Details of a Researcher - NAKASE Hiroshi

Papers - NAKASE Hiroshi

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Associations between serum insulin-like growth factor-related molecules and colorectal cancer risk by tumor location: a nested case-control study.

Yasushi Adachi, Masanori Nojima, Yingsong Lin, Yasushi Sasaki, Hiro-O Yamano, Hiroshi Nakase, Kenji Wakai, Mitsuru Mori, Akiko Tamakoshi

Digestion 1 - 19 2025.03 [International journal]

Introduction, The activity of the mitogen insulin-like growth factor (IGF) is controlled by IGF-binding protein (IGFBP). Colorectal cancers (CRCs) are heterogeneous, with left- and right-sided CRC showing different clinical and molecular characteristics. This case-control study, nested in the Japan Collaborative Cohort study, assessed associations between serum levels of IGF-related molecules and incidences of CRC by location. Methods, A baseline survey obtained serum samples from 39,242 participants. Subjects diagnosed with CRC during follow-up were regarded as cases. Conditional logistic regression modeling was used to calculate odds ratios (ORs) for cancer incidence associated with IGF-related molecules. Results, This analysis included 176 cases and 524 controls. No IGF-related molecules appeared associated with risks of overall or left-sided CRC. Both total IGFBP3 and free IGFBP3 (estimated as IGFBP3-(IGF1+IGF2)) were associated with incidence of right-sided CRC (P-for-trends=0.027 and 0.003, respectively), with the third tertile of total and free IGFBP3 showing the highest risk (OR=6.25 and 7.96, respectively). Free IGF, estimated as (IGF1+IGF2)/IGFBP3, was inversely associated with incidence of right-sided CRC (P-for-trends=0.014), with the third tertile showing the lowest risk (OR=0.18). Among subjects followed for over 3 years, association of IGF-related molecules with overall CRC was similar. Free IGFBP3 was associated with incidence of right-sided CRC (P-for-trends=0.004). Free IGF was inversely associated with incidence of right-sided CRC (P-for-trends=0.002). However, free IGFs were associated with risk of left-sided CRC (P-for-trends=0.041), with the third tertile showing the highest risk (OR=3.10). Conclusions, Serum IGF-related molecules are associated with risk of CRC. These associations might differ by tumor location.

DOI PubMed

Ulcerative Colitis Preceding Asymptomatic Wilson’s Disease: A Case Report and Literature Review

Jun Kunizaki, Yuko Yoto, Yoshinobu Nagaoka, Akira Ishii, Tomoe Kazama, Kohei Wagatsuma, Noriyuki Akutsu, Aki Ishikawa, Toju Tanaka, Shintaro Sugita, Takeshi Tsugawa, Hiroshi Nakase

Gastro Hep Advances ( Elsevier BV ) 4 ( 1 ) 100548 - 100548 2025

DOI

Involvement of Mediterranean fever gene mutations in colchicine-responsive enterocolitis: a retrospective cohort study

Hiroshi Nakase, Kohei Wagatsuma, Taku Kobayashi, Takayuki Matsumoto, Motohiro Esaki, Kenji Watanabe, Reiko Kunisaki, Teruyuki Takeda, Katsuhiro Arai, Takashi Ibuka, Dai Ishikawa, Yuichi Matsuno, Hirotake Sakuraba, Nobuhiro Ueno, Kaoru Yokoyama, Masayuki Saruta, Ryota Hokari, Junji Yokoyama, Shu Tamano, Masanori Nojima, Tadakazu Hisamatsu, Shusaku Yoshikawa, Sohachi Nanjo, Akira Andoh, Takeshi Kimura, Makoto Ooi, Ryosuke Kiyomori, Nobuo Aoyama, Fumihito Hirai, Atsushi Yamaushi, Masanao Nakamura, Fumikazu Koyama, Shuhei Hosomi, Kazuki Kakimoto, Satoshi Motoya, Ryosuke Sakemi, Hideo Suzuki, Tadashi Hosoya, Ken Takeuchi, Manabu Shiraki, Hideyuki Koide, Ichiro Takeuchi, Yosuke Furui, Kento Yoshida, Ayaka Minemura, Asami Matsumoto, Kentaro Oka

eBioMedicine ( Elsevier BV ) 110 105454 - 105454 2024.12

DOI

A rare case of delayed duodenal perforation due to an over-the-scope clip.

Yujiro Kawakami, Shinji Yoshii, Masahiro Taniguchi, Yoshiharu Masaki, Taro Sugawara, Yasutoshi Kimura, Hiroshi Nakase

Endoscopy 56 ( S 01 ) E331-E333 2024.12 [International journal]

DOI PubMed

自己免疫性膵炎診療の現状と課題自己免疫性膵炎診療における消化管精査の意義

川上裕次郎, 柾木喜晴, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 66 ( Suppl.2 ) 2158 - 2158 2024.10

新規デバイスデリバリーシステムEndoSheatherを用いた経乳頭的胆嚢生検

川上裕次郎, 柾木喜晴, 大沼法永, 中村友哉, 石上敬介, 室田文子, 仲瀬裕志

胆道 ( (一社)日本胆道学会 ) 38 ( 3 ) 476 - 476 2024.09

Predictors of occult metastases in potentially Resectable pancreatic ductal adenocarcinoma.

Takeshi Murakami, Yasutoshi Kimura, Masafumi Imamura, Minoru Nagayama, Toru Kato, Kazuharu Kukita, Makoto Yoshida, Yoshiharu Masaki, Hiroshi Nakase, Ichiro Takemasa

Surgery open science 20 222 - 229 2024.08 [International journal]

BACKGROUND: Patients with resectable (R) or borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) sometimes show unexpected liver, peritoneal, and para-aortic lymph node metastases intraoperatively. Despite radical pancreatectomy, a nonnegligible number of patients relapse within 6 months after surgery. The aim of this study was to identify the preoperative predictors of occult metastases (OM), defined as intraoperative distant metastases or within 6 months after pancreatectomy. MATERIALS AND METHODS: This study included patients with R and BR PDAC who underwent curative-intent pancreatectomy or staging laparoscopy between 2006 and 2021. Multivariate logistic regression and Cox hazard analyses were performed to identify the preoperative predictors of OM and to assess the impact of these factors on prognosis after pancreatectomy. RESULTS: Of the 279 patients, OM was observed intraoperatively in 47 and postoperatively in 34. In the OM group, there were no differences in prognosis between patients who had intraoperative metastases and recurrence within 6 months (median survival time [MST], 18.1 vs. 12.9 months), and between patients who underwent pancreatectomy and those who did not (MST, 13.9 vs. 18.1 months). Preoperative tumor size ≥22 mm (odds ratio [OR], 2.03; 95 % confidence interval [CI], 1.16-3.53; p = 0.013) and preoperative CA19-9 level ≥ 118.8 U/mL (OR, 2.64; 95 % CI, 1.22-5.73; p = 0.014) were significant predictors of OM. Additionally, positive OM predictors were strong independent prognostic factors for overall survival after pancreatectomy (hazard ratio, 2.47; 95 % CI, 1.54-3.98; p < 0.001). CONCLUSION: Multidisciplinary treatment strategies should be considered for patients with predictors of OM to avoid inappropriate surgical interventions.

DOI PubMed

若年発症自己免疫性肝炎に対する部分的脾動脈塞栓術後に肝機能改善を認めた1例

沼田泰尚, 阿久津典之, 我妻康平, 川上裕次郎, 石上敬介, 柾木喜晴, 室田文子, 齊藤正人, 仲瀬裕志

日本臨床免疫学会総会プログラム・抄録集 ( (一社)日本臨床免疫学会 ) 52回 113 - 113 2024.08

Unique endoscopic features of primary biliary diffuse large B‐cell lymphoma: A case report with literature review (with video)

Tomoya Nakamura, Yoshiharu Masaki, Naohiro Kameyama, Yujiro Kawakami, Keisuke Ishigami, Yumemi Takada, Shuji Satoh, Taro Sugawara, Shintaro Sugita, Hiroshi Nakase

DEN Open ( Wiley ) 5 ( 1 ) 2024.07

Abstract A 67‐year‐old man visited our hospital complaining of dark‐colored urine and upper abdominal pain. Magnetic resonance cholangiopancreatography showed stricture of the distal bile duct, and contrast‐enhanced computed tomography showed irregular thickening of the distal bile duct wall. However, no enlarged lymph nodes, pancreatic tumors, or other neoplastic lesions were apparent around the bile duct. Endoscopic ultrasonography and intraductal ultrasonography showed irregular thickening of the inner hypoechoic layer without the disappearance of the innermost thin hyperechoic layer. On the basis of these findings, we considered that the bile duct lesion was of non‐epithelial origin. Thus, we repeatedly performed bile duct biopsies from the same site under fluoroscopy to obtain a sample of the submucosal tissue. The pathological diagnosis was diffuse large B‐cell lymphoma, and the patient received systemic chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). After six courses of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, positron emission tomography‐computed tomography showed the disappearance of 18‐fluorodeoxyglucose uptake in the bile duct and endoscopic retrograde cholangiography showed improvement of the bile duct stricture. Endoscopic findings and repeated biopsies were useful in making the diagnosis of primary biliary diffuse large B‐cell lymphoma.

DOI

膵EUS-FNA診断の功罪切除不能膵臓癌のがんゲノムプロファイリング検査のための適正な検体採取方法の検討

室田文子, 大沼法永, 中村友哉, 平野雄大, 我妻康平, 川上裕次郎, 石上敬介, 柾木喜晴, 仲瀬裕志

膵臓 ( (一社)日本膵臓学会 ) 39 ( 3 ) A237 - A237 2024.07

Clinical performance of fecal calprotectin, lactoferrin, and hemoglobin for evaluating the disease activity of IBD and detecting colorectal tumors.

Tsukasa Yamakawa, Takakazu Miyake, Yoshihiro Yokoyama, Tomoe Kazama, Yuki Hayashi, Daisuke Hirayama, Shinji Yoshii, Hiro-O Yamano, Satoshi Takahashi, Hiroshi Nakase

JGH open : an open access journal of gastroenterology and hepatology 8 ( 6 ) e13077 2024.06 [International journal]

BACKGROUND AND AIM: Recently, noninvasive fecal markers have been used as indicators of intestinal inflammation in patients with inflammatory bowel disease (IBD). We conducted a clinical validation study to measure fecal calprotectin (Cp), lactoferrin (Lf), and hemoglobin (Hb) levels using an all-in-one kit in patients with IBD and colorectal tumors and aimed to clarify the utility of these fecal markers. METHODS: In this study, 104 patients were analyzed, including 25 patients with ulcerative colitis (UC), 20 with Crohn's disease (CD), 48 with colorectal tumors, and 13 healthy controls (HC). Of the 48 patients with colorectal tumors, 14 had invasive cancer. We validated the utility of fecal Cp, Lf, and Hb levels by simultaneously measuring fecal markers in patients with IBD and colorectal tumors. RESULTS: Fecal Cp and Lf had almost equivalent abilities in detecting clinical remission in patients with UC; however, fecal Cp was slightly superior to Lf. Regarding colorectal tumors, fecal Cp and Lf levels tended to be higher in patients with adenomas and colorectal cancer than in HCs. Although fecal Hb alone had the best sensitivity and specificity for detecting colorectal cancer, it had relatively low sensitivity for detecting advanced neoplasms and colorectal cancer. CONCLUSION: Fecal Cp and Lf can be used as almost equivalent biomarkers to assess the clinical activity in patients with UC. Fecal Hb is the most useful marker for screening colorectal cancer; however, adding fecal Cp and Lf may compensate for the low sensitivity of detecting for advanced colorectal tumors based on Hb alone.

DOI PubMed

研究者の最新動向難治性腸炎に対する間葉系幹細胞を用いた細胞療法

永石歓和, 仲瀬裕志

Precision Medicine ( (株)北隆館 ) 7 ( 7 ) 593 - 597 2024.06

間葉系幹細胞(Mesenchymal Stem Cells:MSC)は,多彩な生理活性物質を産生・分泌して免疫制御能や組織修復・再生能を発揮する体性幹細胞である。炎症組織では,MSCが局所の炎症性サイトカインによる刺激を受けて活性化する。MSCは,各種方法で3次元培養することで免疫制御能や血管新生能,抗アポトーシス効果などの細胞機能が向上する。MSCは,炎症性腸疾患領域における新しい治療選択肢として実用化とさらなる研究開発が進んでいる。(著者抄録)

Peroral cholangioscopy-guided biopsy with novel biopsy forceps in comprehensive cancer genomic profiling for cystic duct carcinoma

Yujiro Kawakami, Yoshiharu Masaki, Keisuke Ishigami, Takehiro Hirano, Ayako Murota, Shintaro Sugita, Hiroshi Nakase

Endoscopy ( Georg Thieme Verlag KG ) 56 ( S 01 ) E414 - E415 2024.05

DOI

Cytokine Profile in Predicting the Effectiveness of Advanced Therapy for Ulcerative Colitis: A Narrative Review.

Hiroki Kurumi, Yoshihiro Yokoyama, Takehiro Hirano, Kotaro Akita, Yuki Hayashi, Tomoe Kazama, Hajime Isomoto, Hiroshi Nakase

Biomedicines 12 ( 5 ) 2024.04 [International journal]

Cytokine-targeted therapies have shown efficacy in treating patients with ulcerative colitis (UC), but responses to these advanced therapies can vary. This variability may be due to differences in cytokine profiles among patients with UC. While the etiology of UC is not fully understood, abnormalities of the cytokine profiles are deeply involved in its pathophysiology. Therefore, an approach focused on the cytokine profile of individual patients with UC is ideal. Recent studies have demonstrated that molecular analysis of cytokine profiles in UC can predict response to each advanced therapy. This narrative review summarizes the molecules involved in the efficacy of various advanced therapies for UC. Understanding these associations may be helpful in selecting optimal therapeutic agents.

DOI PubMed

Real-world NUDT15 genotyping and thiopurine treatment optimization in inflammatory bowel disease: a multicenter study.

Motoki Makuuchi, Yoichi Kakuta, Junji Umeno, Toshimitsu Fujii, Tetsuya Takagawa, Takashi Ibuka, Miki Miura, Yu Sasaki, Sakuma Takahashi, Hiroshi Nakase, Hiroki Kiyohara, Keiichi Tominaga, Yosuke Shimodaira, Sakiko Hiraoka, Nobuhiro Ueno, Shunichi Yanai, Takeo Yoshihara, Kazuki Kakimoto, Katsuyoshi Matsuoka, Ryohei Hayashi, Sohachi Nanjo, Itaru Iwama, Yoh Ishiguro, Hirofumi Chiba, Katsuya Endo, Takashi Kagaya, Tomohiro Fukuda, Yasuhisa Sakata, Takahiro Kudo, Tomohisa Takagi, Kenichi Takahashi, Makoto Naganuma, Masaru Shinozaki, Noriyuki Ogata, Hiroki Tanaka, Kazuyuki Narimatsu, Haruka Miyazaki, Takashi Ishige, Motoyuki Onodera, Yu Hashimoto, Hiroshi Nagai, Yusuke Shimoyama, Takeo Naito, Rintaro Moroi, Hisashi Shiga, Yoshitaka Kinouchi, Akira Andoh, Tadakazu Hisamatsu, Atsushi Masamune

Journal of gastroenterology 2024.04 [Domestic journal]

BACKGROUND: This study evaluated the effectiveness of NUDT15 codon 139 genotyping in optimizing thiopurine treatment for inflammatory bowel disease (IBD) in Japan, using real-world data, and aimed to establish genotype-based treatment strategies. METHODS: A retrospective analysis of 4628 IBD patients who underwent NUDT15 codon 139 genotyping was conducted. This study assessed the purpose of the genotyping test and subsequent prescriptions following the obtained results. Outcomes were compared between the Genotyping group (thiopurine with genotyping test) and Non-genotyping group (thiopurine without genotyping test). Risk factors for adverse events (AEs) were analyzed by genotype and prior genotyping status. RESULTS: Genotyping test for medical purposes showed no significant difference in thiopurine induction rates between Arg/Arg and Arg/Cys genotypes, but nine Arg/Cys patients opted out of thiopurine treatment. In the Genotyping group, Arg/Arg patients received higher initial doses than the Non-genotyping group, while Arg/Cys patients received lower ones (median 25 mg/day). Fewer AEs occurred in the Genotyping group because of their lower incidence in Arg/Cys cases. Starting with < 25 mg/day of AZA reduced AEs in Arg/Cys patients, while Arg/Arg patients had better retention rates when maintaining ≥ 75 mg AZA. Nausea and liver injury correlated with thiopurine formulation but not dosage. pH-dependent mesalamine reduced leukopenia risk in mesalamine users. CONCLUSIONS: NUDT15 codon 139 genotyping effectively reduces thiopurine-induced AEs and improves treatment retention rates in IBD patients after genotype-based dose adjustments. This study provides data-driven treatment strategies based on genotype and identifies risk factors for specific AEs, contributing to a refined thiopurine treatment approach.

DOI PubMed

ESD後穿孔における縫縮困難例への対策

山川司, 吉井新二, 秋田浩太朗, 三宅高和, 川上裕次郎, 柾木喜晴, 山野泰穂, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 66 ( Suppl.1 ) 1019 - 1019 2024.04

膵腫瘤性病変に対するTrident針とFranseen針を用いたEUS-FNBの比較検討

中村友哉, 川上裕次郎, 大沼法永, 平野雄大, 我妻康平, 沼田泰尚, 石上敬介, 柾木喜晴, 室田文子, 阿久津典之, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 66 ( Suppl.1 ) 995 - 995 2024.04

A rare case of resection of a mucinous cystic neoplasm originating from the extrahepatic bile duct with cholangioscopic imaging.

Yoshiharu Masaki, Yujiro Kawakami, Keisuke Ishigami, Ayako Murota, Masahiro Shitani, Kazuharu Kukita, Yasutoshi Kimura, Keiko Segawa, Tadashi Hasegawa, Hiroshi Nakase

DEN open 4 ( 1 ) e349 2024.04 [International journal]

A 29-year-old woman was admitted to our hospital for examination of obstructive jaundice and an extrahepatic bile duct lesion. Contrast-enhanced computed tomography revealed a 20 mm cystic lesion with a thin external capsule in the common hepatic duct. Cholangioscopy revealed translucent oval masses with capillary vessels attached to the bile duct walls. The surface was mostly smooth yet partially irregular with redness, suggesting that the masses were epithelial neoplasms. Histological findings of cholangioscopy-guided targeted biopsies of the mass showed subepithelial spindle cell proliferation with no atypical epithelium. The patient underwent an extrahepatic bile duct resection to confirm the pathological diagnosis. Immunohistochemistry of surgical specimens revealed that the spindle cells were positive for estrogen and progesterone receptors. Finally, the cystic lesion with ovarian-like stroma was diagnosed as a mucinous cystic neoplasm with low-grade intraepithelial neoplasia. This is the first report of cholangioscopic imaging of a biliary mucinous cyctic neoplasm. Cholangioscopic imaging can be helpful in the differential diagnosis of biliary neoplasms and in the determination of treatment strategies.

DOI PubMed

Effectiveness and Persistency of Ustekinumab Treatment for Ulcerative Colitis: A Phoenix retrospective Cohort Study.

Katsuyoshi Ando, Mikihiro Fujiya, Nobuhiro Ueno, Takahiro Ito, Atsuo Maemoto, Masanao Nasuno, Hiroki Tanaka, Kensuke Sakurai, Takehiko Katsurada, Fumika Orii, Toshifumi Ashida, Satoshi Motoya, Tomoe Kazama, Yoshihiro Yokoyama, Daisuke Hirayama, Hiroshi Nakase

Crohn's & colitis 360 6 ( 2 ) otae024 2024.04 [International journal]

BACKGROUND: Real-world data regarding ustekinumab (UST) for ulcerative colitis (UC) particularly in biologics-naïve patients is currently limited. This study aimed to elucidate the real-world effectiveness and safety of UST for UC. METHODS: Overall, 150 patients with UC treated with UST from March 2020 to January 2023 were enrolled across 7 referral hospitals. To assess the clinical efficacy and persistence of UST, retrospective analyses were conducted from weeks 8 to 56. Predictive factors concerning the response and persistence of UST were examined through univariate and multivariate analyses. RESULTS: Of the 150 patients, 125 received UST for remission induction, including 36% biologics-naïve. The response and remission rates were 72.8% and 56.0% at week 8 and 73.2% and 63.4% at week 56, respectively. Biologics-naïve patients represented higher response and remission rates at week 8 (84.4% and 73.3%) than those with biologics exposure (66.2% and 46.2%). Patients with prior antitumor necrosis factor (anti-TNF) and vedolizumab (VDZ) exposure had relatively lower response and remission rates (34.5% and 24.1%, respectively). The 1-year cumulative persistence rate was 84.0%. Multivariate analysis revealed that the chronic continuous type and prior anti-TNF and VDZ exposure were negative predictive factors for week 8 responsiveness. Clinical response at week 8 was a predictor of 1-year persistence. Adverse event incidence remained notably low at 6.4%. CONCLUSIONS: This study highlights the safety and effectiveness of UST as an induction and maintenance therapy for UC. Chronic continuous type and previous anti-TNF and VDZ exposure negatively contributed to short-term effectiveness, whereas short-term effectiveness provided good persistency.

