Toru Setsu, Kentaro Tominaga, Hiroteru Kamimura, Masaaki Takamura, Shuji Terai

Journal of Gastroenterology and Hepatology (Australia) 33 ( 1 ) 298 - 306 2018年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Blackwell Publishing

Background and Aim: Recent studies have demonstrated that B cells and follicular helper T (Tfh) cells, which are central regulators of humoral immune response, contribute to the development and progression of autoimmune diseases. Because Tfh cells can be divided into several subsets with distinct functional properties, this study aimed to examine the roles of different subsets of circulating Tfh cells in the immune pathogenesis of autoimmune hepatitis (AIH). Methods: Thirty-five patients with AIH, 28 patients with primary biliary cholangitis, 22 patients with chronic hepatitis B (CHB), and 44 health controls (HC) were enrolled. The frequencies of different Tfh subsets in the blood and liver were examined by flow cytometry and immunohistochemical staining. The function of circulating Tfh subsets was examined after in vitro stimulation. Results: In newly diagnosed AIH patients, the frequency of circulating chemokine C-C receptor 7−programmed cell death-1+ Tfh subset was significantly increased compared with that in CHB patients and HC, significantly correlated with clinical parameters, including serum IgG, prothrombin time and albumin levels, and significantly decreased after corticosteroid treatment. In the liver of AIH patients, the frequencies of activated Tfh subsets were significantly increased and positively correlated with those in the blood. Moreover, the ability to produce interleukin-21 and interleukin-17 from circulating Tfh cells was significantly increased in AIH patients compared with HC. Conclusions: These results significantly extend our understanding of Tfh subsets in AIH and suggest a potential role of dysregulated chemokine C-C receptor 7−programmed cell death-1+ Tfh subset in the pathogenesis and disease progression of AIH.

DOI： 10.1111/jgh.13844

Full-layer mucosal histology in achalasia: Histological epithelial wave is characteristic in "pinstripe pattern"-positive achalasia. 査読

Sato H, Takahashi K, Nakajima N, Hasegawa G, Mizuno K, Hashimoto S, Ikarashi S, Hayashi K, Honda Y, Yokoyama J, Sato Y, Terai S

Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society 30 ( 1 ) e13168 - e13168 2018年1月

臨床応用可能な肝臓選択的核酸医薬送達法の確立招待査読

上村顕也, 横尾健, 寺井崇二

BIO Clinica 33 ( 1 ) 34 - 38 2018年1月

Terai, S.

Drug Delivery System 33 ( 5 ) 2018年

Gastrointestinal: A rare case of concomitant type III achalasia and chronic idiopathic intestinal pseudo-obstruction

Sato, H., Abe, H., Nagashima, A., Yokoyama, J., Terai, S.

Journal of Gastroenterology and Hepatology (Australia) 33 ( 3 ) 559 - 559 2018年

Exploration for cell sources for liver regenerative medicine: “CLiP” as a dawn of cell transplantation therapy

Hosaka, K., Katsuda, T., Terai, S., Ochiya, T.

Stem Cells and Cancer in Hepatology: From the Essentials to Application 2018年

Successful closure with over-the-scope clip of an iatrogenic duodenal perforation due to endoscopic ultrasonography

Morita, S., Suda, T., Oda, C., Hoshi, T., Kanefuji, T., Yagi, K., Terai, S.

Endoscopic Forum for Digestive Disease 34 ( 1 ) 2018年

Effective prevention of sorafenib-induced hand-foot syndrome by dried-bonito broth. 査読国際誌

Kenya Kamimura, Yoko Shinagawa-Kobayashi, Ryo Goto, Kohei Ogawa, Takeshi Yokoo, Akira Sakamaki, Satoshi Abe, Hiroteru Kamimura, Takeshi Suda, Hiroshi Baba, Takayuki Tanaka, Yoshizu Nozawa, Naoto Koyama, Masaaki Takamura, Hirokazu Kawai, Satoshi Yamagiwa, Yutaka Aoyagi, Shuji Terai

Cancer management and research 10 805 - 813 2018年

記述言語：英語掲載種別：研究論文（学術雑誌）

Background: Sorafenib (SOR) is a molecular medicine that prolongs the survival of patients with hepatocellular carcinoma (HCC). Therefore, the management of side effects is essential for the longer period of continuous medication. Among the various side effects, hand-foot syndrome (HFS) is the most common, occurring in 30%-50% of patients, and often results in discontinuation of the SOR medication. However, its mechanism has not been clarified, and no effective prevention method has been reported for the symptoms. Therefore, this study aimed to analyze its mechanism and to develop an effective prevention regimen for the symptoms. Materials and methods: To assess the mechanism of SOR-induced HFS, the peripheral blood flow in the hand and foot was carefully monitored by Doppler ultrasound, thermography, and laser speckle flowgraphy in the cases treated with SOR and its contribution was assessed. Then, the effect of dried-bonito broth (DBB), which was reported to improve peripheral blood flow, on the prevention of the symptom was examined by monitoring its occurrence and the peripheral blood flow. Results: A total of 25 patients were enrolled in this study. In all, eight patients developed HFS, and all cases showed a significant decrease in the peripheral blood flow. DBB contributed to an increase in the flow (p = 0.009) and significantly decreased occurrence of HFS (p = 0.005) than control. Multivariable analysis showed that the ingestion of DBB is a significant independent contributor to HFS-free survival period (p = 0.035). Conclusion: The mechanism of SOR-induced HFS involves a decrease in the peripheral blood flow, and the ingestion of DBB effectively prevents the development of the syndrome by maintaining the flow.

DOI： 10.2147/CMAR.S159370

Antireflux Metal Stent for Initial Treatment of Malignant Distal Biliary Obstruction 査読

Shinichi Morita, Yasuaki Arai, Shunsuke Sugawara, Miyuki Sone, Yasunari Sakamoto, Takuji Okusaka, Shigetaka Yoshinaga, Yutaka Saito, Shuji Terai

Gastroenterology Research and Practice 2018 3805173 2018年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Hindawi Limited

Objectives. To compare the use of an antireflux metal stent (ARMS) with that of a conventional covered self-expandable metal stent (c-CSEMS) for initial stenting of malignant distal biliary obstruction (MDBO). Materials and Methods. We retrospectively investigated 59 consecutive patients with unresectable MDBO undergoing initial endoscopic biliary drainage. ARMS was used in 32 patients and c-CSEMS in 27. Technical success, functional success, complications, causes of recurrent biliary obstruction (RBO), time to RBO (TRBO), and reintervention were compared between the groups. Results. Stent placement was technically successful in all patients. There were no significant intergroup differences in functional success (ARMS [96.9%] versus c-CSEMS [96.2%]), complications (6.2 versus 7.4%), and RBO (48.4 versus 42.3%). Food impaction was significantly less frequent for ARMS than for c-CSEMS (P=0.037), but TRBO did not differ significantly between the groups (log-rank test, P=0.967). The median TRBO was 180.0 [interquartile range (IQR), 114.0-349.0] days for ARMS and 137.0 [IQR, 87.0-442.0] days for c-CSEMS. In both groups, reintervention for RBO was successfully completed in all patients thus treated. Conclusion. ARMS offers no advantage for initial stent placement, but food impaction is significantly prevented by the antireflux valve.

DOI： 10.1155/2018/3805173

A Case of Enteritis Induced by Nivolumab 査読

Takamasa Kobayashi, Kazuya Takahashi, Shuji Terai

Clinical Gastroenterology and Hepatology 2018年

Specific gastric blood vessels in sinistral portal hypertension 査読

Hiroteru Kamimura, Toru Ishikawa, Noriko Ishihara, Shuji Terai

Internal Medicine 57 ( 7 ) 1053 - 1054 2018年

Prognostic value of subcutaneous adipose tissue volume in hepatocellular carcinoma treated with transcatheter intra-arterial therapy. 査読国際誌

Takamasa Kobayashi, Hirokazu Kawai, Oki Nakano, Satoshi Abe, Hiroteru Kamimura, Akira Sakamaki, Kenya Kamimura, Atsunori Tsuchiya, Masaaki Takamura, Satoshi Yamagiwa, Shuji Terai

Cancer management and research 10 2231 - 2239 2018年

記述言語：英語掲載種別：研究論文（学術雑誌）

Background: Prognosis of patients with hepatocellular carcinoma (HCC) who undergo transcatheter intra-arterial therapies, including transcatheter arterial chemoembolization and transcatheter arterial infusion chemotherapy, is affected by many clinical factors including liver function and tumor progression. However, the effect of body composition such as skeletal muscle and visceral and subcutaneous adipose tissues (VAT and SAT, respectively) on the prognosis of these patients remains unclear. We investigated the prognostic value of body composition in HCC patients treated with transcatheter intra-arterial therapies. Patients and methods: This study retrospectively evaluated 100 HCC patients treated with transcatheter intra-arterial therapies between 2005 and 2015. Areas of skeletal muscle, VAT, and SAT were measured on computed tomography images at third lumbar vertebra level and normalized by the height squared to calculate the skeletal muscle index, VAT index, and SAT index (SATI). The visceral to subcutaneous adipose tissue area ratio was also calculated. Overall survival (OS) was compared between high- and low-index groups for each body composition. Furthermore, prognostic significance was assessed by univariate and multivariate analyses using Cox proportional hazards models. Results: Among the body composition indexes, only SATI could significantly differentiate OS (p=0.012). Multivariate analysis showed that SATI (low- vs. high-SATI: HR, 2.065; 95% CI, 1.187-3.593; p=0.010), serum albumin (<3.5 vs. ≥3.5 g/dL; HR, 2.007; 95% CI, 1.037-3.886; p=0.039), serum alpha-fetoprotein (<20 vs. ≥20 ng/mL; HR, 0.311; 95% CI, 0.179-0.540; p<0.001), and Modified Response Evaluation Criteria in Solid Tumors assessment (complete response+partial response+stable disease vs. progressive disease; HR, 0.392; 95% CI, 0.221-0.696; p=0.001) were indicated as independent prognostic factors for OS. Conclusion: High SAT volume is associated with better survival outcomes in HCC patients treated with transcatheter intra-arterial therapies. Elucidation of the mechanisms regulating SAT volume may offer a new therapeutic strategy for these patients.

DOI： 10.2147/CMAR.S167417

Dynamics of basal lamina fenestrations in the rat intestinal villous epithelium in response to dietary conditions 査読

Rie Azumi, Keisuke Morita, Yusuke Mizutani, Manabu Hayatsu, Shuji Terai, Tatsuo Ushiki

Biomedical Research (Japan) 39 ( 2 ) 65 - 74 2018年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Biomedical Research Foundation

The epithelial basal lamina of the small intestine forms a felt-like sheet at the base of the epithelium. Previous studies have shown that the basal lamina has numerous fenestrations, which are produced by leukocytes penetrating through the basal lamina. In this study, we aimed to directly visualize fenestrations of the rat basal lamina in intestinal villi by scanning electron microscopy (SEM) after removal of the villous epithelium by osmium maceration and ultrasonic treatment. Structural changes in fenestrations were then investigated in relation to dietary conditions. SEM of these tissues revealed the presence of fenestrations in the villous epithelial basal lamina in all segments of the small intestine, although the number was the highest in the jejunum. The present study also showed that the number and size of fenestrations increased after feeding in the jejunum, whereas changes were unclear in the ileum. These findings suggested that the basal lamina fenestrations were changed through the dynamics of migrating leukocytes in dietary conditions and may also be related to the regulation of nutrient absorption, particularly as lipids are transported from the intercellular space of the epithelium to the lamina propria.

DOI： 10.2220/biomedres.39.65

A rare case of concomitant type III achalasia and chronic idiopathic intestinal pseudo-obstruction. 査読

Sato H, Abe H, Nagashima A, Yokoyama J, Terai S

J Gastroenterol Hepatol 33 ( 3 ) 559 2018年

Jackhammer esophagus accompanied by esophageal intramural pseudodiverticulosis 査読

Kazuya Takahashi, Satoshi Ikarashi, Junji Yokoyama, Shuji Terai

Internal Medicine 57 ( 7 ) 1051 - 1052 2018年

A Case of Pancreatic Schwannoma Diagnosed Preoperatively by Endoscopic Ultrasonography-Guided Fine Needle Aspiration and Treated with Laparoscopic Surgery. 査読国際誌

Hayashi K, Tsuchiya A, Ikarashi S, Takizawa K, Terai S

Journal of pancreatic cancer 4 ( 1 ) 7 - 10 2018年

Gastric Cancer after H. pylori Eradication therapy develops in the Intermediate Zone. Relationship to Spasmolytic Polypeptide-Expressing Metaplasia 査読

Kazuyoshi Yagi, Itsuo Nagayama, Takahiro Hoshi, Satoshi Abe, Shinichi Morita, Takeshi Suda, Yu-ichi Sato, Shuji Terai

Open Access J Surg 9 1 - 6 2018年

Eosinophilic esophagitis in Japanese patients: A mild and slow-progressing disorder. 査読国際誌

Hiroki Sato, Terasu Honma, Yujiro Nozawa, Takashi Owaki, Michitaka Imai, Tomoe Sano, Akito Iwanaga, Keiichi Seki, Toru Ishikawa, Toshiaki Yoshida, Shuji Terai

PloS one 13 ( 11 ) e0206621 2018年

記述言語：英語

BACKGROUND AND AIM: Awareness of eosinophilic esophagitis (EoE) has gradually increased in Japan, therefore the characteristics of this disease in the Japanese patient population need to be elucidated. This study aimed to investigate the features of EoE in the Japanese population. METHODS: During a 2-year period, all gastrointestinal endoscopies were performed with maximum attention being paid to identify EoE through endoscopic findings. Clinical features and findings were analyzed among this population. RESULTS: Among a total of 8589 patients (general gastrointestinal endoscopy, performed for evaluation of symptoms or disease follow-up: 3669; medical check-up endoscopy, routinely performed in asymptomatic patients: 4920), 17 patients (0.20%) were diagnosed with esophageal eosinophilia (mean age ± standard deviation: 44±11.9 years; 1 female). Only 6 patients with esophageal eosinophilia were diagnosed by general gastrointestinal endoscopy; among them, 3 patients had dysphagia and 3 were asymptomatic. The remaining 11 patients were diagnosed by medical check-up endoscopy. All patients were treated with a proton pump inhibitor (PPI); 5 were diagnosed with EoE and 12 with PPI responsive esophageal eosinophilia. Chronological endoscopy analysis showed that EoE findings could be observed for a mean of 6.1 years prior to diagnosis, and the disease did not significantly progress in severity. CONCLUSIONS: Most Japanese patients with EoE have mild and slowly progressing disease, which can be diagnosed when close attention is paid to the endoscopic findings. Medical check-up endoscopy in Japan could be a great opportunity for the early diagnosis of EoE.

DOI： 10.1371/journal.pone.0206621

Effect of Helicobacter pylori eradication on elder cases: Observational study in community-based medicine 査読

Masaki Maruyama, Kenya Kamimura, Ayako Hoshiyama, Koki Hoshiyama, Mari Hoshiyama, Yoshihiro Hoshiyama, Shuji Terai

WORLD JOURNAL OF CLINICAL CASES 5 ( 12 ) 412 - 418 2017年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BAISHIDENG PUBLISHING GROUP INC

AIM
To examine the effect of Helicobacter pylori (H. pylon) eradication therapy on the extra-gastrointestinal factors in elderly patients by a before-after observational study in community medicine.
METHODS
Medical records (1 May 2013-31 January 2014) of 130 patients who underwent H. pylori eradication therapy with 2-year after-eradication observation in our institute were reviewed. Data on sex; age; body weight; body mass index (BMI); mean corpuscular volume (MCV); total protein; low-density lipoprotein cholesterol, triglyceride, haemoglobin A1c and haemoglobin levels and gastric hyperplastic polyps (GHPs) at eradication was extracted. Two-year after-eradication change in data was analysed by paired-sample t-test; relationship between GHPs and subclinical iron deficiency anaemia (IDA) improvement was evaluated.
RESULTS
The mean patient age (median, interquartile range) at eradication was 69.6 (71.5, 64-77) years. Paired-sample t-tests showed that body weight, BMI and MCV increased by 0.52 kg (P = 0.018), 0.25 kg/m(2) (P = 0.006) and 0.83 fL (P < 0.001), respectively. The nonparametric Mann Whitney test showed no significant difference in the change rate of MCV after eradication between the groups with and without GHPs (P = 0.892).
CONCLUSION
H. pylori eradication therapy prevented weight loss and subclinical IDA in elderly individuals. GHPs were not associated with subclinical IDA.

DOI： 10.12998/wjcc.v5.i12.412

Endoscopic ultrasound-guided fine-needle aspiration for diagnosing a rare extraluminal duodenal gastrointestinal tumor. 査読国際誌

Hayashi K, Kamimura K, Hosaka K, Ikarashi S, Kohisa J, Takahashi K, Tominaga K, Mizuno K, Hashimoto S, Yokoyama J, Yamagiwa S, Takizawa K, Wakai T, Umezu H, Terai S

World journal of gastrointestinal endoscopy 9 ( 12 ) 583 - 589 2017年12月

Efficacy and Safety of Pancreas-Targeted Hydrodynamic Gene Delivery in Rats 査読

Kohei Ogawa, Kenya Kamimura, Yuji Kobayashi, Hiroyuki Abe, Takeshi Yokoo, Norihiro Sakai, Takuro Nagoya, Akira Sakamaki, Satoshi Abe, Kazunao Hayashi, Satoshi Ikarashi, Junji Kohisa, Masanori Tsuchida, Yutaka Aoyagi, Guisheng Zhang, Dexi Liu, Shuji Terai

MOLECULAR THERAPY-NUCLEIC ACIDS 9 80 - 88 2017年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：CELL PRESS

Development of an effective, safe, and convenient method for gene delivery to the pancreas is a critical step toward gene therapy for pancreatic diseases. Therefore, we tested the possibility of applying the principle of hydrodynamic gene delivery for successful gene transfer to pancreas using rats as a model. The established procedure involves the insertion of a catheter into the superior mesenteric vein with temporary blood flow occlusion at the portal vein and hydrodynamic injection of DNA solution. We demonstrated that our procedure achieved efficient pancreas-specific gene expression that was 2,000-fold higher than that seen in the pancreas after the systemic hydrodynamic gene delivery. In addition, the level of gene expression achieved in the pancreas by the pancreas-specific gene delivery was comparable to the level in the liver achieved by a liver-specific hydrodynamic gene delivery. The optimal level of reporter gene expression in the pancreas requires an injection volume equivalent to 2.0% body weight with flow rate of 1 mL/s and plasmid DNA concentration at 5 mu g/mL. With the exception of transient expansion of intercellular spaces and elevation of serum amylase levels, which recovered within 3 days, no permanent tissue damage was observed. These results suggest that pancreas-targeted hydrodynamic gene delivery is an effective and safe method for gene delivery to the pancreas and clinically applicable.

DOI： 10.1016/j.omtn.2017.08.009

Changes in esophageal motility after endoscopic submucosal dissection for superficial esophageal cancer: a high-resolution manometry study 査読

K. Takahashi, Y. Sato, M. Takeuchi, H. Sato, N. Nakajima, S. Ikarashi, K. Hayashi, K. -I. Mizuno, Y. Honda, S. Hashimoto, J. Yokoyama, S. Terai

DISEASES OF THE ESOPHAGUS 30 ( 11 ) 2017年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OXFORD UNIV PRESS INC

The effect of endoscopic submucosal dissection (ESD) on esophageal motility remains unknown. Therefore, the aim of this study is to elucidate changes in esophageal motility after ESD along with the cause of dysphagia using high-resolution manometry (HRM). This is a before-and-after trial of the effect of ESD on the esophageal motility. Twenty patients who underwent ESD for superficial esophageal carcinoma were enrolled in this study. Patients filled out a questionnaire about dysphagia and underwent HRM before and after ESD. Results before and after ESD were compared. Data were obtained from 19 patients. The number of patients who complained of dysphagia before and after ESD was 1/19 (5.3%) and 6/19 (31.6%), respectively (P = 0.131). Scores from the five-point Likert scale before and after ESD were 0.1 +/- 0.5 and 1.0 +/- 1.6, respectively (P = 0.043). The distal contractile integral (DCI) before and after ESD and the number of failed, weak, or fragmented contractions were not significantly different. However, in five patients with circumferential ESD, DCI was remarkably decreased and the frequency of fail, weak, or fragmented contractions increased. Univariate regression analysis showed a relatively strong inverse correlation of Delta DCI with the circumferential mucosal defect ratio {P < 0.01, standardized regression coefficient (r) = -0.65}, the number of stricture preventions (P < 0.01, r = -0.601), and the number of stricture resolutions (P < 0.01, r=-0.77). This HRM study showed that impairment of esophageal motility could be caused by ESD. The impairment of esophageal motility was conspicuous, especially in patients with circumferential ESD and subsequent procedures such as endoscopic triamcinolone injection and endoscopic balloon dilatation. Impaired esophageal motility after ESD might explain dysphagia.

DOI： 10.1093/dote/dox057

【臓器間ネットワークからみた肝胆膵の恒常性とその破綻】臓器間ネットワークの破綻による疾患自律神経線維が肝再生に与えるインパクト

上村顕也, 井上良介, 名古屋拓郎, 酒井規裕, 寺井崇二

肝・胆・膵 75 ( 5 ) 967 - 972 2017年11月

Changes in esophageal motility after endoscopic submucosal dissection for superficial esophageal cancer: a high-resolution manometry study. 査読

Takahashi K, Sato Y, Takeuchi M, Sato H, Nakajima N, Ikarashi S, Hayashi K, Mizuno KI, Honda Y, Hashimoto S, Yokoyama J, Terai S

Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus 30 ( 11 ) 1 - 8 2017年11月

Overexpression of a disintegrin and metalloproteinase 21 is associated with motility, metastasis, and poor prognosis in hepatocellular carcinoma 査読

Hiroki Honda, Masaaki Takamura, Satoshi Yamagiwa, Takuya Genda, Ryoko Horigome, Naruhiro Kimura, Toru Setsu, Kentaro Tominaga, Hiroteru Kamimura, Yasunobu Matsuda, Toshifumi Wakai, Yutaka Aoyagi, Shuji Terai

SCIENTIFIC REPORTS 7 ( 1 ) 15485 2017年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Cell motility plays an important role in intrahepatic metastasis of hepatocellular carcinoma (HCC), and predicts poor prognosis in patients. The present study investigated the role of a disintegrin and metalloproteinases (ADAMs) in HCC, since these proteins are known to be associated with cell motility. We confirmed the expression of 12 ADAMs with putative metalloproteinase activity in HCC cells, and established a KYN-2 HCC cell line stably expressing short interfering RNA against ADAM21 to investigate the effect of ADAM21 deficiency on HCC cell motility and metastasis in vitro and in vivo. We also examined ADAM21 expression in a cohort of 119 HCC patients by immunohistochemistry. ADAM21 was overexpressed in KYN-2 cells, and its knockdown reduced invasion, migration, proliferation, and metastasis relative to controls. In clinical specimens, ADAM21 positivity was associated with vascular invasion, large tumor size, high histological grade, and lower overall and recurrence-free survival as compared to cases that were negative for ADAM21 expression. A multivariate analysis revealed that ADAM21 positivity was an independent risk factor for overall (P = 0.003) and recurrence-free (P = 0.001) survival. These results suggest that ADAM21 plays a role in HCC metastasis and can serve as a prognostic marker for disease progression.

DOI： 10.1038/s41598-017-15800-z

Intraductal Papillary Neoplasm of the Bile Duct: A Rare Liver Tumor Complicated by Malignancy 査読

Kentaro Tominaga, Kenya Kamimura, Akira Sakamaki, Shuji Terai

HEPATOLOGY 66 ( 5 ) 1695 - 1697 2017年11月

Magnifying image-enhanced endoscopy for collagenous colitis. 査読

Kobayashi M, Hoshi T, Morita SI, Kanefuji T, Suda T, Hasegawa G, Terai S

Endoscopy international open 5 ( 11 ) E1069 - E1073 2017年11月

Live image and mechanistic analysis of Mesenchymal stem cells (MSCs) and induced bone marrow derived macrophages (id-BMMs) combination therapy for liver cirrhosis in mice 査読

Yusuke Watanabe, Atsunori Tsuchiya, Satoshi Seino, Syunzou Ikarashi, Suguru Takeuchi, Takayuki Watanabe, Kenya Kamimura, Masaaki Takamura, Satoshi Yamagiwa, Shuji Terai

HEPATOLOGY 66 76A - 76A 2017年10月

Usefulness of follicular helper T cell subset frequencies in the diagnosis of autoimmune hepatitis 査読

Naruhiro Kimura, Satoshi Yamagiwa, Ryoko Horigome, Hiroteru Kamimura, Kenya Kamimura, Atsunori Tsuchiya, Masaaki Takamura, Hirokazu Kawai, Shuji Terai

HEPATOLOGY 66 687A - 688A 2017年10月

Persistent reduction of mucosal-associated invariant T cells in primary biliary cholangitis 査読

Toru Setsu, Satoshi Yamagiwa, Naruhiro Kimura, Hiroteru Kamimura, Atsunori Tsuchiya, Masaaki Takamura, Shuji Terai

HEPATOLOGY 66 166A - 166A 2017年10月

Effectiveness and safety of tolvaptan in liver cirrhosis patients with edema: Interim results of post-marketing surveillance of tolvaptan in liver cirrhosis (START study) 査読

Isao Sakaida, Shuji Terai, Masayuki Kurosaki, Moriyoshi Yasuda, Mitsuru Okada, Kosuke Bando, Yasuhiko Fukuta

HEPATOLOGY RESEARCH 47 ( 11 ) 1137 - 1146 2017年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY

Aim: Loop diuretics and spironolactone are used in patients with hepatic edema, but they are sometimes associated with insufficient responses as well as adverse events. Tolvaptan, a vasopressin type 2 receptor antagonist, was approved for hepatic edema in 2013. A large-scale post-marketing surveillance study has been carried out to evaluate the effectiveness and safety of tolvaptan in real-world clinical settings.
Methods: Patients with hepatic cirrhosis with insufficient response to conventional diuretics were enrolled. The observational period was up to 6months. Changes in body weight and clinical symptoms were measured to evaluate effectiveness. The incidence of adverse drug reactions was summarized as a safety measure.
Results: Of 970 patients enrolled, 463 were included in the safety analysis. Of this group, 340 were included in the effectiveness analysis. Decreases in body weight from baseline were -2.38kg on day 7 and -3.52kg on day 14. Ascites and bloated feeling was significantly improved within 14days. The mean change in body weight depended on estimated glomerular filtration rate levels. The most frequently reported adverse drug reaction was thirst (6.9% of patients). Serum sodium level of 146mEq/L was observed in 12 patients (2.7%).
Conclusions: In the real-world clinical setting, tolvaptan showed aquaretic effectiveness in patients with cirrhosis. The mean change in body weight depended on renal function. We recommend tolvaptan use for hepatic cirrhosis at a stage in which the renal function is maintained.

DOI： 10.1111/hepr.12852

A Case of Hepatorenal Syndrome and Abdominal Compartment Syndrome with High Renal Congestion. 査読国際誌

Hiroteru Kamimura, Takayuki Watanabe, Tomoyuki Sugano, Nao Nakajima, Junji Yokoyama, Kenya Kamimura, Atsunori Tsuchiya, Masaaki Takamura, Hirokazu Kawai, Takashi Kato, Gen Watanabe, Satoshi Yamagiwa, Shuji Terai

The American journal of case reports 18 1000 - 1004 2017年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND Hepatorenal syndrome (HRS) is a reversible renal impairment that occurs in patients with acute liver failure and advanced liver cirrhosis. HRS is due to a renal vasoconstriction that results from extreme vasodilatation. It is therefore a functional disorder, not associated with structural kidney damage. On the other hand, end-stage liver diseases are often complicated by massive ascites. Massive ascites may cause abdominal compartment syndrome (ACS), which includes impairment of renal blood flow, but there are no reports indicating that kidney lesions caused by ACS may pathologically contribute to end-stage liver diseases. CASE REPORT A 40-year-old man with acute liver failure was admitted to our hospital. He was diagnosed with type 1 HRS and showed ACS at the same time. He died 30 days after admission. There were signs of congestion in the kidneys upon dissection and advanced erythroid fullness in the renal tubules. CONCLUSIONS We report an autopsy case with HRS and ACS diagnosed with a clinical and histopathological consideration of liver and kidney. Further clinical studies are needed to improve management of renal failure in patients with acute liver failure and advanced liver cirrhosis.

A canine liver fibrosis model to develop a therapy for liver cirrhosis using cultured bone marrow-derived cells. 査読国際誌

Takashi Matsuda, Taro Takami, Ryo Sasaki, Tatsuro Nishimura, Yuki Aibe, Bruno Diaz Paredes, Luiz Fernando Quintanilha, Toshihiko Matsumoto, Tsuyoshi Ishikawa, Naoki Yamamoto, Kenji Tani, Shuji Terai, Yasuho Taura, Isao Sakaida

Hepatology communications 1 ( 7 ) 691 - 703 2017年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

We have been developing a therapy for liver cirrhosis using cultured autologous bone marrow-derived mesenchymal stem cells (BMSCs). Before human clinical trials can be considered, the safety and efficacy of BMSC infusion in medium to large animals must be confirmed; thus, we developed a canine liver fibrosis model. A small amount of bone marrow fluid was aspirated from the canine humerus to assess the characteristics of BMSCs. We implanted a venous catheter in the stomach and a subcutaneous infusion port in the back of the neck of each canine. Repeated injection of CCl4 through the catheter was performed to induce liver cirrhosis. After 10 weeks of CCl4 injection, eight canines were equally divided into two groups: no cell infusion (control group) and autologous BMSC infusion through the peripheral vein (BMSC group). A variety of assays were carried out before and 4 weeks after the infusion. The area of liver fibrosis stained with sirius red was significantly reduced in the BMSC group 4 weeks after BMSC infusion, consistent with a significantly shortened half-life of indocyanine green and improved liver function. Conclusion: We established a useful canine liver fibrosis model and confirmed that cultured autologous BMSC infusion improved liver fibrosis without adverse effects. (Hepatology Communications 2017;1:691-703).

DOI： 10.1002/hep4.1071

A Huge Abdominal Tumor Abdominal Abscess 査読

Norihiro Sakai, Kenya Kamimura, Shuji Terai

GASTROENTEROLOGY 153 ( 3 ) E5 - E6 2017年9月

HHMの肝発癌における分子生物学的メカニズムの解明

小川光平, 上村顕也, 後藤諒, 井上良介, 品川陽子, 酒井規裕, 名古屋拓郎, 小林雄司, 阿部寛幸, 阿部聡司, 坂牧僚, 横尾健, 川合弘一, 山際訓, 高見太郎, 山本直樹, 坂井田功, 寺井崇二

日本消化器病学会雑誌 114 ( 臨増大会 ) A732 - A732 2017年9月

当院におけるBordeline resectable膵癌の治療の現況

林和直, 五十嵐聡, 水野研一, 橋本哲, 横山純二, 山際訓, 寺井崇二

日本消化器病学会雑誌 114 ( 臨増大会 ) A832 - A832 2017年9月

Innovative therapeutic endoscopy 膵仮性嚢胞・感染性WONに対する内視鏡的治療重症急性膵炎後Walled-off necrosisの自然軽快に関連する因子

五十嵐聡, 林和直, 寺井崇二

Gastroenterological Endoscopy 59 ( Suppl.2 ) 2103 - 2103 2017年9月

Innovative therapeutic endoscopy 膵仮性嚢胞・感染性WONに対する内視鏡的治療重症急性膵炎後Walled-off necrosisの自然軽快に関連する因子

五十嵐聡, 林和直, 寺井崇二

日本消化器病学会雑誌 114 ( 臨増大会 ) A689 - A689 2017年9月

YAP determines the cell fate of injured mouse hepatocytes in vivo (vol 8, 16017, 2017) 査読

Norio Miyamura, Shoji Hata, Tohru Itoh, Minoru Tanaka, Miki Nishio, Michiko Itoh, Yoshihiro Ogawa, Shuji Terai, Isao Sakaida, Akira Suzuki, Atsushi Miyajima, Hiroshi Nishina

NATURE COMMUNICATIONS 8 16146 2017年8月

An Automated Self-Learning Quantification System to Identify Visible Areas in Capsule Endoscopy Images 査読

Shinichi Hashimoto, Hiroyuki Ogihara, Masato Suenaga, Yusuke Fujita, Shuji Terai, Yoshihiko Hamamoto, Isao Sakaida

JOURNAL OF MEDICAL SYSTEMS 41 ( 8 ) 119 2017年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER

Visibility in capsule endoscopic images is presently evaluated through intermittent analysis of frames selected by a physician. It is thus subjective and not quantitative. A method to automatically quantify the visibility on capsule endoscopic images has not been reported. Generally, when designing automated image recognition programs, physicians must provide a training image; this process is called supervised learning. We aimed to develop a novel automated self-learning quantification system to identify visible areas on capsule endoscopic images. The technique was developed using 200 capsule endoscopic images retrospectively selected from each of three patients. The rate of detection of visible areas on capsule endoscopic images between a supervised learning program, using training images labeled by a physician, and our novel automated self-learning program, using unlabeled training images without intervention by a physician, was compared. The rate of detection of visible areas was equivalent for the supervised learning program and for our automatic self-learning program. The visible areas automatically identified by self-learning program correlated to the areas identified by an experienced physician. We developed a novel self-learning automated program to identify visible areas in capsule endoscopic images.

DOI： 10.1007/s10916-017-0769-5

YAP determines the cell fate of injured mouse hepatocytes in vivo 査読

Norio Miyamura, Shoji Hata, Tohru Itoh, Minoru Tanaka, Miki Nishio, Michiko Itoh, Yoshihiro Ogawa, Shuji Terai, Isao Sakaida, Akira Suzuki, Atsushi Miyajima, Hiroshi Nishina

NATURE COMMUNICATIONS 8 1 - 9 2017年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

The presence of senescent, transformed or damaged cells can impair tissue function or lead to tumorigenesis; therefore, organisms have evolved quality control mechanisms to eliminate them. Here, we show that YAP activation induced by inactivation of the Hippo pathway specifically in damaged hepatocytes promotes their selective elimination by using in vivo mosaic analysis in mouse liver. These damaged hepatocytes migrate into the hepatic sinusoids, undergo apoptosis and are engulfed by Kupffer cells. In contrast, YAP activation in undamaged hepatocytes leads to proliferation. Cellular stresses such as ethanol that damage both liver sinusoidal endothelial cells and hepatocytes switch cell fate from proliferation to migration/apoptosis in the presence of activated YAP. This involves the activation of CDC42 and Rac that regulate cell migration. Thus, we suggest that YAP acts as a stress sensor that induces elimination of injured cells to maintain tissue and organ homeostasis.

DOI： 10.1038/ncomms16017

Risk of metastasis in adenocarcinoma of the esophagus: a multicenter retrospective study in a Japanese population 査読

Ryu Ishihara, Tsuneo Oyama, Seiichiro Abe, Hiroaki Takahashi, Hiroyuki Ono, Junko Fujisaki, Mitsuru Kaise, Kenichi Goda, Kenro Kawada, Tomoyuki Koike, Manabu Takeuchi, Rie Matsuda, Dai Hirasawa, Masayoshi Yamada, Junichi Kodaira, Masaki Tanaka, Masami Omae, Akira Matsui, Takashi Kanesaka, Akiko Takahashi, Shinichi Hirooka, Masahiro Saito, Yosuke Tsuji, Yuki Maeda, Hiroharu Yamashita, Ichiro Oda, Yasuhiko Tomita, Takashi Matsunaga, Shuji Terai, Soji Ozawa, Tatsuyuki Kawano, Yasuyuki Seto

JOURNAL OF GASTROENTEROLOGY 52 ( 7 ) 800 - 808 2017年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER JAPAN KK

Background Little is known about the specific risks of metastasis in esophageal adenocarcinoma in relation to invasion depth or other pathologic factors.
Methods We conducted a multicenter retrospective study in 13 high-volume centers in Japan from January 2000 to October 2014 to elucidate the risk of metastasis of esophageal adenocarcinoma. A total of 458 patients (217 surgically resected and 241 endoscopically resected) with esophageal adenocarcinoma or esophagogastric adenocarcinoma involving the esophagus were included. Metastasis was considered positive if there was histologically confirmed metastasis in the surgical specimen or clinically confirmed metastasis during follow-up. Metastasis was considered negative if no metastasis was identified in resected specimens and during follow-up in patients treated surgically or no metastasis during follow-up for <5 years in patients treated by endoscopic resection.
Results Metastasis was identified in 72 patients. Multivariate analysis confirmed lymphovascular involvement odds ratio (OR) 6.20; 95 % confidence interval (CI) 3.12-12.32; p < 0.001], a poorly differentiated component (OR 3.69; 95 % CI 1.92-7.10; p < 0.001), and lesion size [ 30 mm (OR 3.12; 95 % CI 1.63-5.97; p = 0.001) as independent risk factors for metastasis. No metastasis was detected in patients with mucosal cancer without lymphovascular involvement and a poorly differentiated component (0/186 lesions) or in patients with cancer invading the submucosa (1-500 mu m) without lymphovascular involvement, a poorly differentiated component, and <= 30 mm (0/32 lesions).
Conclusions Mucosal and submucosal cancers (1-500 mu m invasion) without risk factors have a low incidence of metastasis and may thus be good candidates for endoscopic resection.

DOI： 10.1007/s00535-016-1275-0

The use of clip anchoring to ensure safe transgastric puncture during endoscopic ultrasound-guided transmural drainage 査読

Shinichi Morita, Kazuo Hara, Takeshi Suda, Susumu Hijioka, Nozomi Okuno, Masaaki Kobayashi, Shuji Terai

ENDOSCOPY 49 ( 7 ) E186 - E187 2017年7月

Lusutrombopag increases hematocytes in a compensated liver cirrhosis patient 査読

Akira Sakamaki, Takayuki Watanabe, Satoshi Abe, Kenya Kamimura, Atsunori Tsuchiya, Masaaki Takamura, Hirokazu Kawai, Satoshi Yamagiwa, Shuji Terai

Clinical Journal of Gastroenterology 10 ( 3 ) 261 - 264 2017年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Tokyo

A 56-year-old Japanese man with liver cirrhosis (LC) due to hepatitis C virus was admitted to our hospital for radiofrequency ablation of residual tumor following lusutrombopag administration. Laboratory tests revealed thrombocytopenia and leukopenia. The patient’s LC was managed, and he was classified as Child–Pugh A. After admission, lusutrombopag was administered for 7 days. The platelet count increased to over 50,000/mm3 after 7–14 days and returned to previous levels 50 days after administration. Leukocyte and erythrocyte counts also increased in response to the treatment and stayed elevated for over 120 days. Lusutrombopag acts selectively on human thrombopoietin (TPO) receptors and activates signaling pathways that promote the proliferation and differentiation of bone marrow progenitor cells into megakaryocytes, consequently increasing the blood platelet count. However, the patient treated with lusutrombopag in our case study showed increased blood leukocyte and erythrocyte counts as well. Given that TPO receptors are reportedly expressed in not only megakaryocyte progenitor cells but also hematopoietic progenitors, lusutrombopag may potentially improve pancytopenia caused by LC and can be used for the recovery of blood counts before other treatments.

DOI： 10.1007/s12328-017-0735-2

Spontaneous regression of hepatocellular carcinoma: A mini-review 査読

Akira Sakamaki, Kenya Kamimura, Satoshi Abe, Atsunori Tsuchiya, Masaaki Takamura, Hirokazu Kawai, Satoshi Yamagiwa, Shuji Terai

WORLD JOURNAL OF GASTROENTEROLOGY 23 ( 21 ) 3797 - 3804 2017年6月

記述言語：英語出版者・発行元：BAISHIDENG PUBLISHING GROUP INC

Spontaneous tumor regression is an extremely rare phenomenon in the oncology field. However, there are several case reports resulted in the regression of hepatocellular carcinoma (HCC) and the accumulation of clinical information and analyses of the mechanism can contribute to the development of a novel therapy. For this purpose, we have carefully reviewed 23 cases of spontaneously regressed HCC published in recent 5 years and our case. The information regarding the tumor size, tumor marker, treatments, etc., have been summarized. The mechanism of spontaneous regression has been discussed to date and presumed to be due to many factors, including hypoxia and immunological reactions. In this careful review of the 24 cases based on the clinical information, hypoxia, systemic inflammation, and both upon spontaneous regression were seen in 3, 8, and 4 cases, respectively among the 15 cases for which the information regarding the proposed mechanisms are available. Recent development of immunotherapeutic approaches in oncology shows promising results, therefore, accumulation of additional cases and analysis of mechanisms underlying the spontaneous regression of HCC are essential and could lead to the development of a new generation of immunotherapies including antibodies directed against immune reactions.

DOI： 10.3748/wjg.v23.i21.3797

Effect of double platinum agents, combination of miriplatintransarterial oily chemoembolization and cisplatinhepatic arterial infusion chemotherapy, in patients with hepatocellular carcinoma: Report of two cases 査読

Kohei Ogawa, Kenya Kamimura, Yukari Watanabe, Yosuke Motai, Daisuke Kumaki, Ryoya Seki, Akira Sakamaki, Satoshi Abe, Hirokazu Kawai, Takeshi Suda, Satoshi Yamagiwa, Shuji Terai

WORLD JOURNAL OF CLINICAL CASES 5 ( 6 ) 238 - 246 2017年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BAISHIDENG PUBLISHING GROUP INC

Hepatocellular carcinoma (HCC) is one of the most common cancers and the third highest cause of cancerassociated mortality worldwide. The treatment of HCC is complicated by its variable biological behavior and the frequent coexistence of chronic liver disease, particularly cirrhosis. To date, multiple treatment modalities have been developed according to the stage of the tumor and the hepatic functional reserve, including transarterial treatments such as transarterial chemoembolization, transarterial oily chemoembolization (TOCE), and hepatic arterial infusion chemotherapy (HAIC). We conducted a phase I and II study of the combination therapy with double platinum agents, miriplatin and cisplatin, and confirmed its safety and efficacy. Here, we describe two cases of unresectable HCC who were successfully treated by miriplatin-TOCE/cisplatin-HAIC combination therapy, resulting in complete responses with no significant adverse events. This report will provide that the combination therapy can be the therapeutic option for HCC patients in the advanced stage.

DOI： 10.12998/wjcc.v5.i6.238

Evaluation of the effects of L-carnitine on medaka (Oryzias latipes) fatty liver 査読

Koichi Fujisawa, Taro Takami, Aya Matsuzaki, Toshihiko Matsumoto, Naoki Yamamoto, Shuji Terai, Isao Sakaida

SCIENTIFIC REPORTS 7 ( 1 ) 2749 2017年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Lifestyle-related diseases have become a major issue in recent years. The increasing incidence of fatty liver underlines the urgency with which the issues of non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) need to be addressed. L-carnitine is a compound known to transport fatty acids into the mitochondria to enhance beta-oxidation-mediated metabolism of fats. In this study, the effects of L-carnitine administration on fatty liver of medaka (Oryzias latipes) were analysed, to check for disease improvement and metabolic changes. Additionally, the effects of the concomitant administration of L-carnitine and eicosapentaenoic acid (20:5n-3) (EPA) were investigated. Findings indicated reduced lipid deposition, increase in metabolites associated with beta-oxidation, and significant reduction in fatty acid levels in the liver, implying improvement in fatty liver condition. Concomitant administration of L-carnitine and EPA resulted in further benefits, via changes in fatty acid composition in the medaka fatty liver model.

DOI： 10.1038/s41598-017-02924-5

Long-term efficacy and safety of nalfurafine hydrochloride on pruritus in chronic liver disease patients: Patient-reported outcome based analyses 査読

Kenya Kamimura, Takeshi Yokoo, Hiroteru Kamimura, Akira Sakamaki, Satoshi Abe, Atsunori Tsuchiya, Masaaki Takamura, Hirokazu Kawai, Satoshi Yamagiwa, Shuji Terai

PLOS ONE 12 ( 6 ) e0178991 2017年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PUBLIC LIBRARY SCIENCE

Background and aim
Among various symptoms accompanied with chronic liver disease, pruritus affects the quality of life of patients, causing physical and mental stress, and worsens hepatic function. Recently, kappa-opioid receptor agonist, nalfurafine hydrochloride was approved to treat central pruritus in patients with liver disease in Japan. This study aimed to assess the long-term efficacy and safety of nalfurafine hydrochloride on pruritus in chronic liver disease patients.
Methods
A patient-reported outcome using questionnaire-based methods was used for 41 liver disease patients with or without pruritus symptoms. Nalfurafine hydrochloride (2.5 mu g/day) was orally administered to 18 patients suffering from pruritus symptoms and whose current treatment was not effective. The same questionnaires and visual analogue scales (VAS) were repeatedly followed up for the patients for the entire follow-up period, and biochemical analyses were performed to evaluate the safety of the treatment.
Results
Pruritus completely disappeared in seven of 18 cases, and VAS scores showed a decreasing trend over time from the start of nalfurafine hydrochloride administration in all patients who received the medication. Among 11 patients who were followed up for more than 12 weeks, nine patients showed continuous improvement of symptoms, and this progress was still apparent at >= 20 weeks after starting administration (p < 0.0001). The medication was discontinued in four patients because of progression of primary disease, high cost, oral dryness, and anemia. No significant toxicity was observed on the serum biochemical analyses.
Conclusions
Nalfurafine hydrochloride contributed to long-term suppression of pruritus without significant safety problems.

DOI： 10.1371/journal.pone.0178991

Prevention of esophageal stricture after endoscopic submucosal dissection using RNA-based silencing of carbohydrate sulfo-transferase 15 in a porcine model 査読

Hiroki Sato, Seiji Sagara, Nao Nakajima, Teppei Akimoto, Kenji Suzuki, Hiroyuki Yoneyama, Shuji Terai, Naohisa Yahagi

ENDOSCOPY 49 ( 5 ) 491 - 497 2017年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：GEORG THIEME VERLAG KG

Background and study aims Endoscopic submucosal dissection (ESD) for esophageal carcinoma frequently causes fibrotic strictures that require treatment. A possible preventive effect of small interfering RNA (siRNA) targeting carbohydrate sulfotransferase 15 (CHST15) on esophageal stricture formation after ESD was investigated in 3 pigs.
Materials and methods Two half-circumferential ESD ulcers were created in the oral and anal ends of the esophagus. CHST15 siRNA was injected submucosally in one of the two ESD ulcers. Endoscopic, macroscopic, histological, and polymerase chain reaction analyses were performed.
Results On post-operative day 14, the non-treated ulcers were found to show histological fibrosis and increased expression of the CHST15 messenger RNA. A single endoscopic injection of CHST15 siRNA alleviated stricture development in post-ESD ulcers with significant reduction in the mucosal contraction rate. The deposition of collagen and accumulation of fibroblasts and myofibroblasts were diminished in ulcers treated with CHST15 siRNA, where significant suppression of CHST15, transforming growth factorbeta (TGF-beta), and collagen-1 messenger RNAs was also seen.
Conclusion CHST15 siRNA alleviated esophageal postESD stricture formation via repression of fibrosis, revealing a novel therapeutic role for antifibrotic agents in the prevention of post-ESD strictures.

DOI： 10.1055/s-0042-123189

Transhepatic arterial infusion chemotherapy using a combination of miriplatin and CDDP powder versus miriplatin alone in the treatment of hepatocellular carcinoma: a randomized controlled trial 査読

Kenya Kamimura, Takeshi Suda, Takeshi Yokoo, Hiroteru Kamimura, Tsutomu Kanefuji, Atsunori Tsuchiya, Masaaki Takamura, Hirokazu Kawai, Nobuo Waguri, Satoshi Yamagiwa, Shuji Terai

BMC CANCER 17 ( 1 ) 322 2017年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BIOMED CENTRAL LTD

Background: Based on promising results from a Phase I study of hepatic arterial infusion chemotherapy using a combination of miriplatin and cisplatin powder (DDP-H) for unresectable hepatocellular carcinoma (UMIN-CTR000003541), a multicenter, open-label, randomized phase II study was conducted to evaluate the efficacy and safety of the combination therapy versus miriplatin monotherapy.
Methods: Nineteen patients, five and fourteen Barcelona-Clinic Liver Cancer staging classification A and B cases, respectively, were randomly assigned to receive either miriplatin monotherapy (n = 9) or miriplatin/DDP-H combination therapy (n = 10). DDP-H and/or miriplatin were administered through the hepatic arteries supplying the lobes of the liver containing tumors, and progression free survival was analyzed as a primary end point in addition to other secondary endpoints. The corresponding therapy was repeated unless disease progression or severe adverse events were recorded.
Results: The monotherapy or combination therapy was performed for 15 or 36 sessions in total, respectively. Although there were no significant differences between the two groups for treatment intervals (p = 0.96) or the dose of miriplatin used in each session (p = 0.99), the progression free survival and overall disease control rate were significantly better in the combination therapy group (91 vs 423 days, p = 0.025; 40.0 vs 77.8%, p = 0.0025, respectively). Consistent with these observations, a trend of a significantly slower increase in des-gamma-carboxyprothrombin was observed, and the number of treatment sessions was nearly significantly larger in the combination therapy group (p < 0.0001, p = 0.057, respectively). Conversely, the median survival time did not show a significant difference (706 days, monotherapy vs 733 days, combination therapy; p = 0.40). A significant decrease in cholinesterase was observed during the course of treatment only in patients receiving combination therapy (r = -0.86, p < 0.0001). A few cases in both arms showed hematological and/or non-hematological toxicities that were categorized as grade 1 (NCI-CTCAE).
Conclusions: The higher disease control effects with the combination of miriplatin and DDP-H indicate that it is a promising alternative treatment for cases with multiple HCCs, especially for those that can tolerate the treatment without experiencing a reduction in hepatic reserve.

DOI： 10.1186/s12885-017-3320-7

Development and use of a non-biomaterial model for hands-on training of endoscopic procedures 査読

Hiroki Sato, Ken-Ichi Mizuno, Yuichi Sato, Satoru Hashimoto, Kazunao Hayashi, Satoshi Ikarashi, Yutaka Honda, Junji Yokoyama, Shuji Terai

Annals of Translational Medicine 5 ( 8 ) 182 2017年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AME Publishing Company

Background: Endoscopic submucosal dissection (ESD) and peroral endoscopic myotomy (POEM) are recently developed techniques that have the potential to significantly improve clinical outcomes. However, training opportunities on these techniques remain limited. To address this issue, we developed a novel ex-vivo ESD/POEM training model. Our aim in this paper is to describe the model and provide preliminary evidence of promising feasibility to improve access to ESD/POEM training. Methods: The model was developed using polyvinyl alcohol hydrogel, which can easily be modified to reproduce the stiffness of the different intestinal layers, namely the mucosa, submucosa, and muscle layer. Results: A training workshop, using our ex-vivo model, was held for 28 residents. Satisfaction and feasibility in using the ex-vivo model for endoscopic training were evaluated by using a self-report questionnaire. All participants were satisfied with their training experience (100% satisfaction rate), with 27 of the 28 participants reporting that the model was feasible in replicating all components of the ESD/POEM technique (96.4% feasibility rate). Conclusions: Based on this feedback, we propose that our non-biomaterial model has the feasibility to provide an effective endoscopy education tool and a satisfactory training experience.

