Papers - NAKASE Hiroshi

パンクレリパーゼ使用下で発生した膵頭十二指腸切除後脂肪肝の検討

我妻 康平, 佐々木 茂, 沼田 泰尚, 柾木 喜晴, 志谷 真啓, 阿久津 典之, 本谷 雅代, 木村 康利, 竹政 伊知朗, 仲瀬 裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 )  115 ( 臨増大会 ) A741 - A741  2018.10

MicroRNA-31 reflects IL-6 expression in cancer tissue and is related with poor prognosis in bile duct cancer.

Keisuke Ishigami, Katsuhiko Nosho, Hideyuki Koide, Shinichi Kanno, Kei Mitsuhashi, Hisayoshi Igarashi, Masahiro Shitani, Masayo Motoya, Yasutoshi Kimura, Tadashi Hasegawa, Hiroyuki Kaneto, Ichiro Takemasa, Hiromu Suzuki, Hiroshi Nakase

Carcinogenesis   39 ( 9 ) 1127 - 1134  2018.09  [Refereed]  [International journal]

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Bile duct cancer is a highly aggressive malignancy wherein early diagnosis is difficult and few treatment options are available. MicroRNA-31 (miR-31) is reported to be related with survival in patients with gastrointestinal cancers; however, the regulatory mechanism of miR-31 and association between miR-31 expression and survival in patients with bile duct cancer cases have not been established. Thus, we evaluated miR-31 expression in bile duct cancer tissues and assessed its relationship with prognosis. Additionally, we examined the effects of several cytokines on miR-31 expression. The study included 81 samples of bile duct cancer tissues. MiR-31 expression in bile duct cancer cells was significantly higher than that in normal bile duct epithelial cells (P = 0.038). There were no significant associations between miR-31 expression and clinical or pathological characteristics, except for tumour size (P = 0.012). In Kaplan-Meier analysis, high miR-31 expression was significantly associated with shorter survival (log-rank test, P = 0.0082). In multivariate Cox regression analysis, high miR-31 expression was significantly associated with prognosis (P = 0.043), independent of clinical or pathological features. Interleukin-6 (IL-6) significantly promoted miR-31 expression and cell proliferation in a dose-dependent manner, and the inhibition of STAT-3 signalling significantly suppressed miR-31 expression and cell proliferation. In conclusion, high expression was significantly associated with poor prognosis in bile duct cancer patients. The IL-6-STAT-3 signalling regulated bile duct cancer cell proliferation and miR-31 expression. Our findings suggest that miR-31 may be a promising biomarker that reflects IL-6 expression in bile duct cancer tissues and predicts poor prognosis.

DOI PubMed

Localized Gastrointestinal ALλ Amyloidosis.

Tomoya Iida, Kentaro Yamashita, Hiroshi Nakase

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association   16 ( 9 ) e93  2018.09  [Refereed]  [International journal]

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NUDT15 codon 139 is the best pharmacogenetic marker for predicting thiopurine-induced severe adverse events in Japanese patients with inflammatory bowel disease: a multicenter study.

Yoichi Kakuta, Yosuke Kawai, Daisuke Okamoto, Tetsuya Takagawa, Kentaro Ikeya, Hirotake Sakuraba, Atsushi Nishida, Shoko Nakagawa, Miki Miura, Takahiko Toyonaga, Kei Onodera, Masaru Shinozaki, Yoh Ishiguro, Shinta Mizuno, Masahiro Takahara, Shunichi Yanai, Ryota Hokari, Tomoo Nakagawa, Hiroshi Araki, Satoshi Motoya, Takeo Naito, Rintaro Moroi, Hisashi Shiga, Katsuya Endo, Taku Kobayashi, Makoto Naganuma, Sakiko Hiraoka, Takayuki Matsumoto, Shiro Nakamura, Hiroshi Nakase, Tadakazu Hisamatsu, Makoto Sasaki, Hiroyuki Hanai, Akira Andoh, Masao Nagasaki, Yoshitaka Kinouchi, Tooru Shimosegawa, Atsushi Masamune, Yasuo Suzuki

Journal of gastroenterology   53 ( 9 ) 1065 - 1078  2018.09  [Refereed]  [Domestic journal]