DOI PubMed

十二指腸乳頭部腫瘍に対するhybrid EPの有用性

川上裕次郎, 柾木喜晴, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 66 ( Suppl.1 ) 982 - 982 2024.04

胆道閉塞患者におけるEUS-HGSのための至適ステント選択(Optimal stent selection for endoscopic ultrasound-guided hepaticogastrostomy in patients with biliary obstruction)

柾木喜晴, 大沼法永, 中村友哉, 川上裕次郎, 室田文子, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 66 ( Suppl.1 ) 958 - 958 2024.04

自己免疫性膵炎診療における消化管精査の意義

川上裕次郎, 柾木喜晴, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 66 ( Suppl.1 ) 1017 - 1017 2024.04

Genomic analysis of an aggressive hepatic leiomyosarcoma case following treatment for hepatocellular carcinoma.

Yuto Numata, Noriyuki Akutsu, Masashi Idogawa, Kohei Wagatsuma, Yasunao Numata, Keisuike Ishigami, Tomoya Nakamura, Takehiro Hirano, Yujiro Kawakami, Yoshiharu Masaki, Ayako Murota, Shigeru Sasaki, Hiroshi Nakase

Hepatology research : the official journal of the Japan Society of Hepatology 2024.03 [International journal]

A 70-year-old man undergoing treatment for immunoglobulin G4-related disease developed a liver mass on computed tomography during routine imaging examination. The tumor was located in the hepatic S1/4 region, was 38 mm in size, and showed arterial enhancement on dynamic contrast-enhanced computed tomography. We performed a liver biopsy and diagnosed moderately differentiated hepatocellular carcinoma. The patient underwent proton beam therapy. The tumor remained unchanged but enlarged after 4 years. The patient was diagnosed with hepatocellular carcinoma recurrence and received hepatic arterial chemoembolization. However, 1 year later, the patient developed jaundice, and the liver tumor grew in size. Unfortunately, the patient passed away. Autopsy revealed that the tumor consisted of spindle-shaped cells exhibiting nuclear atypia and a fission pattern and tested positive for α-smooth muscle actin and vimentin. No hepatocellular carcinoma components were observed, and the patient was pathologically diagnosed with hepatic leiomyosarcoma. Next-generation sequencing revealed somatic mutations in CACNA2D4, CTNNB1, DOCK5, IPO8, MTMR1, PABPC5, SEMA6D, and ZFP36L1. Based on the genetic mutation, sarcomatoid hepatocarcinoma was the most likely pathogenesis in this case. This mutation is indicative of the transition from sarcomatoid hepatocarcinoma to hepatic leiomyosarcoma.

DOI PubMed

Downregulation of SMOC1 is associated with progression of colorectal traditional serrated adenomas.

Hironori Aoki, Akira Takasawa, Eiichiro Yamamoto, Takeshi Niinuma, Hiro-O Yamano, Taku Harada, Toshiyuki Kubo, Akira Yorozu, Hiroshi Kitajima, Kazuya Ishiguro, Masahiro Kai, Akio Katanuma, Toshiya Shinohara, Hiroshi Nakase, Tamotsu Sugai, Makoto Osanai, Hiromu Suzuki

BMC gastroenterology 24 ( 1 ) 91 - 91 2024.03 [International journal]

BACKGROUND: Aberrant DNA methylation is prevalent in colorectal serrated lesions. We previously reported that the CpG island of SMOC1 is frequently methylated in traditional serrated adenomas (TSAs) and colorectal cancers (CRCs) but is rarely methylated in sessile serrated lesions (SSLs). In the present study, we aimed to further characterize the expression of SMOC1 in early colorectal lesions. METHODS: SMOC1 expression was analyzed immunohistochemically in a series of colorectal tumors (n = 199) and adjacent normal colonic tissues (n = 112). RESULTS: SMOC1 was abundantly expressed in normal colon and SSLs while it was significantly downregulated in TSAs, advanced adenomas and cancers. Mean immunohistochemistry scores were as follows: normal colon, 24.2; hyperplastic polyp (HP), 18.9; SSL, 23.8; SSL with dysplasia (SSLD)/SSL with early invasive cancer (EIC), 15.8; TSA, 5.4; TSA with high grade dysplasia (HGD)/EIC, 4.7; non-advanced adenoma, 21.4; advanced adenoma, 11.9; EIC, 10.9. Higher levels SMOC1 expression correlated positively with proximal colon locations and flat tumoral morphology, reflecting its abundant expression in SSLs. Among TSAs that contained both flat and protruding components, levels of SMOC1 expression were significantly lower in the protruding components. CONCLUSION: Our results suggest that reduced expression of SMOC1 is associated with progression of TSAs and conventional adenomas and that SMOC1 expression may be a biomarker for diagnosis of serrated lesions and risk prediction in colorectal tumors.

DOI PubMed

膵癌との鑑別を要したIgG4関連動脈周囲炎の1例

大沼法永, 柾木喜晴, 中村友哉, 平野雄大, 川上裕次郎, 石上敬介, 室田文子, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 134回・128回 59 - 59 2024.03

中村友哉, 川上裕次郎, 柾木喜晴, 室田文子, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 134回・128回 36 - 36 2024.03

肝細胞癌に対しデュルバルマブ+トレメリムマブ併用療法中irAE膵炎を発症しEUS-FNAで診断しえた1例

山本智香, 室田文子, 平野雄大, 我妻康平, 川上裕次郎, 沼田泰尚, 石上敬介, 柾木喜晴, 阿久津典之, 長谷川匡, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 134回・128回 45 - 45 2024.03

IgGサブクラス欠損症を背景とした血清IgG4陰性自己免疫性膵炎の1例

中村友哉, 川上裕次郎, 平野雄大, 我妻康平, 沼田泰尚, 石上敬介, 柾木喜晴, 室田文子, 阿久津典之, 佐々木茂, 杉田真太朗, 仲瀬裕志

凍結胚移植後に繰り返し生じた高度な急性薬剤性肝障害の1例

常盤孝介, 我妻康平, 阿久津典之, 山本智香, 大沼法永, 中村友哉, 平野雄大, 川上裕次郎, 沼田泰尚, 石上敬介, 柾木喜晴, 室田文子, 佐々木茂, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 134回・128回 68 - 68 2024.03

IgG4-hepatopathyの臨床病理学的特徴

川上裕次郎, 柾木喜晴, 中村友哉, 平野雄大, 我妻康平, 沼田泰尚, 石上敬介, 室田文子, 阿久津典之, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 121 ( 臨増総会 ) A351 - A351 2024.03

潰瘍性大腸炎におけるトファシチニブの長期治療成績とその位置付け

伊藤貴博, 前本篤男, 横山佳浩, 桂田武彦, 安藤勝祥, 藤谷幹浩, 蘆田知史, 那須野正尚, 田中浩紀, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 121 ( 臨増総会 ) A318 - A318 2024.03

The frequency and pathogenicity of BRCA1 and BRCA2 variants in the general Japanese population.

Masashi Idogawa, Tasuku Mariya, Yumi Tanaka, Tsuyoshi Saito, Hiroshi Nakase, Takashi Tokino, Akihiro Sakurai

Journal of human genetics 2024.02 [International journal]

Hereditary breast and ovarian cancer syndrome (HBOC) resulting from pathogenic variants of BRCA1 or BRCA2 is the most common and well-documented hereditary tumor. Although founder variants have been identified in population-based surveys in various countries, the types of variants are not uniform across races and regions. Recently, the Tohoku Medical Megabank Organization (ToMMo) released whole-genome sequence data including approximately 54,000 individuals from the general population of the Tohoku area in Japan. We analyzed these data and comprehensively identified the prevalence of BRCA1/2 pathogenic and truncating variants. We believe that an accurate understanding of the unique distribution and characteristics of pathogenic BRCA1/2 variants in Japan through this analysis will enable better surveillance and intervention for HBOC patients, not only in Japan but also worldwide.

DOI PubMed

Long Noncoding RNA RP11-278A23.1, a Potential Modulator of p53 Tumor Suppression, Contributes to Colorectal Cancer Progression.

Masayo Kamikokura, Shoichiro Tange, Hiroshi Nakase, Takashi Tokino, Masashi Idogawa

Cancers 16 ( 5 ) 2024.02 [International journal]

Recently, many studies revealed that long noncoding RNAs (lncRNAs) play important roles in cancers. To identify lncRNAs contributing to colorectal cancers, we screened lncRNAs through expression and survival analyses in datasets from The Cancer Genome Atlas (TCGA). The screen revealed that RP11-278A23.1 expression is significantly increased in colorectal cancer tissues compared with normal tissues and that high RP11-278A23.1 expression correlates with poor prognosis. The knockdown of RP11-278A23.1 inhibited the growth of and promoted apoptosis in colorectal cancer cells. Next, to comprehensively examine differentially expressed genes after RP11-278A23.1 knockdown, RNA sequencing was performed in HCT116 cells. The expression of p21, a p53 target gene, was significantly upregulated, and the expression of several p53 target proapoptotic genes was also altered. RP11-278A23.1 knockdown increased p53 expression at the translational level but not at the transcriptional level. Interestingly, RP11-278A23.1 knockdown also altered the expression of these proapoptotic genes in DLD1 cells with mutated p53 and in p53-knockout HCT116 cells. These results suggest that RP11-278A23.1 modifies the expression of these apoptosis-related genes in p53-dependent and p53-independent manners. In summary, lncRNA RP11-278A23.1 contributes to colorectal cancer progression by promoting cell growth and inhibiting apoptosis, suggesting that this lncRNA may be a useful therapeutic target.

DOI PubMed

IgG4関連疾患における消化管生検の検討

川上裕次郎, 平野雄大, 石上敬介, 我妻康平, 柾木喜晴, 室田文子, 仲瀬裕志

日本内科学会雑誌 ( (一社)日本内科学会 ) 113 ( 臨増 ) 142 - 142 2024.02

消化器癌における化学療法と癌関連心不全についての検討

室田文子, 川上裕次郎, 柾木喜晴, 石上敬介, 阿久津典之, 吉井新二, 山野泰穂, 佐々木茂, 仲瀬裕志

日本内科学会雑誌 ( (一社)日本内科学会 ) 113 ( 臨増 ) 143 - 143 2024.02

内視鏡的切除により診断できた皮膚様食道扁平上皮癌

足立靖, 菊地剛史, 後藤啓, 吉田幸成, 石井良文, 高橋宏明, 佐々木泰史, 仲瀬裕志, 遠藤高夫

日本消化管学会雑誌 ( (一社)日本消化管学会 ) 8 ( Suppl. ) 360 - 360 2024.01

Maintenance steroid therapy is associated with decreased risk of malignancy and better prognosis of patients with autoimmune pancreatitis: A multicenter cohort study in Japan

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, Shinji Nakayama, Akira Nakamura, Yoshiharu Masaki, Mako Ushio, Tomohiro Watanabe, Masahiro Tsujimae, Shiro Tanoue, Toru Maruo, Masahiro Shiokawa, Satoki Yamane, Atsuto Kayashima

Pancreatology ( Elsevier BV ) 2024.01

DOI

von Willebrand factor Ristocetin co-factor activity to von Willebrand factor antigen level ratio for diagnosis of acquired von Willebrand syndrome caused by aortic stenosis

Noriyuki Okubo, Shingo Sugawara, Tohru Fujiwara, Ko Sakatsume, Tsuyoshi Doman, Mihoko Yamashita, Kota Goto, Masaki Tateishi, Misako Suzuki, Ryutaro Shirakawa, Yuka Eura, Koichi Kokame, Masaki Hayakawa, Masanori Matsumoto, Yasunori Kawate, Mizuki Miura, Hiroshi Takiguchi, Yoshimitsu Soga, Shinichi Shirai, Kenji Ando, Yoshio Arai, Takaharu Nakayoshi, Yoshihiro Fukumoto, Hiroyuki Takahama, Satoshi Yasuda, Toshihiro Tamura, Shin Watanabe, Takeshi Kimura, Nobuhiro Yaoita, Hiroaki Shimokawa, Yoshikatsu Saiki, Koichi Kaikita, Kenichi Tsujita, Shinji Yoshii, Hiroshi Nakase, Shin-ichi Fujimaki, Hisanori Horiuchi

Research and Practice in Thrombosis and Haemostasis ( Elsevier BV ) 8 ( 1 ) 102284 - 102284 2024.01

DOI

Gut microbiota and metabolites in patients with COVID-19 are altered by the type of SARS-CoV-2 variant.

Yoshihiro Yokoyama, Tomoko Ichiki, Tsukasa Yamakawa, Yoshihisa Tsuji, Koji Kuronuma, Satoshi Takahashi, Eichi Narimatsu, Akio Katanuma, Hiroshi Nakase

Frontiers in microbiology 15 1358530 - 1358530 2024 [International journal]

INTRODUCTION: Patients with COVID-19 have dysbiosis of the intestinal microbiota with altered metabolites in the stool. However, it remains unclear whether the differences among SARS-CoV-2 variants lead to differences in intestinal microbiota and metabolites. Thus, we compared the microbiome and metabolome changes for each SARS-CoV-2 variant in patients with COVID-19. MATERIALS AND METHODS: We conducted a multicenter observational study of patients with COVID-19 and performed fecal microbiome, metabolome, and calprotectin analyses and compared the results among the different SARS-CoV-2 variants. RESULTS: Twenty-one patients with COVID-19 were enrolled and stratified according to the SARS-CoV-2 strain: six with the Alpha, 10 with the Delta, and five with the Omicron variant. Fecal microbiome analysis showed that α-diversity was reduced in the order of the Omicron, Delta, and Alpha variants (p = 0.07). Linear discriminant analysis revealed differences in the abundance of short-chain fatty acid-producing gut microbiota for each SARS-CoV-2 variant. Fecal metabolome analysis showed that the Omicron and Delta variants had markedly reduced propionic and lactic acid levels compared to the Alpha strain (p < 0.05). CONCLUSION: The intestinal microbiota of patients with COVID-19 varies depending on the SARS-CoV-2 variant. Dysbiosis of the intestinal microbiota due to differences in SARS-CoV-2 variants causes a decrease in intestinal short-chain fatty acids.

DOI PubMed

Transcolonic endoscopic ultrasound-guided fine-needle biopsy to diagnose a pancreatic tail adenocarcinoma in a patient with surgically altered anatomy.

Yujiro Kawakami, Yoshiharu Masaki, Masahiro Taniguchi, Keisuke Ishigami, Ayako Murota, Masayo Motoya, Hiroshi Nakase

Endoscopy 55 ( S 01 ) E334-E335 2023.12 [International journal]

DOI PubMed

Single Nucleotide Polymorphisms of the MEFV Gene E148Q Are Highly Associated With Disease Phenotype in Crohn's Disease.

Satoshi Yamada, Yusuke Honzawa, Shuji Yamamoto, Minoru Matsuura, Hiroki Kitamoto, Makoto Okabe, Nobuyuki Kakiuchi, Takahiko Toyonaga, Taku Kobayashi, Toshifumi Hibi, Hiroshi Seno, Hiroshi Nakase

Inflammatory bowel diseases 2023.11 [International journal]

BACKGROUND: Single nucleotide polymorphisms (SNPs) of the MEFV gene may modify inflammatory bowel disease (IBD) activity. The prevalence of MEFV gene SNPs in IBD patients and their involvement in IBD pathophysiology remains unclear. METHODS: We analyzed 12 MEFV gene SNPs in peripheral leukocytes of Japanese IBD patients (Crohn's disease [CD]: 69 patients, ulcerative colitis: 32 patients) by polymerase chain reaction using next-generation DNA sequencing and evaluated their prevalence and association with the disease characteristics. Inflammasome activity and mature interleukin (IL)-1β and IL-18 production were evaluated in peripheral blood mononuclear cells obtained from CD patients stimulated with lipopolysaccharides and adenosine triphosphate, and compared between those with and without the E148Q SNP. COL1A1 and HSP47 gene expression was analyzed in CCD-18Co cells costimulated with IL-1β and other inflammatory cytokines. RESULTS: The prevalence of MEFV gene SNPs in IBD patients was similar to that in the human gene database. E148Q was the most common SNP. Compared with CD patients without E148Q, those with E148Q had a significantly greater frequency of the stricture phenotype, and their peripheral blood mononuclear cells exhibited significantly higher IL-1β and IL-18 levels and higher caspase-1 activity. IL-1β and IL-17A synergistically increased COL1A1 and HSP47 gene expression. CONCLUSIONS: MEFV gene SNPs, including E148Q, modify the behavior of CD. IL-1β and IL-18 are produced through enhanced caspase-1 activity in monocytes of CD patients with E148Q. IL-1β promotes gene expression of fibrosis-related genes by cooperating with IL-17A in myofibroblasts. Therefore, E148Q might be a disease-modifying gene associated with the fibrostenosis phenotype in CD patients.

DOI PubMed

A case of IgG4-related cholecystitis diagnosed by transpapillary gallbladder biopsy using a novel device delivery system

Yujiro Kawakami, Naohiro Kameyama, Yosuke Hirobe, Yoshiharu Masaki, Ayako Murota, Shintaro Sugita, Hiroshi Nakase

Endoscopy ( Georg Thieme Verlag KG ) 55 ( S 01 ) E1108 - E1110 2023.10

DOI

高齢者切除可能膵癌に対する術前化学療法の有用性の検証

柾木喜晴, 川上裕次郎, 我妻康平, 石上敬介, 室田文子, 吉田真誠, 木村康利, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 120 ( 臨増大会 ) A849 - A849 2023.10

切除不能肝細胞癌に対する分子標的治療症例の複数レジメン治療の有用性

阿久津典之, 沼田泰尚, 平野雄大, 我妻康平, 川上裕次郎, 柾木喜晴, 石上敬介, 室田文子, 佐々木茂, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 120 ( 臨増大会 ) A814 - A814 2023.10

後腹膜線維症・動脈周囲炎に対するEUS-FNA

川上裕次郎, 柾木喜晴, 室田文子, 阿久津典之, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 65 ( Suppl.2 ) 2042 - 2042 2023.10

難治性消化器免疫疾患 IgG4関連疾患における消化管生検の検討

平野雄大, 川上裕次郎, 石上敬介, 柾木喜晴, 室田文子, 阿久津典之, 佐々木茂, 仲瀬裕志

日本臨床免疫学会総会プログラム・抄録集 ( (一社)日本臨床免疫学会 ) 51回 69 - 69 2023.10

Systemic mastocytosis observed by image-enhanced endoscopy

Ryota Seto, Shinji Yoshii, Tomoe Kazama, Tsukasa Yamakawa, Shintaro Sugita, Hiro-o Yamano, Hiroshi Nakase

American Journal of Gastroenterology ( Ovid Technologies (Wolters Kluwer Health) ) 2023.09

DOI

血清可溶性Fas値と肝臓癌罹患リスク(Serum soluble Fas levels and incidence of liver cancer)

足立靖, 野島正寛, 森満, 久保俊之, 阿久津典之, 佐々木泰史, 仲瀬裕志, 遠藤高夫, 林櫻松, 若井建志, 玉腰暁子

日本癌学会総会記事 ( (一社)日本癌学会 ) 82回 125 - 125 2023.09

特発性血小板減少性紫斑病(ITP)を合併しTPO受容体作動薬(TPO-RA)を使用することでGnP療法が施行可能となった膵癌の1例

常盤孝介, 室田文子, 平野雄大, 我妻康平, 川上裕次郎, 沼田泰尚, 石上敬介, 柾木喜晴, 阿久津典之, 村瀬和幸, 佐々木茂, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 133回・127回 56 - 56 2023.09

Trajectory analyses to identify persistently low responders to COVID-19 vaccination in patients with inflammatory bowel disease: a prospective multicentre controlled study, J-COMBAT.