DOI： 10.21037/atm.2017.01.27

Herpes virus reactivation during and after direct-acting antiviral therapy for hepatitis C virus infection 査読

Takeshi Yokoo, Atsunori Tsuchiya, Soichi Sugitani, Shuji Terai

DIGESTIVE AND LIVER DISEASE 49 ( 4 ) 453 - 454 2017年4月

Proposed criteria to differentiate heterogeneous eosinophilic gastrointestinal disorders of the esophagus, including eosinophilic esophageal myositis 査読

Hiroki Sato, Nao Nakajima, Kazuya Takahashi, Go Hasegawa, Ken-ichi Mizuno, Satoru Hashimoto, Satoshi Ikarashi, Kazunao Hayashi, Yutaka Honda, Junji Yokoyama, Yuichi Sato, Shuji Terai

WORLD JOURNAL OF GASTROENTEROLOGY 23 ( 13 ) 2414 - 2423 2017年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BAISHIDENG PUBLISHING GROUP INC

AIM
To define clinical criteria to differentiate eosinophilic gastrointestinal disorder (EoGD) in the esophagus.
METHODS
Our criteria were defined based on the analyses of the clinical presentation of eosinophilic esophagitis (EoE), subepithelial eosinophilic esophagitis (sEoE) and eosinophilic esophageal myositis (EoEM), identified by endoscopy, manometry and serum immunoglobulin E levels (s-IgE), in combination with histological and polymerase chain reaction analyses on esophageal tissue samples.
RESULTS
In five patients with EoE, endoscopy revealed longitudinal furrows and white plaques in all, and fixed rings in two. In one patient with sEoE and four with EoEM, endoscopy showed luminal compression only. Using manometry, failed peristalsis was observed in patients with EoE and sEoE with some variation, while EoEM was associated with hypercontractile or hypertensive peristalsis, with elevated s-IgE. Histology revealed the following eosinophils per high-power field values. EoE = 41.4 +/- 7.9 in the epithelium and 2.3 +/- 1.5 in the subepithelium; sEoE = 3 in the epithelium and 35 in the subepithelium (conventional biopsy); EoEM = none in the epithelium, 10.7 +/- 11.7 in the subepithelium (conventional biopsy or endoscopic mucosal resection) and 46.8 +/- 16.5 in the muscularis propria (peroral esophageal muscle biopsy). Presence of dilated epithelial intercellular space and downward papillae elongation were specific to EoE. Eotaxin-3, IL-5 and IL-13 were overexpressed in EoE.
CONCLUSION
Based on clinical and histological data, we identified criteria, which differentiated between EoE, sEoE and EoEM, and reflected a different pathogenesis between these esophageal EoGDs.

DOI： 10.3748/wjg.v23.i13.2414

Long-term outcomes of colorectal endoscopic submucosal dissection in elderly patients 査読

Yoshifumi Takahashi, Ken-ichi Mizuno, Kazuya Takahashi, Hiroki Sato, Satoru Hashimoto, Manabu Takeuchi, Masaaki Kobayashi, Junji Yokoyama, Yuichi Sato, Shuji Terai

INTERNATIONAL JOURNAL OF COLORECTAL DISEASE 32 ( 4 ) 567 - 573 2017年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER

Background and aims The safety and efficacy of endoscopic submucosal dissection (ESD) in elderly patients remain unclear. The aim of this study is to clarify the short- and long-term outcomes of colorectal ESD in elderly patients.
Patients and methods A total of 482 consecutive patients with 501 colorectal lesions treated with ESD from February 2005 to December 2013 were retrospectively reviewed. Patients were divided into two groups: an elderly group (>= 75 years of age) and a non-elderly group (< 75 years of age). Shortterm outcomes of interest were procedure time, complication rate, hospital stay, en bloc resection rate, and non-curative resection rate. Long-term outcomes of interest were disease-specific survival, and overall survival rates in the elderly group (51 patients) and non-elderly group (92 patients) were also analyzed.
Results No significant differences were observed between the groups with respect to short-term outcomes. Two patients in each group required emergency surgery. Of the patients who underwent non-curative resection, 7/12 (58%) in the elderly group and 15/23 (65%) in the non-elderly group underwent additional surgery. The 5-year disease-specific survival rates in the elderly and non-elderly groups were both 100%, and the corresponding 5-year overall survival rates were 86.3 and 93.5%, respectively (p = 0.026).
Conclusions Short-term outcomes after colorectal ESD were equivalent in both groups, and all patients showed favorable long-term outcomes. Considering the benign prognosis of lesions resected with ESD, preoperative screening of comorbidities is essential to improve overall survival.

DOI： 10.1007/s00384-016-2719-y

HHMはDNA損傷ストレスに対する応答機構を介して肝発癌抑制に寄与する

小川光平, 上村顕也, 後藤諒, 井上良介, 品川陽子, 阿部寛幸, 阿部聡司, 坂牧僚, 横尾健, 川合弘一, 山際訓, 高見太郎, 山本直樹, 坂井田功, 寺井崇二

肝臓 58 ( Suppl.1 ) A448 - A448 2017年4月

当科における術後再建腸管の胆管結石症に対する内視鏡治療の検討

林和直, 五十嵐聡, 水野研一, 本田穣, 橋本哲, 横山純二, 佐藤祐一, 山際訓, 寺井崇二

Gastroenterological Endoscopy 59 ( Suppl.1 ) 1036 - 1036 2017年4月

術後再建腸管例に対するERCP関連手技における偶発症の現状と対策

五十嵐聡, 林和直, 水野研一, 本田穣, 橋本哲, 横山純二, 佐藤祐一, 山際訓, 寺井崇二

Gastroenterological Endoscopy 59 ( Suppl.1 ) 1035 - 1035 2017年4月

Muscle layer histopathology and manometry pattern of primary esophageal motility disorders including achalasia 査読

N. Nakajima, H. Sato, K. Takahashi, G. Hasegawa, K. Mizuno, S. Hashimoto, Y. Sato, S. Terai

NEUROGASTROENTEROLOGY AND MOTILITY 29 ( 3 ) 2017年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY

BackgroundHistopathology of muscularis externa in primary esophageal motility disorders has been characterized previously. We aimed to correlate the results of high-resolution manometry with those of histopathology.
MethodsDuring peroral endoscopic myotomy, peroral esophageal muscle biopsy was performed in patients with primary esophageal motility disorders. Immunohistochemical staining for c-kit was performed to assess the interstitial cells of Cajal (ICCs). Hematoxylin Eosin and Azan-Mallory staining were used to detect muscle atrophy, inflammation, and fibrosis, respectively.
Key ResultsSlides from 30 patients with the following motility disorders were analyzed: achalasia (type I: 14, type II: 5, type III: 3), one diffuse esophageal spasm (DES), two outflow obstruction (OO), four jackhammer esophagus (JE), and one nutcracker esophagus (NE). ICCs were preserved in high numbers in type III achalasia (n=9.41.2 cells/high power field [HPF]), compared to types I (n=3.7 +/- 0.3 cells/HPF) and II (n=3.5 +/- 1.0 cells/HPF). Moreover, severe fibrosis was only observed in type I achalasia and not in other types of achalasia, OO, or DES. Four of five patients with JE and NE had severe inflammation with eosinophilic infiltration of the esophageal muscle layer (73.8 +/- 50.3 eosinophils/HPF) with no epithelial eosinophils. One patient with JE showed a visceral myopathy pattern.
Conclusions & InferencesCompared to types I and II, type III achalasia showed preserved ICCs, with variable data regarding DES and OO. In disorders considered as primary esophageal motility disorders, a disease category exists, which shows eosinophilic infiltration in the esophageal muscle layer with no eosinophils in the epithelium.

DOI： 10.1111/nmo.12968

Drug-eluting beads in hepatocellular carcinoma 査読

Hiroyuki Abe, Kenya Kamimura, Shuji Terai

THERAPEUTIC ADVANCES IN GASTROENTEROLOGY 10 ( 3 ) 337 - 338 2017年3月

Re-evaluation of phenotypic expression in differentiated-type early adenocarcinoma of the stomach 査読

Masato Hayakawa, Ken Nishikura, Yoichi Ajioka, Yutaka Aoyagi, Shuji Terai

PATHOLOGY INTERNATIONAL 67 ( 3 ) 131 - 140 2017年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY

A total of 313 cases of differentiated-type early gastric adenocarcinomas, including 113 cases of small-sized carcinoma (5 < x <= 10mm) and 121 cases of microcarcinoma (0 < x <= 5 mm), were examined immunohistochemically to clarify the phenotypic expressions. They were classified into four categories (gastric phenotype (G-type), intestinal phenotype, gastrointestinal phenotype, and null phenotype) by a two-step process: the phenotype based on an immunoprofile of mucin core proteins (MUCs) with CDX2 (w/.CDX2-assessment); and the phenotype of MUCs only (w/o. CDX2-assessment). CDX2 expression was observed in 89.1% (279/313); it was highly expressed in 87.6% (106/121) of microcarcinomas. MUC2 expression increased as tumor size increased (P < 0.05). Compared with w/o. CDX2-assessment, w/.CDX2-assessment showed significantly fewer G-type carcinomas (P < 0.05). Each phenotype marker was less expressed in the submucosal part than in the mucosal part. In conclusion, CDX2 was a sensitive marker for assessing intestinal phenotype. A large portion of the early differentiated-type adenocarcinomas expressed CDX2 from the very early stage of carcinogenesis, and the proportion of G-type was unexpectedly low. Lower expression of each phenotype marker was considered the cause of phenotype alteration during submucosal invasion.

DOI： 10.1111/pin.12506

当科におけるCrohn病に合併した胆石症の検討

林和直, 五十嵐聡, 水野研一, 本田穣, 橋本哲, 横山純二, 佐藤祐一, 山際訓, 寺井崇二

日本消化器病学会雑誌 114 ( 臨増総会 ) A335 - A335 2017年3月

他臓器癌合併IPMNの臨床像

五十嵐聡, 林和直, 水野研一, 本田穣, 橋本哲, 横山純二, 佐藤祐一, 山際訓, 寺井崇二

日本消化器病学会雑誌 114 ( 臨増総会 ) A372 - A372 2017年3月

膵癌非切除例における骨格筋量と体脂肪組成の評価による予後解析

中野応央樹, 川合弘一, 小林隆昌, 五十嵐聡, 林和直, 佐藤祐一, 寺井崇二

日本消化器病学会雑誌 114 ( 臨増総会 ) A271 - A271 2017年3月

自己免疫性肝疾患のパラダイムシフト原発性胆汁性胆管炎におけるMucosal-associated invariant T細胞の検討

薛徹, 山際訓, 寺井崇二

日本消化器病学会雑誌 114 ( 臨増総会 ) A135 - A135 2017年3月

Predictive factors of the pharmacological action of tolvaptan in patients with liver cirrhosis: a post hoc analysis 査読

Isao Sakaida, Shuji Terai, Koji Nakajima, Yoshiyuki Shibasaki, Sayaka Tachikawa, Hidetsugu Tsubouchi

JOURNAL OF GASTROENTEROLOGY 52 ( 2 ) 229 - 236 2017年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER JAPAN KK

Background Tolvaptan has been approved in Japan for the treatment of hepatic edema. An important consideration in providing a clinical benefit to patients with liver cirrhosis is the improvement of ascites-related clinical symptoms. In the present post hoc analysis, we aimed to identify factors that were predictive of the potency of tolvaptan, and to examine the relationship between changes in initial urine volume and improvement in ascites-related clinical symptoms.
Methods This post hoc analysis was based on three previous phase 2 and 3 clinical trials of tolvaptan in patients with liver cirrhosis. Predictive factors associated with a change in initial urine volume were identified. A change of >= 500 mL from baseline confirmed the pharmacological action of tolvaptan treatment. The relationship between the change in initial urine volume and improvement in ascitesrelated clinical symptoms was also examined.
Results A total of 152 patients were enrolled in this study. Body weight and BUN were identified as predictive parameters. Among patients with a change in initial urine volume of >= 500 mL, 75 % demonstrated improvement in ascites-related clinical symptoms, while no improvement was seen in those with a change of >= 500 mL. None of the patients with initial urine volume of >= 500 mL showed resolution of symptoms.
Conclusions Change in urine volume was affected by both baseline body weight and BUN in tolvaptan-treated subjects. Higher urine output was associated with improvements in ascites-related clinical symptoms.

DOI： 10.1007/s00535-016-1233-x

Loss of peristalsis of the esophagus due to diffuse esophageal leiomyomatosis 査読

Kazuya Takahashi, Yui Ishii, Kazunao Hayashi, Satoshi Ikarashi, Hirokazu Kawai, Yuichi Sato, Shuji Terai

ENDOSCOPY 49 ( S 01 ) E95 - E96 2017年2月

lStatus of and candidates for cell therapy in liver cirrhosis: overcoming the "point of no return'' in advanced liver cirrhosis 査読

Shuji Terai, Atsunori Tsuchiya

JOURNAL OF GASTROENTEROLOGY 52 ( 2 ) 129 - 140 2017年2月

記述言語：英語出版者・発行元：SPRINGER JAPAN KK

The treatment of liver cirrhosis is currently being standardized and developed specifically to reduce activation of hepatic stellate cells (HSCs), inhibit fibrosis, increase degradation of matrix components, and reduce activated myofibroblasts. Cell therapy can be applied in the treatment of liver cirrhosis; however, the characteristic features of this therapy differ from those of other treatments because of the involvement of a living body origin and production of multiple cytokines, chemokines, matrix metalloproteinases (MMPs), and growth factors. Thus, cell therapies can potentially have multiple effects on the damaged liver, including alleviating liver cirrhosis and stimulating liver regeneration with affecting the host cells. Cell therapies initially involved autologous bone marrow cell infusion, and have recently developed to include the use of specific cells such as mesenchymal stem cells and macrophages. The associated molecular mechanisms, routes of administration, possibility of allogeneic cell therapy, and host conditions appropriate for cell therapies are now being extensively analyzed. In this review, we summarize the status and future prospects of cell therapy for liver cirrhosis.

DOI： 10.1007/s00535-016-1258-1

Phase 1 Clinical Study of siRNA Targeting Carbohydrate Sulphotransferase 15 in Crohn's Disease Patients with Active Mucosal Lesions 査読

Kenji Suzuki, Junji Yokoyama, Yusuke Kawauchi, Yutaka Honda, Hiroki Sato, Yutaka Aoyagi, Shuji Terai, Kazuichi Okazaki, Yasuo Suzuki, Yukinori Sameshima, Tsuneo Fukushima, Kazuyuki Sugahara, Raja Atreya, Markus F. Neurath, Kenichi Watanabe, Hiroyuki Yoneyama, Hitoshi Asakura

JOURNAL OF CROHNS & COLITIS 11 ( 2 ) 221 - 228 2017年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OXFORD UNIV PRESS

Background and Aims: Carbohydrate sulphotransferase 15 [CHST15] is a specific enzyme biosynthesizing chondroitin sulphate E that binds various pathogenic mediators and is known to create local fibrotic lesions. We evaluated the safety of STNM01, a synthetic double-stranded RNA oligonucleotide directed against CHST15, in Crohn's disease [CD] patients whose mucosal lesions were refractory to conventional therapy.
Methods: This was a randomized, double-blind, placebo-controlled, concentration-escalation study of STNM01 by a single-dose endoscopic submucosal injection in 18 CD patients. Cohorts of increasing concentration of STNM01 were enrolled sequentially as 2.5 nM [n = 3], 25 nM [n = 3], and 250 nM [n = 3] were applied. A cohort of placebo [n = 3] was included in each concentration. Safety was monitored for 30 days. Pharmacokinetics was monitored for 24 h. The changes from baseline in the segmental Simple Endoscopic Score for CD [SES-CD] as well as the histological fibrosis score were evaluated.
Results: STNM01 was well tolerated and showed no drug-related adverse effects in any cohort of treated patients. There were no detectable plasma concentrations of STNM01 at all measured time points in all treatment groups. Seven of nine subjects who received STNM01 showed reduction in segmental SES-CD at Day 30, when compared with those who received placebo. Histological analyses of biopsy specimens revealed that STNM01 reduced the extent of fibrosis.
Conclusion: Local application of STNM01 is safe and well tolerated in CD patients with active mucosal lesions.

DOI： 10.1093/ecco-jcc/jjw143

Lipoprotein-X in cholestatic patients causes xanthomas and promotes foam cell formation in human macrophages 査読

Luka Suzuki, Satoshi Hirayama, Mariko Fukui, Makoto Sasaki, Sadayuki Hiroi, Makoto Ayaori, Shuji Terai, Minoru Tozuka, Hirotaka Watada, Takashi Miida

JOURNAL OF CLINICAL LIPIDOLOGY 11 ( 1 ) 110 - 118 2017年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE INC

BACKGROUND: Lipoprotein-X (Lp-X) is an abnormal phospholipid-rich lipoprotein found in patients with cholestatic liver disease. Some patients exhibit skin xanthomas and severe hyperlipidemia.
OBJECTIVE: We investigated whether Lp-X induces foam cell formation in human-derived macrophages.
METHODS: To compare the atherogenic properties of Lp-X and modified LDL, we isolated Lp-X from 2 patients who had drug-induced cholestasis and xanthoma striata in the interphalangeal folds. We prepared oxidized LDL and acetylated LDL from healthy volunteers for the positive control experiments.
RESULTS: When human monocyte-derived macrophages were incubated with these lipoproteins, the isolated Lp-X induced more prominent lipid accumulation than oxidized LDL or acetylated LDL. One case underwent liver biopsy, with the bile ducts showing marked damage, fulfilling the criteria for vanishing bile duct syndrome. The other case was clinically diagnosed as drug-induced hypersensitivity syndrome. In both cases, Lp-X levels decreased markedly and the xanthomas disappeared completely after the improvement of cholestasis.
CONCLUSION: This study indicates that Lp-X induces foam cell formation in human-derived macrophages. Our findings strongly suggest that persistently elevated Lp-X may cause xanthomas. (C) 2016 National Lipid Association. All rights reserved.

DOI： 10.1016/j.jacl.2016.10.013

A novel technique for biliary biopsy using the sheath of a plastic stent and a non-return valve 査読

Shinichi Morita, Tsutomu Kanefuji, Takahiro Hoshi, Masaaki Kobayashi, Takeshi Suda, Takeshi Mizusawa, Shuji Terai

ENDOSCOPY 49 ( S 01 ) E9 - E10 2017年2月

Early Detection of Hepatocellular Carcinoma Recurrence Using the Highly Sensitive Fucosylated Fraction of Alpha-Fetoprotein 査読

Toru Setsu, Atsunori Tsuchiya, Takayuki Watanabe, Takuro Nagoya, Satoshi Ikarashi, Kazunao Hayashi, Junji Yokoyama, Satoshi Yamagiwa, Shuji Terai

Case Reports in Gastroenterology 11 ( 1 ) 142 - 147 2017年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：S. Karger AG

Alpha-fetoprotein (AFP)-L3 was originally reported as a hepatocellular carcinoma (HCC)-specific tumor marker, and recent accumulation of evidence has revealed that AFP-L3 frequency predicts the biological malignancy potential of HCC. However, AFP-L3 elevation from undetectable levels after curative treatment could not be discussed due to the difficulties of calculating AFP-L3 concentrations when serum AFP levels were low. Here, as a novel method, we used highly sensitive AFP-L3 frequency to predict HCC recurrence after curative treatment. Our cases illustrate that recognizing elevation of AFP-L3 from undetectable levels led to the early detection of recurrent HCC due to more careful surveillance.

DOI： 10.1159/000462969

Immunohistochemical differentiation of eosinophilic esophageal myositis from eosinophilic esophagitis 査読

Hiroki Sato, Nao Nakajima, Go Hasegawa, Yuzo Kawata, Yuichi Sato, Kenji Suzuki, Terasu Honma, Shuji Terai

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 32 ( 1 ) 106 - 113 2017年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

Background and AimEosinophilic esophagitis (EoE) is a Th2-mediated allergic disease of the esophageal epithelium, associated with antigen. We previously reported a case series for eosinophilic esophageal myositis (EoEM)a novel eosinophilic gastrointestinal disorder defined as eosinophilic infiltration localized in the esophageal muscle layerand diagnosed it by peroral endoscopic muscle biopsy. Here, we investigated the immunopathology of EoEM to differentiate it from EoE.
MethodsHistological analysis was performed for three cases of EoEM and EoE, respectively. The results were compared with those of two control samples (non-eosinophilic gastrointestinal disorder full-layer esophagus). Using immunofluorescence, we analyzed the expression of the chemokine receptor CCR3 and its ligands eotaxin-1 and eotaxin-3 to investigate the eosinophilic reaction. Additionally, we determined the expression patterns of desmoglein-1 in the esophageal epithelium, which shows dysregulated expression in EoE.
ResultsEosinophil infiltration was observed in the muscle layer (maximum number, 30, 36, 73/high-power field) and the epithelium (50, 44, 40/high-power field) for EoEM and EoE, respectively. In EoE esophageal epithelium, the number of eotaxin-3-positive epithelial cells was significantly increased together with CCR3-positive infiltrating cells. However, in EoEM, a number of eotaxin-1-positive and eotaxin-3-positive myocytes and vascular endothelial cells were increased in the esophageal muscle layer. A significant loss of desmoglein-1 expression was only observed in EoE, not in EoEM.
ConclusionsEotaxin-1 and eotaxin-3 expression on the smooth muscle and vessels plays a role in the pathogenesis of EoEM, while EoE shows an epithelial eotaxin-3-dominant immunoreaction. Thus, the EoEM immunological pattern displays clear differences from that of EoE.

DOI： 10.1111/jgh.13466

Training sample selection based on self-training for liver cirrhosis classification using ultrasound images 査読

Yusuke Fujita, Yoshihiro Mitani, Yoshihiko Hamamoto, Makoto Segawa, Shuji Terai, Isao Sakaida

THIRTEENTH INTERNATIONAL CONFERENCE ON QUALITY CONTROL BY ARTIFICIAL VISION 2017 10338 103380J 2017年

記述言語：英語掲載種別：研究論文（国際会議プロシーディングス）出版者・発行元：SPIE-INT SOC OPTICAL ENGINEERING

Ultrasound imaging is a popular and non-invasive tool used in the diagnoses of liver disease. Cirrhosis is a chronic liver disease and it can advance to liver cancer. Early detection and appropriate treatment are crucial to prevent liver cancer. However, ultrasound image analysis is very challenging, because of the low signal-to-noise ratio of ultrasound images. To achieve the higher classification performance, selection of training regions of interest (ROIs) is very important that effect to classification accuracy. The purpose of our study is cirrhosis detection with high accuracy using liver ultrasound images. In our previous works, training ROI selection by MILBoost and multiple-ROI classification based on the product rule had been proposed, to achieve high classification performance. In this article, we propose self-training method to select training ROIs effectively. Evaluation experiments were performed to evaluate effect of self-training, using manually selected ROIs and also automatically selected ROIs. Experimental results show that self-training for manually selected ROIs achieved higher classification performance than other approaches, including our conventional methods. The manually ROI definition and sample selection are important to improve classification accuracy in cirrhosis detection using ultrasound images.

DOI： 10.1117/12.2264076

Two cases of cholangiocellular carcinoma complicated with Trousseau’s syndrome

Shinagawa, Y., Kamimura, K., Sakai, N., Kumaki, D., Ogawa, K., Azumi, R., Tominaga, K., Sakamaki, A., Ikarashi, S., Hayashi, K., Yamamoto, T., Mizuno, K., Yamagiwa, S., Terai, S.

Kanzo/Acta Hepatologica Japonica 58 ( 9 ) 2017年

Invasive Liver Abscess Syndrome Caused by Klebsiella pneumoniae 査読

Toru Setsu, Atsunori Tsuchiya, Satoshi Yamagiwa, Shuji Terai

INTERNAL MEDICINE 56 ( 22 ) 3121 - 3122 2017年

Clinical trials using mesenchymal stem cells in liver diseases and inflammatory bowel diseases. 査読国際誌

Tsuchiya A, Kojima Y, Ikarashi S, Seino S, Watanabe Y, Kawata Y, Terai S

Inflammation and regeneration 37 16 - 16 2017年

Increase of Soluble Programmed Cell Death Ligand 1 in Patients with Chronic Hepatitis C 査読

Satoshi Yamagiwa, Toru Ishikawa, Nobuo Waguri, Soichi Sugitani, Kenya Kamimura, Atsunori Tsuchiya, Masaaki Takamura, Hirokazu Kawai, Shuji Terai

INTERNATIONAL JOURNAL OF MEDICAL SCIENCES 14 ( 5 ) 403 - 411 2017年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：IVYSPRING INT PUBL

Objectives: To determine whether the soluble programmed cell death ligand 1 (sPD-L1) levels inpatients with chronic hepatitis C (CHC) are associated with the clinical features of the disease and the efficacy of treatment, including interferon (IFN)-alpha.
Methods: We investigated the sPD-L1 levels in the sera of 80 genotype 1b Japanese patients with CHC who underwent 12 weeks of telaprevir (TVR)-or simeprevir (SMV)-based triple therapy followed by 12 weeks of dual therapy with pegylated IFN-alpha plus ribavirin. Serum was also obtained from 22 patients with chronic hepatitis B (CHB) and from 10 healthy donors (HC). The sPD-L1 levels were measured using an ELISA kit. In addition, we examined the PD-L1 expression on the cell surface of immortalized hepatocytes (HPT1) after incubation with cytokines, including IFN-gamma.
Results: The pretreatment serum sPD-L1 levels were significantly increased in patients with CHC (median 109.3 pg/ml, range 23.1-402.3) compared with patients with CHB (69.2 pg/ml, 15.5-144.8; P < 0.001) and HC (100.3 pg/ml, 40.1-166.6; P = 0.039). No significant differences in the sustained virological response (SVR) rates were found between the TVR-(85.0%, n=40) and SMV-treated (80.0%, n=40) groups, and the pretreatment levels of serum sPD-L1 were not significantly different between patients who achieved SVR (105.0 pg/ml, 23.1-402.3) and non-SVR patients (133.5 pg/ml, 39.9-187.2; P = 0.391). The pretreatment level of sPD-L1 was positively correlated with the alanine aminotransferase and alpha-fetoprotein levels (R-2 = 0.082, P = 0.016, and R-2 = 0.149, P = 0.002, respectively). Although immortalized hepatocytes do not express PD-L1, we confirmed that PD-L1 expression was induced after stimulation with IFN-gamma.
Conclusions: In this study, we first found that sPD-L1 was increased in patients with CHC. Our results indicate that the level of serum sPD-L1 might be associated with the progression of CHC and the generation of hepatocellular carcinoma.

DOI： 10.7150/ijms.18784

Prognostic Impact of Indocyanine Green Plasma Disappearance Rate in Hepatocellular Carcinoma Patients after Radiofrequency Ablation: A Prognostic Nomogram Study 査読

Motoi Azumi, Takeshi Suda, Shuji Terai, Kouhei Akazawa

INTERNAL MEDICINE 56 ( 9 ) 1001 - 1007 2017年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPAN SOC INTERNAL MEDICINE

Objective Radiofrequency ablation has been used widely for the local ablation of hepatocellular carcinoma, particularly in its early stages. The study aim was to identify significant prognostic factors and develop a predictive nomogram for patients with hepatocellular carcinoma who have undergone radiofrequency ablation. We also developed the formula to predict the probability of 3- and 5-year overall survival based on clinical variables.
Methods We retrospectively studied 96 consecutive patients with hepatocellular carcinoma who had undergone radiofrequency ablation as a first-line treatment. Independent and significant factors affecting the overall survival were selected using a Cox proportional hazards model, and a prognostic nomogram was developed based on these factors. The predictive accuracy of the nomogram was determined by Harrell's concordance index and compared with the Cancer of the Liver Italian Program score and Japan Integrated Staging score.
Results A multivariate analysis revealed that age, indocyanine green plasma disappearance rate, and log (des-gamma-carboxy prothrombin) level were independent and significant factors influencing the overall survival. The nomogram was based on these three factors. The mean concordance index of the nomogram was 0.74 +/- 0.08, which was significantly better than that of conventional staging systems using the Cancer of the Liver Italian Program score (0.54 +/- 0.03) and Japan Integrated Staging score (0.59 +/- 0.07).
Conclusion This study suggested that the indocyanine green plasma disappearance rate and age at radiofrequency ablation (RFA) and des-gamma-carboxy-prothrombin (DCP) are good predictors of the prognosis in hepatocellular carcinoma patients after radiofrequency ablation. We successfully developed a nomogram using obtainable variables before treatment.

DOI： 10.2169/internalmedicine.56.7278

Possible involvement of mucosal-associated invariant T cells in the progression of inflammatory bowel diseases 査読

Kentaro Tominaga, Satoshi Yamagiwa, Toru Setsu, Naruhiro Kimura, Hiroki Honda, Hiroteru Kamimura, Yutaka Honda, Masaaki Takamura, Junji Yokoyama, Kenji Suzuki, Toshifumi Wakai, Shuji Terai

BIOMEDICAL RESEARCH-TOKYO 38 ( 2 ) 111 - 121 2017年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BIOMEDICAL RESEARCH PRESS LTD

munity. Recent studies have demonstrated that MAIT cells might be implicated in inflammatory bowel diseases (IBDs), but their precise function in IBD remains to be elucidated. We investigated the possible involvement of MAIT cells in the immunopathogenesis of IBDs. Heparinized peripheral blood and biopsy specimens of the colon were collected from 25 patients with ulcerative colitis (UC), 15 patients with Crohn's disease (CD), and 19 heathy individuals. Lymphocytes were isolated from the blood and colon, and then MAIT cells were analyzed by flow cytometry. The frequency of MAIT cells was significantly lower in the blood of IBD patients compared to healthy donors and significantly higher in the inflamed colons compared to healthy colons (P = 0.001). Among the IBD patients, the frequency of MAIT cells in the blood and colon was correlated with disease activities. In vitro activated MAIT cells from IBD patients secreted significantly more tumor necrosis factor-alpha and interleukin-17 than those from healthy donors. These findings indicate that MAIT cells are activated in IBD patients, and their accumulation in the inflamed mucosa is correlated with disease activities.

DOI： 10.2220/biomedres.38.111

A Mesenteric Desmoid Tumor with Rapid Progression 査読

Kazunao Hayashi, Masaaki Takamura, Hisashi Yokoyama, Yuichi Sato, Satoshi Yamagiwa, Hitoshi Nogami, Toshifumi Wakai, Go Hasegawa, Shuji Terai

INTERNAL MEDICINE 56 ( 5 ) 505 - 508 2017年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPAN SOC INTERNAL MEDICINE

We herein report the case of a rapidly progressive sporadic mesenteric desmoid tumor (DT). A 62-year-old woman presented with a 4-cm-diameter palpable mass in the left supraumbilical area. The mass showed an ill-defined margin with heterogeneous delayed enhancement on computed tomography and heterogeneous high intensity on T2-weighted magnetic resonance imaging. Sixteen months after the initial observation, the mass had grown in size, reaching 13 cm in diameter. The resected mass was histologically confirmed as a DT of the mesentery. Since DT often has an unpredictable clinical course, clinicians should bear in mind the need for imaging follow-up.

DOI： 10.2169/internalmedicine.56.7320

Efficacy and safety of telaprevir- and simeprevir-based triple therapies for older patients with chronic hepatitis C 査読

Satoshi Yamagiwa, Toru Ishikawa, Nobuo Waguri, Soichi Sugitani, Hiroto Wakabayashi, Shogo Ohkoshi, Takashi Tsukishiro, Toru Takahashi, Toshiaki Watanabe, Shuji Terai

World Journal of Hepatology 9 ( 5 ) 252 - 262 2017年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Baishideng Publishing Group Co

AIM To evaluate and compare the efficacy and safety of telaprevir (TVR)-and simeprevir (SMV)-based triple therapies in elderly patients, specifically patients aged 66 years or older. METHODS The present study enrolled 112 and 76 Japanese patients with chronic hepatitis C virus genotype 1b infection who were treated with a 12-wk TVR-based or SMV-based triple therapy, respectively, followed by a dual therapy that included pegylated interferon a and ribavirin (RBV) for 12 wk. The patients were categorized into two groups according to age as follows: A younger group of patients aged ≤ 65 years old and an older group of patients aged &gt
65 years old. Among the patients treated with TVR-based triple therapy, 34 patients were included in the older group. The median ages were 56 years (range: 28-65 years) in the younger group and 69 years (range: 66-81 years) in the older group. Among the patients treated with SMV-based triple therapy, 39 patients were included in the older group. The median ages were 59 years (range: 36-65 years) in the younger group and 71 years (range: 66-86 years) in the older group. The clinical, biochemical and virological data were analyzed before and during treatment. RESULTS Among the patients treated with the TVR-based triple therapy, no significant difference in the sustained virological response (SVR) was found between the younger (80.8%) and older (88.2%) groups. The SVR rates for patients with the interleukin 28B (IL28B) (rs8099917) TG/GGgenotypes (73.9% and 60.0% in the younger and older groups, respectively) were significantly lower than for patients with the IL28B TT-genotype (86.3% and 92.9%, respectively). The cumulative exposure to RBV for the entire 24-wk treatment period (as a percentage of the target dose) was significantly higher in the younger group than in the older group (91.7% vs 66.7%, respectively, P &lt
0.01), but the cumulative exposure to TVR was not significantly different between the younger and older groups (91.6% vs 81.9%, respectively). A multivariate analysis identified the TT-genotype of IL28B (OR = 8.160
95%CI: 1.593-41.804, P = 0.012) and the adherence of RBV ( &gt
60%) (OR = 11.052
95%CI: 1.160-105.273, P = 0.037) as independent factors associated with the SVR. Adverse events resulted in discontinuation of the treatment in 11.3% and 14.7% of the younger and older groups, respectively. Among the patients treated with the SMV-based triple therapy, no significant difference in the SVR rare was found between the younger (81.1%) and older (82.1%) groups. The SVR rates for patients with the IL28B TG/GG-genotypes (77.8% and 64.7% in the younger and older groups, respectively) were significantly lower than for patients with the IL28B TT-genotype (88.2% and 100%, respectively). A multivariate analysis identified the TT-genotype of IL28B as an independent factor associated with the SVR (OR = 9.677
95%CI: 1.114-84.087, P = 0.040). Adverse events resulted in discontinuation of the treatment in 7.0% and 14.3% of patients in the younger and older groups, respectively. CONCLUSION Both TVR- and SMV-based triple therapies can be successfully used to treat patients aged 66 years or older with genotype 1b chronic hepatitis C. Genotyping of the IL28B indicates a potential to achieve SVR in these difficult-to-treat elderly patients.

DOI： 10.4254/wjh.v9.i5.252

Tumor markers for early diagnosis for brain metastasis of hepatocellular carcinoma: A case series and literature review for effective loco-regional treatment 査読

Kenya Kamimura, Yuji Kobayashi, Yoshifumi Takahashi, Hiroyuki Abe, Daisuke Kumaki, Takeshi Yokoo, Hiroteru Kamimura, Norihiro Sakai, Akira Sakamaki, Satoshi Abe, Masaaki Takamura, Hirokazu Kawai, Satoshi Yamagiwa, Shuji Terai

CANCER BIOLOGY & THERAPY 18 ( 2 ) 79 - 84 2017年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：TAYLOR & FRANCIS INC

Intrahepatic lesions of hepatocellular carcinoma (HCC) have been controlled by significant advances in treatment using loco-regional therapies, including, surgery, ablative therapy, catheter-based chemotherapy, and embolization. Consequently, the number of patients with extrahepatic metastatic lesions has increased. Their prognosis remains poor with approximately <1y of survival from the time of diagnosis. A molecularly targeted drug, sorafenib, have been used to treat extrahepatic lesions and shown the prolonged survival time. However, the therapeutic benefit for the brain metastasis remains unclear, since it causes intratumor bleeding leading to the severe brain damage. No guidelines for the brain metastasis of HCC have been developed to date due to the shortage of the experiences and evidences. Therefore, the development of standard therapy for brain metastasis following the early diagnosis is essential by accumulating the information of clinical courses and evidences. For this purpose, we reviewed cases of HCC brain metastasis reported to date and analyzed additional 8 cases from our hospital, reviewing 592 advanced HCC cases to estimate the possible metastatic lesions in the brain. With careful review of cases and literature, we suggest that the cases with lung metastasis with increase tendency of tumor markers within recent 3-6months have higher risks of brain metastasis. Therefore, they should be carefully followed by imaging modalities. In addition, the loco-regional treatment, including surgical resection and radiation therapy should be performed for better prognosis by preventing re-bleeding from the tumors.

DOI： 10.1080/15384047.2016.1276134

An Unusual Case of an Extremely Large α-Fetoprotein-Producing Tumor. 査読

Takahashi K, Tsuchiya A, Terai S

Gastroenterology 151 ( 6 ) 1077 - 1080 2016年12月

Myofibroblast distribution is associated with invasive growth types of colorectal cancer 査読

Masafumi Takatsuna, Satoko Morohashi, Tadashi Yoshizawa, Hideaki Hirai, Toshihiro Haga, Rie Ota, Kensuke Saito, Yunyan Wu, Hiroko Seino, Yutaka Aoyagi, Shuji Terai, Hiroshi Kijima

ONCOLOGY REPORTS 36 ( 6 ) 3154 - 3160 2016年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPANDIDOS PUBL LTD

Both the invasive growth types of colorectal cancer (CRC) and the number of myofibroblasts have been associated with histopathological factors such as lymph node and liver metastasis, and local recurrence. However, there are few studies, that have assessed the association between invasive growth type and myofibroblast distribution in CRC. We aimed to evaluate the relationship between the clinicopathological factors of CRC and two invasive growth types, the expanding and infiltrating types. We categorized 150 cases of pT3 CRC into the expanding and infiltrating types and measured the myofibroblast density of three histological layers: the submucosa (SM), the muscularis propria (MP) and the subserosa (SS). We compared these two invasive growth types and analyzed the relationship between clinicopathological factors and myofibroblast density. Myofibroblast density was significantly higher in the infiltrating type than that in the expanding type (P<0.05). In the lymph node metastasis-positive group of the infiltrating type, myofibroblast density in MP was significantly higher than that in the lymph node metastasis-negative group (P<0.001). In the infiltrating type, the group with the higher level of lymphatic invasion had a significantly higher density of myofibroblasts in the MP than the group with the lower level of lymphatic invasion (P<0.01). These results suggest that myofibroblasts participate more in the infiltrating type compared with the expanding type of CRC. It would appear that myofibroblasts present in the MP play an important role in the malignant potential of the infiltrating type compared to the expanding type.

DOI： 10.3892/or.2016.5202

Transhepatic arterial chemotherapy using a combination of miriplatin and CDDP powder in patients with hepatocellular carcinoma 査読

Kenya Kamimura, Hiroteru Kamimura, Atsunori Tsuchiya, Masaaki Takamura, Hirokazu Kawai, Nobuo Waguri, Toru Ishikawa, Takeshi Suda, Satoshi Yamagiwa, Shuji Terai

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 31 361 - 361 2016年11月

Case of severe alcoholic hepatitis treated with granulocytapheresis 査読

Yukari Watanabe, Kenya Kamimura, Tomohiro Iwasaki, Hiroyuki Abe, Shunsaku Takahashi, Ken-ichi Mizuno, Manabu Takeuchi, Atsushi Eino, Ichiei Narita, Shuji Terai

WORLD JOURNAL OF CLINICAL CASES 4 ( 11 ) 369 - 374 2016年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BAISHIDENG PUBLISHING GROUP INC

Severe alcoholic hepatitis (AH) has a high mortality, and it is associated with encephalopathy, acute renal failure, sepsis, gastrointestinal bleeding, and endotoxemia. The 28-d mortality remains poor (34%-40%), because no effective treatment has been established. Recently, corticosteroids (CS) have been considered effective for significantly improving the prognosis of those with AH, as it prevents the production of pro-inflammatory cytokines. However, CS are not always appropriate as an initial therapeutic option, such as in cases with an infection or resistance to CS. We describe a patient with severe AH complicated by a severe infection caused by the multidrug resistance bacteria (Pseudomonas aeruginosa), and was successfully treated with granulocytapheresis monotherapy without using CS. The experience of this case will provide understanding of the disease and information treating cases without using CS.

DOI： 10.12998/wjcc.v4.i11.369

[Series: Diagnosis at a Glance]. 査読

Kobayashi T, Tsuchiya A, Kuraoka N, Yamamoto T, Honda Y, Yokoyama J, Kawai H, Yamagiwa S, Suda T, Terai S

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 105 ( 11 ) 2263 - 2267 2016年11月

Vonoprazan 20 mg <i>vs</i> lansoprazole 30 mg for endoscopic submucosal dissection-induced gastric ulcers. 査読国際誌

Takahashi K, Sato Y, Kohisa J, Watanabe J, Sato H, Mizuno K, Hashimoto S, Terai S

World journal of gastrointestinal endoscopy 8 ( 19 ) 716 - 722 2016年11月

Significance of hepatic progenitor cell marker-positive hepatocellular carcinoma and its possible prediction by AFP-L3 査読

Atsunori Tsuchiya, Yuichi Kojima, Satoshi Seino, Yusuke Watanabe, Kenya Kamimura, Masaaki Takamura, Hirokazu Kawai, Satoshi Yamagiwa, Shuji Terai

HEPATOLOGY 64 669A - 670A 2016年10月

Liver-targeted hydrodynamic gene therapy: Recent advances in the technique 査読

Takeshi Yokoo, Kenya Kamimura, Hiroyuki Abe, Yuji Kobayashi, Tsutomu Kanefuji, Kohei Ogawa, Ryo Goto, Masafumi Oda, Takeshi Suda, Shuji Terai, Masafumi Oda

WORLD JOURNAL OF GASTROENTEROLOGY 22 ( 40 ) 8862 - 8868 2016年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BAISHIDENG PUBLISHING GROUP INC

One of the major research focuses in the field of gene therapy is the development of clinically applicable, safe, and effective gene-delivery methods. Since the first case of human gene therapy was performed in 1990, a number of gene-delivery methods have been developed, evaluated for efficacy and safety, and modified for human application. To date, viral-vector-mediated deliveries have shown effective therapeutic results. However, the risk of lethal immune response and carcinogenesis have been reported, and it is still controversial to be applied as a standard therapeutic option. On the other hand, delivery methods for non-viral vector systems have been developed, extensively studied, and utilized in in vivo gene-transfer studies. Compared to viral-vector mediated gene transfer, nonviral systems have less risk of biological reactions. However, the lower gene-transfer efficiency was a critical hurdle for applying them to human gene therapy. Among a number of nonviral vector systems, our studies focus on hydrodynamic gene delivery to utilize physical force to deliver naked DNA into the cells in the living animals. This method achieves a high gene-transfer level by DNA solution injections into the tail vein of rodents, especially in the liver. With the development of genome editing methods, in vivo gene-transfer therapy using this method is currently the focus in this research field. This review explains the method principle, efficiency, safety, and procedural modifications to achieve a high level of reproducibility in large-animal models.

DOI： 10.3748/wjg.v22.i40.8862

Platinum-based transhepatic arterial chemotherapy using a combination of miriplatin and CDDP powder in patients with hepatocellular carcinoma 査読

Kohei Ogawa, Kenya Kamimura, Takeshi Suda, Takeshi Yokoo, Akira Sakamaki, Satoshi Abe, Hiroteru Kamimura, Atsunori Tsuchiya, Masaaki Takamura, Hirokazu Kawai, Nobuo Waguri, Toru Ishikawa, Satoshi Yamagiwa, Shuji Terai

HEPATOLOGY 64 652A - 652A 2016年10月

Biological significance of a disintegrin and metalloproteinase 21 expression in hepatocellular carcinoma 査読

Masaaki Takamura, Hiroki Honda, Satoshi Yamagiwa, Naruhiro Kimura, Toru Setsu, Kentaro Tominaga, Hiroteru Kamimura, Takuya Genda, Yasunobu Matsuda, Toshifumi Wakai, Shuji Terai

HEPATOLOGY 64 639A - 639A 2016年10月

Myofibroblasts of the muscle layer stimulate the malignant potential of colorectal cancer 査読

Masafumi Takatsuna, Satoko Morohashi, Tadashi Yoshizawa, Hideaki Hirai, Toshihiro Haga, Rie Ota, Yunyan Wu, Hajime Morohashi, Kenichi Hakamada, Shuji Terai, Hiroshi Kijima

ONCOLOGY REPORTS 36 ( 3 ) 1251 - 1257 2016年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPANDIDOS PUBL LTD

Myofibroblasts of colorectal cancer (CRC) have been associated with histopathological factors such as lymph node metastasis, liver metastasis and local recurrence. However, few studies have assessed the association between these malignant potentials and the myofibroblast distribution in CRC. We aimed to evaluate the relationship between clinical factors and myofibroblast distribution around CRC invasive lesions. The study included 121 cases of pT3 CRC that were diagnosed at stage II or III. Myofibroblast density of the following three histological layers was measured: the submucosa (SM), muscularis propria (MP) and subserosa (SS). We analyzed the relationship between the clinicopathological factors and myofibroblast density by studying the histopathological features of the three layers. The myofibroblast density of the MP layer was significantly higher in the groups with high-frequency lymphatic and venous invasion than the groups with low-frequency lymphatic (P<0.001) and venous (P<0.01) invasion, respectively. In the positive lymph node metastasis group, the myofibroblast density at the MP layer was significantly higher than that in the negative lymph node metastasis group (P<0.001). The high myofibroblast density group at the MP layer was significantly associated with poor overall survival (P<0.003). Our study indicated that myofibroblasts are a type of cancer-associated fibroblasts and that the myofibroblast distribution contributes to the malignant potential of CRC. Furthermore, we demonstrated that myofibroblasts present at the MP layer play an important role in the malignant potential and poor prognosis of patients with CRC.

DOI： 10.3892/or.2016.4932

Assessments of histologic changes after peroral endoscopic myotomy. 査読

Sato H, Sagara S, Suzuki K, Terai S, Yahagi N

Gastrointestinal endoscopy 84 ( 2 ) 377 - 378 2016年8月

Management of gastric and duodenal neuroendocrine tumors 査読

Yuichi Sato, Satoru Hashimoto, Ken-ichi Mizuno, Manabu Takeuchi, Shuji Terai

WORLD JOURNAL OF GASTROENTEROLOGY 22 ( 30 ) 6817 - 6828 2016年8月

記述言語：英語出版者・発行元：BAISHIDENG PUBLISHING GROUP INC

Gastrointestinal neuroendocrine tumors (GI-NETs) are rare neoplasms, like all NETs. However, the incidence of GI-NETS has been increasing in recent years. Gastric NETs (G-NETs) and duodenal NETs (D-NETs) are the common types of upper GI-NETs based on tumor location. G-NETs are classified into three distinct subgroups: type I, II and III. Type I G-NETs, which are the most common subtype (70%-80% of all G-NETs), are associated with chronic atrophic gastritis, including autoimmune gastritis and Helicobacter pylori associated atrophic gastritis. Type II G-NETs (5%-6%) are associated with multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome (MEN1-ZES). Both type I and II G-NETs are related to hypergastrinemia, are small in size, occur in multiple numbers, and are generally benign. In contrast, type III G-NETs (10%-15%) are not associated with hypergastrinemia, are large-sized single tumors, and are usually malignant. Therefore, surgical resection and chemotherapy are generally necessary for type III G-NETs, while endoscopic resection and follow-up, which are acceptable for the treatment of most type I and II G-NETs, are only acceptable for small and well differentiated type III G-NETs. D-NETs include gastrinomas (50%-60%), somatostatin-producing tumors (15%), nonfunctional serotonin-containing tumors (20%), poorly differentiated neuroendocrine carcinomas (< 3%), and gangliocytic paragangliomas (< 2%). Most D-NETs are located in the first or second part of the duodenum, with 20% occurring in the periampullary region. Therapy for D-NETs is based on tumor size, location, histological grade, stage, and tumor type. While endoscopic resection may be considered for small nonfunctional D-NETs (G1) located in the higher papilla region, surgical resection is necessary for most other D-NETs. However, there is no consensus regarding the ideal treatment of D-NETs.

DOI： 10.3748/wjg.v22.i30.6817

Effects of Fibrotic Tissue on Liver-targeted Hydrodynamic Gene Delivery 査読

Yuji Kobayashi, Kenya Kamimura, Hiroyuki Abe, Takeshi Yokoo, Kohei Ogawa, Yoko Shinagawa-Kobayashi, Ryo Goto, Ryosuke Inoue, Masato Ohtsuka, Hiromi Miura, Tsutomu Kanefuji, Takeshi Suda, Masanori Tsuchida, Yutaka Aoyagi, Guisheng Zhang, Dexi Liu, Shuji Terai

MOLECULAR THERAPY-NUCLEIC ACIDS 5 ( 8 ) e359 2016年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：CELL PRESS

Hydrodynamic gene delivery is a common method for gene transfer to the liver of small animals, and its clinical applicability in large animals has been demonstrated. Previous studies focused on functional analyses of therapeutic genes in animals with normal livers and little, however, is known regarding its effectiveness and safety in animals with liver fibrosis. Therefore, this study aimed to examine the effects of liver fibrosis on hydrodynamic gene delivery efficiency using a rat liver fibrosis model. We demonstrated for the first time, using pCMV-Luc plasmid, that this procedure is safe and that the amount of fibrotic tissue in the liver decreases gene delivery efficiency, resulting in decrease in luciferase activity depending on the volume of fibrotic tissue in the liver and the number of hepatocytes that are immunohistochemically stained positive for transgene product. We further demonstrate that antifibrotic gene therapy with matrix metalloproteinase-13 gene reduces liver fibrosis and improves efficiency of hydrodynamic gene delivery. These results demonstrate the negative effects of fibrotic tissue on hydrodynamic gene delivery and its recovery by appropriate antifibrotic therapy.