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BACKGROUND: Despite NUDT15 variants showing significant association with thiopurine-induced adverse events (AEs) in Asians, it remains unclear which variants of NUDT15 or whether additional genetic variants should be tested to predict AEs. To clarify the best pharmacogenetic test to be used clinically, we performed association studies of NUDT15 variants and haplotypes with AEs, genome-wide association study (GWAS) to discover additional variants, and ROC analysis to select the model to predict severe AEs. METHODS: Overall, 2630 patients with inflammatory bowel disease (IBD) were enrolled and genotyped for NUDT15 codon 139; 1291 patients were treated with thiopurines. diplotypes were analyzed in 970 patients, and GWASs of AEs were performed with 1221 patients using population-optimized genotyping array and imputation. RESULTS: We confirmed the association of NUDT15 p.Arg139Cys with leukopenia and alopecia (p = 2.20E-63, 1.32E-69, OR = 6.59, 12.1, respectively), and found a novel association with digestive symptoms (p = 6.39E-04, OR = 1.89). Time to leukopenia was significantly shorter, and when leukopenia was diagnosed, thiopurine doses were significantly lower in Arg/Cys and Cys/Cys than in Arg/Arg. In GWASs, no additional variants were found to be associated with thiopurine-induced AEs. Despite strong correlation of leukopenia frequency with estimated enzyme activities based on the diplotypes (r2 = 0.926, p = 0.0087), there were no significant differences in the AUCs of diplotypes from those of codon 139 to predict severe AEs (AUC = 0.916, 0.921, for acute severe leukopenia, AUC = 0.990, 0.991, for severe alopecia, respectively). CONCLUSIONS: Genotyping of NUDT15 codon 139 was sufficient to predict acute severe leukopenia and alopecia in Japanese patients with IBD.

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Gastric Ulcer Bleeding Due to Left Gastric Artery Pseudoaneurysm.

Gota Sudo, Tokuma Tanuma, Hiroshi Nakase

The American journal of gastroenterology   113 ( 9 ) 1281 - 1281  2018.09  [Refereed]  [International journal]

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慢性胃炎および胃がんに関連する長鎖non-coding RNAの同定と機能解析(Identification and characterization of a long non-coding RNA associated with chronic gastritis and gastric caner)

北嶋 洋志, 丸山 玲緒, 山本 英一郎, 新沼 猛, 甲斐 正広, 佐々木 泰史, 時野 隆至, 仲瀬 裕志, 鈴木 拓

日本癌学会総会記事 ( (一社)日本癌学会 )  77回   512 - 512  2018.09

肝細胞癌におけるBET阻害剤の抗腫瘍メカニズムの解析(Analysis of antitumor mechanism of BET inhibition in hepatocellular carcinoma)

佐々木 基, 新沼 猛, 北嶋 洋志, 山本 英一郎, 石黒 一也, 若杉 英樹, 萬 顕, 須藤 豪太, 甲斐 正広, 鈴木 拓, 仲瀬 裕志

日本癌学会総会記事 ( 日本癌学会 )  77回   1387 - 1387  2018.09

新規大腸がん線維芽細胞関連遺伝子の同定(Identification of cancer-associated fibroblast-related genes in colorectal cancer)

沼田 有斗, 山本 英一郎, 萬 顕, 新沼 猛, 杉本 亮, 北嶋 洋志, 甲斐 正広, 青木 敬則, 須藤 豪太, 時野 隆至, 仲瀬 裕志, 菅井 有, 鈴木 拓

日本癌学会総会記事 ( 日本癌学会 )  77回   2189 - 2189  2018.09

SMOC1のエピジェネティックなサイレンシングは大腸鋸歯状腺腫の発育進展に関与する(Epigenetic silencing of SMOC1 is associated with development of colorectal traditional serrated adenomas)

青木 敬則, 山本 英一郎, 高澤 啓, 新沼 猛, 山野 泰穂, 萬 顕, 北嶋 洋志, 甲斐 正広, 澤田 典均, 仲瀬 裕志, 菅井 有, 鈴木 拓

日本癌学会総会記事 ( 日本癌学会 )  77回   1871 - 1871  2018.09

大腸がんにおける腫瘍血管内皮関連遺伝子の同定(Identification and characterization of a tumor endothelium-related gene in colorectal cancer)

萬 顕, 山本 英一郎, 沼田 有斗, 新沼 猛, 北嶋 洋志, 甲斐 正広, 須藤 豪太, 黒瀬 誠, 時野 隆至, 仲瀬 裕志, 菅井 有, 鈴木 拓

日本癌学会総会記事 ( 日本癌学会 )  77回   1574 - 1574  2018.09

大腸腫瘍の表面構造が反映する腫瘍内不均一性(Microsurface structures are associated with mutational intratumoral heterogeneity in colorectal tumors)

