研究者詳細 - 寺井　崇二

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

Scopus

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

Scopus

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