DOI： 10.1038/mtna.2016.63

A novel training model composed of nonbiological materials for endoscopic submucosal dissection. 査読

Mizuno K, Sato H, Hashimoto S, Sato Y, Terai S

Gastrointestinal endoscopy 84 ( 2 ) 373 - 374 2016年8月

Novel ex-vivo training model for peroral endoscopic myotomy using hydrogel 査読

Hiroki Sato, Ken-ichi Mizuno, Shuji Terai

DIGESTIVE ENDOSCOPY 28 ( 5 ) 620 - 620 2016年7月

Pivotal Role of Carbohydrate Sulfotransferase 15 in Fibrosis and Mucosal Healing in Mouse Colitis 査読

Kenji Suzuki, Somasundaram Arumugam, Junji Yokoyama, Yusuke Kawauchi, Yutaka Honda, Hiroki Sato, Yutaka Aoyagi, Shuji Terai, Kazuichi Okazaki, Yasuo Suzuki, Shuji Mizumoto, Kazuyuki Sugahara, Raja Atreya, Markus F. Neurath, Kenichi Watanabe, Taishi Hashiguchi, Hiroyuki Yoneyama, Hitoshi Asakura

PLOS ONE 11 ( 7 ) e0158967 2016年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PUBLIC LIBRARY SCIENCE

Induction of mucosal healing (MH) is an important treatment goal in inflammatory bowel disease (IBD). Although the molecular mechanisms underlying MH in IBD is not fully explored, local fibrosis would contribute to interfere mucosal repair. Carbohydrate sulfotransferase 15 (CHST15), which catalyzes sulfation of chondroitin sulfate to produce rare E-disaccharide units, is a novel mediator to create local fibrosis. Here we have used siRNA-based approach of silencing CHST15 in dextran sulfate sodium (DSS) induced colitis in mice, human colon fibroblasts and cancer cell lines. In a DSS-induced acute colitis model, CHST15 siRNA reduced CHST15 mRNA in the colon, serum IL-6, disease activity index (DAI) and accumulation of F4/80(+) macrophages and ER-TR7(+) fibroblasts, while increased Ki-67(+) epithelial cells. In DSS-induced chronic colitis models, CHST15 siRNA reduced CHST15 mRNA in the colon, DAI, alpha-smooth muscle actin(+) fibroblasts and collagen deposition, while enhanced MH as evidenced by reduced histological and endoscopic scores. We also found that endoscopic submucosal injection achieved effective pancolonic delivery of CHST15 siRNA in mice. In human CCD-18 Co cells, CHST15 siRNA inhibited the expression of CHST15 mRNA and selectively reduced E-units, a specific product biosynthesized by CHST15, in the culture supernatant. CHST15 siRNA significantly suppressed vimentin in both TGF-beta-stimulated CCD18-Co cells and HCT116 cells while up-regulated BMP7 and Ecadherin in HCT116 cells. The present study demonstrated that blockade CHST15 represses colonic fibrosis and enhances MH partly though reversing EMT pathway, illustrating a novel therapeutic opportunity to refractory and fibrotic lesions in IBD.

DOI： 10.1371/journal.pone.0158967

Therapeutic or spontaneous Helicobacter pylori eradication can obscure magnifying narrow-band imaging of gastric tumors. 査読

Kobayashi M, Hashimoto S, Mizuno K, Takeuchi M, Sato Y, Watanabe G, Ajioka Y, Azumi M, Akazawa K, Terai S

Endoscopy international open 4 ( 6 ) E665 - 72 2016年6月

Deferasirox, an oral iron chelator, prevents hepatocarcinogenesis and adverse effects of sorafenib 査読

Naoki Yamamoto, Takahiro Yamasaki, Taro Takami, Koichi Uchida, Koichi Fujisawa, Toshihiko Matsumoto, Issei Saeki, Shuji Terai, Isao Sakaida

JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION 58 ( 3 ) 202 - 209 2016年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JOURNAL CLINICAL BIOCHEMISTRY & NUTRITION

Although sorafenib is expected to have a chemopreventive effect on hepatocellular carcinoma (HCC) recurrence, there are limitations to its use because of adverse effects, including effects on liver function. We have reported that the iron chelator, deferoxamine can prevent liver fibrosis and preneoplastic lesions. We investigated the influence of administering a new oral iron chelator, deferasirox (DFX), on the effects of sorafenib. We used the choline-deficient t-amino acid-defined (CDAA) diet-induced rat liver fibrosis and HCC model. We divided rats into four groups: CDAA diet only (control group), CDAA diet with sorafenib (sorafenib group), CDAA diet with DFX (DFX group), and CDAA diet with DFX and sorafenib (DFX + sorafenib group). Liver fibrosis and development of preneoplastic lesions were assessed. In addition, we assessed adverse effects such as changes in body and liver weight, skin damage (eruption, dryness, and hair loss), which is defined as hand-foot skin syndrome, in the sorafenib and DFX + sorafenib groups. The combination of DFX + sorafenib markedly prevented liver fibrosis and preneoplastic lesions better than the other treatments. Furthermore, the combination therapy significantly decreased adverse effects compared with the sorafenib group. In conclusion, the combination therapy with DFX and sorafenib may be a useful adjuvant therapy to prevent recurrence after curative treatment of HCC.

DOI： 10.3164/jcbn.15-127

Effective prevention of hand-foot syndrome by the consumption of dried bonito broth 査読

Kenya Kamimura, Yoko Shinagawa, Kohei Ogawa, Yuji Kobayashi, Hiroyuki Abe, Takeshi Yokoo, Hiroteru Kamimura, Hirokazu Kawai, Takeshi Suda, Satoshi Yamagiwa, Hiroshi Baba, Shuji Terai

Japanese Journal of Cancer and Chemotherapy 43 ( 4 ) 463 - 465 2016年4月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Japanese Journal of Cancer and Chemotherapy Publishers Inc.

To examine whether the consumption of dried bonito both is effective for the prevention of hand-foot syndrome (HFS), concentrated bonito broth was administered to 10 patients with HCC who were treated with sorafenib. Among the 10 patients, seven showed an increase in peripheral blood flow, as observed on Doppler ultrasonography. Only one patient showed Grade 1 HFS on day 14 after the initiation of sorafenib (10%)
this incidence rate of HFS was significantly lower than that obtained in our previous studies and reported data. These results suggest that consumption of dried bonito broth contributes to the prevention of HFS by maintaining peripheral blood flow.

当院における悪性胃十二指腸狭窄に対する内視鏡的ステント留置術の有用性の検討

林和直, 山本幹, 水野研一, 本田穣, 橋本哲, 横山純二, 竹内学, 佐藤祐一, 寺井崇二

Gastroenterological Endoscopy 58 ( Suppl.1 ) 790 - 790 2016年4月

Modulation of anti-cancer drug sensitivity through the regulation of mitochondrial activity by adenylate kinase 4 査読国際誌

Fujisawa Koichi, Terai Shuji, Takami Taro, Yamamoto Naoki, Yamasaki Takahiro, Matsumoto Toshihiko, Yamaguch Kazuhito, Owada Yuji, Nishina Hiroshi, Takafumi Noma, Sakaida Isao

Journal of Experimental & Clinical Cancer Research Vol.35 ( No.1 ) 48 - 48 2016年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Background: Adenylate kinase is a key enzyme in the high-energy phosphoryl transfer reaction in living cells. Anisoform of this enzyme, adenylate kinase 4 (AK4), is localized in the mitochondrial matrix and is believed to beinvolved in stress, drug resistance, malignant transformation in cancer, and ATP regulation. However, the molecularbasis for the AK4 functions remained to be determined.Methods: HeLa cells were transiently transfected with an AK4 small interfering RNA (siRNA), an AK4 short hairpinRNA (shRNA) plasmid, a control shRNA plasmid, an AK4 expression vector, and a control expression vector toexamine the effect of the AK4 expression on cell proliferation, sensitivity to anti-cancer drug, metabolome, geneexpression, and mitochondrial activity.Results: AK4 knockdown cells treated with short hairpin RNA increased ATP production and showed greatersensitivity to hypoxia and anti-cancer drug, cis-diamminedichloro-platinum (II) (CDDP). Subcutaneous grafting AK4knockdown cells into nude mice revealed that the grafted cells exhibited both slower proliferation and reduced thetumor sizes in response to CDDP. AK4 knockdown cell showed a increased oxygen consumption rate with FCCPtreatment, while AK4 overexpression lowered it. Metabolome analysis showed the increased levels of thetricarboxylic acid cycle intermediates, fumarate and malate in AK4 knockdown cells, while AK4 overexpressionlowered them. Electron microscopy detected the increased mitochondrial numbers in AK4 knockdown cells.Microarray analysis detected the increased gene expression of two key enzymes in TCA cycle, succinatedehydrogenase A (SDHA) and oxoglutarate dehydrogenease L (OGDHL), which are components of SDH complexand OGDH complex, supporting the metabolomic results.Conclusions: We found that AK4 was involved in hypoxia tolerance, resistance to anti-tumor drug, and theregulation of mitochondrial activity. These findings provide a new potential target for efficient anticancer therapiesby controlling AK4 expression.

DOI： 10.1186/s13046-016-0322-2

Modulation of anti-cancer drug sensitivity through the regulation of mitochondrial activity by adenylate kinase 4. 査読国際誌

Fujisawa K, Terai S, Takami T, Yamamoto N, Yamasaki T, Matsumoto T, Yamaguchi K, Owada Y, Nishina H, Noma T, Sakaida I

Journal of experimental & clinical cancer research : CR 35 48 - 48 2016年3月

Advanced diagnostic endoscopy for gastric cancers discovered after H. Pylori eradication 査読

Masaaki Kobayashi, Takahiro Hoshi, Shin-Ichi Morita, Tsutomu Kanefuji, Takeshi Suda, Ken-Ichi Mizuno, Satoru Hashimoto, Manabu Takeuchi, Yuichi Sato, Shuji Terai

Journal of Japanese Society of Gastroenterology 113 ( 2 ) 235 - 244 2016年2月

Human T-cell leukemia virus type 1 (HTLV-1) Tax1 oncoprotein but not HTLV-2 Tax2 induces the expression of OX40 ligand by interacting with p52/p100 and RelB 査読

Yosuke Motai, Masahiko Takahashi, Takayuki Takachi, Masaya Higuchi, Toshifumi Hara, Mariko Mizuguchi, Yutaka Aoyagi, Shuji Terai, Yuetsu Tanaka, Masahiro Fujii

VIRUS GENES 52 ( 1 ) 4 - 13 2016年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER

Human T-cell leukemia virus type 1 (HTLV-1) is a causative retrovirus of adult T-cell leukemia and HTLV-1-associated myelopathy. Unlike HTLV-1, the same group of retrovirus HTLV-2 has not been found to be associated with these diseases. HTLV-1 and HTLV-2 encode transforming proteins Tax1 and Tax2, and a few distinct activities of Tax1 from those of Tax2 have been proposed to contribute to the HTLV-1-specific pathogenesis of disease. One significant difference of Tax1 from Tax2 is the activation of transcription factor NF-kappa B2/p100/p52. We found that Tax1 but not Tax2 induces the expression of OX40 ligand (OX40L) in a human T-cell line. To induce the OX40L expression, Tax1 but not Tax2 was observed to interact with NF-kappa B2/p100/p52 and RelB and the distinct interaction activity was mediated by the Tax1 amino acid region of 225-232. In addition, Tax1 but not Tax2 or Tax1/225-232 interacted with p65, p50, and c-Rel; however, the interactions were much less than those noted with NF-kappa B2/p100/p52 and RelB. OX40L is a T-cell costimulatory molecule of the tumor necrosis factor family, and its signal plays a critical role in establishing adaptive immunity by inducing the polarized differentiation of T-cells to cells such as T helper type 2 and T follicular helper cells. Therefore, the present findings suggest that Tax1 might alter the immune response to HTLV-1 and/or differentiation of HTLV-1-infected T-cells via OX40L induction, thereby acting as a factor mediating the distinct phenotypes and pathogenesis of HTLV-1 from that of HTLV-2.

DOI： 10.1007/s11262-015-1277-7

Circadian variations in the liver metabolites of medaka (Oryzias latipes) 査読

Koichi Fujisawa, Taro Takami, Yoshitaka Kimoto, Toshihiko Matsumoto, Naoki Yamamoto, Shuji Terai, Isao Sakaida

SCIENTIFIC REPORTS 6 20916 2016年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Circadian rhythms are biological rhythms with a period of around 24 hours. In this study, we compared the metabolome of the liver of medaka during the day and night. To comprehensively analyze the circadian variations in the levels of metabolites in the liver, livers were isolated from Zeitgeber time (ZT)4 and ZT16, and the variations in metabolite levels were evaluated. Inosinemonophosphate (IMP) and uridinemonophosphate (UMP) were found to be increased at night, indicating that nucleotide synthesis is most active during the night. Furthermore, the levels of metabolites of the tricarboxylic acid cycle were also reduced at night. In addition, the levels of many amino acids were reduced during the night, suggesting that the amino acids had been degraded. Moreover, the citrulline/ornithine ratio, which is related to arginine consumption, was lower during the day than at night. This pattern suggests that the urea cycle is activated during the day, whereas large amounts of nitric oxide and citrulline may be produced from arginine via nitric oxide synthase during the night. The results of this metabolomic analysis may be useful in future fundamental research to provide insight into chronobiology as well as applied research on drug evaluations using medaka as a model species.

DOI： 10.1038/srep20916

Percutaneous transhepatic obliteration for hepatic encephalopathy accompanied with chronic renal failure in a super-elderly patient: A case report 査読

Yusuke Watanabe, Toru Ishikawa, Satoshi Abe, Ryousuke Inoue, Tomoyuki Sugano, Akito Iwanaga, Keiichi Seki, Terasu Honma, Toshiaki Yoshida, Takeo Nemoto, Keiko Takeda, Shuji Terai

Acta Hepatologica Japonica 56 ( 12 ) 668 - 674 2016年1月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Japan Society of Hepatology

We herein report the case of a super-elderly patient with hepatic encephalopathy accompanied with chronic renal failure, who successfully underwent percutaneous transhepatic obliteration (PTO). An 85-year-old man was diagnosed with non-alcoholic fatty liver cirrhosis and chronic renal failure. He had a collateral vessel from the left portal vein to the paraesophageal vein, which caused repeated hepatic encephalopathy, and medications poorly controlled his hepatic encephalopathy. PTO was performed using a half dose of contrast medium. After PTO, his portal vein pressure did not increase
however, he had respiratory discomfort with right pleural effusion on the fifth day. The pleural effusion disappeared on increasing the diuretic dose. Although the diuretic dose was increased, his renal function did not worsen and the NH3 level did not increase. Hepatic encephalopathy might be controlled by performing PTO in a super-elderly patient, with minimal reduction in renal function from contrast medium and diuretics.

DOI： 10.2957/kanzo.56.668

Liver regeneration therapy using autologous bone marrow-derived cells for cirrhotic patients 査読

Taro Takami, Isao Sakaida, Shuji Terai

Gene Therapy and Cell Therapy Through the Liver: Current Aspects and Future Prospects 25 - 34 2016年1月

記述言語：英語掲載種別：論文集(書籍)内論文出版者・発行元：Springer Japan

In our animal studies, we have reported that bone marrow cells (BMCs) infused via a peripheral vein effi ciently repopulate the cirrhotic liver. Repopulated BMCs produce collagenases including matrix metalloproteinase-9. As a result, we observed reduced liver fi brosis, elevated serum albumin levels, and a signifi cant increase in survival. Based on these data, we have begun “autologous bone marrow cell infusion (ABM i) therapy” using non-cultured autologous whole BMCs. This therapy was offi cially approved as “advanced medical technology B” in Japan. However, ABM i therapy involves bone marrow (BM) aspiration under general anesthesia. We therefore developed a less-invasive liver regeneration therapy using cultured autologous mesenchymal stem cells (MSCs) isolated from a small amount of BM fl uid aspirated under local anesthesia. We showed that peripheral infusion of cultured human BMCs reduces hepatic fi brosis in immunodefi cient cirrhotic mice, consistent with the maintenance of redox homeostasis in hepatic stellate cells and hepatocytes. To evaluate safety using canine models, cultured autologous MSCs were administered to the same subject in approximately three times the quantity and ten times the concentration used in humans. We then constructed a cell-processing facility with a new isolator system to confer protection from hepatitis virus. Here, we summarize the current status and prospects for our liver regeneration therapy.

DOI： 10.1007/978-4-431-55666-4_3

Effective Prevention of Liver Fibrosis by Liver-targeted Hydrodynamic Gene Delivery of Matrix Metalloproteinase-13 in a Rat Liver Fibrosis Model 査読

Hiroyuki Abe, Kenya Kamimura, Yuji Kobayashi, Masato Ohtsuka, Hiromi Miura, Riuko Ohashi, Takeshi Yokoo, Tsutomu Kanefuji, Takeshi Suda, Masanori Tsuchida, Yutaka Aoyagi, Guisheng Zhang, Dexi Liu, Shuji Terai

MOLECULAR THERAPY-NUCLEIC ACIDS 5 e276 2016年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Liver fibrosis is the final stage of liver diseases that lead to liver failure and cancer. While various diagnostic methods, including the use of serum marker, have been established, no standard therapy has been developed. The objective of this study was to assess the approach of overexpressing matrix metalloproteinase-13 gene (MMP13) in rat liver to prevent liver fibrosis progression. A rat liver fibrosis model was established by ligating the bile duct, followed by liver-targeted hydrodynamic gene delivery of a MMP13 expression vector, containing a CAG promoter-MMP13-IRES-tdTomato-polyA cassette. After 14 days, the serum level of MMP13 peaked at 71.7 pg/ml in MMP13-treated group, whereas the nontreated group only showed a level of similar to 5 pg/ml (P < 0.001). These levels were sustained for the next 60 days. The statistically lower level of the hyaluronic acids in treated group versus the nontreated group (P < 0.05) reveals the therapeutic effect of MMP13 overexpression. Quantitative analysis of tissue stained with sirius red showed a statistically larger volume of fibrotic tissue in the nontreated group compared to that of MMP13-treated rats (P < 0.05). These results suggest that the liver-targeted hydrodynamic delivery of MMP13 gene could be effective in the prevention of liver fibrosis.

DOI： 10.1038/mtna.2015.49

Training ROI selection based on MILBoost for liver cirrhosis classification using ultrasound images 査読

Fujita, Y., Mitani, Y., Hamamoto, Y., Segawa, M., Terai, S., Sakaida, I.

Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) 9799 451 - 459 2016年

Improvement of Pancreatic Tumor-induced NAFLD with Pancrelipase 査読

Naosuke Kuraoka, Atsunori Tsuchiya, Takeshi Suda, Shuji Terai

INTERNAL MEDICINE 55 ( 1 ) 89 - 90 2016年

The Combination Therapy of Dissolution Using Carbonated Liquid and Endoscopic Procedure for Bezoars: Pragmatical and Clinical Review 査読

Kohei Ogawa, Kenya Kamimura, Ken-ichi Mizuno, Yoko Shinagawa, Yuji Kobayashi, Hiroyuki Abe, Yukari Watanabe, Shunsaku Takahashi, Kazunao Hayashi, Junji Yokoyama, Manabu Takeuchi, Masaaki Kobayashi, Satoshi Yamagiwa, Yuichi Sato, Shuji Terai

GASTROENTEROLOGY RESEARCH AND PRACTICE 2016 7456242 2016年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：HINDAWI LTD

Bezoars are relatively rare foreign bodies of gastrointestinal tract and often cause ileus and ulcerative lesions in the stomach and subsequent bleeding and perforation due to their size and stiffness. Therefore, the removal of bezoars is essential and recent development of devices, the endoscopic removal procedure, is often applied. However, due to their stiffness, simple endoscopic removal failed in not a few cases, and surgical removal has also been used. Recently, the efficacy of a combination therapy of endoscopic procedure and dissolution using carbonated liquid has been reported. To develop the safe and effective removal procedure, we carefully reviewed a total of 55 reported cases in this study including our 3 additional cases, successfully treated with dissolution with endoscopic fragmentation. In summary, the data showed the efficiency in the combination therapy, treating the larger size of bezoar and reducing the length of hospital stay. To the best of our knowledge, this is the largest pragmatical and clinical review for the combination therapy of dissolution and endoscopic treatment for bezoars. This review should help physicians to manage bezoars more efficiently.

DOI： 10.1155/2016/7456242

Endoscopic Removal of Ingested Dentures and Dental Instruments: A Retrospective Analysis 査読

Ken-ichi Mizuno, Kazuya Takahashi, Kentaro Tominaga, Yuki Nishigaki, Hiroki Sato, Satoshi Ikarashi, Kazunao Hayashi, Takashi Yamamoto, Yutaka Honda, Satoru Hashimoto, Kenya Kamimura, Manabu Takeuchi, Junji Yokoyama, Yuichi Sato, Masaaki Kobayashi, Shuji Terai

GASTROENTEROLOGY RESEARCH AND PRACTICE 2016 3537147 2016年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：HINDAWI PUBLISHING CORP

Background. Dentures and dental instruments are frequently encountered ingested foreign bodies. The aim of the present study was to assess the safety and efficacy of endoscopically removing ingested dental objects. Methods. Twenty-nine consecutive patients with 29 dental objects who were treated at the Niigata University Medical and Dental Hospital from August 2009 to December 2015 were retrospectively reviewed. Characteristics of the patients and the ingested dental objects, the clinical features and findings of radiological imaging tests, and outcomes of endoscopic removal were analyzed. Results. Patients' mean age was 62.9 + 21.0 years. The ingested dental objects included 23 dentures (13 crowns, 4 bridges, 4 partial dentures, and 2 other dentures) and 6 dental instruments. Twenty-seven upper gastrointestinal endoscopies and 2 colonoscopies were performed, and their success rates were 92.6% and 100%, respectively. There were 2 cases of removal failure; one case involved an impacted partial denture in the cervical esophagus, and this case required surgical removal. Conclusions. Endoscopic removal of ingested dentures and dental instruments is associated with a favorable success rate and acceptable complications. The immediate intervention and appropriate selection of devices are essential for managing ingested dental objects.

DOI： 10.1155/2016/3537147

Three Times Repeated Portal Venous Gas after Meals 査読

Takamasa Kobayashi, Atsunori Tsuchiya, Takeshi Suda, Shuji Terai

INTERNAL MEDICINE 55 ( 7 ) 843 - 845 2016年

Formulation for Effective Screening and Management of Nonalcoholic Steatohepatitis: Noninvasive NAFLD Management Strategy 査読

Kanae Hirose, Tsutomu Kanefuji, Takeshi Suda, Souichi Sugitani, Keisuke Nagasaki, Tomoyuki Kubota, Masato Igarashi, Shuji Terai

GASTROENTEROLOGY RESEARCH AND PRACTICE 2016 6343656 2016年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：HINDAWI PUBLISHING CORP

To establish a versatile means for screening and management of nonalcoholic steatohepatitis (NASH), shear wave velocity was measured in 20 normal controls and 138 consecutive nonalcoholic fatty liver disease (NAFLD) cases. Referencing biochemical properties in 679 healthy volunteers, a formula to distinguish NASH suspects was established and validated in another cohort of 138 histologically proven NAFLD cases. NASH and simple steatosis (SS) suspects were selected based on a plot of shear wave velocity against age. A formula consisting of five factors (gamma-glutamyl transpeptidase, alkaline phosphatase, platelet counts, body mass index, and presence/absence of type 2 diabetes mellitus) distinguished NASH suspects from SS suspects with area under the receiver operating characteristic curve values of 86% and 84% in the development and validation cohorts. Among 25 NAFLD cases in which shear wave velocity was repeatedly measured, 8 and 9 cases revealed an increase or decrease, respectively, of shear wave velocity in the entire liver, and the corresponding change in shear wave velocity was primarily observed in the right lobe or the left lateral segment, respectively. These results suggest that the new formula and sequential shear wave velocity measurements at each segment enable high throughput screening of NASH suspects and noninvasive assessment of pathophysiological alleviation/aggravation in cases of NASH.

DOI： 10.1155/2016/6343656

Stomach Dysfunction Is a Potential Risk Factor for Wernicke's Encephalopathy 査読

Oki Nakano, Atsunori Tsuchiya, Satoshi Yamagiwa, Shuji Terai

INTERNAL MEDICINE 55 ( 24 ) 3679 - 3680 2016年

フルカバー金属ステントが有用であった胆管空腸吻合部良性胆道狭窄の１例

森田慎一, 薛徹, 星隆洋, 兼藤努, 小林正明, 須田剛士, 寺井崇二

日本消化器内視鏡学会雑誌 58 ( 11 ) 2279 - 2286 2016年

記述言語：日本語出版者・発行元：一般社団法人日本消化器内視鏡学会

<p>70歳女性．膵胆管合流異常にて肝外胆管切除，胆管空腸吻合術施行．１年後に急性胆管炎を発症し経皮経肝胆道ドレナージを施行した．その後に内瘻化を企図したが高度の吻合部狭窄にて通過困難であった．経皮経路より気管支内視鏡を用いた観察にて吻合部にpin hole状の瘢痕狭窄を認め，同部をガイドワイヤーで通過し内外瘻チューブを留置しえた．その後，狭窄部にフルカバー金属ステントを留置した．拡張は良好であり，留置４カ月後に抜去した．造影検査でも吻合部は良好に開存しており外瘻チューブも抜去した．フルカバー金属ステントは持続的に狭窄部を拡張し抜去も可能である．本法は良性胆道狭窄に対し有効で実行可能な治療法と考える．</p>

DOI： 10.11280/gee.58.2279

Enhanced survival of mice infused with bone marrow-derived as compared with adipose-derived mesenchymal stem cells 査読

Shogo Shiratsuki, Shuji Terai, Yasuhiko Murata, Taro Takami, Naoki Yamamoto, Koichi Fujisawa, Guzel Burganova, Luiz Fernando Quintanilha, Isao Sakaida

HEPATOLOGY RESEARCH 45 ( 13 ) 1353 - 1359 2015年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

Aim: Less invasive therapies using mesenchymal stem cells (MSC) are being developed to treat patients with severe liver cirrhosis. MSC constitute a promising cell source for regenerative therapy and are frequently isolated from bone marrow (BMSC) or adipose tissue (ASC). Therefore, this study assessed the characteristics of these two cell types and their safety for cell infusion.
Methods: In vitro, exhaustive genetic analysis was performed using human (h)BMSC and hASC. Subsequently, the expression of mRNA and protein was evaluated. In vivo, mouse (m) BMSC or mASC was infused into serial mice via the peripheral vein, and 24-h survival rate, prothrombin time and cause of death were analyzed.
Results: On polymerase chain reaction, western blotting, enzyme-linked immunoassay and fluorescence-activated cell sorting, tissue factor was found to be expressed at higher levels in hASC than in hBMSC. Prothrombin time in mice infused with mASC (> 120s) was markedly longer than that of untreated mice (6.5 +/- 1.7 s) and that of mice infused with BMSC (6.7 +/- 0.8 s) (P< 0.001), indicating that pro-coagulation activity was potently enhanced after ASC infusion. The 24-h survival rates in the mASC-and mBMSC-infused groups were 46.4% (13/28) and 95.5% (21/22), respectively; in the former, the rate decreased with increasing number of infused mASC. This cell number-dependent effect was not observed with mBMSC. A histopathological analysis of mice that died immediately following mASC infusion revealed multiple thrombi in the blood vessels of the lungs.
Conclusion: These results indicate that BMSC are a superior and safer cell source for regenerative therapy.

DOI： 10.1111/hepr.12507

First case of bacteremia caused by Helicobacter cinaedi in a patient with liver cirrhosis: a case report and literature review 査読

Kenya Kamimura, Daisuke Kumaki, Masashi Arita, Yuji Kobayashi, Ken-ichi Mizuno, Fumiko Kusama, Megumi Kobayashi, Hiroyuki Abe, Yoshifumi Takahashi, Kohei Ogawa, Yoko Shinagawa, Manabu Takeuchi, Yuichi Sato, Hirokazu Kawai, Satoshi Yamagiwa, Shuji Terai

Clinical Journal of Gastroenterology 8 ( 5 ) 306 - 317 2015年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer-Verlag Tokyo

Patients with liver cirrhosis are known to be immunocompromised hosts due to the dysfunction of the cellular and humoral immune systems, allowing easier bacterial translocation from the intestine to the systemic circulation via the portal vein. Sepsis can often be seen in these patients
however, approximately 10 % of patients show negative results with the standard culture period (3–4 days) and their pathogens remain undiagnosed. Here we report the first case of a patient with liver cirrhosis diagnosed with bacteremia due to Helicobacter cinaedi after gastrointestinal symptoms and review 62 cases of H. cinaedi infection in patients with other diseases. The patient showed positive results for H. cinaedi after 10 days of culture. Administration of a carbapenem was effective and clinical symptoms recovered 20 days after admission. H. cinaedi is an enterohepatic bacterial species that causes bacteremia in immunocompromised patients. Due to the difficulty of detection, few cases have been reported to date and to the best of our knowledge, this is the first published case of bacteremia due to H. cinaedi infection in a patient with liver cirrhosis. Since bacteremia in patients with liver cirrhosis can result in fatality, we recommend vigilance for H. cinaedi infection, longer periods of blood culture, polymerase chain reaction analysis, and empirical antibiotic therapy to help improve prognosis.

DOI： 10.1007/s12328-015-0600-0

Evaluation of esophageal motility after endoscopic submucosal dissection for superficial esophageal cancer 査読

Kazuya Takahashi, Manabu Takeuchi, Yuichi Sato, Hiroki Sato, Kenichi Mizuno, Satoru Hashimoto, Masaaki Kobayashi, Shuji Terai

EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY 27 ( 10 ) 1187 - 1192 2015年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS

IntroductionEndoscopic submucosal dissection (ESD) is a standard treatment for superficial esophageal cancer. Some patients complain of dysphagia after ESD even without any postoperative strictures. Although ineffective esophageal motility might be associated with dysphagia after ESD, its effect on esophageal motility after ESD remains unknown. Therefore, we aimed to elucidate esophageal motility after ESD and the cause of dysphagia using high-resolution manometry (HRM).Patients and methodsSeventy-six patients (men/women, 64/12; mean age, 71.2 years) who had undergone ESD for superficial esophageal cancer were enrolled. The results of ESD were retrospectively investigated using endoscopic images from the ESD and patient questionnaire for dysphagia. Each patient underwent HRM, and the results were evaluated using metrics and contraction patterns, according to the Chicago classification.ResultsData were obtained from 71 patients. The circumferential mucosal defect ratio (=0.284, P=0.017), number of ESD (=0.346, P=0.003), and number of endoscopic balloon dilatations (EBDs) (=0.416, P<0.001) were correlated with the number of weak contraction with large breaks on HRM. The circumferential mucosal defect (odds ratio=1.074, P<0.001) and number of EBDs (odds ratio=1.200, P=0.035) were also significant predictors for dysphagia after ESD.ConclusionCircumferential mucosal defect ratio, EBD, and repeated ESD were predictors for impaired esophageal motility after ESD. Because circumferential mucosal defect ratios and EBD were also correlated with dysphagia after ESD, impaired esophageal motility could explain dysphagia after ESD.

DOI： 10.1097/MEG.0000000000000431

Histological and Transcriptomic Analysis of Adult Japanese Medaka Sampled Onboard the International Space Station 査読

Yasuhiko Murata, Takako Yasuda, Tomomi Watanabe-Asaka, Shoji Oda, Akiko Mantoku, Kazuhiro Takeyama, Masahiro Chatani, Akira Kudo, Satoko Uchida, Hiromi Suzuki, Fumiaki Tanigaki, Masaki Shirakawa, Koichi Fujisawa, Yoshihiko Hamamoto, Shuji Terai, Hiroshi Mitani

PLOS ONE 10 ( 10 ) e0138799 2015年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PUBLIC LIBRARY SCIENCE

To understand how humans adapt to the space environment, many experiments can be conducted on astronauts as they work aboard the Space Shuttle or the International Space Station (ISS). We also need animal experiments that can apply to human models and help prevent or solve the health issues we face in space travel. The Japanese medaka (Oryzias latipes) is a suitable model fish for studying space adaptation as evidenced by adults of the species having mated successfully in space during 15 days of flight during the second International Microgravity Laboratory mission in 1994. The eggs laid by the fish developed normally and hatched as juveniles in space. In 2012, another space experiment ("Medaka Osteoclast") was conducted. Six-week-old male and female Japanese medaka (Cab strain osteoblast transgenic fish) were maintained in the Aquatic Habitat system for two months in the ISS. Fish of the same strain and age were used as the ground controls. Six fish were fixed with paraformaldehyde or kept in RNA stabilization reagent (n = 4) and dissected for tissue sampling after being returned to the ground, so that several principal investigators working on the project could share samples. Histology indicated no significant changes except in the ovary. However, the RNA-seq analysis of 5345 genes from six tissues revealed highly tissue-specific space responsiveness after a two-month stay in the ISS. Similar responsiveness was observed among the brain and eye, ovary and testis, and the liver and intestine. Among these six tissues, the intestine showed the highest space response with 10 genes categorized as oxidation-reduction processes (gene ontogeny term GO: 0055114), and the expression levels of choriogenin precursor genes were suppressed in the ovary. Eleven genes including klf9, klf13, odc1, hsp70 and hif3a were upregulated in more than four of the tissues examined, thus suggesting common immunoregulatory and stress responses during space adaptation.

DOI： 10.1371/journal.pone.0138799

Endoscopic surveillance of gastric cancers after Helicobacter pylori eradication 査読

Masaaki Kobayashi, Yuichi Sato, Shuji Terai

WORLD JOURNAL OF GASTROENTEROLOGY 21 ( 37 ) 10553 - 10562 2015年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BAISHIDENG PUBLISHING GROUP INC

The incidence and mortality of gastric cancer remains high in East Asian countries. Current data suggest that Helicobacter pylori (H. pylori) eradication might be more effective for preventing gastric cancer in young people before they develop atrophic gastritis and intestinal metaplasia. However, the long-term effect of H. pylori eradication on metachronous cancer prevention after endoscopic resection (ER) of early gastric cancer remains controversial, with some discordance between results published for Japanese and Korean studies. The detection ability of synchronous lesions before ER and eradication of H. pylori directly influences these results. After eradication, some gastric cancers are more difficult to diagnose by endoscopy because of morphologic changes that lead to a flat or depressed appearance. Narrow-band imaging with magnifying endoscopy (NBI-ME) is expected to be useful for identifying metachronous cancers. However, some gastric cancers after eradication show a "gastritislike" appearance under NBI-ME. The gastritis-like appearance correlates with the histological surface differentiation of the cancer tubules and superficial non-neoplastic epithelium atop or interspersed with the cancer. Till date, it remains unclear whether H. pylori eradication could prevent progression of gastric cancer. Until we can establish more useful endoscopic examination methodologies, regular endoscopic surveillance of high-risk groups is expected to be the most beneficial approach for detection.

DOI： 10.3748/wjg.v21.i37.10553

Possible involvement of activating follicular helper T cells in autoimmune hepatitis 査読

Kimura Naruhiro, Yamagiwa Satoshi, Honda Hiroki, Setsu Toru, Tominaga Kentaro, Kamimura Hiroteru, Takamura Masaaki, Terai Shuji

HEPATOLOGY 62 369A - 369A 2015年10月

Site-specific impact of a regional hydrodynamic injection: Computed tomography study during hydrodynamic injection targeting the swine liver 査読

Takeshi Yokoo, Tsutomu Kanefuji, Takeshi Suda, Kenya Kamimura, Dexi Liu, Shuji Terai

Pharmaceutics 7 ( 3 ) 334 - 343 2015年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MDPI AG

A hemodynamic study of hydrodynamic gene delivery (HGD) from the tail vein in rodents has inspired a mechanism and an approach to further improve the efficacy of this procedure. However, there is no report on the hemodynamics of a regional HGD, which is an inevitable approach in large animals. Here, we report the hemodynamics of a regional hydrodynamic injection in detail based on 3D volume data and the dynamism of tissue intensity over time by using computed tomography (CT) both during and after a regional hydrodynamic injection that targeted the liver of a pig weighing 15.6 kg. Contrast medium (CM) was injected at a steady speed of 20 mL/s for 7.5 s under the temporal balloon occlusion of the hepatic vein (HV). A retrograde flow formed a wedge-shaped strong enhancement area downstream of the corresponding HV within 2.5 s, which was followed by drainage into another HV beginning from the target area and the portal vein (PV) toward a non-target area of the liver. After the injection, the CM was readily eliminated from the PV outside the target area. These data suggest that an interventional radiology approach is effective in limiting the hydrodynamic impacts in large animals at a target area and that the burden overflowing into the PV is limited. A further investigation that simultaneously evaluates gene delivery efficiency and hemodynamics using CT is needed to establish feasible parameters for a regional HGD in large animals.

DOI： 10.3390/pharmaceutics7030334

Nutcracker and jackhammer esophagus treatment: a three-case survey, including two novel cases of eosinophilic infiltration into the muscularis propria 査読

Hiroki Sato, Manabu Takeuchi, Kazuya Takahashi, Yuichi Sato, Satoru Hashimoto, Kenichi Mizuno, Kenji Suzuki, Masaaki Kobayashi, Terasu Honma, Haruhiro Inoue, Shuji Terai

ENDOSCOPY 47 ( 9 ) 855 - 857 2015年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：GEORG THIEME VERLAG KG

Nutcracker esophagus and jackhammer esophagus are largely unknown motility disorders, also sometimes called hypertensive and hypercontractile peristalsis, respectively. There is currently no standardized diagnostic or management plan for these diseases. Here, we report on three patients with jackhammer/nutcracker esophagus who were treated with either peroral endoscopic myotomy or a systemic steroid regimen, focusing particularly on two novel presentations of nutcracker and jackhammer esophagus involving eosinophilic infiltration into the muscularis propria, and their responses to both interventions.

DOI： 10.1055/s-0034-1391985

Image-guided hydrodynamic gene delivery: Current status and future directions 査読

Kenya Kamimura, Takeshi Yokoo, Hiroyuki Abe, Yuji Kobayashi, Kohei Ogawa, Yoko Shinagawa, Ryosuke Inoue, Shuji Terai

Pharmaceutics 7 ( 3 ) 213 - 223 2015年8月

記述言語：英語出版者・発行元：MDPI AG

Hydrodynamics-based delivery has been used as an experimental tool to express transgene in small animals. This in vivo gene transfer method is useful for functional analysis of genetic elements, therapeutic effect of oligonucleotides, and cancer cells to establish the metastatic cancer animal model for experimental research. Recent progress in the development of image-guided procedure for hydrodynamics-based gene delivery in large animals directly supports the clinical applicability of this technique. This review summarizes the current status and recent progress in the development of hydrodynamicsbased gene delivery and discusses the future directions for its clinical application.

DOI： 10.3390/pharmaceutics7030213

Evidence for a Role of the Transcriptional Regulator Maid in Tumorigenesis and Aging (vol 10, e0129950, 2015) 査読

Koichi Fujisawa, Shuji Terai, Toshihiko Matsumoto, Taro Takami, Naoki Yamamoto, Hiroshi Nishina, Makoto Furutani-Seiki, Isao Sakaida

PLOS ONE 10 ( 8 ) e0137156 2015年8月

臨床応用の現状非代償性肝硬変症に対する再生療法

寺井崇二, 高見太郎, 坂井田功

メディカル朝日 44 ( 8 ) 36 - 37 2015年8月

抗結核薬による昏睡型急性肝不全の一例

松田崇史, 石川剛, 岩本拓也, 佐伯一成, 日高勲, 高見太郎, 寺井崇二, 坂井田功

肝臓 56 ( 7 ) 387 - 388 2015年7月

Evidence for a Role of the Transcriptional Regulator Maid in Tumorigenesis and Aging 査読

Koichi Fujisawa, Shuji Terai, Toshihiko Matsumoto, Taro Takami, Naoki Yamamoto, Hiroshi Nishina, Makoto Furutani-Seiki, Isao Sakaida

PLOS ONE 10 ( 6 ) e0129950 2015年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PUBLIC LIBRARY SCIENCE

Maid is a helix-loop-helix protein that is involved in cell proliferation. In order to further elucidate its physiological functions, we studied Maid activity in two small fish model systems. We found that Maid expression was greatest in zebrafish liver and that it increased following partial hepatectomy. Maid levels were also high in hepatic preneoplastic foci induced by treatment of zebrafish with diethylnitrosamine (DEN), but low in hepatocellular carcinomas (HCC), mixed tumors, and cholangiocarcinomas developing in these animals. In DEN-treated transgenic medaka overexpressing Maid, hepatic BrdU uptake and proliferation were reduced. After successive breedings, Maid transgenic medaka exhibited decreased movement and a higher incidence of abnormal spine curvature, possibly due to the senescence of spinal cord cells. Taken together, our results suggest that Maid levels can influence the progression of liver cancer. In conclusion, we found that Maid is important regulator of hepatocarconogenesis and aging.

DOI： 10.1371/journal.pone.0129950

Autologous bone marrow cell infusion therapy for hepatitis C virus infected liver cirrhosis. 査読

Aibe Y, Takami T, Terai S, Sakaida I

Nihon rinsho. Japanese journal of clinical medicine 73 Suppl 5 499 - 503 2015年6月

【再生医療-新たな医療を求めて-】再生医療の臨床研究・治験 C型肝炎ウイルス起因肝硬変に対する自己骨髄細胞投与療法

相部祐希, 高見太郎, 寺井崇二, 坂井田功

日本臨床 73 ( 増刊5 再生医療 ) 499 - 503 2015年6月

特発性血小板減少性紫斑病を合併した原発性胆汁性肝硬変自己免疫性肝炎オーバーラップ症候群に部分的脾動脈塞栓術を施行した1例

仁志麻衣子, 石川剛, 相部祐希, 白築祥吾, 松田崇史, 岩本拓也, 高見太郎, 寺井崇二, 坂井田功

日本門脈圧亢進症学会雑誌 21 ( 2 ) 122 - 127 2015年6月

記述言語：日本語出版者・発行元：(一社)日本門脈圧亢進症学会

症例は50歳代女性で、吐血で近医にて食道静脈瘤破裂と診断され、内視鏡的静脈瘤結紮術が行われた。肝硬変症(LC)の精査に前医を紹介され、原発性胆汁性肝硬変症-自己免疫性肝炎のオーバーラップ症候群に起因するLCの診断でウルソデオキシコール酸とプレドニゾロン(PSL)が開始されたが、肝障害の持続と血小板減少を認め、特発性血小板減少性紫斑病(ITP)と診断され、静脈瘤再発で精査目的に当院へ入院した。検査で中等度の脾腫、門脈・脾動静脈の拡張、食道静脈瘤を認め、静脈瘤に対し内視鏡的静脈瘤硬化結紮療法(EISL)を行い、その後にLC・ITPに起因する血小板減少症に対し部分的脾動脈塞栓術(PSE)を行った。1週間後の造影CTで80.6%の脾梗塞を確認し、肺動脈楔入圧、肝静脈圧較差の改善を認め、2週間後に血小板数の上昇で軽快退院した。PSLの漸減・中止後も血小板減少・肝障害の再燃はなく、EISL後18ヵ月、PSE後16ヵ月経過で食道静脈瘤の再発は認めていない。

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J03767&link_issn=&doc_id=20150721240003&doc_link_id=10.11423%2Fjsph.21.122&url=https%3A%2F%2Fdoi.org%2F10.11423%2Fjsph.21.122&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Rheological modification of hydrodynamic gene delivery

Takeshi Yokoo, Tsutomu Kanefuji, Takeshi Suda, Akiomi Ushida, Tomiichi Hasegawa, Kenya Kamimura, Dexi Liu, Shuji Terai

Proceedings of The 18th Annual Meeting of the American Society of Gene and Cell Therapy ( 350594 ) 140 - 141 2015年5月

早期胃癌に対するESD後に発生した遅発性穿孔の検討査読

荒生祥尚, 小林正明, 橋本哲, 水野研一, 竹内学, 本田博樹, 影向一美, 高村昌昭, 佐藤祐一, 寺井崇二

ENDOSCOPIC FORUM for digestive disease 31 ( 1 ) 27 - 32 2015年5月

記述言語：日本語出版者・発行元：(株)癌と化学療法社

当施設で治療した早期胃癌に対するendoscopic submucosal dissection(ESD)1,611例中6例(0.37%)の遅発性穿孔について原因と治療経過を検討した。基礎疾患をもった高齢の男性に多く、2例で抗血栓薬を内服していた。局在はすべて体中部であり、術時間に一定の傾向は認めなかった。過凝固が原因と考えられた症例が4例、残胃内への胆汁の逆流が原因と考えられた症例が1例であった。手術を要した3例は穿孔径が10mm以上で、手術時期が遅れた残胃の1例では術後長期の経過をたどった。穿孔径が大きい場合や残胃症例に対しては迅速な手術を考慮するべきである。(著者抄録)

Effective Prevention of Liver Fibrosis by Liver-Targeted Hydrodynamic Gene Delivery of Matrix Metalloproteinase-13 in Rat Liver Fibrosis Model 査読

Abe Hiroyuki, Kamimura Kenya, Kobayashi Yuji, Ohtsuka Masato, Miura Hiromi, Ohashi Riuko, Yokoo Takeshi, Kanefuji Tsutomu, Suda Takeshi, Tsuchida Masanori, Aoyagi Yutaka, Zhang Guisheng, Liu Dexi, Terai Shuji

MOLECULAR THERAPY 23 S234 2015年5月

A New Therapeutic Assessment Score for Advanced Hepatocellular Carcinoma Patients Receiving Hepatic Arterial Infusion Chemotherapy 査読

Issei Saeki, Takahiro Yamasaki, Norikazu Tanabe, Takuya Iwamoto, Toshihiko Matsumoto, Yohei Urata, Isao Hidaka, Tsuyoshi Ishikawa, Taro Takami, Naoki Yamamoto, Koichi Uchida, Shuji Terai, Isao Sakaida

PLOS ONE 10 ( 5 ) e0126649 2015年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PUBLIC LIBRARY SCIENCE

Background & Aims
Hepatic arterial infusion chemotherapy (HAIC) is an option for treating advanced hepatocellular carcinoma (HCC). Because of the poor prognosis in HAIC non-responders, it is important to identify patients who may benefit from continuous HAIC treatment; however, there are currently no therapeutic assessment scores for this identification. Therefore, we aimed to establish a new therapeutic assessment score for such patients.
Methods
We retrospectively analyzed 90 advanced HCC patients with elevated baseline alpha-fetoprotein (AFP) and/or des-gamma-carboxy prothrombin (DCP) levels and analyzed various parameters for their possible use as predictors of response and survival. AFP and DCP responses were assessed after half a course of HAIC (2 weeks); a positive-response was defined as a reduction of >= 20% from baseline.
Results
Multivariate analysis identified DCP response (odds ratio 16.03, p < 0.001) as an independent predictor of treatment response. In multivariate analysis, Child-Pugh class A (hazard ratio [HR] 1.99, p = 0.018), AFP response (HR 2.17, p = 0.007), and DCP response (HR 1.90, p = 0.030) were independent prognostic predictors. We developed an Assessment for Continuous Treatment with HAIC (ACTH) score, including the above 3 factors, which ranged from 0 to 3. Patients stratified into two groups according to this score showed significantly different prognoses (<= 1 vs. >= 2 points: median survival time, 15.1 vs. 8.7 months; p = 0.003).
Conclusions
The ACTH score may be useful in the therapeutic assessment of HCC patients receiving HAIC.

DOI： 10.1371/journal.pone.0126649

Advances in understanding and treating liver diseases during pregnancy: A review 査読

Kenya Kamimura, Hiroyuki Abe, Hirokazu Kawai, Hiroteru Kamimura, Yuji Kobayashi, Minoru Nomoto, Yutaka Aoyagi, Shuji Terai

WORLD JOURNAL OF GASTROENTEROLOGY 21 ( 17 ) 5183 - 5190 2015年5月

記述言語：英語出版者・発行元：BAISHIDENG PUBLISHING GROUP INC

Liver disease in pregnancy is rare but pregnancy-related liver diseases may cause threat to fetal and maternal survival. It includes pre-eclampsia; eclampsia; haemolysis, elevated liver enzymes, and low platelets syndrome; acute fatty liver of pregnancy; hyperemesis gravidarum; and intrahepatic cholestasis of pregnancy. Recent basic researches have shown the various etiologies involved in this disease entity. With these advances, rapid diagnosis is essential for severe cases since the decision of immediate delivery is important for maternal and fetal survival. The other therapeutic options have also been shown in recent reports based on the clinical trials and cooperation and information sharing between hepatologist and gynecologist is important for timely therapeutic intervention. Therefore, correct understandings of diseases and differential diagnosis from the pre-existing and co-incidental liver diseases during the pregnancy will help to achieve better prognosis. Therefore, here we review and summarized recent advances in understanding the etiologies, clinical courses and management of liver disease in pregnancy. This information will contribute to physicians for diagnosis of disease and optimum management of patients.

DOI： 10.3748/wjg.v21.i17.5183

Effect of Fibrotic Tissue on Liver-Targeted Hydrodynamic Gene Delivery 査読

Kobayashi Yuji, Kamimura Kenya, Abe Hiroyuki, Ohtsuka Masato, Miura Hiromi, Yokoo Takeshi, Kanefuji Tsutomu, Suda Takeshi, Zhang Guisheng, Tsuchida Masanori, Aoyagi Yutaka, Liu Dexi, Terai Shuji

MOLECULAR THERAPY 23 S141 2015年5月

Factors predicting aggressiveness of non-hypervascular hepatic nodules detected on hepatobiliary phase of gadolinium ethoxybenzyl diethylene-triamine-pentaacetic-acid magnetic resonance imaging 査読

Tsutomu Kanefuji, Toru Takano, Takeshi Suda, Kouhei Akazawa, Takeshi Yokoo, Hiroteru Kamimura, Kenya Kamimura, Atsunori Tsuchiya, Masaaki Takamura, Hirokazu Kawai, Satoshi Yamagiwa, Hidefumi Aoyama, Minoru Nomoto, Shuji Terai

WORLD JOURNAL OF GASTROENTEROLOGY 21 ( 15 ) 4583 - 4591 2015年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BAISHIDENG PUBLISHING GROUP INC

AIM: To establish a prognostic formula that distinguishes non-hypervascular hepatic nodules (NHNs) with higher aggressiveness from less hazardous one.
METHODS: Seventy-three NHNs were detected in gadolinium ethoxybenzyl diethylene-triamine-pentaacetic-acid magnetic resonance imaging (Gd-EOB-DTPA-MRI) study and confirmed to change 2 mm or more in size and/or to gain hypervascularity. All images were interpreted independently by an experienced, board-certified abdominal radiologist and hepatologist; both knew that the patients were at risk for hepatocellular carcinoma development but were blinded to the clinical information. A formula predicting NHN destiny was developed using a generalized estimating equation model with thirteen explanatory variables: age, gender, background liver diseases, Child-Pugh class, NHN diameter, T1-weighted imaging/T2-weighted imaging detectability, fat deposition, lower signal intensity in arterial phase, lower signal intensity in equilibrium phase, alpha-fetoprotein, des-gamma-carboxy prothrombin, alpha-fetoprotein-L3, and coexistence of classical hepatocellular carcinoma. The accuracy of the formula was validated in bootstrap samples that were created by resampling of 1000 iterations.
RESULTS: During a median follow-up period of 504 d, 73 NHNs with a median diameter of 9 mm (interquartile range: 8-12 mm) grew or shrank by 68.5% (fifty nodules) or 20.5% (fifteen nodules), respectively, whereas hypervascularity developed in 38.4% (twenty eight nodules). In the fifteen shrank nodules, twelve nodules disappeared, while 11.0% (eight nodules) were stable in size but acquired vascularity. A generalized estimating equation analysis selected five explanatories from the thirteen variables as significant factors to predict NHN progression. The estimated regression coefficients were 0.36 for age, 6.51 for lower signal intensity in arterial phase, 8.70 or 6.03 for positivity of hepatitis B virus or hepatitis C virus, 9.37 for des-gamma- carboxy prothrombin, and -4.05 for fat deposition. A formula incorporating the five coefficients revealed sensitivity, specificity, and accuracy of 88.0%, 86.7%, and 87.7% in the formulating cohort, whereas these of 87.2% +/- 5.7%, 83.8% +/- 13.6%, and 87.3% +/- 4.5% in the bootstrap samples.
CONCLUSION: These data suggest that the formula helps Gd-EOB-DTPA-MRI detect a trend toward hepatocyte transformation by predicting NHN destiny.

