東北大学研究者紹介

研究者詳細

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顔写真

ハマダ　シン

濱田　晋

Shin Hamada

所属

大学院医学系研究科　医科学専攻　内科病態学講座（消化器病態学分野）

職名

講師

学位

博士（医学）（東北大学）

researchmap

https://researchmap.jp/7000006913

J-GLOBAL ID

201401038558041027

e-Rad 研究者番号

20451560

学歴 2

東北大学大学院医学系研究科博士課程修了

～ 2007年3月
東北大学医学部卒業

～ 2000年3月

所属学協会 5

日本消化器内視鏡学会
日本癌学会
日本膵臓学会
日本消化器病学会
日本内科学会

研究分野 2

ライフサイエンス / 腫瘍生物学 /
ライフサイエンス / 消化器内科学 /

受賞 4

黒川利雄がん研究基金研究助成

2019年　黒川利雄がん研究基金　膵癌間質における酸化ストレス応答のダイナミズム解明
医学研究奨励賞

2018年　艮陵医学振興会　手術不能膵胆道癌を標的とした個別化医療開発プラットフォームの構築
日本膵臓病研究財団膵臓病研究奨励賞

2017年　Keap1-Nrf2経路は慢性炎症からの膵発癌に寄与するか
東北大学艮陵同窓会銀賞

2014年　マイクロRNA発現プロファイル解析による膵癌進展機構の解明

論文 142

Which of vonoprazan alone or intravenous proton pump inhibitor followed by vonoprazan is optimal for reducing delayed bleeding in gastric endoscopic submucosal dissection? 国際誌

Hiroko Abe, Kunio Tarasawa, Waku Hatta, Naotaro Tanno, Yutaka Hatayama, Yohei Ogata, Masahiro Saito, Xiaoyi Jin, Tomoyuki Koike, Akira Imatani, Shin Hamada, Kenji Fujimori, Kiyohide Fushimi, Atsushi Masamune

Digestion　1-19　2025年3月25日

DOI： 10.1159/000545253 　

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BACKGROUND: In gastric endoscopic submucosal dissection (ESD), both vonoprazan alone and intravenous proton pump inhibitor (PPI) followed by vonoprazan have lower delayed bleeding risk than PPI alone. This study aimed to clarify an optimal acid-suppressive method in gastric ESD. METHODS: This population-based cohort study included patients who underwent gastric ESD on only vonoprazan (vonoprazan alone group) or intravenous PPI followed by vonoprazan (intravenous PPI group) using the Diagnosis Procedure Combination database in Japan between 2014 and 2021. The primary outcome was delayed bleeding. To balance the two comparison groups, propensity score matching (PSM), based on 18 variables, was performed; subsequently, to compare the bleeding outcome, logistic regression analysis was performed. RESULTS: Of 63,952 patients, 24,710 pairs were compared following PSM. The delayed bleeding risk in the vonoprazan alone group was similar to that in the intravenous PPI group (odds ratio [OR], 1.00; 95% confidence interval, 0.93-1.08; delayed bleeding rate, 5.9% vs. 5.9%). The results were consistent in some sensitivity and subgroup analyses; however, the result was modified by the status of antithrombotic agents (p for interaction = 0.029). In additional analyses, in patients with antithrombotic agent, the vonoprazan alone group had a higher delayed bleeding risk than the intravenous PPI group (OR, 1.15). CONCLUSION: Both vonoprazan alone and intravenous PPI followed by vonoprazan might be acceptable in gastric ESD when antithrombotic agents were not administered, whereas intravenous PPI followed by vonoprazan might be favorable in patients with antithrombotic agents.
Optimal direct oral anticoagulant for upper gastrointestinal endoscopic submucosal dissection.

Yoshitaka Ono, Waku Hatta, Kunio Tarasawa, Yohei Ogata, Hiroko Abe, Isao Sato, Yutaka Hatayama, Masahiro Saito, Xiaoyi Jin, Kaname Uno, Tomoyuki Koike, Akira Imatani, Shin Hamada, Kenji Fujimori, Kiyohide Fushimi, Atsushi Masamune

Journal of gastroenterology　60　(1)　66-76　2025年1月

DOI： 10.1007/s00535-024-02171-2 　

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BACKGROUND: The patients taking direct oral anticoagulants (DOACs) are at high risk for developing ischemic stroke and delayed bleeding in upper gastrointestinal endoscopic submucosal dissection (ESD). We aimed to identify the optimal DOAC based on both adverse events in upper gastrointestinal ESD. METHODS: A retrospective population-based cohort study was conducted using the Diagnosis Procedure Combination database in Japan. We included patients on a DOAC undergoing upper gastrointestinal ESD between 2012 and 2021. The primary outcomes were ischemic stroke occurring after upper gastrointestinal ESD and delayed bleeding in gastroduodenal and esophageal ESD. Inverse probability weightings were applied to balance the four DOAC groups (dabigatran, rivaroxaban, apixaban, and edoxaban), and logistic regression analyses were performed to compare the outcomes. RESULTS: We analyzed 9729 patients on a DOAC undergoing upper gastrointestinal ESD. Ischemic stroke developed after upper gastrointestinal ESD in 1.4%, 0.7%, 0.6%, and 0.8% of patients taking dabigatran, rivaroxaban, apixaban, and edoxaban, respectively, after weighting. Rivaroxaban and apixaban showed significantly lower risk of ischemic stroke compared with dabigatran (odds ratio, 0.15 and 0.12, respectively) in standard doses. The delayed bleeding developed after gastroduodenal ESD in 7.6%, 14.6%, 19.2%, and 17.3% of patients taking each DOAC, respectively, with the lowest risk in dabigatran, followed by rivaroxaban. A similar pattern was observed in delayed bleeding in esophageal ESD (3.2%, 5.4%, 7.5%, and 5.5% in each DOAC), but with no significant results. CONCLUSIONS: Rivaroxaban might be an optimal DOAC for upper gastrointestinal ESD showing a lower risk for both ischemic stroke and delayed bleeding.
Risk factors and a prediction model for pain recurrence after pancreatic stent removal in painful chronic pancreatitis. 国際誌

Tetsuya Takikawa, Kiyoshi Kume, Yu Tanaka, Kazuhiro Kikuta, Yohei Ogata, Waku Hatta, Shin Hamada, Shin Miura, Ryotaro Matsumoto, Takanori Sano, Akira Sasaki, Hidehiro Hayashi, Misako Sakano, Tomoo Manaka, Atsushi Masamune

Pancreas　2024年9月12日

DOI： 10.1097/MPA.0000000000002392 　

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OBJECTIVES: Endoscopic pancreatic stenting (EPS) is an effective treatment modality for painful chronic pancreatitis. However, little is known about the factors that cause pain recurrence after stent removal, and there are no clear criteria for stent removal. We aimed to develop a prediction model for pain recurrence by identifying its risk factors. METHODS: We retrospectively reviewed 95 patients who underwent EPS due to pain for the first time using a single plastic stent between January 2007 and July 2022 at our institute. Univariate and multivariate stepwise Cox proportional hazards models were used to identify the risk factors for pain recurrence, and a prediction model was developed based on the identified factors. RESULTS: Of the 95 enrolled patients, 89 (93.7%) achieved pain relief and 73 (76.8%) did stent removal. Of the 69 patients with a follow-up period ≥6 months after stent removal, 29 (42.0%) had pain recurrence during the median follow-up period of 59 months. Serum lipase level (p = 0.034) and pancreatic parenchymal thickness (p = 0.022) on computed tomography or magnetic resonance imaging were identified as independent risk factors for pain recurrence. The prediction model based on the identified factors had good discrimination ability, with a concordance index of 0.74, and could stratify pain recurrence rates. CONCLUSIONS: We identified the risk factors and developed a new prediction model for pain recurrence following stent removal. This model might be useful for decision-making in pancreatic stent management, such as deciding whether to remove a pancreatic stent, continue EPS, or convert to surgery.
Differential squamous cell fates elicited by NRF2 gain of function versus KEAP1 loss of function 査読有り

Jun Takahashi, Takafumi Suzuki, Miu Sato, Shuji Nitta, Nahoko Yaguchi, Tatsuki Muta, Kouhei Tsuchida, Hiromi Suda, Masanobu Morita, Shin Hamada, Atsushi Masamune, Satoru Takahashi, Takashi Kamei, Masayuki Yamamoto

Cell Reports　2024年4月

DOI： 10.1016/j.celrep.2024.114104 　
Maintenance steroid therapy is associated with decreased risk of malignancy and better prognosis of patients with autoimmune pancreatitis: A multicenter cohort study in Japan. 国際誌

Tetsuya Takikawa, Kazuhiro Kikuta, Takanori Sano, Tsukasa Ikeura, Nao Fujimori, Takeji Umemura, Itaru Naitoh, Hiroshi Nakase, Hiroyuki Isayama, Atsushi Kanno, Ken Kamata, Yuzo Kodama, Dai Inoue, Akio Ido, Toshiharu Ueki, Hiroshi Seno, Hiroaki Yasuda, Eisuke Iwasaki, Takayoshi Nishino, Kensuke Kubota, Toshihiko Arizumi, Atsushi Tanaka, Kazushige Uchida, Ryotaro Matsumoto, Shin Hamada, Seiji Nakamura, Kazuichi Okazaki, Yoshifumi Takeyama, Atsushi Masamune

Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]　2024年1月19日

DOI： 10.1016/j.pan.2024.01.008 　

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BACKGROUND/OBJECTIVES: The association between autoimmune pancreatitis (AIP) and pancreatic cancer (PC) remains controversial. This study aimed to clarify the long-term prognosis and risk of malignancies in AIP patients in Japan. METHODS: We conducted a multicenter retrospective cohort study on 1364 patients with type 1 AIP from 20 institutions in Japan. We calculated the standardized incidence ratio (SIR) for malignancies compared to that in the general population. We analyzed factors associated with overall survival, pancreatic exocrine insufficiency, diabetes mellitus, and osteoporosis. RESULTS: The SIR for all malignancies was increased (1.21 [95 % confidence interval: 1.05-1.41]) in patients with AIP. Among all malignancies, the SIR was highest for PC (3.22 [1.99-5.13]) and increased within 2 years and after 5 years of AIP diagnosis. Steroid use for ≥6 months and ≥50 months increased the risk of subsequent development of diabetes mellitus and osteoporosis, respectively. Age ≥65 years at AIP diagnosis (hazard ratio [HR] = 3.73) and the development of malignancies (HR = 2.63), including PC (HR = 7.81), were associated with a poor prognosis, whereas maintenance steroid therapy was associated with a better prognosis (HR = 0.35) in the multivariate analysis. Maintenance steroid therapy was associated with a better prognosis even after propensity score matching for age and sex. CONCLUSIONS: Patients with AIP are at increased risk of developing malignancy, especially PC. PC is a critical prognostic factor for patients with AIP. Although maintenance steroid therapy negatively impacts diabetes mellitus and osteoporosis, it is associated with decreased cancer risk and improved overall survival.
A novel dry simulator model for learning comprehensive endoscopic retrograde cholangiopancreatography/endoscopic sphincterotomy procedures while minimizing adverse bleeding events (with Video). 国際誌

Yutaka Hatayama, Takeshi Kanno, Tetsuya Takikawa, Ryotaro Matsumoto, Yutaro Arata, Suguo Suzuki, Yohei Ogata, Masahiro Saito, Xiaoyi Jin, Shin Miura, Waku Hatta, Shin Hamada, Kaname Uno, Kiyoshi Kume, Kazuhiro Kikuta, Naoki Asano, Akira Imatani, Tomoyuki Koike, Atsushi Masamune

Digestion　2024年1月10日

DOI： 10.1159/000536217 　

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BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic sphincterotomy (EST) are essential skills for endoscopic cholangio-pancreatic procedures. However, these procedures have a high incidence of adverse events, and most training is currently patient-based. Herein, we aimed to develop an ERCP/EST simulator model to address the need for safer training alternatives, especially for learners with limited ERCP experience. METHODS: The model was designed to facilitate the use of actual endoscopic devices, supporting learning objectives that align with the components of the validated Bethesda ERCP Skill Assessment Tool (BESAT). BESAT focuses on skills such as papillary alignment and maintenance of duodenoscope position, gentle and efficient cannulation, controlled sphincterotomy in the correct trajectory, and guidewire manipulation. Thirty gastroenterology trainees used the simulator between May 2022 and March 2023, and their satisfaction was assessed using a visual analog scale (VAS) and pre- and post-training questionnaires. RESULTS: The novel simulator model comprises a disposable duodenal papillary portion, suitable for incision with an electrosurgical knife, alongside washable upper gastrointestinal tract and bile duct portions, designed for repeated use. The duodenal papillary portion enabled reproduction of a realistic endoscope position and the adverse bleeding events due to improper incisions. The bile duct portion allowed for the reproduction of fluoroscopic-like images, enabling learners to practice guidewire guidance and insert other devices. After training, the median VAS score reflecting the expectation for model learning significantly increased from 69.5 (interquartile range [IQR]:55.5-76.5) to 85.5 (IQR: 78.0-92.0) (P<0.01). All participants expressed their desire for repeated simulator training sessions. CONCLUSIONS: This innovative simulator serves as a practical educational tool, particularly beneficial for novices in ERCP. It facilitates hands-on practice with actual devices, enhancing procedural fluency and understanding of precise incisions to minimize the risk of bleeding complications during EST.
Skeletal muscle mass and function are affected by pancreatic atrophy, pancreatic exocrine insufficiency and poor nutritional status in patients with chronic pancreatitis. 国際誌

Ryotaro Matsumoto, Kazuhiro Kikuta, Tetsuya Takikawa, Takanori Sano, Shin Hamada, Akira Sasaki, Misako Sakano, Hidehiro Hayashi, Tomoo Manaka, Mio Ikeda, Shin Miura, Kiyoshi Kume, Atsushi Masamune

Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]　2024年1月6日

DOI： 10.1016/j.pan.2024.01.002 　

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BACKGROUND/OBJECTIVE: Previous studies have demonstrated that sarcopenia is frequently observed in patients with chronic pancreatitis (CP). However, most studies have defined sarcopenia solely based on skeletal muscle (SM) loss, and muscle weakness such as grip strength (GS) reduction has not been considered. We aimed to clarify whether SM loss and reduced GS have different associations with clinical characteristics and pancreatic imaging findings in patients with CP. METHODS: One hundred two patients with CP were enrolled. We defined SM loss by the SM index at the third lumbar vertebra on CT (<42 cm2/m2 for males and <38 cm2/m2 for females), and reduced GS by < 28 kg for males and <18 kg for females. RESULTS: Fifty-seven (55.9 %) patients had SM loss, 21 (20.6 %) had reduced GS, and 17 (16.7 %) had both. Patients with SM loss had lower body mass index, weaker GS, higher Controlling Nutritional Status score, lower serum lipase level, and lower urinary para-aminobenzoic acid excretion rate, suggesting worse nutritional status and pancreatic exocrine insufficiency. On CT, main pancreatic duct dilatation and parenchymal atrophy were more frequent in patients with SM loss than in those without it. Patients with reduced GS were older and had worse nutritional status than those without it. CONCLUSIONS: SM loss was associated with pancreatic exocrine insufficiency, low nutritional status, and pancreatic imaging findings such as parenchymal atrophy and main pancreatic duct dilatation, whereas older age and low nutritional status led to additional reduced GS.
Clinical Practice and Safety of Endoscopic Balloon Dilation for Crohn's Disease-Related Strictures: A Nationwide Claim Database Analysis in Japan. 国際誌

Rintaro Moroi, Kunio Tarasawa, Hiroshi Nagai, Yusuke Shimoyama, Takeo Naito, Hisashi Shiga, Shin Hamada, Yoichi Kakuta, Kiyohide Fushimi, Kenji Fujimori, Yoshitaka Kinouchi, Atsushi Masamune

Gastroenterology research and practice　2024　1291965-1291965　2024年

DOI： 10.1155/2024/1291965 　

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Introduction: Although endoscopic balloon dilation (EBD) is a common therapeutic approach for managing strictures associated with Crohn's disease (CD), the clinical application and complication rates of EBD remain unclear. Methods: We collected admission data for patients who underwent EBD using a nationwide database. We compared EBD outcomes between ileal and colonic strictures, CD and ulcerative colitis, and CD and anastomotic strictures arising from cancer-related surgery. Subsequently, propensity score matching was employed to facilitate comparisons between each group. Results: The median duration of hospital stay was 4 days. Endoscopic hemostasis and urgent surgery rates after EBD for CD-related strictures were considerably low (0.035% and 0.11%, respectively). Most patients with CD underwent only one EBD procedure during a single admission. Although no significant differences in patient backgrounds and severe complications were observed between ileal and colonic stricture in CD, multiple EBD procedures were more commonly performed for ileal strictures than for colonic stricture. Moreover, EBD for ileal stricture was more frequently conducted in high-volume centers than in low-volume centers. Regarding severe complications after EBD, no significant differences were observed between CD-related strictures and ulcerative colitis or anastomotic strictures related to cancer surgery. Conclusion: Our findings support the safe and effective use of EBD for both ileal and colonic strictures associated with CD. The clinical practice and safety outcomes of EBD for CD-related strictures were comparable to those for strictures stemming from other etiologies.
Porphyromonas gingivalis Lipopolysaccharide Damages Mucosal Barrier to Promote Gastritis-Associated Carcinogenesis

Masayoshi Oriuchi, Sujae Lee, Kaname Uno, Koichiro Sudo, Keisuke Kusano, Naoki Asano, Shin Hamada, Waku Hatta, Tomoyuki Koike, Akira Imatani, Atsushi Masamune

Digestive Diseases and Sciences　69　(1)　95-111　2023年11月9日
出版者・発行元： Springer Science and Business Media LLC
DOI： 10.1007/s10620-023-08142-6 　

ISSN：0163-2116

eISSN：1573-2568
Effectiveness of Antibiotics for Uncomplicated Diverticulitis: A Retrospective Investigation Using a Nationwide Database in Japan. 国際誌

Rintaro Moroi, Kunio Tarasawa, Hiroshi Nagai, Yusukue Shimoyama, Takeo Naito, Hisashi Shiga, Shin Hamada, Yoichi Kakuta, Kiyohide Fushimi, Kenji Fujimori, Yoshitaka Kinouchi, Atsushi Masamune

Digestion　1-9　2023年10月19日

DOI： 10.1159/000534167 　

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INTRODUCTION: The efficacy of antibiotics for diverticulitis without abscess or peritonitis (uncomplicated diverticulitis) is controversial. We aimed to investigate the effectiveness of antibiotics for uncomplicated diverticulitis. METHODS: We collected admission data for patients with acute uncomplicated diverticulitis using a nationwide database. We divided eligible admissions into two groups according to antibiotic initiation within 2 days after admission (antibiotic group vs. nonantibiotic group). We conducted propensity score matching and compared the rates of surgery (intestinal resection and stoma creation), in-hospital death, and medical costs between the groups. We also performed multivariate analysis to identify the clinical factors that affect surgery. RESULTS: We enrolled 131,936 admissions; among these, we obtained 6,061 pairs after propensity score matching. Rates of both intestinal resection and stoma creation in the antibiotic group were lower than those in the nonantibiotic group (0.61 vs. 3.09%, p < 0.0001, and 0.08 vs. 0.26%, p = 0.027, respectively). Median costs in the antibiotic group were higher than those in the nonantibiotic group (315,820 JPY vs. 300,175 JPY, p < 0.0001, respectively). Multivariate analysis showed that non-initiation of antibiotics within 2 days after admission was a clinical factor that increased the risk of intestinal resection (odds ratio [OR] = 5.19, 95% confidence interval [CI]: 4.38-6.16, p < 0.0001) and stoma creation (OR = 2.68, 95% CI: 1.53-4.70, p = 0.0006). CONCLUSION: Our results indicated that antibiotics for uncomplicated diverticulitis expected to have moderate to severe disease activity may reduce the risk of intestinal resection and stoma creation. Further investigations are warranted.
Trends and clinical characteristics of pediatric acute pancreatitis patients in Japan: A comparison with adult cases based on a national administrative inpatient database. 国際誌

Mio Ikeda, Kazuhiro Kikuta, Shin Hamada, Tetsuya Takikawa, Ryotaro Matsumoto, Takanori Sano, Akira Sasaki, Misako Sakano, Kunio Tarasawa, Kenji Fujimori, Kiyohide Fushimi, Atsushi Masamune

Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]　2023年10月4日

DOI： 10.1016/j.pan.2023.10.002 　

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BACKGROUND: /Objectives: Pediatric acute pancreatitis (AP) is not as rare as previously thought, and an increased incidence thereof has been reported. We aimed to clarify the trends and clinical characteristics of pediatric AP in Japan. METHODS: We utilized the Japanese Diagnosis Procedure Combination inpatient database for patients admitted between April 2012 and March 2021, and extracted the data of patients whose principal diagnosis was AP (ICD-10 code K85) or in whom AP accounted for most of the medical expenses. Patients were classified into pediatric (≤18 years) and adult (age >18 years) groups. RESULTS: We included 3941 AP cases in pediatrics and 212,776 in adults. AP cases accounted for 0.08 % of all admissions in pediatrics and 0.33 % in adults, with upward trends during the study period. The proportion of AP patients among all admissions was increased with advancing age in pediatrics. Compared to adults, pediatric AP patients had a smaller proportion of severe cases (22.9 % vs. 28.7 %; P < 0.001), fewer interventions for late complications (0.2 % vs. 1.3 %; P < 0.001), shorter hospital stays (mean 16.6 days vs. 18.0 days; P = 0.001), lower overall mortality (0.7 % vs. 2.9 %; P < 0.001), and lower mortality in severe cases (1.3 % vs. 5.6 %; P < 0.001). Pediatric cases were more frequently transferred from other institutions and treated at academic hospitals than adults (both P < 0.001). CONCLUSIONS: There was an upward trend in the proportion of AP among all admissions in pediatrics, with a lower risk of complications and mortality than adult cases.
CTHRC1 Induces Pancreatic Stellate Cells (PSCs) into Myofibroblast-like Cancer-Associated Fibroblasts (myCAFs). 国際誌

Min Kyung Kang, Fen Jiang, Ye Ji Kim, Kyoungjin Ryu, Atsushi Masamune, Shin Hamada, Yun-Yong Park, Sang Seok Koh

Cancers　15　(13)　2023年6月27日

DOI： 10.3390/cancers15133370 　

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[BACKGROUND] Collagen triple helix repeat containing-1 (CTHRC1) is a secreted protein that contributes to the progression of various cancers, including pancreatic cancer. The higher expression of CTHRC1 in tumor tissues is associated with poorer survival outcomes. However, its specific roles in tumor extracellular matrix (ECM) remodeling remain unclear. Our study aims to investigate the influences of CTHRC1 on pancreatic stellate cells (PSCs), a main source of ECM production in pancreatic cancer. [METHODS AND RESULTS] The analyses of the publicly available pancreatic cancer patient data revealed that CTHRC1 is mainly expressed in cancer stroma and highly correlated with ECM-related genes. An in vitro study showed that more than 40% of these genes can be upregulated by CTHRC1. CTHRC1 specifically activated PSC into myofibroblast-like cancer-associated fibroblasts (myCAFs), which are characterized by a significantly upregulated POSTN gene expression. Periostin (coded by the POSTN gene) has a central role in the CTHRC1-PSCs-cancer metastasis axis. Furthermore, CTHRC1 promoted pancreatic cancer cell proliferation through PSC activation to a greater extent than via direct stimulation. Proof-of-concept experiments showed that the long-term (4-week) inhibition of CTHRC1 led to significant tumor suppression and ECM reduction, and also resulted in an unexpected shift in the CAF subtype from myCAFs to inflammatory CAFs (iCAFs). [CONCLUSION] PSC activation was demonstrated to be the key molecular mechanism responsible for the tumor-promoting effects of CTHRC1, and CTHRC1 has a critical role in CAF subtype differentiation and tumor microenvironment (TME) remodeling. The inhibition of CTHRC1 as a therapeutic strategy for the treatment of pancreatic cancer warrants further investigation.
A case of occult pancreaticobiliary reflux due to endoscopically confirmed relaxation of the Oddi sphincter. 国際誌

Fumiya Kataoka, Shin Miura, Kiyoshi Kume, Kazuhiro Kikuta, Shin Hamada, Tetsuya Takikawa, Ryotaro Matsumoto, Mio Ikeda, Takanori Sano, Akira Sasaki, Atsushi Masamune

DEN open　3　(1)　e161　2023年4月

DOI： 10.1002/deo2.161 　

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An otherwise healthy 45-year-old woman had been experiencing intermittent right upper abdominal pain for the past 1 year. Computed tomography showed pneumobilia and pancreatic duct emphysema despite a normal duodenal papilla. Magnetic resonance cholangiopancreatography and endoscopic ultrasound confirmed bile duct dilation but without a pancreaticobiliary maljunction. Duodenoscopy detected a slightly sunken, unfixed, and spontaneously enlarged duodenal papilla. During the cholangiogram, the Oddi sphincter was relaxed and the catheter could be easily inserted into the bile duct. Further, no findings suggestive of pancreaticobiliary maljunction were observed, and the contrast medium leaked spontaneously from the duodenal papilla. As biliary amylase level was high, we surmised the occurrence of occult pancreaticobiliary reflux due to relaxation of the Oddi sphincter. However, as there are no guidelines on the management of this condition, we did not offer any treatment. Nevertheless, the patient continued to experience similar symptoms and was retested 1 year later with similar results. As occult pancreaticobiliary reflux was reconfirmed, we suggested that the patient undergo laparoscopic extrahepatic bile duct resection and cholecystectomy, which is the standard treatment for pancreaticobiliary maljunction. Pathological evaluation revealed fibrous thickening of the bile duct wall and chronic cholecystitis, which are typical findings of pancreaticobiliary reflux. Even though pancreaticobiliary reflux is mainly observed in pancreaticobiliary maljunction, it has also been reported in normal patients. Here, we describe a novel mechanism of pancreaticobiliary reflux, namely, a relaxed or defective Oddi sphincter.
The Impact of Concomitant Ulcerative Colitis on the Clinical Course in Patients with Primary Sclerosing Cholangitis: An Investigation Using a Nationwide Database in Japan. 国際誌

Rintaro Moroi, Kota Yano, Kunio Tarasawa, Yusuke Shimoyama, Takeo Naito, Hisashi Shiga, Shin Hamada, Yoichi Kakuta, Kiyohide Fushimi, Kenji Fujimori, Yoshitaka Kinouchi, Atsushi Masamune

Inflammatory intestinal diseases　7　(3-4)　147-154　2023年3月

DOI： 10.1159/000529338 　

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INTROODUCTION: Primary sclerosing cholangitis (PSC) is a rare disease, especially in Asian countries. PSC often develops during ulcerative colitis (UC). Little is known about the severity of PSC in patients with UC. Thus, this study aimed to investigate the impact of concomitant UC on the clinical course of patients with PSC using a nationwide database in Japan. METHODS: We collected data on patients who were admitted for PSC using a nationwide database and divided eligible admissions according to concomitant UC (PSC-UC group vs. PSC-alone group). We conducted propensity score matching and compared the rates of liver transplantation, biliary drainage, and other clinical events between the two groups. We also conducted a multivariate analysis to identify the clinical factors that affect biliary drainage, cholangiocarcinoma, and liver transplantation. RESULTS: We enrolled 672 patients after propensity score matching. The rate of liver transplantation in the PSC-UC group was lower than that in the PSC-alone group (2.2 vs. 5.4%, p = 0.002), whereas the rate of biliary drainage did not differ between the two groups (38.1 vs. 33.8%, p = 0.10). On multivariate analysis, concomitant UC was identified as a clinical factor that decreased the risk of liver transplantation (odds ratio = 0.40, 95% confidence interval: 0.23-0.68, p = 0.0007). DISCUSSION: Concomitant UC in patients with PSC may decrease the risk of liver transplantation. The milder disease activity of PSC with UC is more likely compared to that of PSC without UC.
The PRSS3P2 and TRY7 deletion copy number variant modifies risk for chronic pancreatitis. 国際誌

Emmanuelle Masson, Maren Ewers, Sumit Paliwal, Kiyoshi Kume, Virginie Scotet, David N Cooper, Vinciane Rebours, Louis Buscail, Karen Rouault, Amandine Abrantes, Lina Aguilera Munoz, Jérémie Albouys, Laurent Alric, Xavier Amiot, Isabelle Archambeaud, Solène Audiau, Laetitia Bastide, Julien Baudon, Guy Bellaiche, Serge Bellon, Valérie Bertrand, Karine Bideau, Kareen Billiemaz, Claire Billioud, Sabine Bonnefoy, Corinne Borderon, Barbara Bournet, Estelle Breton, Mathias Brugel, Louis Buscail, Guillaume Cadiot, Marine Camus, Marine Carpentier-Pourquier, Patrick Chamouard, Ulriikka Chaput, Jian-Min Chen, Franck Cholet, Dragos Marius Ciocan, Christine Clavel, Benoit Coffin, Laura Coimet-Berger, Simona Cosconea, Isabelle Creveaux, Adrian Culetto, Oussama Daboussi, Louis De Mestier, Thibault Degand, Christelle D'engremont, Bernard Denis, Solène Dermine, Desgrippes, Augustin Drouet D'Aubigny, Raphaël Enaud, Alexandre Fabre, Claude Férec, Dany Gargot, Eve Gelsi, Elena Gentilcore, Rodica Gincul, Emmanuelle Ginglinger-Favre, Marc Giovannini, Cécile Gomercic, Hannah Gondran, Thomas Grainville, Philippe Grandval, Denis Grasset, Stéphane Grimaldi, Sylvie Grimbert, Hervé Hagege, Sophie Heissat, Olivia Hentic, Anne Herber-Mayne, Marc Hervouet, Solene Hoibian, Jérémie Jacques, Bénédicte Jais, Mehdi Kaassis, Stéphane Koch, Elodie Lacaze, Joël Lacroute, Thierry Lamireau, Lucie Laurent, Xavier Le Guillou, Marc Le Rhun, Sarah Leblanc, Philippe Levy, Astrid Lievre, Diane Lorenzo, Frédérique Maire, Kévin Marcel, Emmanuelle Masson, Jacques Mauillon, Stéphanie Morgant, Driffa Moussata, Nelly Muller, Sophie Nambot, Bertrand Napoleon, Anne Olivier, Maël Pagenault, Anne-Laure Pelletier, Olivier Pennec, Fabien Pinard, Mathieu Pioche, Bénédicte Prost, Lucille Queneherve, Vinciane Rebours, Noemi Reboux, Samia Rekik, Ghassan Riachi, Barbara Rohmer, Bertrand Roquelaure, Isabelle Rosa Hezode, Florian Rostain, Jean-Christophe Saurin, Laure Servais, Roxana Stan-Iuga, Clément Subtil, Jérémy Tanneche, Charles Texier, Lucie Thomassin, David Tougeron, Lucine Vuitton, Timothée Wallenhorst, Marc Wangerme, Hélène Zanaldi, Frank Zerbib, Seema Bhaskar, Kazuhiro Kikuta, G Venkat Rao, Shin Hamada, D Nageshwar Reddy, Atsushi Masamune, Giriraj Ratan Chandak, Heiko Witt, Claude Férec, Jian-Min Chen

Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]　23　(1)　48-56　2023年1月

DOI： 10.1016/j.pan.2022.11.013 　

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BACKGROUND: PRSS1 and PRSS2 constitute the only functional copies of a tandemly-arranged five-trypsinogen-gene cluster (i.e., PRSS1, PRSS3P1, PRSS3P2, TRY7 and PRSS2) on chromosome 7q35. Variants in PRSS1 and PRSS2, including missense and copy number variants (CNVs), have been reported to predispose to or protect against chronic pancreatitis (CP). We wondered whether a common trypsinogen pseudogene deletion CNV (that removes two of the three trypsinogen pseudogenes, PRSS3P2 and TRY7) might be associated with CP causation/predisposition. METHODS: We analyzed the common PRSS3P2 and TRY7 deletion CNV in a total of 1536 CP patients and 3506 controls from France, Germany, India and Japan by means of quantitative fluorescent multiplex polymerase chain reaction. RESULTS: We demonstrated that the deletion CNV variant was associated with a protective effect against CP in the French, German and Japanese cohorts whilst a trend toward the same association was noted in the Indian cohort. Meta-analysis under a dominant model yielded a pooled odds ratio (OR) of 0.68 (95% confidence interval (CI) 0.52-0.89; p = 0.005) whereas an allele-based meta-analysis yielded a pooled OR of 0.84 (95% CI 0.77-0.92; p = 0.0001). This protective effect is explicable by reference to the recent finding that the still functional PRSS3P2/TRY7 pseudogene enhancers upregulate pancreatic PRSS2 expression. CONCLUSIONS: The common PRSS3P2 and TRY7 deletion CNV was associated with a reduced risk for CP. This finding provides additional support for the emerging view that dysregulated PRSS2 expression represents a discrete mechanism underlying CP predisposition or protection.
Severity of acute pancreatitis in patients with inflammatory bowel disease in the era of biologics: A propensity-score-matched analysis using a nationwide database in Japan. 国際誌

Rintaro Moroi, Kunio Tarasawa, Mio Ikeda, Ryotaro Matsumoto, Yusuke Shimoyama, Takeo Naito, Tetsuya Takikawa, Hisashi Shiga, Shin Hamada, Yoichi Kakuta, Kazuhiro Kikuta, Kiyohide Fushimi, Kenji Fujimori, Yoshitaka Kinouchi, Atsushi Masamune

JGH open : an open access journal of gastroenterology and hepatology　7　(1)　40-47　2023年1月

DOI： 10.1002/jgh3.12849 　

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BACKGROUND AND AIM: Acute pancreatitis (AP) is a rare extraintestinal manifestation of inflammatory bowel disease (IBD). Several studies from Western countries have reported that the severity of AP in patients with IBD is similar to that in the general population; however, its severity in patients from Eastern countries in the era of biologics remains unclear. This study aimed to investigate the severity of AP in patients with IBD and the effect of biologics on the severity of AP using a nationwide database. METHODS: We divided 1138 eligible AP admissions from the Diagnosis Procedure Combination database system into IBD and non-IBD groups after propensity score matching, and compared the severity of AP. We divided the IBD group into ulcerative colitis (UC) and Crohn's disease (CD) subgroups and compared each with the non-IBD group. Logistic regression analysis was conducted to identify the clinical factors affecting acute pancreatitis. RESULTS: IBD and UC groups had lower rate of severe AP compared to the non-IBD group (13.7% vs 28.3%, P < 0.0001 and 11.0% vs 28.3%, P < 0.0001, respectively). There were no differences in the rates of severe AP between the CD and non-IBD groups. Multivariate analysis showed that biologics did not affect the severity of AP. CONCLUSION: The severity of AP in patients with IBD may be lower than that in the general population; biologics for IBD may not worsen its severity. Further prospective studies are required to clarify the severity of AP in patients with IBD.
The M-ANNHEIM-AiP-Activity-Score is useful for predicting relapse in patients with type 1 autoimmune pancreatitis. 国際誌

Takanori Sano, Kazuhiro Kikuta, Tetsuya Takikawa, Ryotaro Matsumoto, Shin Hamada, Akira Sasaki, Fumiya Kataoka, Mio Ikeda, Shin Miura, Kiyoshi Kume, Atsushi Masamune

Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]　23　(1)　112-119　2022年12月5日

DOI： 10.1016/j.pan.2022.12.001 　

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BACKGROUND/OBJECTIVES: Proper assessment of disease activity and prediction of relapse are crucial for the management of autoimmune pancreatitis (AIP). The M-ANNHEIM-AiP-Activity-Score (MAAS) has been proposed to determine disease activity and predict relapse in German and Swedish patients with AIP. MAAS is calculated using six categories: pain report, pain control, exocrine insufficiency, endocrine insufficiency, imaging, and complications. This study aimed to clarify the usefulness of MAAS to predict relapse in Japanese patients with type 1 AIP. METHODS: We retrospectively analyzed 117 patients with type 1 AIP undergoing initial and maintenance steroid treatments at our institute between April 2006 and March 2021. AIP was diagnosed according to the Japanese Diagnostic Criteria for AIP 2018. We examined the association of MAAS with relapse during and after maintenance treatment. RESULTS: MAAS (median, 8 points) at the start of the initial treatment was reduced after treatment (median, 4 points; P < 0.001). A MAAS ≥11 points at the start of the initial treatment was associated with relapse. The initial treatment-induced reduction of MAAS<60% was more frequent in patients with relapse (75.0%) than in patients without relapse (37.6%; P = 0.007). MAAS at the start of maintenance treatment was higher for patients with relapse (median, 5 points) than that for patients without relapse (median, 4 points; P = 0.007). MAAS ≥4 points at the start of maintenance treatment was associated with subsequent relapse. CONCLUSIONS: MAAS is useful for predicting relapse in patients with type 1 AIP undergoing maintenance therapy.
Clinical features and prognostic impact of asymptomatic pancreatic cancer 国際誌

Tetsuya Takikawa, Kazuhiro Kikuta, Shin Hamada, Kiyoshi Kume, Shin Miura, Naoki Yoshida, Yu Tanaka, Ryotaro Matsumoto, Mio Ikeda, Fumiya Kataoka, Akira Sasaki, Kei Nakagawa, Michiaki Unno, Atsushi Masamune

Scientific Reports　12　(1)　4262-4262　2022年12月

DOI： 10.1038/s41598-022-08083-6 　

eISSN：2045-2322
Loss of CAPS2/Cadps2 leads to exocrine pancreatic cell injury and intracellular accumulation of secretory granules in mice. 国際誌査読有り

Yotaroh Sato, Miho Tsuyusaki, Hiromi Takahashi-Iwanaga, Rena Fujisawa, Atsushi Masamune, Shin Hamada, Ryotaro Matsumoto, Yu Tanaka, Yoichi Kakuta, Yumi Yamaguchi-Kabata, Tamio Furuse, Shigeharu Wakana, Takuya Shimura, Rika Kobayashi, Yo Shinoda, Ryo Goitsuka, So Maezawa, Tetsushi Sadakata, Yoshitake Sano, Teiichi Furuichi

Frontiers in molecular biosciences　9　1040237-1040237　2022年11月7日
出版者・発行元： Frontiers Media SA
DOI： 10.3389/fmolb.2022.1040237 　

eISSN：2296-889X

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The type 2 Ca²⁺-dependent activator protein for secretion (CAPS2/CADPS2) regulates dense-core vesicle trafficking and exocytosis and is involved in the regulated release of catecholamines, peptidergic hormones, and neuromodulators. CAPS2 is expressed in the pancreatic exocrine acinar cells that produce and secrete digestive enzymes. However, the functional role of CAPS2 in vesicular trafficking and/or exocytosis of non-regulatory proteins in the exocrine pancreas remains to be determined. Here, we analyzed the morpho-pathological indicators of the pancreatic exocrine pathway in Cadps2-deficient mouse models using histochemistry, biochemistry, and electron microscopy. We used whole exosome sequencing to identify CADPS2 variants in patients with chronic pancreatitis (CP). Caps2/Cadps2-knockout (KO) mice exhibited morphophysiological abnormalities in the exocrine pancreas, including excessive accumulation of secretory granules (zymogen granules) and their amylase content in the cytoplasm, deterioration of the fine intracellular membrane structures (disorganized rough endoplasmic reticulum, dilated Golgi cisternae, and the appearance of empty vesicles and autophagic-like vacuoles), as well as exocrine pancreatic cell injury, including acinar cell atrophy, increased fibrosis, and inflammatory cell infiltration. Pancreas-specific Cadps2 conditional KO mice exhibited pathological abnormalities in the exocrine pancreas similar to the global Cadps2 KO mice, indicating that these phenotypes were caused either directly or indirectly by CAPS2 deficiency in the pancreas. Furthermore, we identified a rare variant in the exon3 coding region of CADPS2 in a non-alcoholic patient with CP and showed that Cadps2-dex3 mice lacking CAPS2 exon3 exhibited symptoms similar to those exhibited by the Cadps2 KO and cKO mice. These results suggest that CAPS2 is critical for the proper functioning of the pancreatic exocrine pathway, and its deficiency is associated with a risk of pancreatic acinar cell pathology.
Utility of Endoscopic Ultrasound-Guided Fine-Needle Aspiration and Biopsy for Histological Diagnosis of Type 2 Autoimmune Pancreatitis. 国際誌

Hidehiro Hayashi, Shin Miura, Fumiyoshi Fujishima, Shimpei Kuniyoshi, Kiyoshi Kume, Kazuhiro Kikuta, Shin Hamada, Tetsuya Takikawa, Ryotaro Matsumoto, Mio Ikeda, Takanori Sano, Fumiya Kataoka, Akira Sasaki, Misako Sakano, Atsushi Masamune

Diagnostics (Basel, Switzerland)　12　(10)　2022年10月12日

DOI： 10.3390/diagnostics12102464 　

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In Japan, type 1 autoimmune pancreatitis (AIP) is the most common type of AIP; type 2 AIP is rare. The aim of this study was to clarify the usefulness of endoscopic ultrasound-guided fine-needle aspiration and biopsy (EUS-FNAB) for the diagnosis of type 2 AIP. We analyzed the tissue specimens of 10 patients with suspected type 2 AIP who underwent EUS-FNAB at our hospital between April 2009 and March 2021 for tissue volume and histopathological diagnostic performance. The male-to-female ratio of the patients was 8:2, and the patient age (mean ± standard deviation) was 35.6 ± 15.5 years. EUS-FNAB provided sufficient tissue volume, with high-power field >10 in eight patients (80.0%). Based on the International Consensus Diagnostic Criteria (ICDC), four patients (40.0%) had histological findings corresponding to ICDC level 1, and five patients (50.0%) had histological findings corresponding to ICDC level 2. The results of this study show that EUS-FNB can be considered an alternative method to resection and core-needle biopsy for the collection of tissue samples of type 2 AIP.
Senescent Human Pancreatic Stellate Cells Secrete CXCR2 Agonist CXCLs to Promote Proliferation and Migration of Human Pancreatic Cancer AsPC-1 and MIAPaCa-2 Cell Lines. 国際誌

Tetsuya Takikawa, Shin Hamada, Ryotaro Matsumoto, Yu Tanaka, Fumiya Kataoka, Akira Sasaki, Atsushi Masamune

International journal of molecular sciences　23　(16)　2022年8月17日

DOI： 10.3390/ijms23169275 　

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Interactions between pancreatic cancer cells and pancreatic stellate cells (PSCs) play an important role in the progression of pancreatic cancer. Recent studies have shown that cellular senescence and senescence-associated secretory phenotype factors play roles in the progression of cancer. This study aimed to clarify the effects of senescence-induced PSCs on pancreatic cancer cells. Senescence was induced in primary-cultured human PSCs (hPSCs) through treatment with hydrogen peroxide or gemcitabine. Microarray and Gene Ontology analyses showed the alterations in genes and pathways related to cellular senescence and senescence-associated secretory phenotype factors, including the upregulation of C-X-C motif chemokine ligand (CXCL)-1, CXCL2, and CXCL3 through the induction of senescence in hPSCs. Conditioned media of senescent hPSCs increased the proliferation-as found in an assessment with a BrdU incorporation assay-and migration-as found in an assessment with wound-healing and two-chamber assays-of pancreatic cancer AsPC-1 and MIAPaca-2 cell lines. SB225002, a selective CXCR2 antagonist, and SCH-527123, a CXCR1/CXCR2 antagonist, attenuated the effects of conditioned media of senescent hPSCs on the proliferation and migration of pancreatic cancer cells. These results suggest a role of CXCLs as senescence-associated secretory phenotype factors in the interaction between senescent hPSCs and pancreatic cancer cells. Senescent PSCs might be novel therapeutic targets for pancreatic cancer.
Pancreatic mixed acinar-neuroendocrine carcinoma in a patient with a germline BRCA2 mutation: a case report.

Mio Ikeda, Shin Miura, Kiyoshi Kume, Kazuhiro Kikuta, Shin Hamada, Tetsuya Takikawa, Kei Nakagawa, Michiaki Unno, Toru Furukawa, Atsushi Masamune

Clinical journal of gastroenterology　15　(5)　999-1005　2022年7月12日

DOI： 10.1007/s12328-022-01668-8 　

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Loss of function in the BRCA2 gene exacerbates ovarian, breast, and pancreatic ductal cancer risk. Despite being implicated in the pancreatic ductal epithelium carcinogenesis, the involvement of a germline BRCA2 mutation in acinar and endocrine cells is less reported. A 45-year-old woman with a history of breast cancer was referred to our hospital for a detailed examination of epigastric pain. Her father had pancreatic cancer, and her paternal aunt had a history of breast cancer. Contrast-enhanced computed tomography revealed a round tumor with a contrast effect in the pancreatic head. The patient underwent pancreaticoduodenectomy, and postoperative pathology and genetic testing revealed amphicrine-type mixed acinar-neuroendocrine carcinoma with a germline BRCA2 mutation. Recent studies have reported the BRCA2 mutation in genome sequencing of pancreatic acinar cell carcinoma and neuroendocrine tumor; perhaps, genetic testing for the BRCA2 mutation is feasible for patients with mixed neuroendocrine-non-neuroendocrine neoplasm.
Variants in the pancreatic CUB and zona pellucida-like domains 1 (CUZD1) gene in early-onset chronic pancreatitis - A possible new susceptibility gene 国際誌

Agnieszka Magdalena Rygiel, Lara Sophie Unger, Franziska Lena Sörgel, Emmanuelle Masson, Ryotaro Matsumoto, Maren Ewers, Jian Min Chen, Peter Bugert, Louis Buscail, Tomasz Gambin, Grzegorz Oracz, Maria Winiewska-Szajewska, Agnieszka Mianowska, Jarosław Poznanski, Joanna Kosińska, Piotr Stawinski, Rafał Płoski, Dorota Koziel, Stanisław Gluszek, Helmut Laumen, Fredrik Lindgren, J. Matthias Löhr, Anna Orekhova, Vinciane Rebours, Jonas Rosendahl, Andrea Párniczky, Péter Hegyi, Akira Sasaki, Fumiya Kataoka, Yu Tanaka, Shin Hamada, Miklós Sahin-Tóth, Eszter Hegyi, Claude Férec, Atsushi Masamune, Heiko Witt

Pancreatology　22　(5)　564-571　2022年6月

DOI： 10.1016/j.pan.2022.04.015 　

ISSN：1424-3903

eISSN：1424-3911
Pancreatic Stellate Cells and Metabolic Alteration: Physiology and Pathophysiology 国際誌

Shin Hamada, Ryotaro Matsumoto, Atsushi Masamune

Frontiers in Physiology　13　865105-865105　2022年3月15日

DOI： 10.3389/fphys.2022.865105 　

eISSN：1664-042X
Acute Pancreatitis in Japan: Comparison of before and after Revision of the Clinical Guidelines 国際誌

Mio Ikeda, Shin Hamada, Kazuhiro Kikuta, Tetsuya Takikawa, Naoki Yoshida, Ryotaro Matsumoto, Yu Tanaka, Fumiya Kataoka, Akira Sasaki, Kunio Tarasawa, Kenji Fujimori, Kiyohide Fushimi, Atsushi Masamune

Pancreas　51　(3)　261-268　2022年3月1日

DOI： 10.1097/MPA.0000000000002009 　

ISSN：0885-3177

eISSN：1536-4828
Functionally deficient TRPV6 variants contribute to hereditary and familial chronic pancreatitis 国際誌

Shin Hamada, Emmanuelle Masson, Jian Min Chen, Reiko Sakaguchi, Vinciane Rebours, Louis Buscail, Ryotaro Matsumoto, Yu Tanaka, Kazuhiro Kikuta, Fumiya Kataoka, Akira Sasaki, Marc Le Rhun, Hela Audin, Alain Lachaux, Bernard Caumont, Diane Lorenzo, Kareen Billiemaz, Raphael Besnard, Stéphane Koch, Thierry Lamireau, Xavier De Koninck, Emmanuelle Génin, David N. Cooper, Yasuo Mori, Atsushi Masamune, Claude Férec

Human Mutation　43　(2)　228-239　2022年2月

DOI： 10.1002/humu.24315 　

ISSN：1059-7794

eISSN：1098-1004
A New Preoperative Scoring System for Predicting Aggressiveness of Non-Functioning Pancreatic Neuroendocrine Neoplasms 国際誌

Tetsuya Takikawa, Kazuhiro Kikuta, Shin Hamada, Kiyoshi Kume, Shin Miura, Naoki Yoshida, Yu Tanaka, Ryotaro Matsumoto, Mio Ikeda, Fumiya Kataoka, Akira Sasaki, Hidehiro Hayashi, Waku Hatta, Yohei Ogata, Kei Nakagawa, Michiaki Unno, Atsushi Masamune

Diagnostics　12　(2)　2022年2月

DOI： 10.3390/diagnostics12020397 　

eISSN：2075-4418
HIF-1 and NRF2; Key Molecules for Malignant Phenotypes of Pancreatic Cancer 国際誌

Shin Hamada, Ryotaro Matsumoto, Atsushi Masamune

Cancers　14　(2)　2022年1月2日

DOI： 10.3390/cancers14020411 　

eISSN：2072-6694
Decreased Expression of NRF2 Target Genes after Alcohol Exposure in the Background Esophageal Mucosa of Patients with Esophageal Squamous Cell Carcinoma

Shusuke Toda, Waku Hatta, Kiyotaka Asanuma, Naoki Asano, Yoshitaka Ono, Hiroko Abe, Yohei Ogata, Masahiro Saito, Takeshi Kanno, Xiaoyi Jin, Kaname Uno, Tomoyuki Koike, Akira Imatani, Shin Hamada, Tomohiro Nakamura, Naoki Nakaya, Atsushi Masamune

The Tohoku Journal of Experimental Medicine　258　(3)　195-206　2022年
出版者・発行元： Tohoku University Medical Press
DOI： 10.1620/tjem.2022.j077 　

ISSN：0040-8727

eISSN：1349-3329
Editorial: Mechanisms of Inflammation and Fibrosis Interplays in the Digestive Diseases. 国際誌

Atsushi Masamune, Shin Hamada

Frontiers in physiology　13　906742-906742　2022年

DOI： 10.3389/fphys.2022.906742 　
Analysis of the disease activity of ulcerative colitis with and without concomitant primary sclerosing cholangitis: An investigation using a nationwide database in Japan 国際誌

Kota Yano, Rintaro Moroi, Hisashi Shiga, Kunio Tarasawa, Yusuke Shimoyama, Masatake Kuroha, Shin Hamada, Yoichi Kakuta, Kiyohide Fushimi, Kenji Fujimori, Yoshitaka Kinouchi, Atsushi Masamune

JGH Open　6　(1)　50-56　2022年1月

DOI： 10.1002/jgh3.12693 　

eISSN：2397-9070
A case of double common bile duct visually detected only by cholangioscope 国際誌

Shin Miura, Shin Hamada, Kiyoshi Kume, Kazuhiro Kikuta, Tetsuya Takikawa, Naoki Yoshida, Atsushi Masamune

Endoscopy　53　(12)　E457-E458　2021年12月1日

DOI： 10.1055/a-1339-5964 　

ISSN：0013-726X

eISSN：1438-8812
Comprehensive Analysis of microRNA Profiles in Organoids Derived from Human Colorectal Adenoma and Cancer 国際誌

Hiroshi Nagai, Masatake Kuroha, Tomoyuki Handa, Hideaki Karasawa, Shinobu Ohnuma, Takeo Naito, Rintaro Moroi, Yoshitake Kanazawa, Hisashi Shiga, Shin Hamada, Yoichi Kakuta, Takeshi Naitoh, Yoshitaka Kinouchi, Tooru Shimosegawa, Atsushi Masamune

Digestion　102　(6)　860-869　2021年11月1日

DOI： 10.1159/000513882 　

ISSN：0012-2823

eISSN：1421-9867
Nrf2 expression in pancreatic stellate cells promotes progression of cancer 国際誌

Yu Tanaka, Shin Hamada, Ryotaro Matsumoto, Keiko Taguchi, Masayuki Yamamoto, Atsushi Masamune

American Journal of Physiology - Gastrointestinal and Liver Physiology　321　(4)　G378-G388　2021年10月

DOI： 10.1152/ajpgi.00120.2021 　

ISSN：0193-1857

eISSN：1522-1547
Nuclear Factor Erythroid 2–Related Factor 2 Depletion Sensitizes Pancreatic Cancer Cells to Gemcitabine via Aldehyde Dehydrogenase 3a1 Repression 国際誌

Ryotaro Matsumoto, Shin Hamada, Yu Tanaka, Keiko Taguchi, Masayuki Yamamoto, Atsushi Masamune

Journal of Pharmacology and Experimental Therapeutics　379　(1)　33-40　2021年10月1日

DOI： 10.1124/jpet.121.000744 　

ISSN：0022-3565

eISSN：1521-0103
Steatotic Hepatocytes Release Mature VLDL Through Methionine and Tyrosine Metabolism in a Keap1-Nrf2–Dependent Manner 国際誌

Akitoshi Sano, Eiji Kakazu, Shin Hamada, Jun Inoue, Masashi Ninomiya, Tomoaki Iwata, Mio Tsuruoka, Kosuke Sato, Atsushi Masamune

Hepatology　74　(3)　1271-1286　2021年9月

DOI： 10.1002/hep.31808 　

ISSN：0270-9139

eISSN：1527-3350
Focal parenchymal atrophy of the pancreas is frequently observed on pre-diagnostic computed tomography in patients with pancreatic cancer: A case-control study 国際誌

Shin Miura, Tetsuya Takikawa, Kazuhiro Kikuta, Shin Hamada, Kiyoshi Kume, Naoki Yoshida, Yu Tanaka, Ryotaro Matsumoto, Mio Ikeda, Fumiya Kataoka, Akira Sasaki, Waku Hatta, Jun Inoue, Atsushi Masamune

Diagnostics　11　(9)　2021年9月

DOI： 10.3390/diagnostics11091693 　

eISSN：2075-4418
Effective apparent diffusion coefficient parameters for differentiation between mass-forming autoimmune pancreatitis and pancreatic ductal adenocarcinoma 国際誌

Hainan Ren, Naoko Mori, Shin Hamada, Chiaki Takasawa, Shunji Mugikura, Atsushi Masamune, Kei Takase

Abdominal Radiology　46　(4)　1640-1647　2021年4月

DOI： 10.1007/s00261-020-02795-x 　

ISSN：2366-004X

eISSN：2366-0058
Nrf2 activation sensitizes k-ras mutant pancreatic cancer cells to glutaminase inhibition 国際誌

Shin Hamada, Ryotaro Matsumoto, Yu Tanaka, Keiko Taguchi, Masayuki Yamamoto, Atsushi Masamune

International Journal of Molecular Sciences　22　(4)　1-10　2021年2月2日

DOI： 10.3390/ijms22041870 　

ISSN：1661-6596

eISSN：1422-0067
Implementation of Pancreatitis Bundles Is Associated With Reduced Mortality in Patients With Severe Acute Pancreatitis in Japan 国際誌

Atsushi Masamune, Shin Hamada, Kazuhiro Kikuta

Pancreas　50　(2)　e24-e25　2021年2月1日

DOI： 10.1097/MPA.0000000000001750 　

eISSN：1536-4828
IgG4-related diaphragmatic inflammatory pseudotumor

Yu Tanaka, Tetsuya Takikawa, Kiyoshi Kume, Kazuhiro Kikuta, Shin Hamada, Shin Miura, Naoki Yoshida, Seiji Hongo, Ryotaro Matsumoto, Takanori Sano, Mio Ikeda, Michiaki Unno, Atsushi Masamune

Internal Medicine　60　(13)　2067-2074　2021年

DOI： 10.2169/internalmedicine.6589-20 　

ISSN：0918-2918

eISSN：1349-7235
Acinar cell carcinoma with morphological change in one month

Mio Ikeda, Shin Miura, Shin Hamada, Takanori Sano, Ryotaro Matsumoto, Yu Tanaka, Seiji Hongo, Naoki Yoshida, Tetsuya Takikawa, Kazuhiro Kikuta, Kiyoshi Kume, Tatsuo Hata, Michiaki Unno, Yuko Omori, Toru Furukawa, Atsushi Masamune

Internal Medicine　60　(17)　2799-2806　2021年

DOI： 10.2169/internalmedicine.7121-21 　

ISSN：0918-2918

eISSN：1349-7235
Abnormal findings on “T1WI or DWI or MRCP:” An effective Boolean interpretation model in discriminating small pancreatic ductal adenocarcinoma from control group 国際誌

Hainan Ren, Naoko Mori, Minami Hirasawa, Shin Hamada, Shunji Mugikura, Atsushi Masamune, Kei Takase

Journal of Clinical Imaging Science　11　54-54　2021年

DOI： 10.25259/JCIS_158_2021 　

ISSN：2156-7514

eISSN：2156-5597
New-Onset or Exacerbation of Diabetes Mellitus Is a Clue to the Early Diagnosis of Pancreatic Cancer.