山本 英一郎, 山野 泰穂, 青木 敬則, 須藤 豪太, 新沼 猛, 甲斐 正広, 佐々木 泰史, 時野 隆至, 菅井 有, 仲瀬 裕志, 鈴木 拓

日本癌学会総会記事 ( (一社)日本癌学会 )  77回   2405 - 2405  2018.09

DOT1L阻害はIRF4-MYCシグナルの抑制を介して多発性骨髄腫細胞の増殖を抑制する(DOT1L inhibition blocks multiple myeloma cell proliferation by suppressing IRF4-MYC signaling)

石黒 一也, 北嶋 洋志, 新沼 猛, 石田 禎夫, 丸山 玲緒, 池田 博, 山本 英一郎, 甲斐 正広, 佐々木 泰史, 時野 隆至, 仲瀬 裕志, 鈴木 拓

日本癌学会総会記事 ( (一社)日本癌学会 )  77回   988 - 988  2018.09

IgA regulates the composition and metabolic function of gut microbiota by promoting symbiosis between bacteria.

Akira Nakajima, Alexis Vogelzang, Mikako Maruya, Michio Miyajima, Megumi Murata, Aoi Son, Tomomi Kuwahara, Tatsuaki Tsuruyama, Satoshi Yamada, Minoru Matsuura, Hiroshi Nakase, Daniel A Peterson, Sidonia Fagarasan, Keiichiro Suzuki

The Journal of experimental medicine   215 ( 8 ) 2019 - 2034  2018.08  [Refereed]  [International journal]

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Immunoglobulin A (IgA) promotes health by regulating the composition and function of gut microbiota, but the molecular requirements for such homeostatic IgA function remain unknown. We found that a heavily glycosylated monoclonal IgA recognizing ovalbumin coats Bacteroides thetaiotaomicron (B. theta), a prominent gut symbiont of the phylum Bacteroidetes. In vivo, IgA alters the expression of polysaccharide utilization loci (PUL), including a functionally uncharacterized molecular family provisionally named Mucus-Associated Functional Factor (MAFF). In both mice and humans, MAFF is detected predominantly in mucus-resident bacteria, and its expression requires the presence of complex microbiota. Expression of the MAFF system facilitates symbiosis with other members of the phylum Firmicutes and promotes protection from a chemically induced model of colitis. Our data reveal a novel mechanism by which IgA promotes symbiosis and colonic homeostasis.

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Effect of elemental diet combined with infliximab dose escalation in patients with Crohn's disease with loss of response to infliximab: CERISIER trial.

Tadakazu Hisamatsu, Reiko Kunisaki, Shiro Nakamura, Tomoyuki Tsujikawa, Fumihito Hirai, Hiroshi Nakase, Kenji Watanabe, Kaoru Yokoyama, Masakazu Nagahori, Takanori Kanai, Makoto Naganuma, Hirofumi Michimae, Akira Andoh, Akihiro Yamada, Tadashi Yokoyama, Noriko Kamata, Shinji Tanaka, Yasuo Suzuki, Toshifumi Hibi, Mamoru Watanabe

Intestinal research   16 ( 3 ) 494 - 498  2018.07  [Refereed]  [International journal]

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Natural history of gastric cancer from a retrospective review of endoscopic images of older patients with interval gastric cancer.

Tomoya Iida, Kentaro Yamashita, Sae Ohwada, Yosuke Ohkubo, Takehiro Hirano, Takakazu Miyake, Kei Onodera, Toshiyuki Kubo, Hiroo Yamano, Hiroshi Nakase

Geriatrics & gerontology international   18 ( 7 ) 997 - 1002  2018.07  [Refereed]  [Domestic journal]