DOI： 10.3748/wjg.v21.i15.4583

【炎症と線維化】肝線維化に対する骨髄由来細胞を用いた治療戦略

寺井崇二, 高見太郎, 土屋淳紀, 坂井田功

細胞 47 ( 4 ) 176 - 179 2015年4月

記述言語：日本語出版者・発行元：(株)ニュー・サイエンス社

2003年より非代償性肝硬変症に対する自己骨髄細胞投与療法(Autologous Bone Marrow Cell infusion、ABMi療法)の開発を行ってきた。山口大学および多施設にて臨床研究を推進することで、安全性、有効性を明らかにしてきた。さらに現在保険収載をめざし先進医療Bとして多施設無作為臨床研究を推進している。一方で、さらに低侵襲な治療法開発をめざし、培養自己骨髄細胞由来細胞を用いた治療法の開発を進めてきた。本項では現在までの状況、今後の展開について紹介する。(著者抄録)

臨床応用の基盤形成を目指した肝再生研究の新展開自己骨髄細胞による肝臓再生療法の臨床実施とそのメカニズム解析

高見太郎, 寺井崇二, 坂井田功

肝臓 56 ( Suppl.1 ) A146 - A146 2015年4月

定圧炭酸ガス送気システムを用いた大腸内視鏡下腸管内送気圧と検査時の苦痛、最適な内視鏡視野との関連について

高橋祥史, 水野研一, 小林正明, 高橋一也, 西垣祐紀, 林和直, 山本幹, 本田穣, 橋本哲, 横山純二, 竹内学, 佐藤祐一, 寺井崇二

Gastroenterological Endoscopy 57 ( Suppl.1 ) 927 - 927 2015年4月

膵漿液性嚢胞腺腫(SCA)の外科切除例の検討

林和直, 山本幹, 塩路和彦, 小林正明, 若井俊文, 寺井崇二

Gastroenterological Endoscopy 57 ( Suppl.1 ) 985 - 985 2015年4月

Modern Immunologyからみた肝病態原発性胆汁性肝硬変におけるMucosal associated invariant T cellsの検討

薛徹, 山際訓, 寺井崇二

肝臓 56 ( Suppl.1 ) A62 - A62 2015年4月

C型肝炎の肝線維化経時的評価におけるReal-time Tissue Elastography(RTE)の有用性

花園忠相, 日高勲, 佐伯一成, 岩本拓也, 石川剛, 寺井崇二, 坂井田功

肝臓 56 ( Suppl.1 ) A538 - A538 2015年4月

Collagenous gastritis: Review. 査読

Kamimura K, Kobayashi M, Sato Y, Aoyagi Y, Terai S

World journal of gastrointestinal endoscopy 7 ( 3 ) 265 - 273 2015年3月

低侵襲肝臓再生療法

坂井田功, 寺井崇二, 高見太郎

日本消化器病学会雑誌 112 ( 臨増総会 ) A22 - A22 2015年3月

消化器疾患における線維化の病態と診療骨髄細胞を用いた線維化と発癌を標的とした肝臓再生療法の開発と展望

高見太郎, 寺井崇二, 坂井田功

日本消化器病学会雑誌 112 ( 臨増総会 ) A104 - A104 2015年3月

DEB-TACE有効症例の検討 TACE後CT値に注目して

佐伯一成, 相部祐希, 中島崇雄, 田邉規和, 白築祥吾, 花園忠相, 岩本拓也, 日高勲, 石川剛, 寺井崇二, 山崎隆弘, 坂井田功

日本消化器病学会雑誌 112 ( 臨増総会 ) A451 - A451 2015年3月

当科における急性肝不全及び薬物性肝障害の現況

花園忠相, 日高勲, 佐伯一成, 岩本拓也, 石川剛, 寺井崇二, 坂井田功

日本消化器病学会雑誌 112 ( 臨増総会 ) A504 - A504 2015年3月

Interferon β+ribavirin併用療法によりsustained virological responseが得られたCharcot-Marie-Tooth病合併C型慢性肝炎の一例

松浦桂司, 日高勲, 花園忠相, 佐伯一成, 岩本拓也, 石川剛, 高見太郎, 川井元晴, 寺井崇二, 神田隆, 坂井田功

山口医学 64 ( 1 ) 53 - 57 2015年2月

記述言語：日本語出版者・発行元：山口大学医学会

症例は36歳の男性.Charcot-Marie-Tooth(CMT)病type 1Bと診断され,当院の神経内科にて通院加療を受けていた.200X年11月にAST 237IU/ml,ALT 496IU/mlと肝障害を認め,当科紹介となった.精査の結果,C型慢性肝炎genotype 2a,HCV-RNA 5.4logIU/mlと診断され,Interferon(IFN)治療開始目的に,翌年4月に入院となった.IFNには副作用として少数ではあるが末梢神経障害の報告がある.末梢神経障害の機序は不明であるが,神経筋疾患患者においては,一般にIFN投与は好ましくないとされている.国内にて使用されるIFN製剤は数種類あるが,IFNαは0.1〜5%未満の頻度で末梢神経障害を認めるとされているが,IFNβには末梢神経障害の報告はない.そこで,今回神経内科医による厳重な経過観察のもと,IFNβを用いてCMT病合併C型慢性肝炎に対しIFNβ+Rivabirin(RBV)併用療法を行った.神経症状の増悪なく治療を完遂することができ,sustained viral response(SVR)が得られた.末梢神経障害を合併するB型・C型慢性肝炎に対してIFN治療を行う際には,IFNβを使用することにより,神経症状の増悪なく安全に抗ウイルス療法を施行できる可能性が示唆された.(著者抄録)

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J01477&link_issn=&doc_id=20150225440008&doc_link_id=%2Fda5ymgci%2F2015%2F006401%2F008%2F0053-0057%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fda5ymgci%2F2015%2F006401%2F008%2F0053-0057%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

【肥満症診療最前線】肥満に起因する疾患の検査、治療のポイントは? 体重減少の効果を主に非アルコール性肝疾患(脂肪肝)

寺井崇二, 佐伯一成, 日高勲, 丸本芳雄, 橋本真一, 岡本健志, 坂井田功

Modern Physician 35 ( 2 ) 191 - 194 2015年2月

記述言語：日本語出版者・発行元：(株)新興医学出版社

＜ポイント＞肥満の増加に伴い、脂肪肝は検診で30歳男性の約30%に認められるまでになっている。脂肪肝の患者の中で10%が進行性の非アルコール性脂肪肝炎であり、いかに非アルコール性脂肪肝炎を診断し、早期に治療介入するかが臨床上重要である。(著者抄録)

肝細胞癌に対する肝動脈化学塞栓療法施行直後に腫瘍破裂を来した一例

福井悠美, 佐伯一成, 花園忠相, 田邉規和, 浦田洋平, 日高勲, 寺井崇二, 坂井田功

山口医学 64 ( 1 ) 35 - 40 2015年2月

記述言語：日本語出版者・発行元：山口大学医学会

肝細胞癌(HCC;hepatocellular carcinoma)の自然破裂はしばしば遭遇する病態である.しかし,肝動脈化学塞栓療法(TACE;transcatheter arterial chemoembolization)施行直後に破裂を来した症例の報告は比較的まれであり,今回,HCCに対しTACE施行直後に破裂を来した一例を経験したので報告する.患者は73歳男性,背景肝は慢性肝障害(非B非C)であり,20XX年5月に肝S7のHCCに対して,開胸開腹S7亜区域切除術を施行した.翌年5月,肝両葉にHCCの再発を認め,リピオドール併用肝動脈化学療法(Lip-TAI;lipiodol-transcatheter arterial infusion)を施行したが,肝S2の腫瘍はリピオドール貯留不良であった.7月には同S2病変は径38×20mm大に増大し,肝表面に突出していた.同病変に対してTACEを施行したが,治療終了4時間後に心窩部痛が出現し,収縮期血圧は60mmHg台に低下した.細胞外液負荷にて速やかに収縮期血圧90mmHg台まで上昇したため経過観察としたが,徐々に貧血が進行した(術前Hb 11g/dl→術後Hb 6.2g/dl).術後4日目の腹部エコーおよび腹部造影CTで,TACE施行後の肝S2のHCCの周囲に血腫を認めた.明らかな造影剤の漏出は認めなかったが,HCC破裂による貧血進行と判断し,同日再出血予防のため肝動脈塞栓療法(TAE;transcatheter arterial embolization)を施行した.TAE施行後は再出血なく経過した.本症例では,HCCが増大傾向にあり,肝表面に突出していたことから,元々HCC破裂の可能性も考慮すべきであった.加えて,TAE施行時にTACE後の肝S2HCCに血流の残存を認め,塞栓が不十分であったことが判明した.以上のことから,TACEに伴う様々な刺激,血流残存などの要因によりHCC破裂を来したことが推察された.したがって,本症例のように肝表面に局在するHCCに対してTACEを施行する際には,TACE後破裂のリスクも想定して,慎重かつ確実に肝動脈を塞栓し,厳重な経過観察をしていくことが重要と考えられる.(著者抄録)

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J01477&link_issn=&doc_id=20150225440005&doc_link_id=%2Fda5ymgci%2F2015%2F006401%2F005%2F0035-0040%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fda5ymgci%2F2015%2F006401%2F005%2F0035-0040%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Delayed perforation after endoscopic submucosal dissection for early gastric cancer

Arao, Y., Kobayashi, M., Hashimoto, S., Mizuno, K., Takeuchi, M., Honda, H., Yoko, K., Takamura, M., Sato, Y., Terai, S.

Endoscopic Forum for Digestive Disease 31 ( 1 ) 2015年

Three cases of Meckel's diverticulum in adult patients diagnosed using transanal balloon enteroscopy

Azumi, R., Yokoyama, J., Honda, Y., Yamagiwa, S., Terai, S., Komukai, S., Ohashi, Y., Matsuzawa, N., Kobayashi, K., Hashidate, H., Shibuya, H.

Endoscopic Forum for Digestive Disease 31 ( 1 ) 2015年

Epiphrenic diverticulum of the esophagus after peroral endoscopic myotomy 査読

Hiroki Sato, Kazuya Takahashi, Manabu Takeuchi, Yuichi Sato, Satoru Hashimoto, Kenichi Mizuno, Shuji Terai

ENDOSCOPY 47 E509 - E510 2015年

当院で経験した十二指腸静脈瘤破裂の４症例

佐々木嶺, 松田崇史, 相部祐希, 中島崇雄, 白築祥吾, 岩本拓也, 石川剛, 寺井崇二, 坂井田功

山口医学 64 ( 2 ) 145 - 152 2015年

記述言語：日本語出版者・発行元：山口大学医学会

<p>十二指腸静脈瘤（Duodenal varices：DV）は，その豊富な血流のために一旦出血を来すと止血処置が困難で致死的状況となることがある．その治療方法や適応に関しては未だ一定の見解が得られていない．今回，我々はDV破裂の４症例を経験したので，当院のDV破裂に対する治療のフローチャートと文献的考察を加えて報告する．【症例１】C型肝硬変，胃癌術後の80歳代男性．黒色便精査後に十二指腸輸入脚深部のDV破裂の診断に至った．同病変に対して，シングルバルーン内視鏡を用いて67% N-butyl-2-cyanoacrylate（NBCA）による内視鏡的硬化療法（Endoscopic injection sclerotherapy with Cyanoacrylate：CA-EIS）を施行し止血を得た．【症例２】原発性胆汁性肝硬変の40歳代女性．貧血と黒色便精査のため上部消化管内視鏡検査を施行した．十二指腸水平脚に結節状のDVを認め，同部位より湧出性出血が認められたためCA-EISを施行し止血を得た．【症例３】B型肝硬変の50歳代男性．下血精査のため施行した腹部血管造影下CTと上部消化管内視鏡検査でDV破裂と診断した．内視鏡的静脈瘤結紮術（Endoscopic variceal ligation：EVL）で緊急止血を行い，根治目的でバルーン閉塞下逆行性経静脈的塞栓術（Balloon-occluded retrograde transvenous obliteration：B-RTO）を施行した．【症例４】アルコール性肝硬変の60歳代男性．黒色便精査の上部消化管内視鏡検査にて十二指腸下行脚に連珠状DVが認められた．CA-EIS後も滲出性出血が続き，EVLやアルゴンプラズマ凝固を追加し止血に至った．【結語】我々が経験した十二指腸静脈瘤破裂の４症例を報告した．食道胃静脈瘤の治療普及に伴って，今後十二指腸静脈瘤をはじめとした異所性静脈瘤が増加してくることが予想され，症例の蓄積と治療指針の確立が必要と考えられる．</p>

DOI： 10.2342/ymj.64.145

その他リンク： http://www.lib.yamaguchi-u.ac.jp/yunoca/handle/B030064000210

【肝胆膵診療のNew Horizon】肝臓疾患肝硬変肝性浮腫に対するバソプレシンV2受容体拮抗剤トルバプタンの使用法の提案肝性浮腫の発生機序から考える

寺井崇二, 田邊規和, 五嶋敦史, 坂井田功

肝胆膵 69 ( 6 ) 955 - 960 2014年12月

造影エコーにて評価した回腸NETの1例

佐伯一成, 高見太郎, 寺井崇二, 坂井田功

超音波医学 41 ( 6 ) 908 - 908 2014年11月

Association of tyrosine with insulin resistance in hepatitis C virus-related chronic liver disease 査読

Takashi Oono, Takahiro Yamasaki, Junichi Zaitsu, Issei Saeki, Takuya Iwamoto, Yumiko Harima, Yoshio Marumoto, Isao Hidaka, Yohei Urata, Tsuyoshi Ishikawa, Taro Takami, Makoto Segawa, Koichi Uchida, Shuji Terai, Ichiro Kunitugu, Tsuyoshi Tanabe, Isao Sakaida

HEPATOLOGY RESEARCH 44 ( 10 ) E54 - E62 2014年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

Aim: Insulin resistance (IR) increases during the early stages of hepatitis C virus (HCV)-related chronic liver disease and is a sign of poor prognosis as well as a risk factor for hepatic fibrosis and hepatocellular carcinoma. We aimed to determine the factors affecting IR in HCV-related chronic liver disease.
Methods: We retrospectively examined 71 patients with HCV-related chronic liver disease and analyzed various parameters, including amino acids, as possible predictors of IR. IR was assessed using the Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR). Amino acids were assayed by examining branched-chain amino acids (BCAA), tyrosine level, and the ratio of BCAA to tyrosine level (BTR).
Results: HOMA-IR was significantly correlated with body mass index, platelet count, prothrombin time, hemoglobin, total bilirubin, total protein, albumin, total cholesterol, fasting glucose, BTR (r = -0.46, P = 0.0001) and tyrosine (r = 0.55, P < 0.0001). However, BCAA were not significantly correlated with HOMA-IR (r = -0.21, P = 0.082). In multivariate analysis, only two factors were identified as independent parameters contributing to a HOMA-IR of 2.5 or more: total cholesterol (odds ratio [OR], 6.511; 95% confidence interval [95% CI], 1.554-27.284; P = 0.010) and tyrosine (OR, 4.839; 95% CI, 1.087-21.549; P = 0.039).
Conclusion: Serum tyrosine levels may be associated with IR in patients with HCV-related chronic liver disease.

DOI： 10.1111/hepr.12213

Canine mesenchymal stem cells show antioxidant properties against thioacetamide-induced liver injury in vitro and in vivo 査読

Luiz Fernando Quintanilha, Taro Takami, Yoshikazu Hirose, Koichi Fujisawa, Yasuhiko Murata, Naoki Yamamoto, Regina Coeli dos Santos Goldenberg, Shuji Terai, Isao Sakaida

HEPATOLOGY RESEARCH 44 ( 10 ) E206 - E217 2014年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

Aim: To overcome current limitations of therapy for liver diseases, cell-based therapies using mesenchymal stem cells (MSC) have been attempted through basic and clinical approaches. Oxidative stress is a crucial factor in hepatology, and reactive oxygen species (ROS) are well-established molecules responsible for its deleterious effects. The antioxidant properties of MSC were recently demonstrated, and therefore we examined the antioxidant activity of canine MSC (cMSC), their effects on isolated hepatocytes in vitro and their curative potential against thioacetamide (TAA)-induced liver injury in vivo.
Methods: To evaluate the ability of cMSC to challenge oxidative stress, cell viability, cytotoxicity and ROS were measured in cultured cMSC treated with TAA. Also, cMSC were co-cultured with hepatocytes in the same injury condition, and the ROS level was measured exclusively in hepatocytes. Finally, to verify the curative potential of cMSC, 2.0 x 10(6) cells or phosphate-buffered saline were injected systemically in non-obese diabetic/severe combined immunodeficiency mice that received TAA injections twice a week for 13 weeks. We then evaluated histological parameters, serum injury markers and redox homeostasis.
Results: cMSC overcame TAA-induced oxidative stress in vitro, as shown by increased viability and lower cytotoxicity and ROS levels. Moreover, hepatocytes co-cultured with cMSC also showed decreased cellular ROS. The in vivo study showed that mice treated with cMSC presented with an ameliorated histological pattern, suppressed fibrosis, lower serum injury marker levels and better oxidative parameters.
Conclusion: We concluded that cMSC injection reduce TAA-induced liver injury through antioxidant activities and hepatoprotective effects, showing a curative potential in liver diseases.

DOI： 10.1111/hepr.12204

Occlusion of portosystemic shunts improves hyperinsulinemia due to insulin resistance in cirrhotic patients with portal hypertension 査読

Tsuyoshi Ishikawa, Shogo Shiratsuki, Takashi Matsuda, Takuya Iwamoto, Taro Takami, Koichi Uchida, Shuji Terai, Takahiro Yamasaki, Isao Sakaida

JOURNAL OF GASTROENTEROLOGY 49 ( 9 ) 1333 - 1341 2014年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER JAPAN KK

Background Liver cirrhosis (LC) is often complicated by hyperinsulinemia due to insulin resistance (IR), which is considered to be closely related to shunt formation and impaired liver function. This study evaluates whether balloon- occluded retrograde transvenous obliteration (BRTO) can affect glucose and insulin metabolism in patients with LC.
Methods Twenty-five cirrhotic patients (mean age = 69.6 years; female/male = 12/13; hepatitis C virus/alcohol/nonalcoholic steatohepatitis = 14/6/5; Child-Pugh's class A/B = 10/15) with gastric varices and/or hepatic encephalopathy caused by portosystemic shunts (PSS) due to portal hypertension (PH) underwent B-RTO at our hospital. Testing was performed before and at 1 month after the procedure.
Results Shunt occlusion resulted in a decrease in extrahepatic collateral blood flow and an increase in portal venous flow, as well as a dramatic improvement in hepatic function markers. In addition, B-RTO significantly decreased homeostasis model assessment (HOMA) of IR without a statistical decline of HOMA of beta-cell function. The 75-g oral glucose tolerance test (75-OGTT) revealed that occlusion of PSS reduced both fasting immunoreactive insulin (IRI) levels and the area under the curve for IRI. However, no significant change in preprandial or postprandial plasma glucose levels was observed. Furthermore, according to the criteria of the American Diabetes Association, B-RTO led to an improved 75-OGTT profile in 58.3 % of patients who had impaired glucose tolerance or diabetes mellitus before the procedure.
Conclusions Shunt occlusion improves IR-related hyperinsulinemia through increased portal venous flow, ameliorated liver function, and consequent augmented hepatic insulin clearance in cirrhotic patients with PH.

DOI： 10.1007/s00535-013-0893-z

Fatty Acid Binding Protein 7 Regulates Phagocytosis and Cytokine Production in Kupffer Cells during Liver Injury 査読

Hirofumi Miyazaki, Tomoo Sawada, Miwa Kiyohira, Zhiqian Yu, Keiji Nakamura, Yuki Yasumoto, Yoshiteru Kagawa, Majid Ebrahimi, Ariful Islam, Kazem Sharifi, Saki Kawamura, Takanori Kodama, Yui Yamamoto, Yasuhiro Adachi, Nobuko Tokuda, Shuji Terai, Isao Sakaida, Toshizo Ishikawa, Yuji Owada

AMERICAN JOURNAL OF PATHOLOGY 184 ( 9 ) 2505 - 2515 2014年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE INC

Kupffer cells (KCs) are involved in the progression of liver diseases such as hepatitis and Liver cancer. Several members of the fatty acid binding proteins (FABPs) are expressed by tissue macrophages, and FABP7 is Localized only in KCs. To clarify the role of FABP7 in the regulation of KC function, we evaluated pathological changes of Fabp7 knockout mice during carbon tetrachloride-induced Liver injury. During liver injury in Fabp7 knockout mice, serum liver enzymes were increased, cytokine expression (tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and transforming growth factor-beta) was decreased in the Liver, and the number of KCs in the liver necrotic area was significantly decreased. Interestingly, in the FABP7-deficient KCs, phagocytosis of apoptotic cells was impaired, and expression of the scavenger receptor CD36 was markedly decreased. In chronic Liver injury, Fabp7 knockout mice showed less fibrogenic response to carbon tetrachloride compared with wild-type mice. Taken together, FABP7 is involved in the liver injury process through its regulation of KC phagocytic activity and cytokine production. Such modulation of KC function by FABP7 may provide a novel therapeutic approach to the treatment of liver diseases.

DOI： 10.1016/j.ajpath.2014.05.015

急性肝不全予後向上を目指す新規治療法の展望他家骨髄由来の間葉系幹細胞を用いた急性肝不全に対する肝臓再生療法の可能性

寺井崇二, 高見太郎, 坂井田功

肝臓 55 ( Suppl.2 ) A560 - A560 2014年9月

当科における肝硬変による体液貯留に対するトルバプタン投与症例の検討

田邉規和, 寺井崇二, 浦田洋平, 内田耕一, 坂井田功

肝臓 55 ( Suppl.2 ) A670 - A670 2014年9月

高齢C型慢性患者における抗ウイルス療法の効果と肝発癌について

花園忠相, 日高勲, 大野高嗣, 岩本拓也, 佐伯一成, 石川剛, 寺井崇二, 坂井田功

肝臓 55 ( Suppl.2 ) A665 - A665 2014年9月

肝細胞癌(HCC)に対し肝動脈化学塞栓術(TACE)施行後に腫瘍破裂を来した1例

福井悠美, 佐伯一成, 花園忠相, 田邊規和, 浦田洋平, 日高勲, 寺井崇二, 山崎隆弘, 坂井田功

山口医学 63 ( 3 ) 228 - 228 2014年8月

【再生医療の最新の進歩(後篇) 組織工学とその臨床応用】再生医療本格化のための基盤テクノロジー骨髄由来細胞を用いた肝再生療法の現状と展望

田邉規和, 高見太郎, 寺井崇二, 坂井田功

最新医学 69 ( 7月増刊 ) 1438 - 1445 2014年7月

記述言語：日本語出版者・発行元：(株)最新医学社

我々は,マウス基礎研究で自己骨髄細胞投与(ABMi)が肝線維化および肝機能を改善させることを報告し,2003年11月から開始した「肝硬変症に対する自己骨髄細胞投与(ABMi)療法」の国内外での臨床研究により,その肝機能改善・修復効果を確認し論文報告してきた.本稿では,骨髄細胞を用いた肝再生治療の現状と展望について概説する.(著者抄録)

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J00516&link_issn=&doc_id=20140807130004&doc_link_id=issn%3D0370-8241%26volume%3D69%26issue%3D7%26spage%3D1438&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0370-8241%26volume%3D69%26issue%3D7%26spage%3D1438&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

【単球・マクロファージの多様性と病態】骨髄由来細胞を用いた肝線維化改善療法

寺井崇二, 高見太郎, 谷本治子, 岩本拓也, 坂井田功

血管医学 15 ( 2 ) 157 - 160 2014年7月

記述言語：日本語出版者・発行元：(株)メディカルレビュー社

われわれは肝硬変症に対する自己骨髄細胞投与療法(ABMi療法)の臨床研究を行ってきた。その結果、肝硬変症治療において骨髄細胞投与により線維化を改善することにより、それに引き続き肝前駆細胞、内在の肝細胞の活性化が起こり、その結果、肝再生が誘導され肝機能を改善することが明らかになった。さらに低侵襲な治療法を開発するため、体外で自己骨髄細胞を培養する方法を考えた。その過程で骨髄由来培養細胞のうち、どのような細胞が肝線維化改善に有効か、機序も含めて解析したので報告する。(著者抄録)

高齢者肝・胆・膵疾患の治療における諸問題当科における高齢者肝細胞癌患者の現状と治療成績についての検討

田邉規和, 佐伯一成, 浦田洋平, 寺井崇二, 坂井田功

日本高齢消化器病学会誌 17 ( 1 ) 45 - 45 2014年7月

当科における高齢C型慢性肝炎患者に対する抗ウイルス療法の特性

花園忠相, 日高勲, 佐伯一成, 岩本拓也, 石川剛, 寺井崇二, 坂井田功

日本高齢消化器病学会誌 17 ( 1 ) 79 - 79 2014年7月

Veno-occlusive diseaseを呈した薬物性肝障害の一例

石川剛, 内田耕一, 寺井崇二, 山崎隆弘, 坂井田功

肝臓 55 ( 7 ) 441 - 441 2014年7月

Status and Prospects of Liver Cirrhosis Treatment by Using Bone Marrow-Derived Cells and Mesenchymal Cells 査読

Shuji Terai, Taro Takami, Naoki Yamamoto, Koichi Fujisawa, Tsuyoshi Ishikawa, Yohei Urata, Haruko Tanimoto, Takuya Iwamoto, Yuko Mizunaga, Takashi Matsuda, Takashi Oono, Miho Marumoto, Guzel Burganova, Luiz Fernando Quintanilha, Isao Hidaka, Yoshio Marumoto, Issei Saeki, Koichi Uchida, Takahiro Yamasaki, Kenji Tani, Yasuho Taura, Yasuhiko Fujii, Hiroshi Nishina, Kiwamu Okita, Isao Sakaida

TISSUE ENGINEERING PART B-REVIEWS 20 ( 3 ) 206 - 210 2014年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MARY ANN LIEBERT, INC

In 2003, we started autologous bone marrow cell infusion (ABMi) therapy for treating liver cirrhosis. ABMi therapy uses 400mL of autologous bone marrow obtained under general anesthesia and infused mononuclear cells from the peripheral vein. The clinical study expanded and we treated liver cirrhosis induced by HCV and HBV infection and alcohol consumption. We found that the ABMi therapy was effective for cirrhosis patients and now we are treating patients with combined HIV and HCV infection and with metabolic syndrome-induced liver cirrhosis. Currently, to substantiate our findings that liver cirrhosis can be successfully treated by the ABMi therapy, we are conducting randomized multicenter clinical studies designated `` Advanced medical technology B'' for HCV-related liver cirrhosis in Japan. On the basis of our clinical study, we developed a proof-of-concept showing that infusion of bone marrow cells (BMCs) improved liver fibrosis and sequentially activated proliferation of hepatic progenitor cells and hepatocytes, further promoting restoration of liver functions. To treat patients with severe forms of liver cirrhosis, we continued translational research to develop less invasive therapies by using mesenchymal stem cells derived from bone marrow. We obtained a small quantity of BMCs under local anesthesia and expanded them into mesenchymal stem cells that will then be used for treating cirrhosis. In this review, we present our strategy to apply the results of our laboratory research to clinical studies.

DOI： 10.1089/ten.teb.2013.0527

Serum transferrin as a predictor of prognosis for hepatic arterial infusion chemotherapy in advanced hepatocellular carcinoma 査読

Junichi Zaitsu, Takahiro Yamasaki, Issei Saeki, Yohei Harima, Takuya Iwamoto, Yumiko Harima, Toshihiko Matsumoto, Yohei Urata, Isao Hidaka, Yoshio Marumoto, Tsuyoshi Ishikawa, Taro Takami, Naoki Yamamoto, Seiji Kaino, Koichi Uchida, Shuji Terai, Isao Sakaida

HEPATOLOGY RESEARCH 44 ( 5 ) 481 - 490 2014年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

Aim
We recently reported that the iron chelator deferoxamine (DFO) is efficacious in advanced hepatocellular carcinoma (HCC) patients. Iron regulation may thus have an important impact in HCC therapy. Because transferrin is a native chelator that regulates iron homeostasis, it may act as an anticancer agent in a similar manner as DFO. The objective of this study was to evaluate serum transferrin as a prognostic predictor in advanced HCC patients undergoing hepatic arterial infusion chemotherapy (HAIC).
Methods
We retrospectively studied 44 patients receiving HAIC and analyzed various parameters for their possible use as prognostic predictors.
Results
The 1-, 2- and 3-year cumulative survival rates were 36.4%, 18.2% and 8.5%, respectively, and the median survival time (MST) was 7.0 months. The survival rates of patients who had serum transferrin of 190 mg/dL or more (MST, 12.0 months) were significantly better than those of patients who had serum transferrin of less than 190 mg/dL (MST, 4.9 months). Multivariate analysis identified serum transferrin of 190 mg/dL or more (hazard ratio [HR], 0.282; 95% confidence interval [CI], 0.132-0.603; P = 0.001) and Child-Pugh score B (HR, 1.956; 95% CI, 1.034-3.700; P = 0.039) as independent prognostic predictors. There was a significant correlation between serum transferrin level and therapeutic effect (P < 0.001).
Conclusion
Serum transferrin could be useful as a prognostic predictor in advanced HCC patients before HAIC treatment.

DOI： 10.1111/hepr.12141

造影エコーによる部分的脾動脈塞栓術の評価

佐伯一成, 石川剛, 日高勲, 高見太郎, 寺井崇二, 坂井田功

超音波医学 41 ( Suppl. ) S596 - S596 2014年4月

Sorafenibに対する徐放化DFOの血管新生に関する検討

大野高嗣, 寺井崇二, 藤澤浩一, 高見太郎, 齊藤高志, 田畑泰彦, 坂井田功

肝臓 55 ( Suppl.1 ) A467 - A467 2014年4月

当科外来に受診している肝硬変の成因別実態

田邉規和, 寺井崇二, 岩本拓也, 佐伯一成, 浦田洋平, 日高勲, 石川剛, 高見太郎, 瀬川誠, 内田耕一, 坂井田功

肝臓 55 ( Suppl.1 ) A429 - A429 2014年4月

臨床応用を視野に入れた肝再生研究の新たな展開肝硬変に対する培養自己骨髄間葉系幹細胞投与による肝臓再生療法

高見太郎, 寺井崇二, 坂井田功

肝臓 55 ( Suppl.1 ) A76 - A76 2014年4月

C型慢性肝炎に対するIFN治療前後での肝線維化の改善とElastographyによる肝硬度の変化

日高勲, 花園忠相, 大野高嗣, 佐伯一成, 高見太郎, 寺井崇二, 坂井田功

超音波医学 41 ( Suppl. ) S601 - S601 2014年4月

【再生医療技術の新展開】現在実現化に最も近い、外科領域における再生医療研究骨髄細胞を用いた低侵襲な肝臓再生療法の開発

松田崇史, 高見太郎, 寺井崇二, 坂井田功

Surgery Frontier 21 ( 1 ) 19 - 23 2014年3月

記述言語：日本語出版者・発行元：(株)メディカルレビュー社

すでに進行した非代償性肝硬変症や、重症肝疾患の現時点における根治療法は肝移植しかないのが現状であり、ドナー不足や手術侵襲、医療経済面などの問題から対症療法で対応せざるを得ない症例が多い。これらの現状をふまえると、非代償性肝硬変症に対する次世代の治療方法として再生療法・細胞療法の開発が重要と考える。難治性肝疾患に対する新たな治療法の開発を目指して、われわれは骨髄幹細胞の可塑性に着目し基礎研究を進めてきた。慢性炎症という環境下において骨髄細胞が肝細胞へと分化し、さらにその過程で肝合成能・肝線維化・生命予後が有意に改善するという動物実験の結果を基盤として、2003年11月より肝硬変症に対する自己骨髄細胞投与療法(ABMi療法)の臨床研究を開始するに至った。その結果、肝機能改善・修復効果を確認し、さらに国内外からABMi療法の安全性および有効性が追加報告されるなど、自己骨髄細胞を用いた肝硬変に対する再生治療の有効性が明らかになった。今後はより低侵襲な骨髄由来培養細胞を用いた新たな治療法の開発も行っていく。(著者抄録)

【肝硬変-診断と治療の進歩】肝硬変治療の進歩骨髄由来細胞を用いた肝再生治療の現状と展望

白築祥吾, 高見太郎, 寺井崇二, 坂井田功

臨床消化器内科 29 ( 4 ) 479 - 484 2014年3月

記述言語：日本語出版者・発行元：(株)日本メディカルセンター

肝硬変に対する新たな治療法として骨髄細胞を用いた再生療法が注目され,これまでにG-CSFで誘導した自己末梢血CD34陽性細胞の経肝動脈投与や培養骨髄間葉系幹細胞投与などの臨床研究が論文報告されている.筆者らは,マウス基礎研究で自己骨髄細胞投与が肝線維化および肝機能を改善させることを報告し,2003年11月から開始した「肝硬変に対する自己骨髄細胞投与(ABMi)療法」の国内外での臨床研究により,その肝機能改善・修復効果を確認し論文報告してきた.さらに"C型肝炎ウイルスに起因する肝硬変患者に対する自己骨髄細胞投与療法の有効性と安全性に関する研究"が2013年6月に先進医療Bとして認可された.本稿では,骨髄細胞を用いた肝臓再生療法の現状と展望について概説する.(著者抄録)

Systemic Gemcitabine Combined with Hepatic Arterial Infusion Chemotherapy with Cisplatin, 5-Fluorouracil, and Isovorin for the Treatment of Advanced Intrahepatic Cholangiocarcinoma: A Pilot Study 査読

Miho Marumoto, Takahiro Yamasaki, Yoshio Marumoto, Issei Saeki, Yohei Harima, Yohei Urata, Isao Hidaka, Tsuyoshi Ishikawa, Taro Takami, Makoto Segawa, Yuhki Yamaguchi, Koichi Uchida, Shuji Terai, Isao Sakaida

HEPATO-GASTROENTEROLOGY 61 ( 129 ) 162 - 167 2014年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：H G E UPDATE MEDICAL PUBLISHING S A

Background/Aims: Intrahepatic cholangiocarcinoma (ICC) has a poor prognosis and usually presents as advanced disease. Hepatic arterial infusion chemotherapy (HAIC) is a promising option for advanced hepatocellular carcinoma; however, there have been few reports on the use of HAIC in patients with ICC. In the present study, we investigated the efficacy of treatment with systemic gemcitabine (GEM) combined with HAIC with cisplatin (CDDP), 5-fluorouracil (5-FU), and isovorin in patients with advanced ICC. Methodology: Seven patients with advanced ICC, who received systemic GEM combined with HAIC with CDDP, 5-FU, and isovorin were studied. Results: The response rate after the first chemotherapy cycle was 57.1% (partial response, 4; stable disease, 2; progressive disease, 1). The cumulative survival rates at 1 and 2 years were 85.7% and 28.6%, respectively, and the median survival time was 22.3 months. With regard to grade 3 or 4 adverse reactions, the percentages of patients developing leukopenia, neutropenia, thrombocytopenia, anemia, and anorexia were 28.6%, 28.6%, 42.9%, 14.3%, and 14.3%, respectively. No treatment-related deaths were encountered. Conclusions: Although this is a pilot study, we suggest that systemic GEM combined with HAIC with CDDP, 5-FU, and isovorin, may be a useful therapy for patients with advanced ICC.

DOI： 10.5754/hge13455

肝臓肝臓の再生療法

高見太郎, 寺井崇二, 坂井田功

Annual Review消化器 2014 187 - 193 2014年1月

記述言語：日本語出版者・発行元：(株)中外医学社

これまで肝硬変症を対象とした肝臓再生療法として,自己骨髄単核球細胞,G-CSF誘導末梢血CD34陽性細胞や培養骨髄間葉系細胞投与などが実施され,一部の症例で改善したとの報告がある.われわれも,マウス基礎研究により自己骨髄細胞投与が肝線維化および肝機能を改善させることを報告し,その成果を基盤とした国内外での臨床研究「肝硬変症に対する自己骨髄細胞投与療法(ABMi療法)」でも肝機能改善・修復効果を確認した.今後,日本初の先進医療Bとして「C型肝炎ウイルスに起因する肝硬変患者に対するABMi療法の有効性と安全性に関する研究(ランダム化比較試験)」が実施される.一方で,適応が広く患者負担のより少ない肝臓再生療法も求められており,培養骨髄由来細胞等を用いた治療法の開発も必要となってくる.(著者抄録)

A Method of Bubble Removal for Computer-Assisted Diagnosis of Capsule Endoscopic Images. 査読

Masato Suenaga, Yusuke Fujita, Shinichi Hashimoto, Shuji Terai, Isao Sakaida, Yoshihiko Hamamoto

Modern Advances in Applied Intelligence - 27th International Conference on Industrial Engineering and Other Applications of Applied Intelligent Systems, IEA/AIE 2014, Kaohsiung, Taiwan, June 3-6, 2014, Proceedings, Part II 228 - 233 2014年

胃がんを対象とした内視鏡教育のための動画像を用いたシミュレーション型教材の開発（第2報）:医学生へのeラーニングによる教育の実践とその評価-

小柏香穂理, 浜本義彦, 藤田悠介, 西川潤, 寺井崇二, 坂井田功

ITヘルスケア誌 9 ( 2 ) 22 - 33 2014年

記述言語：日本語出版者・発行元：Japan Association of Applied IT Healthcare

本稿は，2009年にITヘルスケア誌に掲載された「胃がんを対象とした内視鏡教育のための動画像を用いたシミュレーション型教材」の続報で，開発した教材の有効性を学生に対する評価から検証したものである．本研究の目的は，先行論文で開発した内視鏡教育のためのシミュレーション型教材を活用して，医学生を対象とした教育実践とその評価について得られた知見を報告することである．本研究では，医学生82名（6年生31名，5年生51名）を対象に教育実践を行い，学生の学習履歴データを分析・評価した．その結果，主成分分析により教材中の8つの問題が，画像に関係する問題と画像に関係しない問題に類別されることがわかった．また，病変の範囲診断の評価では，「検出率－過検出率」という評価量を使って定量的に評価した結果，NBI（色素）画像が通常画像よりも読影に適していることがわかった．今回の調査結果から得られた知見として，内視鏡教育には，画像に関係する問題と画像に関係しない問題の両方を学習する必要性が明らかにされた．画像に関係する問題は従来のテキストによる学習だけでは限界があり，特に読影能力を高めるためには動画像を活用する問題を効果的に学習することが期待できるeラーニングが内視鏡教育に有効であると考えられる．

DOI： 10.11204/ithc.9.22

Tolvaptan for improvement of hepatic edema: A phase 3, multicenter, randomized, double-blind, placebo-controlled trial

Sakaida, I., Kawazoe, S., Kajimura, K., Saito, T., Okuse, C., Takaguchi, K., Okada, M., Okita, K., Masumoto, A., Kaneko, A., Inoue, A., Hasebe, C., Takesaki, E., Hayashi, E., Ohta, H., Morimoto, H., Yoshihara, H., Nishimura, H., Tsuruta, H., Ario, K., Iwase, H., Tanimura, H., Kumada, H., Hasegawa, H., Kohno, H., Hidaka, H., Moriwaki, H., Kobayashi, I., Shimoda, K., Tsuji, K., Yamamoto, K., Yokota, K., Yamauchi, M., Takahashi, M., Inada, M., Kawaguchi, M., Kudo, M., Tanaka, M., Mihara, M., Suzuki, M., Kato, M., Kitamoto, M., Murata, M., Higashi, N., Chida, N., Mano, Y., Inoue, O., Takano, S., Nakayama, S., Hayashi, S., Fujiyama, S., Fujioka, S., Shimizu, S., Katsushima, S., Kitamura, S., Kira, S., Nagaoka, S., Terai, S., Watanabe, S., Takahashi, S., Inoue, S., Yamaguchi, T., Satoh, T., Azuma, T., Igura, T., Komatsu, T., Tamura, T., Ito, T., Ueki, T., Muro, T., Morita, T., Nishigaki, Y., Ohnishi, Y., Karino, Y., Narahara, Y., Osaki, Y.

Hepatology Research 44 ( 1 ) 2014年

Dose-finding trial of tolvaptan in liver cirrhosis patients with hepatic edema: A randomized, double-blind, placebo-controlled trial

Okita, K., Kawazoe, S., Hasebe, C., Kajimura, K., Kaneko, A., Okada, M., Sakaida, I., Inoue, A., Yoshihara, H., Kumada, H., Ikeda, K., Kohno, H., Hidaka, H., Moriwaki, H., Inoue, J., Nakatsuka, K., Chayama, K., Katayama, K., Fujimura, K., Tsuji, K., Kumamoto, M., Yamazaki, M., Kawaguchi, M., Yoneda, M., Tanaka, M., Kato, M., Kitamoto, M., Endo, R., Suzuki, S., Watanabe, S., Kaneda, S., Yamashita, S., Nakayama, S., Kokubu, S., Tanaka, S., Katsushima, S., Aimitsu, S., Terai, S., Kawata, S., Saito, T., Ueki, T., Nouchi, T., Ohnishi, Y., Nishigaki, Y.

Hepatology Research 44 ( 1 ) 2014年

Re-response to tolvaptan after furosemide dose reduction in a patient with refractory ascites 査読

Atsushi Goto, Shuji Terai, Munetaka Nakamura, Masaharu Matsumoto, Isao Sakaida

Clinical Journal of Gastroenterology 8 ( 1 ) 47 - 51 2014年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer-Verlag Tokyo

Tolvaptan is a new drug used for treating ascites induced by liver cirrhosis, and it is covered by health insurance in Japan. In the present report, we describe the case of a 74-year-old man with type C liver cirrhosis and refractory ascites. He was receiving furosemide and spironolactone daily, but still required repeat puncture for ascites removal. Administration of tolvaptan (3.75 mg/day) was started in addition to his existing medications, and was subsequently increased to 7.5 mg/day. However, after 2 months, the ascites again exacerbated. Nevertheless, after we discontinued the administration of furosemide, the tolvaptan became effective. This may be because furosemide administration decreases urine osmolality, resulting in a non-response to tolvaptan.

DOI： 10.1007/s12328-014-0545-8

Hepatic Crown-Like Structure: A Unique Histological Feature in Non-Alcoholic Steatohepatitis in Mice and Humans 査読

Michiko Itoh, Hideaki Kato, Takayoshi Suganami, Kuniha Konuma, Yoshio Marumoto, Shuji Terai, Hiroshi Sakugawa, Sayaka Kanai, Miho Hamaguchi, Takahiro Fukaishi, Seiichiro Aoe, Kazunari Akiyoshi, Yoshihiro Komohara, Motohiro Takeya, Isao Sakaida, Yoshihiro Ogawa

PLOS ONE 8 ( 12 ) e82163 2013年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PUBLIC LIBRARY SCIENCE

Although macrophages are thought to be crucial for the pathogenesis of chronic inflammatory diseases, how they are involved in disease progression from simple steatosis to non-alcoholic steatohepatitis (NASH) is poorly understood. Here we report the unique histological structure termed "hepatic crown-like structures (hCLS)" in the mouse model of human NASH; melanocortin-4 receptor deficient mice fed a Western diet. In hCLS, CD11c-positive macrophages aggregate to surround hepatocytes with large lipid droplets, which is similar to those described in obese adipose tissue. Histological analysis revealed that hCLS is closely associated with activated fibroblasts and collagen deposition. When treatment with clodronate liposomes effectively depletes macrophages scattered in the liver, with those in hCLS intact, hepatic expression of inflammatory and fibrogenic genes is unaffected, suggesting that hCLS is an important source of inflammation and fibrosis during the progression of NASH. Notably, the number of hCLS is positively correlated with the extent of liver fibrosis. We also observed increased number of hCLS in the liver of non-alcoholic fatty liver disease/NASH patients. Collectively, our data provide evidence that hCLS is involved in the development of hepatic inflammation and fibrosis, thereby suggesting its pathophysiologic role in disease progression from simple steatosis to NASH.

DOI： 10.1371/journal.pone.0082163

Improvement of liver fibrosis by infusion of cultured cells derived from human bone marrow 査読

Haruko Tanimoto, Shuji Terai, Takami Taro, Yasuhiko Murata, Kouichi Fujisawa, Naoki Yamamoto, Isao Sakaida

CELL AND TISSUE RESEARCH 354 ( 3 ) 717 - 728 2013年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER

We develop "autologous bone marrow cell infusion (ABMi) therapy" for the treatment of human decompensated liver cirrhosis and confirm the efficacy and safety of this treatment in multicenter clinical studies. With the goal of further expanding the applications of ABMi, we first cultured human bone marrow cells and then determined whether a cell fraction found to be effective in improving liver fibrosis can be amplified. Cells harvested after two passages (P2 cells) consistently contained approximately 94 % mesenchymal stem cells (MSCs); conversely, the cells harvested after only medium change (P0 cells) contained many macrophages. MSCs (2.8 x 10(8)) in P2 cells were harvested from 3.8 x 10(8) bone marrow-derived mononuclear cells after 22 days. DNA-chip analysis also showed during the culturing step that bone marrow-derived cells decreased with macrophage phenotype. The infused 5 x 10(5) P2 cells significantly improved liver fibrosis in the nonobese diabetic/severe combined immunodeficient (NOD-SCID) mouse carbon tetrachloride (CCl4) liver cirrhosis model and induced the expression of matrix metalloproteinase (MMP)-9 and suppressed expressions of alpha smooth muscle actin (alpha SMA), tumor necrosis factor alpha (TNF alpha) and transforming growth factor beta (TGF beta) in the liver. Cultured human bone marrow-derived cells (P2 cells) significantly inhibited liver fibrosis. The increase of MMP-9 and suppressed activation of hepatic stellate cells (HSCs) through the regulation of humoral factors (TNF alpha and TGF beta) contribute to the improvement of liver fibrosis by MSCs comprising about 94 % of P2 cells. MSCs in cultured human bone marrow-derived mono-nuclear cells (BM-MNCs) proliferate sufficiently in cell therapy, so we believe our cultured bone marrow-derived cell therapy can lead to expanded clinical applications and enable outpatient therapy.

DOI： 10.1007/s00441-013-1727-2

ソラフェニブの関与が疑われたネフローゼ症候群の2例

田邉規和, 浦田洋平, 白築祥吾, 岩本拓也, 佐伯一成, 播磨夕美子, 日高勲, 丸本芳雄, 石川剛, 高見太郎, 内田耕一, 寺井崇二, 山崎隆弘, 坂井田功

肝臓 54 ( Suppl.3 ) A857 - A857 2013年11月

限局性結節性過形成と鑑別困難であった巨大肝細胞癌の一例

佐伯一成, 大野高嗣, 浦田洋平, 高見太郎, 寺井崇二, 山崎隆弘, 徳久善弘, 為佐卓夫, 坂井田功

超音波医学 40 ( 6 ) 667 - 667 2013年11月

肝移植と再生医療のクロストーク自己骨髄細胞による肝臓再生療法の取り組み

高見太郎, 寺井崇二, 坂井田功

肝臓 54 ( Suppl.3 ) A666 - A666 2013年11月

エゼチミブのNASHに対する作用機序および臨床使用経験についての検討

大野高嗣, 寺井崇二, 大石俊之, 桑代紳哉, 藤澤浩一, 丸本芳雄, 坂井田功

肝臓 54 ( Suppl.3 ) A799 - A799 2013年11月

A study of liver cirrhosis classification on m-mode ultrasound images by higher-order local auto-correlation features

K. Fujino, Y. Mitani, T. Hayashi, Y. Fujita, Y. Hamamoto, M. Segawa, S. Terai, I. Sakaida

Proceedings of the SICE Annual Conference 1403 - 1404 2013年9月

Ultrasound images are widely used for diagnosis of liver cirrhosis. In liver cirrhosis classification using M- mode ultrasound images, Zhou's method has been shown to be effective. However, in Zhou's approach, the liver cirrhosis classification performance depends on the accuracy of the abdominal aorta wall extraction. Therefore, we examine to classify the liver cirrhosis not using the abdominal aorta wall extraction process. In this paper, we propose a liver cirrhosis classification method using higher-order local auto-correlation (HLAC) features.