Kenji Watanabe, Masanori Nojima, Hiroshi Nakase, Toshiyuki Sato, Minoru Matsuura, Nobuo Aoyama, Taku Kobayashi, Hirotake Sakuraba, Masakazu Nishishita, Kaoru Yokoyama, Motohiro Esaki, Fumihito Hirai, Masakazu Nagahori, Sohachi Nanjo, Teppei Omori, Satoshi Tanida, Yoshihiro Yokoyama, Kei Moriya, Atsuo Maemoto, Osamu Handa, Naoki Ohmiya, Kiichiro Tsuchiya, Shinichiro Shinzaki, Shingo Kato, Toshio Uraoka, Hiroki Tanaka, Noritaka Takatsu, Atsushi Nishida, Junji Umeno, Masanao Nakamura, Yoshiyuki Mishima, Mikihiro Fujiya, Kenji Tsuchida, Sakiko Hiraoka, Makoto Okabe, Takahiko Toyonaga, Katsuyoshi Matsuoka, Akira Andoh, Yoshio Hirota, Tadakazu Hisamatsu

Journal of gastroenterology 2023.08 [Domestic journal]

BACKGROUND: The degree of immune response to COVID-19 vaccination in inflammatory bowel disease (IBD) patients based on actual changes in anti-SARS-CoV-2 antibody titres over time is unknown. METHODS: Data were prospectively acquired at four predetermined time points before and after two vaccine doses in a multicentre observational controlled study. The primary outcome was humoral immune response and vaccination safety in IBD patients. We performed trajectory analysis to identify the degree of immune response and associated factors in IBD patients compared with controls. RESULTS: Overall, 645 IBD patients and 199 control participants were analysed. At 3 months after the second vaccination, the seronegative proportions were 20.3% (combination of anti-tumour necrosis factor [TNF]α and thiopurine) and 70.0% (triple combination including steroids), despite that 80.0% receiving the triple combination therapy were seropositive at 4 weeks after the second vaccination. Trajectory analyses indicated three degrees of change in immune response over time in IBD patients: high (57.7%), medium (35.6%), and persistently low (6.7%). In the control group, there was only one degree, which corresponded with IBD high responders. Older age, combined anti-TNFα and thiopurine (odds ratio [OR], 37.68; 95% confidence interval [CI], 5.64-251.54), steroids (OR, 21.47; 95%CI, 5.47-84.26), and tofacitinib (OR, 10.66; 95%CI, 1.49-76.31) were factors associated with persistently low response. Allergy history (OR, 0.17; 95%CI, 0.04-0.68) was a negatively associated factor. Adverse reactions after the second vaccination were significantly fewer in IBD than controls (31.0% vs 59.8%; p < 0.001). CONCLUSIONS: Most IBD patients showed a sufficient immune response to COVID-19 vaccination regardless of clinical factors. Assessment of changes over time is essential to optimize COVID-19 vaccination, especially in persistently low responders.

DOI PubMed

新規ナトリウム利尿ペプチド薬の開発と臨床応用

市来智子, 沼田泰尚, 佐々木茂, 辻喜久, 仲瀬裕志

細胞 ( (株)ニュー・サイエンス社 ) 55 ( 9 ) 714 - 717 2023.08

ナトリウム利尿ペプチド(Natriuretic Peptide,NP)は心臓・血管内皮など体内で生成される内分泌ホルモンである。ヒトにはANP,BNP,CNPの3種類のNPが存在し,ナトリウム利尿,血管拡張,レニン・アンジオテンシン・アルドステロン系の抑制,心筋肥大や線維化抑制など多彩な生理作用を有し,治療薬としての臨床応用を目指した創薬ターゲットとなっている。NPの創薬では,元来の構造を変化させることで分解を抑制し長期投与に耐えられるペプチドや,複数のレセプターを刺激し多彩な薬理作用を期待できるようなペプチドが合成されている。内因性NPの半減期を延長する経口薬も開発されており,既に心不全や小人症を対象とする薬剤が薬事承認された。NPを用いた新しい治療ターゲットとしてメタボリックシンドロームの関連疾患群も注目されている。本稿ではNPの生理作用,創薬開発及び今後の展望に関して論じる。(著者抄録)

TM4SF1-AS1 inhibits apoptosis by promoting stress granule formation in cancer cells

Hiroshi Kitajima, Reo Maruyama, Takeshi Niinuma, Eiichiro Yamamoto, Akira Takasawa, Kumi Takasawa, Kazuya Ishiguro, Akihiro Tsuyada, Ryo Suzuki, Gota Sudo, Toshiyuki Kubo, Kei Mitsuhashi, Masashi Idogawa, Shoichiro Tange, Mutsumi Toyota, Ayano Yoshido, Kohei Kumegawa, Masahiro Kai, Kazuyoshi Yanagihara, Takashi Tokino, Makoto Osanai, Hiroshi Nakase, Hiromu Suzuki

Cell Death & Disease ( Springer Science and Business Media LLC ) 14 ( 7 ) 2023.07

Abstract Long noncoding RNAs (lncRNAs) play pivotal roles in tumor development. To identify dysregulated lncRNAs in gastric cancer (GC), we analyzed genome-wide trimethylation of histone H3 lysine 4 (H3K4me3) to screen for transcriptionally active lncRNA genes in the non-tumorous gastric mucosa of patients with GC and healthy individuals. We found that H3K4me3 at TM4SF1-AS1 was specifically upregulated in GC patients and that the expression of TM4SF1-AS1 was significantly elevated in primary and cultured GC cells. TM4SF1-AS1 contributes to GC cell growth in vitro and in vivo, and its oncogenic function is mediated, at least in part, through interactions with purine-rich element-binding protein α (Pur-α) and Y-box binding protein 1 (YB-1). TM4SF1-AS1 also activates interferon signaling in GC cells, which is dependent on Pur-α and RIG-I. Chromatin isolation by RNA purification (ChIRP)-mass spectrometry demonstrated that TM4SF1-AS1 was associated with several stress granule (SG)-related proteins, including G3BP2, RACK1, and DDX3. Notably, TM4SF1-AS1 promoted SG formation and inhibited apoptosis in GC cells by sequestering RACK1, an activator of the stress-responsive MAPK pathway, within SGs. TM4SF1-AS1-induced SG formation and apoptosis inhibition are dependent on Pur-α and YB-1. These findings suggested that TM4SF1-AS1 contributes to tumorigenesis by enhancing SG-mediated stress adaptation.

DOI

A novel approach to diagnosing crystal-storing histiocytosis: utility of scanning electron microscopy for formalin-fixed paraffin-embedded tissue specimens.

Kazufumi Magara, Akira Takasawa, Keisuke Kikuchi, Taro Sugawara, Taro Murakami, Daisuke Kyuno, Yusuke Ono, Kumi Takasawa, Yasunao Numata, Shigeru Sasaki, Hiroshi Nakase, Tadashi Hasegawa, Makoto Osanai

Medical molecular morphology 2023.07 [Domestic journal]

Crystal-storing histiocytosis (CSH) is a rare disorder that shows infiltration of histiocytes with an aberrant cytoplasmic accumulation of crystalline structures and is often accompanied by lymphoproliferative-plasma cell disorders (LP-PCD) as background diseases. The diagnosis of CSH requires identification of crystalline structures that accumulate in the infiltrating histiocytes, which may be challenging by optical microscopy alone. In this case report, we describe an atypical course of systemic CSH with multifocal fibrosclerosis of an unknown background disease that was diagnosed by ultrastructural observation, including transmission electron microscopy (TEM) and scanning electron microscopy (SEM), in pathological autopsy. In addition, crystalline structures were successfully identified by scanning electron microscopic observations using formalin-fixed and paraffin-embedded (FFPE) tissue from biopsy specimens taken before death. Since CSH was identified by SEM in a tiny biopsy specimen, observation of histiocytic infiltrative lesions by SEM using FFPE tissue may lead to early detection of and initiation of treatment for CSH.

DOI PubMed

Immunoglobulin G4-related periarteritis successfully diagnosed by endoscopic ultrasonography-guided fine-needle biopsy.

Yujiro Kawakami, Yosuke Hirobe, Hiroshi Nakase

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 35 ( 5 ) e87-e89 2023.07 [International journal]

DOI PubMed

高齢者肝細胞癌に対する経皮的ラジオ波焼灼療法の検討

沼田泰尚, 阿久津典之, 我妻康平, 平野雄大, 川上裕次郎, 石上敬介, 柾木喜晴, 室田文子, 佐々木茂, 仲瀬裕志

日本高齢消化器病学会誌 ( (NPO)日本高齢消化器病学会 ) 26 ( 1 ) 134 - 134 2023.07

Generalized crystal-storing histiocytosis with noncirrhotic portal hypertension: an autopsy case report.

Yasunao Numata, Shigeru Sasaki, Kazufumi Magara, Akira Takasawa, Taro Sugawara, Naruki Ohara, Noriyuki Akutsu, Tadashi Hasegawa, Makoto Osanai, Hiroshi Nakase

Clinical journal of gastroenterology 16 ( 3 ) 450 - 456 2023.04 [Domestic journal]

Crystal-storing histiocytosis (CSH) is a rare disease associated with the accumulation of histiocytes containing crystalline matter within their cytoplasm. Herein, we present the case of a female patient who was diagnosed with Tolosa-Hunt syndrome at 45 years of age and idiopathic retroperitoneal fibrosis when she was 48 years. She developed portal hypertension (PH), but did not present with cirrhosis; as such, the cause of PH was not identified. Her PH gradually worsened when she was 54 years, and at the age of 60 years, she died from an acute subdural hematoma. Autopsy revealed retroperitoneal fibrosis with severe fibrosis extending around the hepatic veins and into the porta hepatis. Histologically, the retroperitoneal tissue showed a dense infiltrate of eosinophilic histiocytes with crystal structures in the cytoplasm, which was pathologically diagnosed as CSH. Nodular regenerative hyperplasia was observed in the liver parenchyma, whereas cirrhosis was not. In the present case, CSH caused fibrosis, which was believed to be the cause of PH. In addition, we considered that nodular regenerative hyperplasia caused by the altered hepatic blood flow due to treatment of gastric varices contributed to worsening PH. Hence, CSH should be considered as an underlying disease in noncirrhotic portal hypertension.

DOI PubMed

Ischemia-induced intestinal de-epithelization and consequent cholangitis lenta after usage of extracorporeal membrane oxygenation in COVID-19 patients: an autopsy series

Sae Hatanaka, Yuki Yamada, Terufumi Kubo, Kazufumi Magara, Yusuke Ono, Shintaro Sugita, Tomohide Tsukahara, Daisuke Kyuno, Michiko Hosaka, Kenta Sasaki, Yoshihiko Hirohashi, Tsukasa Yamakawa, Keisuke Harada, Naofumi Bunya, Eichi Narimatsu, Hiroshi Nakase, Tadashi Hasegawa, Makoto Osanai, Toshihiko Torigoe

Oxford Medical Case Reports ( Oxford University Press (OUP) ) 2023 ( 4 ) 2023.04

Abstract Since its discovery in late 2019, severe acute respiratory syndrome coronavirus 2 has spread around the world, causing millions of deaths due to coronavirus disease 2019 (COVID-19). Numerous clinical and post-mortem investigations of COVID-19 cases have found myriad clinical and pathological manifestations of the disease. In this report, we present three autopsy cases in which, despite weaning from extracorporeal membrane oxygenation (ECMO), extensive intestinal epithelial shedding, probably due to ischemia, was followed by massive watery diarrhea and the spread of infection via the portal vein due to bacterial translocation, which resulted in cholangitis lenta. Thrombophilia was attributed to ECMO usage and COVID-19-related vascular endothelial damage. These cases provide instructive findings showing that the loss of the intestinal barrier may be the underlying cause of severe watery diarrhea and liver failure in COVID-19 patients, especially with ECMO usage.

DOI

胆膵内視鏡診療におけるトラブルシューティング膵管空腸吻合部ロストステントの迷入に対する内視鏡的トラブルシューティング

川上裕次郎, 柾木喜晴, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 65 ( Suppl.1 ) 846 - 846 2023.04

Red blood cell distribution width as a novel marker for predicting bleeding after endoscopic resection for early gastric cancer.

Takada Yumemi, Shinji Yoshii, Tsukasa Yamakawa, Yuki Hayashi, Takakazu Miyake, Yoshihiro Yokoyama, Gota Sudo, Kei Mitsuhashi, Masanori Nojima, Hiro-O Yamano, Hiroshi Nakase

DEN open 3 ( 1 ) e123 2023.04 [International journal]

OBJECTIVES: Endoscopic resection (ER) is a minimally invasive treatment for early gastric cancer (EGC); however, there is a high occurrence of bleeding. This study aimed to clarify the significance of red blood cell distribution width (RDW) as a predictive risk factor for bleeding after ER for EGC. METHODS: We conducted a retrospective study based on data for patients who underwent ER for EGC from 2019 to 2021. This study included 79 lesions in 54 patients who underwent ER for EGC. The primary outcome was the association between RDW before ER and bleeding within 28 days of treatment. Receiver operating characteristic (ROC) curves were constructed, wherein areas under the curve (AUCs) and 95% confidence intervals were calculated to compare the discriminatory power of RDW for predicting bleeding. RESULTS: Endoscopic submucosal dissection was used as the resection method for 73 lesions, whereas endoscopic mucosal resection was used for six lesions. En bloc resection was performed in all cases. There were no cases of perforation; however, bleeding after ER occurred in five cases (9.3%). ROC curve analysis of bleeding after ER showed that the AUC was 0.843 with a good diagnostic performance. When the cut-off value of RDW was set at 14.4%, sensitivity and specificity were 80% and 85.7%, respectively. There was a bleeding rate of 36.4% (4/11) at an RDW of ≥14.4%, which was significantly higher than that of 2.3% (1/43) at an RDW of <14.4%. CONCLUSION: RDW can be a predictor of bleeding risk after ER for EGC.

DOI PubMed

EUS-FNAが診断に有用であったIgG4関連動脈周囲炎の1例

川上裕次郎, 我妻康平, 沼田泰尚, 石上敬介, 柾木喜晴, 室田文子, 阿久津典之, 仲瀬裕志

超音波医学 ( (公社)日本超音波医学会 ) 50 ( Suppl. ) S590 - S590 2023.04

An older patient with active ulcerative colitis and coronavirus disease 2019 (COVID-19) pneumonia successfully treated with the combination of anti-TNFα therapy and azathioprine.

Tsukasa Yamakawa, Keisuke Ishigami, Sae Ohwada, Tomoe Kazama, Daisuke Hirayama, Shinji Yoshii, Hiro-O Yamano, Hiroshi Nakase

Clinical journal of gastroenterology 16 ( 2 ) 187 - 192 2023.04 [Domestic journal]

A 77-year-old patient with ulcerative colitis (UC) was transferred to our department because of worsening bloody diarrhea and abdominal pain, which was consistent with a UC flare. Two days after admission, she complained of cough and high fever. The polymerase chain reaction (PCR) test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was positive, and a computed tomography showed pneumonia in the left lobe, consistent with coronavirus disease 2019 (COVID-19) pneumonia. However, frequent bloody diarrhea and abdominal pain due to the UC flare persisted; therefore, an additional immunosuppressive agent needed to be considered. We initiated infliximab biosimilar (IFX-BS), and her abdominal symptoms improved. However, they deteriorated after the second IFX-BS infusion. After confirming that the patient was negative for SARS-CoV-2 by PCR, we administered a combination of azathioprine and IFX-BS. The combination treatment improved her intestinal symptoms without worsening COVID-19 pneumonia. She has remained in remission for over a year since her discharge.

DOI PubMed

IgG4関連疾患:内視鏡の役割(胆膵/全体) IgG4関連消化管病変の臨床的特徴

川上裕次郎, 柾木喜晴, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 65 ( Suppl.1 ) 742 - 742 2023.04

膵疾患に対するEUS診断の現状膵臓癌に対するがんゲノムプロファイリング検査(CGP)のための適正な検体採取方法の検討

室田文子, 柾木喜晴, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 65 ( Suppl.1 ) 790 - 790 2023.04

側方進展をきたした十二指腸乳頭部腫瘍に対する一括切除を目指したEP with hybrid ESD

川上裕次郎, 柾木喜晴, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 65 ( Suppl.1 ) 856 - 856 2023.04

Diagnosis and Clinical Features of Perianal Lesions in Newly Diagnosed Crohn's Disease: Subgroup Analysis from Inception Cohort Registry Study of Patients with Crohn's Disease (iCREST-CD).

Takayuki Yamamoto, Hiroshi Nakase, Kenji Watanabe, Shinichiro Shinzaki, Noritaka Takatsu, Toshimitsu Fujii, Ryuichi Okamoto, Katsuyoshi Matsuoka, Akihiro Yamada, Reiko Kunisaki, Minoru Matsuura, Hisashi Shiga, Shigeki Bamba, Yohei Mikami, Takahiro Shimoyama, Satoshi Motoya, Takehiro Torisu, Taku Kobayashi, Naoki Ohmiya, Masayuki Saruta, Koichiro Matsuda, Takayuki Matsumoto, Atsuo Maemoto, Yoko Murata, Shinichi Yoshigoe, Shinya Nagasaka, Tsutomu Yajima, Tadakazu Hisamatsu

Journal of Crohn's & colitis 17 ( 8 ) 1193 - 1206 2023.03 [International journal]

BACKGROUND AND AIMS: Perianal lesion is a refractory phenotype of Crohn's disease (CD) with significantly diminished quality of life. We evaluated the clinical characteristics of perianal lesions in newly diagnosed CD patients and the impact of perianal lesions on the quality of life in Japanese patients with CD. METHODS: Patients newly diagnosed with CD after June 2016 were included between December 2018 and June 2020 from the Inception Cohort Registry Study of Patients with CD (iCREST-CD). RESULTS: Perianal lesions were present in 324 (48.2%) of 672 patients with newly diagnosed CD. 71.9% (233/324) were male. The prevalence of perianal lesions was higher in patients aged <40 years versus ≥40 years, and it decreased with age. Perianal fistula (59.9%) and abscess (30.6%) were the most common perianal lesions. In multivariate analyses, male sex, age <40 years, and ileocolonic disease location were significantly associated with a high prevalence of perianal lesions, whereas stricturing behaviour and alcohol intake were associated with low prevalence. Fatigue was more frequent (33.3% vs 21.6%) and, work productivity and activity impairment-work time missed (36.3% vs 29.5%) and activity impairment (51.9% vs 41.1%) were numerically higher in patients with than those without perianal lesions. CONCLUSIONS: At the time of CD diagnosis, approximately half of the patients had perianal lesions; perianal abscesses and perianal fistulas were the most common. Young age, male sex, disease location, and behaviour are significantly associated with the presence of perianal lesions. The presence of perianal lesion was associated with fatigue and impairment of daily activities.