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AIM: Interval gastric cancers (IGC) are defined as those diagnosed after negative results of endoscopy carried out within the past 10 years. We aimed to investigate the characteristics of IGC and the natural history of gastric cancer (GC) from a retrospective view of endoscopic images of older patients with IGC. METHODS: We retrospectively reviewed endoscopic images of 240 patients with GC who were aged >60 years. We compared past endoscopic images with newer ones, in which GC was diagnosed. IGC were classified into two categories: missed cancers and new cancers. RESULTS: Of the 240 patients with GC, 32 had past endoscopic images that qualified for a precise review. A total of 14 cases involved new cancers, whereas 18 involved missed cancers. Most of the IGC were stage I for at least 2 years; however, a small subset was unresectable at >2 years after a negative endoscopy. Furthermore, the rate of endoscopic treatment was significantly higher for IGC compared with that for non-IGC. CONCLUSIONS: In people aged >60 years, most IGC remain in an early stage for at least 2 years; however, at >2 years after a negative endoscopy, some are unresectable. These results suggest that most early-stage GC will not develop into advanced cancers within 2 years; thus, a 2-year interval might be within the permissible range for patients with negative endoscopy results for any lesions. Geriatr Gerontol Int 2018; 18: 997-1002.

DOI PubMed

Subtypes of the Type II Pit Pattern Reflect Distinct Molecular Subclasses in the Serrated Neoplastic Pathway.

Hironori Aoki, Eiichiro Yamamoto, Hiro-O Yamano, Tamotsu Sugai, Tomoaki Kimura, Yoshihito Tanaka, Hiro-O Matsushita, Kenjiro Yoshikawa, Ryo Takagi, Eiji Harada, Michiko Nakaoka, Yuko Yoshida, Taku Harada, Gota Sudo, Makoto Eizuka, Akira Yorozu, Hiroshi Kitajima, Takeshi Niinuma, Masahiro Kai, Masanori Nojima, Hiromu Suzuki, Hiroshi Nakase

Digestive diseases and sciences   63 ( 7 ) 1920 - 1928  2018.07  [Refereed]  [International journal]

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BACKGROUND: Colorectal serrated lesions (SLs) are important premalignant lesions whose clinical and biological features are not fully understood. AIMS: We aimed to establish accurate colonoscopic diagnosis and treatment of SLs through evaluation of associations among the morphological, pathological, and molecular characteristics of SLs. METHODS: A total of 388 premalignant and 18 malignant colorectal lesions were studied. Using magnifying colonoscopy, microsurface structures were assessed based on Kudo's pit pattern classification system, and the Type II pit pattern was subcategorized into classical Type II, Type II-Open (Type II-O) and Type II-Long (Type II-L). BRAF/KRAS mutations and DNA methylation of CpG island methylator phenotype (CIMP) markers (MINT1, - 2, - 12, - 31, p16, and MLH1) were analyzed through pyrosequencing. RESULTS: Type II-O was tightly associated with sessile serrated adenoma/polyps (SSA/Ps) with BRAF mutation and CIMP-high. Most lesions with simple Type II or Type II-L were hyperplastic polyps, while mixtures of Type II or Type II-L plus more advanced pit patterns (III/IV) were characteristic of traditional serrated adenomas (TSAs). Type II-positive TSAs frequently exhibited BRAF mutation and CIMP-low, while Type II-L-positive TSAs were tightly associated with KRAS mutation and CIMP-low. Analysis of lesions containing both premalignant and cancerous components suggested Type II-L-positive TSAs may develop into KRAS-mutated/CIMP-low/microsatellite stable cancers, while Type II-O-positive SSA/Ps develop into BRAF-mutated/CIMP-high/microsatellite unstable cancers. CONCLUSIONS: These results suggest that Type II subtypes reflect distinct molecular subclasses in the serrated neoplasia pathway and that they could be useful hallmarks for identifying SLs at high risk of developing into CRC.

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Chemokine CXCL16 mediates acinar cell necrosis in cerulein induced acute pancreatitis in mice.

Yojiro Sakuma, Yuzo Kodama, Takaaki Eguchi, Norimitsu Uza, Yoshihisa Tsuji, Masahiro Shiokawa, Takahisa Maruno, Katsutoshi Kuriyama, Yoshihiro Nishikawa, Yuki Yamauchi, Motoyuki Tsuda, Tatsuki Ueda, Tomoaki Matsumori, Toshihiro Morita, Teruko Tomono, Nobuyuki Kakiuchi, Atsushi Mima, Yuko Sogabe, Saiko Marui, Takeshi Kuwada, Akihiko Okada, Tomohiro Watanabe, Hiroshi Nakase, Tsutomu Chiba, Hiroshi Seno

Scientific reports   8 ( 1 ) 8829 - 8829  2018.06  [Refereed]  [International journal]