Tetsuya Takikawa, Kazuhiro Kikuta, Kiyoshi Kume, Shin Hamada, Shin Miura, Naoki Yoshida, Seiji Hongo, Yu Tanaka, Ryotaro Matsumoto, Takanori Sano, Mio Ikeda, Masahiro Iseki, Michiaki Unno, Atsushi Masamune

The Tohoku journal of experimental medicine　252　(4)　353-364　2020年12月

DOI： 10.1620/tjem.252.353 　

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Pancreatic ductal adenocarcinoma (PDAC), which accounts for majority of pancreatic cancers, is one of the most lethal human malignancies. Most patients are diagnosed at an advanced stage after symptom development. Early diagnosis of PDAC in asymptomatic subjects is important to improve prognosis. Diabetes mellitus (DM) is a risk factor for PDAC, and DM, especially new-onset DM, has attracted attentions as a diagnostic clue to PDAC. However, the impact of DM as a diagnostic opportunity on the prognosis of PDAC is unclear. We here retrospectively reviewed 489 PDAC patients and compared the clinical characteristics and prognosis according to the opportunities for PDAC diagnosis. PDAC was diagnosed upon presentation of symptoms, such as pain and jaundice, in 318 cases including 151 DM patients, upon new-onset or exacerbation of long-standing DM in 53 asymptomatic patients, and upon incidental detection by medical check-up or follow-up/work-up of other diseases in 118 asymptomatic patients. Asymptomatic patients including those with DM had smaller tumors, earlier disease stage, and higher resectability rates than symptomatic patients. Asymptomatic patients diagnosed in association with DM had better prognosis (median survival time, 771 days) than those diagnosed due to symptoms (343 days, P < 0.001), and similar to those diagnosed by incidental detection (869 days). The survival advantage was not evident in symptomatic patients with DM-associated signs. In conclusion, patients diagnosed in association with DM at asymptomatic stages had better prognosis than those diagnosed with symptoms. DM-associated signs might provide a clue to the early diagnosis of PDAC among asymptomatic subjects.
Nationwide epidemiological survey of chronic pancreatitis in Japan: introduction and validation of the new Japanese diagnostic criteria 2019.

Atsushi Masamune, Kazuhiro Kikuta, Kiyoshi Kume, Shin Hamada, Ichiro Tsuji, Yoshifumi Takeyama, Tooru Shimosegawa, Kazuichi Okazaki

Journal of gastroenterology　55　(11)　1062-1071　2020年11月

DOI： 10.1007/s00535-020-01704-9 　

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OBJECTIVES: To provide updated clinico-epidemiological information on chronic pancreatitis (CP) in Japan. METHODS: We conducted a two-stage nationwide epidemiological survey; the number of CP patients was estimated in the first-stage survey, and their clinical features were examined in the second-stage survey. We surveyed patients with CP who had visited hospitals in 2016 and were diagnosed according to the Japanese diagnostic criteria 2009 (DC2009). Furthermore, we validated the new Japanese diagnostic criteria (DC2019) in patients with early CP diagnosed according to DC2009. RESULTS: The number of patients with definite/probable CP in 2016 was 56,520 (prevalence, 44.5 per 100,000 persons), and that of early CP was 4470 (prevalence, 3.5 per 100,000 persons). We obtained detailed clinical information of 2150 patients with definite/probable CP and 249 patients with early CP. Compared with the early CP cases, the definite/probable CP cases had higher proportions of male (4.8 vs. 1.3), alcohol-related etiology (72.0% vs. 45.8%), smoking history (69.6% vs. 41.0%), diabetes mellitus (42.3% vs. 19.3%), and past history of acute pancreatitis (AP) (50.4% vs. 22.1%). Among the patients with early CP diagnosed according to DC2009, 93 (37.3%) were diagnosed with early CP according to DC2019, but the diagnosis of the remaining 156 (62.7%) patients was downgraded. Alcohol-related etiology, smoking history, early disease onset, and past history of AP were associated with the maintenance of early CP diagnosis in DC2019. CONCLUSION: We clarified the current status of CP in Japan. Further validation studies are warranted to clarify the diagnostic utility of DC2019.
Focal Parenchymal Atrophy and Fat Replacement Are Clues for Early Diagnosis of Pancreatic Cancer with Abnormalities of the Main Pancreatic Duct.

Shin Miura, Kiyoshi Kume, Kazuhiro Kikuta, Shin Hamada, Tetsuya Takikawa, Naoki Yoshida, Seiji Hongo, Yu Tanaka, Ryotaro Matsumoto, Takanori Sano, Mio Ikeda, Toru Furukawa, Masahiro Iseki, Michiaki Unno, Atsushi Masamune

The Tohoku journal of experimental medicine　252　(1)　63-71　2020年9月

DOI： 10.1620/tjem.252.63 　

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Pancreatic cancer is one of the most dangerous solid tumors, but its early diagnosis is difficult. The abnormality of the main pancreatic duct (MPD), such as a single localized stricture and upstream dilatation, might be useful in the early detection of pancreatic cancer. However, these findings are often observed in benign inflammatory cases. This study aimed to clarify whether early pancreatic cancer presenting MPD abnormalities has characteristic features different from those of benign cases. This is a single-center, retrospective study. We analyzed 20 patients who underwent pancreatectomy presenting with a single, localized MPD stricture without identifiable masses on imaging: 10 patients with pancreatic ductal adenocarcinoma (cancer group; 6 with stage 0 and 4 with stage I) and 10 patients with benign strictures (benign group; 8 with inflammation and 2 with low-grade pancreatic intraepithelial neoplasms). Pancreatectomy was performed in these benign cases because high-grade intraepithelial neoplasm was suspected. Although the proportion of patients with diabetes mellitus tended to be higher in the cancer group (6/10) than that in the benign group (1/10) (P = 0.058), other clinical characteristics were not different between the groups. Preoperative cytological malignancies were detected in four patients in the cancer group (4/10) but not in the benign group (P = 0.09). Focal parenchymal atrophy and fat replacement were more frequently detected on computed tomography in the cancer group (7/10) than in the benign group (1/10) (P = 0.02). In conclusion, focal parenchymal atrophy and fat replacement may provide clues for the early diagnosis of pancreatic cancer.
Clinical practice of acute pancreatitis in Japan: An analysis of nationwide epidemiological survey in 2016. 国際誌

Atsushi Masamune, Kazuhiro Kikuta, Shin Hamada, Ichiro Tsuji, Yoshifumi Takeyama, Tooru Shimosegawa, Kazuichi Okazaki

Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]　20　(4)　629-636　2020年6月

DOI： 10.1016/j.pan.2020.04.013 　

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BACKGROUND: To provide updates on clinical practice of acute pancreatitis (AP) in Japan, we conducted a nationwide epidemiological survey. METHODS: This study consisted of a two-staged survey; the number of AP patients was estimated by the first-stage survey and their clinical features were examined by the second-stage survey. We surveyed AP patients who had visited hospitals in 2016. RESULTS: The estimated number of AP patients in 2016 was 78,450, with an overall incidence of 61.8 per 100,000 persons. We obtained detailed clinical information of 2994 AP patients, including 706 (23.6%) severe cases classified according to the Japanese severity criteria. The male-to-female sex ratio was 2.0, and the mean age at onset was 59.9 years in males and 66.5 years in females. Alcohol was the most common etiology (42.8%) in males and gallstones in females (37.7%). The AP-associated mortality was 6.1% in severe AP cases, which was decreased by 40% compared to the 2011 survey. Antibiotics were administered to most cases, with carbapenem being frequently used. Enteral nutrition was given in 31.8% of severe cases, but majority cases received after 48 h. Among the 107 patients who received intervention for walled-off necrosis, five patients received surgery-first approach, 66 received endoscopic ultrasound-guided transluminal drainage, and 19 underwent step-up approach. CONCLUSIONS: We clarified the current status of AP in Japan including the significant reduction of mortality in severe cases, shift to endoscopic approaches for walled-off necrosis, and poor compliance of the recommendations in the guidelines including management of enteral nutrition and antibiotic administration.
Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis 国際誌

Atsushi Masamune, Hiroshi Kotani, Franziska Lena Sörgel, Jian-Min Chen, Shin Hamada, Reiko Sakaguchi, Emmanuelle Masson, Eriko Nakano, Yoichi Kakuta, Tetsuya Niihori, Ryo Funayama, Matsuyuki Shirota, Tatsuya Hirano, Tetsuya Kawamoto, Atsuki Hosokoshi, Kiyoshi Kume, Lara Unger, Maren Ewers, Helmut Laumen, Peter Bugert, Masayuki X. Mori, Volodymyr Tsvilovskyy, Petra Weißgerber, Ulrich Kriebs, Claudia Fecher-Trost, Marc Freichel, Kalliope N. Diakopoulos, Alexandra Berninger, Marina Lesina, Kentaro Ishii, Takao Itoi, Tsukasa Ikeura, Kazuichi Okazaki, Tom Kaune, Jonas Rosendahl, Masao Nagasaki, Yasuhito Uezono, Hana Algül, Keiko Nakayama, Yoichi Matsubara, Yoko Aoki, Claude Férec, Yasuo Mori, Heiko Witt, Tooru Shimosegawa

Gastroenterology　158　(6)　1626-1641.e8　2020年5月
出版者・発行元： Elsevier BV
DOI： 10.1053/j.gastro.2020.01.005 　

ISSN：0016-5085

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BACKGROUND & AIMS: Changes in pancreatic calcium levels affect secretion and might be involved in development of chronic pancreatitis (CP). We investigated the association of CP with the transient receptor potential cation channel subfamily V member 6 gene (TRPV6), which encodes a Ca2+-selective ion channel, in an international cohort of patients and in mice. METHODS: We performed whole-exome DNA sequencing from a patient with idiopathic CP and from his parents, who did not have CP. We validated our findings by sequencing DNA from 300 patients with CP (not associated with alcohol consumption) and 1070 persons from the general population in Japan (control individuals). In replication studies, we sequenced DNA from patients with early-onset CP (20 years or younger) not associated with alcohol consumption from France (n = 470) and Germany (n = 410). We expressed TRPV6 variants in HEK293 cells and measured their activity using Ca2+ imaging assays. CP was induced by repeated injections of cerulein in TRPV6mut/mut mice. RESULTS: We identified the variants c.629C>T (p.A210V) and c.970G>A (p.D324N) in TRPV6 in the index patient. Variants that affected function of the TRPV6 product were found in 13 of 300 patients (4.3%) and 1 of 1070 control individuals (0.1%) from Japan (odds ratio [OR], 48.4; 95% confidence interval [CI], 6.3-371.7; P = 2.4 × 10-8). Twelve of 124 patients (9.7%) with early-onset CP had such variants. In the replication set from Europe, 18 patients with CP (2.0%) carried variants that affected the function of the TRPV6 product compared with 0 control individuals (P = 6.2 × 10-8). Variants that did not affect the function of the TRPV6 product (p.I223T and p.D324N) were overrepresented in Japanese patients vs control individuals (OR, 10.9; 95% CI, 4.5-25.9; P = 7.4 × 10-9 for p.I223T and P = .01 for p.D324N), whereas the p.L299Q was overrepresented in European patients vs control individuals (OR, 3.0; 95% CI, 1.9-4.8; P = 1.2 × 10-5). TRPV6mut/mut mice given cerulein developed more severe pancreatitis than control mice, as shown by increased levels of pancreatic enzymes, histologic alterations, and pancreatic fibrosis. CONCLUSIONS: We found that patients with early-onset CP not associated with alcohol consumption carry variants in TRPV6 that affect the function of its product, perhaps by altering Ca2+ balance in pancreatic cells. TRPV6 regulates Ca2+ homeostasis and pancreatic inflammation.
Nationwide epidemiological survey of autoimmune pancreatitis in Japan in 2016.

Atsushi Masamune, Kazuhiro Kikuta, Shin Hamada, Ichiro Tsuji, Yoshifumi Takeyama, Tooru Shimosegawa, Kazuichi Okazaki

Journal of gastroenterology　55　(4)　462-470　2020年4月

DOI： 10.1007/s00535-019-01658-7 　

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BACKGROUND: To further clarify the clinico-epidemiological features of autoimmune pancreatitis (AIP) in Japan, we conducted the fourth nationwide epidemiological survey. METHODS: This study consisted of two stage surveys; the number of AIP patients was estimated by the first survey and their clinical features were assessed by the second survey. We surveyed the AIP patients who had visited hospitals in 2016. RESULTS: The estimated number of AIP patients in 2016 was 13,436, with an overall prevalence rate of 10.1 per 100,000 persons. The estimated number of newly diagnosed patients was 3984, with an annual incidence rate of 3.1 per 100,000 persons. Compared to the 2011 survey, both numbers more than doubled. We obtained detailed clinical information of 1474 AIP patients. The male-to-female sex ratio was 2.94, the mean age was 68.1, and mean age at diagnosis was 64.8. At diagnosis, 63% patients were symptomatic and nearly half of them presented jaundice. Pancreatic cysts were found in 9% of the patients and calcifications in 6%. Histopathological examination was performed in 64%, mainly by endoscopic ultrasonography-guided fine needle aspiration. Extra-pancreatic lesions were detected in 60% of the patients. Eighty-four % patients received the initial steroid therapy, and 85% received maintenance steroid therapy. Kaplan-Meier analysis revealed that the relapsed survival was 14% at 3 years, 25% at 5 years, 40% at 10 years, and 50% at 15 years. Mortality was favorable, but pancreatic cancer accounted for death in one quarter of fatal cases. CONCLUSION: We clarified the current status of AIP in Japan.
IgG4-related Sclerosing Cholangitis Mimicking Cholangiocarcinoma Diagnosed by Endoscopic Ultrasound-guided Fine-needle Aspiration.

Ryotaro Matsumoto, Shin Miura, Atsushi Kanno, Mio Ikeda, Takanori Sano, Yu Tanaka, Tatsuhide Nabeshima, Seiji Hongou, Tetsuya Takikawa, Shin Hamada, Kiyoshi Kume, Kazuhiro Kikuta, Atsushi Masamune

Internal medicine (Tokyo, Japan)　59　(7)　945-950　2020年4月1日

DOI： 10.2169/internalmedicine.3905-19 　

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A 58-year-old man was referred for obstructive jaundice. Imaging modalities revealed the presence of multiple pancreatic tumors and the stenosis of the middle common bile duct due to a hypoenhanced localized tumor. The multiple pancreatic tumors were histopathologically diagnosed as autoimmune pancreatitis by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). To differentiate between IgG4-related sclerosing cholangitis (IgG4-SC) and cholangiocarcinoma, we diagnosed the biliary tumor as IgG4-SC by EUS-FNA because of insufficient pathological materials obtained in a transpapillary manner. We herein report a case of IgG4-SC diagnosed by EUS-FNA.
Keap1 deletion accelerates mutant K-ras/p53-driven cholangiocarcinoma. 国際誌

Tatsuhide Nabeshima, Shin Hamada, Keiko Taguchi, Yu Tanaka, Ryotaro Matsumoto, Masayuki Yamamoto, Atsushi Masamune

American journal of physiology. Gastrointestinal and liver physiology　318　(3)　G419-G427　2020年3月1日

DOI： 10.1152/ajpgi.00296.2019 　

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The activation of the Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) pathway contributes to cancer progression in addition to oxidative stress responses. Loss-of-function Keap1 mutations were reported to activate Nrf2, leading to cancer progression. We examined the effects of Keap1 deletion in a cholangiocarcinoma mouse model using a mutant K-ras/p53 mouse. Introduction of the Keap1 deletion into liver-specific mutant K-ras/p53 expression resulted in the formation of invasive cholangiocarcinoma. Comprehensive analyses of the gene expression profiles identified broad upregulation of Nrf2-target genes such as Nqo1 and Gstm1 in the Keap1-deleted mutant K-ras/p53 expressing livers, accompanied by upregulation of cholangiocyte-related genes. Among these genes, the transcriptional factor Sox9 was highly expressed in the dysplastic bile duct. The Keap-Nrf2-Sox9 axis might serve as a novel therapeutic target for cholangiocarcinoma.NEW & NOTEWORTHY The Keap1-Nrf2 system has a wide variety of effects in addition to the oxidative stress response in cancer cells. Addition of the liver-specific Keap1 deletion to mice harboring mutant K-ras and p53 accelerated cholangiocarcinoma formation, together with the hallmarks of Nrf2 activation. This process involved the expansion of Sox9-positive cells, indicating increased differentiation toward the cholangiocyte phenotype.
Preoperative biliary drainage of the hepatic lobe to be resected does not affect liver hypertrophy after percutaneous transhepatic portal vein embolization. 国際誌

Shin Miura, Atsushi Kanno, Koji Fukase, Yu Tanaka, Ryotaro Matsumoto, Tatsuhide Nabeshima, Seiji Hongou, Tetsuya Takikawa, Shin Hamada, Kiyoshi Kume, Kazuhiro Kikuta, Kei Nakagawa, Michiaki Unno, Atsushi Masamune

Surgical endoscopy　34　(2)　667-674　2020年2月

DOI： 10.1007/s00464-019-06813-y 　

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BACKGROUND: In patients with malignant perihilar biliary strictures, preoperative biliary drainage (PBD) of the hepatic lobe to be resected may decrease the liver volume of the future liver remnant (FLR) after percutaneous transhepatic portal vein embolization (PVE). However, evidence of its application is insufficient. This study aimed to clarify the effects of PBD on liver hypertrophy after PVE. METHODS: Between January 2008 and December 2017, 169 patients with malignant perihilar biliary strictures underwent major hepatectomy or palliative surgery at our hospital. Of these, 76 patients who underwent PVE were categorized into two groups: group A (n = 29) who received unilateral PBD of the FLR and group B (n = 47) who received bilateral PBD, including that of the hepatic lobe to be resected. FLR ratios after PVE and liver hypertrophy ratios were retrospectively compared in both groups. RESULTS: Group B exhibited significantly severe biliary stenosis (p = 0.0038) and high serum bilirubin before biliary drainage (p = 0.0037). After PVE, the total liver volumes were 1287 ± 260 ml and 1340 ± 257 ml (p = 0.39), respectively. FLR volumes were 555 ± 135 and 577 ± 113 ml (p = 0.45), respectively. FLR ratios were 43.4 ± 8.2% and 43.4 ± 6.4%, respectively (p = 0.98). Liver hypertrophy ratios were 124.2 ± 17.7% and 129.2 ± 20.9%, respectively (p = 0.28). In addition, an examination which excluded patients with Bismuth type I obtained similar result. CONCLUSIONS: PBD of the hepatic lobe to be resected did not decrease the FLR ratios and hypertrophy ratios. Thus, in patients with poor biliary drainage, additional PBD of the target lobe is acceptable.
Prognostic importance of peritoneal washing cytology in patients with otherwise resectable pancreatic ductal adenocarcinoma who underwent pancreatectomy: A nationwide, cancer registry-based study from the Japan Pancreas Society. 国際誌

Hiroyoshi Tsuchida, Tsutomu Fujii, Masamichi Mizuma, Sohei Satoi, Hisato Igarashi, Hidetoshi Eguchi, Tamotsu Kuroki, Yasuhiro Shimizu, Masaji Tani, Satoshi Tanno, Yoshihisa Tsuji, Yoshiki Hirooka, Atsushi Masamune, Kazuhiro Mizumoto, Takao Itoi, Shinichi Egawa, Yuzo Kodama, Shin Hamada, Michiaki Unno, Hiroki Yamaue, Kazuichi Okazaki

Surgery　166　(6)　997-1003　2019年12月

DOI： 10.1016/j.surg.2019.06.023 　

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BACKGROUND: The importance of peritoneal washing cytology status both as a sign of irresectability and as a prognostic factor for pancreatic ductal adenocarcinoma remains controversial. The purpose of this nationwide, cancer registry-based study was to clarify the clinical implications of operative resection in patients who had positive cytology status. METHODS: Clinical data from 1,970 patients who underwent tumor resection were collected from the Pancreatic Cancer Registry in Japan. Clinicopathologic factors and overall survival curves were analyzed, and multivariate Cox proportional hazard models were evaluated. RESULTS: Among the 1,970 patients analyzed, positive cytology status was found in 106 patients and negative cytology status was found in 1,864 patients. The positive cytology status group had a greater frequency of pancreatic body and tail cancer and greater preoperative serum carbohydrate antigen 19-9 levels than the negative cytology status group (P < .001 each). The ratio of peritoneal recurrence tended to be greater in the positive cytology status group (14% vs 43%; P < .001). Overall median survival times were less in the positive cytology status group (17.5 months vs 29.4 months; P < .001). The 5-year survival rates were 13.7% and 31.1% in the positive cytology status and negative cytology status groups, respectively. Multivariate analysis of positive cytology status patients revealed that adjuvant chemotherapy was an independent prognostic factor. CONCLUSION: Positive cytology status was an adverse prognostic factor in patients who underwent resection for pancreatic ductal adenocarcinoma but did not preclude attempted curative resection. Curative resection followed by adjuvant chemotherapy may contribute to long-term prognosis in patients with positive cytology status.
Prospective study of early chronic pancreatitis diagnosed based on the Japanese diagnostic criteria.

Atsushi Masamune, Tatsuhide Nabeshima, Kazuhiro Kikuta, Shin Hamada, Eriko Nakano, Kiyoshi Kume, Atsushi Kanno, Ai Sato, Yuichi Tachibana, Osamu Inatomi, Satoshi Yamamoto, Tsukasa Ikeura, Seiji Futagami, Masashi Taguchi, Keiji Hanada, Kyoko Shimizu, Masanobu Kageoka, Tomotaka Saito, Takaaki Eguchi, Kensuke Kubota, Mamoru Takenaka, Atsushi Mima, Atsushi Irisawa, Tetsuhide Ito, Akira Andoh, Kazuo Inui, Yoshifumi Takeyama, Hiroki Yamaue, Kazuichi Okazaki, Tooru Shimosegawa

Journal of gastroenterology　54　(10)　928-935　2019年10月

DOI： 10.1007/s00535-019-01602-9 　

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BACKGROUND: Chronic pancreatitis (CP) is a fibro-inflammatory disease of the pancreas. Early diagnosis and intervention, before CP becomes established and irreversible, are essential to improve the long-term outcomes. The world's first diagnostic criteria for early CP were proposed in Japan in 2009, but their clinical utility remains elusive. This study aimed to clarify whether patients with early CP progress to definite CP. METHODS: This is a multicenter, prospective study. Patients diagnosed as having early CP according to the Japanese diagnostic criteria were prospectively followed for 2 years. Clinical profiles including symptoms, drinking and smoking status, laboratory data, imaging findings and treatments were analyzed. RESULTS: Among the 83 patients who completed the 2-year follow-up period, four (4.8%) patients progressed to definite CP. The diagnosis of 48 (57.8%) patients was unchanged, and that of 31 (37.3%) patients was downgraded. All the four progressive patients were male, alcohol-related, smokers (3 current and 1 ever), and continued drinking. Comparison of the clinical profiles between the progression group (n = 4) and non-progression group (n = 79) revealed that etiology (alcohol-related), smoking status and presence of acute pancreatitis episodes were associated with the progression to definite CP. CONCLUSIONS: The Japanese diagnostic criteria could identify some patients before the progression to definite CP, while the majority of the patients did not progress. TRIAL REGISTRATION NUMBER: UMIN000015992.
Vasohibin-2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma. 国際誌

Rie Iida-Norita, Minaho Kawamura, Yasuhiro Suzuki, Shin Hamada, Atsushi Masamune, Toru Furukawa, Yasufumi Sato

Cancer science　110　(7)　2296-2308　2019年7月

DOI： 10.1111/cas.14041 　

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Vasohibin-2 (VASH2) is expressed in various cancers and promotes their progression. We recently reported that pancreatic cancer patients with higher VASH2 expression show poorer prognosis. Herein, we sought to characterize the role of VASH2 in pancreatic cancer. We used LSL-KrasG12D ; LSL-Trp53R172H ; Pdx-1-Cre (KPC) mice, a mouse model of pancreatic ductal adenocarcinoma (PDAC), and cells isolated from them (KPC cells). Knockdown of Vash2 from PDAC cells did not affect their proliferation, but decreased their migration. When Vash2-knockdown PDAC cells were orthotopically inoculated, liver metastasis and peritoneal dissemination were reduced, and the survival period was significantly prolonged. When KPC mice were crossed with Vash2-deficient mice, metastasis was significantly decreased in Vash2-deficient KPC mice. VASH2 was recently identified to have tubulin carboxypeptidase activity. VASH2 knockdown decreased, whereas VASH2 overexpression increased tubulin detyrosination of PDAC cells, and tubulin carboxypeptidase (TCP) inhibitor parthenolide inhibited VASH2-induced cell migration. We next clarified its role in the tumor microenvironment. Tumor angiogenesis was significantly abrogated in vivo when VASH2 was knocked down or deleted. We further examined genes downregulated by Vash2 knockdown in KPC cells, and found chemokines and cytokines that were responsible for the recruitment of myeloid derived suppressor cells (MDSC). Indeed, MDSC were accumulated in PDAC of KPC mice, and they were significantly decreased in Vash2-deficient KPC mice. These findings suggest that VASH2 plays an essential role in the metastasis of PDAC with multiple effects on both cancer cells and the tumor microenvironment, including tubulin detyrosination, tumor angiogenesis and evasion of tumor immunity.
Protease-Sensitive Pancreatic Lipase Variants Are Associated With Early Onset Chronic Pancreatitis. 国際誌

Denise Lasher, András Szabó, Atsushi Masamune, Jian-Min Chen, Xunjun Xiao, David C Whitcomb, M Michael Barmada, Maren Ewers, Claudia Ruffert, Sumit Paliwal, Prachand Issarapu, Seema Bhaskar, K Radha Mani, Giriraj R Chandak, Helmut Laumen, Emmanuelle Masson, Kiyoshi Kume, Shin Hamada, Eriko Nakano, Katharina Seltsam, Peter Bugert, Thomas Müller, David A Groneberg, Tooru Shimosegawa, Jonas Rosendahl, Claude Férec, Mark E Lowe, Heiko Witt, Miklós Sahin-Tóth

The American journal of gastroenterology　114　(6)　974-983　2019年6月

DOI： 10.14309/ajg.0000000000000051 　

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OBJECTIVES: Premature activation of the digestive protease trypsin within the pancreatic parenchyma is a critical factor in the pathogenesis of pancreatitis. Alterations in genes that affect intrapancreatic trypsin activity are associated with chronic pancreatitis (CP). Recently, carboxyl ester lipase emerged as a trypsin-independent risk gene. Here, we evaluated pancreatic lipase (PNLIP) as a potential novel susceptibility gene for CP. METHODS: We analyzed all 13 PNLIP exons in 429 nonalcoholic patients with CP and 600 control subjects from Germany, in 632 patients and 957 controls from France, and in 223 patients and 1,070 controls from Japan by DNA sequencing. Additionally, we analyzed selected exons in further 545 patients with CP and 1,849 controls originating from Germany, United States, and India. We assessed the cellular secretion, lipase activity, and proteolytic stability of recombinant PNLIP variants. RESULTS: In the German discovery cohort, 8/429 (1.9%) patients and 2/600 (0.3%) controls carried a PNLIP missense variant (P = 0.02, odds ratio [OR] = 5.7, 95% confidence interval [CI] = 1.1-38.9). Variants detected in patients were prone to proteolytic degradation by trypsin and chymotrypsin. In the French replication cohort, protease-sensitive variants were also enriched in patients with early-onset CP (5/632 [0.8%]) vs controls (1/957 [0.1%]) (P = 0.04, OR = 7.6, 95% CI = 0.9-172.9). In contrast, we detected no protease-sensitive variants in the non-European populations. In the combined European data, protease-sensitive variants were found in 13/1,163 cases (1.1%) and in 3/3,000 controls (0.1%) (OR = 11.3, 95% CI = 3.0-49.9, P < 0.0001). CONCLUSIONS: Our data indicate that protease-sensitive PNLIP variants are novel genetic risk factors for the development of CP.
Pancreatic Acinar Cell Carcinoma with Multiple Liver Metastases Effectively Treated by S-1 Chemotherapy.

Naoki Yoshida, Atsushi Kanno, Atsushi Masamune, Tatsuhide Nabeshima, Seiji Hongo, Shin Miura, Tetsuya Takikawa, Shin Hamada, Kazuhiro Kikuta, Kiyoshi Kume, Masamichi Ueno, Tooru Shimosegawa

Internal medicine (Tokyo, Japan)　57　(24)　3529-3535　2018年12月15日

DOI： 10.2169/internalmedicine.0294-17 　

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A 79-year-old woman was referred for pancreatic tail cancer with multiple liver metastases. The pancreatic tail tumor was diagnosed as acinar cell carcinoma (ACC) histologically by endoscopic ultrasound-guided fine-needle aspiration. Because of multiple liver metastases, S-1 chemotherapy was administered, resulting in a partial response to chemotherapy one year later. After approximately three years, liver atrophy and esophageal varices developed. We suspected S-1 as the cause of the liver cirrhosis. S-1 cessation minimized ascites and improved the esophageal varices. Although S-1 can potentially treat ACC, we should be watchful for liver cirrhosis caused by its long-term administration.
Pyruvate Kinase Isozyme M2 Plays a Critical Role in the Interactions Between Pancreatic Stellate Cells and Cancer Cells. 国際誌

Atsushi Masamune, Shin Hamada, Naoki Yoshida, Tatsuhide Nabeshima, Tooru Shimosegawa

Digestive diseases and sciences　63　(7)　1868-1877　2018年7月

DOI： 10.1007/s10620-018-5051-2 　

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BACKGROUND: The interaction between pancreatic cancer cells and pancreatic stellate cells plays a pivotal role in the progression of pancreatic cancer. Pyruvate kinase isozyme M2 is a key enzyme in glycolysis. Previous studies have shown that pyruvate kinase isozyme M2 is overexpressed in pancreatic cancer and that it regulates the aggressive behaviors of pancreatic cancer cells. AIMS: To clarify the role of pyruvate kinase isozyme M2 in the interactions between pancreatic cancer cells and pancreatic stellate cells. METHODS: Pyruvate kinase isozyme M2-knockdown pancreatic cancer cells (Panc-1 and SUIT-2 cells) and pancreatic stellate cells were generated by the introduction of small interfering RNA-expressing vector against pyruvate kinase isozyme M2. Cell proliferation, migration, and epithelial-mesenchymal transition were examined in vitro. The impact of pyruvate kinase isozyme M2 knockdown on the growth of subcutaneous tumors was examined in nude mice in vivo. RESULTS: Pyruvate kinase isozyme M2-kockdown pancreatic cancer cells and pancreatic stellate cells showed decreased proliferation and migration compared to their respective control cells. Pancreatic stellate cell-induced proliferation, migration, and epithelial-mesenchymal transition were inhibited when pyruvate kinase isozyme M2 expression was knocked down in pancreatic cancer cells. In vivo, co-injection of pancreatic stellate cells increased the size of the tumor developed by the control SUIT-2 cells, but the effects were less evident when pyruvate kinase isozyme M2 was knocked down in SUIT-2 cells or pancreatic stellate cells. CONCLUSIONS: Our results suggested a critical role of pyruvate kinase isozyme M2 in the interaction between pancreatic cancer cells and pancreatic stellate cells.
Leptin Aggravates Reflux Esophagitis by Increasing Tissue Levels of Macrophage Migration Inhibitory Factor in Rats.

Tsugihiro Murata, Kiyotaka Asanuma, Nobuyuki Ara, Katsunori Iijima, Waku Hatta, Shin Hamada, Naoki Asano, Tomoyuki Koike, Akira Imatani, Atsushi Masamune, Tooru Shimosegawa

The Tohoku journal of experimental medicine　245　(1)　45-53　2018年5月

DOI： 10.1620/tjem.245.45 　

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Leptin, produced primarily by the adipose tissue, acts as a pro-inflammatory modulator, thereby contributing to the development of obesity-related disease. Although high levels of leptin in the obese are closely related to gastroesophageal reflux disease, the mechanism by which leptin influences esophageal inflammation remains unknown. Macrophage migration inhibitory factor (MIF) is produced by immune cells, such as T lymphocytes and macrophages, and MIF is known to induce the production of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6). We therefore investigated the mechanism whereby leptin aggravates reflux esophagitis, by focusing on esophageal tissue levels of MIF and CD3+ T lymphocytes, both of which are crucial for the reflux-induced epithelial damage. Esophageal inflammation was surgically induced in male Wistar rats by ligating the forestomach and narrowing the duodenum to facilitate gastroesophageal reflux, followed by administration of leptin or vehicle with an osmotic pump system for 1 week. We demonstrated that the administration of leptin exacerbated the reflux esophagitis with the apparent infiltration of CD3+ T lymphocytes and caused the significant increase in the esophageal tissue levels of MIF. Moreover, the leptin caused increases in the esophageal tissue levels of TNF-α, IL-1β and IL-6, downstream targets of MIF. Importantly, the increases in these pro-inflammatory cytokines were accompanied by increased protein levels of phospho-STAT3 and phospho-AKT, pivotal molecules of leptin signaling pathways. In conclusion, through enhancing the MIF-induced inflammatory signaling, leptin could contribute to the development of gastroesophageal reflux disease.
Elucidating the link between collagen and pancreatic cancer: what's next? 国際誌

Shin Hamada, Atsushi Masamune

Expert review of gastroenterology & hepatology　12　(4)　315-317　2018年4月

DOI： 10.1080/17474124.2018.1448268 　
Detection of Acetaldehyde in the Esophageal Tissue among Healthy Male Subjects after Ethanol Drinking and Subsequent L-Cysteine Intake.

Hideki Okata, Waku Hatta, Katsunori Iijima, Kiyotaka Asanuma, Atsuki Tsuruya, Naoki Asano, Tomoyuki Koike, Shin Hamada, Toru Nakayama, Atsushi Masamune, Tooru Shimosegawa

The Tohoku journal of experimental medicine　244　(4)　317-325　2018年4月

DOI： 10.1620/tjem.244.317 　

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Ethanol is oxidized by alcohol dehydrogenase to acetaldehyde, a recognized carcinogen for the esophagus. However, no previous study has measured the acetaldehyde levels in the esophageal tissue. L-cysteine has been shown to reduce the acetaldehyde levels in the saliva; however, it is unknown whether L-cysteine intake affects the acetaldehyde concentration in the esophageal tissue. The aim of this study was to measure the acetaldehyde concentration in the esophageal tissue after ethanol drinking and evaluate the effect of L-cysteine intake on the acetaldehyde levels in the esophagus. We enrolled 10 male subjects with active acetaldehyde dehydrogenase-2*1/*1 (ALDH2*1/*1) genotype and 10 male subjects with the inactive acetaldehyde dehydrogenase-2*1/*2 (ALDH2*1/*2) genotype, the mean ages of whom were 25.6 and 27.9 years, respectively. In this prospective, single-blind, placebo-controlled study using L-cysteine and placebo lozenges (first and second examination), saliva and blood were collected before and after ethanol drinking. Esophageal tissue was obtained by endoscopic biopsy at 60 minutes after drinking, and the acetaldehyde and ethanol concentrations were measured. The acetaldehyde concentration of the saliva was significantly lower in those taking L-cysteine than in those taking the placebo. Acetaldehyde in the esophageal tissue was detected only in those taking L-cysteine lozenges. There were no correlations between the acetaldehyde concentrations in the esophageal tissue and saliva or blood. In conclusion, we detected acetaldehyde in the human esophageal tissue after ethanol drinking. Unexpectedly, intake of L-cysteine lozenges appears to contribute to detection of acetaldehyde in the esophageal tissue.
Successful Endoscopic Treatment of Severe Pancreaticojejunostomy Strictures by Puncturing the Anastomotic Site with an EUS-guided Guidewire.

Tatsuhide Nabeshima, Atsushi Kanno, Atsushi Masamune, Hiroki Hayashi, Seiji Hongo, Naoki Yoshida, Eriko Nakano, Shin Miura, Shin Hamada, Kazuhiro Kikuta, Kiyoshi Kume, Morihisa Hirota, Michiaki Unno, Tooru Shimosegawa

Internal medicine (Tokyo, Japan)　57　(3)　357-362　2018年2月1日

DOI： 10.2169/internalmedicine.9133-17 　

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Pancreaticojejunostomy stricture (PJS) is a late complication of pancreaticoduodenectomy. The endoscopic treatment of PJS is very challenging due to the difficulty of locating the small anastomotic site and passing the stricture using a guidewire. We herein report two cases of severe PJS. These patients could not be treated using only double-balloon endoscopy or endoscopic ultrasound-guided puncture of the main pancreatic duct because of severe stenosis at the anastomotic site. However, we could treat them by the rendezvous technique using the rigid part of the guidewire to penetrate PJS. This method was useful and safe for treating severe PJS.
Estrogen-Dependent Nrf2 Expression Protects Against Reflux-Induced Esophagitis. 国際誌

Yudai Torihata, Kiyotaka Asanuma, Katsunori Iijima, Tetsuhiko Mikami, Shin Hamada, Naoki Asano, Tomoyuki Koike, Akira Imatani, Atsushi Masamune, Tooru Shimosegawa

Digestive diseases and sciences　63　(2)　345-355　2018年2月

DOI： 10.1007/s10620-017-4885-3 　

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BACKGROUND: Gastroesophageal reflux disease is more common in males than in females. The enhanced antioxidative capacity of estrogen in females might account for the gender difference. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a pivotal role in the host defense mechanism against oxidative stress. AIMS: This study aimed to clarify the role of Nrf2 in reflux-induced esophageal inflammation, focusing on the gender difference and nitric oxide. METHODS: Gastroesophageal reflux was surgically induced in male and female rats. Nitrite and ascorbic acid were administered for 1 week to provoke nitric oxide in the esophageal lumen. Male rats with gastroesophageal reflux were supplemented with 17β-estradiol or tert-butylhydroquinone, an Nrf2-inducing reagent. Esophageal squamous cell carcinoma KYSE30 cells were treated with 17β-estradiol. Nrf2 expression was examined by Western blotting and quantitative real-time PCR. Antioxidant gene expression profiles were examined by a PCR array. RESULTS: In the presence of nitric oxide, reflux-induced esophageal damage was less evident, whereas esophageal expression of Nrf2 and its target genes such as Nqo1 was more evident in female or male rats supplemented with 17β-estradiol than in male rats. 17β-Estradiol increased nuclear Nrf2 expression in KYSE30 cells. tert-Butylhydroquinone increased tissue Nqo1 mRNA expression, leading to a reduction in reflux-induced esophageal damage. CONCLUSIONS: Estrogen-dependent Nrf2 expression might contribute to protection against the development of gastroesophageal reflux disease in females.
Differences in Gut Microbiota Profiles between Autoimmune Pancreatitis and Chronic Pancreatitis.

Shin Hamada, Atsushi Masamune, Tatsuhide Nabeshima, Tooru Shimosegawa

The Tohoku journal of experimental medicine　244　(2)　113-117　2018年2月

DOI： 10.1620/tjem.244.113 　

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Host-derived factors alter gut microenvironment, and changes in gut microbiota also affect biological functions of host. Alterations of gut microbiota have been reported in a wide variety of diseases, but the whole picture of alterations in pancreatic diseases remains to be clarified. In particular, the gut microbiota may be affected by malnutrition or impaired exocrine pancreas function that is associated with pancreatic diseases. We here conducted comprehensive analysis of gut microbiota in patients with type 1 autoimmune pancreatitis (AIP), a pancreatic manifestation of the systemic IgG4-related disease, and chronic pancreatitis (CP). The two diseases were selected, because altered immune reactions in AIP and/or long-standing malnutrition in CP may influence the gut microbiota. Fecal samples were obtained from 12 patients with AIP before the steroid therapy and 8 patients with CP. Metagenome DNA was extracted, and microbiota was analyzed by next generation sequencing. Gut microbiota profiles were different between patients with AIP and those with CP; namely, the proportions of Bacteroides, Streptococcus and Clostridium species were higher in patients with CP. The reasons for the increased proportion of these bacterial species remain unknown, but may reflect malabsorption and/or decreased pancreatic enzymes, both of which are associated with CP. Incidentally, the identified Streptococcus species are oral cavity inhabitants and also known as pathogens for endocarditis. Despite the small sample size, this study has shown the differences in gut microbiota profiles between AIP and CP. Comprehensive analysis of the gut microbiota may be useful for the differential diagnosis of pancreatic diseases.
Nationwide survey of hereditary pancreatitis in Japan.

Atsushi Masamune, Kazuhiro Kikuta, Shin Hamada, Eriko Nakano, Kiyoshi Kume, Ayano Inui, Toshiaki Shimizu, Yoshifumi Takeyama, Masaki Nio, Tooru Shimosegawa

Journal of gastroenterology　53　(1)　152-160　2018年1月

DOI： 10.1007/s00535-017-1388-0 　

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BACKGROUND: Hereditary pancreatitis (HP) is a rare cause of chronic pancreatitis. We here report a nationwide survey to clarify the epidemiological, genetic, and clinical features of HP in Japan. METHODS: Target subjects were patients with HP and their family members who had visited selected hospitals between 2005 and 2014. This study consisted of two-stage surveys; patients with HP were identified by the first questionnaire and their clinical features were assessed by the second questionnaire. RESULTS: Two hundred seventy-one patients (153 males and 118 females) in 100 families diagnosed based on the Japanese criteria or 231 patients (131 males and 100 females) patients in 80 families based on the EUROPAC criteria were reported. Of the families undertaking genetic tests, 41% had the PRSS1 mutations (p.R122H 33%, p.N29I 8%) and 36% had the SPINK1 mutations (p.N34S 22%, c.194+2T>C 14%, p.P45S 1%). The mean age at symptom onset was 17.8 years. The cumulative rates of pancreatic exocrine insufficiency and diabetes mellitus were 16.1 and 5.5% at 20 years old, and 45.3 and 28.2% at 40 years, respectively. Forty-four percent of the patients underwent endoscopic treatment and/or surgery. The cumulative rate of pancreatic cancer diagnosis was 2.8% at 40 years old, 10.8% at 60 years, and 22.8% at 70 years. CONCLUSIONS: HP was characterized by early disease onset, frequent development of pancreatic exocrine insufficiency and diabetes mellitus, requirement of endoscopic treatment and/or surgery, and increased risk of pancreatic cancer. PRSS1 and SPINK1 mutations serve as genetic background for HP in Japan.
Simultaneous K-ras activation and Keap1 deletion cause atrophy of pancreatic parenchyma. 国際誌

Shin Hamada, Tooru Shimosegawa, Keiko Taguchi, Tatsuhide Nabeshima, Masayuki Yamamoto, Atsushi Masamune

American journal of physiology. Gastrointestinal and liver physiology　314　(1)　G65-G74　2018年1月1日

DOI： 10.1152/ajpgi.00228.2017 　

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The Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) system has a wide variety of effects in addition to the oxidative stress response, such as growth promotion and chemoresistance of cancer cells. Nrf2 is constitutively activated in most cancer cells. However, the activation of Nrf2 together with oncogenic mutations does not always result in cancer promotion. K-rasLSL-G12D/+:: p53LSL-R172H/+:: Pdx-1-Cre (KPC) mice are an established model of pancreatic cancer that specifically express mutants of both K-ras and p53 in the pancreas by using Pdx-1-Cre. We here generated Pdx-1-Cre::K-rasLSL-G12D/+:: Keap1fl/fl (KC::Keap1) and KPC:: Keap1fl/fl (KPC::Keap1) mice in which Nrf2 is constitutively activated by Keap1 deletion. KC::Keap1 and KPC::Keap1 mice started to die or showed obvious weakness at approximately around 40 days after birth. Histological examination revealed that KC::Keap1 and KPC::Keap1 mice did not develop pancreatic cancer but, instead, progressive atrophy of the pancreatic parenchyma. In these mice, amylase-positive acinar cells as well as insulin- and glucagon-positive islet cells were decreased and surrounded by fibrotic tissues. KC::Keap1 and KPC::Keap1 mice presented lower body weight and glucose levels than C::Keap1 mice, presumably resulting from pancreatic exocrine insufficiency. Histological changes were not obvious in C::Keap1 and PC::Keap1 mice. The presence of the p53 mutation did not affect the phenotypes in KC::Keap1 mice. Heterologous or homologous Nrf2 deletion ( Nrf2+/- or Nrf2-/-) rescued the pancreatic phenotypes, weight loss, and hypoglycemia in KC::Keap1 mice, suggesting that Nrf2 is a major downstream target of Keap1. In conclusion, simultaneous K-ras activation and Keap1 deletion caused progressive atrophy of the pancreatic parenchyma in mice. NEW & NOTEWORTHY Aberrant activation of the Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) system usually promotes carcinogenesis, and we assumed that simultaneous activation of K-ras and Nrf2 might promote pancreatic carcinogenesis. Conditional expression of mutant K-ras and Keap1 deletion did not result in pancreatic cancer development. Instead, these mice developed progressive loss of pancreatic parenchyma, accompanied by body weight loss and hypoglycemia, presumably because of pancreatic exocrine insufficiency. Nrf2 activation by Keap1 deletion concomitant with K-ras activation cause pancreatic atrophy.
Exosomes derived from pancreatic cancer cells induce activation and profibrogenic activities in pancreatic stellate cells. 国際誌

Atsushi Masamune, Naoki Yoshida, Shin Hamada, Tetsuya Takikawa, Tatsuhide Nabeshima, Tooru Shimosegawa

Biochemical and biophysical research communications　495　(1)　71-77　2018年1月1日

DOI： 10.1016/j.bbrc.2017.10.141 　

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Pancreatic cancer cells (PCCs) interact with pancreatic stellate cells (PSCs), which play a pivotal role in pancreatic fibrogenesis, to develop the cancer-conditioned tumor microenvironment. Exosomes are membrane-enclosed nanovesicles, and have been increasingly recognized as important mediators of cell-to-cell communications. The aim of this study was to clarify the effects of PCC-derived exosomes on cell functions in PSCs. Exosomes were isolated from the conditioned medium of Panc-1 and SUIT-2 PCCs. Human primary PSCs were treated with PCC-derived exosomes. PCC-derived exosomes stimulated the proliferation, migration, activation of ERK and Akt, the mRNA expression of α-smooth muscle actin (ACTA2) and fibrosis-related genes, and procollagen type I C-peptide production in PSCs. Ingenuity pathway analysis of the microarray data identified transforming growth factor β1 and tumor necrosis factor as top upstream regulators. PCCs increased the expression of miR-1246 and miR-1290, abundantly contained in PCC-derived exosomes, in PSCs. Overexpression of miR-1290 induced the expression of ACTA2 and fibrosis-related genes in PSCs. In conclusion, PCC-derived exosomes stimulate activation and profibrogenic activities in PSCs. Exosome-mediated interactions between PSCs and PCCs might play a role in the development of the tumor microenvironment.
Severity assessment of acute pancreatitis using four prognostic factors - a nationwide multicenter study of 3682 cases in Japan. 国際誌

Shin Hamada, Atsushi Masamune, Kazuhiro Kikuta, Tooru Shimosegawa

United European gastroenterology journal　5　(8)　1136-1137　2017年12月

DOI： 10.1177/2050640617725961 　
Nationwide epidemiological survey of early chronic pancreatitis in Japan.