DOI PubMed

膵空腸吻合部ロストステントの膵管内完全迷入に対し、EUS-PDルートを用いて除去に成功した1例

中村隼人, 柾木喜晴, 我妻康平, 川上裕次郎, 石上敬介, 室田文子, 木村康利, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 132回・126回 40 - 40 2023.03

免疫チェックポイント阻害薬関連腸炎における粘膜サイトカインの検討

大和田紗恵, 三宅高和, 横山佳浩, 風間友江, 吉井新二, 山野泰穂, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 120 ( 臨増総会 ) A373 - A373 2023.03

当科の核酸アナログ治療20年の検討

阿久津典之, 佐々木茂, 沼田泰尚, 平野雄大, 我妻康平, 石上敬介, 川上裕次郎, 柾木喜晴, 室田文子, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 120 ( 臨増総会 ) A420 - A420 2023.03

当科における原発性硬化性胆管炎(PSC)症例の検討

沼田泰尚, 阿久津典之, 世戸凌太, 中村隼人, 浪岡万由子, 廣部洋輔, 三浦克与志, 平野雄大, 我妻康平, 川上裕次郎, 石上敬介, 柾木喜晴, 室田文子, 佐々木茂, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 120 ( 臨増総会 ) A399 - A399 2023.03

がん遺伝子パネルを契機に生殖細胞系列のBRCA2変異陽性と診断され,白金製剤使用後にPARP阻害剤が導入可能となった1例

世戸凌太, 室田文子, 我妻康平, 川上裕次郎, 沼田泰尚, 石上敬介, 柾木喜晴, 阿久津典之, 笠原薫, 佐々木茂, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 132回・126回 72 - 72 2023.03

橈骨動脈アプローチによるTACEにより治療しえたHCCの1例

沼田泰尚, 中村隼人, 廣部洋輔, 平野雄大, 我妻康平, 川上裕次郎, 石上敬介, 柾木喜晴, 室田文子, 阿久津典之, 佐々木茂, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 132回・126回 46 - 46 2023.03

メトトレキサートによる肝線維症が原因と考えられた食道静脈瘤の1例

中村隼人, 沼田泰尚, 平野雄大, 我妻康平, 川上裕次郎, 石上敬介, 柾木喜晴, 室田文子, 阿久津典之, 佐々木茂, 仲瀬裕志

新規デバイスデリバリーシステムを用いた経乳頭的胆嚢生検にて診断したIgG4関連胆嚢炎の1例

亀山尚弘, 川上裕次郎, 世戸凌太, 廣部洋輔, 柾木喜晴, 室田文子, 阿久津典之, 木村康利, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 132回・126回 39 - 39 2023.03

当科における切除可能肝門部領域胆管癌の治療成績

川上裕次郎, 柾木喜晴, 我妻康平, 沼田泰尚, 石上敬介, 室田文子, 阿久津典之, 木村康利, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 120 ( 臨増総会 ) A329 - A329 2023.03

EUS-FNAにて診断したIgG4関連動脈周囲炎の1例

廣部洋輔, 川上裕次郎, 我妻康平, 沼田泰尚, 石上敬介, 柾木喜晴, 室田文子, 阿久津典之, 仲瀬裕志

永石歓和, 仲瀬裕志

消化器病学サイエンス ( (株)先端医学社 ) 7 ( 1 ) 33 - 38 2023.03

間葉系幹細胞(mesenchymal stem cells:MSC)は,多彩な生理活性物質を産生・分泌して免疫制御能や組織修復・再生能を発揮する体性幹細胞である.炎症組織では,MSCが局所の炎症性サイトカインによる刺激を受けて活性化する.MSCは,スフェロイドを形成することで免疫制御能や血管新生能,抗アポトーシス効果などの細胞機能が向上する.MSCは,消化器領域の慢性炎症性疾患における新しい治療選択肢として実用化が模索されている.(著者抄録)

肝疾患と便中カルプロテクチンの関連の検討

沼田泰尚, 平野雄大, 我妻康平, 川上裕次郎, 石上敬介, 柾木喜晴, 室田文子, 阿久津典之, 佐々木茂, 仲瀬裕志

日本内科学会雑誌 ( (一社)日本内科学会 ) 112 ( 臨増 ) 144 - 144 2023.02

山野泰穂, 吉井新二, 久保俊之, 山川司, 三宅高和, 風間友江, 柴田泰洋, 三橋慧, 須藤豪太, 赤保内正和, 瀧澤歩, 山本英一郎, 仲瀬裕志

胃と腸 ( (株)医学書院 ) 58 ( 2 ) 135 - 145 2023.02

＜文献概要＞近年,大腸鋸歯状病変,特にSSLは第3の大腸癌への発育進展ルート"serrated neoplastic pathway"として注目されており,癌あるいは癌を疑う所見を伴うSSLに対して的確に内視鏡診断することが重要である.当科にて経験したSSL関連病変115病変の検討で,癌併存SSL病変,SSLD病変とそれ以外の病変群とで拡大内視鏡所見を比較検討した.その結果,癌併存SSL病変では複数のpit patternから構成されており,開II型を背景に軽度から高度異型を示すVI型を必ず伴っていたのに対して,SSLDでは鋸IV型,IIIL型が混在しており,明確なVI型の判断はなされていなかった.なお,大腸鋸歯状病変に対する内視鏡診断では拡大内視鏡診断の考え方,病理組織標本の取り扱いや病理組織学的診断基準などの要因による影響を受けるため注意を要する.

慢性肝疾患患者における骨密度とundercarboxylated osteocalcinの関連

我妻康平, 石上敬介, 阿久津典之, 平野雄大, 川上裕次郎, 沼田泰尚, 柾木喜晴, 室田文子, 佐々木茂, 仲瀬裕志

日本内科学会雑誌 ( (一社)日本内科学会 ) 112 ( 臨増 ) 170 - 170 2023.02

Anxiety and behavioral changes in Japanese patients with inflammatory bowel disease due to COVID-19 pandemic: a national survey.

Hiroshi Nakase, Kohei Wagatsuma, Masanori Nojima, Takayuki Matsumoto, Minoru Matsuura, Hideki Iijima, Katsuyoshi Matsuoka, Naoki Ohmiya, Shunji Ishihara, Fumihito Hirai, Ken Takeuchi, Satoshi Tamura, Fukunori Kinjo, Nobuhiro Ueno, Makoto Naganuma, Kenji Watanabe, Rintaro Moroi, Nobuaki Nishimata, Satoshi Motoya, Koichi Kurahara, Sakuma Takahashi, Atsuo Maemoto, Hirotake Sakuraba, Masayuki Saruta, Keiichi Tominaga, Takashi Hisabe, Hiroki Tanaka, Shuji Terai, Sakiko Hiraoka, Hironobu Takedomi, Kazuyuki Narimatsu, Katsuya Endo, Masanao Nakamura, Tadakazu Hisamatsu

Journal of gastroenterology 58 ( 3 ) 1 - 12 2023.01 [Domestic journal]

BACKGROUND: Given the increasing health concerns for patients with inflammatory bowel disease (IBD), amidst the COVID-19 pandemic, we investigated the impact of the pandemic on the anxiety and behavioral changes in Japanese patients with IBD. METHODS: We analyzed 3032 questionnaires from patients with IBD, aged 16 years or older visiting 30 hospitals and 1 clinic between March 2020 and June 2021. The primary outcome was the score of the anxiety experienced by patients with IBD during the pandemic. RESULTS: Participants reported a median age of 44 years; 43.3% of the patients were women. Moreover, 60.6% and 39.4% were diagnosed with ulcerative colitis and Crohn's disease, respectively, with a median disease duration of 10 years. Participants indicated an average of disease-related anxiety score of 5.1 ± 2.5 on a ten-point scale, with a tendency to increase, 1 month after the number of infected persons per population increased. The top three causes for anxiety were the risk of contracting COVID-19 during hospital visits, SARS-CoV-2 infection due to IBD, and infection by IBD medication. Factors associated with anxiety were gender (women), being a homemaker, hospital visit timings, mode of transportation (train), use of immunosuppressive drugs, and nutritional therapy. Most patients continued attending their scheduled hospital visits, taking their medications, experienced the need for a family doctor, and sought guidance and information regarding COVID-19 from primary doctors, television, and Internet news. CONCLUSIONS: Patients with IBD experienced moderate disease-related anxiety due to the pandemic and should be proactively informed about infectious diseases to relieve their anxiety.

DOI PubMed

Endoscopic full-thickness resection using an over-the-scope clip for colon cancer within a diverticulum.

Takakazu Miyake, Shinji Yoshii, Hiroshi Nakase

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 35 ( 1 ) e30-e32 2023.01 [International journal]

DOI PubMed

Final Analysis of COVID-19 Patients With Inflammatory Bowel Disease in Japan (J-COSMOS): A Multicenter Registry Cohort Study.

Hiroshi Nakase, Yuki Hayashi, Yoshihiro Yokoyama, Takayuki Matsumoto, Minoru Matsuura, Hideki Iijima, Katsuyoshi Matsuoka, Naoki Ohmiya, Shunji Ishihara, Fumihito Hirai, Daiki Abukawa, Tadakazu Hisamatsu

Gastro hep advances 2 ( 8 ) 1056 - 1065 2023 [International journal]

BACKGROUND AND AIMS: Japan has experienced 8 waves of the coronavirus disease 2019 (COVID-19) outbreak over the past 3 years, resulting in an increasing number of deaths and incidence of severe infections. This study aimed to analyze the data from the Japanese inflammatory bowel disease (IBD) patients with COVID-19 registry (J-COSMOS) up to the eighth wave to investigate the clinical course of IBD patients with COVID-19 and factors contributing to disease severity. METHODS: In this multicenter, observational, cohort study, we analyzed a cohort of 1308 IBD patients diagnosed with COVID-19, enrolled across 77 participating facilities in the J-COSMOS registry from June 2020 to December 2022. Data on age, sex, IBD (classification, treatment, and activity), and COVID-19 (symptoms, severity, and treatment) were analyzed. RESULTS: The majority of patients (76%) were in clinical remission. According to the World Health Organization classification of COVID-19 severity, 98.4% of IBD patients had nonsevere disease, while 1.6% of patients had severe or critical disease. COVID-19 did not affect disease activity in most IBD patients. Stepwise logistic regression analysis revealed that high body mass index, and cerebrovascular disease were risk factors for severe COVID-19. Corticosteroids could affect COVID-19 severity, whereas anti-tumor necrosis factor α antibodies and thiopurines were associated with a reduced risk of severe COVID-19. No deaths were observed among IBD patients with COVID-19 registered in this cohort. CONCLUSION: The impact of COVID-19 on IBD disease activity and factors associated with COVID-19 severity were consistent with findings of previous reports. No deaths in Japanese patients with IBD were observed.

DOI PubMed

Long-term effectiveness and safety of infliximab-biosimilar: A multicenter Phoenix retrospective cohort study.

Tomoe Kazama, Katsuyoshi Ando, Nobuhiro Ueno, Mikihiro Fujiya, Takahiro Ito, Atsuo Maemoto, Keisuke Ishigami, Masanori Nojima, Hiroshi Nakase

PloS one 18 ( 9 ) e0288393 2023 [International journal]

BACKGROUND: Infliximab (IFX) effectively treats patients with inflammatory bowel disease (IBD). IFX-biosimilar (IFX-BS) has the same amino acid sequence as that of the IFX originator, and its increasing use is expected to reduce national healthcare costs. Long-term efficacy and safety of IFX-BS in patients with Crohn's disease (CD) and ulcerative colitis (UC) have not been completely investigated. METHODS: We conducted a retrospective, multicenter observational study of patients with IBD who received IFX-BS treatment at three hospitals between October 2016 and April 2022. Clinical data were collected from electronic medical records and evaluated for achieving clinical remission (CR) using Crohn's disease activity index (CDAI) and partial Mayo (pMayo) score, persistency of long-term IFX-BS administration, and clinical response rate in the bio-naïve and bio-failure groups. RESULTS: A total of 117 patients with IBD (90 CD and 27 UC) were included. The study findings indicated that both bio-naïve and bio-failure groups of patients with UC showed similar effectiveness of IFX-BS. The treatment persistence rate in patients with CD was significantly higher in the bio-naïve (P = 0.042) and switch (P = 0.010) groups than in the bio-failure group. In the former two groups, the treatment persistence rate was high at two years after administration (more than 80%). In patients with UC, the findings indicated higher treatment persistence rate in the switch group than in the bio-naïve group. Univariable and multivariable analyses for treatment persistence rate showed that the albumin level at the initial IFX-BS administration and groups (bio-naïve, bio-failure and switch) were effective factors for patients with CD. Adverse events were reported in 18 patients (15.4%). CONCLUSION: The present study demonstrates the long-term effectiveness and safety of IFX-BS. In addition to the favorable remission induction in the bio-naïve and bio-failure groups, we demonstrated remission maintenance and treatment persistence rates beyond two years. Albumin level and groups were associated with better treatment persistence in patients with CD.

DOI PubMed

Mesenchymal stem cellを知る

永石歓和, 仲瀬裕志

消化器病サイエンス 7 33 - 38 2023

Hybrid Endoscopic Resection With Endo-knife and Snare for Colorectal Lesions: A Systematic Review and Meta-analysis

Shinji Yoshii, Takefumi Kikuchi, Yuki Hayashi, Masahiro Nojima, Hiro-o Yamano, Hiroshi Nakase

Techniques and Innovations in Gastrointestinal Endoscopy ( Elsevier BV ) 25 ( 2 ) 135 - 145 2023 [Refereed]

DOI

Serum soluble Fas levels and incidence of liver cancer in nested case-control study.

Yasushi Adachi, Masanori Nojima, Mitsuru Mori, Toshiyuki Kubo, Noriyuki Akutsu, Yasushi Sasaki, Hiroshi Nakase, Yingsong Lin, Youichi Kurozawa, Kenji Wakai, Akiko Tamakoshi

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2022.12 [International journal]

BACKGROUND: Soluble Fas (sFas) plays various roles in carcinogenesis and tumor dissemination by preventing apoptosis via binding to Fas ligand. We analyzed associations of serum sFas levels with the incidence of liver cancer in a prospective case-control study nested in the JACC Study. METHODS: A baseline survey was conducted from 1988, with blood samples obtained from 39,242 subjects. Patients diagnosed with liver cancer were regarded as cases. Two or three controls were selected and matched for sex, age, and geographical area. Conditional logistic regression was used to estimate odds ratios (ORs) for cancer incidence associated with sFas. RESULTS: This study contained 86 cases and 249 controls. After controlling for alcohol intake, body mass index, smoking, and hepatitis viral infection, participants with high sFas showed elevated risk of cancer (P-trend = 0.003) and the third tertile of sFas showed a higher risk compared to the first tertile (OR = 3.53, 95% confidence interval (CI) = 1.28-9.69). In hepatocellular carcinoma, high sFas was associated with elevated risk (P-trend < 0.001). In men and the elderly, subjects in the highest tertiles showed higher cancer risk. Limiting subjects to those followed for 3 years, high sFas was related to liver cancer risk (P-trend = 0.033) and the third tertile showed a higher risk compared to the first (OR = 2.94, 95%CI = 0.94-9.14). CONCLUSIONS: High serum sFas may be related to future risk of liver cancer. IMPACT: Our findings highlight this biomarker for further analysis in pooled investigations with different/larger prospective cohorts.

DOI PubMed

Serum amyloid A1 recruits neutrophils to the invasive front of T1 colorectal cancers.

Ayano Yoshido, Gota Sudo, Akira Takasawa, Hironori Aoki, Hiroshi Kitajima, Eiichiro Yamamoto, Takeshi Niinuma, Taku Harada, Toshiyuki Kubo, Hajime Sasaki, Kazuya Ishiguro, Akira Yorozu, Masahiro Kai, Akio Katanuma, Hiro-O Yamano, Makoto Osanai, Hiroshi Nakase, Hiromu Suzuki

Journal of gastroenterology and hepatology 38 ( 2 ) 301 - 310 2022.11 [International journal]

BACKGROUND AND AIM: The tumor microenvironment plays an essential role in the development and progression of colorectal cancer (CRC). We recently reported that crosstalk between CRC cells and tumor-associated macrophages (TAMs) via serum amyloid A1 (SAA1) promotes invasion by T1 CRCs. In the present study, we aimed to clarify the role of neutrophils in early CRCs. METHODS: Immunohistochemical analysis of CD66b, chemokine CXC motif ligand 8 (CXCL8 or interleukin-8, IL-8) and matrix metalloproteinase-9 (MMP-9) was performed using primary T1 CRCs (n = 49). The HL-60 human promyelocytic leukemia cell line and THP-1 human monocytic leukemia cell line were used to obtain neutrophil-like and macrophage-like cells, respectively. Boyden chamber assays were used to analyze cell migration and invasion, and quantitative RT-PCR was used to analyze gene expression. RESULTS: Immunohistochemical analysis revealed accumulation of neutrophils at the SAA1-positive invasive front of T1 CRCs. Experiments using HL-60 cells suggested that treatment with SAA1 induced neutrophil migration and expression of CXCL8 and MMP-9 in neutrophils and that neutrophils promote CRC cell migration and invasion. Immunohistochemistry confirmed accumulation of CXCL8- or MMP-9-positive neutrophils at the SAA1-positive invasive front of T1 CRCs. Moreover, co-culture experiments using CRC, THP-1 and HL-60 cells suggested that CRC cells activated by macrophages upregulate CXCL8 and MMP-9 in neutrophils. CONCLUSIONS: Our results suggest that interplay between macrophages and CRC cells leads to recruitment of neutrophils to the invasive front of T1 CRCs and that SAA1 secreted by CRC cells activate neutrophils to promote invasion.

DOI PubMed

Guidelines for endoscopic balloon dilation in treating Crohn's disease-associated small intestinal strictures (supplement to the Clinical Practice Guidelines for Enteroscopy)

Hironori Yamamoto, Tomonori Yano, Akihiro Araki, Motohiro Esaki, Kazuo Ohtsuka, Naoki Ohmiya, Shiro Oka, Hiroshi Nakase, Shigeki Bamba, Fumihito Hirai, Naoki Hosoe, Tomoki Matsuda, Keigo Mitsui, Kenji Watanabe, Haruhiko Ogata, Shinichi Katsuki, Takayuki Matsumoto, Mitsuhiro Fujishiro, Kazuma Fujimoto, Haruhiro Inoue

DIGESTIVE ENDOSCOPY ( WILEY ) 34 ( 7 ) 1278 - 1296 2022.11

Balloon-assisted enteroscopy allows endoscopic treatments in the deeper segments of the small bowel. Endoscopic balloon dilation has become a popular minimally invasive alternative for the treatment of Crohn's disease-associated small intestinal strictures. As a supplement to the Clinical Practice Guidelines for Enteroscopy, the Japan Gastroenterological Endoscopy Society's Working Committee has developed the present "Guidelines for endoscopic balloon dilation in treating Crohn's disease-associated small intestinal strictures," based on new scientific techniques and evidence. The guidelines cover standard procedures for the insertion route of the balloon endoscope, bowel preparation, indications, procedure-related complications, efficacy, target diameter and duration, management of multiple strictures, and the current state of combined and alternative treatments. Unresolved future research questions are also listed in this guideline.

DOI

Guidelines for endoscopic balloon dilation in treating Crohn's disease-associated small intestinal strictures (supplement to the Clinical Practice Guidelines for Enteroscopy).

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 34 ( 7 ) 1278 - 1296 2022.11 [International journal]

DOI PubMed

A case of hepatocellular carcinoma with long-term survival by multidisciplinary treatment for cranial and skeletal muscle metastases.

Noriyuki Akutsu, Yujiro Kawakami, Yasunao Numata, Takehiro Hirano, Kohei Wagatsuma, Keisuke Ishigami, Shigeru Sasaki, Hiroshi Nakase

Clinical journal of gastroenterology 15 ( 5 ) 960 - 967 2022.10 [Domestic journal]

We report a case in which multidisciplinary treatment was effective for hepatocellular carcinoma (HCC) with cranial and skeletal muscle metastases. A 55-year-old male with HCC received sorafenib for lung metastases. He was admitted to our hospital due to the skull metastasis detected by fluorodeoxyglucose positron emission tomography (FDG-PET). The patient underwent resection for skull metastasis. After the surgical treatment, he was treated with sorafenib again. Eight months after craniectomy, FDG-PET showed FDG uptake in the semimembranosus and semitendinosus muscles. Histopathological examination of the muscle biopsy revealed HCC muscle metastasis. Sorafenib treatment was discontinued. The investigational new drug (tegafur-gimeracil-oteracil) and tegafur-uracil were used for the treatment. These treatments proved to be ineffective as the lung metastases enlarged and new metastases appeared on the mediastinal lymph nodes and dura cava. The patient was unable to walk due to the enlarged thigh muscle metastases. Sorafenib was re-administered, which reduced the enlargement of the lung and mediastinal lymph nodes. Dural metastases were treated with resection and radiotherapy. Additional radiation therapy to the thigh muscles relieved the patient from pain experienced during walking. Sorafenib treatment was continued for the next 3 years. The patient survived for 4 years after the skull resection.

DOI PubMed

血清SOD活性と大腸癌罹患リスク(Association of serum superoxide dismutase activity and the incidence of colorectal cancer in a nested case-control study)

足立靖, 野島正寛, 森満, 久保俊之, 山野泰穂, 佐々木泰史, 仲瀬裕志, 遠藤高夫, 林櫻松, 若井建志, 玉腰暁子

日本癌学会総会記事 ( (一社)日本癌学会 ) 81回 E - 3034 2022.09

血清SOD活性と大腸癌罹患リスク(Association of serum superoxide dismutase activity and the incidence of colorectal cancer in a nested case-control study)

足立靖, 野島正寛, 森満, 久保俊之, 山野泰穂, 佐々木泰史, 仲瀬裕志, 遠藤高夫, 林櫻松, 若井建志, 玉腰暁子

日本癌学会総会記事 ( (一社)日本癌学会 ) 81回 E - 3034 2022.09

内視鏡診療を想定した体外バキューム装置によるエアロゾル減少効果の報告

山野泰穂, 足立靖, 吉井新二, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 131回・125回 32 - 32 2022.09

小腸原発Gastrointestinal stromal tumor(GIST)に対するイマチニブ投与中に肝転移破裂、腹腔内出血をきたした1例

山本智香, 室田文子, 沼田泰尚, 川上裕次郎, 石上敬介, 柾木喜晴, 阿久津典之, 本谷雅代, 佐々木茂, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 131回・125回 46 - 46 2022.09

当院における悪性肝門部胆管狭窄に対するドレナージの成績

室田文子, 我妻康平, 川上裕次郎, 沼田泰尚, 石上敬介, 柾木喜晴, 阿久津典之, 本谷雅代, 佐々木茂, 仲瀬裕志

胆道 ( (一社)日本胆道学会 ) 36 ( 3 ) 445 - 445 2022.09

十二指腸乳頭部に神経線維腫を合併したvon-Reckling hausen病の1例

三浦克予志, 柾木喜晴, 浪岡万由子, 川上裕次郎, 石上敬介, 室田文子, 本谷雅代, 杉田真太郎, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 131回・125回 53 - 53 2022.09

Sustained Eosinophilic Cholangitis Due to a Mite Allergy Mimicking Sclerosing Cholangitis.