再生医療の最前線肝硬変症に対する骨髄由来細胞を用いた再生療法

寺井崇二, 高見太郎, 坂井田功

日本内分泌学会雑誌 89 ( 2 ) 723 - 723 2013年9月

NASH発症におけるhepatic crown-like structureの意義

伊藤美智子, 菅波孝祥, 小沼邦葉, 丸本芳雄, 寺井崇二, 佐久川廣, 坂井田功, 小川佳宏

肥満研究 19 ( Suppl. ) 156 - 156 2013年9月

当科における肝細胞癌に対するソラフェニブ(SF)治療の検証

花園忠相, 浦田洋平, 岩本拓也, 佐伯一成, 日高勲, 丸本芳雄, 石川剛, 高見太郎, 内田耕一, 寺井崇二, 山崎隆弘, 坂井田功

山口医学 62 ( 3 ) 175 - 175 2013年8月

The expanding role of fish models in understanding non-alcoholic fatty liver disease 査読

Yoichi Asaoka, Shuji Terai, Isao Sakaida, Hiroshi Nishina

DISEASE MODELS & MECHANISMS 6 ( 4 ) 905 - 914 2013年7月

記述言語：英語出版者・発行元：COMPANY OF BIOLOGISTS LTD

Non-alcoholic fatty liver disease (NAFLD) is a condition in which excessive fat accumulates in the liver of an individual who has not consumed excessive alcohol. Non-alcoholic steatohepatitis (NASH), a severe form of NAFLD, can progress to hepatic cirrhosis and/or hepatocellular carcinoma (HCC). NAFLD is considered to be a hepatic manifestation of metabolic syndrome, and its incidence has risen worldwide in lockstep with the increased global prevalence of obesity: Over the last decade, rodent studies have yielded an impressive list of molecules associated with NAFLD and NASH pathogenesis. However, the identification Of currently unknown metabolic factor using Mammalian model Organisms is inefficient and expensive compared with studies using fish models such as zebrafish (Danio rerio) and medaka I (Oryzias latipes): Substantial advances in unraveling the molecular pathogenesis of NAFLD have recently been achieved through unbiased forward genetic screens using small fish models. Furthermore, these easily manipulated organisms have been used to great advantage to evaluate the therapeutic effectiveness of various chemical compounds for the treatment of NAFLD. In this Review, we summarize aspects of NAFLD (specifically focusing on NASH) pathogenesis that have been previously revealed by rodent models, and discuss how small fish are increasingly being used to uncover factors that contribute to normal hepatic lipid metabolism. We describe the various types of fish models in use for this purpose, including those generated by Mutation, transgenesis, or dietary or chemical treatment, and contrast them with rodent models. The use of small fish in identifying novel potential therapeutic agents for the treatment of NAFLD and NASH is also addressed.

DOI： 10.1242/dmm.011981

【細胞移植】肝硬変症に対する自己骨髄由来培養髄細胞を用いた再生細胞療法

寺井崇二, 高見太郎, 坂井田功

細胞 45 ( 7 ) 327 - 329 2013年7月

記述言語：日本語出版者・発行元：(株)ニュー・サイエンス社

平成25年4月26日、再生医療推進法が成立した。同法は生命倫理に配慮しつつ、安全な研究開発や普及に向けて総合的に取り組むことを基本理念に盛りこみ、再生医療の普及を促進する施策を策定・実施する責務が国にあると明記されている。我々は基礎研究を進め、2003年より肝硬変症に対する自己骨髄細胞投与療法の研究開発を世界に先駆け実施しその有効性を明らかにしてきた。さらに低侵襲の再生療法を開発するため、自己骨髄由来培養細胞を用いた再生医療開発を行っている。本特集では我々が実施してきた研究開発について概説する。(著者抄録)

Correlations between Obesity/Metabolic Syndrome-Related Factors and Risk of Developing Colorectal Tumors 査読

Satoko Harima, Shinichi Hashimoto, Hiroaki Shibata, Takaharu Matsunaga, Ryo Tanabe, Shuji Terai, Isao Sakaida

HEPATO-GASTROENTEROLOGY 60 ( 124 ) 733 - 737 2013年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：H G E UPDATE MEDICAL PUBLISHING S A

Background/Aims: Colorectal cancer/adenoma development may correlate with obesity/metabolic syndrome in the Japanese. We sought to clarify the relation between colorectal adenoma prevalence and various factors to develop a better colorectal tumor screening strategy Methodology: Of 2668 patients who underwent colonoscopy, medical records of 837 patients (467 men, 370 women; age, 40-80 years) with available data on measured values of body mass index, waist circumference, body fat percentage, and prior history of hypertension, diabetes and hyperlipidemia were reviewed and analyzed. Results: Of these patients, 460 (55.0%) had colorectal tumor or prior history thereof (lesions >= 1mm), Multivariate analysis revealed significant differences in gender, age and waist circumference between patients with/without colorectal adenoma, with men at significantly higher risk than women of developing colorectal tumor (OR=2.57, 95% CI: 1.84-4.65; p<0.001), In patients with/without colorectal tumor, age, waist circumference and body fat percentage were significantly different among men, but only age was significantly different among women. Conclusions: Present findings that waist circumference and body fat percentage correlated with prevalence of colorectal tumor among men may contribute to more accurate prediction of colorectal tumor risk and an efficient colorectal cancer screening system.

DOI： 10.5754/hge12895

Bortezomib induces tumor-specific cell death and growth inhibition in hepatocellular carcinoma and improves liver fibrosis 査読

Issei Saeki, Shuji Terai, Koichi Fujisawa, Taro Takami, Naoki Yamamoto, Toshihiko Matsumoto, Yoshikazu Hirose, Yasuhiko Murata, Takahiro Yamasaki, Isao Sakaida

Journal of Gastroenterology 48 ( 6 ) 738 - 750 2013年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Background: Human hepatocellular carcinoma (HCC) is highly ubiquitinated. The ubiquitination is important to the generatation of HCC. The antitumor and antifibrosis effects of an ubiquitin-proteasome system inhibitor, bortezomib, on HCC with liver cirrhosis (LC) were analyzed in vitro and in vivo. Methods: The effect of bortezomib was analyzed in the rat hepatocarcinogenesis model using a DEN and CDAA diet (DEN/CDAA model), which shows severe LC and generation of HCC. The decrease of GST-P-positive foci and HCC were analyzed in vivo. Cell death was analyzed by cell death detection kit. Liver fibrosis was checked by sirius-red staining and α-smooth muscle actin staining. The in vitro study involved 3 HCC cell lines (HepG2, HuH7, and HLF) and primary rat and human hepatocytes. The proliferation rate of the HCC cell line was analyzed using the MTT assay and FACS analysis. The toxicity of bortezomib was checked using the LDH release assay for primary human and rat hepatocytes. Results: In the rat hepatocarcinogenesis model, bortezomib prevented the development of preneoplastic lesions during the early stages of hepatocarcinogenesis and specifically induced cell death in HCC. Furthermore, bortezomib inhibited cell proliferation and induced tumor-specific cell death in HCC cell lines with decrease of cyclin D1 and phospho-Rb expression. Further, bortezomib showed no hepatotoxicity of primary rat and human hepatocytes, suggesting that it might be an HCC-specific drug. Bortezomib also prevented the activation of hepatic stellate cells and inhibited the liver fibrosis of the DEN/CDAA model. Conclusions: Bortezomib appears to be an ideal target drug for HCC with LC. © 2012 Springer.

DOI： 10.1007/s00535-012-0675-z

チロシンは、C型慢性肝障害におけるインスリン抵抗性の新たなバイオマーカーとなり得る

在津潤一, 山崎隆弘, 佐伯一成, 岩本拓也, 播磨夕美子, 丸本芳雄, 日高勲, 浦田洋平, 石川剛, 高見太郎, 瀬川誠, 内田耕一, 寺井崇二, 坂井田功

肝臓 54 ( Suppl.1 ) A238 - A238 2013年4月

短期間で興味深いエコー像変化を呈した肝細胞癌の一例

佐伯一成, 日高勲, 松永一仁, 高見太郎, 寺井崇二, 山崎隆弘, 坂井田功

超音波医学 40 ( Suppl. ) S534 - S534 2013年4月

当科における肝細胞癌に対するソラフェニブ治療の検証とくに肝予備能と病勢制御に着目して

浦田洋平, 山崎隆弘, 佐伯一成, 岩本拓也, 播磨夕美子, 日高勲, 石川剛, 高見太郎, 内田耕一, 寺井崇二, 坂井田功

肝臓 54 ( Suppl.1 ) A284 - A284 2013年4月

Bone-marrow-derived cells cultured in serum-free medium reduce liver fibrosis and improve liver function in carbon-tetrachloride-treated cirrhotic mice 査読

Takuya Iwamoto, Shuji Terai, Takuro Hisanaga, Taro Takami, Naoki Yamamoto, Shoko Watanabe, Isao Sakaida

CELL AND TISSUE RESEARCH 351 ( 3 ) 487 - 495 2013年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER

We have previously developed autologous bone marrow cell infusion (ABMi) therapy for liver cirrhosis patients. One problem associated with ABMi therapy is that general anesthesia is required to obtain 400 ml bone marrow fluid from liver cirrhosis patients. However, many patients with decompensated cirrhosis do not meet the criteria, because of decreased liver function or an increased bleeding tendency. To overcome these issues, our aim is to derive liver repair cells from small amounts of autologous bone marrow aspirates obtained under local anesthesia and to use these cells in liver cirrhosis patients. Here, we conducted, by using a mouse model, basic research aimed at achieving novel liver regeneration therapy. We cultured bone marrow cells aspirated from the femurs of C57 BL/6 Tg14 (act-EGFP) OsbY01 mice (green fluoresent protein [GFP]-transgenic mice). After 14 days of culture with serum-free medium (good manufacturing practice grade), the obtained spindle-shaped GFP-positive cells were injected (1x10(4) cells) via the caudal vein into mice with carbon tetrachloride (CCl4)-induced cirrhosis. Numerous cultured macrophages and some mesenchymal stem cells repopulated the cirrhotic liver. The results showed that serum albumin, liver fibrosis and liver function were significantly improved in the group treated with cultured bone marrow cells (P < 0.01). Moreover, matrix metalloproteinase-9 expression was increased in the liver (P < 0.01). Thus, infusion of bone-marrow-derived cultured cells improved liver function and liver fibrosis in mice with CCl4-induced cirrhosis.

DOI： 10.1007/s00441-012-1528-z

【肝疾患と幹細胞をめぐる進歩】骨髄細胞投与による肝硬変症に対する肝再生・発癌抑制療法

高見太郎, 前田雅喜, 寺井崇二, 坂井田功

消化器内科 56 ( 3 ) 324 - 330 2013年3月

Crohn 病の経過中に非アルコール性脂肪性肝炎(NASH)から非代償性肝硬変へと進展した一例

田邉規和, 播磨夕美子, 橋本真一, 寺井崇二, 山崎隆弘, 坂井田功

山口医学 62 ( 1 ) 33 - 37 2013年2月

記述言語：日本語出版者・発行元：山口大学医学会

症例は31歳の女性.18歳時にCrohn病と診断され,当科での治療を開始された.経腸栄養療法や5-ASA製剤,ステロイドや抗TNFα抗体製剤等の内科的治療を行うも効果不十分であり,消化管合併症の悪化から24歳時に回腸部分切除術,26歳時に回盲部切除術,28歳時に回腸および上行結腸切除術を施行し,残存小腸は約280cmとなった.その後も症状は安定せず,成分栄養剤による経腸栄養療法を勧めるも患者の理解が得られず,長期の絶食および中心静脈栄養を施行していた.31歳時頃より,見当識障害および活動性低下が認められたため当科入院となった.腹部骨盤単純CT検査上,肝萎縮を伴う肝硬変の状態と考えられ,血液生化学検査にて著明な肝機能障害およびアンモニア値の上昇を認めたため,非代償性肝硬変症による肝性脳症と診断された.血液検査上HBVおよびHCV感染は否定され,飲酒歴もなく,以前より脂肪肝が認められ,肝胆道系酵素の上昇も認められていたことから,非アルコール性脂肪性肝炎(NASH)による非代償性肝硬変と診断した.年齢と肝機能から肝移植を考慮したが,適したドナーがいなかったことと,患者が肝移植を希望しなかったことから対症療法を継続した.その後もCrohn病や肝硬変の加療で入退院を繰り返し肝不全により死亡した.重症Crohn病の経過中に複数の要因からNASHを併発し非代償性肝硬変症へ進展した,極めてまれな症例を経験したため報告する.The patient was a 31-year-old woman who had been diagnosed with Crohn's disease at age 18 years. Enteral nutrition and medical treatment were given, but their effect was insufficient. Gastrointestinal complications worsened, and ileocecal resection was performed three times. The remaining small intestine was 280 cm. But, her symptoms were unstable. Thus long-term fasting and central venous nutrition were adopted. At 31 years old, she was hospitalized with cognitive dysfunction and decreased activity. CT scan showed liver cirrhosis(LC),and hepatic dysfunction and an elevated ammonia level were seen on blood tests. Therefore, she was diagnosed as hepatic encephalopathy from decompensated LC. Blood tests were negative for HBV and HCV infections, she had no history of drinking alcohol, fatty liver had been presented for some time, and elevated transaminase were seen. This led to a diagnosis of LC resulting from non-alcoholic steatohepatitis(NASH).Liver transplantation was considered, but there was no appropriate donor, and the patient did not desire. Therefore, symptomatic therapy was continued. She was repeatedly hospitalized and finally died from liver failure. We report that the rare case in which NASH occurred due to multiple factors during the course of severe Crohn's disease and progressed to decompensated LC.

DOI： 10.2342/ymj.62.33

Medaka fish, Oryzias latipes, as a model for human obesity-related glomerulopathy 査読

Koichiro Ichimura, Yusuke Kawashima, Tomomi Nakamura, Rebecca Powell, Yuya Hidoh, Shuji Terai, Isao Sakaida, Yoshio Kodera, Takashi Tsuji, Jian-Xing Ma, Tatsuo Sakai, Hiroyuki Matsumoto, Tomoko Obara

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 431 ( 4 ) 712 - 717 2013年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE

Obesity, an ongoing significant public health problem, is a part of complex disease characterized as metabolic syndrome. Medaka and zebrafish are useful aquatic experimental animals widely used in the field of toxicology and environmental health sciences and as a human disease models. In medaka, simple feeding of a high fat diet (HFD) can induce body weight gain, excessive accumulation of visceral adipose tissue, hyperglycemia, hyperlipidemia, and steatohepatitis, which mimics human metabolic syndrome. In the present study, to explore the possibility that the adult medaka fed with HFD (HFD-medaka) can be used as an animal model for human metabolic syndrome-associated glomerular disease, including obesity-related glomerulopathy (ORG), we analyzed structural alterations and protein expression in the mesonephric kidney of HFD-medaka. We found that the histopathology was consistent with glomerulomegaly accompanied by the dilation of glomerular capillaries and proliferative expansion of the mesangium, a condition partially comparable to human ORG. Moreover, expressions of several kinds of kidney disease-related proteins (such as MYH9, SM22 alpha) were significantly elevated. Thus, the HFD-medaka has a high potential as an animal model useful for exploring the mechanism underling human ORG. (C) 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2013.01.053

消化器領域における幹細胞研究の進歩培養骨髄由来細胞を用いた肝硬変症に対する修復療法の開発へのProof of Concept

寺井崇二, 高見太郎, 坂井田功

日本消化器病学会雑誌 110 ( 臨増総会 ) A83 - A83 2013年2月

【再生医療の実現化に向けて】肝硬変症に対する自己骨髄細胞投与療法

丸本美穂, 寺井崇二, 丸本芳雄, 高見太郎, 坂井田功

炎症と免疫 21 ( 2 ) 142 - 147 2013年2月

記述言語：日本語出版者・発行元：(株)先端医学社

難治性肝疾患に対する新たな治療法の開発をめざして、われわれは骨髄幹細胞の可塑性に着目し基礎研究を進めてきた。慢性炎症という環境下において骨髄細胞が肝細胞へと分化し、さらにその過程で肝合成能・肝線維化・生命予後が有意に改善するという動物実験の結果を基盤として、2003年11月より肝硬変症に対する自己骨髄細胞投与療法(ABMi療法)の臨床研究を開始するに至った。その結果、肝機能改善・修復効果を確認し、さらに国内外からABMi療法の安全性および有効性が追加報告されるなど、自己骨髄細胞を用いた肝硬変に対する再生治療の有効性が明らかになった。今後はより低侵襲な骨髄由来培養細胞を用いた新たな治療法の開発もおこなっていく。(著者抄録)

肝線維化の診断と臨床自己骨髄細胞による肝硬変に対する再生修復療法の現状と展望

高見太郎, 寺井崇二, 坂井田功

Japanese Journal of Diagnostic Imaging 31 ( 1 ) 30 - 30 2013年2月

An improvement of liver cirrhosis classification using ultrasonic images

Hayashi, T., Fujita, Y., Mitani, Y., Hamamoto, Y., Segawa, M., Terai, S., Sakaida, I.

IEEJ Transactions on Electronics, Information and Systems 133 ( 2 ) 289 - 296 2013年1月

掲載種別：研究論文（学術雑誌）

Ultrasonic images have been widely used for diagnosis of liver cirrhosis. In practice, there are significant differences in the result of a diagnosis among individuals for physician's experiences. Therefore, the objective and quantitative method for diagnosis is needed. The quality of M-mode image is in general low. Thus, it is very difficult to diagnose liver cirrhosis with M-mode images. In cirrhosis classification using the ultrasonic M-mode image, Zhou's method was proposed. In this paper, compared with the Zhou's method, we propose a method using weighted autocorrelation coefficient to extract an abdominal aorta wall. Furthermore, we propose the use of a bilateral filter to improve the quality of the M-mode images. The bilateral filter is expected to be effective one of smoothing filters preserving an edge to improve image quality in an ultrasonic image. The experimental results show that the weighted autocorrelation coefficient approach leads to improvement in the performance of the abdominal aorta wall extraction and moreover the bilateral filter is effective in both the abdominal aorta wall extraction and cirrhosis classification. © 2013 The Institute of Electrical Engineers of Japan.

DOI： 10.1541/ieejeiss.133.289

肝臓肝臓の再生療法

高見太郎, 寺井崇二, 坂井田功

Annual Review消化器 2013 196 - 202 2013年1月

記述言語：日本語出版者・発行元：(株)中外医学社

これまで肝硬変症を対象とした肝臓再生療法として,自己骨髄単核球細胞,G-CSF誘導末梢血CD34陽性細胞や骨髄間葉系幹細胞投与が実施され,一部の症例で改善したとの報告がある.われわれも,マウス基礎研究により自己骨髄細胞投与が肝線維化および肝機能を改善させることを報告し,その成果を基盤にした臨床研究「肝硬変症に対する自己骨髄細胞投与療法(ABMi療法)」でも肝機能改善・修復効果を確認した.さらに国内外からABMi療法の安全性・有効性が追試報告されるなど,自己骨髄由来細胞を用いた肝硬変症に対する再生療法の有効性が強く示唆された.今後は,エビデンスレベルの高い有効性を示すためのランダマイズドコントロールスタディの実施や,低侵襲な骨髄由来培養細胞を用いた治療法の開発も必要となると思われる.(著者抄録)

A liver cirrhosis detection method using probabilistic ROI combination 査読

Y. Fujita, T. Goto, Y. Mitani, Y. Hamamoto, M. Segawa, S. Terai, I. Sakaida

Proceedings of 11th International Conference on Quality Control by Artificial Vision 81 - 85 2013年

超音波画像を用いた肝硬変識別の高精度化査読

林孝哉, 藤田悠介, 三谷芳弘, 浜本義彦, 瀬川誠, 寺井崇二, 坂井田功

電気学会論文誌C 133 ( 2 ) 289 - 296 2013年

A note of liver cirrhosis classification on M-mode ultrasound images by higher-order local auto-correlation features. 査読

K. Fujino, Yoshihiro Mitani, T. Hayashi, Yusuke Fujita, Yoshihiko Hamamoto, Makoto Segawa, Shuji Terai, Isao Sakaida

2013 International Conference on Soft Computing and Pattern Recognition, SoCPaR 2013, Hanoi, Vietnam, December 15-18, 2013 50 - 53 2013年

Liver Resident Stem Cell 査読

Christina M. Takiya, Bruno Diaz Paredes, Luiz Fernando Quintanilha de Mesquita, Grazielle Suhett Dias, Lanuza Alaby Pinheiro Faccioli, Taro Takami, Shuji Terai, Isao Sakaida, Regina Coeli dos Santos Goldenberg

Resident Stem Cells and Regenerative Therapy 177 - 203 2013年

骨髄細胞投与による酸化ストレス制御を介した肝発癌抑制メカニズムの解明

高見太郎, 寺井崇二, 前田雅喜, 坂井田功

日本消化器病学会雑誌 109 ( 臨増大会 ) A721 - A721 2012年9月

肝疾患に対する先端医療骨髄由来培養細胞を用いた肝臓修復再生療法の実現化準備ヒト幹細胞を用いた臨床指針を踏まえて

寺井崇二, 高見太郎, 坂井田功

日本消化器病学会雑誌 109 ( 臨増大会 ) A424 - A424 2012年9月

Advanced Therapies Using Autologous Bone Marrow Cells for Chronic Liver Disease 査読

Taro Takami, Shuji Terai, Isao Sakaida

DISCOVERY MEDICINE 14 ( 74 ) 7 - 12 2012年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：DISCOVERY MEDICINE

The radical treatment currently for decompensated liver cirrhosis is still liver transplantation. However, liver transplants are not widely performed worldwide and development of genuine regeneration therapy for liver cirrhosis is an urgent task. We have developed a novel murine model [the green fluorescent protein (GFP)/carbon tetrachloride (CCl4) model], and reported that infused GFP-positive bone marrow cells repopulated cirrhotic liver. Moreover, repopulated bone marrow cells ameliorated liver fibrosis through higher expression of matrix metalloproteinase-9, consistent with improved liver functions and better survival rate. Based on these findings, we started a clinical trial of autologous bone marrow cell infusion (ABMi) therapy for decompensated liver cirrhotic patients, and reported the efficacy and the safety of this approach. On the other hand, various other clinical studies for liver disease have been also reported, including hepatic administration of autologous CD34-positive cells induced by granulocyte colony-stimulating factor (G-CSF), portal vein administration of CD133-positive mononuclear cells, and administration of autologous bone marrow derived mesenchymal stem cells (MSCs). Effectiveness of these approaches has been shown in some patients. We provided here an overview of the current status of liver regeneration therapies including our results of the murine GFP/CCl4 model and ABMi therapy for liver cirrhosis and future prospects. [Discovery Medicine 14(74):7-12, July 2012]

【肝硬変update より良き診療のために】肝硬変診療のトピックス自己骨髄細胞を用いた肝修復再生療法の現状

高見太郎, 寺井崇二, 坂井田功

Medicina 49 ( 7 ) 1238 - 1239 2012年7月

Effect of transcatheter arterial infusion chemotherapy using iodized oil and degradable starch microspheres for hepatocellular carcinoma 査読

Takahiro Yamasaki, Issei Saeki, Yohei Harima, Junichi Zaitsu, Masaki Maeda, Haruko Tanimoto, Takuya Iwamoto, Isao Hidaka, Yohei Urata, Tsuyoshi Ishikawa, Taro Takami, Yuhki Yamaguchi, Koichi Uchida, Shuji Terai, Isao Sakaida

JOURNAL OF GASTROENTEROLOGY 47 ( 6 ) 715 - 722 2012年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER TOKYO

Transcatheter arterial infusion chemotherapy (TAI) using a combination of iodized oil (lipiodol) and degradable starch microspheres (DSMs) has been reported to be superior to TAI with either lipiodol or DSMs separately for the treatment of hepatocellular carcinoma (HCC), based on the results of a prospective randomized study. In the study reported here, we investigated the predictors influencing response and survival in HCC patients receiving TAI using lipiodol and DSMs.
A total of 50 HCC patients [Child-Pugh A/B, 34/16 patients; maximum tumor size 2.9 cm (mean); tumor number < 5/a parts per thousand yen5 = 29/21 patients] were administered a mixture of cisplatin and lipiodol, followed by the injection of DSMs.
According to the criteria of the Liver Cancer Study Group of Japan, the response [complete response (CR) + partial response (PR)] rate and CR rate were 72 and 38%, respectively [CR, 19 patients; PR, 17; stable disease, 9; progressive disease, 5]. The 1-, 2-, 3-, and 4-year cumulative survival rates were 85, 67, 41, and 35%, respectively, and the median survival time was 32.6 months. Multivariate analysis identified tumor number < 5 nodules [odds ratio 10.651, 95% confidence interval (CI) 2.168-52.317; P = 0.004] as an independent predictor of response and des-gamma-carboxyprothrombin level < 100 mAU/mL [hazard ratio (HR), 0.268, 95% CI 0.091-0.786, P = 0.017] and therapeutic effect CR or PR (HR 0.255, 95% CI 0.099-0.659; P = 0.005) as independent predictors of survival.
Transcatheter arterial infusion chemotherapy using lipiodol and DSMs might be considered as a potential intervention in HCC patients, especially those with tumors of < 5 nodules.

DOI： 10.1007/s00535-012-0537-8

Therapeutic Potential of Canine Bone Marrow Stromal Cells (BMSCs) in the Carbon Tetrachloride (CCl4) Induced Chronic Liver Dysfunction Mouse Model 査読

Tomoya Haraguchi, Kenji Tani, Ryo Takagishi, Yasutaka Oda, Kazuhito Itamoto, Naoki Yamamoto, Shuji Terai, Isao Sakaida, Hiroshi Nakazawa, Yasuho Taura

JOURNAL OF VETERINARY MEDICAL SCIENCE 74 ( 5 ) 607 - 611 2012年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPAN SOC VET SCI

Regenerative medicine using bone marrow cells is an attractive therapy for the cure of patients with severe liver disease. Here, we show the therapeutic potential of canine bone marrow stromal cells (BMSCs) in mouse models of CCl4-induced chronic liver dysfunction. We used two different models for xenotransplantation, nude mice and cyclosporine A (CSA) immunosuppressed mice. Serum parameters from a standard liver panel were not improved following transplantation. However, fibrotic liver lesions with severe inflammation were decreased in CCl4-treated CSA mice following BMSC transplantation. Effective migration of transplanted canine BMSCs was limited to persistently injured liver in CCl4-treated CSA mice, where they may be effective in resolving inflammatory fibrotic lesions. These results suggest that canine BMSCs are an effective cell source for liver regeneration.

DOI： 10.1292/jvms.11-0505

Stem cell therapy in chronic liver disease 査読

Taro Takami, Shuji Terai, Isao Sakaida

CURRENT OPINION IN GASTROENTEROLOGY 28 ( 3 ) 203 - 208 2012年5月

記述言語：英語出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS

Purpose of review
To provide an overview of the current status of liver regeneration therapies for liver cirrhosis and future prospects.
Recent findings
Various clinical studies for liver disease have been reported, including hepatic administration of autologous CD34-positive cells induced by granulocyte colony-stimulating factor, portal vein administration of CD133-positive mononuclear cells, and administration of autologous bone marrow-derived mesenchymal stem cells. Effectiveness of these approaches has been shown in some patients. We have also reported improved liver fibrosis and function with infusion of autologous bone marrow cells in a basic study with mice, and on the basis of those results started autologous bone marrow cell infusion (ABMi) therapy for liver cirrhosis. The efficacy and safety of ABMi therapy has also been reported by other institutions.
Summary
Results of recent clinical studies strongly suggest that liver function-improving effects can be achieved using infusion of bone marrow (stem) cells for cirrhosis. New treatment methods using less-invasive bone marrow-derived cultured cells need to be developed.

DOI： 10.1097/MOG.0b013e3283521d6a

Timeline for development of autologous bone marrow infusion (ABMi) therapy and perspective for future stem cell therapy 査読

Shuji Terai, Haruko Tanimoto, Masaki Maeda, Junichi Zaitsu, Takuro Hisanaga, Takuya Iwamoto, Koichi Fujisawa, Yuko Mizunaga, Toshihiko Matsumoto, Yohei Urata, Yoshio Marumoto, Isao Hidaka, Tsuyoshi Ishikawa, Yuichiro Yokoyama, Koji Aoyama, Masako Tsuchiya, Taro Takami, Kaoru Omori, Naoki Yamamoto, Makoto Segawa, Koichi Uchida, Takahiro Yamasaki, Kiwamu Okita, Isao Sakaida

JOURNAL OF GASTROENTEROLOGY 47 ( 5 ) 491 - 497 2012年5月

記述言語：英語出版者・発行元：SPRINGER TOKYO

Liver cirrhosis patients generally progress to liver failure. To cure this progressive disease, we developed a novel cell therapy using bone marrow cells; autologous bone marrow cell infusion (ABMi) therapy. We previously described the possible action mechanism of ABMi therapy in the cirrhotic liver, and showed the timeline and results of clinical studies of ABMi therapy. We have also carried out other clinical studies using bone marrow cells and granulocyte colony-stimulating factor. Here, we report a new randomized clinical trial to evaluate the effects of ABMi therapy. However, ABMi therapy may not be possible in patients who are unable to undergo general anesthesia; therefore, we have started to develop a next-generation stem cell therapy using cultured mesenchymal stem cells.

DOI： 10.1007/s00535-012-0580-5

Ezetimibe reduces fatty acid quantity in liver and decreased inflammatory cell infiltration and improved NASH in medaka model 査読

Toshiyuki Oishi, Shuji Terai, Shinya Kuwashiro, Koichi Fujisawa, Toshihiko Matsumoto, Hiroshi Nishina, Isao Sakaida

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 422 ( 1 ) 22 - 27 2012年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE

Purpose: We previously developed medaka non-alcoholic steatohepatitis (NASH) model. The model showed similar histology with human NASH so we analyzed the effect of drug using medaka NASH activity score (MNAS). In this study we analyzed the effect of ezetimibe, a small intestine cholesterol transporter inhibitor, on NASH.
Methods: Medaka NASH model showed steatohepatits with infiltration of D-PAS positive inflammatory cell. In this study we induced medaka NASH and compared the effect of ezetimibe on medaka NASH by HFD.
Results: As compared with the HFD group, ezetimibe reduced total cholesterol and triacyglycerol in the blood. But concerning with liver quantity of fatty acids in the liver were significantly decreased by ezetimibe. Genes related with fatty acid metabolism in liver was also decreased by ezetimibe administration. On histological observations of the liver, increases in the number of inflammatory cells and MNAS were inhibited. With this decrease of fatty acid in liver, medaka NASH was improved by ezetimibe.
Conclusion: Ezetimibe was clarified as a useful drug to improve NASH. (C) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2012.04.087

Matrix Metalloproteinases (MMPs) Activity in Cultured Canine Bone Marrow Stromal Cells (BMSCs) 査読

Tomoya Haraguchi, Kenji Tani, Masato Koga, Yasutaka Oda, Kazuhito Itamoto, Naoki Yamamoto, Shuji Terai, Isao Sakaida, Hiroshi Nakazawa, Yasuho Taura

JOURNAL OF VETERINARY MEDICAL SCIENCE 74 ( 5 ) 633 - 636 2012年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPAN SOC VET SCI

Autologous bone marrow stromal cells (BMSCs) infusion therapy improves the hepatic fibrosis. To investigate the mechanism of remission, we evaluated the matrix metalloproteinase (MMP)-2 and -9 activity in canine BMSCs and the effect of pro-inflammatory cytokines on their expression. The activity and the gene expression of MMPs were analyzed by gelatin zymography and quantitative RT-PCR, respectively. The specific gelatinase bands were indicative effect of MMP-2 and -9 in canine BMSCs. MMP-2 expression seemed to be increased by TNF-alpha and IL-1 beta while MMP-9 was enhanced by TNF-alpha and IL-6. These results suggested that remissive effect on liver fibrosis might be partly attributable to the MMP-2 and -9 activity in BMSCs under the inflammatory condition.

DOI： 10.1292/jvms.11-0395

Clear cell typeの肝細胞癌の一例

土屋昌子, 石川剛, 高見太郎, 寺井崇二, 山崎隆弘, 坂井田功

超音波医学 39 ( Suppl. ) S408 - S408 2012年4月

Splenectomy enhances the anti-fibrotic effect of bone marrow cell infusion and improves liver function in cirrhotic mice and patients 査読

Takuya Iwamoto, Shuji Terai, Yuko Mizunaga, Naoki Yamamoto, Kaoru Omori, Koichi Uchida, Takahiro Yamasaki, Yasuhiko Fujii, Hiroshi Nishina, Isao Sakaida

JOURNAL OF GASTROENTEROLOGY 47 ( 3 ) 300 - 312 2012年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER TOKYO

Background In 2003, we initiated a clinical trial to examine autologous bone marrow cell infusion (ABMi) therapy for cirrhotic patients and reported the clinical effect of the therapy. To analyze how splenectomy may potentiate the effects of bone marrow cell infusion on cirrhosis, we performed a mouse study and a clinical trial on patients with cirrhosis.
Methods In mice, we analyzed the effect of splenectomy on bone marrow cell infusion in four experimental groups (group A, splenectomy + bone marrow cell infusion + CCl4; group B, sham operation + bone marrow cell infusion + CCl4; group C, splenectomy + CCl4; group D, sham operation + CCl4). In clinical, we compared the effect of splenectomy on ABMi therapy.
Results We observed significantly increased average serum albumin levels and higher expression of green fluorescent protein (GFP), matrix metalloproteinase 9 (MMP9), and proliferating cell nuclear antigen in the livers of group A. We observed MMP9/GFP double-positive cells in the cirrhotic livers. A significant decrease in the liver fibrosis areas was observed in group A. Splenectomy enhanced the repopulation of bone marrow cells into the cirrhotic liver and improved the liver microenvironment via expression of MMP9 secreted from repopulating GFP-positive cells. Next, we performed a clinical trial to compare the effect of splenectomy on the efficacy of ABMi therapy. Cirrhotic patients who underwent splenectomy before ABMi therapy tended to have a greater improvement in liver function.
Conclusion ABMi therapy with splenectomy may be an effective therapeutic modality for cirrhosis.

DOI： 10.1007/s00535-011-0486-7

Autologous bone marrow cell infusions suppress tumor initiation in hepatocarcinogenic mice with liver cirrhosis 査読

Masaki Maeda, Taro Takami, Shuji Terai, Isao Sakaida

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 27 104 - 111 2012年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

We have previously reported the efficacy and safety of autologous bone marrow cell infusion (ABMi) therapy for liver cirrhosis patients without hepatocellular carcinoma in a multicenter clinical trial. However, since liver cirrhosis is highly oncogenic, evaluation of the effects of ABMi on the mechanisms of hepatocarcinogenesis is of great importance. Therefore, frequent ABMi was performed in hepatocarcinogenic mice, and its effects on hepatocarcinogenesis were analyzed. The N-nitrosodiethylamine (DEN)/green fluorescent protein (GFP)-carbon tetrachloride (CCl4) model was developed by administering DEN once, followed by repeated administration of CCl4 intraperitoneally as for the control group. In the administration (ABMi) group, GFP-positive bone marrow cells were infused through a tail vein. The kinetics of hepatocarcinogenesis were evaluated histologically 4.5 months after DEN treatment. At 4.5 months, there was significantly lower incidence of foci and tumors in the ABMi group, and they were smaller in number, while their size was almost equal. No GFP-positive tumors were found in ABMi livers. Moreover, ABMi livers showed significantly reduced liver fibrosis, consistent with significantly lower 8-hydroxy-2'-deoxyguanosine levels, higher superoxide dismutase activity, and increased nuclear translocation of nuclear factor-erythroid 2 p45-related factor 2. These results demonstrate that frequent ABMi might contribute to suppressed tumor initiation during stages of hepatocarcinogenesis, consistent with improvements in liver fibrosis and stabilization of redox homeostasis.

DOI： 10.1111/j.1440-1746.2011.07016.x

Hepatic arterial infusion chemotherapy in combination with pegylated interferon-α-2b for advanced hepatocellular carcinoma. 査読

Okita K, Yamasaki T, Hamabe S, Saeki I, Harima Y, Terai S, Sakaida I

Hepato-gastroenterology 59 ( 114 ) 533 - 537 2012年3月

当科における肝細胞癌に対するsorafenibの治療成績

浦田洋平, 山崎隆弘, 在津潤一, 日高勲, 石川剛, 土屋昌子, 内田耕一, 寺井崇二, 坂井田功

日本消化器病学会雑誌 109 ( 臨増総会 ) A281 - A281 2012年3月

肝臓肝臓の再生治療

高見太郎, 寺井崇二, 坂井田功

Annual Review消化器 2012 192 - 197 2012年1月

記述言語：日本語出版者・発行元：(株)中外医学社

非代償性肝硬変症に対する現時点での根治療法は肝移植であるが,慢性的ドナー不足,手術侵襲や免疫拒絶などの諸問題は依然として解決されていない.一方,臨床研究としての肝臓再生療法はこれまでに,G-CSFで誘導した自己末梢血CD34陽性細胞の経肝動脈投与,CD133陽性単核球細胞の経門脈投与や,自己骨髄間葉系幹細胞投与による細胞療法などが報告され,一部の症例での改善が報告されている.また我々も,マウス基礎研究により自己骨髄細胞投与が肝線維化および肝機能を改善させることを報告し,その成果を基盤にした臨床研究「肝硬変症に対する自己骨髄細胞投与療法autologous bone marrow cell infusion therapy(ABMi療法)」でも肝機能改善・修復効果を確認した.さらに国内外からABMi療法の安全性・有効性が追試報告されるなど,自己骨髄由来細胞を用いた肝硬変症に対する再生治療の有効性が強く示唆されている.(著者抄録)

Advanced therapies using autologous bone marrow cells for chronic liver disease.

Takami, T., Terai, S., Sakaida, I.

Discovery medicine 14 ( 74 ) 2012年

Granulocyte colony-stimulating factor and interleukin-1β are important cytokines in repair of the cirrhotic liver after bone marrow cell infusion: comparison of humans and model mice. 査読

Mizunaga Y, Terai S, Yamamoto N, Uchida K, Yamasaki T, Nishina H, Fujita Y, Shinoda K, Hamamoto Y, Sakaida I

Cell transplantation 21 ( 11 ) 2363 - 2375 2012年

Autologous bone marrow cell infusion therapy to repair and regenerate liver 査読

Shuji Terai, Isao Sakaida

Seikagaku 84 ( 8 ) 707 - 711 2012年

内視鏡的静脈瘤結紫術・バルーン閉塞下逆行性経静脈的塞栓術併用療法で止血し得た十二指腸静脈瘤破裂の1例

松田崇史, 石川剛, 末永成之, 五嶋敦史, 浜辺功一, 岩本拓也, 橋本真一, 中島好晃, 岡田宗正, 内田耕一, 寺井崇二, 山崎隆弘, 坂井田功

山口医学 60 ( 6 ) 237 - 242 2011年12月

記述言語：日本語出版者・発行元：山口大学医学会

57歳の男性.B型肝硬変・肝細胞癌に対して外来経過観察中,下血に対する精査加療目的で当科に緊急入院した.上部消化管内視鏡検査(EGD)で十二指腸下行脚に静脈瘤が認められたものの活動性出血および血液貯留の所見はなく,下部消化管内視鏡検査･カプセル内視鏡検査･経肛門的ダブルバルーン内視鏡検査においても回腸~結腸内に凝血塊の貯留が認められたのみで出血源の同定には至らなかった.腹部血管造影検査では十二指腸周辺に著明な門脈系-大循環系短絡路の発達が認められ,血管造影下CTで十二指腸下行脚付近に造影剤の血管外漏出が疑われた.直後の緊急EGDにより十二指腸静脈瘤破裂と診断し,内視鏡的静脈瘤結紮術(EVL)にて一次止血に成功した.しかしその2日後に出血性ショックに陥ったため,EVLで止血した上で引き続きバルーン閉塞下逆行性経静脈的塞栓術(B-RTO)を施行して完全止血を得た.十二指腸静脈瘤破裂は非常に稀な難治性消化管出血であるが,今回我々はEVL･B-RTO併用療法で止血し救命し得た症例を経験したので報告する.A 57-year-old male with hepatitis B virus-related liver cirrhosis, who had undergone right lobectomy and radiofrequency ablation for hepatocellular carcinoma, was admitted to our department for the purpose of examination and treatment of melena. Esophagogastroduodenoscopy (EGD) on admission showed duodenal varices without active bleeding in the 2nd portion of duodenum. In addition, total colonoscopy, capsule endoscopy, and double-balloon endoscopy via the anal demonstrated massive dark-red clot in the ileum and colon, but not pointed out a source of bleeding. Thereafter, the angiography via superior mesenteric artery revealed large portalsystemic shunts around the duodenum and computed tomography during arteriography showed extravasation at the 2nd portion of duodenum. Urgent EGD enabled us to diagnose as ruptured duodenal varices and endoscopic variceal ligation (EVL) was successfully performed. However, two days later, he suffered from hemorrhagic shock because of rebleeding of duodenal varices and balloon-occluded retrograde transvenous obliteration (B-RTO) after second EVL finally led to complete hemostasis. We report this rare case of ruptured duodenal varices treated by combination therapy of EVL and BRTO in a cirrhotic patient.

DOI： 10.2342/ymj.60.237

多発性肝転移に対し, Degradable starch microspheres (DSM) とリピオドールによる肝動脈化学塞栓療法を施行後, オクトレオチド酢酸塩を継続投与した回腸原発神経内分泌腫瘍肝転移の一例

大野高嗣, 瀬川誠, 橋本真一, 内田耕一, 寺井崇二, 山崎隆弘, 星井嘉信, 坂井田功

山口医学 60 ( 6 ) 255 - 261 2011年12月

記述言語：日本語出版者・発行元：山口大学医学会

症例は50歳代女性．健診の腹部超音波検査で多発肝腫瘤を指摘され当院を受診．ダブルバルーン小腸内視鏡で回腸に多発する腫瘤性病変を認め，生検により，回腸原発神経内分泌腫瘍の多発肝転移と診断された．肝転移病巣に対し，微小デンプン球（degradable starch microspheres：DSM）とリピオドールを用いた肝動脈化学塞栓療法を施行し，良好な腫瘍縮小効果を認めた．さらに，術後に持続性ソマトスタチンアナログマイクロスフェア型徐放性製剤（オクトレオチド酢酸塩徐放性製剤：商品名：サンドスタチンLAR筋注用）を継続投与し，長期間にわたる腫瘍の増殖抑制効果を維持し得た．切除不能の消化管神経内分泌腫瘍の肝転移症例に対する治療法として有用であると考えられた．

DOI： 10.2342/ymj.60.255

Melanocortin 4 Receptor-Deficient Mice as a Novel Mouse Model of Nonalcoholic Steatohepatitis 査読

Michiko Itoh, Takayoshi Suganami, Nobutaka Nakagawa, Miyako Tanaka, Yukio Yamamoto, Yasutomi Kamei, Shuji Terai, Isao Sakaida, Yoshihiro Ogawa

AMERICAN JOURNAL OF PATHOLOGY 179 ( 5 ) 2454 - 2463 2011年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE INC

Obesity may be viewed as a state of chronic low-grade inflammation that participates in the development of the metabolic syndrome. Nonalcoholic steatohepatitis (NASH) is considered a hepatic phenotype of the metabolic syndrome and a high risk for progression to cirrhosis and hepatocellular carcinoma. Although the "two hit" hypothesis suggests involvement of excessive hepatic lipid accumulation and chronic inflammation, the molecular mechanisms underlying the development of NASH remain unclear, in part because of lack of appropriate animal models. Herein we report that melanocortin 4 receptor deficient mice (MC4R-KO) develop steatohepatitis when fed a high-fat diet, which is associated with obesity, insulin resistance, and dyslipidemia. Histologic analysis reveals inflammatory cell infiltration, hepatocyte ballooning, and pericellular fibrosis in the liver in MC4R-KO mice. Of note, all of the MC4R-KO mice examined developed well-differentiated hepatocellular carcinoma after being fed a high-fat diet for 1 year. They also demonstrated enhanced adipose tissue inflammation, ie, increased macrophage infiltration and fibrotic changes, which may contribute to excessive lipid accumulation and enhanced fibrosis in the liver. Thus, MC4R-KO mice provide a novel mouse model of NASH with which to investigate the sequence of events that make up diet-induced hepatic steatosis, liver fibrosis, and hepatocellular carcinoma and to aid in understanding the pathogenesis of NASH, pursuing specific biomarkers, and evaluating potential therapeutic strategies. (Am J Pathol 2011, 179:2454-2463; DOI: 10.1016/j.ajpath.2011.07.014)

DOI： 10.1016/j.ajpath.2011.07.014

肝細胞癌・慢性関節リウマチの加療中に悪性リンパ腫を発症した一例

播磨博文, 石川剛, 土屋昌子, 内田耕一, 星井嘉信, 寺井崇二, 山崎隆弘, 坂井田功

肝臓 52 ( Suppl.3 ) A954 - A954 2011年11月

TNFR1-mediated signaling is important to induce the improvement of liver fibrosis by bone marrow cell infusion 査読

Takuro Hisanaga, Shuji Terai, Takuya Iwamoto, Taro Takami, Naoki Yamamoto, Tomoaki Murata, Toshifumi Matsuyama, Hiroshi Nishina, Isao Sakaida

CELL AND TISSUE RESEARCH 346 ( 1 ) 79 - 88 2011年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER

The importance of TNF-alpha signals mediated by tumor necrosis factor receptor type 1 (TNFR1) in inflammation and fibrosis induced by carbon tetrachloride (CCl(4)), and in post-injury liver regeneration including a GFP/CCl(4) model developed as a liver repair model by bone marrow cell (BMC) infusion, was investigated. In mice in which TNFR1 was suppressed by antagonist administration or by knockout, liver fibrosis induced by CCl(4) was significantly decreased. In these mice, intrahepatic macrophage infiltration and TGF-beta 1 expression were reduced and stellate cell activity was decreased; however, expression of MMP-9 was also decreased. With GFP-positive BMC (TNFR1 wildtype, WT) infusion in these mice, fibrosis proliferation, including host endogenous intrahepatic macrophage infiltration, TGF-beta 1 expression and stellate cell activity, increased significantly. There was no significant increase of MMP-9 expression. In this study, TNFR1 in hosts had a promoting effect on CCl(4)-induced hepatotoxicity and fibrosis, whereas BMC infusion in TNFR1 knockout mice enhanced host-derived intrahepatic inflammation and fibrosis proliferation. These findings differed from those in WT recipient mice, in which improvement in inflammation and fibrosis with BMC infusion had previously been reported. TNFR1-mediated signaling might be important to induce the improvement of liver fibrosis by bone marrow cell infusion.

DOI： 10.1007/s00441-011-1236-0

Senescence marker protein 30 (SMP30)/regucalcin (RGN) expression decreases with aging, acute liver injuries and tumors in zebrafish 査読

Koichi Fujisawa, Shuji Terai, Yoshikazu Hirose, Taro Takami, Naoki Yamamoto, Isao Sakaida

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 414 ( 2 ) 331 - 336 2011年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE

Senescence marker protein 30 (SMP30)/regucalcin (RGN) is known to be related to aging, hepatocyte proliferation and tumorigenesis. However, expression and function of non-mammalian SMP30/RGN is poorly understood. We found that zebrafish SMP30/RGN mRNA expression decreases with aging, partial hepatectomy and thioacetamide-induced acute liver injury. SMP30/RGN expression was also greatly decreased in a zebrafish liver cell line. In addition, we induced liver tumors in adult zebrafish by administering diethylnitrosamine. Decreased expression was observed in foci, hepatocellular carcinomas, cholangiocellular carcinomas and mixed tumors as compared to the surrounding area. We thus showed the importance of SMP30/RGN in liver proliferation and tumorigenesis. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2011.09.067

Potential Therapeutic Application of Intravenous Autologous Bone Marrow Infusion in Patients with Alcoholic Liver Cirrhosis 査読

Takafumi Saito, Kazuo Okumoto, Hiroaki Haga, Yuko Nishise, Rika Ishii, Chikako Sato, Hisayoshi Watanabe, Akio Okada, Motoki Ikeda, Hitoshi Togashi, Tsuyoshi Ishikawa, Shuji Terai, Isao Sakaida, Sumio Kawata

STEM CELLS AND DEVELOPMENT 20 ( 9 ) 1504 - 1511 2011年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MARY ANN LIEBERT INC

The present study was conducted to evaluate the application and efficacy of autologous bone marrow infusion (ABMi) for improvement of liver function in patients with alcoholic liver cirrhosis (ALC). Five subjects and 5 control patients with ALC who had abstained from alcohol intake for 24 weeks before the study were enrolled. Autologous bone marrow cells were washed and injected intravenously, and the changes in serum liver function parameters, and the level of the type IV collagen 7S domain as a marker of fibrosis, were monitored for 24 weeks. The distribution of activated bone marrow was assessed by indium-111-chloride bone marrow scintigraphy. The number of cells infused was 8.0 +/- 7.3x10(9) (mean +/- standard error). The serum levels of albumin and total protein and the prothrombin time were significantly higher during the follow-up period after ABMi than during the observation period in treated patients, whereas no such changes were observed in the controls. In the patients who received ABMi, the Child-Pugh score decreased in all 3 who were classified as class B; the serum levels of type IV collagen 7S domain improved in 4 of the 5 patients; and bone marrow scintigraphy demonstrated an increase of indium-111-chloride uptake in 3 of the 4 patients tested. ABMi for patients with ALC helps improve liver function parameters in comparison with observation during abstinence and ameliorates the degree of fibrosis in terms of serum markers and bone marrow activation in most cases.