Atsushi Masamune, Kazuhiro Kikuta, Tatsuhide Nabeshima, Eriko Nakano, Morihisa Hirota, Atsushi Kanno, Kiyoshi Kume, Shin Hamada, Tetsuhide Ito, Motokazu Fujita, Atsushi Irisawa, Masanori Nakashima, Keiji Hanada, Takaaki Eguchi, Ryusuke Kato, Osamu Inatomi, Akio Shirane, Yoshifumi Takeyama, Ichiro Tsuji, Tooru Shimosegawa

Journal of gastroenterology　52　(8)　992-1000　2017年8月

DOI： 10.1007/s00535-017-1311-8 　

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BACKGROUND: The world's first diagnostic criteria for early CP were proposed in 2009 in Japan. This study aimed to clarify the clinico-epidemiological features of early CP in Japan. METHODS: Patients with early CP who were diagnosed according to the diagnostic criteria for early CP and had visited the selected hospitals in 2011 were surveyed. The study consisted of two-stage surveys: the number of patients with early CP was estimated by the first questionnaire and their clinical features were assessed by the second questionnaire. RESULTS: The estimated number of early CP patients was 5410 (95% confidence interval 3675-6945), with an overall prevalence of 4.2 per 100,000 persons. The number of patients who were newly diagnosed with early CP was estimated to be 1330 (95% confidence interval 1058-1602), with an annual incidence of 1.0 per 100,000 persons. Detailed clinical information was obtained in 151 patients in the second survey. The male-to-female sex ratio was 1.32:1. The mean age was 60.4 and the mean age at disease onset was 55.4. Idiopathic (47.7%) and alcoholic (45.0%) were the two most common etiologies. Proportions of female and idiopathic cases were higher in early CP than in definite CP. Hyperechoic foci without shadowing and stranding were the most common findings on endoscopic ultrasonography. The clinical profiles of early CP patients who showed lobularity with honeycombing on endoscopic ultrasonography or previous episodes of acute pancreatitis were similar to those of definite CP patients. CONCLUSIONS: We clarified the current status of early CP in Japan.
Nrf2 promotes mutant K-ras/p53-driven pancreatic carcinogenesis. 国際誌

Shin Hamada, Keiko Taguchi, Atsushi Masamune, Masayuki Yamamoto, Tooru Shimosegawa

Carcinogenesis　38　(6)　661-670　2017年6月1日

DOI： 10.1093/carcin/bgx043 　

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The Keap1-Nrf2 system contributes to the maintenance of homeostasis by regulating oxidative stress responses in normal tissues and organs, and is exploited in various cancers for proliferation, survival and acquisition of therapy resistance. Pancreatic cancer remains one of the intractable cancers, despite the improved clinical outcomes of other types of cancer, due to its invasive and refractory nature to therapeutic intervention. The current study aimed to clarify the contribution of Nrf2 to pancreatic carcinogenesis using a pancreas-specific mutant K-ras and p53 (KPC) mouse model. Deletion of Nrf2 in KPC mice (KPCN) decreased the formation of precancerous lesions as well as the development of invasive pancreatic cancer. The pancreatic tumor-derived cancer cell lines from KPCN mouse showed decreased expression of glutathione S-transferases (GST), UDP glucuronosyltransferases (UGT) and ABC transporters. Along with these biochemical changes, cell lines from KPCN mice revealed increased sensitivity to oxidative stress and chemotherapeutic agent. The current study revealed that Nrf2 contributes to pancreatic carcinogenesis in a way distinct from the chemoresistance of lung and esophagus, and that Nrf2 could be a novel therapeutic target of pancreatic cancer.
Transition of early-phase treatment for acute pancreatitis: An analysis of nationwide epidemiological survey. 国際誌

Shin Hamada, Atsushi Masamune, Tooru Shimosegawa

World journal of gastroenterology　23　(16)　2826-2831　2017年4月28日

DOI： 10.3748/wjg.v23.i16.2826 　

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Treatment of acute pancreatitis (AP) is one of the critical challenges to the field of gastroenterology because of its high mortality rate and high medical costs associated with the treatment of severe cases. Early-phase treatments for AP have been optimized in Japan, and clinical guidelines have been provided. However, changes in early-phase treatments and the relationship between treatment strategy and clinical outcome remain unclear. Retrospective analysis of nationwide epidemiological data shows that time for AP diagnosis has shortened, and the amount of initial fluid resuscitation has increased over time, indicating the compliance with guidelines. In contrast, prophylactic use of broad-spectrum antibiotics has emerged. Despite the potential benefits of early enteral nutrition, its use is still limited. The roles of continuous regional arterial infusion in the improvement of prognosis and the prevention of late complications are uncertain. Furthermore, early-phase treatments have had little impact on late-phase complications, such as walled-off necrosis, surgery requirements and late (> 4 w) AP-related death. Based on these observations, early-phase treatments for AP in Japan have approached the optimal level, but late-phase complications have become concerning issues. Early-phase treatments and the therapeutic strategy for late-phase complications both need to be optimized based on firm clinical evidence and cost-effectiveness.
Kindlin-2 in pancreatic stellate cells promotes the progression of pancreatic cancer. 国際誌

Naoki Yoshida, Atsushi Masamune, Shin Hamada, Kazuhiro Kikuta, Tetsuya Takikawa, Fuyuhiko Motoi, Michiaki Unno, Tooru Shimosegawa

Cancer letters　390　103-114　2017年4月1日

DOI： 10.1016/j.canlet.2017.01.008 　

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Pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrosis associated with pancreatic ductal adenocarcinoma (PDAC). Kindlin-2 is a focal adhesion protein that regulates the activation of integrins. This study aimed to clarify the role of kindlin-2 in PSCs in pancreatic cancer. Kindlin-2 expression in 79 resected pancreatic cancer tissues was examined by immunohistochemical staining. Kindlin-2-knockdown immortalized human PSCs were established using small interfering RNA. Pancreatic cancer cells were treated with conditioned media of PSCs, and the cell proliferation and migration were examined. SUIT-2 pancreatic cancer cells were subcutaneously injected into nude mice alone or with PSCs and the size of the tumors was monitored. Kindlin-2 expression was observed in PDAC and the peritumoral stroma. Stromal kindlin-2 expression was associated with shorter recurrence-free survival time after R0 resection. Knockdown of kindlin-2 resulted in decreased proliferation, migration, and cytokine expression in PSCs. The PSC-induced proliferation and migration of pancreatic cancer cells were suppressed by kindlin-2 knockdown in PSCs. In vivo, co-injection of PSCs increased the size of the tumors, but this effect was abolished by kindlin-2 knockdown in PSCs. In conclusion, kindlin-2 in PSCs promoted the progression of pancreatic cancer.
Randomised controlled trial of long-term maintenance corticosteroid therapy in patients with autoimmune pancreatitis. 国際誌

Atsushi Masamune, Isao Nishimori, Kazuhiro Kikuta, Ichiro Tsuji, Nobumasa Mizuno, Tatsuo Iiyama, Atsushi Kanno, Yuichi Tachibana, Tetsuhide Ito, Terumi Kamisawa, Kazushige Uchida, Hideaki Hamano, Hiroaki Yasuda, Junichi Sakagami, Akira Mitoro, Masashi Taguchi, Yasuyuki Kihara, Hiroyuki Sugimoto, Yoshiki Hirooka, Satoshi Yamamoto, Kazuo Inui, Osamu Inatomi, Akira Andoh, Kazuyuki Nakahara, Hiroyuki Miyakawa, Shin Hamada, Shigeyuki Kawa, Kazuichi Okazaki, Tooru Shimosegawa

Gut　66　(3)　487-494　2017年3月

DOI： 10.1136/gutjnl-2016-312049 　

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OBJECTIVE: Corticosteroid has been established as the standard therapy for autoimmune pancreatitis (AIP), but the requirement for maintenance corticosteroid therapy is controversial. We conducted a randomised controlled trial to clarify the efficacy of maintenance corticosteroid therapy in patients with AIP. DESIGN: We conducted a multicentre, tertiary setting, randomised controlled trial. After the induction of remission with the initial oral prednisolone (PSL) treatment, maintenance therapy with PSL at 5-7.5 mg/day was continued for 3 years or withdrawn at 26 weeks. The primary endpoint was relapse-free survival over 3 years and the secondary endpoint was serious corticosteroid-related complications. All analyses were performed on an intention-to-treat basis. RESULTS: Between April 2009 and March 2012, 49 patients with AIP were randomly assigned to the maintenance therapy group (n=30) or the cessation group (n=19). Baseline characteristics were not different between the two groups. Relapses occurred within 3 years in 11 out of 19 (57.9%) patients assigned to the cessation group, and in 7 of 30 (23.3%) patients in the maintenance therapy group. The relapse rate over 3 years was significantly lower in the maintenance therapy group than that in the cessation group (p=0.011). The relapse-free survival was significantly longer in the maintenance therapy group than that in the cessation group (p=0.007). No serious corticosteroid-related complications requiring discontinuation of PSL were observed. CONCLUSIONS: Maintenance corticosteroid therapy for 3 years may decrease relapses in patients with AIP compared with those who discontinued the therapy at 26 weeks. TRIAL REGISTRATION NUMBER: UMIN000001818; Results.
Disseminated Intravascular Coagulation on Admission Predicts Complications and Poor Prognosis of Acute Pancreatitis: Analysis of the Nationwide Epidemiological Survey in Japan. 国際誌

Shin Hamada, Atsushi Masamune, Kazuhiro Kikuta, Tooru Shimosegawa

Pancreas　46　(2)　e15-e16　2017年2月

DOI： 10.1097/MPA.0000000000000739 　
Exosomes Derived From Pancreatic Stellate Cells: MicroRNA Signature and Effects on Pancreatic Cancer Cells. 国際誌

Tetsuya Takikawa, Atsushi Masamune, Naoki Yoshida, Shin Hamada, Takayuki Kogure, Tooru Shimosegawa

Pancreas　46　(1)　19-27　2017年1月

eISSN：1536-4828

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OBJECTIVES: Pancreatic stellate cells (PSCs) interact with pancreatic cancer cells in the tumor microenvironment. Cell constituents including microRNAs may be exported from cells within membranous nanovesicles termed exosomes. Exosomes might play a pivotal role in intercellular communication. This study aimed to clarify the microRNA signature of PSC-derived exosomes and their effects on pancreatic cancer cells. METHODS: Exosomes were prepared from the conditioned medium of immortalized human PSCs. MicroRNAs were prepared from the exosomes and their source PSCs, and the microRNA expression profiles were compared by microarray. The effects of PSC-derived exosomes on proliferation, migration, and the mRNA expression profiles were examined in pancreatic cancer cells. RESULTS: Pancreatic stellate cell-derived exosomes contained a variety of microRNAs including miR-21-5p. Several microRNAs such as miR-451a were enriched in exosomes compared to their source PSCs. Pancreatic stellate cell-derived exosomes stimulated the proliferation, migration and expression of mRNAs for chemokine (C - X - C motif) ligands 1 and 2 in pancreatic cancer cells. The stimulation of proliferation, migration, and chemokine gene expression by the conditioned medium of PSCs was suppressed by GW4869, an exosome inhibitor. CONCLUSIONS: We clarified the microRNA expression profile in PSC-derived exosomes. Pancreatic stellate cell-derived exosomes might play a role in the interactions between PSCs and pancreatic cancer cells.
Clinicopathological Characteristics of Young Patients With Pancreatic Cancer: An Analysis of Data From Pancreatic Cancer Registry of Japan Pancreas Society. 国際誌

Hidetoshi Eguchi, Hiroki Yamaue, Michiaki Unno, Masamichi Mizuma, Shin Hamada, Hisato Igarashi, Tamotsu Kuroki, Sohei Satoi, Yasuhiro Shimizu, Masaji Tani, Satoshi Tanno, Yoshiki Hirooka, Tsutomu Fujii, Atsushi Masamune, Kazuhiro Mizumoto, Takao Itoi, Shinichi Egawa, Yuzo Kodama, Masao Tanaka, Tooru Shimosegawa

Pancreas　45　(10)　1411-1417　2016年11月

eISSN：1536-4828

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OBJECTIVES: The aim of this study was to determine the characteristics of patients with pancreatic ductal adenocarcinoma younger than 40 years. METHODS: Data from the Japan Pancreas Society's nationwide Pancreatic Cancer Registry were analyzed retrospectively. Clinicopathological characteristics were compared in patients who were grouped according to age, namely, younger than 40 years versus 40 years and older. RESULTS: Of the 36 145 patients in the database, the younger group included 526 (1.5%) patients. A family history of pancreatic cancer was not more frequent in the younger group. The frequency of Union Internationale Contre le Cancer T4 and M1 were both significantly higher in younger patients, resulting in a higher percentage of patients with Union Internationale Contre le Cancer stage IV. Pancreatectomy was performed less frequently in the younger group, and R0 resection was also less frequent. The overall survival rate was significantly better in the older group, whereas in surgically resected patients, the overall survival and recurrence-free survival rates were not different between the 2 groups. CONCLUSIONS: Younger patients with pancreatic adenocarcinoma were more often diagnosed at advanced stages, and the overall survival rate was worse than that in older patients. Family genetic background and the prognoses of patients who underwent surgery were similar between the 2 groups.
Management of acute pancreatitis in Japan: Analysis of nationwide epidemiological survey. 国際誌

Shin Hamada, Atsushi Masamune, Tooru Shimosegawa

World journal of gastroenterology　22　(28)　6335-44　2016年7月28日

DOI： 10.3748/wjg.v22.i28.6335 　

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Acute pancreatitis (AP) is an acute inflammatory disease of the exocrine pancreas. In Japan, nationwide epidemiological surveys have been conducted every 4 to 5 years by the Research Committee of Intractable Pancreatic Diseases, under the support of the Ministry of Health, Labour, and Welfare of Japan. We reviewed the results of the nationwide surveys focusing on the severity assessment and changes in the therapeutic strategy for walled-off necrosis. The severity assessment system currently used in Japan consists of 9 prognostic factors and the imaging grade on contrast-enhanced computed tomography. By univariate analysis, all of the 9 prognostic factors were associated with AP-related death. A multivariate analysis identified 4 out of the 9 prognostic factors (base excess or shock, renal failure, systemic inflammatory response syndrome criteria, and age) that were associated with AP-related death. Receiver-operating characteristics curve analysis showed that the area under the curve was 0.82 for these 4 prognostic factors and 0.84 for the 9 prognostic factors, suggesting the comparable utility of these 4 factors in the severity assessment. We also examined the temporal changes in treatment strategy for walled-off necrosis in Japan according to the 2003, 2007, and 2011 surveys. Step-up approaches and less-invasive endoscopic therapies were uncommon in 2003 and 2007, but became popular in 2011. Mortality has been decreasing in patients who require intervention for walled-off necrosis. In conclusion, the nationwide survey revealed the comparable utility of 4 prognostic factors in the severity assessment and the increased use of less-invasive, step-up approaches with improved clinical outcomes in the management of walled-off necrosis.
MicroRNA-320 family is downregulated in colorectal adenoma and affects tumor proliferation by targeting CDK6. 国際誌

Toshihiro Tadano, Yoichi Kakuta, Shin Hamada, Yosuke Shimodaira, Masatake Kuroha, Yoko Kawakami, Tomoya Kimura, Hisashi Shiga, Katsuya Endo, Atsushi Masamune, Seiichi Takahashi, Yoshitaka Kinouchi, Tooru Shimosegawa

World journal of gastrointestinal oncology　8　(7)　532-42　2016年7月15日

DOI： 10.4251/wjgo.v8.i7.532 　

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AIM: To investigate the microRNA (miRNA) expression during histological progression from colorectal normal mucosa through adenoma to carcinoma within a lesion. METHODS: Using microarray, the sequential changes in miRNA expression profiles were compared in colonic lesions from matched samples; histologically, non-neoplastic mucosa, adenoma, and submucosal invasive carcinoma were microdissected from a tissue sample. Cell proliferation assay was performed to observe the effect of miRNA, and its target genes were predicted using bioinformatics approaches and the expression profile of SW480 transfected with the miRNA mimics. mRNA and protein levels of the target gene in colon cancer cell lines with a mimic control or miRNA mimics were measured using qRT-PCR and Western blotting. The expression levels of miRNA and target gene in colorectal tissue samples were also measured. RESULTS: Microarray analysis identified that the miR-320 family, including miR-320a, miR-320b, miR-320c, miR-320d and miR-320e, were differentially expressed in adenoma and submucosal invasive carcinoma. The miR-320 family, which inhibits cell proliferation, is frequently downregulated in colorectal adenoma and submucosal invasive carcinoma tissues. Seven genes including CDK6 were identified to be common in the results of gene expression array and bioinformatics analyses performed to find the target gene of the miR-320 family. We confirmed that mRNA and protein levels of CDK6 were significantly suppressed in colon cancer cell lines with miR-320 family mimics. CDK6 expression was found to increase from non-neoplastic mucosa through adenoma to submucosal invasive carcinoma tissues and showed an inverse correlation with miR-320 family expression. CONCLUSION: MiR-320 family affects colorectal tumor proliferation by targeting CDK6, plays important role in its growth, and is considered to be a biomarker for its early detection.
IL-6/STAT3 Plays a Regulatory Role in the Interaction Between Pancreatic Stellate Cells and Cancer Cells. 国際誌

Shin Hamada, Atsushi Masamune, Naoki Yoshida, Tetsuya Takikawa, Tooru Shimosegawa

Digestive diseases and sciences　61　(6)　1561-71　2016年6月

DOI： 10.1007/s10620-015-4001-5 　

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BACKGROUND: Pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrosis, a characteristic feature of pancreatic cancer. Although it is still controversial, previous studies have suggested that PSCs promote the progression of pancreatic cancer by regulating the cell functions of cancer cells. PSCs produce large amounts of IL-6, which promotes the accumulation of myeloid-derived suppressor cells via a signal transducers and activator of transcription 3 (STAT3)-dependent mechanism. But the role of IL-6/STAT3 pathway in the interaction between PSCs and pancreatic cancer cells remains largely unknown. AIMS: To clarify the role of IL-6/STAT3 in the interaction between PSCs and cancer cells. METHODS: Human pancreatic cancer cells (Panc-1 and SUIT-2 cells) were treated with conditioned medium of immortalized human PSCs (PSC-CM). The effects of PSC-CM and IL-6 neutralization on the mRNA expression profiles were examined using Agilent's microarray. Activation of STAT3 was assessed by Western blotting using an anti-phospho-specific antibody. Cellular migration was examined by a two-chamber assay. The expression of markers related to epithelial-mesenchymal transition (EMT) was assessed by real-time reverse transcription PCR. RESULTS: PSC-CM induced the activation of STAT3 in pancreatic cancer cells. Neutralization of IL-6 suppressed the PSC-CM-induced upregulation of genes including complement factor B, lipocalin, and chemokine (C-C motif) ligand 20. Inhibition of IL-6/STAT3 pathway by anti-IL-6 antibody or a STAT3 inhibitor (NSC74859) inhibited the PSC-CM-induced migration and the expression of EMT-related markers (Snail and cadherin-2) in pancreatic cancer cells. CONCLUSION: IL-6/STAT3 pathway regulates the PSC-induced EMT and alterations in gene expression in pancreatic cancer cells.
No Association Between CEL-HYB Hybrid Allele and Chronic Pancreatitis in Asian Populations. 国際誌

Wen-Bin Zou, Arnaud Boulling, Atsushi Masamune, Prachand Issarapu, Emmanuelle Masson, Hao Wu, Xiao-Tian Sun, Liang-Hao Hu, Dai-Zhan Zhou, Lin He, Yann Fichou, Eriko Nakano, Shin Hamada, Yoichi Kakuta, Kiyoshi Kume, Hiroyuki Isayama, Sumit Paliwal, K Radha Mani, Seema Bhaskar, David N Cooper, Claude Férec, Tooru Shimosegawa, Giriraj R Chandak, Jian-Min Chen, Zhao-Shen Li, Zhuan Liao

Gastroenterology　150　(7)　1558-1560　2016年6月

DOI： 10.1053/j.gastro.2016.02.071 　

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A hybrid allele between the carboxyl ester lipase gene (CEL) and its pseudogene, CELP (called CEL-HYB), generated by nonallelic homologous recombination between CEL intron 10 and CELP intron 10', was found to increase susceptibility to chronic pancreatitis in a case-control study of patients of European ancestry. We attempted to replicate this finding in 3 independent cohorts from China, Japan, and India, but failed to detect the CEL-HYB allele in any of these populations. The CEL-HYB allele might therefore be an ethnic-specific risk factor for chronic pancreatitis. An alternative hybrid allele (CEL-HYB2) was identified in all 3 Asian populations (1.7% combined carrier frequency), but was not associated with chronic pancreatitis.
Risk factors for recurrent biliary obstruction following placement of self-expandable metallic stents in patients with malignant perihilar biliary stricture. 国際誌

Shin Miura, Atsushi Kanno, Atsushi Masamune, Shin Hamada, Seiji Hongou, Naoki Yoshida, Eriko Nakano, Tetsuya Takikawa, Kiyoshi Kume, Kazuhiro Kikuta, Morihisa Hirota, Hiroshi Yoshida, Yu Katayose, Michiaki Unno, Tooru Shimosegawa

Endoscopy　48　(6)　536-45　2016年6月

DOI： 10.1055/s-0042-102651 　

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BACKGROUND AND STUDY AIM: Self-expandable metallic stents (SEMSs) are used for palliation in patients with malignant perihilar biliary strictures. However, recurrent biliary obstruction occasionally causes cholangitis and jaundice. This study aimed to identify risk factors for recurrent biliary obstruction in such patients. METHODS: Data from consecutive patients with malignant perihilar biliary strictures treated with endoscopic placement of SEMSs between 2007 and 2014 in Tohoku University Hospital were retrospectively reviewed. Risk factors for recurrent biliary obstruction were calculated using the Cox proportional hazards models (with hazard ratios [HRs] and 95 % confidence interval [95 %CIs]), and SEMS patency period was examined using the Kaplan - Meier method. SEMS patency was defined as the period between SEMS insertion and the development of recurrent biliary obstruction. RESULTS: 104 patients were included. Median survival time was 281 days; and 85 patients died during a median follow-up period of 320 days. Recurrent biliary obstruction occurred in 35 patients. Median SEMS patency period was 549 days. Multivariable analyses showed that: compared with bile duct carcinoma, gallbladder carcinoma was associated with shorter SEMS patency (HR 8.18, 95 %CI 2.41 - 26.83); patency of left-sided SEMS was inferior to that of bilateral (HR 0.5, 95 %CI 0.32 - 0.93) and right-sided SEMS (HR 0.1, 95 %CI 0.02 - 0.65). Cholangitis before SEMS placement increased the risk of recurrent biliary obstruction (HR 11.44; 95 %CI 4.48 - 32.35) and reduced the SEMS patency period (746 vs. 210 days). CONCLUSION: Gallbladder carcinoma, left-sided stent placement, and cholangitis before SEMS placement are risk factors for recurrent biliary obstruction after SEMS placement.
Clinical Impact of Elevated Serum Triglycerides in Acute Pancreatitis: Validation from the Nationwide Epidemiological Survey in Japan. 国際誌

Shin Hamada, Atsushi Masamune, Kazuhiro Kikuta, Tooru Shimosegawa

The American journal of gastroenterology　111　(4)　575-6　2016年4月

DOI： 10.1038/ajg.2015.421 　
Ectopic Opening of the Common Bile Duct Accompanied by Choledochocele and Pancreas Divisum.

Tetsuya Takikawa, Atsushi Kanno, Atsushi Masamune, Seiji Hongo, Naoki Yoshida, Eriko Nakano, Shin Miura, Shin Hamada, Kiyoshi Kume, Kazuhiro Kikuta, Morihisa Hirota, Tooru Shimosegawa

Internal medicine (Tokyo, Japan)　55　(9)　1097-102　2016年

DOI： 10.2169/internalmedicine.55.6240 　

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A 32-year-old woman was referred due to abdominal pain and elevated liver enzymes. Computed tomography and magnetic resonance imaging showed ectopic opening of the common bile duct (CBD) into the duodenal bulb. Esophagogastroduodenoscopy showed a hemispheric bulge in the duodenal bulb. Endoscopic retrograde cholangiopancreatography (ERCP) revealed the bulge to be cystic dilatation of the CBD. ERCP also showed no communication between the ventral and dorsal pancreatic ducts. We diagnosed the patient with ectopic opening of the CBD accompanied by choledochocele and pancreas divisum. Endoscopic incision was performed for the treatment of the choledochocele. The patient's symptoms and elevated liver enzymes improved after treatment.
Variants in pancreatic carboxypeptidase genes CPA2 and CPB1 are not associated with chronic pancreatitis. 国際誌

Eriko Nakano, Andrea Geisz, Atsushi Masamune, Tetsuya Niihori, Shin Hamada, Kiyoshi Kume, Yoichi Kakuta, Yoko Aoki, Yoichi Matsubara, Karolin Ebert, Maren Ludwig, Markus Braun, David A Groneberg, Tooru Shimosegawa, Miklós Sahin-Tóth, Heiko Witt

American journal of physiology. Gastrointestinal and liver physiology　309　(8)　G688-94　2015年10月15日

DOI： 10.1152/ajpgi.00241.2015 　

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Genetic alterations in the carboxypeptidase A1 gene (CPA1) are associated with early onset chronic pancreatitis (CP). Besides CPA1, there are two other human pancreatic carboxypeptidases (CPA2 and CPB1). Here we examined whether CPA2 and CPB1 alterations are associated with CP in Japan and Germany. All exons and flanking introns of CPA2 and CPB1 were sequenced in 477 Japanese patients with CP (234 alcoholic, 243 nonalcoholic) and in 497 German patients with nonalcoholic CP by targeted next-generation sequencing and/or Sanger sequencing. Secretion and enzymatic activity of CPA2 and CPB1 variants were determined after transfection into HEK 293T cells. We identified six nonsynonymous CPA2 variants (p.V67I, p.G166R, p.D168E, p.D173H, p.R237W, and p.G388S), eight nonsynonymous CPB1 alterations (p.S65G, p.N120S, p.D172E, p.R195H, p.D208N, p.F232L, p.A317V, and p.D364Y), and one splice-site variant (c.687+1G>T) in CPB1. Functional analysis revealed essentially complete loss of function in CPA2 variants p.R237W and p.G388S and CPB1 variants p.R110H and p.D364Y. None of the CPA2 or CPB1 variants, including those resulting in a marked loss of function, were overrepresented in patients with CP. In conclusion, CPA2 and CPB1 variants are not associated with CP.
IgG4-unrelated type 1 autoimmune pancreatitis. 国際誌

Eriko Nakano, Atsushi Kanno, Atsushi Masamune, Naoki Yoshida, Seiji Hongo, Shin Miura, Tetsuya Takikawa, Shin Hamada, Kiyoshi Kume, Kazuhiro Kikuta, Morihisa Hirota, Keisuke Nakayama, Fumiyoshi Fujishima, Tooru Shimosegawa

World journal of gastroenterology　21　(33)　9808-16　2015年9月7日

DOI： 10.3748/wjg.v21.i33.9808 　

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A 50-year-old male was referred to our hospital for the evaluation of hyperproteinemia. Fluorodeoxyglucose positron emission tomography revealed high fluorodeoxyglucose uptake in the pancreas, bilateral lacrimal glands, submandibular glands, parotid glands, bilateral pulmonary hilar lymph nodes, and kidneys. Laboratory data showed an elevation of hepatobiliary enzymes, renal dysfunction, and remarkably high immunoglobulin (Ig) G levels, without elevated serum IgG4. Abdominal computed tomography revealed swelling of the pancreatic head and bilateral kidneys. Endoscopic retrograde cholangiopancreatography showed an irregular narrowing of the main pancreatic duct in the pancreatic head and stricture of the lower common bile duct. Histological examination by endoscopic ultrasonography-guided fine-needle aspiration revealed findings of lymphoplasmacytic sclerosing pancreatitis without IgG4-positive plasma cells. Abnormal laboratory values and the swelling of several organs were improved by the treatment with steroids. The patient was diagnosed as having type 1 autoimmune pancreatitis (AIP) based on the International Consensus Diagnostic Criteria. Therefore, we encountered a case of compatible type 1 AIP without elevated levels of serum IgG4 or IgG4-positive plasma cells. This case suggests that AIP phenotypes are not always associated with IgG4.
Common variants at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with chronic pancreatitis in Japan. 国際誌

Atsushi Masamune, Eriko Nakano, Shin Hamada, Yoichi Kakuta, Kiyoshi Kume, Tooru Shimosegawa

Gut　64　(8)　1345-6　2015年8月

DOI： 10.1136/gutjnl-2015-309802 　
[Pancreatic cancer stem cell]. 査読有り

Hamada S, Masamune A, Shimosegawa T

Nihon rinsho. Japanese journal of clinical medicine　73　(5)　844-849　2015年5月

ISSN：0047-1852
[Invasion and metastasis of biliary tract cancer]. 査読有り

Hamada S, Masamune A, Shimosegawa T

Nihon rinsho. Japanese journal of clinical medicine　73 Suppl 3　461-465　2015年3月

ISSN：0047-1852
Involvement of epithelial to mesenchymal transition in the development of pancreatic ductal adenocarcinoma.

Kennichi Satoh, Shin Hamada, Tooru Shimosegawa

Journal of gastroenterology　50　(2)　140-6　2015年2月

DOI： 10.1007/s00535-014-0997-0 　

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Pancreatic ductal adenocarcinoma (PDAC) is an intractable disease as a result of its rapid dissemination and resistance to conventional chemotherapy and radiotherapy. Surgical resection is the only curative therapy, but most of the tumors are unresectable at the time of diagnosis. The molecular mechanisms underlying the biological aggressiveness of this tumor type remain to be clarified. Epithelial to mesenchymal transition (EMT) is a developmental process that leads the phenotype shift from an epithelial morphology to a motile, fibroblast-like morphology. Recent studies showed that EMT is involved in the invasion and metastasis of many types of carcinomas including PDAC. In addition, PDAC cells with the EMT phenotype also exhibit chemoresistance and the cancer stem cell property. Various factors such as cytokines, growth factors, or transcriptional factors were found to promote the EMT program in PDAC cells. In this review, we summarize the current knowledge about the EMT in PDAC cells, focusing on the involvement of this process and its regulatory molecules including microRNA during the development of PDAC cells.
Circulating miR-483-3p and miR-21 is highly expressed in plasma of pancreatic cancer. 国際誌

Makoto Abue, Misa Yokoyama, Rie Shibuya, Keiichi Tamai, Kazunori Yamaguchi, Ikuro Sato, Nobuyuki Tanaka, Shin Hamada, Tooru Shimosegawa, Kazuo Sugamura, Kennichi Satoh

International journal of oncology　46　(2)　539-47　2015年2月

DOI： 10.3892/ijo.2014.2743 　

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Several recent studies have revealed that microRNAs (miRNAs) have a role in carcinogenesis and cancer development, and that it is stably detectable in plasma/serum. The aim of this study was to test whether miR‑483-3p as well as miR‑21 could be plasma biomarkers for PDAC. The plasma samples were obtained from three groups including 32 pancreatic ductal adenocarcinoma (PDAC) patients, 12 patients with intraductal papillary mucinous neoplasm (IPMN) patients and 30 healthy controls (HC). We evaluated the plasma miR‑483-3p and miR‑21 expression level by quantitative RT-PCR. We compared the differences in the plasma level of these miRNAs among the three groups, and investigated the relevance of their plasma expression level to the clinical factors in PDAC. The expressions of miR‑483-3p and miR‑21 were detected in all examined plasma samples. The plasma expression levels of these miRNAs were significantly higher in PDAC compared to HC (P<0.01). The plasma miR‑483-3p expression was significantly higher in PDAC patients than IPMN patients (P<0.05). The plasma miR‑21 level was associated with advanced stage (P<0.05), metastasis to lymph node and liver (P<0.01), and shorter survival (P<0.01) of the PDAC patients. Together, these findings suggest that measurement of the plasma miR‑483-3p level is useful for discriminating PDAC from IPMN, and that the plasma miR‑21 level predicts outcome of PDAC patients.
Comprehensive Analysis of Serum microRNAs in Autoimmune Pancreatitis. 国際誌

Shin Hamada, Atsushi Masamune, Atsushi Kanno, Tooru Shimosegawa

Digestion　91　(4)　263-71　2015年

DOI： 10.1159/000381283 　

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BACKGROUND/AIMS: Autoimmune pancreatitis (AIP) is a rare disease that has recently emerged as a unique type of pancreatitis with a presumed autoimmune etiology. MicroRNA (miRNA) is a small non-coding RNA that targets multiple mRNAs. miRNAs might exist in serum in a stabilized form, suggesting its potential application as a biomarker. We here examined the miRNA expression profile in the serum of patients with AIP. METHODS: miRNAs were prepared from serum samples of patients with various pancreatic diseases (AIP (n = 3, each before and after the steroid therapy), chronic pancreatitis (n = 5), pancreatic cancer (n = 5)) or healthy controls (n = 5). A human miRNA Oligo chip containing approximately 2,000 miRNAs was used to identify differentially expressed miRNAs. Ingenuity Pathway Analysis (IPA) was used for the integrated analysis of altered miRNAs. RESULTS: Microarray analysis identified miRNAs highly expressed in the serum of patients with AIP: 13 miRNAs vs. CP, 204 miRNAs vs. pancreatic cancer, and 19 miRNAs vs. healthy controls. miR-150-5p was commonly upregulated in AIP compared to the other samples. IPA revealed the most biological processes affected by the steroid therapy including cellular development, cellular growth, and cell movement. CONCLUSION: Our results identified that miRNAs were differentially expressed in the serum of AIP patients.
The usefulness of endoscopic ultrasound-guided fine-needle aspiration for the diagnosis of pancreatic neuroendocrine tumors based on the World Health Organization classification 国際誌査読有り

Jun Unno, Atsushi Kanno, Atsushi Masamune, Atsuko Kasajima, Fumiyoshi Fujishima, Kazuyuki Ishida, Shin Hamada, Kiyoshi Kume, Kazuhiro Kikuta, Morihisa Hirota, Fuyuhiko Motoi, Michiaki Unno, Tooru Shimosegawa

Scandinavian Journal of Gastroenterology　49　(11)　1367-1374　2014年11月1日
出版者・発行元： Informa UK Limited
DOI： 10.3109/00365521.2014.934909 　

ISSN：0036-5521

eISSN：1502-7708

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BACKGROUND: We assessed the controversial topic of using 22-gauge needles in endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for the diagnosis and evaluation of Ki67 labeling indices (Ki67LI) of pancreatic neuroendocrine tumors (pNET). METHODS: Thirty-eight patients with pNET who underwent EUS-FNA between January 1, 2008 and December 31, 2012 were enrolled in this study. When available, the Ki67LI and WHO classifications obtained by EUS-FNA and surgical resection were compared. RESULTS: EUS-FNA with a 22-gauge needle acquired sufficient histological sample to correctly diagnose pNET in 35 cases (92.1%). Both EUS-FNA and surgical histological specimens were available for 19 cases, and grading classes of the 2 procedures were consistent in 17 cases (89.5%) according to the WHO classification based on the Ki67LI. Tumor size was associated with a difference in the Ki67LI between the 2 procedures, although the Ki67LI was almost completely consistent for tumors less than 18 mm in size. CONCLUSIONS: EUS-FNA with a 22-gauge needle is a safe and highly accurate technique for the diagnosis of pNET. There was a clear correlation between the Ki67LI of histological specimens acquired by EUS-FNA and surgery. EUS-FNA with a 22-gauge needle is useful to predict the WHO classification of pNET.
Alteration of the microRNA expression profile during the activation of pancreatic stellate cells. 国際誌

Atsushi Masamune, Eriko Nakano, Shin Hamada, Tetsuya Takikawa, Naoki Yoshida, Tooru Shimosegawa

Scandinavian journal of gastroenterology　49　(3)　323-31　2014年3月

DOI： 10.3109/00365521.2013.876447 　

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OBJECTIVE. Pancreatic stellate cells (PSCs) play a pivotal role in the pancreatic fibrosis associated with chronic pancreatitis and pancreatic cancer. In response to pancreatic injury or inflammation, PSCs are activated to myofibroblast-like cells. MicroRNA (miRNA) is a small RNA, consisting of 17-25 nucleotides, which targets 3'-untranslated region sequences of mRNA. miRNAs regulate a variety of cell functions such as cell proliferation, differentiation, and carcinogenesis. We examined here whether the miRNA expression profiles are altered during the activation of PSCs. MATERIALS AND METHODS. Rat PSCs were isolated from the pancreas tissue of male Wistar rats. PSCs were activated in vitro by culture in serum-containing medium. miRNAs were prepared from quiescent (day 1) PSCs and culture-activated (day 14) PSCs. Agilent's miRNA microarray containing probes for 680 miRNAs was used to identify differentially expressed miRNAs. Ingenuity Pathway Analysis (IPA) was used for the integrated analysis of altered miRNAs. RESULTS. Upon activation, 42 miRNAs were upregulated (>2.0-fold) and 42 miRNAs were downregulated (<0.5-fold). Upregulated miRNAs included miR-31, miR-143, and miR-221. Downregulated miRNAs included miR-126, miR-146a, and miR-150. IPA revealed the most impacted biological processes including cellular development, cellular growth, and cell movement. Interestingly, IPA identified 22 miRNAs affected both in pancreatic cancer and PSC activation. The top network generated by IPA revealed the interactions of altered miRNAs with signaling pathways such as p38 mitogen-activated protein kinase, extracellular-signal-regulated kinase, and Smad2/3. CONCLUSIONS. Our results suggest a novel role of miRNAs in the activation of PSCs.
Sudden Disappearance of the Blood Flow in a Case of Pancreatic Acinar Cell Carcinoma 査読有り

Atsushi Kanno, Atsushi Masamune, Shin Hamada, Kazuhiro Kikuta, Kiyoshi Kume, Morihisa Hirota, Kentaro Shima, Takaho Okada, Fuyuhiko Motoi, Fumiyoshi Fujishima, Kazuyuki Ishida, Michiaki Unno, Tooru Shimosegawa

Internal Medicine　53　(22)　2589-2593　2014年
出版者・発行元： Japanese Society of Internal Medicine
DOI： 10.2169/internalmedicine.53.2859 　

ISSN：0918-2918

eISSN：1349-7235

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A 55-year-old man was referred to our hospital for a further examination of a pancreatic cystic tumor with a solid component exhibiting vascularity. A few days later, the patient was admitted with a complaint of sudden severe epigastric pain. Enhanced CT showed the loss of vascularity in the tumor. In particular, contrast-enhanced endoscopic ultrasonography (EUS) clearly demonstrated the disappearance of the blood flow, and a histological examination revealed acinar cell carcinoma with central necrosis. To our knowledge, this is the first case in the literature of acinar cell carcinoma associated with the sudden disappearance of vascularity. In this case, contrast-enhanced harmonic EUS was especially useful for assessing the degree of vascularity.
miR-210 regulates the interaction between pancreatic cancer cells and stellate cells. 国際誌

Tetsuya Takikawa, Atsushi Masamune, Shin Hamada, Eriko Nakano, Naoki Yoshida, Tooru Shimosegawa

Biochemical and biophysical research communications　437　(3)　433-9　2013年8月2日

DOI： 10.1016/j.bbrc.2013.06.097 　

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There is accumulating evidence that pancreatic stellate cells (PSCs) promote the progression of pancreatic cancer. microRNAs (miRNAs) are small non-coding RNAs acting as negative regulators of gene expression at the post-transcriptional level. This study aimed to clarify the role of miRNAs in the interaction between PSCs and pancreatic cancer cells. Pancreatic cancer cells were mono-cultured or indirectly co-cultured with PSCs. miRNAs were prepared, and Agilent's miRNA microarray containing probes for 904 human miRNAs was used to identify differentially expressed miRNAs. miR-210 was identified as an upregulated miRNA by co-culture with PSCs. Conditioned media of PSCs activated ERK and Akt, but not hypoxia-inducible factor-1α pathway. PSCs-induced miR-210 upregulation was inhibited by inhibitors of ERK and PI3K/Akt pathways. Inhibition of miR-210 expression decreased migration, decreased the expression of vimentin and snai-1, and increased the membrane-associated expression of β-catenin in Panc-1 cells co-cultured with PSCs. In conclusion, our results suggest a novel role of miR-210 in the interaction between PSCs and pancreatic cancer cells.
miR-197 induces epithelial-mesenchymal transition in pancreatic cancer cells by targeting p120 catenin 国際誌査読有り

Shin Hamada, Kennichi Satoh, Shin Miura, Morihisa Hirota, Atsushi Kanno, Atsushi Masamune, Kazuhiro Kikuta, Kiyoshi Kume, Jun Unno, Shinichi Egawa, Fuyuhiko Motoi, Michiaki Unno, Tooru Shimosegawa

Journal of Cellular Physiology　228　(6)　1255-1263　2013年6月
出版者・発行元： Wiley
DOI： 10.1002/jcp.24280 　

ISSN：0021-9541

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Invasive ductal adenocarcinoma (IDA) of the pancreas manifests poor prognosis due to the early invasion and distant metastasis. In contrast, intraductal papillary mucinous adenoma or carcinoma (IPMA or IPMC) reveals better clinical outcomes. Various molecular mechanisms contribute to these differences but entire picture is still unclear. Recent researches emphasized the important role of miRNA in biological processes including cancer invasion and metastasis. We previously described that miR-126 is down-regulated in IDA compared with IPMA or IPMC, and miR-126 regulates the expression of invasion related molecule disintegrin and metalloproteinase domain-containing protein 9 (ADAM9). Assessing the difference of miRNA expression profiles of IDA, IPMA, and IPMC, we newly identified miR-197 as an up-regulated miRNA specifically in IDA. Expression of miR-197 in pancreatic cancer cells resulted in the induction of epithelial-mesenchymal transition (EMT) along with the down-regulation of p120 catenin which is a putative target of miR-197. Direct interaction between miR-197 and p120 catenin mRNA sequence was confirmed by 3'UTR assay, and knockdown of p120 catenin recapitulated EMT induction in pancreatic cancer cells. In situ hybridization of miR-197 and immunohistochemistry of p120 catenin showed mutually exclusive patterns suggesting pivotal role of miR-197 in the regulation of p120 catenin. This miR-197/p120 catenin axis could be a novel therapeutic target.
The angiotensin II type I receptor blocker olmesartan inhibits the growth of pancreatic cancer by targeting stellate cell activities in mice. 国際誌

Atsushi Masamune, Shin Hamada, Kazuhiro Kikuta, Tetsuya Takikawa, Shin Miura, Eriko Nakano, Tooru Shimosegawa

Scandinavian journal of gastroenterology　48　(5)　602-9　2013年5月

DOI： 10.3109/00365521.2013.777776 　

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There is accumulating evidence that pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, promote the progression of pancreatic cancer. The interactions between PSCs and pancreatic cancer have attracted substantial attention as a novel therapeutic target for the treatment of pancreatic cancer. We examined here the effects of olmesartan, an angiotensin II type I receptor blocker, on pancreatic cancer-associated fibrosis using a subcutaneous tumor model developed by co-injection of pancreatic cancer cells with PSCs in nude mice. Co-injection of pancreatic cancer cells AsPC-1 with PSCs increased the size of tumors compared with AsPC-1 cells alone. Olmesartan administrated at 10 mg/kg in drinking water inhibited the growth of subcutaneous tumors derived from the co-injection, but not those derived from mono-injection. This effect was accompanied by decreased expression of α-smooth muscle actin (a marker of activated PSCs) and collagen deposition. The inhibitory effect of olmesartan was also observed even if it was administrated after significant development of subcutaneous tumors. In addition, olmesartan decreased cell growth and type I collagen production in PSCs in vitro. These results suggest that olmesartan inhibited the growth of tumors by targeting stellate cell activities, and that olmesartan might be useful as an anti-fibrosis therapy in pancreatic cancer.
Pancreatic stellate cells reduce insulin expression and induce apoptosis in pancreatic β-cells. 国際誌

Kazuhiro Kikuta, Atsushi Masamune, Shin Hamada, Tetsuya Takikawa, Eriko Nakano, Tooru Shimosegawa

Biochemical and biophysical research communications　433　(3)　292-7　2013年4月12日

DOI： 10.1016/j.bbrc.2013.02.095 　

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Islet fibrosis, pancreatic β-cell dysfunction, and β-cell apoptosis are features of pancreatic diabetes and type 2 diabetes; however, the underlying mechanisms remain largely unknown. We hypothesized that pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, might affect the phenotype of pancreatic β-cells. α-Smooth muscle actin (a marker of activated PSC)-positive cells were found within and around the fibrotic islets. Indirect co-culture with PSCs reduced insulin expression and induced apoptosis in RIN-5F pancreatic β-cells. Induction of β-cell apoptosis was associated with activation of the caspase pathway and mitochondrial depolarization. Diphenylene iodonium, an inhibitor of PSC activation, inhibited islet fibrosis and protected islets in vivo. Our findings suggest a novel mechanism linking PSCs, islet fibrosis, and diabetes mellitus.
Connexins Regulate Cell Functions in Pancreatic Stellate Cells 国際誌査読有り

Atsushi Masamune, Noriaki Suzuki, Kazuhiro Kikuta, Hiroyuki Ariga, Shintaro Hayashi, Tetsuya Takikawa, Kiyoshi Kume, Shin Hamada, Morihisa Hirota, Atsushi Kanno, Shinichi Egawa, Michiaki Unno, Tooru Shimosegawa

Pancreas　42　(2)　308-316　2013年3月
出版者・発行元： Ovid Technologies (Wolters Kluwer Health)
DOI： 10.1097/mpa.0b013e31825c51d6 　

ISSN：0885-3177

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OBJECTIVES: Pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrosis associated with chronic pancreatitis and pancreatic cancer. Connexins (Cxs) allow direct intercellular communications as components of gap junction but also play important roles in the regulation of cell proliferation, cell differentiation, and tissue development. We here examined the expression of Cxs and Cx-mediated regulation of cell functions in PSCs. METHODS: Human PSCs were isolated from patients undergoing operation for chronic pancreatitis or pancreatic cancer. The expression of Cxs was examined by reverse transcription polymerase chain reaction, Western blotting, and immunofluorescent staining. The roles of Cxs in PSC functions were examined by using carbenoxolone, a broad-spectrum Cx inhibitor, and small interfering RNA for Cx43. RESULTS: Human activated PSCs expressed a variety of Cxs including Cx43 both in vitro and in vivo. Carbenoxolone inhibited platelet-derived growth factor-BB-induced proliferation and migration, and type I collagen expression in PSCs. In addition, carbenoxolone inhibited the activation of quiescent PSCs to a myofibroblastlike phenotype. Decreased Cx43 expression by small interfering RNA resulted in decreased proliferation and type I collagen expression. CONCLUSIONS: Pancreatic stellate cells expressed a variety of Cxs. Connexins, especially Cx43, might regulate the cell functions and activation of PSCs.
[Case report; Multiple gastrointestinal stromal tumors associated with neurofibromatosis type I preoperatively diagnosed by endoscopic ultrasound-guided fine-needle aspiration: report of a case and review of literature]. 査読有り

Miura S, Kume K, Hamada S, Kanno A, Unno J, Kikuta K, Hirota M, Masamune A, Shimosegawa T

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine　101　(12)　3510-3512　2012年12月
出版者・発行元：一般社団法人日本内科学会
DOI： 10.2169/naika.101.3510 　

ISSN：0021-5384

eISSN：1883-2083

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症例は40代，女性．幼少期にNeurofibromatosis type I（NF1）と診断された．貧血，黒色便にて他院を受診した．カプセル内視鏡にて小腸出血と診断され当院紹介となった．腹部造影CT検査では，多発する腫瘤を空腸および膵頭部近傍に認め，EUS-FNAにて多発消化管GISTと診断し，膵頭十二指腸切除術，小腸部分切除術を行った．文献的検討によると，NF1関連性GISTは散発性GISTとは異なる臨床的特徴を有し診療上注意を要すると考えられた．<br>
Do genetic variants in the SPINK1 gene affect the level of serum PSTI? 査読有り

Kiyoshi Kume, Atsushi Masamune, Hiroyuki Ariga, Shintaro Hayashi, Tetsuya Takikawa, Shin Miura, Noriaki Suzuki, Kazuhiro Kikuta, Shin Hamada, Morihisa Hirota, Atsushi Kanno, Tooru Shimosegawa

Journal of Gastroenterology　47　(11)　1267-1274　2012年11月
出版者・発行元： Springer Science and Business Media LLC
DOI： 10.1007/s00535-012-0590-3 　

ISSN：0944-1174

eISSN：1435-5922

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BACKGROUND: The serine protease inhibitor Kazal type 1 (SPINK1), also known as pancreatic secretory trypsin inhibitor (PSTI), is a peptide secreted by pancreatic acinar cells. Genetic studies have shown an association between SPINK1 gene variants and chronic pancreatitis or recurrent acute pancreatitis. The aim of this study was to clarify whether the SPINK1 variants affect the level of serum PSTI. METHODS: One hundred sixty-three patients with chronic pancreatitis or recurrent acute pancreatitis and 73 healthy controls were recruited. Serum PSTI concentrations were determined with a commercial radioimmunoassay kit. RESULTS: Ten patients with the p.N34S variant, 7 with the IVS3+2T>C variant, two with both the p.N34S and the IVS3+2T>C variants, and one with the novel missense p.P45S variant in the SPINK1 gene were identified. The serum PSTI level in patients with no SPINK1 variants was 14.3 ± 9.6 ng/ml (mean ± SD), and that in healthy controls was 10.7 ± 2.2 ng/ml. The PSTI level in patients carrying the IVS3+2T>C variant (5.1 ± 3.4 ng/ml), but not in those with the p.N34S variant (8.9 ± 3.5 ng/ml), was significantly lower than that in the patients without the SPINK1 variants and the healthy controls. The serum PSTI level in the patient with the p.P45S variant was 4.9 ng/ml. Low levels of serum PSTI (<6.0 ng/ml) showed sensitivity of 80 %, specificity of 97 %, and accuracy of 96 % in the differentiation of IVS3+2T>C and p.P45S carriers from non-carriers. CONCLUSION: Serum PSTI levels were decreased in patients with the IVS3+2T>C and p.P45S variants of the SPINK1 gene.
Early Detection of Low Enhanced Pancreatic Parenchyma by Contrast-Enhanced Computed Tomography Predicts Poor Prognosis of Patients With Acute Pancreatitis 国際誌査読有り

Morihisa Hirota, Kennichi Satoh, Kazuhiro Kikuta, Atsushi Masamune, Kiyoshi Kume, Shin Hamada, Akihiko Satoh, Atsushi Kanno, Jun Unno, Hiromichi Ito, Hiroyuki Ariga, Tooru Shimosegawa

Pancreas　41　(7)　1099-1104　2012年10月
出版者・発行元： Ovid Technologies (Wolters Kluwer Health)
DOI： 10.1097/mpa.0b013e318249a904 　

ISSN：0885-3177

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OBJECTIVES: The usefulness of early severity assessment of acute pancreatitis (AP) by contrast-enhanced computed tomography (CECT) was investigated. METHODS: Data were obtained from a 2007 nationwide survey in Japan. Clinical data of 983 patients with AP were analyzed. All were examined by CECT on the day of admission. RESULTS: Early findings of CECT demonstrated that low enhanced pancreatic parenchyma (LEPP) was associated with the incidence of organ failure (OF), multiple OF, and infectious complications as well as mortality (P < 0.0001). Next, patients were further divided into 4 groups according to the CECT findings, which focused on the LEPP and peripancreatic collections (PPCs). The LEPP/PPC (+/+) group was characterized as high morbidity and high mortality. The incidence of OF (28.2%), multiple OF (15.5%), and mortality (11.4%) in patients assigned to the (+/+) group was significantly higher than in those assigned to the other groups. The incidence of infectious complications was significantly higher in patients assigned to the (+/+) group (16.7%), the (+/-) group (9.0%), and the (-/+) group (7.0%) than those assigned to the (-/-) group (1.8%). CONCLUSIONS: The detection of LEPP and PPC was a useful CECT finding for the early assessment of the severity of AP.
Diagnosis of autoimmune pancreatitis by EUS-FNA by using a 22-gauge needle based on the International Consensus Diagnostic Criteria 国際誌査読有り

Atsushi Kanno, Kazuyuki Ishida, Shin Hamada, Fumiyoshi Fujishima, Jun Unno, Kiyoshi Kume, Kazuhiro Kikuta, Morihisa Hirota, Atsushi Masamune, Kennichi Satoh, Kenji Notohara, Tooru Shimosegawa