Masayo Motoya, Shun Takai, Hiroshi Moriya, Takehiro Hirano, Kohei Wagatsuma, Yasunao Numata, Yujiro Kawakami, Yoshiharu Masaki, Keisuke Ishigami, Ayako Murota, Hiroshi Nakase

Internal medicine (Tokyo, Japan) 61 ( 16 ) 2477 - 2482 2022.08 [Domestic journal]

Eosinophilic cholangiopathy (EC) presents with thickening and stenosis of the bile duct wall that is histologically characterized by eosinophil infiltration. The diagnosis is often difficult. We herein report a patient who had been followed up with a diagnosis of primary sclerosing cholangitis but had a final diagnosis of EC based on eosinophilia, histological findings of bile duct and liver biopsy specimens, and a review of a previous surgical specimen of the gallbladder. Antigen tests, isolation from her house, and accidental re-exposure to the antigen revealed that the causative antigen was the mite Dermatophagoides pteronyssinus.

DOI PubMed

Genomic analysis of an aggressive case with metastatic intrahepatic mucinous cholangiocarcinoma.

Yoshiharu Masaki, Noriyuki Akutsu, Yasushi Adachi, Keisuike Ishigami, Norikazu Iwata, Takao Endo, Yoshifumi Ishii, Yasushi Sasaki, Minoru Nagayama, Yasutoshi Kimura, Hiroshi Nakase

Clinical journal of gastroenterology 15 ( 4 ) 809 - 817 2022.08 [Domestic journal]

Intrahepatic mucinous cholangiocarcinoma (IHMC) is rare and behaves notoriously; however, the details of the clinicopathological characteristics of IHMC remain unknown. A 70-year-old man was admitted for examination of the hepatic mass in the S1 segment. He underwent extended left hepatic lobectomy. Histopathological evaluation demonstrated mixed papillary carcinoma that comprised well to moderately differentiated tubular adenocarcinoma and signet-ring cell carcinoma with large amounts of mucus lakes. Tumor was relapsed 9 months after surgery. Although he received chemotherapy with the combination of gemcitabine and cisplatin, he had renal failure and discontinued the chemotherapy. He received palliative radiotherapy for metastasis in the cervical spine. Then, the patient treated with S-1, however, he died 16 months after the initial diagnosis. The autopsy findings showed multiple nodules in the lungs, pleura, kidneys, adrenal glands, stomach, pancreas, and lymph nodes. Histological examination revealed that all nodules were IHMC. Next-generation sequencing revealed that somatic mutations in ADGRB3, TAF1L and EPHA3 may affect carcinogenesis, and those in TAF1, EPHA3, PIK3C2B, FN1, ERBB3, BRIP1, SYNE1 and TGFBR2 may affect metastasis. Molecular carcinogenesis of IHMC may be distinct from that of ordinary cholangiocarcinoma. Further studies are needed to elucidate the genetic mutations and their functions in IHMC.

DOI PubMed

Adrenomedullin for biologic-resistant Crohn's disease: A randomized, double-blind, placebo-controlled phase 2a clinical trial.

Toshihiro Kita, Shinya Ashizuka, Teruyuki Takeda, Takayuki Matsumoto, Naoki Ohmiya, Hiroshi Nakase, Satoshi Motoya, Hidehisa Ohi, Keiichi Mitsuyama, Tadakazu Hisamatsu, Shuji Kanmura, Naoya Kato, Shunji Ishihara, Masanao Nakamura, Tomohiko Moriyama, Masayuki Saruta, Ryoichi Nozaki, Shojiro Yamamoto, Haruhiko Inatsu, Koji Watanabe, Kazuo Kitamura

Journal of gastroenterology and hepatology 37 ( 11 ) 2051 - 2059 2022.07 [International journal]

BACKGROUND AND AIM: Adrenomedullin is a bioactive peptide with many pleiotropic effects, including mucosal healing and immunomodulation. Adrenomedullin has shown beneficial effects in rodent models of inflammatory bowel disease and, more importantly, in clinical trials including patients with ulcerative colitis. We performed a successive clinical trial to investigate the efficacy and safety of adrenomedullin in patients with Crohn's disease (CD). METHODS: This was a multicenter, double-blind, placebo-controlled phase 2a trial that evaluated 24 patients with biologic-resistant CD in Japan. Patients were randomly assigned to three groups and were given an infusion of 10 or 15 ng/kg/min of adrenomedullin or placebo for 8 h per day for 7 days. The primary endpoint was the change in the CD activity index (CDAI) at 8 weeks. The main secondary endpoints included changes in CDAI from week 4 to week 24. RESULTS: No differences in the primary or secondary endpoints were observed between the three groups by the 8th week. Changes in CDAI in the placebo group gradually decreased and disappeared at 24 weeks, but those in the adrenomedullin-treated groups (10 or 15 ng/kg/min group) remained at steady levels for 24 weeks. Therefore, a significant difference was observed between the placebo and adrenomedullin-treated groups at 24 weeks (P = 0.043) in the mixed-effects model. We noted mild adverse events caused by the vasodilatory effect of adrenomedullin. CONCLUSION: In this trial, we observed a long-lasting (24 weeks) decrease in CDAI in the adrenomedullin-treated groups. Adrenomedullin might be beneficial for biologic-resistant CD, but further research is needed.

DOI PubMed

Remitting Seronegative Symmetrical Synovitis with Pitting Edema (RS3PE) Syndrome Precedes the Development of Hepatocellular Carcinoma.

Sae Ohwada, Noriyuki Akutsu, Yoshiharu Masaki, Shigeru Sasaki, Minoru Nagayama, Yasutoshi Kimura, Ichiro Takemasa, Hiroki Takahashi, Hiroshi Nakase

JMA journal 5 ( 3 ) 393 - 397 2022.07 [Domestic journal]

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome is characterized by bilateral synovitis and marked pitting edema of the hands and/or feet. Despite the unknown etiology of RS3PE, several reports have described the putative association of this disease with malignant tumors. We herein report the findings of a 76-year-old man with RS3PE syndrome who developed hepatocellular carcinoma 3 years after achieving clinical remission of RS3PE using corticosteroid treatment; high vascular endothelial growth factor and tumor necrosis factor-alpha levels were considered to have contributed to carcinogenesis in this patient. The sequence of clinical events in this case strongly suggests that careful follow-up, even after clinical remission, is necessary for patients with RS3PE syndrome whose malignancy is not confirmed at diagnosis.

DOI PubMed

Pyogenic spondylitis following endoscopic submucosal dissection for early gastric cancer.

Shun Takai, Gota Sudo, Atsushi Yawata, Hiroshi Nakase

BMJ case reports 15 ( 7 ) 2022.07 [International journal]

A man in his 80s who had a history of diabetes mellitus and aortic valve replacement was referred to our hospital for treatment of early gastric cancer and underwent endoscopic submucosal dissection (ESD). Three days after ESD, the patient presented with low back pain and fever (38.7°). We initially considered adverse events associated with gastric ESD such as delayed perforation. Moreover, thromboembolism and infectious endocarditis were suspected because of his medical history. However, there were no remarkable findings suggestive of these diseases. Finally, based on the results of blood cultures and MRI, the diagnosis of pyogenic spondylitis (PS) was made. We administered antibiotics for 12 weeks, and the patient improved without neurological impairments. This case indicates that bacteraemia and subsequent PS can occur following gastric ESD. Physicians should not overlook the patient's physical signs related to various adverse events after ESD.

DOI PubMed

Double-balloon enteroscopy-assisted polypectomy for a solitary jejunal Peutz-Jeghers polyp causing anemia.

Kazunori Onuma, Gota Sudo, Hiroyuki Inoue, Takahiro Kuriyama, Yumemi Takada, Atsushi Yawata, Hiroshi Nakase

Endoscopy 2022.07 [International journal]

DOI PubMed

Synergistic effect of IFN-γ and IL-1β on PD-L1 expression in hepatocellular carcinoma.

Yasunao Numata, Noriyuki Akutsu, Keisuke Ishigami, Hideyuki Koide, Kohei Wagatsuma, Masayo Motoya, Shigeru Sasaki, Hiroshi Nakase

Biochemistry and biophysics reports 30 101270 - 101270 2022.07 [International journal]

Immunotherapy using anti-programmed death 1 ligand 1 (PD-L1) antibodies has shown clinical efficacy against hepatocellular carcinoma (HCC) and is recognized as the first-line treatment for unresectable HCC. PD-L1 expression is affected by various cytokines produced by immune cells in the tumor microenvironment; however, there is limited information about the effects of cytokine interactions on PD-L1 expression. In this study, we examined how cytokines induce PD-L1 expression in HCC cells. Both interferon gamma (IFN-γ) and interleukin 1 beta (IL-1β) induced PD-L1 expression, and the two cytokines enhanced PD-L1 expression in combination compared to that when administered alone. The Janus kinase/signal transducer and activator of transcription signaling pathway activated by IFN-γ is the major pathway of PD-L1 expression. The increase in interferon regulatory factor 1 expression and IFN-γ receptor expression induced by IL-1β was associated with the synergistic effect of IFN-γ and IL-1β on PD-L1 expression. These findings strongly indicate that IFN-γ and IL-1β affect the mechanism underlying immune resistance in HCC cells.

DOI PubMed

Delayed-onset bleeding after transrectal prostate biopsy presenting as a rectal Dieulafoy's lesion.

Mitsunobu Saito, Gota Sudo, Hiroyuki Inoue, Yumemi Takada, Katsuyoshi Miura, Atsushi Yawata, Hiroshi Nakase

Endoscopy 2022.06 [International journal]

DOI PubMed

Both fecal calprotectin and fecal immunochemical tests are useful in children with inflammatory bowel disease.

Hirotaka Shimizu, Ryo Ebana, Takahiro Kudo, Takuro Sato, Tomoko Hara, Kenji Hosoi, Masaaki Usami, Masashi Yoshida, Ichiro Takeuchi, Hiroshi Nakase, Itaru Iwama, Katsuhiro Arai, Toshiaki Shimizu

Journal of gastroenterology 57 ( 5 ) 344 - 356 2022.05 [Domestic journal]

BACKGROUND: Noninvasive biomarkers of intestinal inflammation can reduce the number of endoscopies in children with inflammatory bowel disease (IBD). This study aimed to prospectively investigate the usefulness of fecal calprotectin (FCP) and fecal immunochemical test (FIT) in pediatric IBD. METHODS: Patients aged 6-17 years who underwent ileocolonoscopy for established or suspected IBD were eligible for this study. Fecal samples for FCP and FIT were collected before colonoscopy. RESULTS: A total of 251 samples were analyzed: 88 from ulcerative colitis (UC), 74 from Crohn's disease (CD), 75 from healthy controls (HC), and 14 from children with functional gastrointestinal disorders and normal colonoscopy (NC). At IBD diagnosis, both FCP and FIT were significantly higher in the newly diagnosed UC/CD group than in the HC/NC group (P < 0.001). The optimal cutoffs of FCP and FIT to predict IBD diagnosis were 217 mg/kg and 87 ng/mL, respectively. Patients without mucosal healing (MH) showed higher FCP and FIT than those with MH in both UC and CD (P < 0.001). The FCP increased exponentially as the endoscopic activity score increased. The optimal cutoff values of FCP and FIT for predicting MH were 161 mg/kg and 106 ng/mL for UC and 367 mg/kg and 57 ng/mL for CD, respectively. FCP showed better specificity than the FIT. Patients with CD and normal ileocolonoscopy had elevated FCP during active small intestinal inflammation. CONCLUSIONS: Both FCP and FIT correlate well with endoscopic activity in pediatric patients with IBD. The FCP is a superior marker for predicting MH.

DOI PubMed

Direct clipping using underwater inversion method for colonic diverticular bleeding.

Mitsunobu Saito, Gota Sudo, Shun Takai, Atsushi Yawata, Hiroshi Nakase

VideoGIE : an official video journal of the American Society for Gastrointestinal Endoscopy 7 ( 5 ) 187 - 189 2022.05 [International journal]

DOI PubMed

【大腸鋸歯状病変のすべて】治療大腸鋸歯状病変はどこまで切除すべきか選択的に切除する立場から

三宅高和, 吉井新二, 山野泰穂, 柴田泰弘, 久保俊之, 仲瀬裕志

消化器内視鏡 ( (株)東京医学社 ) 34 ( 5 ) 974 - 980 2022.05

Positive Pattern Recognition System Using Alanine Aminotransferase, Type IV Collagen 7s, and E Value (Liver Stiffness) for the Diagnosis of Nonalcoholic Steatohepatitis Based on Natural History.

Masayuki Tsujisaki, Shigeru Sasaki, Noriyuki Akutsu, Takenori Takamura, Tetsuyuki Igarashi, Mitsuru Yoshimoto, Hideto Itoh, Yoshio Kurihara, Hiroshi Nakase

JMA journal 5 ( 2 ) 230 - 239 2022.04 [Domestic journal]

Introduction: The use of a simple diagnostic system for nonalcoholic fatty liver disease (NAFLD) instead of a biopsy is expected. We investigated a positive pattern recognition system for the evaluation of nonalcoholic fatty liver (NAFL) and the stages of nonalcoholic steatohepatitis (NASH). Methods: A total of 68 Japanese patients with biopsy-confirmed NAFLD were enrolled. Serological biomarkers and medical imaging markers were investigated to determine candidate markers. The markers were statistically evaluated, and the patients were distributed to pattern combinations. Results: We selected three markers based on natural history and set the critical values: alanine aminotransferase/ALT (persistent ≧ 44 IU/L) as a marker for hepatitis, type IV collagen 7S (≧5.1 ng/mL) for fibrosis, and E value (≧5.5 kPa) for stiffness. After evaluation of statistical accuracies, every patient was classified into their combination patterns. Comparing the relationships between histological classifications and positive patterns, the patients with NAFL were mainly distributed in pattern (ALT, type IV collagen, E value: -, -, -), those with NASH stage 0-1 in (+, -, +), those with NASH stage 2-3 in (+, +, +), and those with NASH stage 4 in (-, +, +). Conclusions: The positive patters changed with the NAFL and NASH conditions. Our results indicated a correlation between the positive patterns using three markers and the histological results. The positive pattern recognition system based on natural history is useful for the differential diagnosis of NAFLD and for the evaluation of the severity of fibrosis in patients with NASH.

DOI PubMed

Extensive mucosal sloughing of the small intestine and colon in a patient with severe COVID‐19

Tsukasa Yamakawa, Keisuke Ishigami, Ayumu Takizawa, Yumemi Takada, Sae Ohwada, Yoshihiro Yokoyama, Tomoe Kazama, Daisuke Hirayama, Shinji Yoshii, Hiro‐O Yamano, Rina Ohizumi, Naofumi Bunya, Taro Sugawara, Mitsuhiro Tsujiwaki, Shintaro Sugita, Satoshi Takahashi, Eichi Narimatsu, Hiroshi Nakase

DEN Open ( Wiley ) 2 ( 1 ) 2022.04

DOI

スライディングチューブを併用した経大腸EUS-FNA

谷口正浩, 川上裕次郎, 沼田有斗, 越前栄次朗, 我妻康平, 沼田泰尚, 石上敬介, 柾木喜晴, 室田文子, 本谷雅代, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 64 ( Suppl.1 ) 830 - 830 2022.04

胆膵癌におけるEUS-FNA検体を用いたMSI検査

川上裕次郎, 本谷雅代, 仲瀬裕志, 我妻康平, 沼田泰尚, 石上敬介, 柾木喜晴, 室田文子, 阿久津典之

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 64 ( Suppl.1 ) 766 - 766 2022.04

ESD、EMRと比較した大腸hybrid ESDの位置付けメタアナリシスによる解析

吉井新二, 菊地剛史, 林優希, 三宅高和, 大和田紗枝, 平山大輔, 菅野伸一, 風間友江, 野島正寛, 山野泰穂, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 64 ( Suppl.1 ) 756 - 756 2022.04

術後5年目に発症した肝門部胆管癌大腸転移の1例

浪岡万由子, 本谷雅代, 世戸凌太, 我妻康平, 川上裕次郎, 柾木喜晴, 石上敬介, 室田文子, 沖田憲司, 木村康利, 竹政伊知朗, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 130回・124回 48 - 48 2022.03

Interim analysis of a multicenter registry study of COVID-19 patients with inflammatory bowel disease in Japan (J-COSMOS).

Hiroshi Nakase, Yuki Hayashi, Daisuke Hirayama, Takayuki Matsumoto, Minoru Matsuura, Hideki Iijima, Katsuyoshi Matsuoka, Naoki Ohmiya, Shunji Ishihara, Fumihito Hirai, Daiki Abukawa, Tadakazu Hisamatsu

Journal of gastroenterology 57 ( 3 ) 174 - 184 2022.03 [Domestic journal]

BACKGROUND: The spread of coronavirus disease 2019 (COVID-19) had a major impact on the health of people worldwide. The clinical background and clinical course of inflammatory bowel disease (IBD) among Japanese patients with COVID-19 remains unclear. METHODS: This study is an observational cohort of Japanese IBD patients diagnosed with COVID-19. Data on age, sex, IBD (classification, treatment, and activity), COVID-19 symptoms and severity, and treatment of COVID-19 were analyzed. RESULTS: From 72 participating facilities in Japan, 187 patients were registered from June 2020 to October 2021. The estimated incidence of COVID19 in Japanese IBD patients was 0.61%. The majority of IBD patients with COVID-19 (73%) were in clinical remission. According to the WHO classification regarding COVID-19 severity, 93% (172/184) of IBD patients had non-severe episodes, while 7% (12/184) were severe cases including serious conditions. 90.9% (165/187) of IBD patients with COVID-19 had no change in IBD disease activity. A logistic regression analysis stepwise method revealed that older age, higher body mass index (BMI), and steroid use were independent risk factors for COVID-19 severity. Six of nine patients who had COVID-19 after vaccination were receiving anti-tumor necrosis factor (TNF)-α antibodies. CONCLUSION: Age, BMI and steroid use were associated with COVID-19 severity in Japanese IBD patients.

DOI PubMed

炎症性腸疾患患者を対象とした日本のCOVID-19調査と質問調査(J-DESIRE)(Japan COVID-19 Survey and Questionnaire in inflammatory bowel disease(J-DESIRE))

我妻康平, 仲瀬裕志, 松本主之, 松岡克善, 松浦稔, 大宮直木, 飯島英樹, 平井郁仁, 石原俊治, 野島正寛, 久松理一

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 119 ( 臨増総会 ) A341 - A341 2022.03

病態解明による大腸腫瘍診療の新展開早期大腸がん浸潤先進部の分子解析による新規バイオマーカー・治療標的の探索

須藤豪太, 鈴木拓, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 119 ( 臨増総会 ) A104 - A104 2022.03

難治性腹水を呈した全身性結晶蓄積性組織球症の1例

大原成喜, 沼田泰尚, 沼田有斗, 谷口正浩, 越前栄次朗, 平野雄大, 我妻康平, 川上裕次郎, 柾木喜晴, 石上敬介, 室田文子, 阿久津典之, 本谷雅代, 佐々木茂, 真柄和史, 菅原太郎, 仲瀬裕志

FDG-PETを契機に診断に至ったIgG4関連消化管病変の1例

沼田有斗, 川上裕次郎, 越前栄次郎, 我妻康平, 沼田泰尚, 石上敬介, 柾木喜晴, 室田文子, 阿久津典之, 本谷雅代, 佐々木茂, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 130回・124回 50 - 50 2022.03

SpyGlass DSによるIPMNの術前診断

川上裕次郎, 本谷雅代, 越前栄次朗, 平野雄大, 我妻康平, 石上敬介, 柾木喜晴, 室田文子, 木村康利, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 119 ( 臨増総会 ) A373 - A373 2022.03

経大腸的EUS-FNAにて確定診断しえた術後再建腸管の膵尾部癌の1例

谷口正浩, 川上裕次郎, 越前栄次朗, 我妻康平, 沼田泰尚, 石上敬介, 柾木喜晴, 室田文子, 本谷雅代, 木村康利, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 130回・124回 45 - 45 2022.03

当科における免疫関連大腸炎の検討

大和田紗恵, 三宅高和, 風間友江, 平山大輔, 菅野伸一, 吉井新二, 山野泰穂, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 119 ( 臨増総会 ) A390 - A390 2022.03

高齢者に対する内視鏡的胃粘膜下層剥離術の偶発症における予後予測因子の検討

三宅高和, 吉井新二, 谷口正浩, 大和田紗恵, 風間友江, 平山大輔, 菅野伸一, 山野泰穂, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 119 ( 臨増総会 ) A336 - A336 2022.03

胆道鏡下生検検体で遺伝パネル検査を施行しえた切除不能胆嚢管癌の1例

越前栄次朗, 川上裕次郎, 我妻康平, 沼田泰尚, 石上敬介, 柾木喜晴, 室田文子, 阿久津典之, 本谷雅代, 佐々木茂, 杉田真太郎, 櫻井晃洋, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 130回・124回 58 - 58 2022.03

治療困難肝内結石に対するSpyGlass DSを用いた胆道鏡下治療の検討

越前栄次朗, 川上裕次郎, 我妻康平, 沼田泰尚, 石上敬介, 柾木喜晴, 室田文子, 阿久津典之, 本谷雅代, 佐々木茂, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 119 ( 臨増総会 ) A372 - A372 2022.03

転移性肺腫瘍に対するEUS-FNAにて診断した後腹膜原発の絨毛癌の1例

廣部洋輔, 川上裕次郎, 越前栄次朗, 我妻康平, 沼田泰尚, 石上敬介, 柾木喜晴, 室田文子, 阿久津典之, 本谷雅代, 佐々木茂, 辻脇光洋, 舛森直哉, 仲瀬裕志

消化器疾患診療に必要なバイオマーカー開発のための研究 HSP47は胆道癌の予後を規定するBiomarkerになりえるか?