DOI： 10.1089/scd.2011.0074

肝疾患と幹細胞炎症、再生、発癌まで骨髄細胞頻回投与による肝細胞がん合併肝硬変症に対する修復再生・抗腫瘍療法開発のための基礎研究

高見太郎, 寺井崇二, 坂井田功

日本消化器病学会雑誌 108 ( 臨増大会 ) A687 - A687 2011年9月

肝疾患動物モデルとtranslational research 肝硬変症に対する骨髄由来培養細胞を用いた修復再生療法開発のために橋渡し研究

寺井崇二, 高見太郎, 坂井田功

日本消化器病学会雑誌 108 ( 臨増大会 ) A566 - A566 2011年9月

Deferoxamine for Advanced Hepatocellular Carcinoma 査読

Takahiro Yamasaki, Shuji Terai, Isao Sakaida

NEW ENGLAND JOURNAL OF MEDICINE 365 ( 6 ) 576 - 578 2011年8月

内視鏡的静脈瘤硬化結紮療法後におけるAT3製剤投与による門脈血栓予防効果

浜辺功一, 石川剛, 岩本拓也, 瀬川誠, 寺井崇二, 山崎隆弘, 坂井田功

日本門脈圧亢進症学会雑誌 17 ( 3 ) 111 - 111 2011年8月

肝細胞癌との鑑別に苦慮した脈絡膜悪性黒色腫肝転移の1例

在津潤一, 石川剛, 播磨陽平, 土屋昌子, 高見太郎, 山口裕樹, 内田耕一, 寺井崇二, 山崎隆弘, 坂井田功

肝臓 52 ( 7 ) 468 - 476 2011年7月

記述言語：日本語出版者・発行元：一般社団法人日本肝臓学会

左脈絡膜悪性黒色腫に対する手術歴（2004年4月，左眼球摘出術）を有する79歳の男性患者が2009年10月に右季肋部痛を主訴に当院外来を受診した．血液検査にて軽度の肝機能障害と高度の凝固系異常が認められたため精査加療目的で同日当科に緊急入院となった．HBs抗原・抗HBs抗体・抗HBc-IgG抗体・抗HCV抗体はいずれも陰性であり，腹部超音波検査・CT検査・MRI検査・血管造影検査で肝両葉に多血性腫瘤が多数認められた．悪性黒色腫に特異的な腫瘍マーカーである5-S-cysteinyldopaが異常高値を呈したがPIVKA IIも著明に上昇していたため画像・血液検査所見からは悪性黒色腫肝転移と肝細胞癌の鑑別には至らなかった．超音波下肝腫瘍生検にて悪性黒色腫の確定診断を得た上で同病変に対してシスプラチンを用いた肝動脈化学塞栓療法を施行した．今回我々は「脈絡膜悪性黒色腫肝転移」という非常に稀な一例を経験したので報告する．<br>

DOI： 10.2957/kanzo.52.468

An abdominal aorta wall extraction for liver cirrhosis classification using ultrasonic images

Takaya Hayashi, Yusuke Fujita, Yoshihiro Mitani, Yoshihiko Hamamoto, Makoto Segawa, Shuji Terai, Isao Sakaida

AIP Conference Proceedings 1371 343 - 344 2011年7月

Splenectomy reduces fibrosis and preneoplastic lesions with increased triglycerides and essential fatty acids in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet 査読

Toshiyuki Oishi, Shuji Terai, Takuya Iwamoto, Taro Takami, Naoki Yamamoto, Isao Sakaida

HEPATOLOGY RESEARCH 41 ( 5 ) 463 - 474 2011年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

Aim:
This study investigated whether splenectomy is of significance in non-alcoholic steatohepatitis (NASH).
Methods:
Five-week-old Wistar rats were fed a choline-deficient diet for 8 weeks to create a NASH model. A sham-operation or splenectomy was then performed, and rats were killed 4 weeks later.
Results:
Liver fibrosis and liver preneoplastic lesions were significantly reduced in the splenectomy group compared to the sham-operation group, and alpha-smooth muscle actin (SMA) expression was significantly inhibited (liver fibrosis area: sham 8.63 +/- 4.09%, splenectomy 5.45 +/- 3.69%, P < 0.01; preneoplastic lesion size: sham 6.56 +/- 3.68 x106 mu m2/cm2, splenectomy 4.63 +/- 3.27 x106 mu m2/cm2, P < 0.05; the number of preneoplastic lesions: sham 8.33 +/- 3.96/cm2, splenectomy 5.17 +/- 1.80/cm2, P < 0.01; alpha-smooth muscle actin-positive area: sham 4.41 +/- 2.48%, splenectomy 2.75 +/- 1.66%, P < 0.01) On the other hand, liver triglycerides and essential fatty acids were significantly increased in the splenectomy group (liver triglycerides: sham 182 +/- 35.0 mg/g, splenectomy 230 +/- 35.0 mg/g, P < 0.05; liver linoleic acid: sham 17.2 +/- 4.9 mg/g, splenectomy 23.3 +/- 6.9 mg/g, P < 0.05; liver alpha-linolenic acid: sham 118 +/- 36.6 mu g/g, splenectomy 162 +/- 51.4 mu g/g, P < 0.05). In addition, expressions of hepatic fatty acid metabolism-related genes (e.g. acyl-CoA oxidase, liver carnitine palmitoyl-CoA transferase I, cytochrome P450 4A, long-chain acyl-CoA dehydrogenase and medium-chain acyl-CoA dehydrogenase) were significantly inhibited in the splenectomy group.
Conclusion:
These findings suggest that spleen plays an important regulatory role in the fibrosis, preneoplastic lesion and lipid metabolism of liver in a rat choline-deficient L-amino acid model.

DOI： 10.1111/j.1872-034X.2011.00784.x

Telmisartan improves nonalcoholic steatohepatitis in medaka (Oryzias latipes) by reducing macrophage infiltration and fat accumulation 査読

Shinya Kuwashiro, Shuji Terai, Toshiyuki Oishi, Koichi Fujisawa, Toshihiko Matsumoto, Hiroshi Nishina, Isao Sakaida

CELL AND TISSUE RESEARCH 344 ( 1 ) 125 - 134 2011年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER

We investigated the efficacy of the antihypertensive drug telmisartan (Tel) and the mechanisms underlying the progression from simple steatosis to nonalcoholic steatohepatitis (NASH) in a medaka (Oryzias latipes) NASH model. We used the NASH activity score (NAS) developed in humans to assess the histology of the medaka NASH model and found that NAS increased with time. Further, TUNEL-positive apoptosis hepatocytes were found in the medaka NASH model. Tel administration resulted in the increased expression of liver peroxisome proliferator-activated receptor-gamma, carnitine palmitoyltransferase 1 and acyl-CoA oxidase 1 and decreased the number of 8-hydroxydeoxyguanosine-positive hepatocytes and the migration of macrophages positive for diastase-periodic-acid-Schiff. Medaka NAS was improved by Tel administration but fatty acid content was not affected. Tel reduced the infiltration of macrophages into the liver and ameliorated NASH pathology.

DOI： 10.1007/s00441-011-1132-7

Imaging mass spectrometry reveals characteristic changes in triglyceride and phospholipid species in regenerating mouse liver 査読

Norio Miyamura, Takashi Nakamura, Naoko Goto-Inoue, Nobuhiro Zaima, Takahiro Hayasaka, Tokiwa Yamasaki, Shuji Terai, Isao Sakaida, Mitsutoshi Setou, Hiroshi Nishina

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 408 ( 1 ) 120 - 125 2011年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE

After partial hepatectomy (PH), regenerating liver accumulates unknown lipid species. Here, we analyzed lipids in murine liver and adipose tissues following PH by thin-layer chromatography (TLC), imaging mass spectrometry (IMS), and real-time RT-PCR. In liver, IMS revealed that a single TLC band comprised major 19 TG species. Similarly, IMS showed a single phospholipid TLC band to be major 13 species. In adipose tissues, PH induced changes to expression of genes regulating lipid metabolism. Finally, IMS of phosphatidylcholine species demonstrated distribution gradients in lobules that resembled hepatic zonation. IMS is thus a novel and power tool for analyzing lipid species with high resolution. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2011.03.133

HHMは肝細胞増殖を抑制する

藤澤浩一, 寺井崇二, 桑代紳哉, 松本俊彦, 高見太郎, 山本直樹, 坂井田功

肝臓 52 ( Suppl.1 ) A198 - A198 2011年4月

肝再生医学研究の新展開効率的な肝硬変症に対する骨髄細胞を用いた修復再生療法の開発のための基礎的検討

寺井崇二, 高見太郎, 坂井田功

肝臓 52 ( Suppl.1 ) A117 - A117 2011年4月

A novel transcatheter arterial infusion chemotherapy using iodized oil and degradable starch microspheres for hepatocellular carcinoma: a prospective randomized trial 査読

Takahiro Yamasaki, Satoe Hamabe, Issei Saeki, Yohei Harima, Yuhki Yamaguchi, Koichi Uchida, Shuji Terai, Isao Sakaida

JOURNAL OF GASTROENTEROLOGY 46 ( 3 ) 359 - 366 2011年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER TOKYO

We designed a novel transcatheter arterial infusion chemotherapy (TAI) using iodized oil (lipiodol) and degradable starch microspheres (DSM) for hepatocellular carcinoma (HCC) patients. In this study, we investigated the efficacy of TAI using lipiodol and DSM in a prospective randomized trial.
We randomly divided 45 patients with HCC into 3 groups: TAI using lipiodol (lipiodol group, n = 15), TAI using DSM (DSM group, n = 15), and TAI using lipiodol and DSM (lipiodol + DSM group, n = 15). In the lipiodol group, a mixture of cisplatin and lipiodol was administered. In the DSM group, a mixture of cisplatin and DSM was administered. In the lipiodol + DSM group, a mixture of cisplatin and lipiodol was administered, followed by DSM.
The response rates were 40% in the lipiodol group, 53.4% in the DSM group, and 80% in the lipiodol + DSM group, respectively. The response rate tended to improve in the lipiodol + DSM group (lipiodol group vs. lipiodol + DSM group, P = 0.07). The median progression-free survival time was 177 days in the lipiodol group, 287 days in the DSM group, and 377 days in the lipiodol + DSM group. The progression-free survival in the lipiodol + DSM group was significantly better than those in the DSM group (P = 0.020) and the lipiodol group (P = 0.035). There were no serious adverse effects among the 3 groups.
TAI using lipiodol and DSM was superior to TAI using lipiodol only and TAI using DSM only because of improvements in therapeutic effects and progression-free survival.

DOI： 10.1007/s00535-010-0306-5

Current State and Future Prospects for Our Liver Regeneration Therapy Using Autologous Bone Marrow Cells for Decompensated Liver Cirrhosis Patients 査読

Taro Takami, Shuji Terai, Isao Sakaida

JOURNAL OF PHARMACOLOGICAL SCIENCES 115 ( 3 ) 274 - 278 2011年3月

記述言語：英語出版者・発行元：JAPANESE PHARMACOLOGICAL SOC

We have developed an in vivo mouse model [the green fluorescent protein (GFP) /carbon tetrachloride (CCl4) model] and reported that infused G FP-positive bone marrow cells administered via a tail vein efficiently repopulated cirrhotic liver tissue under conditions of persistent liver damage induced by CCl4. Moreover, bone marrow cells infused into the liver improved liver function and ameliorated liver fibrosis with higher expression of matrix metalloproteinase 9 (MMP-9), consistent with improved survival rate. Based on these findings, we started a multicenter clinical trial of autologous bone marrow cell infusion (ABMi) therapy for decompensated liver cirrhosis patients and demonstrated the efficacy of this approach without unexpected complications. However, this therapy involves bone marrow aspiration under general anesthesia and is not indicated for patients for whom general anesthesia is difficult. We therefore aimed to develop a new liver regeneration therapy in which cells having a curative effect on liver cirrhosis are isolated and cultured from a small amount of autologous bone marrow aspirated under local anesthesia and infused back into the same subject. Herein, we present results for the GFP/CCl4 model and ABMi therapy and future prospects for a new liver regeneration therapy.

DOI： 10.1254/jphs.10R13FM

非代償性肝硬変の合併症とその対策肝硬変症に対する次世代型骨髄由来培養細胞を用いた修復再生療法の開発

寺井崇二, 高見太郎, 坂井田功

日本消化器病学会雑誌 108 ( 臨増総会 ) A147 - A147 2011年3月

当科で経験したHBVキャリア急性増悪を来たした二例

内田耕一, 瀬川誠, 柴田大明, 植木谷俊之, 播磨陽平, 土屋昌子, 石川剛, 寺井崇二, 山崎隆弘, 坂井田功, 加藤彰, 木村輝明, 山下智省, 沖田極

肝臓 52 ( 3 ) 222 - 222 2011年3月

Autologous bone marrow cell infusion therapy for liver cirrhosis patients 査読

Shuji Terai, Isao Sakaida

JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 18 ( 1 ) 23 - 25 2011年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER TOKYO

We developed a novel cell therapy, autologous bone marrow cell infusion (ABMi) therapy, using autologous bone marrow, for liver cirrhosis patients. Our study depends on the findings from basic studies that bone marrow cell infusion repairs liver fibrosis in the cirrhotic liver, and improves liver function and the survival rate. Beginning in November 2003, we started a clinical study and found that ABMi therapy was safe and effective for liver cirrhosis patients. Multicenter trials in Japan and Korea have also shown the effectiveness of ABMi therapy. In this review, we report the current status of ABMi therapy for liver cirrhosis patients.

DOI： 10.1007/s00534-010-0305-1

Efficient detection of hepatocellular carcinoma by a hybrid blood test of epigenetic and classical protein markers 査読

Norio Iizuka, Masaaki Oka, Isao Sakaida, Toyoki Moribe, Toshiaki Miura, Naoki Kimura, Shigeru Tamatsukuri, Hideo Ishitsuka, Koichi Uchida, Shuji Terai, Satoyoshi Yamashita, Kiwamu Okita, Koichiro Sakata, Yoshiyasu Karino, Joji Toyota, Eiji Ando, Tatsuya Ide, Michio Sata, Ryoichi Tsunedomi, Masahito Tsutsui, Michihisa Iida, Yoshihiro Tokuhisa, Kazuhiko Sakamoto, Takao Tamesa, Yusuke Fujita, Yoshihiko Hamamoto

CLINICA CHIMICA ACTA 412 ( 1-2 ) 152 - 158 2011年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE BV

Background: There are few blood tests for an efficient detection of hepatocellular carcinoma (HCC) associated with hepatitis C virus (HCV) infection.
Methods: The abilities of quantitative analyses of 7 genes hypermethylation in serum DNA, a-fetoprotein (AFP) and prothrombin-induced vitamin K absence II (PIVKA-II), and various combinations to detect HCC were evaluated in a training cohort of 164 HCV-infected patients (108 HCCs; 56 non-HCCs). An optimal hybrid detector, built using data for 2 methylated genes (SPINT2 and SRD5A2), AFP, and PIVKA-II. achieved the most satisfactory ability to detect HCC in the training cohort. We evaluated the ability of the optimal hybrid detector to detect HCC in an independent validation cohort of 258 consecutive HCV-infected patients (112 HCCs; 146 non-HCCs) who were newly enrolled in 4 distinct institutes.
Results: In the validation cohort of 258 patients, accuracy, sensitivity, and specificity of the hybrid detector for detection of HCC were 81.4%, 73.2%, and 87.7%, respectively. Notably, even when detecting HCC <= 2 cm in diameter, the hybrid detector maintained markedly high abilities (84.6% accuracy, 72.2% sensitivity, 87.7% specificity). Youden's index (sensitivity + specificity - 1) for HCC <= 2 cm was 0.60, vastly much superior to the 0.39 for AFP at a cut-off value of 20 ng/ml and the 0.28 for PIVKA-II at a cut-off value of 40 mAU/ml.
Conclusions: These results show that the optimal hybrid blood detector can detect HCV-related HCC more accurately. (C) 2010 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.cca.2010.09.028

肝臓肝疾患の再生治療

高見太郎, 寺井崇二, 坂井田功

Annual Review消化器 2011 223 - 228 2011年1月

記述言語：日本語出版者・発行元：(株)中外医学社

非代償性肝硬変症の根治療法は肝移植である.2010年7月,家族の承諾による脳死臓器提供を認めた改正臓器移植法が全面施行されたが,慢性的ドナー不足,手術侵襲や免疫拒絶などの諸問題は依然として解決されていない.一方,これまでに肝臓再生修復療法の細胞源として骨髄由来(幹)細胞が注目され,G-CSFにより誘導された自己CD34陽性細胞を用いた細胞療法,CD133陽性単核球細胞の門脈内投与療法や,自己間葉系幹細胞投与による細胞療法などの報告がある.我々は,骨髄細胞から肝細胞への分化・増殖評価マウスモデル(GFP/CCl4モデル)により自己骨髄細胞投与が肝機能を改善させることを報告し,その成果を基盤にした臨床研究「肝硬変症に対する自己骨髄細胞投与療法(Autologous bone marrow cell infusion therapy,ABMi療法)」でも肝機能改善・修復効果を確認した.さらに海外で共同実施したABMi療法の臨床研究の結果,自己骨髄由来細胞を用いた肝硬変症に対する再生治療・細胞療法の有効性が明らかになった.(著者抄録)

C型慢性肝炎におけるエラストグラフィの有用性

江角智子, 高見太郎, 岸田由香里, 堤寛子, 松尾亜矢, 石川剛, 瀬川誠, 寺井崇二, 山崎隆弘, 坂井田功

超音波医学 37 ( 6 ) 679 - 679 2010年11月

Sonazoid造影エコー検査では肝細胞癌との鑑別が困難であった脈絡膜悪性黒色腫肝転移の一例

大石俊之, 石川剛, 土屋昌子, 高見太郎, 内田耕一, 寺井崇二, 山崎隆弘, 坂井田功

超音波医学 37 ( 6 ) 676 - 677 2010年11月

門脈圧亢進症における病態進行度の指標としての肝弾性値の有用性

瀬川誠, 浜辺功一, 石川剛, 寺井崇二, 山崎隆弘, 坂井田功

超音波医学 37 ( 6 ) 679 - 679 2010年11月

Helicobacter pylori CagA inhibits endocytosis of cytotoxin VacA in host cells 査読

Junko K. Akada, Hiroki Aoki, Yuji Torigoe, Takao Kitagawa, Hisao Kurazono, Hisashi Hoshida, Jun Nishikawa, Shuji Terai, Masunori Matsuzaki, Toshiya Hirayama, Teruko Nakazawa, Rinji Akada, Kazuyuki Nakamura

DISEASE MODELS & MECHANISMS 3 ( 9-10 ) 605 - 617 2010年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：COMPANY OF BIOLOGISTS LTD

Helicobacter pylori, a common pathogen that causes chronic gastritis and cancer, has evolved to establish persistent infections in the human stomach. Epidemiological evidence suggests that H. pylori with both highly active vacuolating cytotoxin A (VacA) and cytotoxin-associated gene A (CagA), the major virulence factors, has an advantage in adapting to the host environment. However, the mechanistic relationship between VacA and CagA remains obscure. Here, we report that CagA interferes with eukaryotic endocytosis, as revealed by genome-wide screening in yeast. Moreover, CagA suppresses pinocytic endocytosis and the cytotoxicity of VacA in gastric epithelial cells without affecting clathrin-dependent endocytosis. Our data suggest that H. pylori secretes VacA to attack distant host cells while injecting CagA into the gastric epithelial cells to which the bacteria are directly attached, thereby protecting these attached host cells from the cytotoxicity of VacA and creating a local ecological niche. This mechanism might allow H. pylori to balance damage to one population of host cells with the preservation of another, allowing for persistent infection.

DOI： 10.1242/dmm.004879

肝臓の再生機構を考える今後の肝再生医療への展望骨髄由来Liver Repair cell(LR細胞)を用いた肝臓再生修復療法の開発について

寺井崇二, 高見太郎, 坂井田功

肝臓 51 ( Suppl.2 ) A450 - A450 2010年9月

メダカNASHモデルを用いた薬物スクリーニングについて

寺井崇二, 大石俊之, 桑代紳哉, 松本俊彦, 坂井田功

肥満研究 16 ( Suppl. ) 144 - 144 2010年9月

肝胆膵疾患と組織幹細胞/progenitor cell 病態解析と治療戦略 Oval cellの活性化に伴う肝再生・修復過程におけるHGF/c-Metシグナリングの役割

石川剛, 寺井崇二, 坂井田功

肝臓 51 ( Suppl.2 ) A511 - A511 2010年9月

門脈圧亢進症に対するPSEと脾摘の有用性部分的脾動脈塞栓術における血小板増加予測因子と肝予備能改善効果

石川剛, 浜辺功一, 大森薫, 高見太郎, 瀬川誠, 寺井崇二, 山崎隆弘, 坂井田功

日本門脈圧亢進症学会雑誌 16 ( 2 ) 69 - 69 2010年8月

食道・胃静脈瘤の予防的治療バルーン閉塞下逆行性経静脈的塞栓術の肝機能改善効果

石川剛, 浜辺功一, 大森薫, 高見太郎, 瀬川誠, 寺井崇二, 山崎隆弘, 坂井田功

日本門脈圧亢進症学会雑誌 16 ( 2 ) 57 - 57 2010年8月

バルーン閉塞下逆行性経静脈的塞栓術(B-RTO)前後での食道静脈瘤増悪の有無別の検討

浜辺功一, 瀬川誠, 石川剛, 寺井崇二, 山崎隆弘, 坂井田功

日本門脈圧亢進症学会雑誌 16 ( 2 ) 97 - 97 2010年8月

門脈圧亢進症の血行動態門脈圧亢進症における病態進行度の指標としての肝弾性値の有用性

瀬川誠, 浜辺功一, 石川剛, 寺井崇二, 山崎隆弘, 坂井田功

日本門脈圧亢進症学会雑誌 16 ( 2 ) 50 - 50 2010年8月

Medaka as a model for human nonalcoholic steatohepatitis 査読

Toshihiko Matsumoto, Shuji Terai, Toshiyuki Oishi, Shinya Kuwashiro, Koichi Fujisawa, Naoki Yamamoto, Yusuke Fujita, Yoshihiko Hamamoto, Makoto Furutani-Seiki, Hiroshi Nishina, Isao Sakaida

DISEASE MODELS & MECHANISMS 3 ( 7-8 ) 431 - 440 2010年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：COMPANY OF BIOLOGISTS LTD

The global incidence of nonalcoholic steatohepatitis (NASH) is increasing and current mammalian models of NASH are imperfect. We have developed a NASH model in the ricefish medaka (Oryzias latipes), which is based on feeding the fish a high-fat diet (HFD). Medaka that are fed a HFD (HFD-medaka) exhibited hyperlipidemia and hyperglycemia, and histological examination of the liver revealed ballooning degeneration. The expression of lipogenic genes (SREBP-1c, FAS and ACC1) was increased, whereas the expression of lipolytic genes (PPARA and CPT1) was decreased. With respect to liver fatty acid composition, the concentrations of n-3 polyunsaturated fatty acids (PUFAs) and n-6 PUFAs had declined and the n-3: n-6 ratio was reduced. Treatment of HFD-medaka with the n-3 PUFA eicosapentaenoic acid (EPA) mitigated disease, as judged by the restoration of normal liver fatty acid composition and normal expression levels of lipogenic and lipolytic genes. Moreover, medaka that were fed a diet deficient in n-3 PUFAs developed NASH features. Thus, NASH can be induced in medaka by a HFD, and the proportion of n-3 PUFAs in the liver influences the progress of NASH pathology in these fish. Our model should prove helpful for the dissection of the causes of human NASH and for the design of new and effective therapies.

DOI： 10.1242/dmm.002311

【NASH】基礎的メカニズムの解明ヒト類似のメダカ非アルコール性脂肪肝炎(NASH)モデルの開発

寺井崇二, 松本俊彦, 大石俊之, 桑代紳哉, 坂井田功

The Lipid 21 ( 3 ) 235 - 246 2010年7月

記述言語：日本語出版者・発行元：(株)メディカルレビュー社

非アルコール性脂肪肝炎(nonalcoholic steatohepatitis;NASH)は、アルコール多飲なく生じる脂肪肝炎で、メタボリックシンドロームの肝における表現型である。NASHは進行性の慢性肝疾患で、肝炎から肝硬変となり、肝癌を生じる。NASHは世界規模で増加しており、マウスなどのげっ歯類を用いた動物モデルによる研究が進められているが、効率的にNASHを誘導するモデルは少ない。そこでわれわれは、器官形成やヒト疾患のモデル生物として最近注目されているメダカに注目し、高脂肪食を与えることにより、メダカNASHモデルの開発に成功した。メダカNASHモデルは、ヒトと同様に高血糖、脂質異常症となり、NASHの組織学的な特徴である肝細胞の風船様変性を呈した。また、肝細胞における脂肪酸合成遺伝子(SREBP-1c、FAS、ACC1)の発現亢進と脂肪酸酸化遺伝子(PPARα、CPT1)の発現低下を認め、脂肪酸合成の亢進、脂肪酸β酸化の低下が示された。さらに、肝内の脂肪酸分画の解析により、n-3系・n-6系多価不飽和脂肪酸(n-3 PUFA、n-6 PUFA)の減少、特にn-3 PUFAの著明な減少を認めた。これらはヒトNASH患者の病態と共通していた。そこで、メダカNASHモデルにn-3 PUFAであるエイコサペンタエン酸(EPA)を投与したところ、肝内の脂肪酸分画、脂肪酸合成遺伝子と脂肪酸酸化遺伝子の発現が正常化され、NASHの病態が改善した。一方、メダカにn-3 PUFA欠乏食を与えたところ、NASHが誘導された。メダカに高脂肪食を与えることでNASHが誘導され、メダカNASHモデルでは肝内のn-3 PUFAの量比がNASHの病態に関与していることが明らかになった。われわれの開発したメダカNASHモデルは、ヒトNASHの病態を再現しており、NASHの病態解明や薬剤スクリーニングに応用でき新たな治療法の開発に有用である。(著者抄録)

Effect of a late evening snack using branched-chain amino acid-enriched nutrients in patients undergoing hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma 査読

Yohei Harima, Takahiro Yamasaki, Satoe Hamabe, Issei Saeki, Kohsuke Okita, Shuji Terai, Isao Sakaida

HEPATOLOGY RESEARCH 40 ( 6 ) 574 - 584 2010年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

Aim:
A late evening snack (LES) is recommended for protein-energy malnutrition in patients with liver cirrhosis. This study investigated energy metabolism in cirrhotic patients with hepatocellular carcinoma (HCC) and the effects of LES using a branched-chain amino acid (BCAA)-enriched nutrient in cirrhotic patients with advanced HCC undergoing hepatic arterial infusion chemotherapy (HAIC).
Methods:
Energy metabolism was measured using indirect calorimetry for 10 cirrhotic patients without HCC and 36 patients with various stages of HCC. Next, in 23 cirrhotic patients with advanced HCC undergoing HAIC, 13 patients received LES (LES group), and 10 patients received ordinary food (control group). Changes in energy metabolism and glucose tolerance were examined using indirect calorimetry and 75-g oral glucose tolerance test (OGTT) before and after 1 cycle of treatment.
Results:
Non-protein respiratory quotient (npRQ) was significantly lower in patients with advanced HCC than in cirrhotic patients without HCC, or in patients with early-stage HCC. In cirrhotic patients with advanced HCC undergoing HAIC, npRQ, BCAA/tyrosine ratio (BTR), and prealbumin and ALT levels were significantly improved in the LES group, but not in controls. In addition, area under the concentration curve for glucose (AUC glucose) tended to be improved in the LES group.
Conclusions:
LES using BCAA-enriched nutrients appears to improve energy metabolism and glucose tolerance in cirrhotic patients with advanced HCC undergoing HAIC.

DOI： 10.1111/j.1872-034X.2010.00665.x

肝細胞癌との鑑別に苦慮した悪性黒色腫肝転移の一例

在津潤一, 石川剛, 播磨陽平, 土屋昌子, 高見太郎, 山口裕樹, 内田耕一, 寺井崇二, 山崎隆弘, 坂井田功

山口医学 59 ( 3 ) 146 - 146 2010年6月

肝病態形成における酸化ストレスの意義メダカNASHモデルの病態にERストレス、酸化ストレス及び炎症細胞浸潤が関わりテルミサルタンは脂肪酸酸化の増加によりその病態進展を抑制する

桑代紳哉, 寺井崇二, 大石俊之, 藤澤浩一, 松本俊彦, 坂井田功

肝臓 51 ( Suppl.1 ) A91 - A91 2010年4月

肝弾性値と門脈圧との関連性についての検討

瀬川誠, 浜辺功一, 石川剛, 大森薫, 寺井崇二, 山崎隆弘, 坂井田功

肝臓 51 ( Suppl.1 ) A349 - A349 2010年4月

HGF/c-Metシグナリングはoval cell由来肝再生に必須である

石川剛, 寺井崇二, 坂井田功

肝臓 51 ( Suppl.1 ) A257 - A257 2010年4月

Retinoic acid signaling positively regulates liver specification by inducing wnt2bb gene expression in medaka

Negishi, T, Nagai, Y, Asaoka, Y, Ohno, M, Namae, M, Mitani, H, Sasaki, T, Shimizu, N, Terai, S, Sakaida, I, Kondoh, H, Katada, T, Furutani-Seiki, M, Nishina, H

Hepatology 51 ( 3 ) 1037 - 45 2010年3月

UNLABELLED: During vertebrate embryogenesis, the liver develops at a precise location along the endodermal primitive gut tube because of signaling delivered by adjacent mesodermal tissues. Although several signaling molecules have been associated with liver formation, the molecular mechanism that regulates liver specification is still unclear. We previously performed a screen in medaka to isolate mutants with impaired liver development. The medaka hio mutants exhibit a profound (but transient) defect in liver specification that resembles the liver formation defect found in zebrafish prometheus (prt) mutants, whose mutation occurs in the wnt2bb gene. In addition to their liver abnormality, hio mutants lack pectoral fins and die after hatching. Positional cloning indicated that the hio mutation affects the raldh2 gene encoding retinaldehyde dehydrogenase type2 (RALDH2), the enzyme principally responsible for retinoic acid (RA) biosynthesis. Mutations of raldh2 in zebrafish preclude the development of pectoral fins. Interestingly, in hio mutants, expression of wnt2bb in the lateral plate mesoderm (LPM) directly adjacent to the liver-forming endoderm was completely lost. CONCLUSION: Ou

DOI： 10.1002/hep.23387

Retinoic Acid Signaling Positively Regulates Liver Specification by Inducing wnt2bb Gene Expression in Medaka 査読

Takahiro Negishi, Yoko Nagai, Yoichi Asaoka, Mami Ohno, Misako Namae, Hiroshi Mitani, Takashi Sasaki, Nobuyoshi Shimizu, Shuji Terai, Isao Sakajda, Hisato Kondoh, Toshiaki Katada, Makoto Furutani-Seiki, Hiroshi Nishina

HEPATOLOGY 51 ( 3 ) 1037 - 1045 2010年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JOHN WILEY & SONS INC

During vertebrate embryogenesis, the liver develops at a precise location along the endodermal primitive gut tube because of signaling delivered by adjacent mesodermal tissues. Although several signaling molecules have been associated with liver formation, the molecular mechanism that regulates liver specification is still unclear. We previously performed a screen in medaka to isolate mutants with impaired liver development. The medaka hio mutants exhibit a profound (but transient) defect in liver specification that resembles the liver formation defect found in zebrafish prometheus (prt) mutants, whose mutation occurs in the wnt2bb gene. In addition to their liver abnormality, hio mutants lack pectoral fins and die after hatching. Positional cloning indicated that the hio mutation affects the raldh2 gene encoding retinaldehyde dehydrogenase type2 (RALDH2), the enzyme principally responsible for retinoic acid (RA) biosynthesis. Mutations of raldh2 in zebrafish preclude the development of pectoral fins. Interestingly, in hio mutants, expression of wnt2bb in the lateral plate mesoderm (LPM) directly adjacent to the liver-forming endoderm was completely lost. Conclusion: Our data reveal the unexpected finding that RA signaling positively regulates the wnt2bb gene expression required for liver specification in medaka. These results suggest that a common molecular mechanism may underlie liver and pectoral fin specification during piscine embryogenesis. (HEPATOLOGY 2010;51:1037-1045.)

DOI： 10.1002/hep.23387

細胞操作技術の最前線(第7回) 細胞治療技術肝硬変も治る時代へ、自己細胞で肝炎治療

高見太郎, 寺井崇二, 坂井田功

Medical Bio 7 ( 2 ) 54 - 57 2010年3月

HGF/c-Metシグナリングはoval cell由来肝再生に必須である

石川剛, 寺井崇二, 坂井田功

日本消化器病学会雑誌 107 ( 臨増総会 ) A261 - A261 2010年3月

Fish model leads to new findings in liver disease 査読

Shuji Terai

HEPATOLOGY RESEARCH 40 ( 1 ) 111 - 113 2010年1月

肝臓肝疾患における再生治療・細胞療法の展望

高見太郎, 寺井崇二, 坂井田功

Annual Review消化器 2010 201 - 206 2010年1月

記述言語：日本語出版者・発行元：(株)中外医学社

非代償性肝硬変症の根治療法は肝移植であるが,慢性的ドナー不足,手術侵襲や免疫拒絶などの諸問題のため広くは実施されていない.これまでに骨髄幹細胞が肝臓再生療法に使用する細胞源として注目され,G-CSFにより誘導されたCD34陽性細胞を用いた細胞療法,CD133陽性単核球細胞の門脈内投与療法や,自己間葉系幹細胞を用いた細胞療法などの報告がある.また我々もこれまでに,骨髄細胞から肝細胞への分化・増殖評価マウスモデル(GFP/CCl4モデル)で自己骨髄細胞投与が肝機能を改善させることを報告し,その成果を基盤にした臨床研究「肝硬変症に対する自己骨髄細胞投与療法(autologous bone marrow cell infusion therapy,ABMi療法)」でも肝機能改善・修復効果を確認するなど,肝硬変に対する自己骨髄細胞を用いた再生治療・細胞療法の有効性が示唆された.(著者抄録)

An Improved Method for Cirrhosis Detection Using Liver's Ultrasound Images. 査読

Yusuke Fujita, Yoshihiko Hamamoto, Makoto Segawa, Shuji Terai, Isao Sakaida

20th International Conference on Pattern Recognition, ICPR 2010, Istanbul, Turkey, 23-26 August 2010 2294 - 2297 2010年

Autologous Bone Marrow Infusion Activates the Progenitor Cell Compartment in Patients With Advanced Liver Cirrhosis 査読

Ja Kyung Kim, Young Nyun Park, Jin Seok Kim, Mi-Suk Park, Yong Han Paik, Jae-Yeon Seok, Yong Eun Chung, Hyun Ok Kim, Kyung Sik Kim, Sang Hoon Ahn, Do Young Kim, Myeong-Jin Kim, Kwan Sik Lee, Chae Yoon Chon, Soo Jeong Kim, Shuji Terai, Isao Sakaida, Kwang-Hyub Han

CELL TRANSPLANTATION 19 ( 10 ) 1237 - 1246 2010年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：COGNIZANT COMMUNICATION CORP

Several clinical trials of bone marrow cell infusion in patients with liver cirrhosis (LC) have shown clinical improvement, despite conflicting results from animal models. We investigated serial pathological features and the clinical impact after autologous bone marrow infusion (ABM1) in patients with advanced LC. Ten patients with advanced LC due to chronic hepatitis B virus infection underwent ABMI. Serological tests, MRI, and liver biopsies were performed, and quality of life was assessed by a questionnaire. Median serum albumin and hemoglobin levels increased significantly after ABM1. All patients showed an improvement in quality of life, with no serious adverse events. Liver volume, measured by MRI, increased in 80% of the patients, and ascites decreased after ABMI. Child-Pugh scores were also significantly improved at 6 months after ABMI. In the serially biopsied livers, a gradually increasing activation of the hepatic progenitor cell (HPC) compartment, including HPC activation (ductular reaction) and HPC differentiation (intermediate hepatocyte), reached a peak after 3 months, with continued proliferation of hepatocytes, and returned to baseline levels after 6 months. There was no significant change in grade or stage of liver fibrosis or stellate cell activation after ABMI. ABMI is suggested to improve liver function and to activate the progenitor cell compartment. Although clinical improvement was sustained for more than 6 months, histological changes in the liver returned to baseline 6 months after ABMI. Further comparative studies are warranted.

DOI： 10.3727/096368910X506863

【幹細胞を用いた消化器再生医療の展望】肝硬変症は幹細胞再生医療で治せるか

高見太郎, 寺井崇二, 坂井田功

分子消化器病 6 ( 4 ) 359 - 364 2009年12月

記述言語：日本語出版者・発行元：(株)先端医学社

非代償性肝硬変症の根治療法は肝移植であるが、慢性的ドナー不足、手術侵襲、免疫拒絶や医療経済的な面から広く実施されていない。肝再生療法に使用する細胞源として骨髄幹細胞が注目され、G-CSFにより誘導されたCD34陽性細胞を用いた細胞療法、CD133陽性単核球細胞の門脈内投与療法や、自己間葉系幹細胞を用いた細胞療法などの報告がある。またこれまでにわれわれは、骨髄細胞から肝細胞への分化・増殖評価マウスモデル(GFP/CCl4モデル)を開発し、自己骨髄細胞投与が肝機能を改善させることを報告し、その成果を基盤にした臨床研究「肝硬変症に対する自己骨髄細胞投与療法(ABMi療法)」でも肝機能改善・修復効果を確認するなど、肝硬変症に対する幹細胞再生医療の有効性が強く示唆されている。(著者抄録)

経皮的ドレナージ術と経過観察に Sonazoid^【○!R】造影超音波検査が有用であった, 肝膿瘍の1例

大森薫, 谷本治子, 寺井崇二, 山崎隆弘, 坂井田功

肝臓 50 ( 11 ) 657 - 664 2009年11月

記述言語：日本語出版者・発行元：一般社団法人日本肝臓学会

症例は60代男性．主訴は発熱と右季肋部痛．CTで肝右葉に60&times;40 mmの膿瘍を指摘された．腹部超音波検査Bモードでは，膿瘍と背景肝の境界が不明瞭で，安全かつ確実な穿刺ドレナージが困難であった．Sonazoid<sup>&reg;</sup>造影超音波検査のKupffer imageでは50 mmの膿瘍腔・壊死部が明瞭に描出され，経皮経肝膿瘍ドレナージ術を施行した．その後もSonazoid<sup>&reg;</sup>造影超音波検査により，治癒経過を観察しえた．肝膿瘍の経皮的ドレナージ術と経過観察に，造影超音波検査が有用であった肝膿瘍の1例を経験した．<br>

DOI： 10.2957/kanzo.50.657

Sonazoid造影超音波検査が治療と評価に有用であった肝膿瘍の一例

高見太郎, 大森薫, 谷本治子, 土屋昌子, 寺井崇二, 山崎隆弘, 坂井田功

超音波医学 36 ( 6 ) 701 - 701 2009年11月

Sonazoid造影超音波検査が診断に有用であった肝細胞癌の一例

土屋昌子, 高見太郎, 寺井崇二, 山崎隆弘, 坂井田功

超音波医学 36 ( 6 ) 701 - 701 2009年11月

肝硬変の対策原因療法から合併症の対策非代償性肝硬変症に対する自己骨髄細胞投与療法の現状と今後の展開

高見太郎, 寺井崇二, 坂井田功

肝臓 50 ( Suppl.3 ) A626 - A626 2009年10月

【NASH 非アルコール性脂肪肝炎治療の現状と課題】NASHの治療瀉血療法の可能性

寺井崇二, 松本俊彦, 坂井田功

治療学 43 ( 10 ) 1107 - 1110 2009年10月

NASH研究の最前線メダカNASHモデルの特性を生かした薬物スクリーニングについて

寺井崇二, 松本俊彦, 坂井田功

肝臓 50 ( Suppl.3 ) A606 - A606 2009年10月

門脈圧亢進症に対する総合的なアプローチ B-RTOとPSE

大森薫, 浜辺功一, 石川剛, 瀬川誠, 寺井崇二, 山崎隆弘, 坂井田功

肝臓 50 ( Suppl.3 ) A721 - A721 2009年10月

Telmisartanの投与によるマクロファージ浸潤抑制を含めたNASHの改善効果検討

桑代紳哉, 寺井崇二, 大石俊之, 藤澤浩一, 松本俊彦, 坂井田功

肥満研究 15 ( Suppl. ) 185 - 185 2009年9月

肝癌発生・進展の分子機構と臨床への還元 HHM(Maid)の肝発癌の制御分子としての重要性について

寺井崇二, 藤澤浩一, 高見太郎, 山崎隆弘, 坂井田功

肝臓 50 ( Suppl.1 ) A97 - A97 2009年4月

TelmisartanはメダカNASHモデルにおいてER stressを改善し炎症細胞浸潤を抑制し病態を改善する

桑代紳哉, 寺井崇二, 大石俊之, 藤澤浩一, 松本俊彦, 坂井田功

肝臓 50 ( Suppl.1 ) A384 - A384 2009年4月

Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma: Is the addition of subcutaneous interferon-alpha-2b beneficial? 査読

Satoe Takaki-Hamabe, Takahiro Yamasaki, Issei Saeki, Yohei Harima, Kohsuke Okita, Shuji Terai, Isao Sakaida

HEPATOLOGY RESEARCH 39 ( 3 ) 223 - 230 2009年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC

We previously reported the benefits of hepatic arterial infusion chemotherapy (HAIC) using cisplatin (CDDP), 5-fluorouracil (5-FU) [low-dose FP], and leucovorin/isovorin for advanced hepatocellular carcinoma (HCC). In this study, we investigated the efficacy of combination therapy with HAIC and subcutaneous interferon (IFN)- alpha-2b in patients with advanced HCC.
Of the 48 patients, 31 received low-dose FP with leucovorin/isovorin (HAIC group) and 17 received combination therapy comprising low-dose FP with isovorin and subcutaneous IFN-alpha-2b (combination group). Prognostic factors were evaluated by univariate and multivariate analyses of the patient and the disease characteristics.
There were no significant differences in the response rate (patients with complete or partial response/all patients; P = 0.736) and survival (P = 0.399) between both groups. Univariate analysis revealed that IFN therapy was not a significant prognostic factor. Multivariate analysis showed 3 variables, namely, Child-Pugh score (P = 0.010), alpha-fetoprotein level (P = 0.0047), and additional therapy (P = 0.002), to be significant prognostic factors.
We considered that combination therapy with HAIC and subcutaneous interferon (IFN)-alpha-2b was not beneficial for advanced HCC.

DOI： 10.1111/j.1872-034X.2008.00458.x

Hematopoiesis-dependent expression of CD44 in murine hepatic progenitor cells 査読

Shinya Ohata, Makiko Nawa, Takeshi Kasama, Tokiwa Yamasaki, Kenji Sawanobori, Shoji Hata, Takashi Nakamura, Yoichi Asaoka, Toshio Watanabe, Hitoshi Okamoto, Takahiko Hara, Shuji Terai, Isao Sakaida, Toshiaki Katada, Hiroshi Nishina

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 379 ( 4 ) 817 - 823 2009年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE

The fetal liver serves as the predominant hematopoietic organ until birth. However, the mechanisms underlying this link between hematopoiesis and hepatogenesis are unclear. Previously, we reported the isolation of a monoclonal antibody (anti-Liv8) that specifically recognizes an antigen (Liv8) present in murine fetal livers at embryonic day 11.5 (E11.5). Liv8 is a cell surface molecule expressed by hematopoietic cells in both fetal liver and adult mouse bone marrow. Here, we report that Liv8 is also transiently expressed by hepatoblasts at E11.5. Using protein purification and mass spectrometry, we have identified Liv8 as the CD44 protein. Interestingly, the expression of Liv8/CD44 in fetal liver was completely lost in AML1(-/-) murine embryos, which lack definitive hematopoiesis. These results show that hepatoblasts change from Liv8/CD44-negative to Liv8/CD44-positive status in a hematopoiesis-dependent manner by E11.5, and indicate that Liv8/CD44 expression is an important link between hematopoiesis and hepatogenesis during fetal liver development. (C) 2008 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2008.12.149

On a diagnostic imaging teaching system for endoscopic education 査読

K. Ogashiwa, Y. Hamamoto, Y. Fujita, K. Murokawa, H. Yoneda, M. Saito, S. Terai, I. Sakaida

Proceedings of 1st Asia Pacific Conference on Health Promotion and Education 2009年1月

Continuos intravenous infusion of atrial natriuretic peptide(ANP) prevented liver fibrosis in rat 査読

Noriko Ishigaki, Naold Yamamoto, Haiyan Jin, Kouichi Uchida, Shuji Terai, Isao Sakaida

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 378 ( 3 ) 354 - 359 2009年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE

The atrial natriuretic peptide (ANP) are used as the acute heart failure treatment in clinical and reported the suppression of fibrosis in the heart, lung recently. The aim of this Study was to analyze the suppressive effect of liver fibrosis about ANP. In vitro, rat hepatic stellate cell line (HSC-T6) were treated with ANP. In vivo, Wister rats were injected with dimethylnitrosamine (DMN) twice a week via intra-peritoneal for 4 weeks. ANP group was given by continuance intravenous dosage system used 24 h infusion pump for 3 weeks after 1 week of DMN administration. In vitro, ANP suppressed alpha-SMA expression and was inhibited the growth of HSC, and reduced the expression of type 1 procollagen, TIMP-1, -2 expression. In vivo, The ANP group showed lower serum AST, ALT, HA level. Liver fibrosis was suppressed by ANP. ANP also decreased gene expression of type 1 procollagen, TIMP-1, -2 and alpha-SMA, TGF-beta 1 expression. Our results showed that continuous ANP infusion has the specific capacity of inhibiting HSC activation and protecting hepatocytes and the useful capacity to suppress the liver fibrosis. (C) 2008 Published by Elsevier Inc.

DOI： 10.1016/j.bbrc.2008.10.154

肝硬変症に対する自己骨髄細胞投与療法の現状と今後の展望

寺井崇二, 坂井田功

日本医科大学医学会雑誌 5 ( 1 ) 27 - 32 2009年

Current status of autologous bone marrow cell infusion therapy for liver cirrhosis patients 査読

Shuji Terai, Isao Sakaida

HEPATOLOGY RESEARCH 38 S72 - S75 2008年11月

記述言語：英語出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC

This article reviews recent translational research on the development of cell therapy using autologous bone marrow cell for liver cirrhosis patients. A clinical study of autologous bone marrow cell infusion (ABMI) therapy for liver cirrhosis patient was begun on Nov. 14, 2003. We previously reported nine liver cirrhosis (LC) cases that underwent ABMI from the peripheral vein and followed their progress up to 24 weeks. Subjects were LC patients with total bilirubin TB of < 3.0 mg/dL, platelets > 5 (10(10)/L) and no viable hepatocellular carcinoma on diagnostic imaging. Mononuclear cells (MNCs) were separated by cell washing and were infused via the peripheral vein. After ABMI therapy liver function and Child-Pugh Score were significantly improved at 4 weeks and 24 weeks (P < 0.05). A total of 23 cases of ABMI therapy have been performed for LC patients to date. No major adverse effects were noted due to ABMI therapy. In conclusion, ABMI therapy should be considered as a novel treatment for LC patients.

DOI： 10.1111/j.1872-034X.2008.00430.x

Relation between serum levels of cell-free DNA and inflammation status in hepatitis C virus-related hepatocellular carcinoma 査読

Michihisa Iida, Norio Iizuka, Isao Sakaida, Toyoki Moribe, Nozomi Fujita, Toshiaki Miura, Shigeru Tamatsukuri, Hideo Ishitsuka, Koichi Uchida, Shuji Terai, Yoshihiro Tokuhisa, Kazuhiko Sakamoto, Takao Tamesa, Takanobu Miyamoto, Yoshihiko Hamamoto, Masaaki Oka

ONCOLOGY REPORTS 20 ( 4 ) 761 - 765 2008年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPANDIDOS PUBL LTD

Our study revealed that the level of circulating cell-free DNA (cfDNA) is increased in the serum of patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). To gain insight into the mechanism underlying this phenomenon, we examined the association between cfDNA levels and various clinicopathological factors in 96 patients with HCV-related HCC and 99 non-HCC patients with HCV. Using pooled DNA microarray data, we profiled the expression patterns of inflammatory cytokine genes in 14 primary tumors from the group of HCC patients. We found that there were positive associations between the cfDNA level, aspartate aminotransferase levels and the number of leukocytes and neutrophils in patients with HCV-related HCC but not in non-HCC patients with HCV. The serum cfDNA level was not associated with other clinicopathological factors in HCC or non-HCC patients. A cluster analysis based on the inflammatory cytokine gene data revealed that HCCs with a high serum cfDNA level had increased levels of several inflammatory cytokine genes, suggesting that the serum cfDNA level is associated with the inflammatory status in primary tumors in HCV-related HCC.

DOI： 10.3892/or_00000071

消化器疾患の分子遺伝学的病態 HGF/c-Met signalingによるredox homeostasisの維持が肝発癌増殖を抑制する

高見太郎, 寺井崇二, 坂井田功

日本消化器病学会雑誌 105 ( 臨増大会 ) A672 - A672 2008年9月

Hepatocyte growth factor/c-met signaling pathwayの欠損はDEN誘発肝発癌早期段階を促進させる(Loss of hepatocyte growth factor/c-met signaling pathway accelerates early stages of DEN-induced hepatocarcinogenesis)

高見太郎, 内田耕一, 寺井崇二, 坂井田功

日本癌学会総会記事 67回 179 - 179 2008年9月

生活習慣病合併肝癌患者におけるHeat shock proteinおよび小胞体ストレス関連分子の発現の検討

大石俊之, 寺井崇二, 桑代紳哉, 松本俊彦, 坂井田功

肥満研究 14 ( Suppl. ) 202 - 202 2008年9月

メダカNASHモデルを用いた治療剤開発のストラテジー

寺井崇二, 桑代紳哉, 大石俊之, 松本俊彦, 坂井田功

肥満研究 14 ( Suppl. ) 189 - 189 2008年9月

メダカNASHモデルを用いたTelmisartanの効果検討

桑代紳哉, 寺井崇二, 大石俊之, 松本俊彦, 坂井田功

肥満研究 14 ( Suppl. ) 235 - 235 2008年9月

Pilot study of combination therapy with transcatheter arterial infusion chemotherapy using iodized oil and percutaneous radiofrequency ablation during occlusion of hepatic blood flow for hepatocellular carcinoma 査読

Ryt Shiraishi, Takahiro Yamasaki, Issei Saeki, Kohsuke Ok-Ita, Ytthki Yamaguchi, Koichi Uchida, Shuji Terai, Isao Salfaida

AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS 31 ( 4 ) 311 - 316 2008年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS

Objective: We have reported that radiofrequency (RF) ablation with balloon Occlusion of the hepatic artery (balloon-occluded RF ablation) increases the Coagulation area compared with standard RF ablation. In this study, We evaluated the efficacy and safety of combination therapy with transcatheter arterial infusion chemotherapy (TAI) using iodized oil and balloon-occluded RF ablation in patients with hepatocellular carcinoma
Patients and Methods: We studied 12 patients with 12 HCC nodules (mean tumor diameter, 27.3 mm). All patients were classified as Child-Pugh Class A. Immediately after TAI using iodized oil, we performed balloon-occluded RF ablation.
Results: One treatment session of the combination therapy was done for 10 of 12 nodules (83%). The greatest long-axis and short-axis dimensions of the area coagulated after the combination therapy were 48.8 +/- 5.5 mm and 41.9 +/- 4.1 mm, respectively. During follow-up (mean, 33.4 months), there was no local recurrence. The 1, 2, and 3-year survival rates were 100%, 92%, and 83%, respectively. No fatal complications were observed.
Conclusions: The combination therapy is an effective and safe treatment Under favorable liver reserve capacity. Using the combination therapy, it is possible to finish one treatment session for patients with HCC nodules measuring less than 3 cm in greatest dimension.