Gastrointestinal Endoscopy　76　(3)　594-602　2012年9月
出版者・発行元： Elsevier BV
DOI： 10.1016/j.gie.2012.05.014 　

ISSN：0016-5107

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BACKGROUND: It is controversial whether EUS-guided FNA by using 22-gauge (G) needles is useful for the diagnosis or evaluation of autoimmune pancreatitis (AIP). OBJECTIVE: To evaluate the usefulness of EUS-FNA by 22-G needles for the histopathological diagnosis of AIP. DESIGN: A retrospective study. SETTING: Single academic center. PATIENTS: A total of 273 patients, including 25 with AIP, underwent EUS-FNA and histological examinations. RESULTS: EUS-FNA by using 22-G needles provided adequate tissue samples for histopathological evaluation because more than 10 high-power fields were available for evaluation in 20 of 25 patients (80%). The mean immunoglobulin G4-positive plasma cell count was 13.7/high-power field. Obliterative phlebitis was observed in 10 of 25 patients (40%). In the context of the International Consensus Diagnostic Criteria for AIP, 14 and 6 of 25 patients were judged to have level 1 (positive for 3 or 4 items) and level 2 (positive for 2 items) histological findings, respectively, meaning that 20 of 25 patients were suggested to have lymphoplasmacytic sclerosing pancreatitis based on the International Consensus Diagnostic Criteria. The diagnosis in 1 patient was type 2 AIP because a granulocytic epithelial lesion was identified in this patient. LIMITATIONS: A retrospective study with a small number of patients. CONCLUSIONS: The results of this study suggest that EUS-FNA by using 22-G needles provides tissue samples adequate for histopathological evaluation and greatly contributes to the histological diagnosis of AIP.
Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells 国際誌査読有り

Shin Hamada, Atsushi Masamune, Tetsuya Takikawa, Noriaki Suzuki, Kazuhiro Kikuta, Morihisa Hirota, Hirofumi Hamada, Masayoshi Kobune, Kennichi Satoh, Tooru Shimosegawa

Biochemical and Biophysical Research Communications　421　(2)　349-354　2012年5月
出版者・発行元： Elsevier BV
DOI： 10.1016/j.bbrc.2012.04.014 　

ISSN：0006-291X

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The interaction between pancreatic cancer cells and pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, is receiving increasing attention. There is accumulating evidence that PSCs promote the progression of pancreatic cancer by increasing cancer cell proliferation and invasion as well as by protecting them from radiation- and gemcitabine-induced apoptosis. Recent studies have identified that a portion of cancer cells, called "cancer stem cells", within the entire cancer tissue harbor highly tumorigenic and chemo-resistant phenotypes, which lead to the recurrence after surgery or re-growth of the tumor. The mechanisms that maintain the "stemness" of these cells remain largely unknown. We hypothesized that PSCs might enhance the cancer stem cell-like phenotypes in pancreatic cancer cells. Indirect co-culture of pancreatic cancer cells with PSCs enhanced the spheroid-forming ability of cancer cells and induced the expression of cancer stem cell-related genes ABCG2, Nestin and LIN28. In addition, co-injection of PSCs enhanced tumorigenicity of pancreatic cancer cells in vivo. These results suggested a novel role of PSCs as a part of the cancer stem cell niche.
The sixth nationwide epidemiological survey of chronic pancreatitis in Japan 国際誌査読有り

Morihisa Hirota, Tooru Shimosegawa, Atsushi Masamune, Kazuhiro Kikuta, Kiyoshi Kume, Shin Hamada, Yasuyuki Kihara, Akihiko Satoh, Kenji Kimura, Ichiro Tsuji, Shinichi Kuriyama

Pancreatology　12　(2)　79-84　2012年3月
出版者・発行元： Elsevier BV
DOI： 10.1016/j.pan.2012.02.005 　

ISSN：1424-3903

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OBJECTIVES: A nationwide survey was conducted to clarify the epidemiological features of patients with chronic pancreatitis (CP) in Japan. METHODS: Two sequential surveys were conducted. In the first survey, both the prevalence and incidence of CP in Japan in 2007 were estimated by a questionnaire, which was mailed to 3027 randomly chosen Japanese facilities. In the second survey, the second questionnaire was then mailed to 1110 facilities selected by the first survey to clarify the clinicoepidemiological features of the patients. RESULTS: The estimated annual prevalence of CP was 36.9 per 100,000; 53.2 in males and 21.2 in females. The estimated annual incidence was 11.9 per 100,000. The prevalence and the incidence of CP gradually increased in Japan as compared to former surveys. The sex ratio (male/female) of definitive and probable CP patients was 4.5, with a mean age of 59.4 years; 59.2 years in males and 60.2 years in females. Alcoholic (69.7%) was most the common and idiopathic (21.0%) was the second most common cause of CP. The proportion of alcoholic CP increased as compared to the 55.5% found in 1994. The clinical features of overall Japanese patients with CP were: abdominal pain (60.6%), malabsorbtion (12.2%), diabetes mellitus (39.7%) and pancreatolithiasis (75.7%). Alcoholic patients were characterized by high morbidity as compared to nonalcoholic patients: abdominal pain (alcoholic 65.0% vs nonalcoholic 53.0%, p < 0.0001), diabetes mellitus (44.8% vs 31.4%, p < 0.0001) and pancreatolithiasis (84.0% vs 60.8%, p < 0.0001). CONCLUSION: The prevalence and the incidence of CP, especially alcoholic CP, have been increasing in Japan.
The homeobox gene MSX2 determines chemosensitivity of pancreatic cancer cells via the regulation of transporter gene ABCG2 国際誌査読有り

Shin Hamada, Kennichi Satoh, Morihisa Hirota, Atsushi Kanno, Jun Umino, Hiromichi Ito, Atsushi Masamune, Kazuhiro Kikuta, Kiyoshi Kume, Tooru Shimosegawa

Journal of Cellular Physiology　227　(2)　729-738　2012年2月
出版者・発行元： Wiley
DOI： 10.1002/jcp.22781 　

ISSN：0021-9541

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Pancreatic cancer is one of the life-threatening cancers due to the difficulty in the curative surgery and resistance against conventional therapeutic strategies. Recent studies indicated that cancer stem cells, which exist as a small number of cells within the entire cancer tissue, contribute to the disease progression. Cancer stem cells reveal resistance against conventional chemotherapy, which is derived from the high-expression of multiple transporter genes. Our previous study demonstrated the aggravating role of the homeobox gene MSX2 as an inducer of epithelial-mesenchymal transition, and MSX2 turned out to correlate with the chemoresistance in the current study. Comprehensive analysis of the MSX2-target gene has identified ABCG2 as the responsible gene. Since previous studies reported the pivotal role of ABCG2 as a determining factor of cancer stem cells, the detailed regulatory mechanism of ABCG2 expression by MSX2 was investigated. As a result, the MSX2 expression level in each cell line well correlated with the ABCG2 expression level, and alteration of the MSX2 expression level by over-expression or siRNA-based knockdown affected the ABCG2 expression accordingly. Finally, we identified the functional cooperation of MSX2 and SP1 in the transcriptional regulation of ABCG2 via the SP1 binding elements within the ABCG2 promoter. These findings clarified the intriguing regulatory mechanism of the cancer stem cell-related gene, and will delineate a novel therapeutic target in pancreatic cancer.
Pancreatic cancer stem cell and mesenchymal stem cell

Shin Hamada, Tooru Shimosegawa

2012年
出版者・発行元： Transworld Research Network

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Pancreatic cancer is one of the most life-threatening cancers and its prognosis has not been improved despite advances in diagnostic and therapeutic strategies. The reasons for resistance against conventional therapy and re-growth of untreatable tumor are now attributed to the existence of cancer stem cells (CSC), which occupy only a small part of the entire cancer tissue. CSC has characteristic features such as chemoresistance, establishment of metastasis and reconstruction of a hierarchical population of tumor cells. Specific surface markers have been identified, enabling the purification of CSC fractions from cell lines or clinical samples, serving to dissect the nature of CSCs. In addition, tumor stromal cells also contribute to the malignant behavior of cancer cells by promoting an invasive phenotype and the development of metastasis. Among those stromal cells, a mesenchymal stem cell (MSC) has unique contributions to the cancer tissue since this type of cell could accumulate in the tumor from distant organs such as bone marrow. MSC also acts as a defender of cancer cells by infiltrating into the tumor. This unique feature is now applied to generating cancer-specific delivery systems by utilizing MSC as a vehicle of therapeutic agents. The tumor microenvironment, which is created by the complex interaction between cancer cells and stromal cells, yields cancer promoting effects, especially induction of a hypoxic environment. Hypoxia- induced signals activate cellular adaptation machinery such as increased cell survival or enhanced stemness in pancreatic cancer cells. Tumor stromal cells also support engraftment of metastatic nodules which provide a partial CSC niche. Targeting the tumor stroma, CSCs, and MSCs will possibly lead to the development of novel therapeutic methods against pancreatic cancer.
Regulators of epithelial mesenchymal transition in pancreatic cancer. 国際誌

Shin Hamada, Kennichi Satoh, Atsushi Masamune, Tooru Shimosegawa

Frontiers in physiology　3　254-254　2012年

DOI： 10.3389/fphys.2012.00254 　

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Pancreatic cancer is a leading cause of cancer-related death due to its invasive nature. Despite the improvement of diagnostic strategy, early diagnosis of pancreatic cancer is still challenging. Surgical resection is the only curative therapy, while vast majority of patients are not eligible for this therapeutic option. Complex biological processes are involved in the establishment of invasion and metastasis of pancreatic cancer and epithelial-mesenchymal transition (EMT) has been reported to play crucial role. EMT is part of the normal developmental processes which mobilizes epithelial cells and yields mesenchymal phenotype. Deregulation of EMT inducing molecules in pancreatic cancer is reported, such as multiple cytokines, growth factors and downstream transcriptional factors. In addition to these molecules, non-coding RNA including miRNA also contributes to EMT. EMT of cancer cell also correlates with cancer stem cell (CSC) properties such as chemoresistance or tumorigenicity, therefore these upstream regulators of EMT could be attractive therapeutic targets and several candidates are examined for clinical application. This review summarizes recent advances in this field, focusing the regulatory molecules of EMT and their downstream targets. Further understanding and research advances will clarify the cryptic mechanism of cancer metastasis and delineate novel therapeutic targets.
MSX2 in pancreatic tumor development and its clinical application for the diagnosis of pancreatic ductal adenocarcinoma. 国際誌

Kennichi Satoh, Shin Hamada, Tooru Shimosegawa

Frontiers in physiology　3　430-430　2012年

DOI： 10.3389/fphys.2012.00430 　

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MSX2, a member of the homeobox genes family, is demonstrated to be the downstream target for ras signaling pathway and is expressed in a variety of carcinoma cells, suggesting its relevance to the development of ductal pancreatic tumors since pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary-mucinous neoplasia (IPMN) harbor frequent K-ras gene mutations. Recent studies revealed the roles of MSX2 in the development of carcinoma of various origins including pancreas. Among gastrointestinal tumors, PDAC is one of the most malignant. PDAC progresses rapidly to develop metastatic lesions, frequently by the time of diagnosis, and these tumors are usually resistant to conventional chemotherapy and radiation therapy. The molecular mechanisms regulating the aggressive behavior of PDAC still remain to be clarified. On the other hand, IPMN of the pancreas is distinct from PDAC because of its intraductal growth in the main pancreatic duct or secondary branches with rare invasion and metastasis to distant organs. However, recent evidence indicated that once IPMN showed stromal invasion, it progresses like PDAC. Therefore, it is important to determin how IPMN progresses to malignant phenotype. In this review, we focus on the involvement of MSX2 in the enhancement of malignant behavior in PDAC and IPMN, and further highlight the clinical approach to differentiate PDAC from chronic pancreatitis by evaluating MSX2 expression level.
Distinct Clinical Features of Two Patients That Progressed from the Early Phase of Chronic Pancreatitis to the Advanced Phase 査読有り

Morihisa Hirota, Tooru Shimosegawa, Atsushi Kanno, Kazuhiro Kikuta, Kiyoshi Kume, Shin Hamada, Jun Unno, Atsushi Masamune

The Tohoku Journal of Experimental Medicine　228　(3)　173-180　2012年
出版者・発行元： Tohoku University Medical Press
DOI： 10.1620/tjem.228.173 　

ISSN：0040-8727

eISSN：1349-3329

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Chronic pancreatitis (CP) has been considered an intractable inflammatory disease that is progressive and irreversible after definite structural changes appear in the pancreas. The Japanese diagnostic criteria for CP were revised in 2009. One of the reasons for this revision was to define a diagnostic criterion for the early phase of CP (early CP) to improve a patient's clinical outcome, because the disease progression might be reversed in this phase by a therapeutic intervention. However, the clinical features and outcome of early CP remain largely unknown, and the diagnostic reliability of early CP needs to be verified. Here, we show two patients who met the diagnostic criteria of early CP and then progressed to the advanced, late phase of CP (definite CP). A 64-year-old man with recurrent acute pancreatitis was diagnosed as early CP and later progressed to definite CP with multiple pancreatic calcifications at the age of 69. The etiology of CP in this patient was thought to be idiopathic. The other patient was a 57-year-old man with alcohol abuse (ethanol consumption>120 g/day). He was diagnosed as early CP and then rapidly progressed to definite CP without any acute attack. He could not remain abstinent after the diagnosis of early CP. In the present report, we retrospectively demonstrated distinct clinical features of the two patients, both of whom were diagnosed as early CP first and then progressed to definite CP. Thus, our findings support the disease concept of early CP and also suggest the validity of the revised Japanese criteria for the diagnosis of early CP.
Perfusion Computed Tomography Findings of Autoimmune Pancreatitis 国際誌査読有り

Morihisa Hirota, Masashi Tsuda, Yoshihisa Tsuji, Atsushi Kanno, Kazuhiro Kikuta, Kiyoshi Kume, Shin Hamada, Jun Unno, Hiromichi Ito, Hiroyuki Ariga, Tsutomu Chiba, Atsushi Masamune, Kennichi Satoh, Tooru Shimosegawa

Pancreas　40　(8)　1295-1301　2011年11月
出版者・発行元： Ovid Technologies (Wolters Kluwer Health)
DOI： 10.1097/mpa.0b013e31821fcc4f 　

ISSN：0885-3177

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OBJECTIVES: The aim of this study was to clarify the pancreatic blood perfusion in patients with autoimmune pancreatitis (AIP) and the changes after steroid treatment. METHODS: Perfusion computed tomography was performed in 11 patients with AIP and 12 control subjects. Pancreatic volumetric blood flow (F(V)), volume of distribution (V(D)), and blood transit time τ were determined from a single-compartment kinetic model. Nine patients with AIP were reexamined by perfusion computed tomography after corticosteroid administration. RESULTS: The pancreatic F(V) values of the 11 patients with AIP (82.7/min) were significantly lower than those of control subjects (163.5/min, P = 0.0006). On the other hand, the pancreatic V(D) and τ values were not significantly different between AIP and normal. After steroid treatment, the F(V) values of 9 reexamined patients with AIP (76.2/min) were significantly elevated (109.8/min, P = 0.0391). However, the changes of the values after the treatment differed in degree among individuals. The values of 4 patients were dramatically elevated to greater than 100/min, whereas those of 4 other patients did not improve well. The value of the remaining patient whose initial F(V) value was normal (168.09/min) did not change after the treatment. CONCLUSIONS: Pancreatic volumetric perfusion was attenuated in AIP patients. The perfusion was improved after the steroid treatment.
Long-Period Pancreatic Stenting for Painful Chronic Calcified Pancreatitis Required Higher Medical Costs and Frequent Hospitalizations Compared With Surgery 国際誌査読有り

Morihisa Hirota, Tohru Asakura, Atsushi Kanno, Kazuhiro Kikuta, Kiyoshi Kume, Shin Hamada, Jun Unno, Hiromichi Ito, Hiroyuki Ariga, Atsushi Masamune, Kennichi Satoh, Fuyuhiko Motoi, Shinichi Egawa, Michiaki Unno, Tooru Shimosegawa

Pancreas　40　(6)　946-950　2011年8月
出版者・発行元： Ovid Technologies (Wolters Kluwer Health)
DOI： 10.1097/mpa.0b013e31821a9215 　

ISSN：0885-3177

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OBJECTIVES: The aim of this study was to compare the benefits between endoscopic drainage and surgical drainage of the pancreatic duct for patients with chronic calcified pancreatitis. METHODS: A total of 68 patients were classified into endoscopic (n = 34) or surgical (n = 34) treatment groups. Patients receiving endoscopic treatment were further divided into 2 subgroups: a short-period group, patients who could discontinue serial pancreatic stenting within 1 year (n = 19); and a long-period group, patients who needed pancreatic drainage by serial endoscopic stenting for more than 1 year (n = 15). The medical records of these patients were retrospectively analyzed. RESULTS: Hospital stays, frequency of hospitalizations, and medical expense were similar between the short-period endoscopic treatment group and surgery group. On the other hand, patients in the long-period endoscopic treatment group required significantly longer hospital stays, more frequent hospitalizations, and had higher medical expenses than the short-period endoscopic treatment group as well as than the surgery group. CONCLUSIONS: Patients who underwent serial endoscopic stenting for more than 1 year showed no benefit compared with surgical treatment in terms of the frequency of hospital stays and medical costs.
Nationwide Epidemiological Survey of Acute Pancreatitis in Japan 国際誌査読有り

Kennichi Satoh, Tooru Shimosegawa, Atsushi Masamune, Morihisa Hirota, Kazuhiro Kikuta, Yasuyuki Kihara, Shinichi Kuriyama, Ichiro Tsuji, Akihiko Satoh, Shin Hamada

Pancreas　40　(4)　503-507　2011年5月
出版者・発行元： Ovid Technologies (Wolters Kluwer Health)
DOI： 10.1097/mpa.0b013e318214812b 　

ISSN：0885-3177

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OBJECTIVES: A nationwide epidemiological survey was conducted to estimate the number of patients treated for acute pancreatitis (AP) in 2007 in Japan and to clarify the clinicoepidemiological features of AP. METHODS: In the first survey, a simple questionnaire was used to inquire about the number of patients with AP who visited the hospital in the year 2007. This questionnaire was directly mailed to the heads of 3027 facilities. The second questionnaire was forwarded to those facilities from which patients with AP were reported on the first questionnaire. RESULTS: The estimated total number of patients treated for AP in 2007 was 57,560 (95% confidence interval, 48,571-66,549), with an overall prevalence rate of 45.1 per 100,000 population. The sex ratio (male-female) of the patients was 2.0, with a mean age of 56.6 years in men and 64.6 years in women. Alcoholic AP was most common in men and gallstone AP in women. The overall mortality rate of AP was 1.9% and, in severe cases, 8.0%. CONCLUSION: The number of patients with AP increased about 3-fold during this decade (19,500 in 1998 to 57,560 in 2007), and the mortality rate of AP was reduced from 7.4% in 1998 and 2.9% in 2003 to 1.9% in 2007.
The evaluation of MSX2 mRNA expression level in biliary brush cytological specimens. 国際誌

Hiromichi Ito, Kennichi Satoh, Shin Hamada, Morihisa Hirota, Atsushi Kanno, Kazuyuki Ishida, Jun Unno, Atsushi Masamune, Yu Katayose, Michiaki Unno, Tooru Shimosegawa

Anticancer research　31　(3)　1011-7　2011年3月

eISSN：1791-7530

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BACKGROUND: To distinguish cholangiocarcinoma from inflammatory disease remains difficult when stricture is present in the bile duct. Endoscopic brushing cytology is a convenient method for stricture in the bile duct, however, the diagnostic sensitivity of this method for malignancy is reported to be low (<60%). Msh homeobox 2 is frequently expressed in carcinoma cells of epithelial origin but not in normal tissues. AIM: To assess whether MSX2 expression level in brushing samples allows differentiation of malignant from benign bile duct stricture. PATIENTS AND METHODS: Cytological brushing specimens were obtained from strictures of the bile duct during endoscopic retrograde cholangiopancreaticography (ERCP) in 71 patients. The brushing fluid was subjected to cytological diagnosis and RNA extraction. The expression level of MSX2 was evaluated by one-step real-time RT-PCR. RESULTS: MSX2 expression levels were significantly higher in malignant than in benign bile duct stricture (p=0.004). The sensitivity and specificity for cholangiocarcinoma of cytology and MSX2 expression in strictures of the bile duct were: 55.3% and 100%, and 72.3% and 58.3%, respectively. CONCLUSION: The sensitivity of MSX2 expression level for cholangiocarcinoma was much higher than that of cytology. This suggests that the evaluation of MSX2 level in ERCP brushing samples would be a useful tool to distinguish malignant from benign bile duct stricture.
Evaluation of MSX2 mRNA in brush cytology specimens distinguished pancreatic carcinoma from chronic pancreatitis 国際誌査読有り

Kennichi Satoh, Shin Hamada, Atsushi Kanno, Kazuyuki Ishida, Hiromichi Ito, Morihisa Hirota, Atsushi Masamune, Shinichi Egawa, Michiaki Unno, Tooru Shimosegawa

Cancer Science　102　(1)　157-161　2011年1月
出版者・発行元： Wiley
DOI： 10.1111/j.1349-7006.2010.01759.x 　

ISSN：1347-9032

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It is difficult to distinguish pancreatic ductal adenocarcinoma (PDAC) from chronic pancreatitis (CP) when stricture is present in the pancreatic duct. Endoscopic brushing cytology is a convenient method for investigating strictures in the pancreatic duct, however, the diagnostic sensitivity of this method for PDAC is reported to be low (40-70%). Recently, we revealed that MSX2 is frequently expressed in PDAC cells but not in normal cultured pancreatic duct or stellate cells. Thus, we analyzed MSX2 expression levels in brushing samples to examine whether this would differentiate PDAC from CP. Cytologic brushing specimens were obtained from pancreatic duct strictures during endoscopic retrograde cholangiopancreaticography in 82 patients. The brushing fluid was subjected to cytological diagnosis and RNA extraction. The expression level of MSX2 was evaluated by one-step real-time RT-PCR. MSX2 expression levels were significantly higher in PDAC than in CP (P = 0.0000007), and the expression level was associated with positive cytology (P = 0.013). The sensitivity, specificity, and diagnostic accuracy for PDAC of cytology and MSX2 expression in ductal strictures were: 47.4%, 100%, and 63.4%, and 73.7%, 84.0%, and 79.3%, respectively. The sensitivity and accuracy of MSX2 expression levels for diagnosis were much higher than those of cytology. This suggests that the evaluation of MSX2 levels in endoscopic retrograde cholangiopancreaticography brushing samples would be useful for distinguishing PDAC from CP.
Calcium-binding protein S100P is a novel diagnostic marker of cholangiocarcinoma 国際誌査読有り

Shin Hamada, Kennichi Satoh, Morihisa Hirota, Atsushi Kanno, Kazuyuki Ishida, Jun Umino, Hiromichi Ito, Kazuhiro Kikuta, Kiyoshi Kume, Atsushi Masamune, Yu Katayose, Michiaki Unno, Tooru Shimosegawa

Cancer Science　102　(1)　150-156　2011年1月
出版者・発行元： Wiley
DOI： 10.1111/j.1349-7006.2010.01757.x 　

ISSN：1347-9032

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The incidence and mortality of cholangiocarcinoma are increasing despite improvements in the diagnostic method. Since the sensitivity of brushing cytology for cholangiocarcinoma is not satisfactory, a novel diagnostic marker needs to be established. A recent report has suggested upregulation of the calcium-binding protein S100P in cholangiocarcinoma. The expression status of S100P in normal bile duct and cholangiocarcinoma tissues was assessed by immunohistochemistry. The expression levels of S100P mRNA in the brushing cytology samples during endoscopic retrograde cholangiopancreatography (ERCP) from benign biliary strictures and cholangiocarcinoma were assessed by real-time reverse transcription-polymerase chain reaction (RT-PCR). The sensitivity and specificity of each diagnostic strategy was compared. S100P was frequently expressed in the cholangiocarcinoma tissues, but not in the normal bile duct. The brushing cytology samples from the cholangiocarcinoma cases revealed higher expression levels of S100P compared with the benign biliary strictures. The relative expression level of S100P could determine the cholangiocarcinoma at higher sensitivity than classical cytology, and the combination of the S100P expression level and cytology yielded a sensitivity of 90.0%, with a specificity of 92.0%. Calcium-binding protein S100P is a novel marker of cholangiocarcinoma. Detecting the S100P expression levels in brushing cytology samples has a diagnostic value, which will be helpful for better diagnosis of cholangiocarcinoma.
Serous Cystic Neoplasms of the Whole Pancreas in a Patient with von Hippel-Lindau Disease 査読有り

Atsushi Kanno, Kennichi Satoh, Shin Hamada, Morihisa Hirota, Atsushi Masamune, Fuyuhiko Motoi, Shinichi Egawa, Michiaki Unno, Kazuyuki Ishida, Kenji Kimura, Taro Shuin, Tooru Shimosegawa

Internal Medicine　50　(12)　1293-1298　2011年
出版者・発行元： Japanese Society of Internal Medicine
DOI： 10.2169/internalmedicine.50.4946 　

ISSN：0918-2918

eISSN：1349-7235

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We describe here a case of von Hippel-Lindau (VHL) disease with a serous cystic neoplasm of the whole pancreas. The patient was a 35-year-old woman suffering from a palpable abdominal tumor. She had a history of hemangioblastomas of the cerebellum. CT revealed large solid tumors in the pancreatic head and body, and multiple cystic lesions in the whole pancreas as well as a right renal tumor. When endoscopic retrograde cholangiopancreatography (ERCP) was performed, bleeding from the duodenal papilla was detected. Since she had some distinguishing clinical features, the diagnosis of VHL disease was made. The preoperative diagnosis of the pancreatic lesion was serous cystic neoplasms with hemosuccus pancreaticus and total pancreatectomy was performed. Histological examination of the specimen revealed serous cystic neoplasms which occupied the entire pancreas. VHL cases operated on for serous cystic neoplasms of the entire pancreas are very rare.
Pancreatic stellate cells promote epithelial-mesenchymal transition in pancreatic cancer cells. 国際誌

Kazuhiro Kikuta, Atsushi Masamune, Takashi Watanabe, Hiroyuki Ariga, Hiromichi Itoh, Shin Hamada, Kennichi Satoh, Shinichi Egawa, Michiaki Unno, Tooru Shimosegawa

Biochemical and biophysical research communications　403　(3-4)　380-4　2010年12月17日

DOI： 10.1016/j.bbrc.2010.11.040 　

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The interaction between pancreatic cancer cells and pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, is receiving increasing attention. There is accumulating evidence that PSCs promote the progression of pancreatic cancer by increasing cancer cell proliferation and invasion as well as by protecting them from radiation- and gemcitabine-induced apoptosis. Because epithelial-mesenchymal transition (EMT) plays a critical role in the progression of pancreatic cancer, we hypothesized that PSCs promote EMT in pancreatic cancer cells. Panc-1 and SUIT-2 pancreatic cancer cells were indirectly co-cultured with human PSCs isolated from patients undergoing operation for pancreatic cancer. The expression of epithelial and mesenchymal markers was examined by real-time PCR and immunofluorescent staining. The migration of pancreatic cancer cells was examined by scratch and two-chamber assays. Pancreatic cancer cells co-cultured with PSCs showed loose cell contacts and a scattered, fibroblast-like appearance. The expression of E-cadherin, cytokeratin 19, and membrane-associated β-catenin was decreased, whereas vimentin and Snail (Snai-1) expression was increased more in cancer cells co-cultured with PSCs than in mono-cultured cells. The migration of pancreatic cancer cells was increased by co-culture with PSCs. The PSC-induced decrease of E-cadherin expression was not altered by treatment with anti-TGF-β-neutralizing antibody, excluding a central role of TGF-β in this process. In conclusion, PSCs promoted EMT in pancreatic cancer cells suggesting a novel mechanism by which PSCs contribute to the aggressive behavior of pancreatic cancer cells.
Expression of MSX2 predicts malignancy of branch duct intraductal papillary mucinous neoplasm of the pancreas 査読有り

Kennichi Satoh, Shin Hamada, Atsushi Kanno, Morihisa Hirota, Jun Umino, Hiromichi Ito, Atsushi Masamune, Shinichi Egawa, Michiaki Unno, Tooru Shimosegawa

Journal of Gastroenterology　45　(7)　763-770　2010年7月
出版者・発行元： Springer Science and Business Media LLC
DOI： 10.1007/s00535-010-0200-1 　

ISSN：0944-1174

eISSN：1435-5922

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BACKGROUND: To distinguish malignant from benign branch duct (BD)-intraductal papillary mucinous neoplasm (IPMN) still remains difficult. Recently, we revealed that MSX2 was frequently expressed in pancreatic cancer and its expression was correlated with aggressive behavior of the cancer. The aim of this study was to assess the involvement of MSX2 in IPMN development and whether its expression would differentiate malignant from benign IPMN. METHODS: Seventeen microdissected lesions and 45 IPMN tissues were used for quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry, respectively. The role of MSX2 in the pancreatic duct cell was assessed by the induced expression of MSX2 in a normal human pancreatic duct epithelial cell line (HPDE). RESULTS: Malignant IPMN expressed significantly higher levels of MSX2 mRNA than benign IPMN lesions. MSX2 protein expression was frequently found in borderline and malignant lesions (20/29, 68.9%), while its expression was seen in only one of 16 benign IPMN tissues. Univariate analysis showed that nodules of 6 mm or more and MSX2 expression were significantly correlated with the malignancy of BD-IPMN (P = 0.022 and 0.0026, respectively), and multivariate analysis revealed that only MSX2 expression was identified as an independent factor to predict malignant BD-IPMN. HPDE cells expressing MSX2 showed increased cellular proliferation compared to control cells. CONCLUSIONS: Based on our results, MSX2 plays a pivotal role in the development of IPMN through growth stimulation of tumor cells, and its expression was identified as an independent predictive factor for malignancy of BD-IPMN.
Granular cell tumor of the pancreas: A case report and review of literature 国際誌査読有り

Atsushi Kanno, Kennichi Satoh, Morihisa Hirota, Shin Hamada, Jun Umino, Hiromichi Itoh, Atsushi Masamune, Shinichi Egawa, Fuyuhiko Motoi, Michiaki Unno, Kazuyuki Ishida, Tooru Shimosegawa

WORLD JOURNAL OF GASTROINTESTINAL ONCOLOGY　2　(2)　121-124　2010年2月

DOI： 10.4251/wjgo.v2.i1.121 　

ISSN：1948-5204
LIV-1 enhances the aggressive phenotype through the induction of epithelial to mesenchymal transition in human pancreatic carcinoma cells. 国際誌

Jun Unno, Kennichi Satoh, Morihisa Hirota, Atsushi Kanno, Shin Hamada, Hiromichi Ito, Atsushi Masamune, Nobukazu Tsukamoto, Fuyuhiko Motoi, Shinichi Egawa, Michiaki Unno, Akira Horii, Tooru Shimosegawa

International journal of oncology　35　(4)　813-21　2009年10月

eISSN：1791-2423

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LIV-1 is a downstream target of STAT3 and is essential for the nuclear localization of Snail, a master regulator of epithelial to mesenchymal transition (EMT). Little is known about the association of LIV-1 with pancreatic carcinoma development, therefore, expression of LIV-1 mRNA was analyzed by real-time reverse transcriptase polymerase chain reaction (RT-PCR) in 9 cultured cell lines (8 carcinoma and 1 normal duct cell lines) and 24 pancreatic tissues (12 carcinoma and 12 normal tissues). Localization of this gene product was investigated by immunohistochemistry in 72 pancreatic carcinoma and the relation between its expression and clinicopathological findings was examined. To assess the function of LIV-1 in pancreatic carcinoma cells, stable siRNA expressing Panc-1 cells were generated. Higher expression of LIV-1 mRNA was found in both pancreatic carcinoma cell lines and pancreatic carcinoma tissues compared to normal duct cell line and histologically normal tissues, respectively. Immunohistochemical analysis revealed that LIV-1 expression was frequently found in 76.4% of pancreatic carcinoma tissues and its expression level was associated with tumor size and lymphatic infiltration. Down-regulated LIV-1 cells showed significant inhibition of anchorage-dependent or -independent proliferation and cell motility in vitro and reduction of tumor growth and metastasis in vivo. Furthermore, nuclear expression of Snail was decreased and E-cadherin expression was restored in LIV-1 siRNA expressing pancreatic carcinoma cells. These findings indicate that LIV-1 may be involved in acquisition of the aggressive phenotype of human pancreatic carcinoma cells through the induction of epithelial to mesenchymal transition.
Expression of the calcium-binding protein S100P is regulated by bone morphogenetic protein in pancreatic duct epithelial cell lines 国際誌査読有り

Shin Hamada, Kennichi Satoh, Morihisa Hirota, Wataru Fujibuchi, Atsushi Kanno, Jun Umino, Hiromichi Ito, Akihiko Satoh, Kazuhiro Kikuta, Kiyoshi Kume, Atsushi Masamune, Tooru Shimosegawa

Cancer Science　100　(1)　103-110　2009年1月
出版者・発行元： Wiley
DOI： 10.1111/j.1349-7006.2008.00993.x 　

ISSN：1347-9032

eISSN：1349-7006

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We previously reported that bone morphogenetic protein (BMP)-4 induces epithelial-mesenchymal transition in a pancreatic cancer cell line. To further investigate the detailed molecular mechanism of BMP action in pancreatic cancer, we carried out comprehensive microarray analysis in Panc-1 cells. The microarray analysis elucidated novel BMP target genes, and among them, the calcium-binding protein S100P was identified as an upregulated gene. S100P induction by BMP4 was confirmed by real-time reverse transcription-polymerase chain reaction and western blot analysis in Panc-1 and HPDE cells. Short interfering RNA-based knockdown of S100P expression sufficiently repressed BMP4-induced cell migration in Panc-1 cells. Because Panc-1 and HPDE cells express wild-type Smad4, we hypothesized that Smad4 might be indispensable for S100P induction by BMP4. S100P induction by BMP4 was not observed in the Smad4-null cell line BxPC3, and was sufficiently attenuated in short interfering RNA-based Smad4-knockdown Panc-1 cells. Interestingly, detailed promoter analysis revealed that upregulation of S100P by BMP4 was independent of the Smad-binding element, indicating that an additional unknown downstream factor of the Smad4-dependent pathway is necessary for this induction. These findings are the first of their kind, and this Smad4-dependent regulation of S100P by BMP signaling might explain the migratory mechanism of cancer cells, which is still unknown.
Smad2 functions as a co-activator of canonical Wnt/beta-catenin signaling pathway independent of Smad4 through histone acetyltransferase activity of p300. 国際誌

Morihisa Hirota, Kazuhide Watanabe, Shin Hamada, Youping Sun, Luigi Strizzi, Mario Mancino, Tadahiro Nagaoka, Monica Gonzales, Masaharu Seno, Caterina Bianco, David S Salomon

Cellular signalling　20　(9)　1632-41　2008年9月

DOI： 10.1016/j.cellsig.2008.05.003 　

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Both canonical Wnt/beta-catenin and TGFbeta/Smad signaling pathways coordinately regulate pattern formation during embryogenesis as well as tumor progression. Evidence of cross-talk between these two pathways has been reported. Here we demonstrated that the Activin-like kinase 4 (Alk4)/Smad2 pathway facilitates the transcriptional activity of the oncogenic Wnt/beta-catenin/Tcf4 pathway through a novel Smad4-independent mechanism. Upon activation, Smad2 physically interacted with Tcf4, beta-catenin and the co-activator p300 to enhance transcriptional activity of beta-catenin/Tcf4 through the histone acetyltransferase activity of p300. Transactivation by Smad2 was independent of a Smad-binding element (SBE) and Smad4. Indeed, the enhancement of beta-catenin/Tcf4 transcriptional activity by activated Smad2 was negatively regulated by the presence of Smad4. Moreover, a tumor-derived missense mutant of Smad2, lacking the ability to bind to Smad4 was still able to enhance the Tcf4 transcriptional reporter in the presence of beta-catenin and Tcf4. Our findings suggest that Smad2 may function as an activator of canonical Wnt/beta-catenin/Tcf4 signaling through a SBE/Smad4-independent pathway.
Expression of Sonic hedgehog signaling pathway correlates with the tumorigenesis of intraductal papillary mucinous neoplasm of the pancreas. 国際誌

Kennichi Satoh, Atsushi Kanno, Shin Hamada, Morihisa Hirota, Jun Umino, Atsushi Masamune, Shinichi Egawa, Fuyuhiko Motoi, Michiaki Unno, Tooru Shimosegawa

Oncology reports　19　(5)　1185-90　2008年5月

ISSN：1021-335X

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Sonic hedgehog (SHH) is frequently expressed in pre-cancerous lesions and carcinoma of the pancreas. A recent study revealed that its expression was higher in the intraductal papillary mucinous neoplasm (IPMN) of the pancreas than in the pancreatic carcinoma. However, the correlation between its signaling pathway and tumorigenesis of IPMN has not yet been well documented. We investigated the expression of mRNA and protein of SHH as well as its downstream transcription factor Gli1 in 19 microdissected lesions from 15 cases and in 75 lesions from 33 cases of the IPMN by one-step quantitative real-time reverse transcription-polymerase chain reaction and immunohistochemistry, respectively. SHH and Gli1 mRNAs were detected in all the examined lesions and 8 out of 19 lesions in IPMNs, respectively. SHH and Gli1 mRNAs were likely to be up-regulated from the adenoma and from borderline to carcinoma cells, respectively. Immunohistochemical analysis also reported that SHH and Gli1 expression was correlated with the grade of cell atypia. These findings suggested that HH signaling was activated in IPMNs and contributed to tumorigenesis in these types of neoplasms.
Regulation of human Cripto-1 gene expression by TGF-beta1 and BMP-4 in embryonal and colon cancer cells. 国際誌

Mario Mancino, Luigi Strizzi, Christian Wechselberger, Kazuhide Watanabe, Monica Gonzales, Shin Hamada, Nicola Normanno, David S Salomon, Caterina Bianco

Journal of cellular physiology　215　(1)　192-203　2008年4月

eISSN：1097-4652

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Human Cripto-1 (CR-1) is a cell membrane protein that is overexpressed in several different types of human carcinomas. In the present study we investigated the mechanisms that regulate the expression of CR-1 gene in cancer cells. We cloned a 2,481 bp 5'-flanking region of the human CR-1 gene into a luciferase reporter vector and transfected NTERA-2 human embryonal carcinoma cells and LS174-T colon cancer cells to test for promoter activity. Activity of CR-1 promoter in both cell lines was modulated by two TGF-beta family members, TGF-beta1 and BMP-4. In particular, TGF-beta1 significantly up-regulated CR-1 promoter activity, whereas a dramatic reduction in CR-1 promoter activity was observed with BMP-4 in NTERA-2 and LS174-T cells. Changes in the CR-1 promoter activity following TGF-beta1 and BMP-4 treatments correlated with changes in CR-1 mRNA and protein expression in NTERA-2 and LS174-T cells. We also identified three Smad binding elements (SBEs) within the CR-1 promoter and point mutation of SBE1 (-2,197/-2,189) significantly reduced response of the CR-1 promoter to both TGF-beta1 and BMP-4 in NTERA-2 and LS174-T cells. Chromatin immunoprecipitation assay also demonstrated binding of Smad-4 to a CR-1 promoter DNA sequence containing SBE1 in LS174-T cells. Finally, BMP-4 inhibited migration of LS174-T cells and F9 mouse embryonal carcinoma cells by downregulation of CR-1 protein. In conclusion, these results suggest a differential modulation of CR-1 gene expression in embryonal and colon cancer cells by two different members of the TGF-beta family.
Up-Regulation of MSX2 Enhances the Malignant Phenotype and Is Associated with Twist 1 Expression in Human Pancreatic Cancer Cells 国際誌査読有り

Kennichi Satoh, Shin Hamada, Kenji Kimura, Atsushi Kanno, Morihisa Hirota, Jun Umino, Wataru Fujibuchi, Atsushi Masamune, Naoki Tanaka, Koh Miura, Shinichi Egawa, Fuyuhiko Motoi, Michiaki Unno, Barbara K. Vonderhaar, Tooru Shimosegawa

The American Journal of Pathology　172　(4)　926-939　2008年4月
出版者・発行元： Elsevier BV
DOI： 10.2353/ajpath.2008.070346 　

ISSN：0002-9440

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MSX2 is thought to be a regulator of organ development and a downstream target of the ras signaling pathway; however, little is known about the role of MSX2 in the development of pancreatic cancers, most of which harbor a K-ras gene mutation. Therefore, we examined whether the presence of MSX2 correlates with the malignant behavior of pancreatic cancer cells. BxPC3 pancreatic cancer cells that stably overexpress MSX2 showed a flattened and scattered morphology accompanied by a change in localization of E-cadherin and beta-catenin from membrane to cytoplasm. Cell proliferation rate, cell migration, and anchorage-independent cell growth were enhanced in MSX2-expressing cells. Injection of MSX2-expressing cells into the pancreas of nude mice resulted in a significant increase in liver metastases and peritoneal disseminations compared with injection of control cells. Microarray analysis revealed a significant induction of Twist 1 expression in cells that express MSX2. When MSX2 was inactivated in pancreatic cancer cells following transfection with an MSX2-specific small interfering RNA, Twist 1 was down-regulated. Immunohistochemistry of human pancreatic carcinoma tissue revealed that MSX2 was frequently expressed in cancer cells, and that increased expression of MSX2 significantly correlated with higher tumor grade, vascular invasion, and Twist 1 expression. These data indicate that MSX2 plays a crucial role in pancreatic cancer development by inducing changes consistent with epithelial to mesenchymal transition through enhanced expression of Twist 1.
Regulation of Cripto-1 signaling and biological activity by caveolin-1 in mammary epithelial cells. 国際誌

Caterina Bianco, Luigi Strizzi, Mario Mancino, Kazuhide Watanabe, Monica Gonzales, Shin Hamada, Ahmed Raafat, Lawson Sahlah, Cindy Chang, Federica Sotgia, Nicola Normanno, Michael Lisanti, David S Salomon

The American journal of pathology　172　(2)　345-57　2008年2月

DOI： 10.2353/ajpath.2008.070696 　

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Human and mouse Cripto-1 (CR-1/Cr-1) proteins play an important role in mammary gland development and tumorigenesis. In this study, we examined the relationship between Cripto-1 and caveolin-1 (Cav-1), a membrane protein that acts as a tumor suppressor in the mammary gland. Cripto-1 was found to interact with Cav-1 in COS7 cells and mammary epithelial cells. Using EpH4 mouse mammary epithelial cells expressing Cr-1 (EpH4 Cr-1) or Cr-1 and Cav-1 (EpH4 Cr-1/Cav-1), we demonstrate that Cav-1 expression markedly reduced the ability of Cr-1 to enhance migration, invasion, and formation of branching structures in EpH4 Cr-1/Cav-1 cells as compared to EpH4 Cr-1 cells. Furthermore, coexpression of Cav-1 together with Cr-1 in EpH4 Cr-1/Cav-1 cells inhibited Cr-1-mediated activation of c-src and mitogen-activated protein kinase signaling pathways. Conversely, primary mammary epithelial cells isolated from Cav-1 null(-/-)/mouse mammary tumor virus-CR-1 transgenic animals showed enhanced motility and activation of mitogen-activated protein kinase and c-src as compared to Cav-1(+/-)/CR-1 mammary cells. Finally, mammary tumors derived from mouse mammary tumor virus-CR-1 mice showed a dramatic reduction of Cav-1 expression as compared to mammary tissue from normal FVB/N mice, suggesting that in vivo Cav-1 is down-regulated during the process of CR-1-mediated mammary tumorigenesis.
Requirement of glycosylphosphatidylinositol anchor of Cripto-1 for trans activity as a Nodal co-receptor. 国際誌

Kazuhide Watanabe, Shin Hamada, Caterina Bianco, Mario Mancino, Tadahiro Nagaoka, Monica Gonzales, Veronique Bailly, Luigi Strizzi, David S Salomon

The Journal of biological chemistry　282　(49)　35772-86　2007年12月7日

ISSN：0021-9258

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Cripto-1 (CR-1) has an indispensable role as a Nodal co-receptor for patterning of body axis in embryonic development. CR-1 is reported to have a paracrine activity as a Nodal co-receptor, although CR-1 is primarily produced as a glycosylphosphatidylinositol (GPI)-anchored membrane protein. Regulation of cis and trans function of CR-1 should be important to establish the precise body patterning. However, the mechanism by which GPI-anchored CR-1 can act in trans is not well known. Here we confirmed the paracrine activity of CR-1 by fluorescent cell-labeling and immunofluorescent staining. We generated COOH-terminal-truncated soluble forms of CR-1 based on the attachment site for the GPI moiety (omega-site), which we identified in the present study. GPI-anchored CR-1 has a significantly higher activity than COOH-terminal-truncated soluble forms to induce Nodal signal in trans as well as in cis. Moreover, transmembrane forms of CR-1 partially retained their ability to induce Nodal signaling only when type I receptor Activin-like kinase 4 was overexpressed. NTERA2/D1 cells, which express endogenous CR-1, lost the cell-surface expression of CR-1 after phosphatidylinositol-phospholipase C treatment and became refractory to stimulation of Nodal. These observations suggest that GPI attachment of CR-1 is required for the paracrine activity as a Nodal co-receptor.
Bone morphogenetic protein 4 induces epithelial-mesenchymal transition through MSX2 induction on pancreatic cancer cell line 国際誌査読有り

Shin Hamada, Kennichi Satoh, Morihisa Hirota, Kenji Kimura, Atsushi Kanno, Atsushi Masamune, Tooru Shimosegawa

Journal of Cellular Physiology　213　(3)　768-774　2007年12月
出版者・発行元： Wiley
DOI： 10.1002/jcp.21148 　

ISSN：0021-9541

eISSN：1097-4652

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In our study, we found that bone morphogenetic protein 4 (BMP4) has a novel effect as an inducer of epithelial-mesenchymal transition (EMT) on Panc-1 cells, a human pancreatic carcinoma cell line. BMP4-treated Panc-1 cells showed loose cell contacts and a scattered, fibroblast-like appearance along with E-cadherin downregulation, Vimentin upregulation and enhanced cell migration, which are characteristic of EMT. BMP4 treatment also induced homeobox gene MSX2 expression, which we previously showed to be associated with EMT in pancreatic carcinoma cells. BMP4 treatment activated the Smad signaling pathway, and extracellular signal-related kinase (ERK) and p38 mitogen-activated kinase (MAPK) pathways in these cells. MSX2 was markedly induced by BMP4 through the ERK and p38 MAPK pathways in collaboration with the Smad signaling pathway. The repression of E-cadherin, induction of Vimentin and enhanced cell migration disappeared when siRNA-based MSX2 downregulated pancreatic cancer cells were treated with BMP4. These findings indicate that BMP4 may be involved in pancreatic carcinoma development through the promotion of EMT and that MSX2 is indispensable to this process.
Growth factor induction of Cripto-1 shedding by glycosylphosphatidylinositol-phospholipase D and enhancement of endothelial cell migration. 国際誌

Kazuhide Watanabe, Caterina Bianco, Luigi Strizzi, Shin Hamada, Mario Mancino, Veronique Bailly, Wenjun Mo, Dingyi Wen, Konrad Miatkowski, Monica Gonzales, Michele Sanicola, Masaharu Seno, David S Salomon

The Journal of biological chemistry　282　(43)　31643-55　2007年10月26日

ISSN：0021-9258

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Cripto-1 (CR-1) is a glycosylphosphatidylinositol (GPI)-anchored membrane glycoprotein that has been shown to play an important role in embryogenesis and cellular transformation. CR-1 is reported to function as a membrane-bound co-receptor and as a soluble ligand. Although a number of studies implicate the role of CR-1 as a soluble ligand in tumor progression, it is unclear how transition from the membrane-bound to the soluble form is physiologically regulated and whether differences in biological activity exist between these forms. Here, we demonstrate that CR-1 protein is secreted from tumor cells into the conditioned medium after treatment with serum, epidermal growth factor, or lysophosphatidic acid, and this soluble form of CR-1 exhibits the ability to promote endothelial cell migration as a paracrine chemoattractant. On the other hand, membrane-bound CR-1 can stimulate endothelial cell sprouting through direct cell-cell interaction. Shedding of CR-1 occurs at the GPI-anchorage site by the activity of GPI-phospholipase D (GPI-PLD), because CR-1 shedding was suppressed by siRNA knockdown of GPI-PLD and enhanced by overexpression of GPI-PLD. These findings describe a novel molecular mechanism of CR-1 shedding, which may contribute to endothelial cell migration and possibly tumor angiogenesis.
beta-Catenin/TCF/LEF regulate expression of the short form human Cripto-1. 国際誌

Shin Hamada, Kazuhide Watanabe, Morihisa Hirota, Caterina Bianco, Luigi Strizzi, Mario Mancino, Monica Gonzales, David S Salomon

Biochemical and biophysical research communications　355　(1)　240-4　2007年3月30日

ISSN：0006-291X

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The human gene Teratocarcinoma-derived growth factor 1 (TDGF1)/Cripto-1/CR-1 which is expressed in a wide variety of human carcinomas is a member of the EGF-cripto FRL1 cryptic (EGF-CFC) gene family. A majority of human colorectal tumors and hepatomas are known to possess a constitutively active canonical Wnt/beta-catenin/TCF signaling pathway, also express CR-1. Expression of a short form of CR-1 mRNA in colon carcinoma and hepatoma cell lines suggests that there may be differential regulation of CR-1 expression by the canonical Wnt signaling pathway in colon cancer as well as hepatoma cell lines. The present study demonstrates a direct transcriptional regulation of the short form CR-1 expression by the canonical Wnt signaling pathway through an intronic-exonic enhancer element, containing three tandem TCF/LEF binding sites within the CR-1 gene.
Activation of Notch signaling in tumorigenesis of experimental pancreatic cancer induced by dimethylbenzanthracene in mice 国際誌査読有り

Kenji Kimura, Kennichi Satoh, Atsushi Kanno, Shin Hamada, Morihisa Hirota, Mareyuki Endoh, Atsushi Masamune, Tooru Shimosegawa

Cancer Science　98　(2)　155-162　2007年2月
出版者・発行元： Wiley
DOI： 10.1111/j.1349-7006.2006.00369.x 　

ISSN：1347-9032

eISSN：1349-7006

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To establish pancreatic cancer in mice, dimethylbenzanthracene (DMBA) was administered into mice pancreata. The formation of tubular complex lesions was found in the pancreatic sections from 2 weeks after DMBA treatment. Abnormal tubular complex formations with ductal metaplasia were found from 1 month after the administration. By 3 months after DMBA injection into the pancreas, 6 of 10 mice showed visually recognizable tumors with precursor lesions of various types of cell atypia. In contrast, there were no visually or histologically detectable tumors in the placebo-treated animals. The expression profiles of smad 4, cyclin D1 and p53 in the DMBA-induced tumors were similar to those of human pancreatic cancer, suggesting that this would be a useful mouse model for studying the morphological and molecular mechanisms involved in pancreatic carcinogenesis. Immunohistochemical study using specific antibodies revealed that Notch-1 and Hes-1 were expressed in lesions ranging from tubular complexes to carcinoma in these chemically induced pancreatic tumors. Semiquantitative reverse transcription-polymerase chain reaction with microdissection demonstrated that Notch-1 expression was continuous from precursor lesions to carcinoma cells, whereas Pdx-1 expression was attenuated in carcinoma cells compared to precursor lesions. In addition, inhibition of the Notch signaling pathway by the gamma-secretase inhibitor N-(N-[3,5-difluorophenacetyl]-L-alanyl)-S-phenylglycine t-butyl ester reduced pancreatic cancer cell growth. Therefore, Notch signaling is required to form the tubular complexes and its continuous activation might lead to the transition from tubular complexes to premalignant or malignant lesions and carcinoma cell development in the pancreas.
Identification of cripto-1 as a novel serologic marker for breast and colon cancer. 国際誌

Caterina Bianco, Luigi Strizzi, Mario Mancino, Aasia Rehman, Shin Hamada, Kazuhide Watanabe, Antonella De Luca, Brenda Jones, Gabriela Balogh, Jose Russo, Daniel Mailo, Raffaele Palaia, Giuseppe D'Aiuto, Gerardo Botti, Francesco Perrone, David S Salomon, Nicola Normanno

Clinical cancer research : an official journal of the American Association for Cancer Research　12　(17)　5158-64　2006年9月1日

ISSN：1078-0432

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PURPOSE: Human Cripto-1 (CR-1), a cell membrane glycosylphosphatidylinositol-anchored glycoprotein that can also be cleaved from the membrane, is expressed at high levels in several different types of human tumors. We evaluated whether CR-1 is present in the plasma of patients with breast and colon cancer, and if it can represent a new biomarker for these malignancies. EXPERIMENTAL DESIGN: We determined CR-1 plasma levels using a sandwich-type ELISA in 21 healthy volunteers, 54 patients with breast cancer, 33 patients with colon carcinoma, and 21 patients with benign breast lesions. Immunohistochemical analysis was also used to assess CR-1 expression in cancerous tissues. RESULTS: Very low levels of CR-1 (mean+/-SD) were detected in the plasma of healthy volunteers (0.32+/-0.19 ng/mL). A statistically significant increase in the levels of plasma CR-1 was found in patients with colon carcinoma (4.68+/-3.5 ng/mL) and in patients with breast carcinoma (2.97+/-1.48 ng/mL; P<0.001). Although moderate levels of plasma CR-1 were found in women with benign lesions of the breast (1.7+/-0.99 ng/mL), these levels were significantly lower than in patients with breast cancer (P<0.001). Finally, immunohistochemical analysis and real-time reverse transcription-PCR confirmed strong positivity for CR-1 in colon and/or breast tumor tissues. CONCLUSION: This study suggests that plasma CR-1 might represent a novel biomarker for the detection of breast and colon carcinomas.
MSX2 overexpression inhibits gemcitabine-induced caspase-3 activity in pancreatic cancer cells. 国際誌

Shin Hamada, Kennichi Satoh, Kenji Kimura, Atsushi Kanno, Atsushi Masamune, Tooru Shimosegawa

World journal of gastroenterology　11　(43)　6867-70　2005年11月21日

ISSN：1007-9327

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AIM: To evaluate the effect of MSX2 on gemcitabine-induced caspase-3 activation in pancreatic cancer cell line Panc-1. METHODS: Using V5-tagged MSX2 expression vector, stable transfectant of MSX2 was generated from Panc-1 cells (Px14 cells). Cell viability under gemcitabine administration was determined by MTT assay relative to control cell line (empty-vector transfected Panc-1 cells; P-3EV cells). Hoechst staining was used for the detection of apoptotic cell. Activation of caspase-3 was assessed using Western blotting analysis and direct measurement of caspase-3 specific activities. RESULTS: MSX2 overexpression in Panc-1 cells resulted in decreased gemcitabine-induced caspase-3 activation and increased cell viability under gemcitabine treatment in Px14 cells. CONCLUSION: MSX2 exerts repressive effects on gemcitabine-induced apoptotic pathway. This novel apoptosis-regulating function of MSX2 may provide a new therapeutic target for pancreatic cancer.
Netrin-1 regulates invasion and migration of mouse mammary epithelial cells overexpressing Cripto-1 in vitro and in vivo. 国際誌

Luigi Strizzi, Caterina Bianco, Ahmed Raafat, Wissam Abdallah, Cindy Chang, Dina Raafat, Morihisa Hirota, Shin Hamada, Youping Sun, Nicola Normanno, Robert Callahan, Lindsay Hinck, David Salomon

Journal of cell science　118　(Pt 20)　4633-43　2005年10月15日

ISSN：0021-9533

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The neuronal guidance molecule, Netrin-1, has been suggested to play a role in the adhesion and migration of the mammary gland epithelium. Human and mouse Cripto-1 induce proliferation, migration, invasion and colony formation by epithelial cells in 3D matrices. Here we investigate whether Netrin-1 affects these Cripto-1-dependent activities in mouse mammary epithelial cells. Overexpression of Cripto-1 in EpH4 and HC-11 cells (EpH4/Cripto-1 or HC-11/Cripto-1) was associated with low expression of Netrin-1 and increased expression of its receptor Neogenin compared to that of wild-type cells. No change was observed in the expression of the other Netrin-1 receptor, UNC5H1. Treating EpH4/Cripto-1 or HC-11/Cripto-1 mammary cells with exogenous soluble Netrin-1 resulted in increased expression of E-cadherin and UNC5H1, decreased expression of vimentin and decreased activation of Akt as determined by western blotting. Colony formation by Eph4/Cripto-1 cells in 3D gels was significantly reduced in proximity to a Netrin-1 source, and mammary glands of transgenic mice overexpressing human Cripto-1 showed altered ductal growth in proximity to implanted Netrin-1-releasing pellets. Terminal end buds in the treated transgenic mice mammary glands also showed increased expression of E-cadherin and UNC5H1 and decreased expression of active Akt determined by immunohistochemistry. Together, these results suggest that regulation of Netrin-1 expression is important in regulating Cripto-1-dependent invasion and migration of mammary epithelial cells.
[Usefulness of percutaneous endoscopic gastrostomy (PEG) in home health care--investigation from the viewpoint of cost effectiveness].