本谷雅代, 柾木喜晴, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 119 ( 臨増総会 ) A172 - A172 2022.03

Gel immersion endoscopic mucosal resection for early gastric cancer near the pyloric ring.

Katsuyoshi Miura, Gota Sudo, Mitsunobu Saito, Kazunori Onuma, Yumemi Takada, Atsushi Yawata, Hiroshi Nakase

Endoscopy 2022.02 [International journal]

DOI PubMed

高齢者切除不能膵癌患者に対するGEM+nabPTX療法の有効性と安全性

大和田紗恵, 室田文子, 本谷雅代, 我妻康平, 沼田泰尚, 川上裕次郎, 石上敬介, 柾木喜晴, 阿久津典之, 佐々木茂, 仲瀬裕志

日本高齢消化器病学会誌 ( (NPO)日本高齢消化器病学会 ) 24 ( 2 ) 81 - 88 2022.02

GEM+nabPTX(GnP)を施行した切除不能膵癌をO群(≧75歳)28例とY群(<75歳)52例の2群に分け、有効性・安全性を比較検討した。無増悪生存期間はO群8.9ヵ月、Y群7.8ヵ月(P=0.59)、生存期間はO群17.2ヵ月、Y群22.1ヵ月(P=0.22)であり、多変量解析の結果、年齢はいずれにおいても独立した予後因子とはならなかった。4ヵ月目までのRelative dose intensityはO群で有意に低かった(O群64%、Y群84%、P=0.025)。有害事象の頻度は両群で同等であったが、O群の有害事象中止症例は全例二次治療に移行できなかった。高齢者でもGnPを実施可能だが、より緻密な忍容性評価を要する。(著者抄録)

Impaired tryptophan metabolism in the gastrointestinal tract of patients with critical coronavirus disease 2019.

Yoshihiro Yokoyama, Tomoko Ichiki, Tsukasa Yamakawa, Yoshihisa Tsuji, Koji Kuronuma, Satoshi Takahashi, Eichi Narimatsu, Hiroshi Nakase

Frontiers in medicine 9 941422 - 941422 2022 [International journal]

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is still causing a global pandemic. But the mechanism of COVID-19 severity is not well elucidated. MATERIALS AND METHODS: We conducted two single-center observational studies of patients with COVID-19. In the first study, the enrolled patients were distinguished based on critical vs. non-critical COVID-19. We collected blood samples from the patients at admission to measure markers related to inflammation and thrombosis and stool samples to analyze the fecal microbiome, metabolome, and calprotectin level. In the second study, we collected ileum and colon tissue samples from patients with critical COVID-19 who required colonoscopy due to severe gastrointestinal symptoms and analyzed mucosal gene expression. RESULTS: A total of 19 blood samples and 10 stool samples were collected. Interleukin (IL)-6 was the only serum inflammatory marker with significantly higher levels in the critical group than in the non-critical group. The fecal calprotectin level in the critical group was significantly higher than that in the non-critical group (P = 0.03), regardless of the presence of gastrointestinal symptoms. Stool metabolomic analysis showed that the level of indole-3-propionic acid, a ligand for aryl hydrocarbon receptor (AhR), was markedly decreased in the critical group compared to that in the non-critical group (P = 0.01). The expression of genes involved in tryptophan metabolism, including ACE2, AHR, CARD9, and IL22, was downregulated in the ileum of critical COVID-19 patients who required a colonoscopy. DISCUSSION: Critical COVID-19 patients have gastrointestinal inflammation potentially caused by impaired tryptophan metabolism in the small intestine due to decreased expression of genes involved in tryptophan metabolism.

DOI PubMed

間葉系幹細胞を用いた炎症性疾患の細胞治療

永石歓和, 仲瀬裕志

BIO Clinica 37 87 - 90 2022

Snapshots of lymphatic pathways in colorectal cancer surgery using near-infrared fluorescence, in vivo and ex vivo.

Yu Sato, Tetsuta Satoyoshi, Kenji Okita, Daisuke Kyuno, Atsushi Hamabe, Koichi Okuya, Toshihiko Nishidate, Emi Akizuki, Masayuki Ishii, Hiro-O Yamano, Shintaro Sugita, Hiroshi Nakase, Tadashi Hasegawa, Ichiro Takemasa

European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 47 ( 12 ) 3130 - 3136 2021.12 [International journal]

INTRODUCTION: Indocyanine green (ICG) fluorescence imaging has been used for blood flow assessment in anastomoses in the field of colorectal cancer surgery. However, whether ICG fluorescence is related to the presence of cancer cells in the lymph nodes is unclear. We explored the utilization of ICG fluorescence in colorectal cancer surgery. MATERIALS AND METHODS: ICG was injected into the submucosa around the tumor before radical resection in colorectal cancer patients. Intraoperatively, near-infrared (NIR) fluorescence was used for lymphatic flow visualization. After specimen removal, harvested lymph nodes were classified as positive or negative based on the detection of fluorescence, followed by pathological examination. ICG distribution on a section of each lymph node was examined by fluorescence microscopy. RESULTS: Overall, 155 patients underwent real-time NIR fluorescence imaging-guided surgery. Altogether, 1,017 lymph nodes were retrieved from these patients. Metastatic lymph nodes were present in 36 (5.8%) of 622 fluorescence-negative lymph nodes, which was significantly higher than 11 (2.8%) of 395 fluorescence-positive lymph nodes (odds ratio: 2.15, P = 0.03). Fluorescence microscopy of metastatic lymph nodes showed that ICG fluorescence was present in the normal structural region but not in the cancerous region of the lymph nodes. Furthermore, ICG fluorescence was observed in all metastatic lymph nodes, except those with cancer cells occupying >90% of the total area. CONCLUSIONS: ICG fluorescence detected only the normal parts of the lymph node draining from the peritumoral area and not the cancer tissues. This finding is important for developing appropriate strategies for navigation surgery using NIR fluorescence.

DOI PubMed

Mediterranean fever gene-associated enterocolitis in an elderly Japanese woman.

Yasuhiro Shibata, Keisuke Ishigami, Tomoe Kazama, Toshiyuki Kubo, Hiro-O Yamano, Shintaro Sugita, Masaki Murata, Hiroshi Nakase

Clinical journal of gastroenterology 14 ( 6 ) 1661 - 1666 2021.12 [Domestic journal]

An 86-year-old woman was admitted to our hospital with anemia. She had never experienced symptoms of serositis. Colonoscopy revealed colitis with erosions and a friable mucosa. First, she was diagnosed with unclassified inflammatory bowel disease (IBD-U). We suspected familial Mediterranean fever as a differential diagnosis of IBD-U, and MEFV gene analysis showed heterozygosity for Exon2 R202Q. The patient was treated with colchicine 0.5 mg. After 4 months, a follow-up colonoscopy showed remarkable improvement of the mucosal inflammation throughout the entire colon. MEFV gene-associated enterocolitis responding to colchicine may be observed in patients with IBD-U and elucidating the role of MEFV gene mutations in intestinal inflammation is a future challenge.

DOI PubMed

Crohn's disease and early exposure to thiopurines are independent risk factors for mosaic chromosomal alterations in patients with inflammatory bowel diseases.

Yoichi Kakuta, Hideya Iwaki, Junji Umeno, Yosuke Kawai, Masahiro Kawahara, Tetsuya Takagawa, Yusuke Shimoyama, Takeo Naito, Rintaro Moroi, Masatake Kuroha, Hisashi Shiga, Kenji Watanabe, Shiro Nakamura, Hiroshi Nakase, Makoto Sasaki, Hiroyuki Hanai, Yuta Fuyuno, Atsushi Hirano, Takayuki Matsumoto, Hisaaki Kudo, Naoko Minegishi, Minoru Nakamura, Tadakazu Hisamatsu, Akira Andoh, Masao Nagasaki, Katsushi Tokunaga, Yoshitaka Kinouchi, Atsushi Masamune

Journal of Crohn's & colitis 16 ( 4 ) 643 - 655 2021.11 [International journal]

BACKGROUND AND AIMS: Mosaic chromosomal alterations (mCAs) increase the risk for hematopoietic malignancies and may be risk factors for several other diseases. Inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), are associated with mCAs, and patients may be at risk for hematopoietic malignancy development and/or modification of IBD phenotypes. In the present study, we screened patients with IBD for the presence of mCAs and explored the possible pathophysiological and genetic risk factors for mCAs. METHODS: We analyzed mCAs in peripheral blood from 3,339 patients with IBD and investigated the clinical and genetic risk factors for mCAs. RESULTS: CD and exposure to thiopurines before the age of 20 years were identified as novel independent risk factors for mCAs (odds ratio = 2.15 and 5.68, P = 1.17e-2 and 1.60e-3, respectively). In contrast, there were no significant associations of disease duration, anti-tumor necrosis factor alpha antibodies, or other clinical factors with mCAs. Gene ontology enrichment analysis revealed that genes specifically located in the mCAs in patients with CD were significantly associated with factors related to mucosal immune responses. A genome-wide association study revealed that ERBIN, CD96, and AC068672.2 were significantly associated with mCAs in patients with CD (P = 1.56e-8, 1.65e-8, and 4.92e-8, respectively). CONCLUSION: The difference in mCAs between patients with CD and UC supports the higher incidence of hematopoietic malignancies in CD. Caution should be exercised when using thiopurines in young patients with IBD, particularly CD, in light of possible chromosomal alterations.

DOI PubMed

Association of the Low-density Lipoprotein Cholesterol/High-density Lipoprotein Cholesterol Ratio with Glecaprevir-pibrentasvir Treatment.

Noriyuki Akutsu, Shigeru Sasaki, Takeshi Matsui, Hirofumi Akashi, Kazuhiko Yonezawa, Keisuke Ishigami, Masayuki Tsujisaki, Hiroyuki Isshiki, Atsushi Yawata, Satoshi Yamaoka, Toshihiro Ban, Takeya Adachi, Seiya Nakahara, Hideyasu Takagi, Kohei Nakachi, Katsunori Tanaka, Takehiro Hirano, Itaru Yamamoto, Hiroyuki Kaneto, Kohei Wagatsuma, Yasunao Numata, Hiroshi Nakase

Internal medicine (Tokyo, Japan) 60 ( 21 ) 3369 - 3376 2021.11 [Domestic journal]

Objective The change in serum lipid levels by direct-acting antiviral (DAA) treatment for chronic hepatitis C varies depending on the type of DAA. How the lipid level changes induced by glecaprevir-pibrentasvir (G/P) treatment contribute to the clinical outcome remains unclear. We conducted a prospective observational study to evaluate the effectiveness of G/P treatment and the lipid level changes. Methods The primary endpoint was a sustained virologic response at 12 weeks (SVR12). The total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels and LDL-C/HDL-C (L/H) ratio were measured every two weeks. Patients This study included 101 patients. Seventeen cases of liver cirrhosis and nine cases of DAA retreatment were registered. The G/P treatment period was 8 weeks in 74 cases and 12 weeks in 27 cases. Results SVR12 was evaluated in 96 patients. The rate of achievement of SVR12 in the evaluable cases was 100%. We found significantly elevated TC and LDL-C levels over the observation period compared to baseline. The serum levels of HDL-C did not change during treatment but were significantly increased after treatment compared to baseline. The L/H ratio was significantly increased two weeks after the start of treatment but returned to the baseline after treatment. Conclusion The primary endpoint of the SVR12 achievement rate was 100%. G/P treatment changed the serum lipid levels. Specifically, the TC and LDL-C levels increased during and after treatment, and the HDL-C levels increased after treatment. G/P treatment may be associated with a reduced thrombotic risk. Therefore, validation in large trials is recommended.

DOI PubMed

Mixed neuroendocrine non-neuroendocrine neoplasm of the gallbladder complicated by a pancreaticobiliary maljunction of a non-dilated biliary duct: A case report.

Kohei Wagatsuma, Kotaro Akita, Masayo Motoya, Yasutoshi Kimura, Shintaro Sugita, Takehiro Hirano, Yujiro Kawakami, Yasunao Numata, Keisuke Ishigami, Yoshiharu Masaki, Ayako Murota, Masahiro Shitani, Noriyuki Akutsu, Shigeru Sasaki, Hiroshi Nakase

Medicine 100 ( 39 ) e27336 2021.10 [International journal]

RATIONALE: Mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN) is a rare tumor. MiNEN of the gallbladder (GB) with pancreaticobiliary maljunction (PMJ) is extremely rare. The origin of MiNEN of the GB remains unknown; the biliary tract normally lacks neuroendocrine cells. MiNEN of the GB has a poor prognosis; because of its rarity, no treatment or management guidelines have been established yet. PATIENT CONCERNS: A 47-year-old male presenting with right hypochondrial pain and malaise for 3 months was referred to our hospital for further management. DIAGNOSIS: The neuron-specific enolase level was increased. Contrast-enhanced computed tomography revealed a mass of 70 mm in size with unclear boundaries in the liver. The GB was surrounded by this mass, narrowing the lumen of the GB. Many swollen lymph nodes were observed in the hepatoduodenal ligament. Endoscopic retrograde cholangiopancreatography revealed a PMJ with a non-dilated biliary duct. A percutaneous biopsy was performed on the liver mass, and the pathological findings were neuroendocrine carcinoma (NEC) (small cell type). We diagnosed a NEC of the GB, T3N1M0, stage IIIB (Union for International Cancer Control, 7th edition). INTERVENTIONS: Because of advanced lymph node metastasis, we considered this tumor difficult to cure solely by surgical intervention. After initial chemotherapy consisting of cisplatin and irinotecan, a marked reduction in both tumor and lymph node sizes enabled conversion surgery. The pathological diagnosis of the resected tumor was MiNEN consisting of NEC and adenocarcinoma. The primary lesion was the adenocarcinoma occupying the luminal side of the GB. As a postsurgical treatment, the patient received additional irradiation therapy to the common hepatic duct and liver stump because of positive surgical margins. OUTCOMES: At 13 months postoperatively, computed tomography findings revealed the appearance of a hypervascular liver tumor, and laboratory data showed increased serum neuron-specific enolase levels. Chemotherapy was unsuccessful, leading to the death of the patient 36 months from the date of diagnosis. LESSONS: There are several reports on the development of MiNEN of the GB. In our case, a PMJ-related adenocarcinoma of the GB transdifferentiated into NEC. Further accumulation of cases is necessary to establish a treatment strategy for MiNEN of the GB.

DOI PubMed

The clinical efficacy of azathioprine as maintenance treatment for autoimmune pancreatitis: a systematic review and meta-analysis.

Yoshiharu Masaki, Hiroshi Nakase, Yoshihisa Tsuji, Masanori Nojima, Kyoko Shimizu, Nobumasa Mizuno, Tsukasa Ikeura, Kazushige Uchida, Akio Ido, Yuzo Kodama, Hiroshi Seno, Kazuichi Okazaki, Seiji Nakamura, Atsushi Masamune

Journal of gastroenterology 56 ( 10 ) 869 - 880 2021.10 [Domestic journal]

The effectiveness of azathioprine (AZA) in preventing relapse and maintaining autoimmune pancreatitis (AIP) remission has been reported; however, most of these studies are case series with no randomized control trials available in the literature. Therefore, this study performed a systematic review and meta-analysis of the existing literature on this subject to determine the clinical efficacy of AZA as maintenance therapy for AIP patients. A systematic search was performed to identify studies on the clinical efficacy of AZA as maintenance therapy in AIP patients. The crude multiple relapse rate was estimated to assess the ability of AZA to control relapses in AIP. Pooled estimates were obtained using a random-effects model with the DerSimonian-Laird method. We identified AIP patients who did not respond to initial steroid treatment, experienced steroid weaning failure, or those who relapsed during remission as refractory cases. After reviewing the studies, ten articles fulfilled the inclusion criteria and were selected for meta-analysis. Of all 4504 patients, 3534 patients were treated with steroids, and 346 patients were treated with AZA for relapsed AIP. In this meta-analysis, 14/73 (19.2%) patients receiving AZA for refractory AIP relapsed. Meanwhile, 14/47 (29.8%) patients without AZA experienced relapse. The integrated odds ratio for relapse risk in patients receiving AZA was estimated to be 0.52 (p = 0.15). This systematic review and meta-analysis demonstrated the efficacy of AZA in preventing relapse of AIP, which supports the use of AZA as a maintenance treatment in patients with AIP who relapse upon withdrawal of steroid therapy.

DOI PubMed

後腹膜線維症に対するEUS-FNAの可能性

川上裕次郎, 本谷雅代, 高田夢実, 平野雄大, 我妻康平, 沼田泰尚, 石上敬介, 柾木喜晴, 室田文子, 阿久津典之, 佐々木茂, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 63 ( Suppl.2 ) 2047 - 2047 2021.10

当科における胆道癌に対する化学放射線療法の治療成績

平野雄大, 本谷雅代, 我妻康平, 沼田泰尚, 川上裕次郎, 石上敬介, 柾木喜晴, 室田文子, 阿久津典之, 佐々木茂, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 118 ( 臨増大会 ) A468 - A468 2021.10

炎症性腸疾患のモニタリングと治療選択潰瘍性大腸炎に対するウステキヌマブの実臨床での治療成績と短期有効性予測因子

安藤勝祥, 藤谷幹浩, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 118 ( 臨増大会 ) A652 - A652 2021.10

当科における胆道癌に対する化学放射線療法の治療成績

平野雄大, 本谷雅代, 我妻康平, 沼田泰尚, 川上裕次郎, 石上敬介, 柾木喜晴, 室田文子, 阿久津典之, 佐々木茂, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 118 ( 臨増大会 ) A468 - A468 2021.10

限局性膵管狭窄に対する連続膵液細胞診の有用性の検討

柾木喜晴, 平野雄大, 我妻康平, 沼田泰尚, 川上裕次郎, 石上敬介, 室田文子, 本谷雅代, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 118 ( 臨増大会 ) A780 - A780 2021.10

Multicenter, cross-sectional, observational study on Epstein-Barr viral infection status and thiopurine use by age group in patients with inflammatory bowel disease in Japan (EBISU study).

Miki Miura, Hirotaka Shimizu, Daisuke Saito, Jun Miyoshi, Minoru Matsuura, Takahiro Kudo, Daisuke Hirayama, Masashi Yoshida, Katsuhiro Arai, Itaru Iwama, Hiroshi Nakase, Toshiaki Shimizu, Tadakazu Hisamatsu

Journal of gastroenterology 2021.09 [Domestic journal]

BACKGROUND: The Epstein-Barr virus (EBV) infection status in patients with inflammatory bowel disease (IBD), particularly those using thiopurines, may be associated with the risk of lymphoproliferative disorder and hemophagocytic lymphohistiocytosis. This was the first multicenter survey of EBV infection in Japanese patients with IBD. Factors related to the EBV infection status were also investigated. METHODS: Five tertiary institutions in Japan participated in this study to examine pediatric and adult patients with IBD. Serum EBV anti-viral capsid antigen (VCA) IgG, EBV anti-VCA IgM, and anti-EBV nuclear antigen-antibody were measured in 495 patients with IBD. The patients' information was obtained from their medical records. Prior EBV infection was defined as anti-VCA IgM negativity and anti-VCA IgG positivity (UMIN000033004). RESULTS: The patients' median age was 25 years (range 0-92 years). Of the 495 patients, nine were anti-VCA IgM-positive and 354 were anti-VCA IgG-positive (seroprevalence: 72.8%). The proportion of patients with prior EBV infection was 0% for those aged < 5 years, < 60% for those aged < 30 years, and > 90% for those aged > 30 years. The proportion of EBV-uninfected patients using thiopurines was 28.4% (52/183) for all patients and 51.8% (44/85) for pediatric patients. Age was significantly associated with anti-VCA IgG seropositivity (p < 0.01, odds ratio: 0.902, 95% confidence interval: 0.880-0.925). No cases of lymphoproliferative disorder, hemophagocytic lymphohistiocytosis, or chronic active EBV infection were reported. CONCLUSIONS: Approximately 30% of Japanese patients with IBD were EBV-uninfected, including those using thiopurines. Age was a significant factor for anti-VCA IgG seropositivity.