DOI： 10.1097/COC.0b013e31815e4539

c-Metシグナル伝達経路はredox制御機構の安定化から肝発癌増殖抑制作用を有する

高見太郎, 内田耕一, 寺井崇二, 坂井田功

G.I.Research 16 ( 4 ) 372 - 373 2008年8月

肝の発癌と進展における分子代謝学的研究 Hepatocyte growth factor(HGF)/c-met signaling pathwayの肝発癌機構における意義

高見太郎, 内田耕一, 寺井崇二, 坂井田功

肝臓 49 ( Suppl.1 ) A44 - A44 2008年4月

非アルコール性脂肪性肝疾患の病態と治療メダカモデルから人へ NASH治療剤の開発の新ストラテジー

寺井崇二, 松本俊彦, 坂井田功

肝臓 49 ( Suppl.1 ) A36 - A36 2008年4月

Increased expression of heat shock protein-binding protein 1 and heat shock protein 70 in human hepatocellular carcinoma tissues 査読

Yuichiro Yokoyama, Yasuhiro Kuramitsu, Motonari Takashima, Masanori Fujimoto, Norio Iizuka, Shuji Terai, Kiwamu Okita, Isao Sakaida, Masaaki Oka, Deborah A. Raynes, Vince Guerriero, Kazuyuki Nakamura

MOLECULAR MEDICINE REPORTS 1 ( 2 ) 197 - 201 2008年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPANDIDOS PUBL LTD

Heat shock protein-binding protein 1 (HspBP1) is a co-chaperone that inhibits heat shock 70-kDa protein (Hsp70) activity. In mouse neuroblastomas and lung tumors, the protein levels of HspBP1 and Hsp70 are elevated by a similar amount compared to non-tumor tissues. However, no studies have been reported regarding the levels of HspBP1 in human cancer tissues. Our previous proteomic study demonstrated that the expression of Hsp70 was increased in human hepatitis C virus-related hepatocellular carcinoma (HCV-HCC) tissues. Here, we investigated the expression of HspBP1 in human HCV-HCC. Immunoblotting analysis of HspBP1 and Hsp70 was performed in human HCV-HCC tissues from 20 patients. In 80% of the patients, Hsp70 increased an average of 3.55-fold, and in 50% of the patients, HspBP1 increased an average of 2.02-fold. Comparison and analysis of expression and clinical data revealed a significant difference between moderately-differentiated HCC and non-tumor tissues. In addition, there was a significant difference between the ratio of HspBP1 to Hsp70 levels and tumor size (<3 cm vs. >= 3cm) with larger tumors having a lower ratio. This ratio was significantly lower in moderately-differentiated HCC tissues than in non-tumor HCC tissues. In conclusion, HspBP1 was up-regulated in human HCV-HCC, an increase which correlated with the increase of Hsp70 levels. The ratio of HspBP1 to Hsp70 in HCC may provide novel information concerning the characterization of tumors, tumor progression and resistance to treatment.

Continuous high expression of XBP1 and GRP78 is important for the survival of bone marrow cells in CCl4-treated cirrhotic liver 査読

Yoshio Marumoto, Shuji Tera, Yohei Urata, Toshihiko Matsumoto, Yuko Mizunaga, Naoki Yamamoto, Haiyan Jina, Koichi Fujisawa, Tomoaki Murata, Koh Shinoda, Hiroshi Nishina, Isao Sakaida

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 367 ( 3 ) 546 - 552 2008年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE

We have previously shown that infusion of bone marrow cells (BMC) improves CCl4-induced cirrhosis. However, it is unclear why the injected BMC are resistant to CCl4 damage and subsequently improve the local microenvironment in damaged liver. To analyze the cellular phenomena involved in this process, we studied the damaged liver using electron microscopy. We found that CCl4 caused rough endoplasmic reticula to swell in hepatocytes. To analyze the gene expression patterns associated with this process, we conducted PCR-selected suppressive subtractive hybridization. We found that expression levels of HSP84, HSP40, and XBP1 differed markedly between control liver and liver infused with BMC. Immunohistochemical staining revealed that expression levels of HSP84 and HSP40 were markedly higher in the early phase of differentiation immediately after BMC infusion, but decreased over time. XBP1 expression remained high during the late phase, and GRP78 expression increased with XBP1 activation. We also found that GFP-positive BMC expressed XBP1 and GRP78. XBP1 and GRP78 are associated with ER stress. Thus, continuous high XBP1 and GRP78 expression might be essential for the survival and proliferation of BMC in a CCl4-induced persistent liver damage environment. (C) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2007.12.171

A new hepatic encephalopathy model to monitor the change of neural amino acids and astrocytes with behaviour disorder 査読

Yumiko Isobe-Harima, Shuji Terai, Izumi Miura, Makoto Segawa, Tomoaki Murata, Kazuhito Itamoto, Yasuho Taura, Koh Shinoda, Isao Sakaida

LIVER INTERNATIONAL 28 ( 1 ) 117 - 125 2008年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BLACKWELL PUBLISHING

Background/Aims: To elucidate the pathogenesis of hepatic encephalopathy (HE), we developed a new HE model with behaviour disorder. Methods: Male Wistar rats were divided into four treatment groups: a HE model: acetaminophen (APAP)+3-methylcholanthrene (3-MC) group (APAP+MC group); control group: acetaminophen group; 3-methylcholanthrene group; and a no-treatment group. We monitored the changes of neural amino acids in the synaptic cleft and astrocytes in the brain during behaviour disorder. Results: In the APAP+MC group, alanine amino transferase, blood ammonia and glucose increased from 3 h and total bilirubin increased at 6 h. Prothrombin time was prolonged from 3 h in the APAP+MC group. The APAP+MC group exhibited centrilobular necrosis in the liver after 8 h. In the APAP+MC group, rats jumped vertically and this vertical activity increased significantly from 4 to 7 h. During the behaviour disorder, we found that glutamate and aspartate increased in the synaptic cleft from 4 h after treatment with APAP+3-MC, glutamate increased 23.9-fold at 7 h and aspartate increased 16.1-fold at 4 h, whereas glutamine did not change. At that time, we observed morphological changes of the astrocytes by immunostaining for the glial fibrillary acidic protein. Conclusion: Our new HE model demonstrated that increased excitatory neural amino acids and morphological change in astrocytes were involved in the behaviour disorder that occurs with HE.

DOI： 10.1111/j.1478-3231.2007.01589.x

Serum S100b (astrocyte-specific protein) is a useful marker of hepatic encephalopathy in patients with fulminant hepatitis 査読

Yumiko Isobe-Harima, Shuji Terai, Makoto Segawa, Koichi Uchida, Takahiro Yamasaki, Isao Sakaida

LIVER INTERNATIONAL 28 ( 1 ) 146 - 147 2008年1月

FibroScanを用いた食道静脈瘤の存在診断の現状

瀬川誠, 寺井崇二, 山崎隆弘, 坂井田功

日本門脈圧亢進症学会雑誌 14 ( 4 ) 313 - 316 2008年

記述言語：日本語出版者・発行元：日本門脈圧亢進症学会

肝硬変の診断方法として, 肝臓の硬さの診断は, 主として触診によってなされてきたが, 最近の技術の進歩により, 超音波を用いて非侵襲的に肝臓の硬さ (肝硬度, 肝弾性値) を測定する機器 (FibroScan) が臨床応用され, 肝線維化の進行と肝弾性値が相関することが明らかとなり, 肝線維化の非侵襲的な評価方法として確立しつつある.一方で, 肝弾性値は, 肝線維化などの静的因子に加え, 血流, 炎症, 胆汁鬱滞などの動的因子も関与していることが明らかになってきた.肝弾性値と門脈圧との関連性が検討されつつあり, 肝弾性値測定による門脈圧亢進症診断への応用が試みられている.肝弾性値測定により, 門脈圧亢進症の合併症である食道静脈瘤の存在診断が可能となれば, 現在肝硬変患者に対しての非侵襲的な定期検査の実施も期待できる.本総説では, 肝弾性値測定による門脈圧亢進症診断に関する現状を述べる.

DOI： 10.11423/jsph1999.14.4_313

その他リンク： http://search.jamas.or.jp/link/ui/2009287768

Telmisartan prevents hepatic fibrosis and enzyme-altered lesions in liver cirrhosis rat induced by a choline-deficient L-amino acid-defined diet 査読

Haiyan Jin, Naoki Yamamoto, Koichi Uchida, Shuji Terai, Isao Sakaida

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 364 ( 4 ) 801 - 807 2007年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE

Rennin-angiotensin system is involved in liver fibrogenesis through activating hepatic stellate cells (HSCs). Telmisartan (Tel) is an angiotensin II type 1 receptor antagonist, could function as a selective peroxisome proliferator-activated receptor gamma activator. Here we studied the effect of Tel on liver fibrosis, pre-neoplastic lesions in vivo and primary HSCs in vitro. In vivo study, we used the choline-deficient L-amino acid-defined (CDAA)-diet induced rat NASH model. The rats were fed the CDAA diet for 8 weeks to induce liver fibrosis and pre-neoplastic lesions, and then co-administrated with Tel for another 10 weeks. Tel prevented liver fibrogenesis and pre-neoplastic lesions by down-regulating TGF beta 1 and TIMP-1, 2 and increasing MMP-13 expression. Tel inhibited HSCs activation and proliferation. These results suggested that Tel could be a promising drug for NASH related liver fibrosis. (C) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2007.10.083

強皮症に肝細胞癌と乳癌を合併した一例

佐伯一成, 是永匡紹, 岩本拓也, 松本俊彦, 瀬川誠, 山口裕樹, 是永圭子, 内田耕一, 寺井崇二, 山崎隆弘, 為佐卓夫, 岡正朗, 坂井田功

肝臓 48 ( Suppl3 ) A622 - A622 2007年11月

NASHにおける肝線維化と発癌をめぐって耐糖能異常は脂肪肝症例における肝線維化・発癌のリスクファクターの可能性がある

松本俊彦, 寺井崇二, 坂井田功

肝臓 48 ( Suppl3 ) A514 - A514 2007年11月

The development of new drug screening system using steatohepatitis medaka fish model induced by high-fat diet 査読

Matsumoto Toshihiko, Terai Shuji, Kuwashiro Shinya, Fujisawa Koichi, Yamamoto Naoki, Hamamoto Yoshihiko, Sakaida Isao

HEPATOLOGY 46 ( 4 ) 756A 2007年10月

Is an arterial infusion chemotherapy with pegylated interferon-alpha-2b effective for advanced hepatocellular carcinoma? 査読

Yamasaki Takahiro, Saeki Issei, Okita Kousuke, Yamaguchi Yuhki, Uchida Koichi, Terai Shuji, Sakaida Isao

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 22 A193 2007年10月

肝の再生医学・医療/人工肝臓の現状と展望肝硬変症に対する自己骨髄細胞投与療法(ABMI療法)の現状および今後の工夫について

寺井崇二, 丸本芳雄, 坂井田功

肝臓 48 ( Suppl.2 ) A357 - A357 2007年9月

メダカNASHモデルにおける病態解析

松本俊彦, 寺井崇二, 坂井田功

肝臓 48 ( Suppl.2 ) A474 - A474 2007年9月

Importance of inhibitor of DNA binding/differentiation 2 in hepatic stellate cell differentiation and proliferation 査読

Kunihiko Tajima, Shuji Terai, Taro Takami, Kotaro Kawaguchi, Kiwamu Okita, Isao Sakaida

HEPATOLOGY RESEARCH 37 ( 8 ) 647 - 655 2007年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BLACKWELL PUBLISHING

Background/Aim: in liver fibrosis, activated hepatic stellate cells (HSC) are transformed into myofibroblasts. Helix-loop-helix (HLH) transcriptional factors such as MyoD regulate the differentiation of myocytes, and the inhibitor of DNA binding/ differentiation (Id) family comprises dominant negative HLH transcriptional regulators that inhibit differentiation and promote cell proliferation. In the present study, we investigated how the Id family proteins regulate HSC.
Methods: in primary rat HSC, inhibitor of DNA binding/ differentiation (ld)2 and alpha-smooth muscle actin (alpha-SIVIA) mRNA expression increased 4 days after isolation. Next we established ld2 expressing HSC (HSC-T6-Id2-green fluorescent protein (GFP)) using HSC-T6 cells with retrovirus that expressed GFP-tagged ld2.
Results: HSC-T6-Id2-GFP increased cell proliferation with cyclin D1 expression. In contrast, alpha-SMA expression was suppressed. Real-time reverse transcri ption-polym erase chain reaction analysis showed ld2 induction significantly suppressed alpha-SMA, collagen-1, matrix metalloproteinase (MMP)-2, and MMP-9 mRNA (P < 0.05) but had no effect on tissue inhibitor of metalloproteinase or transforming growth factor-beta 1 levels.
Conclusion: These findings suggest ld2, an HLH transcriptional regulator, plays an important regulatory role in the proliferation and differentiation of HSC.

DOI： 10.1111/j.1872-034X.2007.00089.x

The iron chelator deferoxamine causes activated hepatic stellate cells to become quiescent and to undergo apoptosis 査読

Haiyan Jin, Shuii Terai, Isao Sakaida

JOURNAL OF GASTROENTEROLOGY 42 ( 6 ) 475 - 484 2007年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER TOKYO

Background. Hepatic stellate cells (HSCs) play a pivotal role in liver fibrogenesis. Here, we studied whether the iron chelator deferoxamine (DFO) affected cultured HSC activation and apoptosis. Methods. The effect of DFO on HSCs was investigated using quiescent and activated stellate cells. Results. Treatment with DFO inhibited HSC activation, resulting in the reduced expression of a-smooth muscle actin protein and type I procollagen, matrix metalloproteinase-2 and -9, and tissue inhibitors of metalloproteinase-1 and -2 mRNAs. DFO induced apoptosis of activated HSCs, which was associated with decreasing Bcl-2 expression and the release of cytochrome c from the mitochondria to the cytosol with enhanced caspase-3 activity. DFO also induced activated HSCs to express peroxisome proliferator-activated receptor gamma with the reaccumulation of intracellular lipids. Conclusions. The iron chelation of stellate cells inhibits their activation, causing them to become deactivated as well as to undergo apoptosis. These data suggest a potential role for an iron chelation treatment of liver fibrosis.

DOI： 10.1007/s00535-007-2020-5

[Candidate drugs for non-alcoholic steatohepatitis (NASH)]. 査読

Terai S, Matsumoto T, Sakaida I

Nihon yakurigaku zasshi. Folia pharmacologica Japonica 129 ( 4 ) 271 - 275 2007年4月

記述言語：日本語出版者・発行元：公益社団法人日本薬理学会

非アルコール性脂肪性肝炎（NASH）は肝硬変症に進行する病態であり，その病態としてFree fatty acid（FFA），Tumor necrosis factor-α（TNF-α），レプチン，レジスチンの上昇とアディポネクチンの低下が報告されている．これらの変化は体重の減量によって可逆的で，NASHの改善につながることが知られているが，実際には生活習慣の改善が難しい症例が多く，NASHの病態から考えた薬物療法が必要とされている．薬物療法は4つの方向性が考えられる．(1)インスリン抵抗性の改善（インスリン抵抗性改善薬），(2)脂肪酸生合成の抑制と肝内に蓄積した脂肪酸の燃焼（高脂血症薬），(3)脂肪酸の代謝過程で生じた酸化ストレスからの保護（抗酸化剤や肝庇護剤）である．(4)さらに抗NASH作用を持つアディポネクチンのレセプターに対するアゴニストや抗TNF-α剤なども，今後，検討すべきだろう．また，肝線維化抑制の側面より，アンジオテンシンIIレセプター拮抗薬が，NASHにおける肝線維化抑制薬として作用する可能性が期待される．<br>

DOI： 10.1254/fpj.129.271

その他リンク： https://jlc.jst.go.jp/DN/JALC/00291948050?from=CiNii

治療薬シリーズ高脂血症非アルコール性脂肪性肝疾患、肝炎に対する薬物療法について

寺井崇二, 松本俊彦, 坂井田功

日本薬理学雑誌 129 ( 4 ) 271 - 275 2007年4月

記述言語：日本語出版者・発行元：(公社)日本薬理学会

非アルコール性脂肪性肝炎(NASH)は肝硬変症に進行する病態であり、その病態としてFree fatty acid(FFA),Tumor necrosis factor-α(TNF-α)、レプチン、レジスチンの上昇とアディポネクチンの低下が報告されている。これらの変化は体重の減量によって可逆的で、NASHの改善につながることが知られているが、実際には生活習慣の改善が難しい症例が多く、NASHの病態から考えた薬物療法が必要とされている。薬物療法は4つの方向性が考えられる。(1)インスリン抵抗性の改善(インスリン抵抗性改善薬)、(2)脂肪酸生合成の抑制と肝内に蓄積した脂肪酸の燃焼(高脂血症薬)、(3)脂肪酸の代謝過程で生じた酸化ストレスからの保護(抗酸化剤や肝庇護剤)である。(4)さらに抗NASH作用を持つアディポネクチンのレセプターに対するアゴニストや抗TNF-α剤なども、今後、検討すべきだろう。また、肝線維化抑制の側面より、アンジオテンシンIIレセプター拮抗薬が、NASHにおける肝線維化抑制薬として作用する可能性が期待される。(著者抄録)

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2007&ichushi_jid=J01200&link_issn=&doc_id=20070406440007&doc_link_id=10019563323&url=https%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F10019563323&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

Administration of fibroblast growth factor 2 in combination with bone marrow transplantation synergistically improves carbon-tetrachloride-induced liver fibrosis in mice 査読

Tsuyoshi Ishikawa, Shuji Terai, Yohei Urata, Yoshio Marumoto, Koji Aoyama, Tomoaki Murata, Yuko Mizunaga, Naoki Yamamoto, Hiroshi Nishina, Koh Shinoda, Isao Sakaida

CELL AND TISSUE RESEARCH 327 ( 3 ) 463 - 470 2007年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER

We previously reported that fibroblast growth factor 2 (FGF2) facilitated the differentiation of transplanted bone marrow cells (BMCs) into hepatocytes. Our earlier study also demonstrated that administration of FGF2 in combination with bone marrow transplantation (BMT) synergistically activated tumor necrosis factor-alpha signaling and significantly improved liver function and prognosis more than BMT alone. However, the way that it affected the extracellular matrix remained unclear. Here, we investigated the effect of FGF2 treatment together with BMT on liver fibrosis in mice treated with carbon tetrachloride (CCl4). Transplantation of BMCs and concurrent treatment with FGF2 caused a statistically significant reduction in CCl4-induced liver fibrosis that was accompanied by strong expression of matrix metalloproteinase 9 as compared with FGF2-only treatment or BMT alone. Moreover, in this process, the proliferation of bone-marrow-derived cells was accelerated without causing apoptosis. Thus, the administration of FGF2 in combination with BMT synergistically improves CCl4-induced liver fibrosis in mice. This treatment has the potential of being an effective therapy for patients with liver cirrhosis.

DOI： 10.1007/s00441-006-0334-x

Circulating cell-free DNA as a predictive marker for distant metastasis of hepatitis C virus-related hepatocellular carcinoma 査読

Tokuhisa, Y., Iizuka, N., Sakaida, I., Moribe, T., Fujita, N., Miura, T., Tamatsukuri, S., Ishitsuka, H., Uchida, K., Terai, S., Sakamoto, K., Tamesa, T., Oka, M.

British Journal of Cancer 97 ( 10 ) 1399 - 1403 2007年

Elevated levels of circulating cell-free DNA in the blood of patients with hepatitis C virus-associated hepatocellular carcinoma 査読

Norio Iizuka, Isao Sakaida, Toyoki Moribe, Nozomi Fujita, Toshiaki Miura, Markus Stark, Shigeru Tamatsukuri, Hideo Ishitsuka, Koichi Uchida, Shuji Terai, Kazuhiko Sakamoto, Takao Tamesa, Masaaki Oka

ANTICANCER RESEARCH 26 ( 6C ) 4713 - 4719 2006年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：INT INST ANTICANCER RESEARCH

Background: Circulating cell-free DNA is present in increased amounts in the blood of patients with one of several forms of cancer. Materials and Methods: A real-time PCR assay with glutathione S-transferase pi (GSTP1) gene was used to measure cell-free DNA levels in the sera of 52 patients with hepatocellular carcinoma (HCC) associated with hepatitis C virus (HCV), which included 30 HCV carriers without known HCC and 16 HCV-negative non-cancer patients (controls). Results: Cell-free DNA levels were significantly higher in the sera from HCC patients than in the sera from HCV carriers or the control subjects. Cell-free DNA levels were associated with the degree of tumor differentiation and size but not patient age, gender, TNM stage or levels of alpha-fetoprotein (AFP) or protein induced by vitamin K absence (PIVKA-II). The cell-free DNA assay had a sensitivity of 69.2% and a specificity of 93.3% in discriminating HCC and HCV carriers at the optimal cut-off value of 73.0 ng/ml, with an area of 0.90 (95% CI 0.83-0.96) under the receiver operating characteristic curve. The discriminative power of cell-free DNA was superior to that of AFP or PIM-II. Conclusion: Our results showed that levels of circulating cell-free DNA are significantly increased in sera of patients with HCV-associated HCC, suggesting that circulating cell-free DNA may be a good biomarker specific for HCV-associated HCC.

Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy 査読

Shuji Terai, Tsuyoshi Ishikawa, Kaoru Omori, Koji Aoyama, Yoshio Marumoto, Yohei Urata, Yuichirou Yokoyama, Koichi Uchida, Takahiro Yamasaki, Yasuhiko Fujii, Kiwamu Okita, Isao Sakaida

STEM CELLS 24 ( 10 ) 2292 - 2298 2006年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ALPHAMED PRESS

We here report nine liver cirrhosis (LC) patients that underwent autologous bone marrow cell infusion (ABMI) from the peripheral vein. Subjects were patients with LC with total bilirubin of less than 3.0 mg/dl, platelet count of more than 5 (10(10)/l), and no viable hepatocellular carcinoma on diagnostic imaging. Autologous bone marrow (BM; 400 ml) was isolated from the ilium under general anesthesia. Mononuclear cells (MNCs) were separated by cell washing and were infused via the peripheral vein. MNC characteristics were confirmed by fluorescence-activated cell sorting analysis (CD34, CD45, and c-kit). After ABMI therapy, liver function was monitored by blood examination for 24 weeks. From 400 ml of BM, we obtained 7.81 +/- 0.98 x 10(9) MNCs. After washing, 5.20 +/- 0.63 x 10(9) MNCs were infused into patients with LC. Significant improvements in serum albumin levels and total protein were observed at 24 weeks after ABMI therapy (p <.05). Significantly improved Child-Pugh scores were seen at 4 and 24 weeks (p <.05). a-Fetoprotein and proliferating cell nuclear antigen (PCNA) expression in liver biopsy tissue was significantly elevated after ABMI therapy (p <.05). No major adverse effects were noted. In conclusion, ABMI therapy should be considered as a novel treatment for patients with decompensated LC.

DOI： 10.1634/stemcells.2005-0542

【消化器疾患 state of arts II.肝・胆・膵】治療法をめぐる最近の進歩肝再生医療の現況と展望細胞療法を用いた肝再生医療自己骨髄細胞を用いた肝再生療法の開発

丸本芳雄, 寺井崇二, 坂井田功

医学のあゆみ別冊 ( 消化器疾患Ver.3 ) 495 - 498 2006年10月

rFGF2併用骨髄移植の肝線維化改善効果とその分子制御機構

石川剛, 寺井崇二, 坂井田功

肝臓 47 ( Suppl.2 ) A477 - A477 2006年9月

消化器疾患の再生医療自己骨髄細胞を用いた肝臓再生療法の現状と今後の展開

寺井崇二, 石川剛, 坂井田功

日本消化器病学会雑誌 103 ( 臨増大会 ) A413 - A413 2006年9月

Proteomic analysis of serum marker proteins in recipient mice with liver cirrhosis after bone marrow cell transplantation 査読

Y Yokoyama, S Terai, T Ishikawa, K Aoyama, Y Urata, Y Marumoto, N Hiroshi, K Nakamura, K Okita, Sakaida, I

PROTEOMICS 6 ( 8 ) 2564 - 2570 2006年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-V C H VERLAG GMBH

We previously found that transplantation with bone marrow cells (BMCs) improves liver function and liver fibrosis in cirrhotic mice. In the presence of liver damage induced by carbon tetrachloride (CCI4), transplanted BMC migrated into the peri-portal region and trans-differentiated into hepatocytes that produce albumin. Thus under these conditions, BMC transplantation induces liver regeneration. Detecting serum marker proteins is important to monitor the recovery of liver function of cirrhotic mice after BMC transplantation. We therefore initially resolved proteins extracted from serum samples at 48 h after BMC transplantation by 2-DE and compared spot intensity between control and BMC groups of mice. Six protein spots increased in the BMC group compared with the control group. MS revealed that these spots comprised apolipoprotein A1 (apoA1), apolipoprotein C3 (apoC3), vitamin D-binding protein, alpha-l-antitrypsin and proteasome subunit alpha type 1. We subsequently confirmed the levels of apoA1 in serum and liver samples by immunoblotting. ApoA1 increased at early stage (48 h and 1 wk) after BMC transplantation in this mouse model of liver cirrhosis. The early elevation of apoA1 might be useful to predict liver regeneration in cirrhotic mice after BMC transplantation.

DOI： 10.1002/pmic.200500018

XBP-1は骨髄細胞から肝細胞への分化に関与する

丸本芳雄, 寺井崇二, 水永裕子, 松本俊彦, 浦田洋平, 青山浩司, 石川剛, 坂井田功

肝臓 47 ( Suppl.1 ) A292 - A292 2006年4月

メダカを用いた新規脂肪肝モデルの作成と,脂肪肝形成過程における遺伝子発現の検討

松本俊彦, 寺井崇二, 丸本芳雄, 仁科博史, 坂井田功

肝臓 47 ( Suppl.1 ) A97 - A97 2006年4月

肝線維化の分子機構と治療 rFGF2併用骨髄移植の肝線維化改善効果とその分子制御機構

石川剛, 寺井崇二, 坂井田功

肝臓 47 ( Suppl.1 ) A41 - A41 2006年4月

Protein level of apolipoprotein E increased in human hepatocellular carcinoma 査読

Y Yokoyama, Y Kuramitsu, M Takashima, N Iizuka, S Terai, M Oka, K Nakamura, K Okita, Sakaida, I

INTERNATIONAL JOURNAL OF ONCOLOGY 28 ( 3 ) 625 - 631 2006年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PROFESSOR D A SPANDIDOS

Many reports suggest that hepatic steatosis leads to hepatocellular carcinoma (HCC), including hepatitis C virus or non-alcoholic steatollepatitis. Proteomic study Of tumor tissues from HCC patients, focusing oil apolipoprotein (apo) of apoA1, apoB 100 and apoE, was performed by immunoblotting. Although the significant changes of apoA1 or apoB 100 could not be shown statistically, the irninunoblotting showed the increase in protein level of apoE in the tumor tissues of 88% of patients without increase of apoE gene expression and serum level. These results suggest the accumulation of apoE by impaired secretion. Moreover, immunoblot analysis oil twodimensional electrophoresis showed a strong possibility that sialylated forms of apoE also were increased in tumorous tissues of HCC. ApoE level in tumorous tissues is frequently elevated and may be a good histological marker for HCC.

炎症と発癌肝持続炎症環境下における小胞体ストレス関連分子XBP-1とHSPの発現についての解析

丸本芳雄, 寺井崇二, 坂井田功

日本消化器病学会雑誌 103 ( 臨増総会 ) A127 - A127 2006年3月

Fibroblast growth factor 2 facilitates the differentiation of transplanted bone marrow cells into hepatocytes 査読

T Ishikawa, S Terai, Y Urata, Y Marumoto, K Aoyama, Sakaida, I, T Murata, H Nishina, K Shinoda, S Uchimura, Y Hamamoto, K Okita

CELL AND TISSUE RESEARCH 323 ( 2 ) 221 - 231 2006年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER

We have developed an in vivo mouse model, the green fluorescent protein (GFP)/carbon tetrachloride (CCl4) model, and have previously reported that transplanted GFP-positive bone marrow cells (BMCs) differentiate into hepatocytes via hepatoblast intermediates. Here, we have investigated the growth factors that are closely related to the differentiation of transplanted BMCs into hepatocytes, and the way that a specific growth factor affects the differentiation process in the GFP/CCl4 model. We performed immunohistochemical analysis to identify an important growth factor in our model, viz., fibroblast growth factor (FGF). In liver samples, the expression of FGF1 and FGF2 and of FGF receptors (FGFRs; FGFR1, FGFR2) was significantly elevated with time after bone marrow transplantation (BMT) compared with other factors, and co-expression of GFP and FGFs or FGFRs could be detected. We then analyzed the effect and molecular mechanism of FGF signaling on the enhancement of BMC differentiation into hepatocytes by immunohistochemistry, immunoblotting, and microarray analysis. Treatment with recombinant FGF (rFGF), especially rFGF2, elevated the repopulation rate of GFP-positive cells in the liver and significantly increased the expression of both Liv2 (hepatoblast marker) and albumin (hepatocyte marker). Administration of rFGF2 at BMT also raised serum albumin levels and improved the survival rate. Transplantation of BMCs with rFGF2 specifically activated tumor necrosis factor-alpha (TNF-alpha) signaling. Thus, FGF2 facilitates the differentiation of transplanted BMCs into albumin-producing hepatocytes via Liv2-positive hepatoblast intermediates through the activation of TNF-alpha signaling. Administration of FGF2 in combination with BMT improves the liver function and prognosis of mice with CCl4-induced liver damage.

DOI： 10.1007/s00441-005-0077-0

【ここまで進んだ幹細胞研究と再生医療2006 幹細胞の分化を運命づけるメカニズムから臨床応用の取り組み,産業化の展望まで】幹細胞の臨床応用ここまで来ている再生医療自己骨髄細胞を用いた肝臓再生療法の開発基礎研究から臨床研究へ

石川剛, 寺井崇二, 坂井田功

実験医学 24 ( 2 ) 268 - 273 2006年1月

記述言語：日本語出版者・発行元：(株)羊土社

難治性肝疾患に対する新たな治療法の開発を目指して,われわれは骨髄幹細胞の可塑性に着目し基礎研究を進めてきた.慢性炎症という特殊環境下(分化Niche)において骨髄細胞が肝細胞へと分化し,さらにその過程で肝合成能・肝線維化・生命予後が有意に改善するという動物実験の結果を基盤として,われわれは2003年11月より国内初の臨床研究「自己骨髄細胞を用いた肝臓再生療法」を開始するに至った.今後より効率の良い治療法の開発に向けてさらなる基礎・臨床研究を重ね,詳細な解析・検討を進めていこうと考えている(著者抄録)

脂肪肝に対するイコサペント酸エチル(エパデールS)の有用性の検討

松本俊彦, 寺井崇二, 坂井田功

肝臓 46 ( Suppl.3 ) A562 - A562 2005年11月

急性肝不全における肝再生療法の現状 rFGF2併用骨髄移植による肝障害改善効果とその分子制御機構

石川剛, 寺井崇二, 坂井田功, 沖田極

肝臓 46 ( 11 ) 678 - 678 2005年11月

肝病変進展抑制をめざす新しい視点基礎と臨床 rFGF2併用骨髄移植による肝病変改善効果とその分子制御機構

石川剛, 寺井崇二, 沖田極

日本消化器病学会雑誌 102 ( 臨増大会 ) A574 - A574 2005年9月

肝病変進展抑制をめざす新しい視点基礎と臨床 rFGF2併用骨髄移植による肝病変改善効果とその分子制御機構

石川剛, 寺井崇二, 沖田極

肝臓 46 ( Suppl.2 ) A374 - A374 2005年9月

Leptin enhances TNF-alpha production via p38 and JNK MAPK in LPS-stimulated Kupffer cells 査読

JH Shen, Sakaida, I, K Uchida, S Terai, K Okita

LIFE SCIENCES 77 ( 13 ) 1502 - 1515 2005年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

Leptin is now recognized as a proinflammatory cytokine and thought to be a progressive factor for nonalcoholic steatohepatitis (NASH). Here we showed the effects of leptin on the production of TNF-alpha(tumor necrosis factor-alpha) by Kupffer cells (KCs) with signal transduction. Leptin enhanced TNF-alpha production accompanied by a dose-dependent increase of MAPK activity in lipopolysaccharide (LPS)-stimulated KCs. SB203580 and JNK inhibitor I, specific inhibitors of P38 and JNK, inhibited TNF-alpha production in KCs but PD98059, an inhibitor of the ERK pathway, did not affect TNF-alpha production by KCs. Recombinant constitutively active adenovirus (Ad)-MKK6 and-MKK7 increased TNF-alpha production in KCs with activation of P38 and JNK without any change by Ad-MEK1 delivery. On the other hand, KCs isolated from the Zucker rat (fa/fa), a leptin receptor-deficient rat, showed reduced production of TNF-alpha on stimulation with LPS. The delivery of Ad-MKK6 and-MKK7, but not Ad-MEK1, increased TNF-alpha production in KCs of Zucker rats with activation of P38 and JNK. Addition of leptin to normal rats increased LPS-induced hepatic TNF-alpha production in vivo and leptin receptor-deficient Zucker rats showed reduced hepatic TNF-alpha production on addition of LPS in vivo. These findings indicate that P38 and JNK pathways are involved in the signal transduction of leptin enhancement of LPS-induced TNF-alpha production. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.lfs.2005.04.004

Human homologue of maid is a useful marker protein in hepatocarcinogenesis 査読

T Takami, S Terai, Y Yokoyama, H Tanimoto, K Tajima, K Uchida, T Yamasaki, Sakaida, I, H Nishina, SS Thorgeirsson, K Okita

GASTROENTEROLOGY 128 ( 5 ) 1369 - 1380 2005年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：W B SAUNDERS CO

Background & Aims: Human homologue of maid (HHM) is a helix-loop-helix (HLH) transcriptional regulatory protein that is involved in the hepatic stem cell development and differentiation. We analyzed the potential involvement of HHM in hepatocarcinogenesis. Methods: We analyzed HHM expression in the choline-deficient L-amino acid defined (CDAA) diet model of rat hepatocarcinogenesis and in human adenomatous hyperplasia (AH) and hepatocellular carcinoma (HCC) biopsy samples. We assessed the effects of HHM on cell proliferation. We screened proteins that bind to HHM protein using a yeast 2-hybrid screen. Results: High HHM expression was seen in foci and HCC induced in the rat CDAA diet model. HHM protein was expressed in 23 of 32 AH samples (72%), 19 of 28 well-differentiated HCC samples (68%), and 9 of 18 poorly-moderately differentiated HCC samples (50%). Over-expressed HHM enhanced the S phase. HHM interference RNA significantly inhibited cell proliferation. A yeast 2-hybrid screen identified Jun activation domain-binding protein I (Jab1) as a binding partner for HHM. We confirmed HHM and Jab1 binding by immunoprecipitation and immunofluorescent histochemistry. The expression of Jab1 was found in human AH and HCC samples. We found an association between levels of expression of HHM and those of Jabl in AH and HCC tissues examined (P =.027 by χ(2) test). Conclusions: High-level HHM expression was found from the very early stages of hepatocarcinogenesis, suggesting that HHM may be a useful marker protein to detect.

DOI： 10.1053/j.gastro.2005.03.014

レトロウイルスベクターを用いたId2持続強制発現HSc-T6での線維化抑制の検討

田島邦彦, 寺井崇二, 金海燕, 磯部夕美子, 松本俊彦, 浦田洋平, 丸本芳雄, 川口浩太郎, 高見太郎, 土屋昌子, 内田耕一, 坂井田功, 沖田極

肝臓 46 ( Suppl.1 ) A68 - A68 2005年5月

骨髄細胞から肝細胞への分化過程における線維芽細胞増殖因子の促進効果

石川剛, 寺井崇二, 磯部夕美子, 松本俊彦, 浦田洋平, 丸本芳雄, 青山浩司, 大森薫, 坂井田功, 沖田極

肝臓 46 ( Suppl.1 ) A157 - A157 2005年5月

Liv-8陰性分画骨髄細胞移植による肝線維化改善時における,ECM関連遺伝子群の経時的発現変化の検討

青山浩司, 坂井田功, 磯部夕美子, 松本俊彦, 浦田洋平, 丸本芳雄, 石川剛, 大森薫, 寺井崇二, 沖田極

肝臓 46 ( Suppl.1 ) A71 - A71 2005年5月

PCR-selected cDNA subtractionシステムを用いた骨髄細胞から肝細胞への分化制御遺伝子の検索

丸本芳雄, 寺井崇二, 松本俊彦, 浦田洋平, 青山浩司, 石川剛, 大森薫, 坂井田功, 仁科博史, 沖田極

肝臓 46 ( Suppl.1 ) A101 - A101 2005年5月

臨床研究(自己骨髄細胞を用いた肝臓再生療法)の途中経過と頻回骨髄細胞の投与法への工夫

寺井崇二, 大森薫, 石川剛, 青山浩司, 浦田洋平, 丸本芳雄, 坂井田功, 沖田極

肝臓 46 ( Suppl.1 ) A57 - A57 2005年5月

骨髄幹細胞移植による肝疾患の治療

沖田極, 寺井崇二, 坂井田功

日本内科学会雑誌 94 ( 4 ) 769 - 774 2005年4月

記述言語：日本語出版者・発行元：The Japanese Society of Internal Medicine

骨髄には造血幹細胞が存在し白血病患者に対する骨髄移植によって患者の体内で一生に渡り血球細胞を供給することが可能である.骨髄移植は既に20年以上の実績を積んだ体性幹細胞を用いた再生医療である.最近になり男女間での骨髄移植の結果,骨髄由来の肝細胞,小腸細胞への分化が確認され,骨髄中に多分化能を持つ"骨髄由来幹細胞"の存在が考えられるようになった.すでに循環器領域では虚血性疾患に対して臨床応用として血管新生を誘導するために自己の骨髄細胞を患部に自家移植する試みがすでに行われてきた.我々は自己骨髄細胞を用いた肝臓再生療法を開発するため,どんな状況で骨髄細胞移植が有効であるかを検討し,持続肝障害が続く状態において骨髄細胞が肝再生誘導,肝線維化制御に役立つことを見出した.さらにそれらの基礎研究の結果を基盤とし,国内最初の臨床研究:自己骨髄細胞を用いた肝臓再生療法のPhasel研究を平成15年11月より開始し現在進行中である.

DOI： 10.2169/naika.94.769

その他リンク： https://jlc.jst.go.jp/DN/JALC/00249900949?from=CiNii

Use of bone marrow cells for the development of cellular therapy in liver diseases 査読

Sakaida, I, S Terai, K Okita

HEPATOLOGY RESEARCH 31 ( 4 ) 195 - 196 2005年4月

Treatment of hepatic diseases with bone marrow stem cell transplantation 査読

Okita, K., Terai, S., Sakaida, I.

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 94 ( 4 ) 769 - 774 2005年4月

消化器領域における細胞増殖因子と組織再生療法を目指したニューフロンティア基礎から臨床へ骨髄細胞から肝細胞への分化過程における線維芽細胞増殖因子の促進効果

石川剛, 寺井崇二, 沖田極

日本消化器病学会雑誌 102 ( 臨増総会 ) A156 - A156 2005年3月

Percutaneous radiofrequency ablation with cooled electrodes combined with hepatic arterial balloon occlusion in hepatocellular carcinoma 査読

T Yamasaki, T Kimura, F Kurokawa, KJ Aoyama, T Ishikawa, K Tajima, Y Yokoyama, T Takami, K Omori, K Kawaguchi, M Tsuchiya, S Terai, Sakaida, I, K Okita

JOURNAL OF GASTROENTEROLOGY 40 ( 2 ) 171 - 178 2005年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER TOKYO

Background. We have reported that percutaneous radiofrequency ablation (RFA) with balloon occlusion of the hepatic artery (balloon-occluded RFA), using an expandable electrode, increases the coagulation area. In this study, we investigated the efficacy of balloon-occluded RFA and balloon-microcatheter-occluded RFA, using a cool RF single electrode. Methods. We studies 41 patients with 47 hepatocellular carcinoma (HCC) lesions. We treated 28 patients (32 nodules) with balloon-occluded RFA, 5 patients (6 nodules) with balloon-microcatheter-occluded RFA, and 8 patients (9 nodules) with standard RFA. Initial therapeutic efficacy was evaluated with dynamic computed tomography performed 1 week after one session of treatment. Results. One session of treatment was done for 20 nodules (62.5%) in the balloon-occluded RFA group and for 4 nodules (66.7%) in the balloon-microcatheter-occluded RFA group. We compared the coagulation diameter for balloon-occluded RFA (7 nodules), balloon-microcatheter-occluded RFA (6 nodules), and standard RFA (9 nodules) after one application cycle (12 min). The greatest dimension of the area coagulated by balloon-occluded RFA was significantly larger (greatest long-axis dimension, 47.6 +/- 7.8 mm; greatest short-axis dimension, 33.4 +/- 7.5 mm) than that coagulated by standard RFA (greatest long-axis dimension, 35.3 +/- 4.7 mm; greatest short-axis dimension, 25.9 +/- 3.7 mm; P = 0.002 for greatest long-axis dimension; P 0.041 for greatest short-axis dimension). However, there was significant difference only in the greatest short-axis dimension of the area coagulated comparing balloon-microcatheter-occluded RFA and standard RFA. Conclusions. We consider balloon-occluded RFA using a cool RF electrode to be superior to standard RFA for the treatment of HCC, especially when larger coagulation volumes are required.

DOI： 10.1007/s00535-004-15L6-5

Prognostic factors in patients with advanced hepatocellular carcinoma receiving hepatic arterial infusion chemotherapy 査読

T Yamasaki, T Kimura, F Kurokawa, K Aoyama, T Ishikawa, K Tajima, Y Yokoyama, T Takami, K Omori, K Kawaguchi, M Tsuchiya, S Terai, Sakaida, I, K Okita

JOURNAL OF GASTROENTEROLOGY 40 ( 1 ) 70 - 78 2005年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER TOKYO

Background. The prognosis of patients with advanced hepatocellular carcinoma (HCC) is poor. We aimed to clarify the prognostic factors in patients with advanced HCC receiving hepatic arterial infusion chemotherapy (HAIC). Methods. Forty-four HCC patients were treated with HAIC, using low-dose cisplatin (CDDP) and 5-fluorouracil (5-FU) with/without leucovorin (or isovorin). Of these 44 patients, 15 received low-dose CDDP and 5-FU, and 29 received low-dose CDDP, 5-FU, and leucovorin or isovorin. Prognostic factors were evaluated by univariate and multivariate analyses of patient and disease characteristics. Results. Of all patients, 5 and 12 patients respectively, exhibited a complete response (CR) and a partial response (PR) (response rate, 38%). The response rate (48.3%) in the low-dose CDDP and 5-FU with leucovorin/isovorin group was significantly better than that (20%) in the low-dose CDDP and 5-FU group (P = 0.002). The 1-, 2-, 3-, and 5-year cumulative survival rates of the 44 patients were 39%, 18%, 12%, and 9%, respectively. The regimen using low-dose CDDP and 5-FU with leucovorin/isovorin tended to improve survival rates (P = 0.097). Univariate and multivariate analyses showed the same variables' the Child-Pugh score (P = 0.013, P = 0.018), alpha-fetoprotein (AFP) level (P = 0.010, P = 0.009), and therapeutic effect after HAIC (P = 0.003, P = 0.01), respectively, to be significant prognostic factors. Conclusions. Patients who had advanced HCC with favorable hepatic reserve capacity and a lower AFP level were suitable candidates for HAIC. Moreover, the regimen using low-dose CDDP and 5-FU with leucovorin/isovorin may be suitable for advanced HCC patients, because of the improvement in the response rate and survival compared with the low-dose CDDP and 5-FU regimen without leucovorin/isovorin.

DOI： 10.1007/s00535-004-1494-7

Development of New Therapy in Fulminant Hepatitis from Glucagon-Insulin Therapy to Bone Marrow Cell Transplantation

Kiwamu Okita, Isao Sakaida, Shuji Terai, Naoki Yamamoto, Kaoru Omori, Tsuyoshi Ishikawa, Kouji Aoyama, Koh Shinoda, Yoshihiko Hamamoto

International Journal of Oncology 52 ( 3-4 ) 25 - 31 2005年

Development of cell therapy using autologous bone marrow cells for liver cirrhosis 査読

Isao Sakaida, Shuji Terai, Hiroshi Nishina, Kiwamu Okita

Medical Molecular Morphology 38 ( 4 ) 197 - 202 2005年

記述言語：英語掲載種別：研究論文（国際会議プロシーディングス）

The plasticity of bone marrow has been confirmed by the autopsy of a female recipient of bone marrow cell transplantation from a male donor. To establish new clinical cell therapies using autologous bone marrow cells for patients with liver failure, we developed a new in vivo model named the green fluorescent protein (GFP)/carbon tetrachloride (CCl4) model. Using the GFP/CCl4 model, we found that transplanted Liv8-negative cells efficiently repopulated into cirrhotic liver tissue and differentiated into albumin-producing hepatocytes under persistent liver damage induced by carbon tetrachloride. Moreover, bone marrow cell transplantation into mice with liver cirrhosis improved liver function and liver fibrosis with the strong expression of matrix metalloproteinases (MMPs), especially MMP-9 activity, resulting in an improved survival rate. Results from the GFP/CCl4 model showed that cell therapy using autologous bone marrow cells has the potential to become an effective treatment for patients with liver failure. A summary of findings from the GFP/CCl4 model is described. © The Japanese Society for Clinical Molecular Morphology 2005.

DOI： 10.1007/s00795-005-0298-z

Lesson from the GFP/CCl4 model - Translational Research Project: the development of cell therapy using autologous bone marrow cells in patients with liver cirrhosis 査読

S Terai, Sakaida, I, H Nishina, K Okita

JOURNAL OF HEPATO-BILIARY-PANCREATIC SURGERY 12 ( 3 ) 203 - 207 2005年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER TOKYO

The plasticity of bone marrow has been confirmed by the analysis of autopsy findings in female recipients of bone marrow cells transplanted from male donors. To establish new clinical cell therapies using autologous bone marrow cells for patients with liver failure, we developed a new in vivo model, the "green fluorescent protein (GFP)/carbon tetrachloride (CCl4) model". Using the GFP/CCl4 model, we found that transplanted Liv8-negative cells efficiently repopulated into cirrhotic liver tissue and trans-differentiated into albumin-producing hepatocytes under conditions of persistent liver damage induced by CCl4. Moreover, one marrow cell transplantation into liver cirrhosis mice improved their liver function, ameliorated liver fibrosis, and improved their survival rate. Results from the GFP/CCl4 model showed that cell therapy using autologous bone marrow cells has the potential to become an effective treatment for patients with liver failure. Here we describe the findings from the GFP/CCl4 model and the scope of the translational research project.

DOI： 10.1007/s00534-005-0977-0

Molecular signature associated with plasticity of bone marrow cell under persistent liver damage by self-organizing-map-based gene expression 査読

K Omori, S Terai, T Ishikawa, K Aoyama, Sakaida, I, H Nishina, K Shinoda, S Uchimura, Y Hamamoto, K Okita

FEBS LETTERS 578 ( 1-2 ) 10 - 20 2004年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE BV

The mechanism that regulates the plasticity of bone marrow cells (BMCs) into hepatocytes is poorly understood. We developed a green fluorescent protein/carbon tetrachloride model to find that BMC transplantation recovered liver damage. Serum albumin level and liver fibrosis were recovered by BMC transplantation. To understand the mechanism, we used DNA-chip technology to profile the change of transient gene expression before and after BMC transplantation. On the basis of gene expression with self-organizing map using specific equation, genes were classified into 153 clusters. The information is useful to understand the dramatic gene activation during the process of the plasticity of BMC. (C) 2004 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.

DOI： 10.1016/j.febslet.2004.09.090

Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice 査読

Sakaida, I, S Terai, N Yamamoto, K Aoyama, T Ishikawa, H Nishina, K Okita

HEPATOLOGY 40 ( 6 ) 1304 - 1311 2004年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JOHN WILEY & SONS INC

We investigated the effect of bone marrow cell (BMC) transplantation on established liver fibrosis. BMCs of green fluorescent protein (GFP) mice were transplanted into 4-week carbon tetrachloride (CCl4)-treated C57BL6 mice through the tail vein, and the mice were treated for 4 more weeks with CCl4 (total, 8 weeks). Sirius red and GFP staining clearly indicated migrated BMCs existing along with fibers, with strong expression of matrix metalloproteinase (MMP)-9 shown by anti-MMP-9 antibodies and in situ hybridization. Double fluorescent immunohistochemistry showed the expression of MMP-9 on the GFP-positive cell surface. Film in situ zymographic analysis revealed strong gelatinolytic activity in the periportal area coinciding with the location of MMP-9-positive BMCs. Four weeks after BMC transplantation, mice had significantly reduced liver fibrosis, as assessed by hydroxyproline content of the livers, compared to that of mice treated with CCl4 alone. Subpopulation of Liv8-negative BMCs was responsible for this fibrolytic effect. In conclusion, mice with BMC transplants with continuous CCl4 injection had reduced liver fibrosis and a significantly improved survival rate after BMC transplantation compared with mice treated with CCl4 alone. This finding introduces a new concept for the therapy of liver fibrosis.