Michio Kuroki, Katsuhisa Sato, Jun Inoue, Kenji Uno, Katsuya Endo, Shin Hamada, Kenji Noguchi, Toshiaki Ojima, Takatoshi Kamiya, Junya Kashimura, Shinichi Ikeya, Itaru Endo, Haruo Nakayama, Yoshiki Sugai, Nobuo Hiwatashi

Gan to kagaku ryoho. Cancer & chemotherapy　30 Suppl 1　161-4　2003年12月

ISSN：0385-0684

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The use of percutaneous endoscopic gastrostomy (PEG) has widely spread in recent years, even in Japan. In our hospital, we have performed this procedure in over 20 patients per year recently. In this study, we investigated the usefulness of PEG in home health care from the view point of cost effectiveness. We found that medical expenses decreased remarkably when patients underwent PEG because they could switch from hospital care to home health care, shortening there by the period of hospital care. The role of PEG in home health care will be more important also from cost effectiveness.
[Usefulness of percutaneous endoscopic gastrostomy (PEG) in home health care--investigation from the viewpoint of cost effectiveness].

Michio Kuroki, Katsuhisa Sato, Jun Inoue, Kenji Uno, Katsuya Endo, Shin Hamada, Kenji Noguchi, Toshiaki Ojima, Takatoshi Kamiya, Junya Kashimura, Shinichi Ikeya, Itaru Endo, Haruo Nakayama, Yoshiki Sugai, Nobuo Hiwatashi

Gan to kagaku ryoho. Cancer & chemotherapy　30　(1 Suppl)　161-4　2003年12月

ISSN：0385-0684

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The use of percutaneous endoscopic gastrostomy (PEG) has widely spread in recent years, even in Japan. In our hospital, we have performed this procedure in over 20 patients per year recently. In this study, we investigated the usefulness of PEG in home health care from the view point of cost effectiveness. We found that medical expenses decreased remarkably when patients underwent PEG because they could switch from hospital care to home health care, shortening there by the period of hospital care. The role of PEG in home health care will be more important also from cost effectiveness.
[A case of type 4 colorectal carcinoma with rapid progression observed radiographically].

Michio Kuroki, Itaru Endo, Katsuya Endo, Naoko Mori, Jun Inoue, Kenji Uno, Shin Hamada, Kenji Noguchi, Toshiaki Ojima, Takatoshi Kamiya, Junya Kashimura, Shinichi Ikeya, Haruo Nakayama, Katsuhisa Sato, Eiji Hoshino, Yoshiki Sugai, Nobuo Hiwatashi, Humiaki Shinya

Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology　100　(11)　1302-6　2003年11月

ISSN：0446-6586
注腸X線検査上短期間で急速な進行を確認し得た4型大腸癌の1例

黒木実智雄, 遠藤到, 遠藤克哉, 森菜緒子, 井上淳, 宇野健司, 濱田晋, 野口謙治, 小島敏明, 神谷尚則, 鹿志村純也, 池谷伸一, 中山晴夫, 佐藤勝久, 星野英二, 須貝吉樹, 樋渡信夫, 新谷史明

日本消化器病学会雑誌　100　(11)　1302-1306　2003年11月
出版者・発行元： (一財)日本消化器病学会
ISSN：0446-6586
[A case of poorly differentiated mucinous carcinoma of the gallbladder with remarkable imaging features].

Michio Kuroki, Katsuhisa Sato, Junya Kashimura, Naoko Mori, Jun Inoue, Kenji Uno, Katsuya Endo, Shin Hamada, Kenji Noguchi, Toshiaki Ojima, Takatoshi Kamiya, Shinichi Ikeya, Itaru Endo, Haruo Nakayama, Yoshiki Sugai, Nobuo Hiwatashi, Humiaki Shinya

Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology　100　(10)　1224-8　2003年10月

ISSN：0446-6586
興味ある画像所見を呈した胆嚢低分化型粘液癌の1例

黒木実智雄, 佐藤勝久, 鹿志村純也, 森菜緒子, 井上淳, 宇野健司, 遠藤克哉, 濱田晋, 野口謙治, 小島敏明, 神谷尚則, 池谷伸一, 遠藤到, 中山晴夫, 須貝吉樹, 樋渡信夫, 新谷史明

日本消化器病学会雑誌　100　(10)　1224-1228　2003年10月
出版者・発行元： (一財)日本消化器病学会
ISSN：0446-6586
食道に発生したPyogenic Granulomaの1例

井上淳, 佐藤勝久, 飯島克則, 宇野健司, 遠藤克也, 濱田晋, 野口謙治, 小島敏明, 黒木実智雄, 神谷尚則, 鹿志村純也, 池谷伸一, 遠藤到, 中山晴夫, 須貝吉樹, 樋渡信夫

消化器内視鏡　15　(7)　1023-1028　2003年7月
出版者・発行元： (株)東京医学社
ISSN：0915-3217

︎全件表示 ︎最初の5件までを表示

MISC 373

膵炎の遺伝的背景

濱田晋, 佐々木滉, 松本諒太郎, 滝川哲也, 菊田和宏, 正宗淳

胆膵の病態生理　40　(1)　2024年

ISSN： 2185-4564
多発性内分泌腫瘍症1型における膵・十二指腸神経内分泌腫瘍の臨床的特徴

滝川哲也, 八田和久, 池田未緒, 佐野貴紀, 松本涼太郎, 三浦晋, 濱田晋, 粂潔, 菊田和宏, 正宗淳

日本消化器病学会雑誌(Web)　121　2024年

ISSN： 1349-7693
膵仮性嚢胞に対する経消化管的ドレナージの治療成績と入院経費の評価

粂潔, 佐々木滉, 池田未緒, 佐野貴紀, 松本諒太郎, 滝川哲也, 三浦晋, 濱田晋, 菊田和宏, 正宗淳

日本消化器病学会雑誌(Web)　121　2024年

ISSN： 1349-7693
カルシウムチャネルTRPV6は膵癌の環境適応に寄与するか

濱田晋, 佐々木滉, 松本諒太郎, 坂野美紗子, 林秀大, 滝川哲也, 正宗淳

日本消化器病学会雑誌(Web)　121　2024年

ISSN： 1349-7693
膵脂肪浸潤と膵癌発症の関連性

三浦晋, 粂潔, 菊田和宏, 濱田晋, 滝川哲也, 松本諒太郎, 佐野貴紀, 池田未緒, 佐々木滉, 坂野美紗子, 林秀大, 間中友王, 正宗淳

日本消化器病学会雑誌(Web)　121　2024年

ISSN： 1349-7693
自己免疫性膵炎の臨床像と飲酒習慣の関連に関する検討

菊田和宏, 松本諒太郎, 滝川哲也, 濱田晋, 正宗淳

日本胆膵病態・生理研究会プログラム・抄録集　41st　2024年
TRPV6チャネル阻害は膵癌細胞のsurvivin発現を抑制する

濱田晋, 松本諒太郎, 滝川哲也, 菊田和宏, 正宗淳

日本胆膵病態・生理研究会プログラム・抄録集　41st　2024年
【胆道癌と膵癌のリスクファクター】遺伝性膵炎と膵癌の関連性

濱田晋, 松本諒太郎, 滝川哲也, 佐々木滉, 坂野美紗子, 林秀大, 正宗淳

胆と膵　44　(9)　873-878　2023年9月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
【新時代のKRAS変異～診断の主役から治療の標的へ～】KRAS変異が起点となる細胞内ストレスと発現における意義

濱田晋, 松本諒太郎, 滝川哲也, 佐々木滉, 坂野美紗子, 林秀大, 正宗淳

胆と膵　44　(7)　631-636　2023年7月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
慢性膵炎における簡易型自記式食事歴法質問票の有用性の検討

菊田和宏, 松本諒太郎, 滝川哲也, 濱田晋, 正宗淳

消化と吸収　45　(2)　135-139　2023年7月
出版者・発行元： (NPO)日本消化吸収学会
ISSN： 0389-3626
【超高齢社会における肝胆膵疾患診療】高齢の自己免疫性膵炎・慢性膵炎患者をめぐる諸問題発癌・サルコペニア・フレイル

滝川哲也, 菊田和宏, 松本諒太郎, 佐々木滉, 池田未緒, 佐野貴紀, 濱田晋, 三浦晋, 粂潔, 正宗淳

肝胆膵　86　(6)　749-753　2023年6月
出版者・発行元： (株)アークメディア
ISSN： 0389-4991
【急性膵炎診療ガイドライン改訂とPancreatitis Bundlesを読み解く】急性膵炎の疫学近年増加している急性膵炎

池田未緒, 濱田晋, 菊田和宏, 滝川哲也, 松本諒太郎, 正宗淳

臨床消化器内科　38　(8)　1019-1024　2023年6月
出版者・発行元： (株)日本メディカルセンター
ISSN： 0911-601X

eISSN： 2433-2488
膵癌の薬剤抵抗性におけるKeap1-Nrf2経路の寄与に関する検討

松本諒太郎, 濱田晋, 正宗淳

胆膵の病態生理　39　(1)　7-12　2023年6月
出版者・発行元：日本胆膵病態・生理研究会
ISSN： 2185-4564
【超高齢社会における肝胆膵疾患診療】高齢の自己免疫性膵炎・慢性膵炎患者をめぐる諸問題発癌・サルコペニア・フレイル

滝川哲也, 菊田和宏, 松本諒太郎, 佐々木滉, 池田未緒, 佐野貴紀, 濱田晋, 三浦晋, 粂潔, 正宗淳

肝胆膵　86　(6)　749-753　2023年6月
出版者・発行元： (株)アークメディア
ISSN： 0389-4991
【急性膵炎診療ガイドライン改訂とPancreatitis Bundlesを読み解く】急性膵炎の疫学近年増加している急性膵炎

池田未緒, 濱田晋, 菊田和宏, 滝川哲也, 松本諒太郎, 正宗淳

臨床消化器内科　38　(8)　1019-1024　2023年6月
出版者・発行元： (株)日本メディカルセンター
ISSN： 0911-601X

eISSN： 2433-2488
膵癌の薬剤抵抗性におけるKeap1-Nrf2経路の寄与に関する検討

松本諒太郎, 濱田晋, 正宗淳

胆膵の病態生理　39　(1)　7-12　2023年6月
出版者・発行元：日本胆膵病態・生理研究会
ISSN： 2185-4564
【膵癌・胆道癌2023(下)胆道癌編-基礎・臨床の最新研究動向-】基礎編胆道癌の浸潤・転移機構

滝川哲也, 濱田晋, 正宗淳

日本臨床　81　(増刊4 膵癌・胆道癌2023(下)胆道癌編)　24-28　2023年4月
出版者・発行元： (株)日本臨床社
ISSN： 0047-1852
【肝胆膵領域におけるアルコール医学の新潮流】アルコールと膵疾患における新知見アルコール性膵炎の現状

菊田和宏, 粂潔, 濱田晋, 三浦晋, 滝川哲也, 松本諒太郎, 正宗淳

肝胆膵　86　(4)　529-534　2023年4月
出版者・発行元： (株)アークメディア
ISSN： 0389-4991
EndoSheatherを用いて肝内胆管内のガイドワイヤーを確保してPTBD下ランデブー法を成功した1例

三浦晋, 粂潔, 菊田和宏, 濱田晋, 滝川哲也, 松本諒太郎, 池田未緒, 佐野貴紀, 佐々木滉, 片岡史弥, 林秀大, 坂野美紗子

日本消化器病学会雑誌　120　(臨増総会)　A354-A354　2023年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
消化器領域におけるがん微小環境研究の最前線 Nrf2阻害は膵癌間質に対する新規治療となりうるか

濱田晋, 松本諒太郎, 正宗淳

日本消化器病学会雑誌　120　(臨増総会)　A52-A52　2023年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
アルコールと消化器疾患,現状と課題 DPCデータベースからみたアルコール性急性膵炎の現況

池田未緒, 濱田晋, 正宗淳

日本消化器病学会雑誌　120　(臨増総会)　A171-A171　2023年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
WONに対する内視鏡的ネクロセクトミーの当科における現況

粂潔, 林秀大, 坂野美紗子, 佐々木滉, 片岡史也, 池田未緒, 佐野貴紀, 松本諒太郎, 滝川哲也, 三浦晋, 濱田晋, 菊田和宏, 正宗淳

日本消化器病学会雑誌　120　(臨増総会)　A284-A284　2023年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
消化器領域におけるがん微小環境研究の最前線 Nrf2阻害は膵癌間質に対する新規治療となりうるか

濱田晋, 松本諒太郎, 正宗淳

日本消化器病学会雑誌　120　(臨増総会)　A52-A52　2023年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
WONに対する内視鏡的ネクロセクトミーの当科における現況

粂潔, 林秀大, 坂野美紗子, 佐々木滉, 片岡史也, 池田未緒, 佐野貴紀, 松本諒太郎, 滝川哲也, 三浦晋, 濱田晋, 菊田和宏, 正宗淳

日本消化器病学会雑誌　120　(臨増総会)　A284-A284　2023年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
EndoSheatherを用いて肝内胆管内のガイドワイヤーを確保してPTBD下ランデブー法を成功した1例

三浦晋, 粂潔, 菊田和宏, 濱田晋, 滝川哲也, 松本諒太郎, 池田未緒, 佐野貴紀, 佐々木滉, 片岡史弥, 林秀大, 坂野美紗子

日本消化器病学会雑誌　120　(臨増総会)　A354-A354　2023年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
【膵癌・胆道癌2023(上)膵癌編-基礎・臨床の最新研究動向-】総論基礎編膵癌の腫瘍微小環境(TME)

濱田晋, 松本諒太郎, 正宗淳

日本臨床　81　(増刊2 膵癌・胆道癌2023(上)膵癌編)　23-28　2023年2月
出版者・発行元： (株)日本臨床社
ISSN： 0047-1852
慢性炎症と膵臓がん—特集基礎と臨床から膵臓がんに挑む

濱田晋, 松本諒太郎, 滝川哲也, 佐々木滉, 片岡史弥, 林秀大, 坂野美紗子, 正宗淳

消化器病学サイエンス = Science of gastroenterology / 「消化器病学サイエンス」編集委員会編　6　(4)　231-234　2022年12月

ISSN： 2432-7549
わが国における急性膵炎診療の実態と課題―急性膵炎全国疫学調査の解析から―

濱田晋, 正宗淳

膵臓　37　(5)　208-214　2022年10月31日
出版者・発行元：一般社団法人日本膵臓学会
DOI： 10.2958/suizo.37.208 　

ISSN： 0913-0071

eISSN： 1881-2805

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『急性膵炎診療ガイドライン2021 第5版』では，最新の全国調査に基づく急性膵炎の診療実態を受けて様々な改訂がなされた．診療の適正化による予後の改善は実現されているものの，いまだに死亡例が存在する急性膵炎診療においてはハイリスク症例を認識するとともに，遵守すべき治療方針をよく理解する必要がある．新たなガイドラインで改訂されたPancreatitis bundles 2021では，浸透率が十分とはいえない早期の経腸栄養開始や軽症例での予防的抗菌薬の不使用といった項目が取り入れられた．輸液管理に関する記載や急性期治療における使用薬剤，後期合併症に対する治療方針などのガイドライン改訂項目が実際の急性膵炎診療に与える影響や，予後改善に寄与するかは，今後の全国調査にて明らかにする必要がある．
【高齢者(75歳以上)の膵胆道疾患の特徴と診断・治療方針】高齢者(75歳以上)の慢性膵炎の特徴と診断・治療方針

滝川哲也, 菊田和宏, 松本諒太郎, 濱田晋, 佐々木滉, 粂潔, 三浦晋, 佐野貴紀, 池田未緒, 片岡史弥, 林秀大, 坂野美紗子, 正宗淳

胆と膵　43　(10)　999-1003　2022年10月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
【IgG4関連疾患大全-自己免疫性膵炎とIgG4関連硬化性胆管炎を中心に-】自己免疫性膵炎自己免疫性膵炎のステロイド治療と再燃予測因子

滝川哲也, 菊田和宏, 佐野貴紀, 濱田晋, 松本諒太郎, 粂潔, 三浦晋, 池田未緒, 佐々木滉, 片岡史弥, 林秀大, 坂野美紗子, 正宗淳

胆と膵　43　(臨増特大)　1159-1164　2022年10月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
膵局所合併症の当科のおける治療成績と早期治療介入の可能性について

粂潔, 佐々木滉, 片岡史弥, 池田未緒, 佐野貴紀, 松本諒太郎, 滝川哲也, 三浦晋, 濱田晋, 菊田和宏, 正宗淳

Gastroenterological Endoscopy　64　(Suppl.2)　2125-2125　2022年10月
出版者・発行元： (一社)日本消化器内視鏡学会
ISSN： 0387-1207

eISSN： 1884-5738
全国調査をもとにした高齢者急性膵炎の実態

濱田晋, 菊田和宏, 正宗淳

日本消化器病学会雑誌　119　(臨増大会)　A736-A736　2022年10月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
早期慢性膵炎,慢性膵炎の遺伝子異常の特徴—Characteristics of genetic abnormalities in chronic pancreatitis—特集早期慢性膵炎,慢性膵炎をめぐる諸問題

佐々木滉, 濱田晋, 菊田和宏, 滝川哲也, 松本諒太郎, 池田美緒, 佐野貴紀, 片岡史弥, 坂野美紗子, 林秀大, 三浦晋, 粂潔, 正宗淳

消化器・肝臓内科 = Gastroenterology & hepatology / 消化器・肝臓内科編集委員会編　12　(4)　378-383　2022年10月

ISSN： 2432-3446
膵局所合併症の当科のおける治療成績と早期治療介入の可能性について

粂潔, 佐々木滉, 片岡史弥, 池田未緒, 佐野貴紀, 松本諒太郎, 滝川哲也, 三浦晋, 濱田晋, 菊田和宏, 正宗淳

Gastroenterological Endoscopy　64　(Suppl.2)　2125-2125　2022年10月
出版者・発行元： (一社)日本消化器内視鏡学会
ISSN： 0387-1207

eISSN： 1884-5738
【高齢者(75歳以上)の膵胆道疾患の特徴と診断・治療方針】高齢者(75歳以上)の慢性膵炎の特徴と診断・治療方針

滝川哲也, 菊田和宏, 松本諒太郎, 濱田晋, 佐々木滉, 粂潔, 三浦晋, 佐野貴紀, 池田未緒, 片岡史弥, 林秀大, 坂野美紗子, 正宗淳

胆と膵　43　(10)　999-1003　2022年10月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
【IgG4関連疾患大全-自己免疫性膵炎とIgG4関連硬化性胆管炎を中心に-】自己免疫性膵炎自己免疫性膵炎のステロイド治療と再燃予測因子

滝川哲也, 菊田和宏, 佐野貴紀, 濱田晋, 松本諒太郎, 粂潔, 三浦晋, 池田未緒, 佐々木滉, 片岡史弥, 林秀大, 坂野美紗子, 正宗淳

胆と膵　43　(臨増特大)　1159-1164　2022年10月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
慢性膵炎における簡易型自記式食事歴法質問票の有用性の検討

菊田和宏, 松本諒太郎, 滝川哲也, 濱田晋, 正宗淳

消化と吸収　45　(1)　62-62　2022年9月
出版者・発行元： (NPO)日本消化吸収学会
ISSN： 0389-3626
【膵臓の発生・生理・解剖から膵炎・膵癌の病態解明に至る最新の知見】オルガノイド培養による膵管上皮モデルの現状と課題

濱田晋, 松本諒太郎, 滝川哲也, 佐々木滉, 片岡史弥, 林秀大, 正宗淳

胆と膵　43　(8)　737-742　2022年8月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
【膵臓の発生・生理・解剖から膵炎・膵癌の病態解明に至る最新の知見】膵癌の酸化ストレス応答とグルタミン依存性の意義

濱田晋, 松本諒太郎, 滝川哲也, 佐々木滉, 片岡史弥, 林秀大, 正宗淳

胆と膵　43　(8)　759-764　2022年8月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
【膵臓の発生・生理・解剖から膵炎・膵癌の病態解明に至る最新の知見】オルガノイド培養による膵管上皮モデルの現状と課題

濱田晋, 松本諒太郎, 滝川哲也, 佐々木滉, 片岡史弥, 林秀大, 正宗淳

胆と膵　43　(8)　737-742　2022年8月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
【膵臓の発生・生理・解剖から膵炎・膵癌の病態解明に至る最新の知見】膵癌の酸化ストレス応答とグルタミン依存性の意義

濱田晋, 松本諒太郎, 滝川哲也, 佐々木滉, 片岡史弥, 林秀大, 正宗淳

胆と膵　43　(8)　759-764　2022年8月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
外科的治療の適応のない膵頭部の混合型IPMN由来の再発性急性膵炎に対して放射線治療が著効した一例

坂野美紗子, 粂潔, 林秀大, 佐々木滉, 片岡史弥, 池田未緒, 佐野貴紀, 松本諒太郎, 滝川哲也, 三浦晋, 濱田晋, 菊田和宏, 正宗淳

日本消化器病学会東北支部例会プログラム・抄録集　213回　68-68　2022年7月
出版者・発行元：日本消化器病学会-東北支部
外科的治療の適応のない膵頭部の混合型IPMN由来の再発性急性膵炎に対して放射線治療が著効した一例

坂野美紗子, 粂潔, 林秀大, 佐々木滉, 片岡史弥, 池田未緒, 佐野貴紀, 松本諒太郎, 滝川哲也, 三浦晋, 濱田晋, 菊田和宏, 正宗淳

日本消化器病学会東北支部例会プログラム・抄録集　213回　68-68　2022年7月
出版者・発行元：日本消化器病学会-東北支部
膵臓の線維化と代謝病態・膵発癌—特集臓器線維化へのアプローチ : 肝臓・膵臓のアンチエイジングを見据えて

濱田晋, 正宗淳

Anti-aging medicine / 日本抗加齢医学会 [編]　18　(3)　177-181　2022年6月

ISSN： 1880-1579
高齢者慢性膵炎における疼痛管理の実態

菊田和宏, 濱田晋, 正宗淳

胆膵の病態生理　38　(1)　17-20　2022年6月
出版者・発行元：日本胆膵病態・生理研究会
ISSN： 2185-4564
内臓逆位に対する当科の胆膵内視鏡治療経験

三浦晋, 佐々木滉, 正宗淳, 粂潔, 菊田和宏, 濱田晋, 滝川哲也, 吉田直樹, 松本諒太郎, 田中裕, 池田未緒, 片岡史弥

Gastroenterological Endoscopy　64　(Suppl.1)　763-763　2022年4月
出版者・発行元： (一社)日本消化器内視鏡学会
ISSN： 0387-1207

eISSN： 1884-5738
内臓逆位に対する当科の胆膵内視鏡治療経験

三浦晋, 佐々木滉, 正宗淳, 粂潔, 菊田和宏, 濱田晋, 滝川哲也, 吉田直樹, 松本諒太郎, 田中裕, 池田未緒, 片岡史弥

Gastroenterological Endoscopy　64　(Suppl.1)　763-763　2022年4月
出版者・発行元： (一社)日本消化器内視鏡学会
ISSN： 0387-1207

eISSN： 1884-5738
慢性膵炎患者の脂質摂取状況に関する検討

菊田和宏, 松本諒太郎, 佐々木滉, 片岡史弥, 佐野貴紀, 池田未緒, 田中裕, 吉田直樹, 滝川哲也, 三浦晋, 濱田晋, 粂潔, 正宗淳

日本消化器病学会雑誌　119　(臨増総会)　A345-A345　2022年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
重症急性膵炎の病態解明と治療戦略 DPCデータベースに基づく急性膵炎の入院経路の検討

池田未緒, 濱田晋, 正宗淳

日本消化器病学会雑誌　119　(臨増総会)　A147-A147　2022年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
老化と消化器がんの病態・診療膵星細胞の細胞老化とSASPを介した膵癌制御機構の解明

滝川哲也, 濱田晋, 正宗淳

日本消化器病学会雑誌　119　(臨増総会)　A187-A187　2022年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
慢性膵炎患者の脂質摂取状況に関する検討

菊田和宏, 松本諒太郎, 佐々木滉, 片岡史弥, 佐野貴紀, 池田未緒, 田中裕, 吉田直樹, 滝川哲也, 三浦晋, 濱田晋, 粂潔, 正宗淳

日本消化器病学会雑誌　119　(臨増総会)　A345-A345　2022年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
超音波内視鏡下穿刺吸引法により組織学的に確定診断した2型自己免疫性膵炎の1例

林秀大, 三浦晋, 佐々木滉, 片岡史弥, 佐野貴紀, 池田未緒, 松本諒太郎, 田中裕, 吉田直樹, 滝川哲也, 濱田晋, 菊田和宏, 粂潔, 正宗淳

日本消化器病学会東北支部例会・日本消化器内視鏡学会東北支部例会プログラム・抄録集　212回・167回　169-169　2022年1月
出版者・発行元：日本消化器病学会-東北支部
超音波内視鏡下穿刺吸引法により組織学的に確定診断した2型自己免疫性膵炎の1例

林秀大, 三浦晋, 佐々木滉, 片岡史弥, 佐野貴紀, 池田未緒, 松本諒太郎, 田中裕, 吉田直樹, 滝川哲也, 濱田晋, 菊田和宏, 粂潔, 正宗淳

日本消化器病学会東北支部例会・日本消化器内視鏡学会東北支部例会プログラム・抄録集　212回・167回　169-169　2022年1月
出版者・発行元：日本消化器病学会-東北支部
【小児遺伝子疾患事典】腫瘍性疾患 VHL(関連疾患:von Hippel-Lindau病)

濱田晋, 正宗淳

小児科診療　84　(11)　1666-1668　2021年11月
出版者・発行元： (株)診断と治療社
ISSN： 0386-9806
【胆と膵のスペシャリストが取るべき専門医/指導医とは?】膵癌登録について登録の実際

水間正道, 海野倫明, 糸井隆夫, 江川新一, 児玉裕三, 里井壯平, 仲田興平, 濱田晋, 安田一朗, 竹山宜典

胆と膵　42　(11)　1371-1374　2021年11月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
膵癌の進展機構の解明と新たな治療膵星細胞での酸化ストレス応答活性化はグルタミン酸依存性を誘導する

田中裕, 濱田晋, 正宗淳

日本消化器病学会雑誌　118　(臨増大会)　A637-A637　2021年10月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
消化器領域における再生医療の研究と新たな臨床応用 Trpv6欠損膵オルガノイドにおける導管細胞トランスポーター発現変化

濱田晋, 松本諒太郎, 正宗淳

日本消化器病学会雑誌　118　(臨増大会)　A647-A647　2021年10月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
当院における黄色肉芽腫性胆嚢炎の検討

吉田直樹, 粂潔, 池田未緒, 佐野貴紀, 田中裕, 松本諒太郎, 滝川哲也, 三浦晋, 濱田晋, 菊田和宏, 中川圭, 森川孝則, 海野倫明, 正宗淳

日本消化器病学会雑誌　118　(臨増大会)　A708-A708　2021年10月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
急性膵炎の診断と治療急性膵炎で推奨される標準治療急性膵炎診療ガイドライン2020より

土谷飛鳥, 向井俊太郎, 濱田晋, 廣田衛久, 北村伸哉, 正宗淳, 吉田雅博, 真弓俊彦, 高田忠敬

日本集中治療医学会雑誌　28　(Suppl.2)　229-229　2021年9月
出版者・発行元： (一社)日本集中治療医学会
ISSN： 1340-7988

eISSN： 1882-966X
【膵癌研究最前線】膵癌間質における酸化ストレス応答

濱田晋, 松本諒太郎, 田中裕, 池田未緒, 佐野貴紀, 佐々木滉, 片岡史弥, 正宗淳

消化器・肝臓内科　10　(3)　368-374　2021年9月
出版者・発行元： (有)科学評論社
ISSN： 2432-3446
【膵癌、膵炎の病態解明と新規治療開発にむけた研究の最前線】膵癌進展における酸化ストレス応答Keap1-Nrf2経路の関与

濱田晋, 松本諒太郎, 田中裕, 池田未緒, 佐野貴紀, 佐々木滉, 片岡史弥, 正宗淳

胆と膵　42　(8)　689-694　2021年8月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
【膵癌、膵炎の病態解明と新規治療開発にむけた研究の最前線】慢性膵炎のゲノム解析に関する最新の知見

濱田晋, 正宗淳

胆と膵　42　(8)　757-762　2021年8月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
急性膵炎診療をめぐる諸問題急性膵炎に伴うWONに対する超音波内視鏡下瘻孔形成術の実施時期に対する検討

池田未緒, 濱田晋, 佐野貴紀, 松本諒太郎, 田中裕, 本郷星仁, 吉田直樹, 滝川哲也, 三浦晋, 菊田和宏, 粂潔, 正宗淳

膵臓　36　(3)　A141-A141　2021年8月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
アルコール性慢性膵炎患者のマネージメント(メディカルスタッフ) 全国調査からみたアルコール性慢性膵炎における断酒指導と喫煙状況、併存疾患の現況

菊田和宏, 濱田晋, 正宗淳

膵臓　36　(3)　A218-A218　2021年8月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
膵神経内分泌腫瘍の画像診断と臨床病理学的バイオマーカー膵神経内分泌腫瘍における術前因子を指標とした悪性度予測モデルの検討

滝川哲也, 粂潔, 菊田和宏, 濱田晋, 三浦晋, 吉田直樹, 本郷星仁, 田中裕, 松本諒太郎, 佐野貴紀, 池田未緒, 正宗淳

膵臓　36　(3)　A226-A226　2021年8月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
臨床の基盤になる膵臓の発生、解剖、生理、病理の新知見オルガノイドを用いた二次元培養による膵管上皮モデルの構築

松本諒太郎, 濱田晋, 田中裕, 滝川哲也, 正宗淳

膵臓　36　(3)　A230-A230　2021年8月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
膵炎・膵癌のbench to bed:病態解明から新規治療法開発に向けて Nrf2活性化は膵癌細胞のグルタミン酸依存性を促進する

濱田晋, 松本諒太郎, 田中裕, 正宗淳

膵臓　36　(3)　A236-A236　2021年8月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
膵癌早期発見の工夫と取り組み膵臓のくびれ所見は膵癌発症の前兆か?

三浦晋, 滝川哲也, 粂潔, 菊田和宏, 濱田晋, 吉田直樹, 池田美緒, 佐野貴紀, 松本諒太郎, 田中裕, 正宗淳

膵臓　36　(3)　A244-A244　2021年8月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
膵癌治療(ステント) 膵消化管吻合例に対する膵内視鏡検査・治療の当科における現況について

粂潔, 池田未緒, 佐野貴紀, 松本諒太郎, 田中裕, 本郷星仁, 滝川哲也, 三浦晋, 濱田晋, 菊田和宏, 正宗淳

膵臓　36　(3)　A296-A296　2021年8月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
Nrf2活性化とアミノ酸依存性

濱田晋, 松本諒太郎, 田中裕, 池田未緒, 佐野貴紀, 佐々木滉, 片岡史弥, 正宗淳

消化と吸収　43　(2)　107-109　2021年7月
出版者・発行元： (NPO)日本消化吸収学会
ISSN： 0389-3626
十二指腸乳頭の形態異常を伴い膵・胆管合流異常類似の病態を呈した1例

片岡史弥, 三浦晋, 粂潔, 菊田和宏, 濱田晋, 滝川哲也, 吉田直樹, 松本諒太郎, 田中裕, 池田未緒, 佐々木滉, 三浦孝之, 海野倫明, 正宗淳

日本消化器病学会東北支部例会プログラム・抄録集　211回　55-55　2021年7月
出版者・発行元：日本消化器病学会-東北支部
慢性膵炎患者における消化酵素薬使用状況膵炎全国疫学調査の解析

滝川哲也, 菊田和宏, 濱田晋, 正宗淳

消化と吸収　43　(2)　103-106　2021年7月
出版者・発行元： (NPO)日本消化吸収学会
ISSN： 0389-3626
胆道癌進展メカニズム研究の現状

濱田晋, 正宗淳

胆膵の病態生理　37　(1)　1-5　2021年6月
出版者・発行元：日本胆膵病態・生理研究会
ISSN： 2185-4564
【膵臓症候群(第3版)-その他の膵臓疾患を含めて-】膵炎遺伝性膵炎・家族性膵炎・熱帯性膵炎

濱田晋, 正宗淳

日本臨床　別冊　(膵臓症候群)　319-323　2021年6月
出版者・発行元： (株)日本臨床社
ISSN： 0047-1852
NRF2 CONTRIBUTES TO GAMCITABINE RESISTANCE VIA ALDEHYDE DEHYDROGENASE 3A1 IN PANCREATIC CANCER CELLS

Ryotaro Matsumoto, Shin Hamada, Yu Tanaka, Atsushi Masamune

GASTROENTEROLOGY　160　(6)　S474-S474　2021年5月

ISSN： 0016-5085

eISSN： 1528-0012
【消化器内科医のためのIgG4関連疾患】自己免疫性膵炎疫学

菊田和宏, 濱田晋, 正宗淳

臨床消化器内科　36　(6)　601-604　2021年5月
出版者・発行元： (株)日本メディカルセンター
ISSN： 0911-601X

eISSN： 2433-2488
胆管空腸吻合部狭窄に対するバルーン拡張術のバルーン径に関する検討

滝川哲也, 粂潔, 正宗淳, 菊田和宏, 濱田晋, 三浦晋, 吉田直樹, 本郷星仁, 松本諒太郎, 田中裕, 池田美緒, 佐野貴紀

Gastroenterological Endoscopy　63　(Suppl.1)　930-930　2021年4月
出版者・発行元： (一社)日本消化器内視鏡学会
ISSN： 0387-1207

eISSN： 1884-5738
消化器領域におけるアルコール関連研究最近の進歩膵炎とアルコール 2016年膵炎全国調査からみた実態

濱田晋, 菊田和宏, 正宗淳

日本消化器病学会雑誌　118　(臨増総会)　A38-A38　2021年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
消化吸収と臓器相関全国調査からみた慢性膵炎における膵内外分泌機能と臨床像の相関

菊田和宏, 濱田晋, 正宗淳

日本消化器病学会雑誌　118　(臨増総会)　A146-A146　2021年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
胆膵疾患研究の最前線〜from bench to bedside, from bedside to bench〜膵癌間質における酸化ストレス応答機構の解析

田中裕, 濱田晋, 正宗淳

日本消化器病学会雑誌　118　(臨増総会)　A234-A234　2021年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
消化器領域の救急医療、集中治療:急性膵炎ガイドライン改訂に伴う急性膵炎治療の変遷 DPCデータからの検討

池田未緒, 濱田晋, 正宗淳

日本消化器病学会雑誌　118　(臨増総会)　A250-A250　2021年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
急性膵炎に対する局所合併症治療戦略全国調査からみた急性膵炎後の被包化壊死の現況

菊田和宏, 濱田晋, 正宗淳

日本腹部救急医学会雑誌　41　(2)　206-206　2021年2月
出版者・発行元： (一社)日本腹部救急医学会
ISSN： 1340-2242

eISSN： 1882-4781
【慢性膵炎診療の最前線】慢性膵炎の疫学のupdate

濱田晋, 菊田和宏, 粂潔, 三浦晋, 滝川哲也, 吉田直樹, 正宗淳

胆と膵　42　(2)　107-111　2021年2月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
【慢性膵炎診療の最前線】トピックス膵炎発症に関連する遺伝子異常

滝川哲也, 菊田和宏, 粂潔, 濱田晋, 三浦晋, 吉田直樹, 本郷星仁, 松本諒太郎, 田中裕, 佐野貴紀, 池田美緒, 正宗淳

胆と膵　42　(2)　157-161　2021年2月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
【急性膵炎診療up-to-date】疫学、実態急性膵炎の疫学

菊田和宏, 濱田晋, 正宗淳

肝胆膵　82　(1)　33-37　2021年1月
出版者・発行元： (株)アークメディア
ISSN： 0389-4991
【膵炎診療update】膵炎全国調査を通してみた本邦の膵炎の疫学

濱田晋, 菊田和宏, 粂潔, 三浦晋, 滝川哲也, 吉田直樹, 正宗淳

消化器・肝臓内科　9　(1)　57-62　2021年1月
出版者・発行元： (有)科学評論社
ISSN： 2432-3446
緊急内視鏡の現状と課題〜トータルマネージメントの観点から EST後出血に対する治療成績

佐野貴紀, 粂潔, 濱田晋, 菊田和宏, 正宗淳

日本消化器内視鏡学会東北支部例会　165回　40-40　2021年1月
出版者・発行元：日本消化器内視鏡学会-東北支部
【新型コロナウイルス感染症と肝胆膵】COVID-19感染症に合併する肝胆膵疾患 COVID-19と急性膵炎

濱田晋, 菊田和宏, 粂潔, 滝川哲也, 三浦晋, 吉田直樹, 正宗淳

肝胆膵　81　(6)　1103-1108　2020年12月
出版者・発行元： (株)アークメディア
ISSN： 0389-4991
【IPMN大全】併存膵癌も念頭においたスクリーニングとサーベイランス膵外病変の合併

粂潔, 菊田和宏, 濱田晋, 三浦晋, 滝川哲也, 吉田直樹, 本郷星仁, 田中裕, 松本諒太郎, 佐野貴紀, 池田未緒, 正宗淳

胆と膵　41　(臨増特大)　1375-1379　2020年11月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
持続的Nrf2活性化による膵癌細胞グルタミン依存性の誘導

濱田晋, 田中裕, 松本諒太郎, 正宗淳

消化と吸収　43　(1)　54-54　2020年10月
出版者・発行元： (NPO)日本消化吸収学会
ISSN： 0389-3626
慢性膵炎患者における消化酵素薬使用状況膵炎全国疫学調査の解析

滝川哲也, 菊田和宏, 濱田晋, 正宗淳

消化と吸収　43　(1)　64-64　2020年10月
出版者・発行元： (NPO)日本消化吸収学会
ISSN： 0389-3626
膵癌患者における栄養学的指標とサルコペニアに関する検討

菊田和宏, 濱田晋, 正宗淳

消化と吸収　43　(1)　65-65　2020年10月
出版者・発行元： (NPO)日本消化吸収学会
ISSN： 0389-3626
当院における膵消化管吻合部狭窄に対する治療成績

三浦晋, 池田未緒, 佐野貴紀, 松本諒太郎, 本郷星仁, 滝川哲也, 濱田晋, 菊田和宏, 粂潔, 正宗淳

Gastroenterological Endoscopy　62　(Suppl.2)　2133-2133　2020年10月
出版者・発行元： (一社)日本消化器内視鏡学会
ISSN： 0387-1207

eISSN： 1884-5738
【自己免疫性膵炎の最前線】自己免疫性膵炎の全国調査

菊田和宏, 濱田晋, 正宗淳

胆と膵　41　(10)　939-943　2020年10月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
胆膵領域における炎症と発癌膵星細胞のNrf2欠損は膵癌細胞の増殖促進効果を減弱させる

濱田晋, 田中裕, 正宗淳

日本消化器病学会雑誌　117　(臨増大会)　A653-A653　2020年10月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
内視鏡的ネクロセクトミー後のWONの再発要因について

粂潔, 池田未緒, 佐野貴紀, 松本諒太郎, 田中裕, 本郷星仁, 滝川哲也, 三浦晋, 濱田晋, 菊田和宏, 海野倫明, 正宗淳

日本消化器病学会雑誌　117　(臨増大会)　A719-A719　2020年10月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
【慢性膵炎-ガイドライン改訂に向けて】慢性膵炎の病態分子メカニズム

濱田晋, 菊田和宏, 粂潔, 正宗淳

臨床消化器内科　35　(11)　1303-1308　2020年9月
出版者・発行元： (株)日本メディカルセンター
ISSN： 0911-601X

eISSN： 2433-2488
難治性総胆管結石に対する治療戦略胆管結石に対する内視鏡治療の現況と外科治療移行例について

粂潔, 滝川哲也, 正宗淳, 池田未緒, 佐野貴紀, 松本諒太郎, 田中裕, 本郷星仁, 三浦晋, 濱田晋, 菊田和宏

胆道　34　(3)　444-444　2020年8月
出版者・発行元： (一社)日本胆道学会
ISSN： 0914-0077

eISSN： 1883-6879
難渋する胆道ドレナージの工夫 Inside stent抜去困難となる危険因子は何か?