DOI PubMed

Dead or alive? Pitfall of survival analysis with TCGA datasets.

Masashi Idogawa, Masayo Koizumi, Tomomi Hirano, Shoichiro Tange, Hiroshi Nakase, Takashi Tokino

Cancer biology & therapy 22 ( 10-12 ) 1 - 2 2021.09 [International journal]

We often encounter situations in which data from the TCGA that have been analyzed in papers we read or reviewed cannot be reproduced, even when TCGA datasets are used, especially in survival analyses. Therefore, we attempted to confirm the data source for TCGA survival analysis and found that several websites used to analyze the survival data of TCGA datasets inappropriately handle the survival data, causing differences in statistical analyses. This causes the misinterpretation of results because figures of survival analysis results in several papers are sometimes exactly as generated by these sites, and the results depend on only the tools provided by these sites. We would like to make this situation widely known and raise the problem for scientific soundness.

DOI PubMed

Retrograde Colonic Intussusception Caused by a Pedunculated Adenoma.

Gota Sudo, Hideyasu Takagi, Akira Goto, Seiya Nakahara, Yuji Hinoda, Hiroshi Nakase

The American journal of gastroenterology 116 ( 9 ) 1822 - 1822 2021.09 [International journal]

DOI PubMed

活性化マクロファージはIL-1β-SAA1 axisを介して早期大腸がんの浸潤を促進する

須藤豪太, 山本英一郎, 青木敬則, 高澤啓, 新沼猛, 久保俊之, 萬顕, 吉戸文乃, 北嶋洋志, 甲斐正広, 小山内誠, 仲瀬裕志, 鈴木拓

日本癌学会総会記事 ( (一社)日本癌学会 ) 80回 [P14 - 3] 2021.09

Helicobacter pylori除菌後胃がんと背景胃粘膜におけるDNAメチローム解析

山本英一郎, 吉戸文乃, 須藤豪太, 三橋慧, 北嶋洋志, 新沼猛, 甲斐正広, 原田拓, 佐々木基, 久保俊之, 山野泰穂, 仲瀬裕志, 菅井有, 鈴木拓

日本癌学会総会記事 ( (一社)日本癌学会 ) 80回 [P14 - 5] 2021.09

エピジェネティクス阻害剤のGIST細胞におけるエピゲノム修飾、遺伝子発現への影響の統合解析

吉戸文乃, 須藤豪太, 北嶋洋志, 新沼猛, 甲斐正広, 原田拓, 佐々木基, 久保俊之, 仲瀬裕志, 菅井有, 鈴木拓

日本癌学会総会記事 ( (一社)日本癌学会 ) 80回 [P14 - 7] 2021.09

内視鏡診療で目指す大腸腫瘍性病変に対するTranslational researchの確立

三宅高和, 吉井新二, 鈴木拓, 山野泰穂, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 129回・123回 26 - 26 2021.09

EUS-FNAが診断に有用であったサルコイドーシスの2症例

室田文子, 川上裕次郎, 柾木喜晴, 石上敬介, 阿久津典之, 本谷雅代, 佐々木茂, 菅原太郎, 杉田真太郎, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 129回・123回 45 - 45 2021.09

ステロイド抵抗性の自己免疫性膵炎・IgG4関連硬化性胆管炎合併例に対し、アザチオプリンが有効であった1例

沼田有斗, 柾木喜晴, 我妻康平, 沼田泰尚, 川上裕次郎, 石上敬介, 室田文子, 元谷雅代, 佐々木基, 有村佳昭, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 129回・123回 44 - 44 2021.09

大腸癌のParaneoplastic syndromeと考えられた自己免疫性膵炎の1例

世戸凌太, 川上裕次郎, 平野雄大, 我妻康平, 沼田泰尚, 石上敬介, 柾木喜晴, 室田文子, 本谷雅代, 杉田真太朗, 沖田憲司, 竹政伊知朗, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 129回・123回 43 - 43 2021.09

Immunoglobulin G4-related autoimmune hepatitis simultaneously concomitant with autoimmune pancreatitis: a case report.

Yoshihiro Yokoyama, Noriyuki Akutsu, Yasunao Numata, Keiko Okuda, Rena Morita, Yoshiharu Masaki, Hajime Sasaki, Ryo Suzuki, Takashi Yabana, Yoshiaki Arimura, Yoshihiro Kondo, Hiroshi Nakase

Clinical journal of gastroenterology 14 ( 6 ) 1740 - 1745 2021.08 [Domestic journal]

Thus far, there have been limited case reports on immunoglobulin G4-related autoimmune hepatitis (IgG4-AIH), and its clinical features have not been elucidated. We herein report a rare case of IgG4-AIH simultaneously concomitant with autoimmune pancreatitis (AIP). A 73-year-old female was admitted to our hospital for further investigation of elevated levels of liver transaminase and pancreatic enzymes. Her serological tests showed a high antinuclear antibody titer, and elevated IgG and IgG4 levels. Liver biopsy revealed interface hepatitis and bridging necrosis with IgG4-positive lymphoplasmacytic infiltration in the portal area. Moreover, contrast-enhanced computed tomography (CECT) showed pancreatic tail enlargement, and magnetic resonance cholangiopancreatography showed skipped narrowing of the main pancreatic duct in the pancreatic tail. Endoscopic ultrasonography-fine needle aspiration specimens showed no malignant cells. Based on these results, we diagnosed her with IgG4-AIH simultaneously concomitant with probable type 1 AIP. She was started on prednisolone (PSL) at 35 mg/d, and her symptoms and liver transaminase levels improved. One month after starting treatment, CECT showed improvement of pancreatic tail enlargement. She is maintained on 5 mg PSL/d and has been in remission for two years.

DOI PubMed

Gastrointestinal involvement in a patient with familial Mediterranean fever mimicking Crohn’s disease: a case report

Yoshihiro Yokoyama, Tsukasa Yamakawa, Tadashi Ichimiya, Tomoe Kazama, Daisuke Hirayama, Kohei Wagatsuma, Hiroshi Nakase

Clinical Journal of Gastroenterology ( Springer Japan ) 14 ( 4 ) 1103 - 1107 2021.08

Familial Mediterranean fever (FMF) in gastrointestinal involvement has been considered rare, but resent reports suggest that FMF causes enterocolitis which is similar endoscopic findings to inflammatory bowel disease. The clinical characteristics and endoscopic findings of FMF with enterocolitis remain unclear. Here, we report a case of an FMF patient who had enterocolitis with stricture of the terminal ileum whose endoscopic and clinical features mimicked Crohn’s disease. A 23-year-old man who was diagnosed with FMF 10 years ago presented with abdominal pain and diarrhea. Colonoscopy showed terminal ileitis and aphthous colitis however, these findings, including the histopathology, did not confirm Crohn’s disease. Therefore, we diagnosed FMF with enterocolitis and administered anti-interleukin-1β monoclonal antibody (canakinumab). The patient’s symptoms improved with treatment, but after 1 year, lower abdominal pain recurred. Colonoscopy revealed a stricture of the terminal ileum. Endoscopic balloon dilation relieved his symptoms. At present, he has been followed up without surgical treatment by endoscopic balloon dilation every 6 month. Clinicians should be aware that FMF accompanied with enterocolitis may resemble Crohn’s disease.

DOI PubMed

Successful hemostasis of bleeding gastric inflammatory fibroid polyp by endoscopic treatment in a patient with severe COVID-19.

Ayako Murota, Shinji Yoshi, Ryu Okuda, Sae Oowada, Tsukasa Yamakawa, Tomoe Kazama, Daisuke Hirayama, Keisuke Ishigami, Hiro-O Yamano, Eichi Narimatu, Shintaro Sugita, Tadashi Hasegawa, Hiroshi Nakase

Clinical journal of gastroenterology 14 ( 4 ) 1008 - 1013 2021.08 [Domestic journal]

The coronavirus disease-2019 (COVID-19) has rapidly become a pandemic, resulting in a global suspension of non-emergency medical procedures such as screening endoscopic examinations. There have been several reports of COVID-19 patients presenting with gastrointestinal symptoms such as diarrhea and vomiting. In this report, we present a case of successful hemostasis of bleeding gastric inflammatory fibroid polyp by endoscopic treatment in a patient with severe COVID-19. The case was under mechanical ventilation with extracorporeal membrane oxygenation (ECMO), and the airway was on a closed circuit. This indicates that COVID-19 is associated with not only lung injury but also intestinal damage, and that proper protective protocols are essential in guaranteeing the best outcomes for patients and clinical professionals during this pandemic.

DOI PubMed

Activated macrophages promote invasion by early colorectal cancer via an interleukin 1β-serum amyloid A1 axis.

Gota Sudo, Hironori Aoki, Eiichiro Yamamoto, Akira Takasawa, Takeshi Niinuma, Ayano Yoshido, Hiroshi Kitajima, Akira Yorozu, Toshiyuki Kubo, Taku Harada, Kazuya Ishiguro, Masahiro Kai, Akio Katanuma, Hiro-O Yamano, Makoto Osanai, Hiroshi Nakase, Hiromu Suzuki

Cancer science 112 ( 10 ) 4151 - 4165 2021.07 [International journal]

Submucosal invasion and lymph node metastasis are important issues affecting treatment options for early colorectal cancer (CRC). In this study, we aimed to unravel the molecular mechanism underlying the invasiveness of early CRCs. We performed RNA-sequencing (RNA-seq) with poorly differentiated components (PORs) and their normal counterparts isolated from T1 CRC tissues and detected significant upregulation of serum amyloid A1 (SAA1) in PORs. Immunohistochemical analysis revealed that SAA1 was specifically expressed in PORs at the invasive front of T1b CRCs. Upregulation of SAA1 in CRC cells promoted cell migration and invasion. Coculture experiments using CRC cell lines and THP-1 cells suggested that interleukin 1β (IL-1β) produced by macrophages induces SAA1 expression in CRC cells. Induction of SAA1 and promotion of CRC cell migration and invasion by macrophages were inhibited by blocking IL-1β. These findings were supported by immunohistochemical analysis of primary T1 CRCs showing accumulation of M1-like/M2-like macrophages at SAA1-positive invasive front regions. Moreover, SAA1 produced by CRC cells stimulated upregulation of matrix metalloproteinase-9 in macrophages. Our data suggest that tumor-associated macrophages at the invasive front of early CRCs promote cancer cell migration and invasion through induction of SAA1 and that SAA1 may be a predictive biomarker and a useful therapeutic target.

DOI PubMed

Traction-assisted endoscopic submucosal dissection for a previously tattooed colonic laterally spreading tumor.

Gota Sudo, Tokuma Tanuma, Takashi Fujisawa, Yuji Hinoda, Hiroshi Nakase

VideoGIE : an official video journal of the American Society for Gastrointestinal Endoscopy 6 ( 7 ) 329 - 332 2021.07 [International journal]

DOI PubMed

高齢者消化器がん化学療法〜高齢者のがん治療を安全・効果的に遂行するための取り組み当院における高齢者切除不能膵癌の診療実態

大和田紗恵, 室田文子, 我妻康平, 川上裕次郎, 沼田泰尚, 石上敬介, 柾木喜晴, 阿久津典之, 本谷雅代, 佐々木茂, 仲瀬裕志

日本高齢消化器病学会誌 ( (NPO)日本高齢消化器病学会 ) 24 ( 1 ) 117 - 117 2021.07

An Integrated Epigenome and Transcriptome Analysis to Clarify the Effect of Epigenetic Inhibitors on GIST.

Takeshi Niinuma, Hiroshi Kitajima, Eiichiro Yamamoto, Reo Maruyama, Hironori Aoki, Taku Harada, Kazuya Ishiguro, Gota Sudo, Mutsumi Toyota, Ayano Yoshido, Masahiro Kai, Hiroshi Nakase, Tamotsu Sugai, Hiromu Suzuki

Anticancer research 41 ( 6 ) 2817 - 2828 2021.06 [International journal]

BACKGROUND/AIM: Epigenetic alterations play an important role in the pathogenesis of gastrointestinal stromal tumors (GISTs). To obtain further insight into the GIST epigenome, we analyzed genome-wide histone modification and DNA methylation in GIST cells. MATERIALS AND METHODS: To reverse epigenetic silencing, GIST-T1 cells were treated with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor, and subsequently H3K4me3 levels, the DNA methylome, and the transcriptome were analyzed. RESULTS: Treatment with epigenetic inhibitors not only up-regulated genes with DNA methylation, but also genes related to interferon signaling. ChIP-seq analysis revealed that drug treatment up-regulated H3K4me3 levels in retrotransposons, including endogenous retroviruses (ERV). Finally, utilizing the omics data, we found that hypermethylation of MEG3 is a frequent event and an indicator of poorer prognosis in GIST patients. CONCLUSION: Epigenetic inhibitors may activate interferon signaling via viral mimicry in GIST cells. Moreover, epigenome data could be a useful resource to identify novel GIST-related genes.

DOI PubMed

Evidence-based clinical practice guidelines for inflammatory bowel disease 2020.

Hiroshi Nakase, Motoi Uchino, Shinichiro Shinzaki, Minoru Matsuura, Katsuyoshi Matsuoka, Taku Kobayashi, Masayuki Saruta, Fumihito Hirai, Keisuke Hata, Sakiko Hiraoka, Motohiro Esaki, Ken Sugimoto, Toshimitsu Fuji, Kenji Watanabe, Shiro Nakamura, Nagamu Inoue, Toshiyuki Itoh, Makoto Naganuma, Tadakazu Hisamatsu, Mamoru Watanabe, Hiroto Miwa, Nobuyuki Enomoto, Tooru Shimosegawa, Kazuhiko Koike

Journal of gastroenterology 56 ( 6 ) 489 - 526 2021.06 [Domestic journal]

Inflammatory bowel disease (IBD) is a general term for chronic or remitting/relapsing inflammatory diseases of the intestinal tract and generally refers to ulcerative colitis (UC) and Crohn's disease (CD). Since 1950, the number of patients with IBD in Japan has been increasing. The etiology of IBD remains unclear; however, recent research data indicate that the pathophysiology of IBD involves abnormalities in disease susceptibility genes, environmental factors and intestinal bacteria. The elucidation of the mechanism of IBD has facilitated therapeutic development. UC and CD display heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management depends on the understanding and tailoring of evidence-based interventions by physicians. In 2020, seventeen IBD experts of the Japanese Society of Gastroenterology revised the previous guidelines for IBD management published in 2016. This English version was produced and modified based on the existing updated guidelines in Japanese. The Clinical Questions (CQs) of the previous guidelines were completely revised and categorized as follows: Background Questions (BQs), CQs, and Future Research Questions (FRQs). The guideline was composed of a total of 69 questions: 39 BQs, 15 CQs, and 15 FRQs. The overall quality of the evidence for each CQ was determined by assessing it with reference to the Grading of Recommendations Assessment, Development and Evaluation approach, and the strength of the recommendation was determined by the Delphi consensus process. Comprehensive up-to-date guidance for on-site physicians is provided regarding indications for proceeding with the diagnosis and treatment.

DOI PubMed

Discontinuation of infliximab in patients with ulcerative colitis in remission (HAYABUSA): a multicentre, open-label, randomised controlled trial.

Taku Kobayashi, Satoshi Motoya, Shiro Nakamura, Takayuki Yamamoto, Masakazu Nagahori, Shinji Tanaka, Tadakazu Hisamatsu, Fumihito Hirai, Hiroshi Nakase, Kenji Watanabe, Takayuki Matsumoto, Masanori Tanaka, Takayuki Abe, Yasuo Suzuki, Mamoru Watanabe, Toshifumi Hibi

The lancet. Gastroenterology & hepatology 6 ( 6 ) 429 - 437 2021.06 [International journal]

BACKGROUND: Anti-tumour necrosis factor (TNF) agents are the mainstay of long-term treatment for refractory ulcerative colitis. However, long-term use of anti-TNF therapy might lead to an increased risk of malignancy or infection. To date, no randomised controlled trial has evaluated whether anti-TNF agents can be safely discontinued in patients with ulcerative colitis in remission. We therefore aimed to compare outcomes in these patients who continued infliximab with those who discontinued infliximab. METHODS: We did a multicentre, open-label randomised controlled trial at 24 specialist centres in Japan. We enrolled patients with ulcerative colitis who were in remission, had been treated with intravenous infliximab (5 mg/kg) every 8 weeks, and had started infliximab at least 14 weeks before study enrolment. No restrictions regarding age and comorbidities were used to exclude participation. Patients who were confirmed to be in remission for more than 6 months, to be corticosteroid-free, and to have a Mayo Endoscopic Subscore (MES) of 0 or 1 were centrally randomised. An independent organisation randomly assigned patients (1:1) into either the infliximab-continued group or infliximab-discontinued group, using a computer-generated stratified randomisation procedure. The stratified factors were the use of immunomodulators (yes or no) and MES (0 or 1). Neither patients nor health-care providers were masked to the randomisation. The primary endpoint was the remission rate at week 48 in the full analysis set, which was based on the intention-to-treat principle and excluded participants with no efficacy data after randomisation. This study was registered with the University Hospital Medical Information Network Center Trials registry, UMIN000012092. FINDINGS: Between June 16, 2014, and July 28, 2017, 122 patients were eligible for screening and a total of 95 patients were randomly assigned to the infliximab-continued group (n=48) or the infliximab-discontinued group (n=47). 92 patients (n=46 for both groups) were included in the full analysis set. 37 (80·4% [95% CI 66·1-90·6]) of 46 patients in the infliximab-continued group and 25 (54·3% [39·0-69·1]) of 46 patients in the infliximab-discontinued group were in remission at week 48. The between-group difference was 26·1% (95% CI 7·7-44·5; p=0·0076) before adjustment and 27·3% (95% CI 8·0-44·1; p=0·0059) after adjustment for stratification factors. Eight (17%) of 48 patients in the infliximab-continued group and six (13%) of 47 in the infliximab-discontinued group developed adverse events (between-group difference 3·9% [95% CI -10·3 to 18·1]; p=0·59). In the infliximab-continued group, one patient had an infusion reaction and two patients had psoriatic skin lesions. Eight (66·7%, 95% CI 34·9-90·1) of the 12 patients in the infliximab-discontinuation group who were re-treated with infliximab after relapsing were in remission within 8 weeks of re-treatment; none had infusion reactions. INTERPRETATION: Maintenance of remission was significantly more common in patients who continued infliximab than in those who discontinued. Discontinuing infliximab should therefore be discussed with caution, taking both risk of relapse and efficacy of re-treatment into account. FUNDING: Mitsubishi Tanabe Pharma Corporation and the Intractable Disease Project of the Ministry of Health, Labour and Welfare of Japan. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

DOI PubMed

縦隔内に進展した膵仮性嚢胞に対して内視鏡的に診断・治療し得た1例

中村友哉, 柾木喜晴, 川上裕次郎, 石上敬介, 室田文子, 本谷雅代, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 118 ( 6 ) 578 - 585 2021.06

症例は60歳男性.CTで縦隔内嚢胞を指摘され,膵由来病変が疑われ当科紹介となった.ERPで頭部主膵管から造影剤の膵管外漏出を認め,EUS下嚢胞穿刺で内液中の膵酵素高値が示されたため縦隔内膵仮性嚢胞と診断した.EUS下嚢胞ドレナージの後に長期的な内視鏡的経鼻膵管ドレナージ術を行うことで,膵液漏出部の自然閉鎖が得られた.縦隔内膵仮性嚢胞の診断・治療における内視鏡的手技の有用性を,本邦報告と合わせて考察した.(著者抄録)

Autoimmune gastritis concomitant with gastric adenoma and subacute combined degeneration of the spinal cord.

Masahiro Taniguchi, Gota Sudo, Yuzufumi Sekiguchi, Hiroshi Nakase

BMJ case reports 14 ( 5 ) 2021.05 [International journal]

A 62-year-old woman was referred to our department for further investigation of anaemia. Blood test showed macrocytic anaemia. Oesophagogastroduodenoscopy (OGD) revealed proximal-predominant gastric atrophy and flat elevated lesion in the gastric body. Several days after OGD, she complained of gait disturbance and was diagnosed with subacute combined degeneration of the spinal cord. Furthermore, laboratory tests showed positive for both anti-parietal cell and anti-intrinsic factor antibodies, as well as increased serum gastrin level and decreased pepsinogen I level, which confirmed the diagnosis of autoimmune gastritis (AIG). Anaemia and neurological symptoms were improved after vitamin B12 supplementation. Subsequently, the patient underwent gastric endoscopic submucosal dissection; histopathological examination revealed gastric adenoma. AIG can cause gastric neoplasms and vitamin B12 deficiency, with the latter resulting in pernicious anaemia and neurological disorders. These diseases are treatable but potentially life-threatening. This case highlights the importance of early diagnosis of AIG and proper management of its comorbidities.