DOI： 10.1002/hep.20452

自己骨髄細胞を用いた肝硬変症に対する肝臓再生療法

寺井崇二, 大森薫, 石川剛, 青山浩司, 高見太郎, 横山雄一郎, 田島邦彦, 坂井田功, 沖田極

治療学 38 ( 10 ) 1158 - 1159 2004年10月

記述言語：日本語出版者・発行元：ライフサイエンス出版(株)

肝不全患者に対し生体肝移植が行われているが,ドナーの問題,外科侵襲の多さという問題点があり,次世代の肝臓再生療法の開発が求められている.われわれは骨髄細胞(肝幹細胞)の移植療法の有効性を評価するため,GFP/CCl4モデルを開発し解析してきた.さらに基盤研究を基に臨床研究(自己骨髄細胞を用いた肝臓再生療法)へと展開した.われわれは,肝移植が受けられない肝不全患者に対する新たな治療方法の開発を慎重に進めている(著者抄録)

肝発癌機構におけるhelix-loop-helix(HLH)型転写制御分子の発現とその制御

高見太郎, 寺井崇二, 沖田極

肝臓 45 ( Suppl.2 ) A486 - A486 2004年9月

骨髄細胞の肝細胞への分化過程において変動する血清蛋白質の解析

横山雄一郎, 寺井崇二, 大森薫, 青山浩司, 石川剛, 高見太郎, 坂井田功, 沖田極

日本癌学会総会記事 63回 505 - 506 2004年9月

肝発癌早期に高発現するHHM(Human Homologue of Maid)のプロモーター解析と,肝疾患患者血清中の抗HHM抗体の検出

高見太郎, 寺井崇二, 横山雄一郎, 田島邦彦, 谷本治子, 仁科博史, 坂井田功, 沖田極

日本癌学会総会記事 63回 295 - 295 2004年9月

肝細胞癌に対する新しいバルーンマイクロカテーテルを用いたリピオドール併用肝動脈バルーン閉塞下ラジオ波凝固療法

山崎隆弘, 木村輝昭, 浦田洋平, 丸本芳雄, 青山浩司, 石川剛, 田島邦彦, 横山雄一郎, 大森薫, 川口浩太郎, 高見太郎, 土屋昌子, 山口裕樹, 寺井崇二, 黒川典枝, 坂井田功, 沖田極

肝臓 45 ( 9 ) 505 - 506 2004年9月

記述言語：日本語出版者・発行元：(一社)日本肝臓学会

肝細胞癌4例を対象に,新しいバルーンマイクロカテーテルを用いたリピオドール併用肝動脈バルーン閉塞下ラジオ波凝固療法を施行した.通常の腹部血管造影の手技にて,5Frカテーテルを用い,精査を行い,マイクロカテーテルにてTranscatheter arterial chemoembolizationを施行し,腫瘍内にリピオドールをpoolingさせた後,Equinox occlusion balloon catheterを胆癌領域の肝動脈に留置し,バルーン閉塞後に経皮的ラジオ波凝固療法を施行した.治療効果判定として1週間後の造影CTで凝固範囲を測定した.12分間1回穿刺での凝固範囲が検討できたのは2例で,各々50×47mm,55×44mmであった.1週間後の造影CTでは,全例で治療部位の早期濃染像は認めなかったが,1例で脈管近傍のsafety marginが不足していたため,経皮的エタノール注入療法を追加した.合併症として発熱の遷延1例,肝梗塞1例を認めたが保存的に改善し,その他は全例に発熱と疼痛を認めたが対処療法で改善した.また一時的に肝機能悪化を認めたが,1週間後に前値に復した

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2004&ichushi_jid=J00263&link_issn=&doc_id=20041005370008&doc_link_id=10.2957%2Fkanzo.45.505&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.45.505&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

骨髄細胞から肝細胞への分化転換における線維芽細胞増殖因子の関与

石川剛, 寺井崇二, 浦田洋平, 丸本芳雄, 青山浩司, 大森薫, 坂井田功, 沖田極

肝臓 45 ( Suppl.2 ) A509 - A509 2004年9月

Proteomic profiling of proteins decreased in hepatocellular carcinoma from patients infected with hepatitis C virus 査読

Y Yokoyama, Y Kuramitsu, M Takashima, N Iizuka, T Toda, S Terai, Sakaida, I, M Oka, K Nakamura, K Okita

PROTEOMICS 4 ( 7 ) 2111 - 2116 2004年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

Hepatocellular carcinoma (HCC) is a major cause of death in Japan. It has been suggested that hepatitis C virus (HCV) plays an important role in hepatocarcinogenesis, because of high incidence among the patients. To understand the mechanism of hepatocarcinogenesis after HCV infection, we performed a comparative study on the protein profiles between tumorous and nontumorous specimens from the patients infected with HCV by means of two-dimensional electrophoresis. Eleven spots were decreased in HCC tissues from over 50% of the patients. Eight proteins out of 11 spots were identified using peptide mass fingerprinting with matrix-assisted laser desorption/ionization-time of flight-mass spectrometry. These proteins were liver type aldolase, tropomyosin beta-chain, ketohexokinase, enoyl-CoA hydratase, albumin, smoothelin, ferritin light chain, and arginase 1. The intensity of enoyl-CoA hydratase, tropomyosin beta-chain, ketohexokinase, liver type aldolase, and arginase 1 was significantly different (p < 0.05). The decrease of 8 proteins was characteristic in HCC. We will discuss the implication of these proteins for the loss of function of hepatocytes and for the possibility of carcinogenesis of HCV-related HCC.

DOI： 10.1002/pmic.200300712

Helix-loop-helix(HLH)型転写制御分子Human homologue of Maid(HHM)からみた肝発癌

高見太郎, 寺井崇二, 谷本治子, 坂井田功, 沖田極

山口医学 53 ( 3 ) 185 - 185 2004年6月

肝発癌におけるHuman homologue of Maid(HHM)の機能とその発現制御

高見太郎, 寺井崇二, 沖田極

肝臓 45 ( Suppl.1 ) A96 - A96 2004年4月

肝硬変患者の就寝前肝不全経口栄養剤投与についての検討

土屋昌子, 坂井田功, 青山浩司, 石川剛, 田島邦彦, 横山雄一郎, 大森薫, 川口浩太郎, 高見太郎, 木村輝昭, 寺井崇二, 山崎隆弘, 黒川典枝, 沖田極

肝臓 45 ( Suppl.1 ) A258 - A258 2004年4月

骨髄細胞による肝再生モデルマウスにおける血清プロテオミクス

横山雄一郎, 寺井崇二, 大森薫, 青山浩司, 石川剛, 高見太郎, 坂井田功, 沖田極

肝臓 45 ( Suppl.1 ) A225 - A225 2004年4月

骨髄細胞移植による肝線維化治療の検討

坂井田功, 山浩司, 石川剛, 大森薫, 寺井崇二, 仁科博史, 沖田極

マトリックス研究会大会 ( 51 ) 52 - 52 2004年4月

【幹細胞と消化器疾患】骨髄細胞から肝細胞への分化転換の制御機構の解析とその臨床応用自己骨髄細胞を用いた肝臓再生療法の基礎的検討

寺井崇二, 石川剛, 大森薫, 青山浩司, 坂井田功, 沖田極

G.I.Research 12 ( 2 ) 117 - 125 2004年4月

記述言語：日本語出版者・発行元：(株)先端医学社

われわれは「自己骨髄細胞を用いた肝臓再生療法」の開発のため,骨髄細胞の肝細胞への分化評価モデル"GFP/CCl4モデル"を開発した.このモデルにおいては持続肝障害が続く肝硬変症において骨髄細胞は肝臓へ定着し肝細胞への分化転換していく.一方,肝発生過程において炎症性シグナルは肝芽細胞の発生,増殖は必須であり,肝発生と再生には共通のメカニズムが存在する.さらに,骨髄中の肝幹細胞群の同定のための新規モノクローナル抗体Liv 8抗体を用いて基礎的検討をおこなった.これらの結果は自己骨髄細胞を用いた肝臓再生療法は次世代の治療法になり得る可能性を示したのでここに紹介する(著者抄録)

線維芽細胞増殖因子は骨髄細胞から肝細胞への分化転換を促進する

石川剛, 寺井崇二, 浦田洋平, 丸本芳雄, 青山浩司, 大森薫, 坂井田功, 沖田極

肝臓 45 ( Suppl.1 ) A43 - A43 2004年4月

骨髄細胞から肝細胞への分化転換の素過程に関与する遺伝子群の抽出及び可視化

大森薫, 寺井崇二, 浦田洋平, 丸本芳雄, 石川剛, 青山浩司, 坂井田功, 仁科博史, 内村俊二, 浜本義彦, 沖田極

肝臓 45 ( Suppl.1 ) A84 - A84 2004年4月

Liv-8陰性分画骨髄細胞の移植による肝線維化改善の検討

青山浩司, 坂井田功, 浦田洋平, 丸本芳雄, 石川剛, 大森薫, 寺井崇二, 沖田極

肝臓 45 ( Suppl.1 ) A89 - A89 2004年4月

Herbal medicine Sho-saiko-to (TJ-9) increases expression matrix metalloproteinases (MMPs) with reduced expression of tissue inhibitor of metalloproteinases (TIMPs) in rat stellate cell 査読

Sakaida, I, K Hironaka, T Kimura, S Terai, T Yamasaki, K Okita

LIFE SCIENCES 74 ( 18 ) 2251 - 2263 2004年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

We have reported that Sho-saiko-to (TJ-9) prevents liver fibrosis in vivo. To gain further insights into the effect of TJ-9, the matrix metalloprotemases (MMPs)/tissue inhibitors of metalloproteinases (TIMPs) balance was examined. Hepatic stellate cells (HSCs) were isolated from male Wistar rats and cultured with TJ-9 (0-1000 mug/ml) on uncoated plastic dishes for 4 days. To elucidate the effects on the MMPs/TIMPs balance by TJ-9, quantitative analysis of type IV collagen-degrading activity, gelatin zymography and reverse zymography were carried out. Northern blot analysis was performed to determine the expression of MMP-2, 13 and TIMP-1 mRNAs. TJ-9 treatment resulted in dose-dependent upregulation of MMP-2, 13 mRNA and downregulation of TIMP-1 mRNA up to 500 mug/ml. Gelatin zymography, reverse zymography and quantitative analysis of type IV collagen-degrading activity confirmed that TJ-9 increased MMP-2 activity and prevented TIMP-1, 2 activities in a dose-dependent manner. SB203580 diminished the reduction of mRNA as well as the activity of TIMP-I by TJ-9 and induction of mRNA as well as the activity of MMP-2. These results show that TJ-9 increased MMP-2, 13 activity with reduced TIMP-1, 2 activities on HSCs possibly via P38 pathway. (C) 2004 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.lfs.2003.09.059

A subpopulation of bone marrow cells depleted by a novel antibody, anti-Liv8, is useful for cell therapy to repair damaged liver 査読

N Yamamoto, S Terai, S Ohata, T Watanabe, K Omori, K Shinoda, K Miyamoto, T Katada, Sakaida, I, H Nishina, K Okita

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 313 ( 4 ) 1110 - 1118 2004年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE

We previously reported a new in vivo model named as "GFP/CCl4 model" for monitoring the transdifferentiation of green fluorescent protein (GFP) positive bone marrow cell (BMC) into albumin-positive hepatocyte under the specific "niche" made by CCl4 induced persistent liver damage, but the subpopulation which BMCs transdifferentiate into hepatocytes remains unknown. Here we developed a new monoclonal antibody, anti-Liv8, using mouse E 11.5 fetal liver as an antigen. Anti-Liv8 recognized both hematopoietic progenitor cells in fetal liver at E 11.5 and CD45-positive hematopoietic cells in adult bone marrow. We separated Liv8-positive and Liv8-negative cells and then transplanted these cells into a continuous liver damaged model. At 4 weeks after BMC transplantation, more efficient repopulation and transdifferentiation of BMC into hepatocytes were seen with Liv8-negative cells. These findings suggest that the subpopulation of Liv8-negative cells includes useful cells to perform cell therapy on repair damaged liver. (C) 2003 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2003.12.044

肝臓肝細胞癌の病態と診断

高見太郎, 寺井崇二, 沖田極

Annual Review消化器 2004 303 - 307 2004年1月

Strategy for the development of cell therapy using bone marrow cells to repair damaged liver 査読

S Terai, Sakaida, I, N Yamamoto, K Omori, K Okita

STEM CELL AND LIVER REGENERATION 51 - 56 2004年

記述言語：英語掲載種別：研究論文（国際会議プロシーディングス）出版者・発行元：SPRINGER-VERLAG TOKYO

Recently, the plasticity of stem cells in bone marrow to differentiate into other cell lineages has been reported. if we can use stem cells in bone marrow, we can easily isolate hepatic stem cells to regenerate liver. In particular, cell therapy using autologous bone marrow cells to regenerate blood vessels has already been done clinically. To develop cell therapy using bone marrow cells to repair damaged liver, we have to understand the mechanism by which bone marrow cells differentiate into hepatocytes. in this chapter, we report a strategy for the development of cell therapy for liver regeneration.

An in vivo model for monitoring trans-differentiation of bone marrow cells into functional hepatocytes 査読

S Terai, Sakaida, I, N Yamamoto, K Omori, T Watanabe, S Ohata, T Katada, K Miyamoto, K Shinoda, H Nishina, K Okita

JOURNAL OF BIOCHEMISTRY 134 ( 4 ) 551 - 558 2003年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPANESE BIOCHEMICAL SOC

The plasticity of bone marrow cells (BMCs) remains controversial. The present study found that persistent injury induces efficient trans-differentiation of BMCs into functional hepatocytes. Mice with liver cirrhosis induced by carbon tetrachloride were injected with 1 x 10(5) non-treated green fluorescent protein (GFP)-positive BMCs via the tail vein. In these mice, transplanted GFP-positive BMCs efficiently migrated into the peri-portal area of liver lobules after one day, repopulating 25% of the recipient liver by 4 weeks. In contrast, no GFP-positive BMCs were detected following transplantation into control mice with undamaged livers. BMCs trans-differentiated into functional mature hepatocytes via immature hepatoblasts. Serum albumin levels were significantly elevated to compensate for chronic liver failure in BMC transplantation. These results reveal that recipient conditions and microenvironments represent key factors for successful cell therapy using BMCs.

DOI： 10.1093/jb/mvg173

Arterial infusion chemotherapy using cisplatin, 5-fluorouracil, and isovorin for patients with advanced hepatocellular carcinoma, pilot study: Is a high dose of the biochemical modulator effective? 査読

T Yamasaki, F Kurokawa, T Takami, K Omori, K Kawaguchi, M Tsuchiya, N Yamamoto, M Okamoto, K Hironaka, T Kimura, S Terai, Sakaida, I, K Okita

HEPATOLOGY RESEARCH 27 ( 1 ) 36 - 44 2003年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCI IRELAND LTD

The authors report the efficacy of arterial infusion chemotherapy using cisplatin (CDDP), 5-fluorouracil (5-FU), and leucovorin (LV) for patients with advanced hepatocellular carcinoma (HCC). In this study, we evaluated the efficacy of our regimen with high-dose LV, using isovorin (IV) (high dose group), comparing the previous regimen (low-dose LV; low dose group). This is a retrospective, historical, and non-controlled trial. In the high dose group (n = 15), one course of chemotherapy consisted of the daily administration of CDDP (10 mg/1 h, for 5 days) and IV (12.5 mg/10 min, for 5 days) followed by 5-FU (250 mg/5 h, for 5 days). In the low dose group (n = 9), changing to the administration of LV (12 mg/day), the same regimen was employed. In principle, we did this 20 times. In the high dose group, complete response (CR) was found in two patients, and partial response (PR) in six patients. Thus, the response rate was 53%. In the low dose group, CR was found in two patients, and PR in three patients. Thus, the response rate was 56%. There were no significant differences in the response rate (P = 0.71), the survival rate (P = 0.29) and the toxicity between the two groups. We considered the recommended dose of LV to be 12 mg/day in our regimen, although this is a preliminary study. (C) 2003 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S1386-6346(03)00195-5

Leptin receptor-deficient Zucker (fa/fa) rat retards the development of pig serum-induced liver fibrosis with Kupffer cell dysfunction 査読

Sakaida, I, S Jinhua, K Uchida, S Terai, K Okita

LIFE SCIENCES 73 ( 19 ) 2491 - 2501 2003年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

The aim of this study was to investigate the role of leptin in the development of liver fibrosis with Kupffer cell function using leptin receptor deficient rats. Male Zucker (fa/fa) and control (fa/-) rats received pig serum for 8 weeks. Animals were sacrificed to estimate the degree of liver fibrosis and stellate cell activation with the expression of alpha smooth muscle actin (alphaSMA). Microarray analysis was performed. Isolated Kuppfer cells of Zucker and control rats were treated with LPS. LPS uptake and TNF-alpha production were examined. Stellate cells were also isolated from Zucker and control rats. The expression of procollagen type I mRNAs was examined. Control rats developed liver fibrosis 8 weeks after injection of pig serum and showed an increased liver hydroxyproline content of 348 +/- 34 mug/g (n = 10) compared with Zucker rats (225 +/- 13, n = 10, P < 0.01). The procollagen type I mRNA level and alphaSMA expression of Zucker rats were also significantly reduced. Microarray analysis indicated significantly reduced expression of TNF-alpha, LPS-binding protein, urokinase-type plasminogen activator (uPA), IGF, IGF-binding protein (IGFBP)-3,5, and increased expression of apolipoprotein IV Isolated Kupffer cells of Zucker rats showed significantly reduced LPS uptake as well as TNF-alpha production compared with control rats. However, no significant change was observed in procollagen type I mRNA levels of isolated stellate cells after 4 days of culture on plastic dishes. These results suggest that leptin receptor deficiency retards the development of liver fibrosis due to the dysfunction of Kuppfer cells. (C) 2003 Elsevier Inc. All rights reserved.

DOI： 10.1016/S0024-3205(03)00653-2

【コンセンサス肝細胞癌の治療】肝細胞癌治療後のフォローアップと補助療法

山崎隆弘, 高見太郎, 大森薫, 川口浩太郎, 土屋昌子, 木村輝昭, 寺井崇二, 黒川典枝, 坂井田功, 沖田極

コンセンサス癌治療 2 ( 3 ) 162 - 163 2003年8月

肝臓の発生分化再生過程におけるHLH型転写制御分子の解析

谷本治子, 寺井崇二, 高見太郎, 横山雄一郎, 田島邦彦, 仁科博史, 沖田極

日本癌学会総会記事 62回 324 - 324 2003年8月

HHM(Human Homologue of Maid)は肝発癌をinitiateする

高見太郎, 寺井崇二, 横山雄一郎, 田島邦彦, 谷本治子, 内田耕一, 木村輝昭, 宮本康嗣, 黒川典枝, 仁科博史, 坂井田功, 沖田極

日本癌学会総会記事 62回 284 - 284 2003年8月

Herbal medicine inchin-ko-to (TJ-135) prevents liver fibrosis and enzyme-altered lesions in rat liver cirrhosis induced by a cholinedeficient (L)-amino acid-defined diet 査読

Sakaida, I, M Tsuchiya, K Kawaguchi, T Kimura, S Terai, K Okita

JOURNAL OF HEPATOLOGY 38 ( 6 ) 762 - 769 2003年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE BV

Background/Aims: The herbal medicine Inchin-ko-to (TJ-135), extract power from three herbs, has recently been reported possessing anti-apoptotic activity. The aim of this study was to investigate whether TJ-135 has any influence on the development of preneoplastic lesions as well as liver fibrosis.
Methods: The effects of the TJ-135 were examined using the choline-deficient L-amino acid-defined diet-induced liver fibrosis model. In addition, the effect of TJ-135 on mitogen-activated protein (MAP) kinase, type III procollagen mRNA expression and the medium N-terminal procollagen III propeptide (PIIINP) concentration in a hepatic stellate cell line (L190) were examined.
Results: TJ-135 prevented fibrosis in a dose-dependent manner up to 1.5% (w/w). TJ-135 also reduced the expression of type III procollagen mRNA in the liver, as well as the number of activated stellate cells. Furthermore, TJ-135 reduced the area of preneoplastic lesions in the liver. With L190 cells, TJ-135 reduced MAP kinase (ERK and JNK but not P38) activities resulting in reduced type III procollagen mRNA and PIIINP concentrations in the medium in a dose-dependent manner.
Conclusions: These results indicate that although TJ-135 has anti-apoptotic activity, TJ-135 does not increase preneoplastic lesions but significantly reduces liver fibrosis through the inhibition of stellate cell activation without a reduction of hepatocyte cell death. (C) 2003 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0168-8278(03)00094-1

【肝細胞癌の治療方針最近の進歩】肝細胞癌に対する経皮的局所治療

山崎隆弘, 木村輝昭, 高見太郎, 大森薫, 川口浩太郎, 土屋昌子, 山本直樹, 岡本真理子, 寺井崇二, 黒川典枝, 坂井田功, 沖田極

消化器外科 26 ( 5 ) 563 - 569 2003年5月

記述言語：日本語出版者・発行元：(株)へるす出版

肝細胞癌の経皮的局所治療は,経皮的エタノール注入療法(PEI)に始まり,マイクロ波凝固療法(MCT)を経由して,ラジオ波凝固療法(RFA)へと発展してきた.現在,RFAは1回あたりの獲得しうる壊死範囲が広いことから,局所療法の主流となっている.著者等の施設でもRFA導入後,MCTは施行していない.しかし大きな脈管や胆嚢に接する腫瘍に対しては,安全性を考えて,PEIを選択している.またPEIとRFAの使い分けとしては,肝予備能の点を考える必要がある.現時点で経皮的局所療法の主流はRFAであるが,PEIもなくてはならない治療法の一つと考えている

ラット肝星細胞のMAPKシグナル伝達経路におけるMMPsの制御

土屋昌子, 坂井田功, 青山浩司, 石川剛, 田島邦彦, 横山雄一郎, 大森薫, 川口浩太郎, 高見太郎, 寺井崇二, 沖田極

肝臓 44 ( Suppl.1 ) A142 - A142 2003年4月

骨髄細胞移植による肝繊維化治療の検討

青山浩司, 坂井田功, 石川剛, 田島邦彦, 横山雄一郎, 大森薫, 川口浩太郎, 高見太郎, 土屋昌子, 山本直樹, 寺井崇二, 沖田極

肝臓 44 ( Suppl.1 ) A103 - A103 2003年4月

Gadolinium chloride reverses dimethylnitrosamine (DMN)-induced rat liver fibrosis with increased matrix metalloproteinases (MMPs) of Kupffer cells 査読

Sakaida, I., Hironaka, K., Terai, S., Okita, K.

Life Sciences 72 ( 8 ) 943 - 959 2003年

劇症肝炎時におけるアポトーシス誘導因子であるチトクロムc血清中濃度の臨床的検討について

木村輝昭, 坂井田功, 大森薫, 川口浩太郎, 土屋昌子, 高見太郎, 岡本真理子, 山本直己, 坂口栄樹, 瀬川誠, 寺井崇二, 萱野幸三, 山崎隆弘, 沖田極

肝臓 43 ( 12 ) 600 - 601 2002年12月

Ubiquitin is a possible new predictive marker for the recurrence of human hepatocellular carcinoma 査読

H Shirahashi, Sakaida, I, S Terai, K Hironaka, N Kusano, K Okita

LIVER 22 ( 5 ) 413 - 418 2002年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BLACKWELL MUNKSGAARD

Background/Aim: Ubiquitin (Ub)-dependent degradation of regulatory proteins controls many cellular processes such as cell cycle progression, morphogenesis and signal transduction. In this study, we evaluated the meaning of ubiquitination in chronic liver diseases, especially human hepatocellular carcinoma, with regard to recurrence. Methods. A total 74 of liver tissues (8 of chronic hepatitis [CH], 9 of liver cirrhosis [LC], 7 of dysplastic nodule low grade (DSL), or dysplastic nodule high grade (DSH) and 50 of hepatocellular carcinoma [HCC]) were analyzed for ubiquitination by immunohistochemisty. Cell proliferation was also analyzed using Ki-67 staining. As a comparative marker for progression of HCC, PIVKA-II (protein induced by vitamin K absence-II) was employed to examine the recurrence rate of HCC. Results: Ubiquitin (Ub) was positive in nuclei and cytoplasm of HCC in immunohistochemistry. The labeling index (L.I.) of ubiquitination was significantly higher with HCC than with other chronic liver diseases and tended to correlate with the lack of poorly- differentiated of HCC. The L.I. of Ki-67 staining was also correlated (P < 0.0001) with that of ubiquitination. The hepatocellular carcinoma (HCC) samples from potentially curatively operated patients having a ubiquitination L.I. of more than 20% suffered significantly higher recurrence of HCC than did patients with an L.I. of less than 20%. On the other hand, PIVA-II did not show such a difference. Conclusion: Ubiquitin (Ub) may reflect the growth activity of neoplasms and will be a possible new predictive marker for the recurrence of human hepatocellular carcinoma after potentially curative operation.

DOI： 10.1034/j.1600-0676.2002.01541.x

骨髄細胞から肝細胞への分化制御に関する遺伝子群の検索

大森薫, 寺井崇二, 山本直樹, 川口浩太郎, 高見太郎, 土屋昌子, 内田耕一, 宮本康嗣, 坂井田功, 仁科博史, 沖田極

日本消化吸収学会総会プログラム・講演抄録集 33回 107 - 107 2002年10月

骨髄細胞を用いた肝臓再生療法の開発を目指して GFP/CCI4モデルの開発と解析及び骨髄中の幹細胞の同定法

寺井崇二, 山本直樹, 大森薫, 川口浩太郎, 高見太郎, 宮本康嗣, 坂井田功, 仁科博史, 沖田極

日本癌学会総会記事 61回 464 - 465 2002年10月

肝幹細胞の発生分化と肝発癌に関与するHLH型転写制御分子Human Homologue of Maid(HHM)

高見太郎, 寺井崇二, 内田耕一, 川口浩太郎, 大森薫, 土屋昌子, 山本直樹, 木村輝昭, 黒川典枝, 宮本康嗣, 坂井田功, 沖田極

日本癌学会総会記事 61回 78 - 78 2002年10月

骨髄細胞から肝細胞への分化制御に関する遺伝子群の検索

大森薫, 寺井崇二, 山本直樹, 川口浩太郎, 高見太郎, 土屋昌子, 内田耕一, 宮本康嗣, 坂井田功, 仁科博史, 沖田極

Gastroenterological Endoscopy 44 ( Suppl.2 ) 1476 - 1476 2002年9月

骨髄細胞から肝細胞への分化制御に関する遺伝子群の検索

大森薫, 寺井崇二, 山本直樹, 川口浩太郎, 高見太郎, 土屋昌子, 内田耕一, 宮本康嗣, 坂井田功, 仁科博史, 沖田極

日本消化器集団検診学会雑誌 40 ( 5 ) 106 - 106 2002年9月

Liv8抗体を用いた臨床応用可能な骨髄中の肝幹細胞群の同定への試み

山本直樹, 寺井崇二, 大森薫, 高見太郎, 川口浩太郎, 宮本康嗣, 坂井田功, 仁科博史, 沖田極

肝臓 43 ( Suppl.2 ) A369 - A369 2002年9月

骨髄細胞から肝細胞への分化制御に関する遺伝子群の検索

大森薫, 寺井崇二, 山本直樹, 川口浩太郎, 高見太郎, 土屋昌子, 内田耕一, 宮本康嗣, 坂井田功, 仁科博史, 沖田極

肝臓 43 ( Suppl.2 ) A337 - A337 2002年9月

肝細胞癌破裂における肝動脈塞栓術(TAE)の意義

山本直樹, 山崎隆弘, 高見太郎, 大森薫, 川口浩太郎, 木村輝昭, 寺井崇二, 黒川典枝, 坂井田功, 沖田極

山口医学 51 ( 3 ) 89 - 90 2002年6月

星細胞活性化に伴う新規転写制御因子HHM(Human homologue of Maid)とMyoDの発現動態についての検討

川口浩太郎, 坂井田功, 寺井崇二, 高見太郎, 大森薫, 山本直樹, 木村輝昭, 萱野幸三, 沖田極

肝臓 43 ( Suppl.1 ) A43 - A43 2002年5月

【これからの肝発癌研究をどう考えるか】遺伝子「DNAチップを用いた遺伝子発現パターン」肝発癌に関与する転写制御分子HHM

寺井崇二, 坂井田功, 高見太郎, 内田耕一, 白橋斉, 山本直樹, 大森薫, 川口浩太郎, 宮本康嗣, 沖田極

医学と薬学 47 ( Suppl. ) 4 - 10 2002年5月

記述言語：日本語出版者・発行元：(株)自然科学社

肝臓の発生・分化・増殖の制御機構に関与するMyoDと同様な肝臓のMaster geneの存在を推測し,その同定を目的とし以下の実験を行った.1)Yeast Two Hybrid Screen,2)5' Rapid Amplification of cDNA,3)遺伝子発現プロファイリング,4)実験モデル,5)Luciferase Assay,6)細胞周期に対する影響の解析,7)ヒト肝癌組織におけるHHM蛋白の発現の検討.その結果肝再生時での発現上昇はあまり顕著でなく,むしろ肝幹細胞を誘導する肝細胞への分化モデルにおいて,foci部に一致し発現量が増加していた.又,化学発癌モデルのコリン欠乏アミノ酸置換食ラットモデルでのfoci部及び実際にヒト肝細胞癌症例に対する染色にて高率に陽性細胞の存在を確認し得た.これらの結果は,肝発癌過程におけるHHMの重要な意味を示した

新規マウスモノクローナル抗体Liv抗体群及びMaid抗体を用いた肝幹細胞同定への試み

山本直樹, 寺井崇二, 大森薫, 高見太郎, 川口浩太郎, 内田耕一, 宮本康嗣, 坂井田功, 仁科博史, 沖田極

肝臓 43 ( Suppl.1 ) A102 - A102 2002年5月

骨髄細胞から肝細胞への分化制御に関する遺伝子群の検索

大森薫, 寺井崇二, 山本直樹, 川口浩太郎, 高見太郎, 内田耕一, 宮本康嗣, 坂井田功, 仁科博史, 沖田極

肝臓 43 ( Suppl.1 ) A100 - A100 2002年5月

肝発癌に関与する転写制御分子HHMの機能解析

高見太郎, 寺井崇二, 内田耕一, 川口浩太郎, 大森薫, 山本直樹, 瀬川誠, 木村輝昭, 萱野幸三, 山崎隆弘

肝臓 43 ( Suppl.1 ) A35 - A35 2002年5月

HHM: A dominant inhibitory helix-loop-helix protein associated with liver-specific gene expression and liver stem cells 査読

S Terai, SS Thorgeirsson, K Okita

GROWTH, PROLIFERATION, AND APOPTOSIS IN HEPATOCYTES 1 - 9 2002年

記述言語：英語掲載種別：研究論文（国際会議プロシーディングス）出版者・発行元：SPRINGER-VERLAG TOKYO

The helix-loop-helix (HLH) family of transcriptional regulatory proteins are key regulators in numerous organ development. We had identified a novel HLH factor, (h) under bar uman (h) under bar omologue of (M) under bar aid (HHM), from a human fetal liver cDNA library. HHM is composed of 360 amino acids (aa). The HHM has an HLH region (150-184 aa) with a leucine zipper motif (240-260 aa) lacking the basic region. The homology of the HLH region for HHM shared 82% identity with that for maternal Id-likemolecule (Maid), but showed low homology with other dominant inhibitory HLH proteins such as Ids, HHM is expressed at a high level in fetal liver as well as in brain, placenta, bone marrow, and lung and is transiently high during liver stem cell activation in the 2-acetylaminofluorene/partial hepatectomy (AAF/PH) model. HHM also inhibited luciferase gene activation induced by the hepatic nuclear factor 4 (HNF-4) promoter. These results suggest that HHM is a novel type of dominant inhibitory HLH protein that might be associated with liver-specific gene expression and liver stem cells.

A new cell therapy using bone marrow cells to repair damaged liver 査読

S Terai, N Yamamoto, K Omori, Sakaida, I, K Okita

JOURNAL OF GASTROENTEROLOGY 37 162 - 163 2002年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER-VERLAG TOKYO

Hepatic stem cells can transdifferentiate into hepatocytes, bile duct cells, pancreatic cells, or intestinal cells. Hepatic stem cells had been thought to be located in the canal of Hering in the liver, but recent work has demonstrated the existence of hepatic stem cells in bone marrow as well. Cell therapy using autologous bone marrow cells has few ethical problems and many applications for treating severe liver disease. Further in vitro and in vivo analysis is crucial to develop the therapy for clinical use.

Herbal medicine Inchin-ko-to (TJ-135) prevents liver fibrosis in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet 査読

Sakaida, I, T Yamasaki, S Terai, K Okita

ASIAN PACIFIC ASSOCIATION FOR THE STUDY OF THE LIVER MEETING 2002 153 - 158 2002年

記述言語：英語掲載種別：研究論文（国際会議プロシーディングス）出版者・発行元：MEDIMOND S R L

The aim of this study was to investigate whether TJ-135 has any influence on the development of liver fibrosis in rats. The effects of the TJ-135 were examined using the choline-deficient L-amino acid-defined (CDAA) diet-induced liver fibrosis and human hepatic stellate cell line (LI90). TJ-135 prevented fibrosis in a dose-dependent manner up to 1.5% (w/w), as indicated by reduced hydroxyproline content in the liver, without reducing the increase in serum ALT. TJ-135 also reduced the number of activated stellate cells. With LI90 cells, TJ-135 reduced MAP kinase activities resulting in reduced PIIIP concentration in the medium in a dose-dependent manner. These results indicate that TJ-135 significantly reduces liver fibrosis through the inhibition of stellate cell activation.

生体部分肝移植で救命し得たB型劇症肝炎急性型の成人例

大森薫, 木村輝昭, 丸本芳雄, 川口浩太郎, 高見太郎, 岡本真理子, 瀬川誠, 坂口栄樹, 岡崎宗子, 寺井崇二

山口医学 50 ( 6 ) 829 - 829 2001年12月

近未来医療移植から再生医療 GFP transgenic mouseを用いた肝臓再生療法の基礎的検討

山本直樹, 寺井崇二, 坂井田功, 大森薫, 川口浩太郎, 高見太郎, 坂口栄樹, 宮本康嗣, 沖田極

肝臓 42 ( Suppl.3 ) A479 - A479 2001年11月

肝細胞癌に対するバルーンマイクロカテーテルを用いた肝動脈バルーン閉塞下ラジオ波凝固療法

山崎隆弘, 黒川典枝, 高見太郎, 山本直樹, 是永匡紹, 木村輝昭, 寺井崇二, 萱野幸三, 坂井田功, 沖田極

肝臓 42 688 - 689 2001年

Human homologue of maid: A dominant inhibitory helix-loop-helix protein associated with liver-specific gene expression 査読

S Terai, H Aoki, K Ashida, SS Thorgeirsson

HEPATOLOGY 32 ( 2 ) 357 - 366 2000年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：W B SAUNDERS CO

The helix-loop-helix (HLH) family of transcriptional. regulatory proteins are key regulators in numerous developmental processes. The class I HLH proteins, such as E12 are ubiquitously expressed. Class II HLH proteins, such as MyoD, are expressed in a tissue-specific manner, Class I and II heterodimers can bind to E-boxes (CANNTG) and regulate lineage commitments of embryonic cells. In an attempt to identify partners for the E12 protein that may exert control during liver development, we performed the yeast 2-hybrid screen using an expression complementary DNA library from human fetal liver. A novel dominant inhibitory HLH factor, designated HHM (human homologue of maid), was isolated and characterized. HHM is structurally related to the Id family and was highly expressed in brain, pituitary gland, lung, heart, placenta, fetal liver, and bone marrow. HHM physically interacted with E12 in vitro and in mammalian cells. Comparison of the dominant inhibitory effects of HHM and Id2 on the binding of E12/MyoD dimer to an E-box element revealed a weaker inhibition by HHM. However, HHM but not Id2 specifically inhibited the luciferase gene activation induced by hepatic nuclear factor 4 (HNF4) promoter. The HHM was transiently expressed during stem-cell-driven regeneration of the liver at the stage in which the early basophilic foci of hepatocytes started to appear. These results suggest that HHM is a novel type of dominant inhibitory HLH protein that might modulate liver-specific gene expression.

Does cytoplasmic cyclin D1 regulate the cell cycle directly? 査読

Terai S, Okita K

J Gastroenterol. 32 ( 2 ) 357 - 66 2000年8月

Antitumor effect of vesnarinone on human hepatocellular carcinoma cell lines 査読

K Kubo, Y Matsuzaki, A Kato, S Terai, K Okita

INTERNATIONAL JOURNAL OF ONCOLOGY 14 ( 1 ) 41 - 46 1999年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PROFESSOR D A SPANDIDOS

Vesnarinone, a quinolinone derivative, induces apoptosis and differentiation in some tumor cell lines. We examined the antitumor effect of vesnarinone on three human hepatocellular carcinoma (HCC) cell lines. Vesnarinone suppressed the proliferation of all three HCC cell lines, but did not induce apoptosis and differentiation. Vesnarinone has also been reported to inhibit both nucleoside and nucleobase transport. Concomitant administration of vesnarinone and a de novo nucleotide synthesis inhibitor potentiated the growth-inhibitory effect of vesnarinone on HCC cells. Vesnarinone may be useful as a new biochemical modulator of anticancer agents.

肝細胞癌に対する経皮的熱湯局注療法併用下マイクロ波凝固治療

山崎隆弘, 加藤彰, 草野倫好, 弘中孝治, 久保圭子, 寺井崇二, 黒川典枝, 藪下芳子, 森健治, 水町宗治, 沖田極

Journal of Microwave Surgery 16 37 - 41 1998年

出版者・発行元：Study Group of Microwave Surgery

We compared the usefulness of percutaneous hot water injection and microwave coagulation therapy (PHMCT) and percutaneous microwave coagulation therapy (PMCT) in patients with hepatocellular carcinomas (HCCs). We performed PHMCT in 18 patients with HCCs (23 nodules) measuring less than 30 mm in diameter and PMCT in 5 patients with HCCs (7 nodules).<br>After 1 week of treatment, we performed a dynamic computed tomography (CT) scan to examine the maximum area of necrosis. There was significant difference in long and short axes diameter of the necrotic area between the PHMCT group injected hot water with more than 15 ml and the PMCT group. Our findings indicate that PHMCT is an effective treatment for small HCCs.

DOI： 10.3380/jmicrowavesurg.16.37

その他リンク： http://search.jamas.or.jp/link/ui/1999230833

Inhibition of tumor necrosis factor-alpha production retards liver regeneration after partial hepatectomy in rats 査読

T Kimura, Sakaida, I, S Terai, Y Matsumura, K Uchida, K Okita

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 231 ( 3 ) 557 - 560 1997年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS

We studied the effects of a tumor necrosis factor-alpha (TNF-alpha) production inhibitor E3330, [(2E)-3-[5-(2,3-dimethoxy-6-methyl-1,4-benzoquinolyl)]-2-nonyl-2-propenoic acid] on liver regeneration in rats subjected to 70% partial hepatectomy, The BrdU labeling index was 53.5 +/- 3.8% 24 h after partial hepatectomy alone and was significantly inhibited by E3330 (25 and 50 mg/kg) in a dose-dependent manner (43.3 +/- 2.1% and 19.0 +/- 10.3%, respectively; p<0.05, p<0.01). In these 3 groups, TNF-alpha protein levels in liver tissue were 187 +/- 18, 123 +/- 47, and 89 +/- 33 pg/mg total protein, respectively, with a significant decrease by E3330 administration (p<0.01), TNF-alpha mRNA expression in liver tissue was also reduced by E3330, These results suggest that TNF-alpha promotes liver regeneration after partial hepatectomy. (C) 1997 Academic Press.

Wild-type p53 gene-induced morphological changes and growth suppression in hepatoma cells 査読

Shuji Terai, Takafumi Noma, Teruaki Kimura, Atsushi Nakazawa, Fumie Kurokawa, Kiwamu Okita

Journal of Gastroenterology 32 ( 3 ) 330 - 337 1997年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Tokyo

The human hepatocellular carcinoma (HCC) cell line, HLF, expresses only mutant-type p53 (mt-p53), which has an amino acid substitution at the 244th residue from glycine to alanine. HLF cells were transfected with wild-type p53 (wt-p53) cDNA construct pC53-SN3, mt-p53 cDNA construct pC53-SCX [which differs by a single nucleotide, resulting in alanine instead of valine at the 143rd residue in p53 (p53-143)], or pCMV-Neo-Bam, as a control, by a liposome method. After G418 selection, three wt-p53 stable transformants (WT), four mt-p53 transformants (MT), and three control vector transformants (VT) were obtained. We analyzed the cell growth and morphological changes of these transformants under different culture conditions [fetal calf serum (FCS), 10%, 1%, and 0%]. Whereas no difference from control in the growth rate and morphology was observed under the 10% FCS conditions, serum starvation induced remarkable phenotypical changes in all three WTs, but not in the other transformant. Corresponding to these phenotypical changes, the transcriptional activity of wt-p53 was increased more than nine fold. These results indicated that serum starvation would induce wt-p53 biological function, which is tightly linked to morphological changes and growth suppression. To induce these changes, the introduction of the wt-p53 gene itself was not sufficient, and additional triggering, i.e., serum starvation, was indispensable.

DOI： 10.1007/BF02934489

肝細胞癌の門脈1次分枝内腫瘍塞栓(Vp3)に対する経皮的熱湯局注療法の試み

山崎隆弘, 黒川典枝, 加藤彰, 久保圭子, 祐徳浩紀, 寺井崇二, 松崎祐子, 安永満, 沖田極

肝臓 37 ( 9 ) 526 - 527 1996年9月

Clinicopathologic features of early hepatocellular carcinoma 査読

T Yamasaki, F Kurokawa, A Kato, K Irie, K Yutoku, S Terai, Y Matsuzaki, M Yasunaga, K Okita

HEPATO-GASTROENTEROLOGY 43 ( 10 ) 926 - 931 1996年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：H G E UPDATE MEDICAL PUBL LTD.

Background/Aims: This study attempts to clarify the clinicopathologic definition of early hepatocellular carcinomas (HCCs).
Materials and Methods: We evaluated 57 patients, with HCCs less than 3 cm in diameter, in terms of prognosis, incidence of extrahepatic metastasis, and tumor recurrence rate following treatment.
Results: Survival was related to both tumor number and histologic differentiation, but was not related to tumor size. Furthermore, prognosis appeared to depend on the functional reserver of the liver. The incidence of extrahepatic metastasis was related to histologic differentiation. There was no significant difference in the recurrence rates of patients with uninodular tumors in terms of tumor size.
Conclusions: Our findings indicate that early HCCs measure 15 mm or less in diameter, are uninodular, and are histologically well-differentiated. Finally, the functional reserve of the liver will likely be an additional parameter that will further characterize early HCCs.

Cell death induced by baicalein in human hepatocellular carcinoma cell lines 査読

Y Matsuzaki, N Kurokawa, S Terai, Y Matsumura, N Kobayashi, K Okita

JAPANESE JOURNAL OF CANCER RESEARCH 87 ( 2 ) 170 - 177 1996年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPANESE CANCER ASSOCIATION

We examined the action of baicalein, a flavonoid contained in the herbal medicine sho-saiko-to (TJ-9), on three cell lines of human hepatocellular carcinoma (HCC). Treatment with baicalein strongly inhibited the activity of topoisomerase II and suppressed the proliferation of all three HCC cell lines. But the mode of cell death induced by baicalein differed according to the cell line. Baicalein induced apoptosis in a concentration-dependent mannner in only one cell line, and an increased concentration of baicalein produced cell death via necrosis in the other two lines, These results suggest that the inhibition of topoisomerase ZI is not by itself sufficient for induction of apoptosis, and that there is a more important mechanism which can account for the difference in susceptibility of cells to apoptosis induced by baicalein.

Hepatocyte proliferation induced in rats by lead nitrate is suppressed by several tumor necrosis factor alpha inhibitors 査読

Y Kubo, M Yasunaga, M Masuhara, S Terai, T Nakamura, K Okita

HEPATOLOGY 23 ( 1 ) 104 - 114 1996年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：W B SAUNDERS CO

Lead nitrate induces liver cell proliferation in rats without accompanying liver cell necrosis. However, the mechanism of this proliferation and its effect on hepatocytes remain unknown. Therefore, we examined the liver and blood level of hepatocyte growth factor and tumor necrosis factor alpha (TNF-alpha) at various intervals to determine whether lead nitrate modifies hepatocyte proliferation by altering the production of these cytokines. We also administered several TNF-alpha inhibitors, dexamethasone, adenosine, (2E)-3-[5-(2,3-dimethoxy-6-methyl-1,4-benzoquinoyl)]-2-nonyl-2-propenoic acid (E3330), and pentoxifylline, to rats to clarify whether pretreatment with these inhibitors suppresses the increase of TNF-alpha messenger RNA (mRNA) in the liver and prevents the hepatocyte proliferation induced by lead nitrate. Hepatocyte proliferation occurred by 24 hours and reached a peak 48 hours after a single intravenous injection of lead nitrate (100 mu/mol/kg). TNF-alpha mRNA expression in the Liver was increased 1, 6, and 12 hours after the injection, whereas no alteration was observed in liver or blood level of hepatocyte growth factor. Pretreatment with dexamethasone (4.0 mg/kg), E3330 (100 mg/kg) adenosine (0.3 mmol/kg), and pentoxifylline (100 mg/kg), inhibited both TNF-alpha mRNA expression and hepatocyte proliferation 48 hours after the injection, These experimental results strongly support the hypothesis that TNF-alpha positively regulates the hepatocyte proliferation induced in rats by the mitogen, lead nitrate.

DOI： 10.1053/jhep.1996.v23.pm0008550029

HIGH MDM2 MESSENGER-RNA EXPRESSION IN HEPATOBLASTOMA CELL-LINES 査読

S TERAI, Y MATSUZAKI, M MASUHARA, S KONDOU, M YASUNAGA, K OKITA

INTERNATIONAL HEPATOLOGY COMMUNICATIONS 3 ( 6 ) 330 - 336 1995年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCI PUBL IRELAND LTD

Both p53 and MDM2 genes are parts of a physiological pathway frequently impaired in human cancer. This is the report on the analysis of p53 and MDM2 genes in a group of four hepatocellular carcinoma cell-lines and one hepatoblastoma cell-line. Four cell-lines were screened for the presence of p53 mutations using the polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) method. Investigation of the MDM2 gene revealed neither gene amplification nor rearrangement in all cell-lines. However MDM2 mRNA in a hepatoblastoma cell line(HepG2) was elevated to about 2.4 times the level of normal human liver.

PERCUTANEOUS HOT-WATER INJECTION THERAPY (PHOT) FOR TREATMENT OF HEPATOCELLULAR-CARCINOMA - A COMPARISION WITH PERCUTANEOUS ETHANOL INJECTION THERAPY (PEIT)

T YAMASAKI, Y MATSUZAKI, K IRIE, S TERAI, A YAMASHITA, F KUROKAWA, M YASUNAGA, K OKITA

INTERNATIONAL HEPATOLOGY COMMUNICATIONS 3 ( 6 ) 305 - 309 1995年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCI PUBL IRELAND LTD

We investigated the safety and efficacy of percutaneous hot water injection therapy (PHoT) in six patients with hepatocellular carcinoma (HCC). PHoT produced the marked effect in five (62.5%) of eight lesions. No serious adverse effects have been encountered. We also compared the usefulness of percutaneous ethanol injection therapy (PEIT) (22 patients, 32 lesions) and PHoT (five patients, seven lesions) in patients with HCC with diameter of 3 cm or less. Patients in the PHoT group received significantly fewer treatments than in the PEIT group (P < 0.01), because the volume injected per treatment was greater. Residual cancer was found in five (15.6%) of 32 lesions after PEIT and in three (42.9%) of seven lesions after PHoT, but the difference was not statistically significant. Pain tended to be less frequent in patients treated with PHoT than in patients treated with PEIT. We could not determine whether PHoT was superior to PEIT, but our findings indicate that PHoT may be a safe and effective for treating HCC.

肝細胞癌に対する熱湯局注療法(PHoT)の臨床的検討経皮的エタノール注入療法(PEIT)との比較

山崎隆弘, 松崎祐子, 入江和彦, 寺井崇二, 山下仰, 黒川典枝, 安永満, 沖田極

肝臓 35 ( 7 ) 570 - 571 1994年7月

Endoscopic ligation of gastric varices using a detachable snare 査読

T. Yoshida, N. Hayashi, N. Suzumi, S. Miyazaki, S. Terai, T. Itoh, S. Nishimura, T. Noguchi, K. Hino, M. Yasunaga, M. Tada, K. Okita

Endoscopy 26 ( 5 ) 502 - 505 1994年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Georg Thieme Verlag

A new technique of endoscopic treatment for gastric varices is presented here, which was applied in 10 patients, either electively (n=9) or as emergency therapy for bleeding (n=9) or as emergency therapy for bleeding (n=1). A detachable snare is placed endoscopically, tightened around the varix, and then detached using a similar principle to that of band ligation. Following one or two treatment sessions (one snare applied in seven cases, two snares applied in three cases), eradication of gastric varices was observed in all patients. No significant complications were encountered, and nine of 13 snares passed spontaneously, the remaining ones being removed when found during follow-up endoscopy. Short-term follow-up (4-12 months, mean: 7.2 months) did not show either reappearance of varices or rebleeding in any of the patients. Anigography and endoscopic ultrasonography performed in four patients before and after treatment showed regression or disappearance of intramural vessels. Further studies will show the relative value of this new technique compared to other treatment modalities such as banding or cyanoacrylate injection.

DOI： 10.1055/s-2007-1009013

A case of chronic hepatitis exacerbated by alpha-interferon therapy 査読

Yuko Matsuzaki, Keisuke Hino, Yuko Nishizaki, Shuji Terai, Michiari Okuda, Kouzou Kayano, Masafumi Kubota, Kazuyuki Takenaka, Kenji Mori, Aogu Yamashita, Masaaki Masuhara, Norie Kurokawa, Osamu Sakaida, Fujio Murakami, Mitsuru Yasunaga, Kiwamu Okita

Japanese Journal of Gastroenterology 91 ( 4 ) 933 - 937 1994年

Combination Therapy for Intestinal Amebiasis Using an Anti‐amebic Drug and Total Parenteral Nutrition —Report of Two Cases— 査読

Shuji TERAI, Isao SAKAIDA, Mitsuru YASUNAGA, Kiwamu OKITA, Yasushi SHINGAI, Mitsuru SAITO, Harushige FURUTANI, Kojiro SHIGETA, Motoshige INOUE, Motohiro TAKESHIGE

Digestive Endoscopy 5 ( 1 ) 89 - 93 1993年

記述言語：英語掲載種別：研究論文（学術雑誌）

Abstract: In this study we report on two cases of amebic colitis treated in our hospital. On admission both patients were in a severe state of malnutrition due to intermittent diarrhea which had continued for one month. Both patients suffered from amebic colitis presumably transmitted by homosexual intercourse. A definite diagnosis of amebic colitis was made from both fecal examination and colonoscopic biopsy. After the diagnosis was made, the patients were treated with metronidazole. This medication can eliminate Entamoeba histolytica, although it was insufficient for the treatment of the patients’malnutrition. Therefore we used total parenteral nutrition to treat their malnutrition. It was successful and resulted in their recovery and discharge. These two cases indicate that total parenteral nutrition therapy is useful for supporting the recovery of patients with amebiasis. Copyright © 1993, Wiley Blackwell. All rights reserved

DOI： 10.1111/j.1443-1661.1993.tb00599.x

Endoscopic Findings of Primary Sclerosing Cholangitis—‐Report of a Case— 査読

Shuji TERAI, Tetsuji AKIYAMA, Masaaki NAKAMURA, Tsuyoshi AIBE, Kiwamu OKITA, Kazutoshi SANUKI

Digestive Endoscopy 4 ( 1 ) 50 - 55 1992年

記述言語：英語掲載種別：研究論文（学術雑誌）

Abstract: A case of primary sclerosing cholangitis in which an endoscopic inspection through the fistula produced by percutaneous transhepatic biliary drainage was performed for the treatment of progressive jaundice and supprative cholangitis is presented. These treatments benefited the patient to some degree. After 3 years from the onset, the patient died of multi‐organ failure caused by disseminated intravascular coagulopathy. An autopsy revealed primary sclerosing cholangitis. No evidence of ductal stricture due to malignancy or underlying cholelithiasis was noted. This report may be the first which discusses the endoscopic findings of a biliary tract stricture in a patient with sclerosing cholangitis. Copyright © 1992, Wiley Blackwell. All rights reserved

DOI： 10.1111/j.1443-1661.1992.tb00225.x

JAPANESE BETA-THALASSEMIA [CODON-90 (GAG-]TAG)] HAS AT LEAST 2 ORIGINS 査読

Y HATTORI, Y YAMASHIRO, Y OHBA, T MIYAJI, S TERAI, M MORISHITA, K YAMAMOTO, K YAMAMOTO, N MATSUMOTO, F KAWANO

HEMOGLOBIN 16 ( 4 ) 303 - 308 1992年

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