三浦晋, 濱田晋, 正宗淳

胆道　34　(3)　455-455　2020年8月
出版者・発行元： (一社)日本胆道学会
ISSN： 0914-0077

eISSN： 1883-6879
当院でのEUS-FNAにおける偶発症の検討

滝川哲也, 菅野敦, 池田美緒, 佐野貴紀, 松本諒太郎, 田中裕, 鍋島立秀, 本郷星仁, 三浦晋, 濱田晋, 粂潔, 菊田和宏, 正宗淳

Gastroenterological Endoscopy　62　(Suppl.1)　1236-1236　2020年8月
出版者・発行元： (一社)日本消化器内視鏡学会
ISSN： 0387-1207

eISSN： 1884-5738
膵全摘術の現状と展望 National clinical databaseによる膵全摘術の術後重症合併症リスクモデル

橋本大輔, 水間正道, 隈丸拓, 宮田裕章, 近本亮, 五十嵐久人, 糸井隆夫, 江川新一, 児玉裕三, 里井壯平, 濱田晋, 水元一博, 山上裕機, 山本雅一, 掛地吉弘, 瀬戸泰之, 馬場秀夫, 海野倫明, 下瀬川徹, 岡崎和一

膵臓　35　(3)　A119-A119　2020年7月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
膵全摘術の現状と展望 National clinical databaseによる膵全摘術の術後重症合併症リスクモデル

橋本大輔, 水間正道, 隈丸拓, 宮田裕章, 近本亮, 五十嵐久人, 糸井隆夫, 江川新一, 児玉裕三, 里井壯平, 濱田晋, 水元一博, 山上裕機, 山本雅一, 掛地吉弘, 瀬戸泰之, 馬場秀夫, 海野倫明, 下瀬川徹, 岡崎和一

膵臓　35　(3)　A119-A119　2020年7月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
急性膵炎ガイドライン2020公聴会急性膵炎全国疫学調査2016

濱田晋, 菊田和宏, 正宗淳

膵臓　35　(3)　A131-A131　2020年7月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
p-NEN診療ガイドラインの問題点腫瘍径が小さい膵神経内分泌腫瘍に対する診断能の検討

滝川哲也, 池田美緒, 佐野貴紀, 松本諒太郎, 田中裕, 鍋島立秀, 本郷星仁, 三浦晋, 濱田晋, 粂潔, 菊田和宏, 海野倫明, 正宗淳

膵臓　35　(3)　A154-A154　2020年7月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
自己免疫性膵炎の長期予後自己免疫性膵炎の前向き追跡調査

佐野貴紀, 菊田和宏, 鍋島立秀, 本郷星仁, 濱田晋, 粂潔, 正宗淳

膵臓　35　(3)　A177-A177　2020年7月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
急性膵炎に対する局所合併症治療内視鏡的ネクロセクトミー後のWONの再発要因について

粂潔, 菅野敦, 池田未緒, 佐野貴紀, 松本諒太郎, 田中裕, 鍋島立秀, 本郷星仁, 滝川哲也, 三浦晋, 濱田晋, 菊田和宏, 海野倫明, 正宗淳

膵臓　35　(3)　A208-A208　2020年7月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
膵癌微小環境に関する基礎研究膵星細胞による膵癌促進効果は膵星細胞のNrf2に依存する

濱田晋, 田中裕, 松本諒太郎, 正宗淳

膵臓　35　(3)　A233-A233　2020年7月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
膵炎研究の最前線:基礎から臨床へ不死化膵星細胞と初代培養膵星細胞の遺伝子発現の違い

田中裕, 濱田晋, 松本諒太郎, 滝川哲也, 正宗淳

膵臓　35　(3)　A253-A253　2020年7月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
膵炎研究の最前線:基礎から臨床へ DPCデータに基づく急性膵炎治療に対する検討

池田未緒, 濱田晋, 菊田和宏, 粂潔, 正宗淳

膵臓　35　(3)　A254-A254　2020年7月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
糖尿病関連症状を契機に発見された膵癌患者の臨床学的特徴と予後

滝川哲也, 池田美緒, 佐野貴紀, 松本諒太郎, 田中裕, 鍋島立秀, 本郷星仁, 三浦晋, 濱田晋, 粂潔, 菊田和宏, 海野倫明, 正宗淳

膵臓　35　(3)　A270-A270　2020年7月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
膵癌の薬剤抵抗性におけるKeap1-Nrf2経路の意義

松本諒太郎, 濱田晋, 田中裕, 滝川哲也, 正宗淳

膵臓　35　(3)　A316-A316　2020年7月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
マウスモデルを用いた低栄養時の臓器変化の検討

松本諒太郎, 濱田晋, 池田未緒, 田中裕, 滝川哲也, 正宗淳

日本消化器病学会雑誌　117　(臨増総会)　A211-A211　2020年7月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
DPCデータに基づく急性膵炎致命率の検討

池田未緒, 濱田晋, 松本諒太郎, 田中裕, 菊田和宏, 正宗淳

日本消化器病学会雑誌　117　(臨増総会)　A215-A215　2020年7月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
マウスモデルによる胆管癌Nrf2依存性の検証

濱田晋, 鍋島立秀, 正宗淳

日本消化器病学会雑誌　117　(臨増総会)　A245-A245　2020年7月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
初代培養膵星細胞における酸化ストレス応答機構の役割の解明

田中裕, 濱田晋, 松本諒太郎, 鍋島立秀, 正宗淳

日本消化器病学会雑誌　117　(臨増総会)　A245-A245　2020年7月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
遺伝子改変慢性膵炎モデルマウスの現状

濱田晋, 正宗淳

消化と吸収　42　(2)　155-157　2020年7月
出版者・発行元： (NPO)日本消化吸収学会
ISSN： 0389-3626
膵胆道疾患における酸化ストレス応答機構の役割

濱田晋, 鍋島立秀, 正宗淳

胆膵の病態生理　36　(1)　9-13　2020年6月
出版者・発行元：日本胆膵病態・生理研究会
ISSN： 2185-4564
ASSESSMENT OF GENE EXPRESSION PROFILE IN PANCREATIC ORGANOID WITH MUTANT K-RAS AND KEAP1 DELETION

Ryotaro Matsumoto, Shin Hamada, Yu Tanaka, Atsushi Masamune

GASTROENTEROLOGY　158　(6)　S868-S869　2020年5月

ISSN： 0016-5085

eISSN： 1528-0012
【膵炎・膵がん診療のUp To Date】膵炎と遺伝子変化

濱田晋, 正宗淳

臨牀と研究　97　(5)　526-529　2020年5月
出版者・発行元：大道学館出版部
ISSN： 0021-4965
【膵疾患(膵癌)(慢性膵炎を含む)のサポーティブ・ケア】慢性膵炎患者の就労可能性に関連する因子の検討

菊田和宏, 濱田晋, 粂潔, 正宗淳

膵臓　35　(2)　187-192　2020年4月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
【肝膵内視鏡治療におけるトラブルシューティング】ERCP関連治療における偶発症予防とトラブルシューティング ERCP後膵炎の予防と対策こうすれば重症化しない

滝川哲也, 菅野敦, 三浦晋, 濱田晋, 粂潔, 菊田和宏, 正宗淳

消化器内視鏡　32　(3)　324-327　2020年3月
出版者・発行元： (株)東京医学社
ISSN： 0915-3217
【膵癌をめぐる最近の話題】膵癌早期発見のストラテジー

菅野敦, 佐野貴紀, 池田未緒, 田中裕, 松本諒太郎, 鍋島立秀, 本郷星仁, 三浦晋, 滝川哲也, 濱田晋, 粂潔, 菊田和宏, 正宗淳

消化器・肝臓内科　7　(3)　197-203　2020年3月
出版者・発行元： (有)科学評論社
ISSN： 2432-3446
【慢性膵炎診療2020】基礎研究・病態膵炎関連遺伝子異常はどこまでわかったか

濱田晋, 正宗淳

肝胆膵　80　(2)　247-252　2020年2月
出版者・発行元： (株)アークメディア
ISSN： 0389-4991
抗HIV療法中に自己免疫性膵炎を発症した慢性膵炎の1例

池田未緒, 三浦晋, 佐野貴紀, 田中裕, 松本諒太郎, 鍋島立秀, 本郷星仁, 滝川哲也, 菊田和宏, 濱田晋, 粂潔, 菅野敦, 正宗淳

日本消化器病学会東北支部例会・日本消化器内視鏡学会東北支部例会プログラム・抄録集　208回・164回　116-116　2020年1月
出版者・発行元：日本消化器病学会-東北支部
【術前治療時代の膵癌診断・治療戦略】術前治療時代のEUS-FNA

菅野敦, 田中裕, 松本諒太郎, 鍋島立秀, 本郷星仁, 三浦晋, 滝川哲也, 濱田晋, 粂潔, 菊田和宏, 正宗淳

胆と膵　40　(11)　971-975　2019年11月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
【膵炎大全II〜膵炎・Up to date〜】膵炎の疾患概念と診断基準本邦における膵炎の疫学

濱田晋, 正宗淳

胆と膵　40　(臨増特大)　1079-1084　2019年11月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
【膵炎大全II〜膵炎・Up to date〜】膵炎各論慢性膵炎と膵癌

粂潔, 濱田晋, 正宗淳

胆と膵　40　(臨増特大)　1277-1281　2019年11月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
膵星細胞におけるNrf2欠損は膵癌促進効果を抑制する

濱田晋, 鍋島立秀, 松本諒太郎, 田中裕, 滝川哲也, 正宗淳

日本消化器病学会雑誌　116　(臨増大会)　A804-A804　2019年11月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
膵萎縮モデルマウスにおける臓器病変の検討

濱田晋, 鍋島立秀, 松本諒太郎, 田中裕, 正宗淳

消化と吸収　42　(1)　62-62　2019年9月
出版者・発行元： (NPO)日本消化吸収学会
ISSN： 0389-3626
【糖尿病とがん】日本人における糖尿病と膵がん

濱田晋, 正宗淳

月刊糖尿病　11　(3)　69-75　2019年9月
出版者・発行元： (株)医学出版
膵萎縮モデルマウスにおける臓器病変の検討

濱田晋, 鍋島立秀, 松本諒太郎, 田中裕, 正宗淳

消化と吸収　42　(1)　62-62　2019年9月
出版者・発行元： (NPO)日本消化吸収学会
ISSN： 0389-3626
【IgG4関連硬化性胆管炎の診療ガイドラインと残された問題点】IgG4関連硬化性胆管炎の病理学的診断と問題点

菅野敦, 佐野貴紀, 池田未緒, 田中裕, 松本諒太郎, 鍋島立秀, 本郷星仁, 三浦晋, 滝川哲也, 濱田晋, 粂潔, 菊田和宏, 正宗淳

胆と膵　40　(8)　711-715　2019年8月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
【膵炎診療の最新トピックス】急性膵炎高齢者急性膵炎診療の実際

菊田和宏, 濱田晋, 正宗淳

消化器の臨床　22　(3)　214-218　2019年8月
出版者・発行元： (株)ヴァンメディカル
ISSN： 1344-3070
術後に挿入され迷入した膵管ステントを内視鏡的に回収し得た1例

佐野貴紀, 菅野敦, 池田未緒, 田中裕, 松本諒太郎, 鍋島立秀, 本郷星仁, 滝川哲也, 三浦晋, 濱田晋, 菊田和宏, 粂潔, 正宗淳

日本消化器病学会東北支部例会プログラム・抄録集　207回　51-51　2019年7月
出版者・発行元：日本消化器病学会-東北支部
短期間で形態変化を認めた膵腺房細胞癌の1例

池田未緒, 三浦晋, 佐野貴紀, 田中裕, 松本諒太郎, 鍋島立秀, 本郷星仁, 滝川哲也, 菊田和宏, 濱田晋, 粂潔, 菅野敦, 畠達夫, 元井冬彦, 海野倫明, 大森優子, 古川徹, 正宗淳

日本消化器病学会東北支部例会プログラム・抄録集　207回　50-50　2019年7月
出版者・発行元：日本消化器病学会-東北支部
短期間で形態変化を認めた膵腺房細胞癌の1例

池田未緒, 三浦晋, 佐野貴紀, 田中裕, 松本諒太郎, 鍋島立秀, 本郷星仁, 滝川哲也, 菊田和宏, 濱田晋, 粂潔, 菅野敦, 畠達夫, 元井冬彦, 海野倫明, 大森優子, 古川徹, 正宗淳

日本消化器病学会東北支部例会プログラム・抄録集　207回　50-50　2019年7月
出版者・発行元：日本消化器病学会-東北支部
術後に挿入され迷入した膵管ステントを内視鏡的に回収し得た1例

佐野貴紀, 菅野敦, 池田未緒, 田中裕, 松本諒太郎, 鍋島立秀, 本郷星仁, 滝川哲也, 三浦晋, 濱田晋, 菊田和宏, 粂潔, 正宗淳

日本消化器病学会東北支部例会プログラム・抄録集　207回　51-51　2019年7月
出版者・発行元：日本消化器病学会-東北支部
急性膵炎:診断と治療の最前線高齢者急性膵炎の患者特性と予後全国調査結果からの解析

濱田晋, 菊田和宏, 正宗淳

膵臓　34　(3)　A27-A27　2019年6月
出版者・発行元：日本膵臓学会
ISSN： 0913-0071
膵がん患者のサポーティブケア当科における膵癌患者に対する栄養アセスメントの現況

菊田和宏, 菅野敦, 粂潔, 濱田晋, 三浦晋, 滝川哲也, 本郷星仁, 鍋島立秀, 田中裕, 松本諒太郎, 正宗淳

膵臓　34　(3)　A43-A43　2019年6月
出版者・発行元：日本膵臓学会
ISSN： 0913-0071
慢性膵炎患者のサポーティブケア慢性膵炎患者の社会復帰に関連する因子の検討

菊田和宏, 濱田晋, 正宗淳

膵臓　34　(3)　A72-A72　2019年6月
出版者・発行元：日本膵臓学会
ISSN： 0913-0071
急性膵炎の重症度分類を再考する全国調査データを用いた重症度判定基準とRevised Atlanta Classificationの比較

濱田晋, 菊田和宏, 正宗淳

膵臓　34　(3)　A100-A100　2019年6月
出版者・発行元：日本膵臓学会
ISSN： 0913-0071
急性膵炎全国調査2016

濱田晋, 菊田和宏, 正宗淳

膵臓　34　(3)　A108-A109　2019年6月
出版者・発行元：日本膵臓学会
ISSN： 0913-0071
MCN疑い病変の取扱い-経過観察可能な病変はあるか? Mucinous cystic neoplasmsの術前診断能と良悪性診断に関する検討

三浦晋, 菅野敦, 松本裕, 松本遼太郎, 本郷星仁, 滝川哲也, 濱田晋, 菊田和宏, 粂潔, 元井冬彦, 海野倫明, 正宗淳

膵臓　34　(3)　A78-A78　2019年6月
出版者・発行元：日本膵臓学会
ISSN： 0913-0071
膵神経内分泌腫瘍の切除適応と切除範囲非機能性膵神経内分泌腫瘍における悪性因子と長期予後に関する検討

滝川哲也, 菅野敦, 松本諒太郎, 田中裕, 本郷星仁, 鍋島立秀, 三浦晋, 濱田晋, 粂潔, 菊田和宏, 中川圭, 元井冬彦, 海野倫明, 正宗淳

膵臓　34　(3)　A83-A84　2019年6月
出版者・発行元：日本膵臓学会
ISSN： 0913-0071
【胆膵内視鏡トラブルシューティング-こうやって切り抜けろ-】ERCP後膵炎の予防と治療重症化をいかに防ぐか

菅野敦, 田中裕, 松本諒太郎, 鍋島立秀, 本郷星仁, 三浦晋, 滝川哲也, 濱田晋, 粂潔, 菊田和宏, 正宗淳

胆と膵　40　(6)　467-472　2019年6月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
急性膵炎:診断と治療の最前線高齢者急性膵炎の患者特性と予後全国調査結果からの解析

濱田晋, 菊田和宏, 正宗淳

膵臓　34　(3)　A27-A27　2019年6月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
膵がん患者のサポーティブケア当科における膵癌患者に対する栄養アセスメントの現況

菊田和宏, 菅野敦, 粂潔, 濱田晋, 三浦晋, 滝川哲也, 本郷星仁, 鍋島立秀, 田中裕, 松本諒太郎, 正宗淳

膵臓　34　(3)　A43-A43　2019年6月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
慢性膵炎患者のサポーティブケア慢性膵炎患者の社会復帰に関連する因子の検討

菊田和宏, 濱田晋, 正宗淳

膵臓　34　(3)　A72-A72　2019年6月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
MCN疑い病変の取扱い-経過観察可能な病変はあるか? Mucinous cystic neoplasmsの術前診断能と良悪性診断に関する検討

三浦晋, 菅野敦, 松本裕, 松本遼太郎, 本郷星仁, 滝川哲也, 濱田晋, 菊田和宏, 粂潔, 元井冬彦, 海野倫明, 正宗淳

膵臓　34　(3)　A78-A78　2019年6月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
膵神経内分泌腫瘍の切除適応と切除範囲非機能性膵神経内分泌腫瘍における悪性因子と長期予後に関する検討

滝川哲也, 菅野敦, 松本諒太郎, 田中裕, 本郷星仁, 鍋島立秀, 三浦晋, 濱田晋, 粂潔, 菊田和宏, 中川圭, 元井冬彦, 海野倫明, 正宗淳

膵臓　34　(3)　A83-A84　2019年6月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
急性膵炎の重症度分類を再考する全国調査データを用いた重症度判定基準とRevised Atlanta Classificationの比較

濱田晋, 菊田和宏, 正宗淳

膵臓　34　(3)　A100-A100　2019年6月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
急性膵炎全国調査2016

濱田晋, 菊田和宏, 正宗淳

膵臓　34　(3)　A108-A109　2019年6月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
治療困難胆管結石に対するESWLとEHLに有用性についての検討

滝川哲也, 菅野敦, 正宗淳, 田中裕, 松本諒太郎, 鍋島立秀, 本郷星仁, 三浦晋, 濱田晋, 粂潔, 菊田和宏

Gastroenterological Endoscopy　61　(Suppl.1)　998-998　2019年5月
出版者・発行元： (一社)日本消化器内視鏡学会
ISSN： 0387-1207
治療困難胆管結石に対するESWLとEHLに有用性についての検討

滝川哲也, 菅野敦, 正宗淳, 田中裕, 松本諒太郎, 鍋島立秀, 本郷星仁, 三浦晋, 濱田晋, 粂潔, 菊田和宏

Gastroenterological Endoscopy　61　(Suppl.1)　998-998　2019年5月
出版者・発行元： (一社)日本消化器内視鏡学会
ISSN： 0387-1207

eISSN： 1884-5738
超高齢社会における消化器疾患診療高齢者急性膵炎に対する治療アプローチの実態

濱田晋, 菊田和宏, 正宗淳

日本消化器病学会雑誌　116　(臨増総会)　A93-A93　2019年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
Nrf2欠損はマウス急性膵炎モデルにおいて炎症を増悪させるか

鍋島立秀, 濱田晋, 田口恵子, 田中裕, 松本諒太郎, 山本雅之, 正宗淳

日本消化器病学会雑誌　116　(臨増総会)　A263-A263　2019年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
経過観察中の膵石症における糖尿病の現況

菊田和宏, 菅野敦, 粂潔, 濱田晋, 三浦晋, 滝川哲也, 本郷星仁, 鍋島立秀, 田中裕, 松本諒太郎, 正宗淳

日本消化器病学会雑誌　116　(臨増総会)　A314-A314　2019年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
重症急性膵炎急性期・後期合併症に対するトロンボモジュリンアルファ使用経験

濱田晋, 松本諒太郎, 田中裕, 鍋島立秀, 本郷星仁, 滝川哲也, 三浦晋, 粂潔, 菊田和宏, 菅野敦, 正宗淳

日本消化器病学会雑誌　116　(臨増総会)　A407-A407　2019年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
【自己免疫性膵炎2019】AIPの実態自己免疫性膵炎の疫学全国調査の歴史を振り返りながら

正宗淳, 菊田和宏, 濱田晋, 菅野敦, 鍋島立秀

肝胆膵　78　(2)　165-170　2019年2月
出版者・発行元： (株)アークメディア
ISSN： 0389-4991
【自己免疫性膵炎2019】AIPの治療と予後ステロイド抵抗例の治療免疫調節薬の現状と使用経験

菅野敦, 田中裕, 松本諒太郎, 鍋島立秀, 本郷星仁, 三浦晋, 滝川哲也, 濱田晋, 粂潔, 菊田和宏, 正宗淳

肝胆膵　78　(2)　261-267　2019年2月
出版者・発行元： (株)アークメディア
ISSN： 0389-4991
【消化器癌の危険因子・予防対策】膵癌と危険因子

滝川哲也, 濱田晋, 菊田和宏, 松本諒太郎, 田中裕, 鍋島立秀, 本郷星仁, 三浦晋, 粂潔, 菅野敦, 正宗淳

消化器・肝臓内科　5　(2)　207-214　2019年2月
出版者・発行元： (有)科学評論社
ISSN： 2432-3446
自己免疫性膵炎の維持療法中に膵上皮内癌の発生が疑われ、膵体尾部切除術を施行した1例

松本諒太郎, 菅野敦, 田中裕, 鍋島立秀, 本郷星仁, 滝川哲也, 三浦晋, 濱田晋, 粂潔, 菊田和宏, 石田晶玄, 元井冬彦, 海野倫明, 藤島史喜, 大森優子, 古川徹, 正宗淳

日本消化器病学会東北支部例会プログラム・抄録集　206回　75-75　2019年2月
出版者・発行元：日本消化器病学会-東北支部
Nrf2欠損はマウス急性膵炎モデルにおいて炎症を増悪させるか

鍋島立秀, 濱田晋, 田口恵子, 田中裕, 松本諒太郎, 山本雅之, 正宗淳

日本消化器病学会雑誌(Web)　116　2019年

ISSN： 1349-7693
Keap1-Nrf2経路は慢性炎症からの膵発癌に寄与するか

濱田晋

日本膵臓病研究財団研究報告書　25回　5-11　2018年12月
出版者・発行元： (公財)日本膵臓病研究財団
Keap1欠損によるNrf2の持続的活性化は膵癌のサイトケラチン発現変化をもたらす

濱田晋, 鍋島立秀, 下瀬川徹, 正宗淳

日本消化器病学会雑誌　115　(臨増大会)　A750-A750　2018年10月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
TRPV6の消化器疾患発症に果たす役割に関する分子機能解析

小谷拓史, 濱田晋, 平野達也, 川本哲也, 坂口怜子, 森誠之, 森泰生, 正宗淳

日本生化学会大会プログラム・講演要旨集　91回　[1P-202]　2018年9月
出版者・発行元： (公社)日本生化学会
DOI： 10.1254/jpssuppl.93.0_2-p-241 　

eISSN： 2435-4953
膵がんにおけるVasohibin-2の役割(Roles of Vasohibin-2 in pancreatic cancer)

飯田理恵, 小森和樹, 鈴木康弘, 李殷瑞, 川村美夏帆, 濱田晋, 正宗淳

日本癌学会総会記事　77回　279-279　2018年9月
出版者・発行元：日本癌学会
ISSN： 0546-0476
TRPV6の消化器疾患発症に果たす役割に関する分子機能解析

小谷拓史, 濱田晋, 平野達也, 川本哲也, 坂口怜子, 森誠之, 森泰生, 正宗淳

日本生化学会大会プログラム・講演要旨集　91回　[1P-202]　2018年9月
出版者・発行元： (公社)日本生化学会
DOI： 10.1254/jpssuppl.93.0_2-p-241 　

eISSN： 2435-4953
Vasohibin-2は膵癌の浸潤・転移において重要な役割を果たす(Vasohibin-2 plays essential role in invasion and metastasis of pancreatic ductal adenocarcinoma)

川村美夏帆, 飯田理恵, 鈴木康弘, 濱田晋, 正宗淳, 古川徹, 佐藤靖史

日本癌学会総会記事　77回　1017-1017　2018年9月
出版者・発行元：日本癌学会
ISSN： 0546-0476
膵がんにおけるVasohibin-2の役割(Roles of Vasohibin-2 in pancreatic cancer)

飯田理恵, 小森和樹, 鈴木康弘, 李殷瑞, 川村美夏帆, 濱田晋, 正宗淳

日本癌学会総会記事　77回　279-279　2018年9月
出版者・発行元： (一社)日本癌学会
ISSN： 0546-0476
Vasohibin-2は膵癌の浸潤・転移において重要な役割を果たす(Vasohibin-2 plays essential role in invasion and metastasis of pancreatic ductal adenocarcinoma)

川村美夏帆, 飯田理恵, 鈴木康弘, 濱田晋, 正宗淳, 古川徹, 佐藤靖史

日本癌学会総会記事　77回　1017-1017　2018年9月
出版者・発行元： (一社)日本癌学会
ISSN： 0546-0476
1．慢性膵炎・膵萎縮関連遺伝子の同定と機能解析

濱田晋, 正宗淳

膵臓　33　(4)　707-714　2018年8月25日
出版者・発行元：一般社団法人日本膵臓学会
DOI： 10.2958/suizo.33.707 　

ISSN： 0913-0071

eISSN： 1881-2805

詳細を見る詳細を閉じる

膵消化酵素，特にトリプシン活性の増加につながる遺伝子変異は遺伝性膵炎の原因として注目されてきた．トリプシン活性の持続・トリプシンインヒビターの機能異常につながる遺伝子変異がその好例であり，そのような変異は特発性慢性膵炎患者でも見出されている．トリプシン活性の亢進以外にも，膵腺房細胞内での小胞体ストレスの増加につながる遺伝子変異は細胞死を誘導し，膵炎の原因となることが判明している．近年実用化された次世代シークエンス技術は大量の遺伝子配列を高速で解析可能であり，膵炎関連遺伝子の網羅的解析に応用されている．既知の膵炎関連遺伝子スクリーニングのためのターゲットリシークエンスや全エクソーム・全ゲノム解析による新規膵炎関連遺伝子の同定により，膵炎の遺伝的背景が更に明らかになることが期待される．
【膵炎の基礎研究・病態解明】慢性膵炎・膵萎縮関連遺伝子の同定と機能解析

濱田晋, 正宗淳

膵臓　33　(4)　707-714　2018年8月
出版者・発行元：日本膵臓学会
ISSN： 0913-0071
アルコール関連消化器疾患:最近の知見アルコール性膵炎の危険因子

菊田和宏, 濱田晋, 粂潔, 正宗淳

日本アルコール・薬物医学会雑誌　53　(4)　103-103　2018年8月
出版者・発行元：日本アルコール・アディクション医学会
ISSN： 1341-8963
【膵炎の基礎研究・病態解明】慢性膵炎・膵萎縮関連遺伝子の同定と機能解析

濱田晋, 正宗淳

膵臓　33　(4)　707-714　2018年8月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
アルコール関連消化器疾患:最近の知見アルコール性膵炎の危険因子

菊田和宏, 濱田晋, 粂潔, 正宗淳

日本アルコール・薬物医学会雑誌　53　(4)　103-103　2018年8月
出版者・発行元： (一社)日本アルコール・アディクション医学会
ISSN： 1341-8963
【Acute on chronic-慢性病態の急性増悪-】膵臓慢性膵炎の急性増悪

滝川哲也, 本郷星仁, 鍋島立秀, 三浦晋, 濱田晋, 粂潔, 菊田和宏, 菅野敦, 正宗淳

肝・胆・膵　76　(6)　1137-1145　2018年6月
出版者・発行元： (株)アークメディア
ISSN： 0389-4991
【Acute on chronic-慢性病態の急性増悪-】膵臓慢性膵炎の急性増悪

滝川哲也, 本郷星仁, 鍋島立秀, 三浦晋, 濱田晋, 粂潔, 菊田和宏, 菅野敦, 正宗淳

肝胆膵　76　(6)　1137-1145　2018年6月
出版者・発行元： (株)アークメディア
ISSN： 0389-4991
急性膵炎重症度判定基準をめぐる諸問題急性膵炎の予後に関わる発症早期因子の検討

濱田晋, 正宗淳, 菊田和宏, 下瀬川徹

膵臓　33　(3)　320-320　2018年5月
出版者・発行元：日本膵臓学会
ISSN： 0913-0071
保存的に経過観察を行っている膵石症における糖尿病の現況

菊田和宏, 菅野敦, 粂潔, 濱田晋, 三浦晋, 滝川哲也, 本郷星仁, 鍋島立秀, 正宗淳

膵臓　33　(3)　388-388　2018年5月
出版者・発行元：日本膵臓学会
ISSN： 0913-0071
壊死性膵炎に対する内視鏡的ネクロセクトミーの治療適応とその合併症について

粂潔, 菅野敦, 鍋島立秀, 本郷星仁, 三浦晋, 滝川哲也, 濱田晋, 菊田和宏, 正宗淳

膵臓　33　(3)　396-396　2018年5月
出版者・発行元：日本膵臓学会
ISSN： 0913-0071
当院における非機能性pNENの予後についての検討

滝川哲也, 菅野敦, 本郷星仁, 鍋島立秀, 三浦晋, 濱田晋, 粂潔, 菊田和宏, 元井冬彦, 海野倫明, 藤島史喜, 下瀬川徹, 正宗淳

膵臓　33　(3)　527-527　2018年5月
出版者・発行元：日本膵臓学会
ISSN： 0913-0071
急性膵炎重症度判定基準をめぐる諸問題急性膵炎の予後に関わる発症早期因子の検討

濱田晋, 正宗淳, 菊田和宏, 下瀬川徹

膵臓　33　(3)　320-320　2018年5月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
保存的に経過観察を行っている膵石症における糖尿病の現況

菊田和宏, 菅野敦, 粂潔, 濱田晋, 三浦晋, 滝川哲也, 本郷星仁, 鍋島立秀, 正宗淳

膵臓　33　(3)　388-388　2018年5月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
壊死性膵炎に対する内視鏡的ネクロセクトミーの治療適応とその合併症について

粂潔, 菅野敦, 鍋島立秀, 本郷星仁, 三浦晋, 滝川哲也, 濱田晋, 菊田和宏, 正宗淳

膵臓　33　(3)　396-396　2018年5月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
当院における非機能性pNENの予後についての検討

滝川哲也, 菅野敦, 本郷星仁, 鍋島立秀, 三浦晋, 濱田晋, 粂潔, 菊田和宏, 元井冬彦, 海野倫明, 藤島史喜, 下瀬川徹, 正宗淳

膵臓　33　(3)　527-527　2018年5月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
急性膵炎診療Up-to-date 急性膵炎予後因子スコア簡略化の試み

濱田晋, 正宗淳, 下瀬川徹

日本消化器病学会雑誌　115　(臨増総会)　A174-A174　2018年4月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586
基礎研究から紐解く膵・胆道の恒常性とその破綻新規Nrf2阻害剤ハロフギノンによる膵癌治療の可能性

濱田晋, 正宗淳, 下瀬川徹

日本消化器病学会雑誌　115　(臨増総会)　A187-A187　2018年4月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586
飲酒後の食道組織中アセトアルデヒドに関する検討

大方英樹, 八田和久, 飯島克則, 淺沼清孝, 宇野要, 浅野直喜, 小池智幸, 今谷晃, 濱田晋, 正宗淳, 下瀬川徹

日本消化器病学会雑誌　115　(臨増総会)　A266-A266　2018年4月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586
pNETに対するEUS-FNAの有用性についての検討

滝川哲也, 菅野敦, 正宗淳, 本郷星仁, 鍋島立秀, 三浦晋, 濱田晋, 粂潔, 菊田和宏, 下瀬川徹

Gastroenterological Endoscopy　60　(Suppl.1)　671-671　2018年4月
出版者・発行元： (一社)日本消化器内視鏡学会
ISSN： 0387-1207
pNETに対するEUS-FNAの有用性についての検討

滝川哲也, 菅野敦, 正宗淳, 本郷星仁, 鍋島立秀, 三浦晋, 濱田晋, 粂潔, 菊田和宏, 下瀬川徹

Gastroenterological Endoscopy　60　(Suppl.1)　671-671　2018年4月
出版者・発行元： (一社)日本消化器内視鏡学会
ISSN： 0387-1207

eISSN： 1884-5738
【胆嚢癌-術前診断に応じた治療を再考する-】胆嚢癌の鑑別診断と進展度診断超音波内視鏡

菅野敦, 正宗淳, 鍋島立秀, 本郷星仁, 滝川哲也, 三浦晋, 濱田晋, 菊田和宏, 粂潔, 下瀬川徹, 海野倫明

胆と膵　39　(3)　217-227　2018年3月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
急性膵炎診療Up-to-date 急性膵炎予後因子スコア簡略化の試み

濱田晋, 正宗淳, 下瀬川徹

日本消化器病学会雑誌　115　(臨増総会)　A174-A174　2018年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
基礎研究から紐解く膵・胆道の恒常性とその破綻新規Nrf2阻害剤ハロフギノンによる膵癌治療の可能性

濱田晋, 正宗淳, 下瀬川徹

日本消化器病学会雑誌　115　(臨増総会)　A187-A187　2018年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
飲酒後の食道組織中アセトアルデヒドに関する検討

大方英樹, 八田和久, 飯島克則, 淺沼清孝, 宇野要, 浅野直喜, 小池智幸, 今谷晃, 濱田晋, 正宗淳, 下瀬川徹

日本消化器病学会雑誌　115　(臨増総会)　A266-A266　2018年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
【オートファジー〜胆膵疾患とのかかわりについて〜】選択的オートファジーとKeap1-Nrf2系の関連

濱田晋, 正宗淳, 下瀬川徹

胆と膵　39　(2)　125-131　2018年2月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
【肝胆膵とアルコール-serendipityを目指して-】アルコール性膵炎本邦におけるアルコール性膵炎の現状飲酒量や性差の関連も含めて

菊田和宏, 正宗淳, 濱田晋, 粂潔, 下瀬川徹

肝胆膵　76　(1)　113-120　2018年1月
出版者・発行元： (株)アークメディア
ISSN： 0389-4991
【肝胆膵とアルコール-serendipityを目指して-】アルコール性膵炎アルコール性膵炎の遺伝的背景

正宗淳, 濱田晋, 粂潔, 菊田和宏, 下瀬川徹

肝胆膵　76　(1)　127-133　2018年1月
出版者・発行元： (株)アークメディア
ISSN： 0389-4991
診療の秘訣膵臓の「嚢胞」を指摘されたら

濱田晋, 正宗淳, 下瀬川徹

Modern Physician　37　(12)　1322-1322　2017年12月
出版者・発行元： (株)新興医学出版社
ISSN： 0913-7963
【膵癌研究Cutting Edge-from Carcinogenesis to Metastatic Colonization-】Microenvironment エクソソーム・マイクロRNAを介した膵星細胞-膵癌細胞間相互作用の制御

正宗淳, 滝川哲也, 濱田晋, 下瀬川徹

肝胆膵　75　(4)　831-840　2017年10月
出版者・発行元： (株)アークメディア
ISSN： 0389-4991
【胆膵EUSを極める-私ならこうする(There is always a better way)-】診断 EUS-FNA 私はこうする

菅野敦, 正宗淳, 鍋島立秀, 本郷星仁, 中野絵里子, 滝川哲也, 三浦晋, 濱田晋, 菊田和宏, 粂潔, 下瀬川徹

胆と膵　38　(臨増特大)　973-981　2017年10月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
【膵・胆道癌の早期診断を目指せ!】主膵管発生の上皮内癌膵上皮内癌をいかに診断するか

菅野敦, 正宗淳, 鍋島立秀, 本郷星仁, 中野絵里子, 滝川哲也, 三浦晋, 濱田晋, 菊田和宏, 粂潔, 下瀬川徹

肝胆膵　75　(3)　589-594　2017年9月
出版者・発行元： (株)アークメディア
ISSN： 0389-4991
膵癌細胞におけるNrf2欠損が細胞内代謝に与えるインパクト

濱田晋, 正宗淳, 下瀬川徹

日本消化器病学会雑誌　114　(臨増大会)　A742-A742　2017年9月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
【実地診療で遭遇する胆膵疾患基本病態のアップデートと新しい疾患概念の理解】進歩した胆膵疾患の知識とその実地医療への活用急性膵炎診療ガイドライン初期治療方針と重症度判定

濱田晋, 正宗淳

Medical Practice　34　(7)　1143-1147　2017年7月
出版者・発行元： (株)文光堂
ISSN： 0910-1551
【ニュートリゲノミクスから斬る肝胆膵疾患】糖代謝膵星細胞による膵癌細胞の代謝調節

濱田晋, 正宗淳, 下瀬川徹

肝胆膵　75　(1)　47-52　2017年7月
出版者・発行元： (株)アークメディア
ISSN： 0389-4991
膵癌の早期診断・治療の現状と展望膵癌登録における2cm以下(TS1)膵癌の解析

水間正道, 海野倫明, 五十嵐久人, 糸井隆夫, 江川新一, 児玉裕三, 里井壯平, 濱田晋, 水元一博, 岡崎和一, 日本膵臓学会膵癌登録委員会

膵臓　32　(3)　321-321　2017年5月
出版者・発行元：日本膵臓学会
ISSN： 0913-0071
【ERCPのエキスパートを目指して】トラブルシューティング ERCP後膵炎の予防と対処

菅野敦, 正宗淳, 鍋島立秀, 吉田直樹, 本郷星仁, 中野絵里子, 三浦晋, 濱田晋, 菊田和宏, 粂潔, 廣田衛久, 下瀬川徹

消化器内視鏡　29　(5)　946-951　2017年5月
出版者・発行元： (株)東京医学社
ISSN： 0915-3217
膵炎の病態解明を目指した最新の基礎研究膵特異的K-ras変異とKeap1喪失による膵萎縮はNrf2に依存する

濱田晋, 正宗淳, 下瀬川徹

膵臓　32　(3)　337-337　2017年5月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
急性膵炎の後期合併症に対する手術・インターベンション治療の現状と課題急性膵炎の初期診療は後期合併症を予防しうるか全国疫学調査の解析

濱田晋, 正宗淳, 下瀬川徹

膵臓　32　(3)　372-372　2017年5月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
全国調査からみた超高齢者急性膵炎の実態

菊田和宏, 正宗淳, 濱田晋, 下瀬川徹

膵臓　32　(3)　532-532　2017年5月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
壊死性膵炎における内視鏡的ネクロセクトミーの治療成績と合併症に関する検討

粂潔, 菅野敦, 鍋島立秀, 本郷星仁, 吉田直樹, 中野絵里子, 三浦晋, 濱田晋, 菊田和宏, 廣田衛久, 正宗淳, 下瀬川徹

膵臓　32　(3)　535-535　2017年5月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
膵癌登録における膵癌リンパ節転移個数の予後解析膵癌取扱い規約改訂におけるビッグデータ利活用

水間正道, 海野倫明, 伊佐地秀司, 五十嵐久人, 糸井隆夫, 江川新一, 児玉裕三, 里井壯平, 濱田晋, 水元一博, 岸和田昌之, 北川裕久, 高折恭一, 谷眞至, 羽鳥隆, 藤井努, 村上義昭, 山口幸二, 吉富秀幸, 岡崎和一, 日本膵臓学会膵癌登録委員会

日本外科学会定期学術集会抄録集　117回　SF-74　2017年4月
出版者・発行元： (一社)日本外科学会
EUS-FNAにより組織採取が可能であった膵漿液性嚢胞腫瘍の3例

鍋島立秀, 菅野敦, 正宗淳, 本郷星仁, 吉田直樹, 中野絵里子, 三浦晋, 濱田晋, 粂潔, 菊田和宏, 廣田衛久, 藤島史喜, 海野倫明, 下瀬川徹

Gastroenterological Endoscopy　59　(Suppl.1)　1108-1108　2017年4月
出版者・発行元： (一社)日本消化器内視鏡学会
ISSN： 0387-1207

eISSN： 1884-5738
【エキスパートオピニオン:超高齢者の肝胆膵疾患診療】超高齢者における病態の特性、治療の適応、治療の実際膵疾患急性・慢性膵炎

菊田和宏, 正宗淳, 濱田晋, 廣田衛久, 下瀬川徹

肝胆膵　74　(3)　437-442　2017年3月
出版者・発行元： (株)アークメディア
ISSN： 0389-4991
当院における膵粘液性嚢胞腫瘍(MCN)症例の検討

鍋島立秀, 菅野敦, 正宗淳, 本郷星仁, 吉田直樹, 中野絵里子, 三浦晋, 濱田晋, 粂潔, 菊田和宏, 廣田衛久, 元井冬彦, 海野倫明, 藤島史喜, 下瀬川徹

日本消化器病学会雑誌　114　(臨増総会)　A283-A283　2017年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
急性膵炎におけるDICスコアは予後を反映する

濱田晋, 正宗淳, 下瀬川徹

日本消化器病学会雑誌　114　(臨増総会)　A344-A344　2017年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
私の処方膵外分泌機能不全に対する酵素補充療法

濱田晋, 正宗淳, 下瀬川徹

Modern Physician　36　(12)　1305-1305　2016年12月
出版者・発行元： (株)新興医学出版社
ISSN： 0913-7963
【いわゆる"早期の膵癌"-その発生機序と診断】"早期の膵癌"の診断膵癌の高リスク群とその管理

濱田晋, 正宗淳, 下瀬川徹

臨床消化器内科　31　(13)　1695-1702　2016年11月
出版者・発行元： (株)日本メディカルセンター
ISSN： 0911-601X

eISSN： 2433-2488
【胆膵内視鏡自由自在〜基本手技を学び応用力をつける集中講座〜】ERCP関連手技編膵管Intervention 膵管狭窄困難例への対処

菅野敦, 正宗淳, 中野絵里子, 鍋島立秀, 吉田直樹, 本郷星仁, 三浦晋, 濱田晋, 菊田和宏, 粂潔, 廣田衛久, 下瀬川徹

胆と膵　37　(臨増特大)　1333-1337　2016年11月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
【Interventional EUSのすべて】膵実質病変におけるEUS-FNAの実際

菅野敦, 正宗淳, 鍋島立秀, 吉田直樹, 本郷星仁, 中野絵里子, 三浦晋, 濱田晋, 菊田和宏, 粂潔, 廣田衛久, 下瀬川徹

消化器内視鏡　28　(10)　1593-1599　2016年10月
出版者・発行元： (株)東京医学社
ISSN： 0915-3217
酸化ストレス応答欠損膵発癌モデルマウスを用いた抗癌剤感受性マーカー候補の同定

濱田晋, 正宗淳, 下瀬川徹

日本消化器病学会雑誌　113　(臨増大会)　A670-A670　2016年9月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
【診療ガイドライン改訂後の膵炎診療】急性膵炎わが国における急性膵炎診療の実際全国調査から

濱田晋, 正宗淳, 下瀬川徹

肝胆膵　72　(6)　989-996　2016年6月
出版者・発行元： (株)アークメディア
ISSN： 0389-4991
【急性膵炎-診療ガイドラインの改訂を受けて】急性膵炎の疫学

廣田衛久, 濱田晋, 正宗淳, 菊田和宏, 下瀬川徹

臨床消化器内科　31　(5)　509-513　2016年4月
出版者・発行元： (株)日本メディカルセンター
ISSN： 0911-601X

eISSN： 2433-2488
消化器から生活習慣病を診る全国調査からみた急性膵炎と生活習慣病の関連

濱田晋, 正宗淳, 下瀬川徹

日本消化器病学会雑誌　113　(臨増総会)　A92-A92　2016年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
【新たに定義された"肝門部領域胆管癌"の診断と治療】治療方針決定のための診断法 EUS・IDUSを用いた肝門部領域胆管癌の診断

菅野敦, 正宗淳, 三浦晋, 吉田直樹, 本郷星仁, 中野絵里子, 濱田晋, 菊田和宏, 粂潔, 廣田衛久, 下瀬川徹, 深瀬耕二, 海野倫明

胆と膵　37　(1)　37-44　2016年1月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
【消化器疾患におけるsmall RNAの役割を解明する】Small RNAsは膵胆道疾患の病態にどのようにかかわっているのか?

濱田晋, 正宗淳, 下瀬川徹

分子消化器病　12　(4)　378-383　2015年12月
出版者・発行元： (株)先端医学社
ISSN： 1348-995X
膵原発Mixed acinar-endocrine carcinoma(MAEC)の1例

中野絵里子, 菅野敦, 正宗淳, 本郷星仁, 吉田直樹, 三浦晋, 濱田晋, 粂潔, 菊田和宏, 廣田衛久, 下瀬川徹, 深瀬耕二, 元井冬彦, 海野倫明, 笠島敦子

東北医学雑誌　127　(2)　186-187　2015年12月
出版者・発行元：東北医学会
ISSN： 0040-8700
【そこが知りたい!がん患者の糖尿病マネジメント〜糖尿病とがんの「危険な関係」〜】膵癌と糖尿病最近の話題

正宗淳, 濱田晋, 下瀬川徹

月刊糖尿病　7　(11)　74-80　2015年11月
出版者・発行元： (株)医学出版
【大きく変化する神経内分泌腫瘍(NET)の概念と治療】診断 EUS-FNAによる膵神経内分泌腫瘍診断の実際

菅野敦, 正宗淳, 吉田直樹, 本郷星仁, 中野絵里子, 三浦晋, 濱田晋, 菊田和宏, 粂潔, 廣田衛久, 下瀬川徹

最新医学　70　(10)　1955-1965　2015年10月
出版者・発行元： (株)最新医学社
ISSN： 0370-8241
【生活習慣病と消化器疾患】生活習慣病と膵炎

濱田晋, 正宗淳, 下瀬川徹

Modern Physician　35　(10)　1251-1254　2015年10月
出版者・発行元： (株)新興医学出版社
ISSN： 0913-7963
若手に役立つ議論・オピニオンリーダーからのメッセージ胆管狭窄をどのように診断するか? IgG4関連硬化性胆管炎の診断

菅野敦, 正宗淳, 吉田直樹, 本郷星仁, 中野絵里子, 三浦晋, 濱田晋, 菊田和宏, 粂潔, 廣田衛久, 下瀬川徹

肝臓クリニカルアップデート　1　(2)　215-222　2015年10月
出版者・発行元：医学図書出版(株)
ISSN： 2189-4469
【ERCPマスターへのロードマップ】基本編経乳頭的胆管・膵管生検細胞診

菅野敦, 正宗淳, 吉田直樹, 本郷星仁, 中野絵里子, 三浦晋, 濱田晋, 菊田和宏, 粂潔, 廣田衛久, 下瀬川徹

胆と膵　36　(臨増特大)　947-954　2015年10月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
【消化器癌予防up-to-date】膵癌慢性膵炎と膵癌

濱田晋, 正宗淳, 下瀬川徹

臨床消化器内科　30　(11)　1443-1450　2015年9月
出版者・発行元： (株)日本メディカルセンター
ISSN： 0911-601X

eISSN： 2433-2488
【膵癌診療ガイドライン-グローバル・スタンダードへの潮流-】膵癌のバイオマーカー

濱田晋, 正宗淳, 下瀬川徹

胆と膵　36　(9)　811-816　2015年9月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
全国調査からみたWON・仮性嚢胞に対する治療の変遷

濱田晋, 正宗淳, 下瀬川徹

日本消化器病学会雑誌　112　(臨増大会)　A554-A554　2015年9月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
疾患メタボロミクスの現状と将来膵星細胞培養上清による膵癌細胞メタボローム変化の網羅的解析

濱田晋, 正宗淳, 下瀬川徹

日本消化器病学会雑誌　112　(臨増大会)　A774-A774　2015年9月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
【膵臓癌のリスクファクター】慢性膵炎と膵癌

正宗淳, 濱田晋, 下瀬川徹

日本消化器病学会雑誌　112　(8)　1464-1473　2015年8月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
【検査と臨床のコラボで理解する腫瘍マーカー】CA19-9 臨床編

濱田晋, 正宗淳, 下瀬川徹

臨床検査　59　(7)　638-643　2015年7月
出版者・発行元： (株)医学書院
ISSN： 0485-1420

eISSN： 1882-1367
【膵における超音波検査を今見直す】膵腫瘍性病変における造影EUSによる鑑別診断

菅野敦, 正宗淳, 吉田直樹, 本郷星仁, 中野絵里子, 三浦晋, 滝川哲也, 濱田晋, 菊田和宏, 粂潔, 廣田衛久, 下瀬川徹

胆と膵　36　(7)　691-698　2015年7月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
【がん幹細胞-新しい医療を求めて-】臨床研究動向膵癌幹細胞

濱田晋, 正宗淳, 下瀬川徹

日本臨床　73　(5)　844-849　2015年5月
出版者・発行元： (株)日本臨床社
ISSN： 0047-1852
miR-197は膵癌細胞においてミトコンドリア機能を抑制する

濱田晋, 正宗淳, 下瀬川徹

膵臓　30　(3)　434-434　2015年5月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
S-1単独療法が著効した多発肝転移を伴う膵腺房細胞癌の1例

吉田直樹, 菅野敦, 正宗淳, 本郷星仁, 中野絵里子, 滝川哲也, 三浦晋, 濱田晋, 菊田和宏, 粂潔, 廣田衛久, 上野正道, 下瀬川徹

膵臓　30　(3)　522-522　2015年5月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
【これだけは知っておきたい検査のポイント-第9集】腫瘍マーカー消化器系 CA50,Span-1,DU-PAN-2

濱田晋, 正宗淳, 下瀬川徹

Medicina　52　(4)　474-475　2015年4月
出版者・発行元： (株)医学書院
ISSN： 0025-7699

eISSN： 1882-1189
【これだけは知っておきたい検査のポイント-第9集】腫瘍マーカー消化器系 NCC-ST-439

濱田晋, 正宗淳, 下瀬川徹

Medicina　52　(4)　476-477　2015年4月
出版者・発行元： (株)医学書院
ISSN： 0025-7699

eISSN： 1882-1189
当施設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検討

中野絵里子, 菅野敦, 正宗淳, 吉田直樹, 本郷星仁, 三浦晋, 滝川哲也, 濱田晋, 粂潔, 菊田和宏, 廣田衛久, 下瀬川徹

Gastroenterological Endoscopy　57　(Suppl.1)　783-783　2015年4月
出版者・発行元： (一社)日本消化器内視鏡学会
ISSN： 0387-1207

eISSN： 1884-5738
Choledochoceleを合併した異所性胆管開口の1例

滝川哲也, 菅野敦, 正宗淳, 本郷星仁, 吉田直樹, 中野絵里子, 三浦晋, 濱田晋, 粂潔, 菊田和宏, 廣田衛久, 下瀬川徹

Gastroenterological Endoscopy　57　(Suppl.1)　957-957　2015年4月
出版者・発行元： (一社)日本消化器内視鏡学会
ISSN： 0387-1207

eISSN： 1884-5738
シグナル伝達を理解するために必要な知識(第45回)(No.88) 膵星細胞のシグナル伝達機構

正宗淳, 濱田晋, 下瀬川徹

分子消化器病　12　(1)　75-80　2015年3月
出版者・発行元： (株)先端医学社
ISSN： 1348-995X
【膵癌・胆道癌-基礎と臨床の最新研究動向-】膵癌基礎編膵癌のdesmoplastic reaction

正宗淳, 濱田晋, 下瀬川徹

日本臨床　73　(増刊3 膵癌・胆道癌)　26-30　2015年3月
出版者・発行元： (株)日本臨床社
ISSN： 0047-1852
【膵癌・胆道癌-基礎と臨床の最新研究動向-】胆道癌基礎編胆道癌の浸潤・転移機構

濱田晋, 正宗淳, 下瀬川徹

日本臨床　73　(増刊3 膵癌・胆道癌)　461-465　2015年3月
出版者・発行元： (株)日本臨床社
ISSN： 0047-1852
膵癌患者のオーダーメード治療を目指した抗癌剤効果予測キットの開発

正宗淳, 濱田晋

大和証券ヘルス財団研究業績集　(38)　9-13　2015年3月
出版者・発行元： (公財)大和証券ヘルス財団
日本の急性膵炎診療全国調査2011より

廣田衛久, 下瀬川徹, 正宗淳, 濱田晋, 菊田和宏, 辻一郎

膵臓　30　(1)　123-136　2015年2月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
[Chronic pancreatitis is a risk factor of pancreatic cancer].

Masamune, Atsushi, Hamada, Shin, Shimosegawa, Tooru

Nihon Shokakibyo Gakkai Zasshi　112　(8)　1464-1473　2015年

DOI： 10.11405/nisshoshi.112.1464 　
Bismuth classification is associated with the requirement for multiple biliary drainage in preoperative patients with malignant perihilar biliary stricture 国際誌

Miura S, Kanno A, Masamune A, Hamada S, Takikawa T, Nakano E, Yoshida N, Hongo S, Kikuta K, Kume K, Hirota M, Yoshida H, Katayose Y, Unno M, Shimosegawa T

Surg Endosc　29　(7)　1862-70　2015年

DOI： 10.1007/s00464-014-3878-y 　

詳細を見る詳細を閉じる

BACKGROUND: Single preoperative biliary drainage for malignant perihilar biliary stricture occasionally fails to control jaundice and cholangitis. Multiple biliary drainage is required in such cases, but their clinical background is unclear. We determined the clinical characteristics associated with the requirement for multiple biliary drainage. METHODS: The consecutive 122 patients with malignant perihilar biliary stricture were enrolled in a single-center retrospective study. Preoperative biliary drainage was initially performed on the future remnant hepatic lobe. Additional drainage was performed if jaundice failed to improve or cholangitis developed in undrained hepatic lobes. Detailed clinical characteristics and the number of preoperative biliary drainage procedures required before operation were analyzed. RESULTS: Thirty-one patients (25.4%) initially underwent multiple biliary drainage. However, 69 (56.7%) required multiple biliary drainage by the time of the operation. In the univariate analysis, the initial serum bilirubin level, cholangitis, percutaneous portal vein embolization, history of inserted endoscopic biliary stenting, length of preoperative period, operative procedure, and Bismuth classification were significant factors. In the multivariate analysis using these factors, Bismuth classification was independently associated with the requirement for multiple biliary drainage. The number of patients who required multiple biliary drainage was higher in those with Bismuth-II (91.9%), Bismuth-IIIa (65.7%), and Bismuth-IV (92.9%) than in those with Bismuth-I (22.2%) and Bismuth-IIIb (18.2%). CONCLUSIONS: Patients with Bismuth-II, Bismuth-IIIa, and Bismuth-IV are at higher risk for multiple biliary drainage. A strategy based on the Bismuth classification for performing preoperative biliary drainage is important for patients with malignant perihilar biliary stricture.
胆膵膵臓膵癌と膵星細胞の相互作用

濱田晋, 正宗淳, 下瀬川徹

Annual Review消化器　2015　138-144　2015年1月
出版者・発行元： (株)中外医学社
医の焦点膵がん膵がんの早期診断法

濱田晋, 下瀬川徹, 正宗淳

アニムス　19　(4)　44-48　2014年10月
出版者・発行元：アニムス編集委員会
ISSN： 1342-0119
【膵炎大全〜もう膵炎なんて怖くない〜】膵炎の概念と分類膵炎の疫学全国調査より

正宗淳, 濱田晋, 菊田和宏, 廣田衛久, 下瀬川徹

胆と膵　35　(臨増特大)　1011-1014　2014年10月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
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検討

中野絵里子, 菅野敦, 正宗淳, 吉田直樹, 本郷星仁, 三浦晋, 滝川哲也, 有賀啓之, 濱田晋, 粂潔, 菊田和宏, 廣田衛久, 下瀬川徹

Gastroenterological Endoscopy　56　(Suppl.2)　3117-3117　2014年9月
出版者・発行元： (一社)日本消化器内視鏡学会
ISSN： 0387-1207

eISSN： 1884-5738
重症急性膵炎の病態と有効な初期治療をめざして急性膵炎患者搬送の実態重症急性膵炎患者をgolden timeに高次医療施設へ搬送することが可能か?