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Severe acute pancreatitis is a lethal inflammatory disease frequently accompanied by pancreatic necrosis. We aimed to identify a key regulator in the development of pancreatic necrosis. A cytokine/chemokine array using sera from patients with acute pancreatitis (AP) revealed that serum CXCL16 levels were elevated according to the severity of pancreatitis. In a mouse model of AP, Cxcl16 expression was induced in pancreatic acini in the late phase with the development of pancreatic necrosis. Cxcl16-/- mice revealed similar sensitivity as wild-type (WT) mice to the onset of pancreatitis, but better resisted development of acinar cell necrosis with attenuated neutrophil infiltration. A cytokine array and immunohistochemistry revealed lower expression of Ccl9, a neutrophil chemoattractant, in the pancreatic acini of Cxcl16-/- mice than WT mice. Ccl9 mRNA expression was induced by stimulation with Cxcl16 protein in pancreatic acinar cells in vitro, suggesting a Cxcl16/Ccl9 cascade. Neutralizing antibody against Cxcl16 ameliorated pancreatic injury in the mouse AP model with decreased Ccl9 expression and less neutrophil accumulation. In conclusion, Cxcl16 expressed in pancreatic acini contributes to the development of acinar cell necrosis through the induction of Ccl9 and subsequent neutrophil infiltration. CXCL16 could be a new therapeutic target in AP.

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A case of nodal malignant lymphoma presenting with arterial bleeding related to its duodenal penetration.

Takakazu Miyake, Tomoya Iida, Yoshiharu Masaki, Kei Onodera, Toshiyuki Kubo, Kentaro Yamashita, Hiroo Yamano, Hiroshi Nakase

Clinical journal of gastroenterology   11 ( 3 ) 229 - 234  2018.06  [Refereed]  [Domestic journal]

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A 62-year-old man with a chief complaint of dysphagia visited our hospital. Enhanced computed tomography showed the tumor near the duodenal wall and lymphadenopathy in the left supraclavicular fossa and para-aortic lymph node. Upper gastrointestinal endoscopy showed an ulcer accompanied with a fistula in the anterior wall of duodenal bulb, suggesting that the tumor penetrated into duodenal wall. Biopsy from the lymph node in the left supraclavicular fossa indicated diffuse large B-cell lymphoma. Although chemotherapy was planned, massive arterial bleeding occurred from the part of duodenal penetration. Endoscopic hemostasis was unsuccessfully performed. Therefore, we performed transcathether arterial embolization for hemostasis. After the procedure, the patient received six cycles of chemotherapy, and he achieved complete response. He has been alive 5 years without recurrence. There were many cases of gastrointestinal bleeding from primary gastrointestinal lymphomas, while there were few cases with nodal involvement by malignant lymphoma resulting in bleeding from gastrointestinal tract. We herein report a case of duodenal bleeding by nodal involvement of diffuse large B-cell lymphoma with review of literature.

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Hepatic portal venous gas due to polystyrene sulfonate-induced enteritis.

Toshiyuki Kubo, Kentaro Yamashita, Yoshihiro Yokoyama, Daisuke Hirayama, Tomohiro Shirata, Kei Mitsuhashi, Kei Onodera, Eiichiro Yamamoto, Katsuhiko Nosho, Hiroo Yamano, Terufumi Kubo, Shintaro Sugita, Tadashi Hasegawa, Hiroshi Nakase

Clinical journal of gastroenterology   11 ( 3 ) 220 - 223  2018.06  [Refereed]  [Domestic journal]

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A 78-year-old man with acute right lower abdominal pain and nausea was referred to our hospital. Computed tomography (CT) demonstrated hepatic portal venous gas and a thickened wall of the terminal ileum, and colonoscopy demonstrated ulcers and erosions of the ileocecal region. Histological examination of biopsy samples revealed basophilic crystals consistent with the component of calcium polystyrene sulfonate (CPS). This patient started taking CPS 2 months prior for chronic hyperkalemia. The symptoms resolved soon after ceasing CPS, and subsequent imaging studies confirmed the disappearance of the portal venous gas and ileocolitis.

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Prognostic nutritional index and early mortality with percutaneous endoscopic gastrostomy.

Adachi Y, Akino K, Nojima M, Himori R, Kikuchi T, Mita H, Nakamura M, Tsukuda H, Yamano HO, Sasaki Y, Yoshida Y, Kato Y, Nakase H, Endo T

QJM : monthly journal of the Association of Physicians   111 ( 9 ) 635 - 641  2018.06  [Refereed]

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