廣田衛久, 濱田晋, 下瀬川徹

日本消化器病学会雑誌　111　(臨増大会)　A598-A598　2014年9月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
重症急性膵炎の病態と有効な初期治療をめざして全国調査に基づく急性膵炎新重症度判定基準の検証

濱田晋, 正宗淳, 下瀬川徹

日本消化器病学会雑誌　111　(臨増大会)　A600-A600　2014年9月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
膵/胆道癌の分子標的・免疫と治療応用 miR-197による癌細胞特異的代謝機構の制御

濱田晋, 正宗淳, 下瀬川徹

日本消化器病学会雑誌　111　(臨増大会)　A703-A703　2014年9月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
急性膵炎発症早期の造影CTによる膵壊死予測診断能

菊田和宏, 正宗淳, 濱田晋, 廣田衛久, 下瀬川徹

日本消化器病学会雑誌　111　(臨増大会)　A955-A955　2014年9月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
【遺伝性消化器癌とその対策】遺伝性膵癌

濱田晋, 正宗淳, 下瀬川徹

G.I.Research　22　(3)　256-262　2014年6月
出版者・発行元： (株)先端医学社
ISSN： 0918-9408
【膵がん退治の始まり】膵癌の疫学とハイリスク群

濱田晋, 正宗淳, 下瀬川徹

肝胆膵　68　(6)　829-835　2014年6月
出版者・発行元： (株)アークメディア
ISSN： 0389-4991
miR-365によるアポトーシス関連分子の発現制御

濱田晋, 正宗淳, 三浦晋, 佐藤賢一, 下瀬川徹

膵臓　29　(3)　607-607　2014年6月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
マイクロRNA発現プロファイル解析による膵癌進展機構の解明

濱田晋

東北医学雑誌　126　(1)　53-56　2014年6月
出版者・発行元：東北医学会
ISSN： 0040-8700
【修復の病理学】病理像修復後の新たな病態発生自己免疫性膵炎と膵癌

濱田晋, 正宗淳, 下瀬川徹

肝胆膵　68　(5)　765-770　2014年5月
出版者・発行元： (株)アークメディア
ISSN： 0389-4991
【新しい視点にたった膵内外分泌相関】膵星細胞と膵島細胞の相関

菊田和宏, 正宗淳, 濱田晋, 滝川哲也, 中野絵里子, 下瀬川徹

胆と膵　35　(4)　339-342　2014年4月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
【急性膵炎の診断と治療:新しい動向】我が国の急性膵炎の予後全国調査から

菊田和宏, 正宗淳, 濱田晋, 下瀬川徹

膵臓　29　(2)　151-156　2014年4月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
当施設における悪性十二指腸狭窄に対する十二指腸ステント留置術の検討

中野絵里子, 菅野敦, 正宗淳, 吉田直樹, 本郷星仁, 三浦晋, 滝川哲也, 有賀啓之, 濱田晋, 粂潔, 菊田和宏, 廣田衛久, 下瀬川徹

Gastroenterological Endoscopy　56　(Suppl.1)　1146-1146　2014年4月
出版者・発行元： (一社)日本消化器内視鏡学会
ISSN： 0387-1207

eISSN： 1884-5738
【肝胆膵腫瘍のバイオインフォマティクス】腫瘍の性質と分子プロファイリング胆膵腫瘍のトランスクリプトーム・プロテオーム解析

濱田晋, 正宗淳, 下瀬川徹

肝胆膵　68　(3)　379-384　2014年3月
出版者・発行元： (株)アークメディア
ISSN： 0389-4991
【膵基礎研究:膵疾患の原因・病態解明に挑む】膵腫瘍における上皮間葉形質転換(EMT) EMT誘導分子MSX2の膵腫瘍悪性化への関与を中心に

佐藤賢一, 濱田晋, 下瀬川徹

膵臓　29　(1)　13-22　2014年

DOI： 10.2958/suizo.29.13 　
Nationwide epidemiological survey of acute pancreatitis in Japan. 国際誌

Hamada, Shin, Masamune, Atsushi, Kikuta, Kazuhiro, Hirota, Morihisa, Tsuji, Ichiro, Shimosegawa, Tooru, Research Committee of Intractable, Diseases of, the, Pancreas

Pancreas　43　(8)　1244-1248　2014年

DOI： 10.1097/MPA.0000000000000200 　
MiR-365 induces gemcitabine resistance in pancreatic cancer cells by targeting the adaptor protein SHC1 and pro-apoptotic regulator BAX. 国際誌

Hamada, Shin, Masamune, Atsushi, Miura, Shin, Satoh, Kennichi, Shimosegawa, Tooru

Cell Signal　26　(2)　179-185　2014年

DOI： 10.1016/j.cellsig.2013.11.003 　

詳細を見る詳細を閉じる

The poor prognosis of invasive ductal adenocarcinoma of the pancreas is mainly due to its resistance against therapeutic agents. The molecular mechanism by which morbidity enhances cell survival has been extensively studied, but radical improvements in the therapeutic strategy have not yet been achieved. Recent reports have indicated the substantial contribution of miRNA in multiple cell functions by comprehensively targeting clusters of genes. We identified several miRNAs highly expressed in invasive ductal adenocarcinoma in our previous study, and clarified their contribution to the epithelial-mesenchymal transition. Among the differentially expressed miRNAs, miR-365 was highly expressed in invasive ductal adenocarcinoma, whose functional role has not been reported. In the current study, we found that miR-365 induced gemcitabine resistance in pancreatic cancer cells. MiR-365 directly targeted adaptor protein Src Homology 2 Domain Containing 1 (SHC1) and apoptosis-promoting protein BAX. The siRNA-based knockdown of SHC1 and BAX increased gemcitabine resistance, indicating the miR-365/SHC1/BAX axis influences the survival of pancreatic cancer cells. In addition, miR-365 up-regulated cancer-promoting molecules such as Inhibitor of DNA binding 2 and S100P, suggesting the existence of cross-talk with other cancer-promoting signals. MiR-365 could exert orchestrated effects on pancreatic cancer cell survival.
The zinc transporter LIV-1 is a novel regulator of stemness in pancreatic cancer cells. 国際誌

Unno, Jun, Masamune, Atsushi, Hamada, Shin, Shimosegawa, Tooru

Scand J Gastroenterol　49　(2)　215-221　2014年

DOI： 10.3109/00365521.2013.865075 　

詳細を見る詳細を閉じる

OBJECTIVE: Recent studies have identified the existence a portion of cancer cells, called "cancer stem cells", within the entire cancer tissue. Cancer stem cells harbor highly tumorigenic and chemo-resistant phenotypes, which lead to recurrence or re-growth of the tumor after surgery. The mechanisms that regulate the stemness of cancer cells remain largely unknown. We hypothesized that LIV-1, a zinc transporter, regulates the stemness in pancreatic cancer cells. MATERIAL AND METHODS: We established two stable Panc-1 pancreatic cancer cell lines in which LIV-1 expression was knocked down by the introduction of siRNA against LIV-1. Expression of cancer stem cell-related molecules was examined by quantitative real-time PCR. Expression of ATP-binding cassette sub-family G member 2 was also determined by flow cytometry. Spheroid culture was performed in low-adhesion coated plates. Cell migration was determined by using a modified 2-chamber migration assay. In vivo tumor formation was assessed in nude mice after the subcutaneous injection of cancer cells. The Agilent's miRNA microarray was used to identify differentially expressed miRNAs. RESULTS: Knockdown of LIV-1 expression resulted in (i) decreased expression of cancer stem cell-related molecules such as LIN28 and ATP-binding cassette sub-family G member 2, (ii) decreased spheroid-forming ability, (iii) decreased migration, (iv) decreased incidence of tumor formation in nude mice, and (v) upregulation of miR-7 expression. CONCLUSIONS: Our results suggest that LIV-1 might act as a novel regulator of stemness in pancreatic cancer cells.
CUB-domain containing protein 1 represses the epithelial phenotype of pancreatic cancer cells. 国際誌

Miura, Shi, Hamada, Shin, Masamune, Atsushi, Satoh, Kennichi, Shimosegawa, Tooru

Exp Cell Res　321　(2)　209-218　2014年

DOI： 10.1016/j.yexcr.2013.12.019 　

詳細を見る詳細を閉じる

The prognosis of pancreatic cancer is dismal due to the frequent metastasis and invasion to surrounding organs. Numerous molecules are involved in the malignant behavior of pancreatic cancer cells, but the entire process remains unclear. Several reports have suggested that CUB-domain containing protein-1 (CDCP1) is highly expressed in pancreatic cancer, but its impact on the invasive growth and the upstream regulator remain elusive. To clarify the role of CDCP1 in pancreatic cancer, we here examined the effects of CDCP1 knockdown on the cell behaviors of pancreatic cancer cells. Knockdown of CDCP1 expression in Panc-1 resulted in reduced cellular migration accompanied by the increased expression of E-cadherin and decreased expression of N-cadherin. Knockdown of CDCP1 attenuated the spheroid formation and resistance against gemcitabine, which are some of the cancer stem cell-related phenotypes. Bone morphogenetic protein 4 (BMP4) was found to induce CDCP1 expression via the extracellular signal regulated kinase pathway, suggesting that CDCP1 has a substantial role in the BMP4-induced epithelial-mesenchymal transition. These results indicate that CDCP1 represses the epithelial phenotype of pancreatic cancer cells.
Targeted Next-Generation Sequencing Effectively Analyzed the Cystic Fibrosis Transmembrane Conductance Regulator Gene in Pancreatitis. 国際誌

Nakano, Eriko, Masamune, Atsushi, Niihori, Tetsuya, Kume, Kiyoshi, Hamada, Shin, Aoki, Yoko, Matsubara, Yoichi, Shimosegawa, Tooru

Dig Dis Sci　60　(5)　1297-307　2014年

DOI： 10.1007/s10620-014-3476-9 　

詳細を見る詳細を閉じる

BACKGROUND: The cystic fibrosis transmembrane conductance regulator (CFTR) gene, responsible for the development of cystic fibrosis, is known as a pancreatitis susceptibility gene. Direct DNA sequencing of PCR-amplified CFTR gene segments is a first-line method to detect unknown mutations, but it is a tedious and labor-intensive endeavor given the large size of the gene (27 exons, 1,480 amino acids). Next-generation sequencing (NGS) is becoming standardized, reducing the cost of DNA sequencing, and enabling the generation of millions of reads per run. We here report a comprehensive analysis of CFTR variants in Japanese patients with chronic pancreatitis using NGS coupling with target capture. METHODS: Exon sequences of the CFTR gene from 193 patients with chronic pancreatitis (121 idiopathic, 46 alcoholic, 17 hereditary, and nine familial) were captured by HaloPlex target enrichment technology, followed by NGS. RESULTS: The sequencing data covered 91.6 % of the coding regions of the CFTR gene by ≥ 20 reads with a mean read depth of 449. We could identify 12 non-synonymous variants including three novel ones [c.A1231G (p.K411E), c.1753G>T (p.E585X) and c.2869delC (p.L957fs)] and seven synonymous variants including three novel ones in the exonic regions. The frequencies of the c.4056G>C (p.Q1352H) and the c.3468G>T (p.L1156F) variants were higher in patients with chronic pancreatitis than those in controls. CONCLUSIONS: Target sequence capture combined with NGS is an effective method for the analysis of pancreatitis susceptibility genes.
The seventh nationwide epidemiological survey for chronic pancreatitis in Japan: clinical significance of smoking habit in Japanese patients. 国際誌

Hirota, Morihisa, Shimosegawa, Tooru, Masamune, Atsushi, Kikuta, Kazuhiro, Kume, Kiyoshi, Hamada, Shin, Kanno, Atsushi, Kimura, Kenji, Tsuji, Ichiro, Kuriyama, Shinichi, Research Committee of Intractable Pancreatic Diseases

Pancreatology　14　(6)　490-496　2014年

DOI： 10.1016/j.pan.2014.08.008 　

詳細を見る詳細を閉じる

OBJECTIVES: A nationwide survey was conducted to clarify the epidemiological features of patients with chronic pancreatitis (CP) in Japan. METHODS: In the first survey, both the prevalence and the incidence of CP in 2011 were estimated. In the second survey, the clinicoepidemiological features of the patients were clarified by mailed questionnaires. Patients were diagnosed by the Japanese diagnostic criteria for chronic pancreatitis 2009. RESULTS: The estimated annual prevalence and incidence of CP in 2011 were 52.4/100,000 and 14.0/100,000, respectively. The sex ratio (male/female) of patients was 4.6, with a mean age of 62.3 years. Alcoholic (67.5%) was the most common and idiopathic (20.0%) was the second most common cause of CP. Comorbidity with diabetes mellitus (DM) and pancreatic calcifications (PC) occurred more frequent in ever smokers independently of their drinking status. Among patients without drinking habit, the incidences of DM and PC were significantly higher in ever smokers than in never smokers. The multiple logistic regression analysis revealed smoking was an independent factor of DM and PC in CP patients: DM, Odds ratio (OR) 1.644, 95% confidence interval (CI) 1.202 to 2.247 (P = 0.002): PC, OR 2.010, 95% CI 1.458 to 2.773 (P < 0.001). On the other hand, smoking was not identified as an independent factor for the appearance of abdominal pain by this analysis. CONCLUSION: The prevalence of Japanese patients with CP has been increasing. Smoking was identified as an independent factor related to DM and PC in Japanese CP patients.
【活性酸素-基礎から病態解明・制御まで】疾患病態・臨床編消化器疾患と酸化ストレス

正宗淳, 濱田晋, 下瀬川徹

医学のあゆみ　247　(9)　890-894　2013年11月
出版者・発行元：医歯薬出版(株)
ISSN： 0039-2359
膵癌における血漿中miR-483-3pの発現解析(Circulating miR-483-3p is highly expressed in plasma of pancreatic cancer)

虻江誠, 濱田晋, 玉井恵一, 田中伸幸, 山口壹範, 菅村和夫, 佐藤郁郎, 佐藤賢一

日本癌学会総会記事　72回　443-443　2013年10月
出版者・発行元：日本癌学会
ISSN： 0546-0476
【知っていますか?急性膵炎はこう治す!】日本における急性膵炎の実態全国調査より

正宗淳, 濱田晋, 廣田衛久, 菊田和宏, 下瀬川徹

胆と膵　34　(10)　1031-1034　2013年10月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
自己免疫性膵炎類似の間質所見を呈した膵尾部癌の1例

中野絵里子, 菅野敦, 正宗淳, 三浦晋, 滝川哲也, 有賀啓之, 海野純, 濱田晋, 粂潔, 菊田和宏, 廣田衛久, 坂田直昭, 元井冬彦, 江川新一, 海野倫明, 藤島史喜, 石田和之, 下瀬川徹

膵臓　28　(5)　627-635　2013年10月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
MiR-365によるゲムシタビン耐性誘導機構の検討

濱田晋, 佐藤賢一, 正宗淳, 菅野敦, 菊田和宏, 粂潔, 廣田衛久, 下瀬川徹

日本消化器病学会雑誌　110　(臨増大会)　A852-A852　2013年9月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
【検査値を読む2013】腫瘍マーカー検査膵癌糖鎖抗原19-9

濱田晋, 正宗淳, 下瀬川徹

内科　111　(6)　1593-1593　2013年6月
出版者・発行元： (株)南江堂
ISSN： 0022-1961

eISSN： 2432-9452
【検査値を読む2013】腫瘍マーカー検査膵癌糖鎖抗原50

濱田晋, 正宗淳, 下瀬川徹

内科　111　(6)　1594-1594　2013年6月
出版者・発行元： (株)南江堂
ISSN： 0022-1961

eISSN： 2432-9452
【検査値を読む2013】腫瘍マーカー検査膵癌 Span-1

濱田晋, 正宗淳, 下瀬川徹

内科　111　(6)　1595-1595　2013年6月
出版者・発行元： (株)南江堂
ISSN： 0022-1961

eISSN： 2432-9452
【検査値を読む2013】腫瘍マーカー検査膵癌 DUPAN-2

濱田晋, 正宗淳, 下瀬川徹

内科　111　(6)　1596-1596　2013年6月
出版者・発行元： (株)南江堂
ISSN： 0022-1961

eISSN： 2432-9452
【検査値を読む2013】腫瘍マーカー検査膵癌 NCC-ST-439

濱田晋, 正宗淳, 下瀬川徹

内科　111　(6)　1597-1597　2013年6月
出版者・発行元： (株)南江堂
ISSN： 0022-1961

eISSN： 2432-9452
【検査値を読む2013】腫瘍マーカー検査膵癌尿中遊離型フコース

濱田晋, 正宗淳, 下瀬川徹

内科　111　(6)　1598-1598　2013年6月
出版者・発行元： (株)南江堂
ISSN： 0022-1961

eISSN： 2432-9452
浸潤性膵癌特異的oncomiRであるmiR-197はVDAC1発現を制御し好気的解糖を促進する

濱田晋, 佐藤賢一, 正宗淳, 菅野敦, 菊田和宏, 粂潔, 廣田衛久, 下瀬川徹

膵臓　28　(3)　424-424　2013年6月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
Intraductal papillary mucinous carcinoma, high-grade gastric typeの1例

菅野敦, 中野絵里子, 滝川哲也, 三浦晋, 有賀啓之, 海野純, 濱田晋, 粂潔, 菊田和宏, 廣田衛久, 正宗淳, 下瀬川徹, 乙供茂, 元井冬彦, 海野倫明, 笠島敦子, 藤島史善, 古川徹

膵臓　28　(3)　495-495　2013年6月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
男性に発症し、特異な形態を呈したSolid-pseudo papillary neoplasmの1例

三浦晋, 菅野敦, 中野絵里子, 滝川哲也, 有賀啓之, 濱田晋, 海野純, 粂潔, 菊田和宏, 廣田衛久, 正宗淳, 元井冬彦, 海野倫明, 藤島史喜, 下瀬川徹

膵臓　28　(3)　495-495　2013年6月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
IgG4陰性自己免疫性膵炎の1例

中野絵里子, 菅野敦, 滝川哲也, 三浦晋, 有賀啓之, 海野純, 濱田晋, 粂潔, 菊田和宏, 廣田衛久, 正宗淳, 中山恵輔, 藤島史喜, 下瀬川徹

膵臓　28　(3)　522-522　2013年6月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
【膵胆道癌の早期診断】胆管癌におけるカルシウム結合蛋白質S100P発現の診断的意義

濱田晋, 正宗淳, 下瀬川徹

消化器内科　56　(5)　532-537　2013年5月
出版者・発行元： (有)科学評論社
ISSN： 1884-2895
【胆膵癌の早期診断フロントライン】膵臨床膵癌高危険群疫学からみた膵癌の高危険群と早期診断

江川新一, 水間正道, 濱田晋, 海野倫明, 下瀬川徹

肝胆膵　66　(2)　251-259　2013年2月
出版者・発行元： (株)アークメディア
ISSN： 0389-4991
Alteration of pancreatic cancer cell functions by tumor-stromal cell interaction. 国際誌

Hamada, Shin, Masamune, Atsushi, Shimosegawa, Tooru

Front Physiol　4　318-318　2013年

DOI： 10.3389/fphys.2013.00318 　

詳細を見る詳細を閉じる

Pancreatic cancer shows a characteristic tissue structure called desmoplasia, which consists of dense fibrotic stroma surrounding cancer cells. Interactions between pancreatic cancer cells and stromal cells promote invasive growth of cancer cells and establish a specific microenvironment such as hypoxia which further aggravates the malignant behavior of cancer cells. Pancreatic stellate cells (PSCs) play a pivotal role in the development of fibrosis within the pancreatic cancer tissue, and also affect cancer cell function. PSCs induce epithelial-mesenchymal transition and cancer stem cell (CSC)-related phenotypes in pancreatic cancer cells by activating multiple signaling pathways. In addition, pancreatic cancer cells and PSCs recruit myeloid-derived suppressor cells which attenuate the immune reaction against pancreatic cancer cells. As a result, pancreatic cancer cells become refractory against conventional therapies. The formation of the CSC-niche by stromal cells facilitates postoperative recurrence, re-growth of therapy-resistant tumors and distant metastasis. Conventional therapies targeting cancer cells alone have failed to conquer pancreatic cancer, but targeting the stromal cells and immune cells in animal experiments has provided evidence of improved therapeutic responses. A combination of novel strategies altering stromal cell functions could contribute to improving the pancreatic cancer prognosis.
Novel therapeutic strategies targeting tumor-stromal interactions in pancreatic cancer. 国際誌

Hamada, Shin, Masamune, Atsushi, Shimosegawa, Tooru

Front Physiol　4　331-331　2013年

DOI： 10.3389/fphys.2013.00331 　

詳細を見る詳細を閉じる

Therapy-resistance and postoperative recurrence are causes of the poor prognosis in pancreatic cancer. Conventional therapies have a limited impact on the control of pancreatic cancer, resulting in the rapid re-growth of the tumor. The indispensable role of tumor-stromal interaction, which acts as a defender of cancer cells and enhances malignant potential, is being uncovered now. For example, specific signaling pathways for desmoplasia induction have been identified, such as sonic hedgehog (Shh) or connective tissue growth factor (CTGF), whose inhibition causes desmoplasia depletion and therapeutic advantages at least in in vivo mouse models of pancreatic cancer. Revolutions in drug delivery methods have led to the establishment of novel chemotherapeutic regimens, with better patient survival. Furthermore, mechanisms of immunosuppression in the pancreatic cancer-bearing host were clarified by the identification of myeloid-derived suppressor cells (MDSCs), which also promote disease progression. Strategies to target these components of the tumor stroma revealed certain anticancer effects in vitro and in vivo, suggesting the possibility of stroma-targeting therapy. Suppression of the stromal cell function increases the sensitivity of pancreatic cancer cells to therapeutic intervention. Further study will clarify the complex nature of the tumor microenvironment, the targeting of which has the potential to improve clinical outcome.
Inflammation and pancreatic cancer: disease promoter and new therapeutic target.

Hamada, Shin, Masamune, Atsushi, Shimosegawa, Tooru

J Gastroenterol　49　(4)　605-17　2013年

DOI： 10.1007/s00535-013-0915-x 　

詳細を見る詳細を閉じる

Chronic inflammation has a certain impact on the carcinogenesis of the digestive organs. The characteristic tissue structure of pancreatic cancer, desmoplasia, results from inflammatory processes induced by cancer cells and stromal cells. Concerning the progression of pancreatic cancer, recent research has clarified the pivotal role of tumor-stromal interaction, which promotes the development of an invasive phenotype of cancer and provides survival advantages against chemotherapeutic agents or immune surveillance. Tumor stromal cells such as pancreatic stellate cells and immune cells establish a microenvironment that protects cancer cells through complex interactions. The microenvironment of pancreatic cancer acts as a niche for pancreatic cancer stem cells from which therapy-resistance and disease recurrence develop. Inhibition of the stromal functions or restoration of the immune reaction against cancer cells has therapeutic benefits that enhance the efficacy of conventional therapies. Some of the recent advances in this field are now under evaluation in clinical settings, but many problems must be overcome to establish a radical therapy for pancreatic cancer. This review summarizes current knowledge about the tumor-promoting stromal functions, immune system modulation and therapeutic strategies targeting tumor-stromal interactions in pancreatic cancer.
Pancreatic duct drainage using EUS-guided rendezvous technique for stenotic pancreaticojejunostomy. 国際誌

Takikawa, Tetsuya, Kanno, Atsushi, Masamune, Atsushi, Hamada, Shin, Nakano, Eriko, Miura, Shin, Ariga, Hiroyuki, Unno, Jun, Kume, Kiyoshi, Kikuta, Kazuhiro, Hirota, Morihisa, Yoshida, Hiroshi, Katayose, Yu, Unno, Michiaki, Shimosegawa, Tooru

World J Gastroenterol　19　(31)　5182-5186　2013年

DOI： 10.3748/wjg.v19.i31.5182 　

詳細を見る詳細を閉じる

The patient was a 30-year-old female who had undergone excision of the extrahepatic bile duct and Roux-en-Y hepaticojejunostomy for congenital biliary dilatation at the age of 7. Thereafter, she suffered from recurrent acute pancreatitis due to pancreaticobiliary maljunction and received subtotal stomach-preserving pancreaticoduodenectomy. She developed a pancreatic fistula and an intra-abdominal abscess after the operation. These complications were improved by percutaneous abscess drainage and antibiotic therapy. However, upper abdominal discomfort and the elevation of serum pancreatic enzymes persisted due to stenosis from the pancreaticojejunostomy. Because we could not accomplish dilation of the stenosis by endoscopic retrograde cholangiopancreatography, we tried an endoscopic ultrasonography (EUS) guided rendezvous technique for pancreatic duct drainage. After transgastric puncture of the pancreatic duct using an EUS-fine needle aspiration needle, the guidewire was inserted into the pancreatic duct and finally reached to the jejunum through the stenotic anastomosis. We changed the echoendoscope to an oblique-viewing endoscope, then grasped the guidewire and withdrew it through the scope. The stenosis of the pancreaticojejunostomy was dilated up to 4 mm, and a pancreatic stent was put in place. Though the pancreatic stent was removed after three months, the patient remained symptom-free. Pancreatic duct drainage using an EUS-guided rendezvous technique was useful for the treatment of a stenotic pancreaticojejunostomy after pancreaticoduodenectomy.
胆膵膵臓膵発癌とmiRNA

濱田晋, 下瀬川徹

Annual Review消化器　2013　238-243　2013年1月
出版者・発行元： (株)中外医学社
EUS-FNAにて術前診断し外科的切除を行ったNeurofibromatosis typeIに合併した多発消化管GISTの1例

三浦晋, 粂潔, 濱田晋, 菅野敦, 海野純, 菊田和宏, 廣田衛久, 正宗淳, 下瀬川徹

日本内科学会雑誌　101　(12)　3510-3512　2012年12月
出版者・発行元： (一社)日本内科学会
ISSN： 0021-5384

eISSN： 1883-2083
【EMTのUP DATE】EMTの概論

濱田晋, 下瀬川徹

Surgery Frontier　19　(3)　261-265　2012年9月
出版者・発行元： (株)メディカルレビュー社
ISSN： 1340-5594
miR-197は膵癌細胞のEMT誘導因子であり、p120 catenin発現を制御する

濱田晋, 佐藤賢一, 三浦晋, 廣田衛久, 菅野敦, 正宗淳, 菊田和宏, 粂潔, 海野純, 江川新一, 元井冬彦, 海野倫明, 下瀬川徹

日本消化器病学会雑誌　109　(臨増大会)　A741-A741　2012年9月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
膵星細胞は膵癌細胞の癌幹細胞様形質を増強する

滝川哲也, 正宗淳, 濱田晋, 廣田衛久, 菊田和宏, 鈴木範明, 粂潔, 管野敦, 海野純, 佐藤賢一, 下瀬川徹

日本消化器病学会雑誌　109　(臨増大会)　A742-A742　2012年9月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
早期慢性膵炎の臨床像早期から確診に進行した2症例の比較

廣田衛久, 下瀬川徹, 菅野敦, 粂潔, 菊田和宏, 濱田晋, 海野純, 正宗淳

日本消化器病学会雑誌　109　(臨増大会)　A762-A762　2012年9月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
自己免疫性膵炎の合併が疑われた通常型膵癌の1例

菅野敦, 滝川哲也, 三浦晋, 有賀啓之, 海野純, 濱田晋, 粂潔, 菊田和宏, 廣田衛久, 正宗淳, 坂田直昭, 元井冬彦, 海野倫明, 石田和之, 下瀬川徹

Gastroenterological Endoscopy　54　(Suppl.2)　2826-2826　2012年9月
出版者・発行元： (一社)日本消化器内視鏡学会
ISSN： 0387-1207

eISSN： 1884-5738
栄養改善からみた慢性膵炎に対する内視鏡的治療の意義

海野純, 廣田衛久, 正宗淳, 菅野敦, 菊田和宏, 粂潔, 濱田晋, 有賀啓之, 下瀬川徹

膵臓　27　(4)　593-600　2012年8月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
膵血流解析による自己免疫性膵炎と膵癌の鑑別

廣田衛久, 津田雅視, 辻喜久, 菅野敦, 菊田和宏, 粂潔, 濱田晋, 海野純, 有賀宏之, 滝川哲也, 林晋太郎, 三浦晋, 千葉勉, 正宗淳, 下瀬川徹

膵臓　27　(4)　601-607　2012年8月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
【知っておきたい内科症候群】内分泌《副腎髄質および傍神経節腫に関連した症候群(MEN2を除く)》フォン・ヒッペル・リンドウ症候群

濱田晋, 下瀬川徹

内科　109　(6)　1294-1295　2012年6月
出版者・発行元： (株)南江堂
ISSN： 0022-1961

eISSN： 2432-9452
浸潤性膵癌特異的に高発現がみられるmiR-197は膵癌細胞のEMTを誘導する

濱田晋, 佐藤賢一, 廣田衛久, 菅野敦, 正宗淳, 菊田和宏, 粂潔, 海野純, 下瀬川徹

膵臓　27　(3)　452-452　2012年5月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
【再発性膵炎の病態と治療】慢性膵炎の内視鏡的治療による栄養改善とその意義

海野純, 廣田衛久, 正宗淳, 菅野敦, 菊田和宏, 粂潔, 濱田晋, 有賀啓之, 下瀬川徹

胆と膵　33　(4)　345-350　2012年4月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
内視鏡的膵管ドレナージ術が有効であった、膵性胸水の一例

三浦晋, 菅野敦, 濱田晋, 滝川哲也, 林晋太郎, 鈴木範明, 海野純, 粂潔, 有賀啓之, 菊田和宏, 廣田衛久, 正宗淳, 下瀬川徹

Gastroenterological Endoscopy　54　(Suppl.1)　1214-1214　2012年4月
出版者・発行元： (一社)日本消化器内視鏡学会
ISSN： 0387-1207

eISSN： 1884-5738
膵胆道癌の早期診断胆管癌におけるカルシウム結合蛋白質S100P発現の診断的意義

濱田晋, 佐藤賢一, 下瀬川徹

日本消化器病学会雑誌　109　(臨増総会)　A80-A80　2012年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
膵内分泌腫瘍におけるFDG-PETの有用性

滝川哲也, 菅野敦, 三浦晋, 林晋太郎, 有賀啓之, 海野純, 濱田晋, 鈴木範明, 粂潔, 菊田和宏, 廣田衛久, 正宗淳, 下瀬川徹

日本消化器病学会雑誌　109　(臨増総会)　A337-A337　2012年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
【明らかにされた自己免疫性膵炎および周辺疾患】AIPおよびその周辺疾患に関連する生化学・画像診断up to date EUS-FNAによる自己免疫性膵炎の診断能の検討

菅野敦, 濱田晋, 石田和之, 能登原憲司, 下瀬川徹

肝胆膵　64　(1)　45-51　2012年1月
出版者・発行元： (株)アークメディア
ISSN： 0389-4991
主膵管型IPMN oncocytic typeの1例

林晋太郎, 海野純, 三浦晋, 滝川哲也, 有賀啓之, 鈴木範明, 濱田晋, 粂潔, 菅野敦, 廣田衛久, 正宗淳, 下瀬川徹, 元井冬彦, 江川新一, 海野倫明, 石田和之

東北医学雑誌　123　(2)　216-216　2011年12月
出版者・発行元：東北医学会
ISSN： 0040-8700
消化器癌の悪性度・予後における分子診断膵癌特異的なマイクロRNA発現プロファイル解析からの悪性化因子の同定

濱田晋, 佐藤賢一, 下瀬川徹

日本消化器病学会雑誌　108　(臨増大会)　A640-A640　2011年9月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
【消化器癌のサーベイランス】膵臓癌

濱田晋, 下瀬川徹

The GI Forefront　7　(1)　34-37　2011年6月
出版者・発行元： (株)メディカルレビュー社
ISSN： 1349-9629
再発性膵炎の治療栄養改善からみた慢性再発性膵炎に対する内視鏡的治療の意義

海野純, 廣田衛久, 有賀啓之, 伊藤広通, 濱田晋, 粂潔, 菊田和宏, 菅野敦, 正宗淳, 下瀬川徹

膵臓　26　(3)　313-313　2011年6月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
膵癌細胞株におけるEMT誘導因子MSX2の標的miRNAの検討

濱田晋, 佐藤賢一, 廣田衛久, 菅野敦, 正宗淳, 菊田和宏, 粂潔, 海野純, 下瀬川徹

膵臓　26　(3)　371-371　2011年6月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
【早期膵癌の病態解明】膵癌高危険群はどこまで明らかになったか遺伝性膵炎

濱田晋, 下瀬川徹

肝胆膵　62　(3)　533-538　2011年3月
出版者・発行元： (株)アークメディア
ISSN： 0389-4991
【消化器癌のCancer Stem Cell、Cancer Initiating Cell】膵癌幹細胞を探る

濱田晋, 下瀬川徹

分子消化器病　8　(1)　42-46　2011年3月
出版者・発行元： (株)先端医学社
ISSN： 1348-995X
DNA・マイクロRNA解析からの消化器疾患の診断・治療・病態解明膵癌の浸潤傾向を規定するmicroRNAの同定とその標的遺伝子の検討

濱田晋, 佐藤賢一, 下瀬川徹

日本消化器病学会雑誌　108　(臨増総会)　A133-A133　2011年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
Biomarkers of pancreatic cancer. 国際誌

Hamada Shin, Shimosegawa Tooru

Pancreatology　11 Suppl 2　14-19　2011年

DOI： 10.1159/000323479 　
MiR-126 Acts as a Tumor Suppressor in Pancreatic Cancer Cells via the Regulation of ADAM9. 国際誌

Hamada S, Satoh K, Fujibuchi W, Hirota M, Kanno A, Unno J, Masamune A, Kikuta K, Kume K, Shimosegawa T

Mol Cancer Res　10　(1)　--10　2011年

DOI： 10.1158/1541-7786.MCR-11-0272 　
胆膵膵癌における癌幹細胞の役割

濱田晋, 下瀬川徹

Annual Review消化器　2011　280-285　2011年1月
出版者・発行元： (株)中外医学社
【これだけは知っておきたい検査のポイント】腫瘍マーカー消化器系 NCC-ST-439

濱田晋, 下瀬川徹

Medicina　47　(11)　536-537　2010年10月
出版者・発行元： (株)医学書院
ISSN： 0025-7699

eISSN： 1882-1189
【これだけは知っておきたい検査のポイント】腫瘍マーカー消化器系 DU-PAN-2

濱田晋, 下瀬川徹

Medicina　47　(11)　538-539　2010年10月
出版者・発行元： (株)医学書院
ISSN： 0025-7699

eISSN： 1882-1189
Prediction of invasive carcinoma in branch type intraductal papillary mucinous neoplasms of the pancreas

KANNO Atsushi, SATOH Kennichi, HIROTA Morihisa, HAMADA Shin, UMINO Jun, ITOH Hiromichi, MASAMUNE Atsushi, ASAKURA Tohru, SHIMOSEGAWA Tooru

Journal of gastroenterology　45　(9)　952-959　2010年9月1日

DOI： 10.1007/s00535-010-0238-0 　

ISSN： 0944-1174
消化器癌における幹細胞研究の現状ホメオボックス遺伝子MSX2はトランスポーター遺伝子ABCG2の転写を制御することによりstem cell-like phenotypeを規定する

濱田晋, 佐藤賢一, 下瀬川徹

日本消化器病学会雑誌　107　(臨増大会)　A510-A510　2010年9月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
消化器内視鏡と癌の分子生物学膵胆管擦過細胞中のMSX2、S100P発現量解析による癌診断への応用

佐藤賢一, 濱田晋, 下瀬川徹

日本消化器病学会雑誌　107　(臨増大会)　A519-A519　2010年9月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
【肝胆膵の悪性腫瘍の早期診断をめざしてハイリスクグループの設定と画像診断】膵癌のハイリスクグループ慢性膵炎と膵癌

粂潔, 正宗淳, 菅野敦, 伊藤広通, 渡辺崇, 濱田晋, 菊田和宏, 廣田衛久, 佐藤賢一, 朝倉徹, 下瀬川徹

肝胆膵画像　12　(2)　215-222　2010年3月
出版者・発行元： (株)医学書院
ISSN： 1882-5087

eISSN： 1882-5095
肥満と膵疾患

下瀬川徹, 濱田晋

日本消化器病学会雑誌　107　(臨増総会)　A26-A26　2010年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
消化器幹細胞研究の進歩病態から治療へヒト膵癌におけるstem cell-like phenotypeとmicroRNA発現プロファイル

濱田晋, 佐藤賢一, 下瀬川徹

日本消化器病学会雑誌　107　(臨増総会)　A193-A193　2010年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
消化器疾患における分子腫瘍マーカーの新展開膵胆管擦過細胞におけるS100P発現量解析による膵胆道癌診断への応用

佐藤賢一, 濱田晋, 下瀬川徹

日本消化器病学会雑誌　107　(臨増総会)　A198-A198　2010年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
【膵臓癌におけるトランスレーショナルリサーチの展望】膵癌とEMT BMPシグナルとMSX2による膵癌細胞のEMT誘導機構を中心に

佐藤賢一, 濱田晋, 下瀬川徹

膵臓　25　(1)　13-22　2010年2月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
ガイドラインの検証と普及 (1)急性胆道炎(2)急性膵炎急性膵炎診療ガイドライン2010の検証初期治療と感染合併症

廣田衛久, 佐藤晃彦, 正宗淳, 佐藤賢一, 菅野敦, 菊田和宏, 粂潔, 濱田晋, 渡辺崇, 伊藤広通, 下瀬川徹

日本腹部救急医学会雑誌　30　(2)　255-255　2010年2月
出版者・発行元： (一社)日本腹部救急医学会
ISSN： 1340-2242

eISSN： 1882-4781
胆膵モデル動物による膵発癌の分子機構最前線

濱田晋, 下瀬川徹

Annual Review消化器　2010　207-211　2010年1月
出版者・発行元： (株)中外医学社
【慢性膵炎診療のベストプラクティス2009】Cost-benefitからみた慢性膵炎に対する内科的治療と外科的治療の比較

廣田衛久, 朝倉徹, 菅野敦, 佐藤賢一, 正宗淳, 菊田和宏, 粂潔, 濱田晋, 渡辺崇, 伊藤広通, 下瀬川徹

胆と膵　30　(11)　1389-1393　2009年11月
出版者・発行元：医学図書出版(株)
ISSN： 0388-9408
消化器幹細胞研究の進歩とその応用ホメオボックス遺伝子MSX2はヒト膵癌においてstem cell-like phenotypeを規定する

濱田晋, 佐藤賢一, 下瀬川徹

日本消化器病学会雑誌　106　(臨増大会)　A714-A714　2009年9月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
慢性膵炎からの膵発癌機序の検討

佐藤賢一, 濱田晋, 正宗淳, 菅野敦, 廣田衛久, 伊藤広通, 下瀬川徹

日本消化器病学会雑誌　106　(臨増大会)　A923-A923　2009年9月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
胆管癌におけるS100P高発現とその意義について(Frequent expression of S100P in the cholangiocarcinoma and its functional role)

濱田晋, 佐藤賢一, 廣田衛久, 片寄友, 海野倫明, 下瀬川徹

日本癌学会総会記事　68回　262-262　2009年8月
出版者・発行元： (一社)日本癌学会
ISSN： 0546-0476
膵癌に対するトランスレーショナルリサーチの展望 bench to bed,bed to bench 膵癌におけるBMPシグナルの役割と臨床応用についての検討

佐藤賢一, 濱田晋, 菅野敦, 廣田衛久, 伊藤広通, 下瀬川徹

膵臓　24　(3)　289-289　2009年6月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
ヒト膵癌細胞株におけるMSX2によるゲムシタビン耐性の誘導機構

濱田晋, 佐藤賢一, 廣田衛久, 菅野敦, 海野純, 伊藤広通, 下瀬川徹

膵臓　24　(3)　376-376　2009年6月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
【消化器疾患と糖代謝異常】膵癌と糖尿病

濱田晋, 下瀬川徹

内分泌・糖尿病科　28　(5)　393-396　2009年5月
出版者・発行元： (有)科学評論社
ISSN： 1341-3724
内視鏡的憩室切除により膵炎発作が軽快したIntralumimal duodenal diverticulumの1例

渡辺崇, 正宗淳, 小池智幸, 伊藤広通, 海野純, 高木康彦, 菅野敦, 濱田晋, 粂潔, 菊田和宏, 廣田衛久, 佐藤賢一, 朝倉徹, 下瀬川徹

Gastroenterological Endoscopy　51　(Suppl.1)　965-965　2009年4月
出版者・発行元： (一社)日本消化器内視鏡学会
ISSN： 0387-1207

eISSN： 1884-5738
【メタボリックシンドロームから消化器疾患に迫る】メタボリックシンドロームと膵病変進展の関連を探る

濱田晋, 下瀬川徹

分子消化器病　6　(1)　31-34　2009年3月
出版者・発行元： (株)先端医学社
ISSN： 1348-995X
ホメオボックス遺伝子MSX2は膵癌細胞株においてトランスポーター遺伝子ABCG2の発現を促進する

濱田晋, 佐藤賢一, 廣田衛久, 菅野敦, 海野純, 伊藤広通, 下瀬川徹

日本消化器病学会雑誌　106　(臨増総会)　A246-A246　2009年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
陰茎転移を契機として発見され、GEM・TS-1併用療法の治療効果を認めた膵癌の一例

濱田晋, 佐藤賢一, 菅野敦, 正宗淳, 廣田衛久, 菊田和宏, 粂潔, 海野純, 高木康彦, 渡辺崇, 伊藤広通, 朝倉徹, 下瀬川徹

日本消化器病学会雑誌　106　(臨増総会)　A439-A439　2009年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
【長期予後からみた慢性膵炎の治療内科vs.外科】社会的要因からみた慢性膵炎に対する内視鏡治療の限界

廣田衛久, 朝倉徹, 菅野敦, 佐藤賢一, 正宗淳, 菊田和宏, 粂潔, 濱田晋, 海野純, 高木康彦, 渡辺崇, 伊藤広通, 下瀬川徹

膵臓　24　(1)　79-83　2009年2月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
【消化器疾患の分子医学基礎医学から臨床へ】膵臓疾患の分子機構

下瀬川徹, 粂潔, 濱田晋

臨床消化器内科　24　(2)　233-238　2009年1月
出版者・発行元： (株)日本メディカルセンター
ISSN： 0911-601X

eISSN： 2433-2488
膵癌細胞株におけるBMP4によるカルシウム結合蛋白S100Pの発現誘導とその機能についての検討

濱田晋, 佐藤賢一, 廣田衛久, 菅野敦, 海野純, 伊藤広通, 下瀬川徹

日本消化器病学会雑誌　105　(臨増大会)　A895-A895　2008年9月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
膵管内乳頭粘液性腫瘍におけるMSX2の発現

佐藤賢一, 菅野敦, 濱田晋, 伊藤広通, 廣田衛久, 海野純, 江川新一, 元井冬彦, 下瀬川徹

日本消化器病学会雑誌　105　(臨増大会)　A900-A900　2008年9月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
膵癌細胞Panc-1においてSmad4機能欠損はEMTを抑制し転移能を低下させる(Loss of Smad4 function blocks EMT and attenuates the metastatic potential of human pancreatic cancer Panc-1 cells)

廣田衛久, 佐藤賢一, 濱田晋, 菅野敦, 海野純, 伊藤広通, 下瀬川徹

日本癌学会総会記事　67回　199-199　2008年9月
出版者・発行元： (一社)日本癌学会
ISSN： 0546-0476
胆管内乳頭粘液腫瘍の一例

菅野敦, 佐藤賢一, 正宗淳, 佐藤晃彦, 廣田衛久, 菊田和弘, 粂潔, 濱田晋, 海野純, 高木康彦, 渡辺崇, 伊藤広通, 下瀬川徹, 片寄友, 海野倫明, 石田和之

胆道　22　(3)　470-470　2008年8月
出版者・発行元： (一社)日本胆道学会
ISSN： 0914-0077

eISSN： 1883-6879
長期予後からみた慢性膵炎の治療内科vs外科長期成績からみた慢性膵炎に対する内科的治療の適応

廣田衛久, 朝倉徹, 菅野敦, 佐藤賢一, 正宗淳, 佐藤晃彦, 粂潔, 菊田和宏, 濱田晋, 木村洋, 海野純, 高木康彦, 渡辺崇, 伊藤広通, 下瀬川徹

膵臓　23　(3)　271-271　2008年6月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
Intraductal Tubular Carcinomaの一例

菅野敦, 佐藤賢一, 伊藤広通, 渡辺崇, 海野純, 高木康彦, 木村洋, 濱田晋, 菊田和宏, 粂潔, 廣田衛久, 佐藤晃彦, 正宗淳, 朝倉徹, 下瀬川徹, 元井冬彦, 江川新一, 海野倫明

膵臓　23　(3)　464-464　2008年6月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
ヒト膵癌細胞株におけるBone morphogenetic protein 4によるEMT誘導経路の検討

濱田晋, 佐藤賢一, 廣田衛久, 菅野敦, 海野純, 伊藤広通, 下瀬川徹

日本消化器病学会雑誌　105　(臨増総会)　A193-A193　2008年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
【膵炎研究モデルの作製、選択、適用】化学物質DMBAによる膵発癌マウスモデルはヒト膵研究に適用できるか?

佐藤賢一, 木村憲治, 菅野敦, 濱田晋, 廣田衛久, 下瀬川徹

膵臓　23　(1)　46-53　2008年2月
出版者・発行元： (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
Periostin, secreted from stromal cells, has biphagic effect on cell migration and correlates with the epithelial mesenchymal transition of human pancreatic cancer cells. 国際誌

Kanno A. Satoh, K. Masamune, A. Hirota, M. Kimura, K. Umino, J, Hamada, S. Satoh, A. Egawa, S. Motoi, F, Unno M, Shimosegawa T

Int J Cancer.　122　(12)　2707-2712　2008年

DOI： 10.1002/ijc.23332 　

詳細を見る詳細を閉じる

Periostin is a secretory protein that has been suggested to function as a cell adhesion molecule and promote the invasiveness or growth rate of tumors. However, little is known about the association of its expression and epithelial to mesenchymal transition (EMT), which is considered to play a crucial role in cancer cell metastasis. Thus, the authors investigated whether periostin could be involved in the process of EMT and the role of this gene in pancreatic cancer development. The expression of periostin was observed mainly in stromal cells but very little in cancer cells by immunohistochemistry and real-time RT-PCR. In vitro, pancreatic stellate cells (PSCs) exhibited a much higher basal expression of periostin compared with cancer cells. Periostin secreted in the supernatant from 293T cells that expressed periostin (approximately 150 ng/ml) inhibited the migration of pancreatic cancer cells. Coculture assay revealed that periostin expression in PSC was induced by pancreatic cancer cells. To assess the direct role of periostin in pancreatic cancer cells, the authors generated pancreatic cancer cell lines that stably express periostin. The induced expression of periostin (to 150 ng/ml) altered the morphology of cancer cells, changing them from mesenchymal to epithelial phenotypes with the induction of epithelial markers and a reduction of mesenchymal markers, and showed reduced cell migration in vitro and formed smaller tumors as well as suppressed metastasis in vivo. On the other hand, high concentration of recombinant periostin (1 microg/ml) promoted cell migration with AKT activation. The findings suggest that periostin has biphasic effect on the development of pancreatic cancer.
Fibrinogen induces cytokine and collagen production in pancreatic stellate cells.

Masamune A, Kikuta K, Watanabe T, Satoh K, Hirota M, Hamada S, Shimosegawa T

Gut　1　2008年

DOI： 10.1136/gut.2008.154401 　
ヒト膵癌細胞においてSmad4機能の喪失はE-カドヘリンの発現低下により細胞移動を促進する(Loss of Smad4 function promotes cell migration with reduced expression of E-cadherin in human pancreatic cancer cells)

廣田衛久, 佐藤賢一, 濱田晋, 菅野敦, 海野純, 伊藤広通, 下瀬川徹

日本癌学会総会記事　66回　442-442　2007年8月
出版者・発行元： (一社)日本癌学会
ISSN： 0546-0476
膵がん診療におけるトランスレーショナルリサーチの現状と展望 MSX 2遺伝子を標的にした膵癌治療の可能性の検討

佐藤賢一, 濱田晋, 下瀬川徹

日本消化器病学会雑誌　103　(臨増大会)　A444-A444　2006年9月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
膵癌細胞におけるBMP signalのepithelial-mesenchymal transition(EMT)への関与とその機序

佐藤賢一, 濱田晋, 菅野敦, 廣田衛久, 海野純, 下瀬川徹

日本消化器病学会雑誌　103　(臨増総会)　A150-A150　2006年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
Sonic hedgehogシグナルの膵癌とIPMNの進展に対する検討

菅野敦, 佐藤賢一, 濱田晋, 廣田衛久, 海野純, 下瀬川徹

日本消化器病学会雑誌　103　(臨増総会)　A150-A150　2006年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
MSX2の発現は膵癌細胞株Panc-1のGemcitabineに対する感受性を低下させる

佐藤賢一, 濱田晋, 菅野敦, 下瀬川徹

日本消化器病学会雑誌　102　(臨増大会)　A850-A850　2005年9月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
膵癌細胞におけるBMP4のepithelial-mesenchymal transition(EMT)への関与とその機序の検討

佐藤賢一, 濱田晋, 木村憲治, 菅野敦, 下瀬川徹

日本消化器病学会雑誌　102　(臨増総会)　A248-A248　2005年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
膵発癌過程におけるNotch signalingの役割の検討

木村憲治, 佐藤賢一, 濱田晋, 下瀬川徹

日本消化器病学会雑誌　101　(臨増大会)　A854-A854　2004年9月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
膵癌細胞におけるBMP 4のMSX 2発現誘導ならびにMSX 2遺伝子のepithelial-to-mesenchymal transition(EMT)への関与の検討

佐藤賢一, 濱田晋, 木村憲治, 下瀬川徹

日本消化器病学会雑誌　101　(臨増大会)　A856-A856　2004年9月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
膵癌細胞株の増殖に対するBMP4の効果

濱田晋, 佐藤賢一, 木村憲治, 下瀬川徹

適応医学　8　(1)　46-46　2004年6月
出版者・発行元：日本適応医学会
ISSN： 1342-9787
慢性膵炎患者におけるkeratin8の遺伝子変異の検討

粂潔, 正宗淳, 水溜浩弥, 菊田和宏, 佐藤真広, 鈴木範明, 濱田晋, 佐藤賢一, 木村憲治, 山極哲也, 下瀬川徹

日本消化器病学会雑誌　101　(臨増総会)　A174-A174　2004年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
正常膵管細胞および膵癌細胞株におけるBMP4の役割の検討

濱田晋, 佐藤賢一, 木村憲治, 下瀬川徹

日本消化器病学会雑誌　101　(臨増総会)　A178-A178　2004年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
膵癌におけるMSX2遺伝子の機能の検討

佐藤賢一, 濱田晋, 木村憲治, 下瀬川徹

日本消化器病学会雑誌　101　(臨増総会)　A179-A179　2004年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
膵発癌機構におけるNotchの役割マウス膵発癌モデルを用いた検討

木村憲治, 佐藤賢一, 濱田晋, 下瀬川徹

日本消化器病学会雑誌　101　(臨増総会)　A180-A180　2004年3月
出版者・発行元： (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693

︎全件表示 ︎最初の5件までを表示

書籍等出版物 38

慢性膵炎患者における国際標準化身体活動質問票による身体活動量評価と骨格筋量の関連に関する検討

菊田和宏, 松本諒太郎, 滝川哲也, 濱田晋, 正宗淳

(NPO)日本消化吸収学会　2024年10月
急性膵炎に対するNrf2欠損の効果

濱田晋, 松本諒太郎, 菊田和宏, 正宗淳

(NPO)日本消化吸収学会　2024年10月
当院における胆嚢癌術前診断の現況

坂野美紗子, 三浦晋, 正宗淳, 粂潔, 菊田和宏, 濱田晋, 滝川哲也, 田中裕, 松本諒太郎, 佐々木滉, 林秀大

(一社)日本胆道学会　2024年9月
【今推しの肝胆膵研究手法と疾患モデル】新規モデルによる肝胆膵研究マウスモデルを用いた膵炎・膵癌の病態解明

濱田晋, 松本諒太郎, 林秀大, 滝川哲也, 佐々木滉, 坂野美紗子, 菊田和宏, 正宗淳

(株)アークメディア　2024年8月
【今推しの肝胆膵研究手法と疾患モデル】新規モデルによる肝胆膵研究マウスモデルを用いた膵炎・膵癌の病態解明

濱田晋, 松本諒太郎, 林秀大, 滝川哲也, 佐々木滉, 坂野美紗子, 菊田和宏, 正宗淳

(株)アークメディア　2024年8月
新規膵炎関連遺伝子異常に関する国際共同研究

正宗淳, 濱田晋

(一社)日本膵臓学会　2024年7月
慢性膵炎臨床診断基準2019の検証と次回改訂に向けた展開慢性膵炎臨床診断基準2019による早期慢性膵炎の臨床的特徴

松本諒太郎, 菊田和宏, 滝川哲也, 佐野貴紀, 濱田晋, 佐々木滉, 坂野美紗子, 林秀大, 間中友王, 三浦晋, 粂潔, 正宗淳

(一社)日本膵臓学会　2024年7月
膵癌・膵IPMN手術における膵断端評価と長期予後腫瘤を認めない早期膵癌の進展範囲

三浦晋, 粂潔, 菊田和宏, 濱田晋, 滝川哲也, 松本諒太郎, 佐野孝紀, 佐々木滉, 林秀大, 坂野美紗子, 間中友王, 石田晶玄, 水間正道, 海野倫明, 正宗淳

(一社)日本膵臓学会　2024年7月
重症急性膵炎と被包化壊死のベストプラクティス発症後3週目の高度炎症持続例は予後不良であり,治療介入すべきか

粂潔, 佐野貴紀, 池田未緒, 松本諒太郎, 滝川哲也, 三浦晋, 間中友王, 坂野美紗子, 林秀大, 佐々木滉, 濱田晋, 菊田和宏, 中川圭, 海野倫明, 正宗淳

(一社)日本膵臓学会　2024年7月
胆膵内視鏡室の効率的な運用,リスクマネージメントと課題 ERCP/ESTシミュレータ学習はリスク低減に寄与できるか新規モデル開発と教育介入研究

畑山裕, 菅野武, 滝川哲也, 池田未緒, 佐野貴紀, 松本諒太郎, 三浦晋, 濱田晋, 粂潔, 菊田和宏, 正宗淳

(一社)日本膵臓学会　2024年7月
HRSを伴う高齢者IPMNの非手術症例の予後について

粂潔, 佐々木滉, 坂野美紗子, 間中友王, 林秀大, 池田未緒, 佐野貴紀, 松本諒太郎, 滝川哲也, 三浦晋, 濱田晋, 菊田和宏, 中川圭, 海野倫明, 正宗淳

(一社)日本膵臓学会　2024年7月
膵良性疾患患者の膵癌早期診断におけるCA19-9の有用性

滝川哲也, 菊田和宏, 粂潔, 濱田晋, 三浦晋, 松本諒太郎, 佐野貴紀, 片岡史弥, 佐々木滉, 林秀人, 坂野美紗子, 間中友王, 正宗淳

(一社)日本膵臓学会　2024年7月
膵癌診断においてAPOA2-i Indexは診断に寄与するか

濱田晋, 菊田和宏, 滝川哲也, 松本諒太郎, 粂潔, 三浦晋, 佐野貴紀, 池田未緒, 佐々木滉, 林秀大, 坂野美紗子, 間中友王, 片岡史弥, 正宗淳

(一社)日本膵臓学会　2024年7月
Fatty Acid Binding Protein 5(FABP5)が膵癌細胞増殖に与える影響の検討

浜本佳織, 篠田崇平, 品川右京, 田原祥子, 津山高典, 末永成之, 山本直樹, 濱田晋, 正宗淳, 高見太郎

(一社)日本膵臓学会　2024年7月
慢性膵炎における骨格筋量と膵画像所見に関する検討

松本諒太郎, 菊田和宏, 滝川哲也, 濱田晋, 正宗淳

(NPO)日本消化吸収学会　2024年7月
慢性膵炎患者における食習慣の検討

菊田和宏, 松本諒太郎, 滝川哲也, 濱田晋, 正宗淳

(NPO)日本消化吸収学会　2024年7月
慢性膵炎における生活習慣改善の意向と生活習慣の実態

菊田和宏, 松本諒太郎, 滝川哲也, 濱田晋, 正宗淳

日本胆膵病態・生理研究会　2024年6月
慢性膵炎における生活習慣改善の意向と生活習慣の実態

菊田和宏, 松本諒太郎, 滝川哲也, 濱田晋, 正宗淳

日本胆膵病態・生理研究会　2024年6月
【75歳以上高齢者胆膵疾患の病態と高齢者機能評価による治療戦略】高齢者膵疾患診療における注意すべき生理機能変化について

松本諒太郎, 菊田和宏, 滝川哲也, 佐野貴紀, 濱田晋, 佐々木滉, 坂野美紗子, 林秀大, 間中友王, 池田未緒, 三浦晋, 粂潔, 正宗淳

医学図書出版(株)　2024年5月

ISBN: 9784865175882
【75歳以上高齢者胆膵疾患の病態と高齢者機能評価による治療戦略】高齢者膵疾患診療における注意すべき生理機能変化について

松本諒太郎, 菊田和宏, 滝川哲也, 佐野貴紀, 濱田晋, 佐々木滉, 坂野美紗子, 林秀大, 間中友王, 池田未緒, 三浦晋, 粂潔, 正宗淳

医学図書出版(株)　2024年5月

ISBN: 9784865175882
胆管空腸吻合部狭窄に対するバルーンによる過拡張の有効性の検討

池田未緒, 滝川哲也, 粂潔, 菊田和宏, 濱田晋, 三浦晋, 松本諒太郎, 佐野貴紀, 佐々木滉, 坂野美紗子, 間中友王, 正宗淳

(一社)日本消化器内視鏡学会　2024年4月
胆管空腸吻合部狭窄に対するバルーンによる過拡張の有効性の検討

池田未緒, 滝川哲也, 粂潔, 菊田和宏, 濱田晋, 三浦晋, 松本諒太郎, 佐野貴紀, 佐々木滉, 坂野美紗子, 間中友王, 正宗淳

(一社)日本消化器内視鏡学会　2024年4月
膵癌の分子異常と個別化治療カルシウムチャネルTRPV6は膵癌の環境適応に寄与するか

濱田晋, 佐々木滉, 松本諒太郎, 坂野美紗子, 林秀大, 滝川哲也, 正宗淳

(一財)日本消化器病学会　2024年3月
知っておくべき消化器希少疾患:その臨床像と病態多発性内分泌腫瘍症1型における膵・十二指腸神経内分泌腫瘍の臨床的特徴

滝川哲也, 八田和久, 池田未緒, 佐野貴紀, 松本涼太郎, 三浦晋, 濱田晋, 粂潔, 菊田和宏, 正宗淳

(一財)日本消化器病学会　2024年3月
膵脂肪浸潤と膵癌発症の関連性

三浦晋, 粂潔, 菊田和宏, 濱田晋, 滝川哲也, 松本諒太郎, 佐野貴紀, 池田未緒, 佐々木滉, 坂野美紗子, 林秀大, 間中友王, 正宗淳

(一財)日本消化器病学会　2024年3月
膵仮性嚢胞に対する経消化管的ドレナージの治療成績と入院経費の評価

粂潔, 佐々木滉, 池田未緒, 佐野貴紀, 松本諒太郎, 滝川哲也, 三浦晋, 濱田晋, 菊田和宏, 正宗淳

(一財)日本消化器病学会　2024年3月
膵癌の分子異常と個別化治療カルシウムチャネルTRPV6は膵癌の環境適応に寄与するか

濱田晋, 佐々木滉, 松本諒太郎, 坂野美紗子, 林秀大, 滝川哲也, 正宗淳

(一財)日本消化器病学会　2024年3月
知っておくべき消化器希少疾患:その臨床像と病態多発性内分泌腫瘍症1型における膵・十二指腸神経内分泌腫瘍の臨床的特徴

滝川哲也, 八田和久, 池田未緒, 佐野貴紀, 松本涼太郎, 三浦晋, 濱田晋, 粂潔, 菊田和宏, 正宗淳

(一財)日本消化器病学会　2024年3月
膵脂肪浸潤と膵癌発症の関連性

三浦晋, 粂潔, 菊田和宏, 濱田晋, 滝川哲也, 松本諒太郎, 佐野貴紀, 池田未緒, 佐々木滉, 坂野美紗子, 林秀大, 間中友王, 正宗淳

(一財)日本消化器病学会　2024年3月
膵仮性嚢胞に対する経消化管的ドレナージの治療成績と入院経費の評価

粂潔, 佐々木滉, 池田未緒, 佐野貴紀, 松本諒太郎, 滝川哲也, 三浦晋, 濱田晋, 菊田和宏, 正宗淳

(一財)日本消化器病学会　2024年3月
膵管門脈瘻を生じたアルコール性慢性膵炎の1例

間中友王, 佐野貴紀, 林秀大, 坂野美紗子, 佐々木滉, 池田未緒, 松本諒太郎, 滝川哲也, 三浦晋, 濱田晋, 菊田和宏, 粂潔, 正宗淳

日本消化器病学会-東北支部　2024年2月
【超高齢社会(高齢化率21%以上)の膵疾患診療】超高齢社会における慢性膵炎診療

滝川哲也, 菊田和宏, 松本諒太郎, 佐々木滉, 坂野美紗子, 佐野貴紀, 濱田晋, 粂潔, 正宗淳

(一社)日本膵臓学会　2024年2月
【膵癌基礎研究の最前線RELOADED】膵癌間質における酸化ストレス応答の役割

濱田晋, 佐々木滉, 松本諒太郎, 坂野美紗子, 林秀大, 滝川哲也, 菊田和宏, 正宗淳

医学図書出版(株)　2024年2月

ISBN: 9784865175738
【サルコペニアと消化器疾患】サルコペニアと非腫瘍性疾患(肝・膵臓・消化管) 慢性膵炎とサルコペニア

松本諒太郎, 菊田和宏, 濱田晋, 滝川哲也, 佐々木滉, 正宗淳

(株)日本メディカルセンター　2024年2月
膵管門脈瘻を生じたアルコール性慢性膵炎の1例

間中友王, 佐野貴紀, 林秀大, 坂野美紗子, 佐々木滉, 池田未緒, 松本諒太郎, 滝川哲也, 三浦晋, 濱田晋, 菊田和宏, 粂潔, 正宗淳

日本消化器病学会-東北支部　2024年2月
【超高齢社会(高齢化率21%以上)の膵疾患診療】超高齢社会における慢性膵炎診療

滝川哲也, 菊田和宏, 松本諒太郎, 佐々木滉, 坂野美紗子, 佐野貴紀, 濱田晋, 粂潔, 正宗淳

(一社)日本膵臓学会　2024年2月
【サルコペニアと消化器疾患】サルコペニアと非腫瘍性疾患(肝・膵臓・消化管) 慢性膵炎とサルコペニア

松本諒太郎, 菊田和宏, 濱田晋, 滝川哲也, 佐々木滉, 正宗淳

(株)日本メディカルセンター　2024年2月
【膵癌基礎研究の最前線RELOADED】膵癌間質における酸化ストレス応答の役割

濱田晋, 佐々木滉, 松本諒太郎, 坂野美紗子, 林秀大, 滝川哲也, 菊田和宏, 正宗淳

医学図書出版(株)　2024年2月

ISBN: 9784865175738

︎全件表示 ︎最初の5件までを表示

講演・口頭発表等 66

DPCデータベースからみた急性膵炎の性差

池田未緒, 濱田晋, 正宗淳

日本消化器病学会雑誌　2023年10月
シミュレータ学習プログラムは安全なESTの達成および自覚的習熟度の向上に寄与する前向き教育介入研究

畑山裕, 菅野武, 滝川哲也, 松本諒太郎, 齊藤真弘, 金笑奕, 三浦晋, 八田和久, 濱田晋, 宇野要, 粂潔, 菊田和宏, 浅野直喜, 今谷晃, 小池智幸, 正宗淳

Gastroenterological Endoscopy　2023年10月
DPCデータベースからみた急性膵炎の性差

池田未緒, 濱田晋, 正宗淳

日本消化器病学会雑誌　2023年10月
消化器の機能と栄養療法慢性膵炎における骨格筋量と膵画像所見に関する検討

松本諒太郎, 菊田和宏, 坂野美紗子, 滝川哲也, 濱田晋, 佐々木滉, 林秀大, 佐野貴紀, 池田未緒, 三浦晋, 粂潔, 正宗淳

消化と吸収　2023年9月
慢性膵炎患者における食習慣に関する検討

菊田和宏, 松本諒太郎, 滝川哲也, 濱田晋, 正宗淳

消化と吸収　2023年9月
急性膵炎の致命率改善への集学的治療 DPCデータベースに基づく急性膵炎患者の現況とガイドライン遵守に関する検討

池田未緒, 濱田晋, 坂野美紗子, 林秀大, 片岡史弥, 佐々木滉, 佐野貴紀, 松本諒太郎, 滝川哲也, 三浦晋, 菊田和宏, 粂潔, 正宗淳

膵臓　2023年7月
膵仮性嚢胞に対するベストプラクティス当院における膵仮性嚢胞の治療の現況について

粂潔, 坂野美紗子, 林秀大, 佐々木滉, 片岡史弥, 池田未緒, 佐野貴紀, 松本諒太郎, 滝川哲也, 三浦晋, 濱田晋, 菊田和宏, 正宗淳

膵臓　2023年7月
膵疾患に対する高齢者医療の現状と課題慢性膵炎全国調査からみた高齢者慢性膵炎(75歳以上)の臨床学的特徴

滝川哲也, 菊田和宏, 粂潔, 濱田晋, 三浦晋, 松本諒太郎, 佐野貴紀, 池田未緒, 片岡史弥, 佐々木滉, 林秀大, 坂野美紗子, 正宗淳

膵臓　2023年7月
自己免疫性膵炎の非典型例の取り扱い血清IgG4陰性1型自己免疫性膵炎の診断と特徴

佐野貴紀, 菊田和宏, 粂潔, 濱田晋, 滝川哲也, 三浦晋, 松本諒太郎, 池田未緒, 片岡史弥, 佐々木滉, 坂野美紗子, 林秀大, 正宗淳

膵臓　2023年7月
臨床応用を見据えた膵臓基礎研究膵特異的Trpv6欠損はSpink1欠損による膵腺房細胞脱落を促進する

濱田晋, 佐々木滉, 松本諒太郎, 菊田和宏, 滝川哲也, 坂野美紗子, 林秀大, 正宗淳

膵臓　2023年7月
カチオニックトリプシノーゲン(PRSS1)遺伝子変異を認めた遺伝性膵炎の一家系

有賀啓之, 鹿志村純也, 滝川哲也, 濱田晋, 菊田和宏, 正宗淳

膵臓　2023年7月
慢性膵炎における簡易型自記式食事歴法質問票の有用性の検討

菊田和宏, 松本諒太郎, 滝川哲也, 濱田晋, 正宗淳

消化と吸収　2023年7月
慢性膵炎における生活習慣改善の意向と生活習慣の実態

菊田和宏, 松本諒太郎, 滝川哲也, 濱田晋, 正宗淳

日本胆膵病態・生理研究会プログラム・抄録集　2023年6月
カルシウムチャネルTRPV6はアミノ酸代謝阻害剤感受性に関与する

濱田晋, 松本諒太郎, 滝川哲也, 佐々木滉, 片岡史弥, 林秀大, 坂野美紗子, 菊田和宏, 正宗淳

日本胆膵病態・生理研究会プログラム・抄録集　2023年6月
【肝胆膵領域におけるアルコール医学の新潮流】アルコールと膵疾患における新知見アルコール性膵炎の現状

菊田和宏, 粂潔, 濱田晋, 三浦晋, 滝川哲也, 松本諒太郎, 正宗淳

肝胆膵　2023年4月
【膵癌・胆道癌2023(下)胆道癌編-基礎・臨床の最新研究動向-】基礎編胆道癌の浸潤・転移機構

滝川哲也, 濱田晋, 正宗淳

日本臨床　2023年4月
【IgG4関連疾患大全-自己免疫性膵炎とIgG4関連硬化性胆管炎を中心に-】自己免疫性膵炎自己免疫性膵炎の全国疫学調査

菊田和宏, 濱田晋, 正宗淳

胆と膵　2022年10月
出血を再現した十二指腸ESTシミュレータモデルの開発

畑山裕, 菅野武, 滝川哲也, 齊藤真弘, 金笑奕, 三浦晋, 八田和久, 濱田晋, 宇野要, 粂潔, 浅野直喜, 今谷晃, 小池智幸, 正宗淳

Gastroenterological Endoscopy　2022年10月
慢性膵炎における簡易型自記式食事歴法質問票の有用性の検討

菊田和宏, 松本諒太郎, 滝川哲也, 濱田晋, 正宗淳

消化と吸収　2022年9月
高齢者慢性膵炎における疼痛管理の実態

菊田和宏, 濱田晋, 正宗淳

胆膵の病態生理　2022年6月
Halofuginone, a novel Nrf2 inhibitor, shows synergistic effect with gemcitabine in pancreatic cancer. 国際会議

Hamada S, Masamune A, Shimosegawa T

DDW 2018　2018年6月1日
急性膵炎予後因子スコア簡略化の試み

濱田晋, 正宗淳, 下瀬川徹

第104回消化器病学会総会　2018年4月19日
膵特異的K-ras変異とKeap1喪失による膵萎縮はNrf2に依存する

濱田晋, 正宗淳, 下瀬川徹

第48回日本膵臓学会大会　2017年7月15日
Simultaneous activation of K-ras and NRF2 induce pancreatic atrophy. 国際会議

Hamada S, Masamune A, Taguchi K, Yamamoto M, Shimosegawa T

DDW 2017　2017年5月6日
酸化ストレス応答欠損膵発癌モデルマウスを用いた抗癌剤感受性マーカー候補の同定

濱田晋, 正宗淳, 下瀬川徹

JDDW 2016　2016年11月3日
Impact of Nrf2 on pancreatic carcinogenesis in mice. 国際会議

Hamada S, Masamune A, Taguchi K, Yamamoto M, Shimosegawa T

JPS&IAP&AOPA 2016　2016年8月4日
Trend in the treatment of walled-off necrosis; from nationwide epidemiological survey data of acute pancreatitis in Japan. 国際会議

Hamada S, Masamune A, Shimosegawa T

JPS&IAP&AOPA 2016　2016年8月4日
Nrf2 knockout suppresses pancreatic carcinogenesis in a mouse model 国際会議

Hamada S, Masamune A, Taguchi K, Yamamoto M, Shimosegawa T

DDW 2016　2016年5月21日
新規Nrf2阻害剤ハロフギノンによる膵癌治療の可能性

濱田晋, 正宗淳, 下瀬川徹

第104回消化器病学会総会　2016年4月21日
全国調査からみた急性膵炎と生活習慣病の関連

濱田晋, 正宗淳, 下瀬川徹

第102回消化器病学会総会　2016年4月21日
膵星細胞培養上清による膵癌細胞メタボローム変化の網羅的解析

濱田晋, 正宗淳, 下瀬川徹

JDDW 2015　2015年10月9日
全国調査からみたWON・仮性嚢胞に対する治療の変遷

濱田晋, 正宗淳, 下瀬川徹

JDDW 2015　2015年10月8日
miR-197は膵癌細胞においてミトコンドリア機能を抑制する

濱田晋, 正宗淳, 下瀬川徹

第46回日本膵臓学会大会　2015年6月20日
Multimodal regulation of cellular metabolism in pancreatic cancer cells 国際会議

Hamada S, Masamune A, Shimosegawa T

The 3rd JSGE International Topic Conference　2015年4月24日
miR-197による癌細胞特異的代謝機構の制御

濱田晋, 正宗淳, 下瀬川徹

JDDW 2014　2014年11月23日
全国調査に基づく急性膵炎新重症度判定基準の検証

濱田晋, 正宗淳, 下瀬川徹

JDDW 2014　2014年11月23日
The MiR-365 Increases Gemcitabine Resistance by Regulating Cell Cycle and Apoptosis-related Molecules 国際会議

Hamada S, Masamune A, Shimosegawa T

45th Anniversary Meeting of APA/JPS　2014年11月7日
miR-365によるアポトーシス関連分子の発現制御

濱田晋, 正宗淳, 三浦晋, 佐藤賢一, 下瀬川徹

第45回日本膵臓学会大会　2014年7月11日
Comprehensive analysis of serum miRNA in autoimmune pancreatitis 国際会議

Hamada S, Masamune A, Kanno A, Shimosegawa T

International Symposium on IgG4-RD and Associated Conditions　2014年2月16日
MiR-365によるゲムシタビン耐性誘導機構の検討

濱田晋, 佐藤賢一, 正宗淳, 菅野敦, 菊田和宏, 粂潔, 廣田衛久, 下瀬川徹

JDDW 2013　2013年10月9日
浸潤性膵癌特異的oncomiRであるmiR-197はVDAC1発現を制御し好気的解糖を促進する

濱田晋, 佐藤賢一, 正宗淳, 菅野敦, 菊田和宏, 粂潔, 廣田衛久, 下瀬川徹

第44回日本膵臓学会大会　2013年7月25日
MiR-365 indirectly regulates drug resistance-related molecule Aryl hydrocarbon receptor nuclear translocator expression in pancreatic ductal adenocarcinoma cells. 国際会議

Hamada S, Satoh K, Masamune A, Kanno A, Kikuta K, Kume K, Unno J, Hirota M, Shimosegawa T

DDW 2013　2013年5月18日
Identification of inflammatory signal-stimulating microRNA in pancreatic duct cell carcinoma. 国際会議

Hamada S, Satoh K, Masamune A, Shimosegawa T

JSGE-ITC 2013　2013年3月21日
Assessment of the efficacy of pancreatic enzyme supplement therapy in patients with exocrine pancreas insufficiency by CONUT score. 国際会議招待有り

Hamada S, Masamune A, Hirota M, Kanno A, Kikuta K, Kume K, Unno J, Shimosegawa T

JSGE-APAGE Joint Conference 第3回 Asian Pacific Topic Conference　2012年11月3日
Identification of invasion-related microRNAs in pancreatic cancer by comprehensive analysis. 国際会議

Hamada S, Satoh K, Hirota M, Kanno A, Masamune A, Kikuta K, Kume K, Unno J, Shimosegawa T

UEGW 2012　2012年10月21日
miR-197は膵癌細胞のEMT誘導因子であり、p120 catenin発現を制御する

濱田晋, 佐藤賢一, 三浦晋, 廣田衛久, 菅野敦, 正宗淳, 菊田和宏, 粂潔, 海野純, 江川新一, 元井冬彦, 海野倫明, 下瀬川徹

JDDW 2012　2012年10月10日
浸潤性膵癌特異的に高発現がみられるmiR-197は膵癌細胞のEMTを誘導する

濱田晋, 佐藤賢一, 廣田衛久, 菅野敦, 正宗淳, 菊田和宏, 粂潔, 海野純, 下瀬川徹

第43回日本膵臓学会大会　2012年6月28日
胆管癌におけるカルシウム結合蛋白質S100P発現の診断的意義

濱田晋, 佐藤賢一, 下瀬川徹

第98回消化器病学会総会　2012年4月19日
膵癌特異的なマイクロRNA発現プロファイル解析からの悪性化因子の同定

濱田晋, 佐藤賢一, 下瀬川徹

JDDW 2011　2011年10月20日
膵癌細胞株におけるEMT誘導因子MSX2の標的miRNAの検討

濱田晋, 佐藤賢一, 廣田衛久, 菅野敦, 正宗淳, 菊田和宏, 粂潔, 海野純, 下瀬川徹

第42回日本膵臓学会大会　2011年7月29日
膵癌の浸潤傾向を規定するmicroRNAの同定とその標的遺伝子の検討

濱田晋, 佐藤賢一, 下瀬川徹

第97回消化器病学会総会　2011年5月13日
THE TRANSCRIPTIONAL REGULATION OF CANCER STEM CELL-RELATED GENE ABCG2 BY THE HOMEOBOX GENE MSX2. 国際会議招待有り

Hamada S, Satoh K, Hirota M, Kanno A, Masamune A, Kikuta K, Kume K, Unno J, Shimosegawa T

Joint Conference of the International Association of Pancreatology & The Indian Pancreas Club　2011年2月10日
ホメオボックス遺伝子MSX2による癌幹細胞関連分子ABCG2の発現制御

濱田晋, 佐藤賢一, 下瀬川徹

第18回浜名湖シンポジウム　2010年12月25日
ホメオボックス遺伝子MSX2はトランスポーター遺伝子ABCG2の転写を制御することによりstem cell-like phenotypeを規定する

濱田晋, 佐藤賢一, 下瀬川徹

JDDW 2010　2010年10月13日
REGULATORY MECHANISM OF STEM-CELL LIKE PHENOTYPE IN PANCREATIC CANCER CELLS.

Hamada S, Satoh K, Shimosegawa T

1st JSGE International Topic Conference　2010年9月25日
Jagged1 contributes to the epithelial-mesenchymal transition as a target gene of TGF beta and BMP signals in pancreatic cancer cell line. 国際会議

Hamada S, Satoh K, Hirota M, Kanno A, Ito H, Shimosegawa T

Joint Meeting of the IAP and JPS 2010　2010年7月11日
The regulation of stem cell related genes by the homeobox gene MSX2 in pancreatic cancer cells. 国際会議

Hamada S, Satoh K, Hirota M, Kanno A, Ito H, Shimosegawa T

DDW 2010　2010年5月1日
ヒト膵癌におけるstem cell-like phenotypeとmicroRNA発現プロファイル

濱田晋, 佐藤賢一, 下瀬川徹

第96回消化器病学会総会　2010年4月22日
ホメオボックス遺伝子MSX2はヒト膵癌においてstem cell-like phenotypeを規定する

濱田晋, 佐藤賢一, 下瀬川徹

JDDW 2009　2009年10月14日
Frequent expression of S100P in the cholangiocarcinoma and its functional role.

Hamada S, Satoh K, Hirota M, Katayose Y, Unno M, Shimosegawa T

第68回癌学会　2009年10月1日
ヒト膵癌細胞株におけるMSX2によるゲムシタビン耐性の誘導機構

濱田晋, 佐藤賢一, 廣田衛久, 菅野敦, 海野純, 伊藤広通, 下瀬川徹

第40回日本膵臓学会大会　2009年7月30日
ホメオボックス遺伝子MSX2は膵癌細胞株においてトランスポーター遺伝子ABCG2の発現を促進する

濱田晋, 佐藤賢一, 廣田衛久, 菅野敦, 海野純, 伊藤広通, 下瀬川徹

第95回消化器病学会総会　2009年5月7日
膵癌における新規BMP標的遺伝子の同定とEMT誘導過程への寄与について

濱田晋, 佐藤賢一, 廣田衛久, 下瀬川徹

第16回浜名湖シンポジウム　2008年12月20日
膵癌細胞株におけるBMP4によるカルシウム結合蛋白S100Pの発現誘導とその機能についての検討

濱田晋, 佐藤賢一, 廣田衛久, 菅野敦, 海野純, 伊藤広通, 下瀬川徹

JDDW 2008　2008年10月1日
ヒト膵癌細胞株におけるBone morphogenetic protein 4によるEMT誘導経路の検討

濱田晋, 佐藤賢一, 廣田衛久, 菅野敦, 海野純, 伊藤広通, 下瀬川徹

第94回日本消化器病学会総会　2008年5月8日
Comprehensive analysis of BMP target gene in pancreatic cancer cell line and its functional role during cancer cell migration. 国際会議

Hamada S, Satoh K, Hirota M, Kanno A, Umino J, Itoh H, Masamune A, Shimosegawa T

AACR Annual Meeting 2008　2008年4月12日

︎全件表示 ︎最初の5件までを表示

共同研究・競争的資金等の研究課題 26

ストレス応答機構制御による腫瘍免疫賦活療法の開発

濱田晋, 松本諒太郎, 正宗淳

2023年4月1日～ 2026年3月31日
硫黄生物学から紐解く膵癌難治化機構の解明と治療応用

正宗淳, 赤池孝章, 濱田晋, 田口恵子

2022年4月1日～ 2025年3月31日

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本年度は研究初年度として、Cars2ヘテロノックアウト付加KPCマウスの作製を実施した。Cars2ヘテロノックアウトKPCマウス（膵特異的変異Kras, p53発現）、Cars2ヘテロノックアウトKCマウス（膵特異的変異Kras発現）が得られ、野生型KPCマウスと同様に生後90日まで生存することを確認した。Cars2ヘテロノックアウトKCマウス膵組織においては前癌病変であるpancreatic intraepithelial neoplasmの形成数が減少する傾向がみられた。Cars2ヘテロノックアウトKPCマウス1頭で膵発癌がみられたが、組織型は野生型KPCマウスと類似した腺癌を呈していた。Cars2ヘテロノックアウトマウスより膵星細胞を分離し、SV40導入により不死化し細胞株を樹立した。樹立細胞株は10％ウシ胎児血清添加DMEMにて継代可能であったが、野生型膵星細胞株に比べて細胞増殖能・遊走能は低下していた。Cars2ヘテロノックアウト膵星細胞の酸化ストレス耐性を評価するためにマレイン酸ジエチル処理後の細胞生存率を野生型膵星細胞株と比較したが、Nrf2欠損膵星細胞株とは異なり明らかな脆弱性は認めなかった。我々はこれまでにヒトおよびマウス膵星細胞の培養上清刺激が膵癌細胞の増殖を促進することを報告してきたが（Takikawa, Pancreas 2017; Tanaka, AJP-GI 2021）、Cars2ヘテロノックアウト膵星細胞株の培養上清刺激ではむしろ増殖が抑制されることが判明した。処理後のKPCマウス膵癌細胞株では細胞周期の抑制因子であるp21発現が増加し、促進因子のcyclin D1は減少していた。
硫黄生物学から紐解く膵癌難治化機構の解明と治療応用

正宗淳, 赤池孝章, 濱田晋, 田口恵子

2022年4月1日～ 2025年3月31日
慢性膵炎早期診断バイオマーカーの開発

菊田和宏, 濱田晋, 正宗淳

2021年4月1日～ 2024年3月31日

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慢性膵炎における十二指腸粘膜機能については、十二指腸粘膜を用いた検討を進めている。更に、診療上の必要性から膵液ドレナージ（ENPD）を行った場合には、その排液の一部を分子生物学的検討に用いることとし、研究計画の修正作業を進めているところである。早期慢性膵炎の臨床像については、観察研究の計画に基づき、症例の登録を行い経過観察中である。慢性膵炎における膵外分泌機能と膵内分泌機能（糖尿病）と臨床像の関連については、糖尿病は年齢層別では60代での合併が最も多く（51.2%）、女性より男性での合併が多かった（男性45.9%、女性35.0%）。また喫煙歴がある患者に糖尿病の合併が多かった（喫煙歴なし34.4%、あり47.9%）。糖尿病がない患者に比べ糖尿病を合併している患者にPFD試験低下例が多かった（糖尿病なし68.0%、糖尿病あり82.3%）。アルコール性慢性膵炎については、喫煙経験者が多く、アルコール関連問題（アルコール性肝障害、アルコール依存症）の他に、不眠症や慢性閉塞性肺疾患、胃癌の合併が特発性慢性膵炎より多いことを明らかにした。慢性膵炎におけるサルコペニアについては、骨格筋量の低下は膵外分泌機能の低下、栄養摂取量、特に脂質摂取量の低下と関連していたが、日常的な身体活動との明らかな相関は認めなかった。慢性膵炎の疼痛に対しては、内科的治療のほか、侵襲的治療（体外衝撃波膵石破砕術、内視鏡治療、外科的治療）が考慮されるが、侵襲的治療を行わずに疼痛が消失する例もあることを示し、特に高齢者慢性膵炎の疼痛に対しては慎重に方針を決定することが重要と考えられた。
ハイブリッドPETプローブによる膵癌早期診断法の開発

正宗淳, 古本祥三, 濱田晋

2020年7月30日～ 2023年3月31日

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本年度は市販のリコンビナントヒトβガラクトシダーゼを用いた活性測定・HEK293細胞にヒトβガラクトシダーゼを導入した細胞株のライセートを用いた活性測定により、薬剤スクリーニングが可能であるか検証した。本年度に使用したリコンビナントβガラクトシダーゼでは、2-Nitrophenyl-β-D-galactopyranoside分解による発色反応を利用した活性測定キットで検出可能な活性を確認できないとの結果であった。βガラクトシダーゼ導入HEK293細胞についても、発現レベルの低下や細胞自体の老化誘導による非特異反応など、培養条件による活性の変化のため、安定したスクリーニング系としての使用は困難と判断した。確実なヒトβガラクトシダーゼの発現があり、培養条件による細胞老化の誘導が内因性のβガラクトシダーゼ活性を変化させない細胞を探索したところ、βガラクトシダーゼノックアウトマウス由来線維芽細胞へヒトβガラクトシダーゼ遺伝子を導入した不死化細胞株が存在することが明らかになったため、細胞バンクから入手しβガラクトシダーゼ活性を評価した。該当細胞は大量培養が可能であり、複数回の継代によっても細胞ライセート中のβガラクトシダーゼ活性が安定的に評価可能であった。薬剤スクリーニングの実施には発色反応系のスケールアップが必要であるため、既報にしたがいアッセイ条件の最適化を進める予定である。より高感度な活性測定法の利用が必要な場合に備え、SPiDER-βGal等の蛍光ベースでの検出系も確立予定である。
Nrf2依存的リプログラミングを標的とした膵癌新規治療法開発

濱田晋, 正宗淳

2020年4月1日～ 2023年3月31日

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本年度はKeap1欠損により恒常的にNrf2活性化を来した膵癌細胞株において、Keap1・Nrf2欠損膵癌細胞とで発現変動遺伝子の比較を行った。その結果、Nrf2の恒常的活性化により多数のSLCファミリー遺伝子の発現増加を認めたが、glutaminase自体の発現増加や、Nrf2標的遺伝子であるグルタミン・システイン交換輸送体をコードするSLC7A11遺伝子の発現増加は認められなかった。同様の変化を有する膵星細胞株樹立のため、野生型マウス膵星細胞株を用いてKeap1ノックダウン細胞株の樹立に着手した。Nrf2活性化剤による誘導・阻害剤による発現抑制がみられるかも検討する。酸化ストレス応答改変マウスに加えて、膵癌進展に寄与する膵内の炎症に着目し、複数の膵炎原因遺伝子改変マウスを利用することとした。既報にて進行性の膵萎縮を来すとされているSpink1ノックアウトマウスを参考に、膵特異的なSpink1ノックアウト付加KPCマウスへNrf2ノックアウトを付加したマウスの作成に着手した。予備実験として作成したSpink1コンディショナルノックアウトマウスでは、生後90日の段階で腺房細胞の脱落と線維化がみられることを確認している。Spink1ノックアウトにより起こる膵腺房細胞の脱落に際し、Nrf2活性化または阻害が影響を与えるか検証予定である。Nrf2活性化剤としてはCDDO-IM、阻害剤としてはhalofuginoneを使用し、Spink1ノックアウト付加KPCマウスへの投与も行いその効果を明らかにする。
肝細胞脂肪変性における遊離アミノ酸の細胞内ストレス応答機構に与えるインパクト

嘉数英二, 濱田晋, 岩田朋晃, 井上淳, 小暮高之, 二宮匡史

2020年4月1日～ 2023年3月31日

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飽食の時代背景を基に全世界で肥満・糖尿病が増加しており、それに伴い非アルコール性脂肪性肝疾患（NAFLD）も急増している。約25%のNAFLDは非アルコール性脂肪性肝炎（NASH）に進行することが知られ、2018年日本肝臓学会の肝硬変実態調査により我が国のNASHによる肝硬変・肝癌の急速な増加が明らかとなった。現在、NASHに対する治療は食事・運動療法が中心で治療薬がなく、病態解明・バイオマーカーの同定・治療薬開発は急務である。NASHの発症機序は不明であるが、様々な環境因子・遺伝因子によりこれらの病態が惹起されると考えられている。過栄養状態でも飢餓状態でも脂肪肝は起こるため、食事から吸収される栄養素・代謝産物の解析はNAFLD/NASHの環境因子解明に極めて重要である。門脈血由来の過剰なTGや脂肪酸は肝細胞内に脂肪滴として蓄えられる。脂質に関しても飽和脂肪酸のパルミチン酸は細胞内でTGとなるだけでなく脂肪毒性（lipotoxicity）をもち、NASH発症の主な環境要因と考えられている。過剰な糖質・脂質の肝細胞脂肪化への関与は明らかだが、遊離アミノ酸の関与はこれまであまり知られていない。脂肪滴の一部はVLDLとして血中に放出されるが、飢餓状態ではタンパク質（アミノ酸）欠乏によりアポ蛋白によるVLDLの放出が障害されると考えられている。また、Metとコリンを欠損させた食餌（MCD diet）がマウスに肝細胞脂肪化と炎症細胞浸潤をきたすことが知られている。しかしこれらの現象に対する遊離アミノ酸の作用メカニズムは明らかではない。本研究では門脈血中遊離アミノ酸の不均衡と脂肪肝の発症メカニズムを明らかにすることを目的とした。
酸化ストレス応答依存性評価と人為的制御を基盤とした革新的膵癌治療戦略の開発

正宗淳, 濱田晋, 田口恵子

提供機関：Japan Society for the Promotion of Science

制度名：Grants-in-Aid for Scientific Research

研究種目：Grant-in-Aid for Scientific Research (B)

研究機関：Tohoku University

2019年4月1日～ 2022年3月31日

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本年度は膵星細胞のNrf2依存的な膵癌促進作用を明らかにするため、膵星細胞における酸化ストレス応答が細胞機能に与える影響を評価した。ヒト膵星細胞およびマウス膵星細胞を酸化ストレス誘導剤で処理することにより、典型的なNrf2標的遺伝子であるNqo1・Gstm1の発現誘導が起こることを確認した。Nrf2欠損マウスより得られた初代培養膵星細胞と野生型マウス由来の初代培養膵星細胞の遺伝子発現プロファイルを比較した結果では、Nrf2欠損細胞でNrf2標的遺伝子の発現低下がみられるとともに、これまで酸化ストレスによる発現変化が報告されていない複数のシグナル伝達分子の発現が低下していた。ヒト膵星細胞でのNrf2抑制による影響を評価するため、ゲノム編集によるNrf2ノックアウト細胞の作製に着手した。薬剤によるNrf2抑制実験として、これまでに報告されているNrf2阻害剤4種による処理を行い、Nrf2阻害効果を示すとされている濃度においてヒト膵星細胞の細胞生存率が低下しないことを確認した。来年度の研究では膵星細胞でも酸化ストレス応答が起こることが確認できたことを受け、酸化ストレスの付与により変化する膵星細胞機能の詳細を明らかにする。Nrf2の有無が発現変動に関わる新規分子については、酸化ストレス誘導により発現変動がみられるかを明らかにするとともにプロモーター領域の機能解析を行い、Nrf2の直接標的であるかを明らかにする。本年度は膵星細胞の機能解析を中心に進めたため、来年度以降は薬剤スクリーニングの実施を重点的に進める。
膵上皮内癌周囲の膵腺房細胞萎縮に着目した膵癌早期診断の基礎的研究

菅野敦, 濱田晋

提供機関：Japan Society for the Promotion of Science

制度名：Grants-in-Aid for Scientific Research

研究種目：Grant-in-Aid for Scientific Research (C)

2018年4月1日～ 2021年3月31日

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膵腺房細胞を萎縮させ膵発癌を促進させるmRNA,miRNA,分泌蛋白の候補を絞り込むべく、現在手術を施行した膵癌症例から採取した膵癌組織は術後一部を凍結切片とし、Lasercapture microdissectionの手法を用いて採取されたmRNA, miRNA発現プロファイル、および蛋白の発現の差異を検討している。同様にmicroarrayの手法を用いてその変化を調べ、膵腺房細胞の萎縮と膵癌の進展に関連mRNA, miRNA発現プロファイル、および蛋白候補を抽出している。膵癌細胞株膵星細胞は従来の方法を用いて不死化した人膵星細胞株を用いることは可能であるが、膵腺房細胞は、手術標本から人膵腺房細胞のprimary cultureを分離を試みている最中である。膵特異的にCre-recombinaseを発現するPdx-CreトランスジェニックマウスとLSL-KrasG12D:LSL-p53 R172Hノックインマウスを交配することによって、膵特異的に活性化型変異Krasと機能喪失型p53を発現し、生後半年以内に高率に膵発癌を来すマウスモデル(KPCマウス) (Hingorani, 2005)においては膵前癌病変としてacinoductal metaplasiaおよびPanIN形成がみられる。KPCマウスとKeap1欠損マウスを交配すると膵萎縮が認められることから（Hamada , 2017）、膵上皮内癌に似た膵萎縮の分子機構が起きていることが推測される。現在、採取された組織からLasercapture microdissectionの手法を用いてmRNA, miRNAの検討、またマウス血液中のバイオマーカー候補としてはプロテオミクス解析・メタボローム解析を行っている。さらに、臨床症例を報告するべく、学会発表を行ってた。
慢性膵炎における身体活動の実態と作用の解明

菊田和宏, 正宗淳, 濱田晋

提供機関：Japan Society for the Promotion of Science

制度名：Grants-in-Aid for Scientific Research

研究種目：Grant-in-Aid for Scientific Research (C)

研究機関：Tohoku University

2018年4月1日～ 2021年3月31日

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東北大学医学系研究科倫理委員会の承認が得られ、慢性膵炎患者における身体活動と栄養状態の実態に関する観察研究を開始した。身体活動量の計測にはウェアラブル加速度計と国際標準化身体活動質問票を用いる。栄養状態は体重、BMIの計測、血液生化学データに加え、インピーダンス法による体組成計測、CT画像による骨格筋計測により行う。合わせてSF-36を用いてQOLを評価する。食習慣、栄養素摂取量の評価も行うため、倫理委員会に修正申請を行い、簡易式自記式食事歴法質問票を用いた検討も行うこととした。これまで、国際標準化身体活動質問票を用いた身体活動量計測は23症例に、インピーダンス法による体組成計測は33症例に、CT画像による骨格筋計測は29例に、QOL評価は28症例に、栄養素摂取量評価は13症例に実施済みであり、症例登録を継続中である。並行して、保存的に経過観察している膵石症における糖尿病について後ろ向き観察研究を行い、膵萎縮がある慢性膵炎に糖尿病の合併が有意に多いことを示し、学会報告を行った。更に慢性膵炎の社会復帰に関する後ろ向き検討を行い、自覚症状のみならず飲酒習慣や栄養状態が社会復帰状況と関連していることを学会報告し、論文投稿した（in press）。本邦における早期慢性膵炎の実態についての解析も行い、アルコール性であること、急性膵炎の既往があること、喫煙歴があることが慢性膵炎確診への進行の危険因子であることを示し、学会報告を行った。
膵癌間質のもたらす免疫抑制機能の網羅的解析と治療応用

下瀬川徹, 濱田晋, 正宗淳

提供機関：Japan Society for the Promotion of Science

制度名：Grants-in-Aid for Scientific Research

研究種目：Grant-in-Aid for Scientific Research (B)

研究機関：Tohoku University

2017年4月1日～ 2020年3月31日

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ヒト膵癌の進展に寄与することが明らかとなっている膵星細胞においてインテグリンシグナルの調節分子のノックダウンを行い、癌進展促進機能に与える影響を評価した。また、酸化ストレス応答の制御分子であるNrf2欠損バックグラウンドを膵癌モデルマウスへ導入し、膵癌細胞・膵星細胞株を樹立し、機能解析を行った。インテグリンシグナル調節分子のノックダウンにより膵星細胞の活性化が抑制された。また、Nrf2欠損膵癌細胞における炎症関連分子の発現低下、Nrf2欠損膵星細胞における癌進展促進作用の減弱が明らかになった。
胆管癌進展過程に酸化ストレス応答機構が果たす役割の解析競争的資金

濱田晋

2017年～ 2020年
遺伝性膵炎患者由来iPS細胞を用いたヒト膵炎細胞モデルの構築と創薬への応用

正宗淳, 濱田晋, 児玉裕三, 長船健二

提供機関：Japan Society for the Promotion of Science

制度名：Grants-in-Aid for Scientific Research

研究種目：Grant-in-Aid for Challenging Exploratory Research

研究機関：Tohoku University

2016年4月1日～ 2019年3月31日

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本研究の目的は膵炎関連遺伝子異常を有する患者由来iPS細胞作成・腺房細胞への分化誘導法開発である。まず、遺伝性膵炎患者よりインフォームドコンセントに基づき採取した末梢血を用いて研究を実施した。末梢血より単核球を分離し、初期化6因子を遺伝子導入してiPS細胞を樹立した。検体採取を行ったすべての患者でiPS細胞の樹立が可能であり、細胞株として維持・保存した。二次元培養条件下での分化誘導法スクリーニングにより、新規低分子化合物を用いた誘導条件でアミラーゼ等膵腺房細胞マーカー発現が認められることを確認した。最終分化誘導には課題を残したが、遺伝的素因を有する膵炎患者のiPSライブラリー化を可能とした。
膵疾患における酸化ストレスのダイナミズム解明と治療応用

正宗淳, 濱田晋, 田口恵子

提供機関：Japan Society for the Promotion of Science

制度名：Grants-in-Aid for Scientific Research

研究種目：Grant-in-Aid for Scientific Research (B)

研究機関：Tohoku University

2015年4月1日～ 2018年3月31日

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本研究では、膵発癌において持続的なNrf2活性化が癌進展を促進しうるかを検討した。膵特異的に変異Kras・p53を発現するKPC::Keap1 CKOマウス、膵特異的に変異Krasのみを発現するKC::Keap1 CKOマウスは進行性の膵実質脱落を来して早期に死亡することが明らかとなった。これらのマウスへNrf2+/-またはNrf2-/-バックグラウンドを導入することで膵萎縮は抑制され、変異KrasとKeap1欠損による組織変化がNrf2に依存することを確認した。KPC::Keap1 CKO::Nrf2+/-マウス膵癌組織に由来する細胞株の解析ではサイトケラチン発現低下が確認された。
膵発癌過程におけるselection pressureの網羅的解析と治療応用

下瀬川徹, 濱田晋, 正宗淳

提供機関：Japan Society for the Promotion of Science

制度名：Grants-in-Aid for Scientific Research

研究種目：Grant-in-Aid for Scientific Research (B)

研究機関：Tohoku University

2014年4月1日～ 2017年3月31日

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本研究では、膵癌進行過程における癌細胞・間質細胞に対するselection pressureが腫瘍内のコンポーネントへ与える影響を解析し、浸潤性増殖や治療抵抗性等の形質を獲得させないための新たな治療法開発に向けた基礎検討を行うことを目的とした。膵発癌モデルマウス、KPCマウスにおいて酸化ストレス応答機構を欠損させた場合の影響を検討し、発癌・進展過程の抑制と抗癌剤感受性の回復がみられることを確認。酸化ストレス応答機構の中核を担うKeap1-Nrf2経路が膵癌進展に寄与することを明らかにした。また、膵癌宿主側の要因として腸内細菌叢変化に着目し、他の膵疾患と膵癌症例での細菌叢の差異を見出した。
膵癌におけるWarburg効果誘導因子の同定と治療応用競争的資金

濱田晋

2014年～ 2017年
臨床検体から導き出す膵癌幹細胞関連 miRNAを用いた膵癌治療の確立

菅野敦, 濱田晋

提供機関：Japan Society for the Promotion of Science

制度名：Grants-in-Aid for Scientific Research

研究種目：Grant-in-Aid for Scientific Research (C)

研究機関：Tohoku University

2013年4月1日～ 2016年3月31日

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術前化学療法前の膵癌症例から超音波内視鏡下穿刺吸引報を用いた膵癌組織のtotal RNAを採取し、そのprofile 作成を継続した。合わせて、採取された組織のCD44やCD133といった膵癌幹細胞のマーカー検出を行ったが同定できなかった。採取される組織量が少ないと推測されたため、切除標本を用いて膵癌幹細胞のマーカー検出を継続している。NAC前後にEUS-FNAを行う事が困難なため、NAC後に手術した膵癌症例から組織を譲り受け、遺伝子profileの作成を行っている。
マイクロRNA関連遺伝子多型の網羅的解析による膵炎遺伝子異常の検討

下瀬川徹, 正宗淳, 粂潔, 濱田晋

提供機関：Japan Society for the Promotion of Science

制度名：Grants-in-Aid for Scientific Research

研究種目：Grant-in-Aid for Challenging Exploratory Research

研究機関：Tohoku University

2013年4月1日～ 2015年3月31日

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本検討では膵炎発症に関与する遺伝子のうち、マイクロRNAの機能に影響する遺伝子多型を同定するための基礎検討として、次世代シークエンスを用いた広範な遺伝子領域の網羅的解析が可能であるかを明らかにすることを目的とした。対象として遺伝子に含まれるエクソン数が27と多数であり、従来法では解析が困難なCFTR遺伝子を選択した。その結果、10個の非同義多型と6個の同義多型を同定し、そのうち非同義多型であるc.4056G>C (p.Q1352H)多型が慢性膵炎患者において有意に高頻度であることを明らかにした。
骨髄由来細胞の機能改変による癌幹細胞特異的ｎｉｃｈｅを標的とした膵癌治療法の開発

下瀬川徹, 正宗淳, 佐藤賢一, 濱田晋

提供機関：Japan Society for the Promotion of Science

制度名：Grants-in-Aid for Scientific Research

研究種目：Grant-in-Aid for Scientific Research (B)

研究機関：Tohoku University

2011年4月1日～ 2014年3月31日

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本研究では膵癌のcancer stem cell維持に必要なnicheを標的とした新規治療法開発のため、cancer stem cellに関連する細胞形質の制御因子の同定と新たなcancer stem cellマーカーの機能解析を行った。検討の結果、IPMNに比べ膵癌で高発現がみられるmiR-197はp120 cateninの発現抑制を介して上皮間葉形質転換（EMT）を誘導することが判明した。また、膜蛋白質であるCDCP1の発現はcancer stem cell関連細胞形質維持に重要であることを明らかにし、BMP4・ERK経路によりその発現が制御されることを確認した。
膵癌微小環境中の炎症持続因子の同定と治療応用競争的資金

濱田晋

2012年～ 2014年
膵星細胞による膵癌幹細胞ｓｔｅｍｎｅｓｓ制御機構の解明とその治療応用

正宗淳, 濱田晋

提供機関：Japan Society for the Promotion of Science

制度名：Grants-in-Aid for Scientific Research

研究種目：Grant-in-Aid for Scientific Research (C)

研究機関：Tohoku University

2011年～ 2013年

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膵星細胞との共培養により、膵癌幹細胞性の指標である、スフェロイド形成能や、上皮間葉形質転換誘導性転写因子であるSnailやABCG2などの発現増加が確認された。膵癌細胞を膵星細胞とともにヌードマウスの皮下に接種した場合、膵癌細胞単独に比べて腫瘍径の増大がみられ、膵星細胞が膵癌幹細胞性を増強することが示された。マイクロアレイによる解析に基づき、この相互作用を担うマイクロRNAとして、miR-210を同定した。さらに高血圧の治療薬であるオルメサルタン投与により、膵星細胞―膵癌細胞間相互作用を阻害したところ、腫瘍増大の抑制作用がみられ、新たな膵癌治療のターゲットである可能性が示唆された。
膵癌幹細胞抑制性microRNAの同定と治療応用競争的資金

濱田晋

2010年～ 2011年
膵癌組織中に存在する骨髄由来細胞の網羅的発現解析とそれを標的とする治療法の開発

廣田衛久, 濱田晋, 菅野敦, 佐藤賢一

提供機関：Japan Society for the Promotion of Science

制度名：Grants-in-Aid for Scientific Research

研究種目：Grant-in-Aid for Scientific Research (C)

研究機関：Tohoku University

2009年～ 2011年

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化学発癌物質DMBAを膵に注入することによりマウス膵癌モデルを作成した。このマウス膵癌モデルにおいて、癌組織の全細胞の約50%が骨髄由来の細胞で占められていた。それらの細胞を免疫染色にて解析したところ、膵星細胞マーカーのαSMAや上皮マーカーCK19、間質マーカーVimentinは陰性であり、血管内皮細胞マーカーであるCD31やマクロファージのマーカーCD68が一部の細胞で陽性であった。これらの骨髄由来細胞は癌の浸潤部に多く認められ、癌の進展機序に関与している可能性が示唆された。
進行膵癌の幹細胞ならびにEMT化癌細胞を特異的に老化誘導させる治療法の開発

佐藤賢一, 濱田晋

提供機関：Japan Society for the Promotion of Science

制度名：Grants-in-Aid for Scientific Research

研究種目：Grant-in-Aid for Scientific Research (C)

2009年～ 2011年

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EMT化癌細胞の老化を特異的に誘導する治療法を開発することを最終目的として、期間中に以下のことを行った:(1)膵癌のEMTに関連する分子を同定する;(2) EMT関連分子発現値測定による膵癌診断への有用性を検討する;(3) EMTが誘導された膵癌細胞が癌幹細胞形質を獲得するか否か検討する。その結果、(1)マイクロダイゼクションで分離した浸潤性膵癌細胞で非浸潤IPMN細胞に比べmiR126の発現低下を認めた。膵癌細胞株にmiR126を強制発現させるとEMTが抑制されることから、miR126はEMT制御分子であることが判明した;(2)膵癌のEMT誘導分子であるMSX2は、臨床検体でその発現量を解析することによって膵癌診断へ有用であることが示唆されるとともに;(3)膵癌細胞に強制発現させると癌幹細胞形質の一つである抗がん剤耐性を示した。これらの結果はEMT関連分子の測定が診断に有用であり、EMT化癌細胞が癌幹細胞と同義の効果的な治療標的となる可能性を示唆するものであった。
マイクロRNAによる浸潤性膵癌特異的な高効率アポトーシス誘導治療の開発

下瀬川徹, 佐藤賢一, 濱田晋

提供機関：Japan Society for the Promotion of Science

制度名：Grants-in-Aid for Scientific Research

研究種目：Grant-in-Aid for Scientific Research (B)

研究機関：Tohoku University

2008年～ 2010年

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本研究においては浸潤性膵癌を標的とした新規治療の開発のため、膵癌の浸潤傾向を規定するmicroRNAの同定とその標的遺伝子の解析を行った。浸潤性膵癌においてはmiR-126の発現が低下していることを見出し、細胞遊走能と浸潤能を抑制していることを確認した。miR-126の標的遺伝子としてADAM9を新規に同定し、miR-126の下流で細胞遊走能・浸潤能を制御することを確認した。miR-126/ADAM9を介する経路は浸潤性膵癌特異的な治療標的となりうるものと考えられた。
MSX2拘束性ベクターによる膵癌遺伝子治療の検討競争的資金

濱田晋

2007年～ 2008年

︎全件表示 ︎最初の5件までを表示