DOI PubMed

Correction to: The characteristics of gastrointestinal symptoms in patients with severe COVID-19: a systematic review and meta-analysis (Journal of Gastroenterology, (2021), 56, 5, (409-420), 10.1007/s00535-021-01778-z)

Yuki Hayashi, Kohei Wagatsuma, Masanori Nojima, Tsukasa Yamakawa, Tadashi Ichimiya, Yoshihiro Yokoyama, Tomoe Kazama, Daisuke Hirayama, Hiroshi Nakase

Journal of Gastroenterology ( Springer Japan ) 56 ( 5 ) 421 2021.05

In the original publication of the article, the second sentence in second paragraph under the heading ‘‘What are the symptoms characteristic of severe COVID-19?’’ in page 4, should read as ‘‘Patients with severe COVID-19 had a signiﬁcantly higher incidence of abdominal pain than those non-severe illness (OR 2.70 [95% CI 1.17–6.27 p = 0.02 I2 = 0%]) (Fig. 2).’’ In Table 2, the value of ‘‘Effect estimate’’ for ‘‘2.4 Vomiting’’ should read as ‘‘0.53 [0.31, 0.92]’’.

DOI PubMed

Lynch症候群を背景とした多発微小大腸癌症例

柴田泰洋, 山野泰穂, 久保俊之, 吉井新二, 赤保内正和, 横山佳浩, 山川司, 風間友江, 山下健太郎, 能正勝彦, 須藤豪太, 山本英一郎, 鈴木拓, 杉田真太郎, 長谷川匡, 永塚真, 菅井有, 仲瀬裕志

日本大腸肛門病学会雑誌 ( (一社)日本大腸肛門病学会 ) 74 ( 5 ) 332 - 332 2021.05

Lower gastrointestinal bleeding from Dieulafoy's lesion in the transverse colon.

Gota Sudo, Hideyasu Takagi, Hiroshi Nakase

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 33 ( 4 ) e56-e57 2021.05 [International journal]

DOI PubMed

Lynch症候群を背景とした多発微小大腸癌症例

日本大腸肛門病学会雑誌 ( (一社)日本大腸肛門病学会 ) 74 ( 5 ) 332 - 332 2021.05

Does anti-tumor necrosis factor alpha prevent the recurrence of Crohn's disease? Systematic review and meta-analysis.

Motoi Uchino, Hiroki Ikeuchi, Keisuke Hata, Tomohiro Minagawa, Yuki Horio, Ryuichi Kuwahara, Shiro Nakamura, Kenji Watanabe, Masayuki Saruta, Toshimitsu Fujii, Taku Kobayashi, Ken Sugimoto, Fumihito Hirai, Motohiro Esaki, Sakiko Hiraoka, Katsuyoshi Matsuoka, Shinichiro Shinzaki, Minoru Matsuura, Nagamu Inoue, Hiroshi Nakase, Mamoru Watanabe

Journal of gastroenterology and hepatology 36 ( 4 ) 864 - 872 2021.04 [International journal]

BACKGROUND AND AIM: Anti-tumor necrosis factor (TNF) α agents are now well known to function as effective treatments for Crohn's disease (CD). Several meta-analyses have revealed the efficacy of anti-TNF therapy for preventing recurrence after surgery; however, the efficacies reported in some prospective studies differed according to the outcomes. Moreover, adverse events (AEs) were not well evaluated. We conducted this systematic review and meta-analysis to evaluate both the efficacy of anti-TNF therapy after stratification by the outcome of interest and the AEs. METHODS: We performed a systematic literature review of studies investigating anti-TNF therapy, CD, and postoperative recurrence. Meta-analyses were performed for endoscopic and clinical recurrence and AEs. RESULTS: A total of 570 participants, including 254 patients in the intervention group and 316 patients in the control group, in eight studies, were analyzed for recurrence. Based on the results of the meta-analysis, the efficacies of anti-TNF therapy at preventing endoscopic and clinical recurrence were as follows: relative risk (RR) 0.34, 95% confidence interval (CI) 0.22-0.53 and RR 0.60, 95% CI 0.36-1.02, respectively. The RR of AEs with anti-TNF therapy was 1.75 (95% CI 0.81-3.79). CONCLUSIONS: Anti-TNF therapy after surgery for CD displays efficacy at preventing endoscopic recurrence for 1-2 years, without increasing the incidence of AEs. However, clinical recurrence was not significantly reduced. The efficacy of postoperative anti-TNF therapy may differ in terms of the outcomes, which include long-term prevention, the avoidance of further surgery, and cost-effectiveness.

DOI PubMed

当科における連続膵液細胞診(SPACE:Serial Pancreatic juice Aspiration Cytological Examination)の有用性の検討

瀧澤歩, 征木喜晴, 平野雄大, 我妻康平, 沼田泰尚, 川上裕次郎, 石上敬介, 室田文子, 阿久津典之, 本谷雅代, 佐々木茂, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 63 ( Suppl.1 ) 959 - 959 2021.04

大腸観察法を考える Non traumatic tubeを用いた大腸内視鏡観察法の工夫

吉井新二, 柴田泰洋, 久保俊之, 山川司, 横山佳浩, 風間友江, 赤保内正和, 仲地耕平, 能正勝彦, 山下健太郎, 山野泰穂, 仲瀬裕志

日本大腸検査学会雑誌 ( 日本大腸検査学会 ) 37 ( 2 ) 126 - 126 2021.04

Interval between the First Cancer and the Genetic Diagnosis in Lynch Syndrome Probands.

Kentaro Yamashita, Hisayo Fukushima, Mizue Teramoto, Kenji Okita, Aki Ishikawa, Akihiro Sakurai, Kiwamu Akagi, Hiroshi Nakase

Internal medicine (Tokyo, Japan) 60 ( 17 ) 2719 - 2724 2021.03 [Domestic journal]

Objective Little is known about the time from developing a first cancer to confirming the presence of a mismatch repair (MMR) gene mutation for Lynch syndrome (LS) probands. Methods This was a retrospective single center study. LS probands, who have an MMR gene mutation that was confirmed first in a pedigree and thereafter developed at least one cancer, were included in this study. Results There were 21 LS probands who had developed at least one cancer; 6 with MLH1 mutations, 9 with MSH2 mutations, 4 with MSH6 mutations, and 2 with EPCAM deletions. The median ages at the first cancer and the genetic diagnosis were 47 (34-71) and 62 (38-84) years old, respectively. The mean interval between the first cancer and the genetic diagnosis was 11.0 (0-25) years, and 20 years or longer interval was required for the 5 probands. Six (28.6%) probands were older than 70 years, and 3 (14.3%) were in their 80s when they were diagnosed to have LS. The genetic diagnosis was confirmed at the first, second, third, and fourth cancer or later in 5, 5, 6, and 5 probands, respectively. Of the 16 cancers examined, 2 (12.5%) were microsatellite stable (MSS), both of whom had germline MSH6 mutations. All 17 LS probands who developed colorectal cancer met the revised Bethesda guidelines at the genetic diagnosis, but only 7 of 11 (63.6%) met them at the first cancer. Twelve out of 21 (57.1%) met the revised Amsterdam criteria. Conclusion It took 11 years for the LS probands from the first cancer to the diagnostic confirmation by genetic tests. A quarter of the probands were in their 70s or 80s at genetic diagnosis.

DOI PubMed

胆道鏡下生検によって仮性動脈瘤を伴う胆道出血をきたした、肝門部領域胆管癌の一例

柾木喜晴, 平野雄大, 我妻康平, 沼田泰尚, 川上裕次郎, 石上敬介, 室田文子, 阿久津典之, 本谷雅代, 佐々木茂, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 128回・122回 52 - 52 2021.03

腫瘍生検組織を用いた次世代シークエンシングによりIDH1変異を同定した超高齢者Cholangiolocarcinomaの1例

吉田幸成, 岩田徳和, 佐々木泰史, 石井良文, 安達靖代, 足立靖, 佐々木茂, 仲瀬裕志, 遠藤高夫

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 118 ( 臨増総会 ) A364 - A364 2021.03

異所性再燃で診断されたIgG4関連胆嚢炎の臨床病理学的特徴

川上裕次郎, 本谷雅代, 高田夢実, 瀧澤歩, 平野雄大, 我妻康平, 沼田泰尚, 石上敬介, 柾木喜晴, 室田文子, 阿久津典之, 佐々木茂, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 118 ( 臨増総会 ) A409 - A409 2021.03

切除可能膵癌に対するGemcitabine+S-1療法による術前化学療法の安全性

本谷雅代, 柾木喜晴, 室田文子, 川上裕次郎, 平野雄大, 沼田泰尚, 我妻康平, 石上敬介, 阿久津典之, 佐々木茂, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 118 ( 臨増総会 ) A398 - A398 2021.03

当院における高齢者切除不能膵癌の診療実態

大和田紗恵, 室田文子, 平野雄大, 我妻康平, 川上裕次郎, 沼田泰尚, 石上敬介, 柾木喜晴, 阿久津典之, 本谷雅代, 佐々木茂, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 118 ( 臨増総会 ) A395 - A395 2021.03

当科における肝門部領域胆管癌に対する化学放射線療法の治療成績

平野雄大, 本谷雅代, 高田夢実, 瀧澤歩, 我妻康平, 沼田泰尚, 川上裕次郎, 柾木喜晴, 石上啓介, 室田文子, 阿久津典之, 佐々木茂, 仲瀬裕志

当科における膵病変に対する連続膵液細胞診の有用性の検討

瀧澤歩, 柾木喜晴, 平野雄大, 我妻康平, 川上裕次郎, 沼田泰尚, 石上敬介, 室田文子, 阿久津典之, 本谷雅代, 佐々木茂, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 128回・122回 42 - 42 2021.03

Lynch症候群における陥凹型病変

柴田泰洋, 山野泰穂, 高田夢実, 大和田沙恵, 山川司, 風間友江, 平山大輔, 久保俊之, 吉井新二, 能正勝彦, 杉田真太郎, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 128回・122回 64 - 64 2021.03

【内視鏡医も知っておくべき病理診断リファレンス-下部消化管腫瘍】下部消化管腫瘍画像診断において臨床医が病理医に求めるもの

山野泰穂, 吉井新二, 松下弘雄, 吉川健二郎, 高木亮, 中岡宙子, 加藤文一朗, 東海林琢男, 辻脇光洋, 杉田真太朗, 長谷川匡, 永塚真, 田中義人, 菅井有, 仲瀬裕志

胃と腸 ( (株)医学書院 ) 56 ( 3 ) 265 - 273 2021.03

＜文献概要＞消化管臨床における画像診断は病理組織診断に一致することを求めて発展してきた.特に内視鏡を用いた画像診断において拡大・超拡大内視鏡,IEEの発達により目覚ましい発展を遂げている.拡大内視鏡により内視鏡医はミクロの変化を捉えることが可能となり,より病理組織像や病態を想起しながら病理組織診断に肉薄する臨床診断を目指している.さらに,近年登場した超拡大内視鏡が一般化されると,この傾向はさらに顕著となると考えられる.このような背景のもと,この環境下で切除された病変に対して内視鏡医が病理組織診断に求めるものも必然的に変化していると筆者は考える.内視鏡医と病理医は対等な立場で,あるいは立場を越えて互いに尊重しながら真理を追究することが求められており,新たに医学を進歩させる原動力でもあると考えられる.

MEFV遺伝子関連腸炎の1例

柴田泰洋, 瀧澤歩, 大和田紗恵, 山川司, 風間友江, 平山大輔, 久保俊之, 吉井新二, 能正勝彦, 山野泰穂, 遠藤高夫, 仲瀬裕志

日本大腸肛門病学会雑誌 ( (一社)日本大腸肛門病学会 ) 74 ( 3 ) 190 - 190 2021.03

ESDにおける新型デバイス(ISSEN)の使用経験

吉井新二, 瀧澤歩, 大和田紗恵, 山川司, 風間友江, 平山大輔, 能正勝彦, 山野泰穂, 仲瀬裕志

日本大腸肛門病学会雑誌 ( (一社)日本大腸肛門病学会 ) 74 ( 3 ) 197 - 197 2021.03

メサラジン製剤の効果が示唆された放射線性直腸炎の1例

平山大輔, 瀧澤歩, 大和田紗恵, 山川司, 風間友江, 吉井新二, 山野泰穂, 仲瀬裕志

日本大腸肛門病学会雑誌 ( (一社)日本大腸肛門病学会 ) 74 ( 3 ) 190 - 191 2021.03

胆膵癌でのMSI検査におけるEUS-FNA検体の検討

川上裕次郎, 本谷雅代, 平野雄大, 我妻康平, 沼田泰尚, 石上敬介, 柾木喜晴, 室田文子, 阿久津典之, 佐々木茂, 杉田真太朗, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 128回・122回 72 - 72 2021.03

異所性再燃で診断されたIgG4関連胆嚢炎の2例

高田夢実, 川上裕次郎, 平野雄大, 我妻康平, 沼田泰尚, 石上敬介, 柾木喜晴, 室田文子, 阿久津典之, 本谷雅代, 佐々木茂, 木村康利, 高橋裕樹, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 128回・122回 55 - 55 2021.03

Adrenomedullin for steroid-resistant ulcerative colitis: a randomized, double-blind, placebo-controlled phase-2a clinical trial.

Toshihiro Kita, Sinya Ashizuka, Naoki Ohmiya, Takayuki Yamamoto, Takanori Kanai, Satoshi Motoya, Fumihito Hirai, Hiroshi Nakase, Tomohiko Moriyama, Masanao Nakamura, Yasuo Suzuki, Shuji Kanmura, Taku Kobayashi, Hidehisa Ohi, Ryoichi Nozaki, Keiichi Mitsuyama, Shojiro Yamamoto, Haruhiko Inatsu, Koji Watanabe, Toshifumi Hibi, Kazuo Kitamura

Journal of gastroenterology 56 ( 2 ) 147 - 157 2021.02 [Domestic journal]

BACKGROUND: Adrenomedullin (AM) is a bioactive peptide having many pleiotropic effects, including mucosal healing and immunomodulation. AM has shown beneficial effects in rodent models and in preliminary study for patients with ulcerative colitis (UC). We performed a clinical trial to investigate the efficacy and safety of AM in patients with UC. METHODS: This was a multi-center, double-blind, placebo-controlled phase-2a trial evaluating 28 patients in Japan with steroid-resistant UC. Patients were randomly assigned to four groups and given an infusion of 5, 10, 15 ng/kg/min of AM or placebo for 8 h per day for 14 days. The primary endpoint was the change in Mayo scores at 2 weeks. Main secondary endpoints included the change in Mayo scores and the rate of clinical remission at 8 weeks, defined as a Mayo score 0. RESULTS: No differences in the primary or secondary endpoints were observed among the four groups at 2 weeks. Despite the insufficient tracking rate, the Mayo score at 8 weeks was only significantly decreased in the high-dose AM group (15 ng/kg/min) compared with the placebo group (- 9.3 ± 1.2 vs. - 3.0 ± 2.8, P = 0.035), with its rate of clinical remission at 8 weeks being significantly higher (3/3, 100% vs. 0/2, 0%, P = 0.025). We noted mild but no serious adverse events caused by the vasodilatory effect of AM. CONCLUSIONS: In this double-blind randomized trial, we observed the complete remission at 8 weeks in patients with steroid-resistant UC receiving a high dose of AM. CLINICAL TRIAL REGISTRY: JAPIC clinical trials information; Japic CTI-205255 (200410115290). https://www.clinicaltrials.jp/cti-user/trial/Search.jsp .

DOI PubMed

Dual EZH2 and G9a inhibition suppresses multiple myeloma cell proliferation by regulating the interferon signal and IRF4-MYC axis.

Kazuya Ishiguro, Hiroshi Kitajima, Takeshi Niinuma, Reo Maruyama, Naotaka Nishiyama, Hitoshi Ohtani, Gota Sudo, Mutsumi Toyota, Hajime Sasaki, Eiichiro Yamamoto, Masahiro Kai, Hiroshi Nakase, Hiromu Suzuki

Cell death discovery 7 ( 1 ) 7 - 7 2021.01 [International journal]

Epigenetic mechanisms such as histone modification play key roles in the pathogenesis of multiple myeloma (MM). We previously showed that EZH2, a histone H3 lysine 27 (H3K27) methyltransferase, and G9, a H3K9 methyltransferase, are potential therapeutic targets in MM. Moreover, recent studies suggest EZH2 and G9a cooperate to regulate gene expression. We therefore evaluated the antitumor effect of dual EZH2 and G9a inhibition in MM. A combination of an EZH2 inhibitor and a G9a inhibitor strongly suppressed MM cell proliferation in vitro by inducing cell cycle arrest and apoptosis. Dual EZH2/G9a inhibition also suppressed xenograft formation by MM cells in vivo. In datasets from the Gene Expression Omnibus, higher EZH2 and EHMT2 (encoding G9a) expression was significantly associated with poorer prognoses in MM patients. Microarray analysis revealed that EZH2/G9a inhibition significantly upregulated interferon (IFN)-stimulated genes and suppressed IRF4-MYC axis genes in MM cells. Notably, dual EZH2/G9a inhibition reduced H3K27/H3K9 methylation levels in MM cells and increased expression of endogenous retrovirus (ERV) genes, which suggests that activation of ERV genes may induce the IFN response. These results suggest that dual targeting of EZH2 and G9a may be an effective therapeutic strategy for MM.

DOI PubMed

COVID-19パンデミック状況下における適切なIBD診療の実践を目指して JAPAN IBD COVID-19 TASKFORCEからの提言と取り組み

松浦稔, 仲瀬裕志, 松本主之, 飯島英樹, 松岡克善, 大宮直木, 石原俊治, 平井郁仁, 久松理一

日本消化管学会雑誌 ( (一社)日本消化管学会 ) 5 ( Suppl. ) 124 - 124 2021.01

Idiopathic retroperitoneal fibrosis diagnosed by endoscopic ultrasonography-guided fine-needle biopsy.

Yujiro Kawakami, Yumemi Takada, Keisuke Ishigami, Takehiro Hirano, Kohei Wagatsuma, Yoshiharu Masaki, Ayako Murota, Masayo Motoya, Mitsuhiro Tsujiwaki, Hiroki Takahashi, Hiroshi Nakase

JGH open : an open access journal of gastroenterology and hepatology 5 ( 1 ) 151 - 152 2021.01 [International journal]

DOI PubMed

Expert Opinions on the Current Therapeutic Management of Inflammatory Bowel Disease during the COVID-19 Pandemic: Japan IBD COVID-19 Taskforce, Intractable Diseases, the Health and Labor Sciences Research.

Hiroshi Nakase, Takayuki Matsumoto, Minoru Matsuura, Hideki Iijima, Katsuyoshi Matsuoka, Naoki Ohmiya, Shunji Ishihara, Fumihito Hirai, Kouhei Wagatsuma, Yoshihiro Yokoyama, Tadakazu Hisamatsu

Digestion 102 ( 5 ) 814 - 822 2021 [International journal]

BACKGROUND: The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a dramatic challenge for all healthcare systems worldwide. This outbreak immediately affected gastroenterologists as well as global physicians worldwide because COVID-19 can be associated with not only triggering respiratory inflammation but also gastrointestinal (GI) inflammation based on the mechanism by which SARS-CoV-2 enters cells via its receptor the angiotensin-converting enzyme 2, which is expressed on GI cells. However, the comorbidity spectrum of digestive system in patients with COVID-19 remains unknown. Because the inflammatory bowel disease (IBD) management involves treating uncontrolled inflammation with immune-based therapies, physicians, and patients have great concern about whether IBD patients are more susceptible to SARS-CoV-2 infection and have worsened disease courses. SUMMARY: It is necessary to precisely ascertain the risk of SARS-CoV-2 infection and the COVID-19 severity in IBD patients and to acknowledge the IBD management during the COVID-19 pandemic with clinically reliable information from COVID-19 cohorts and IBD experts' opinions. In this review, we highlight clinical questions regarding IBD management during the COVID-19 pandemic and make comments corresponding to each question based on recent publications. Key Messages: We propose that there is (1) no evidence that IBD itself increases the risk of SARS-CoV-2 infection, (2) to basically prioritize the control of disease activity of IBD, (3) no need for physicians to suddenly discontinue immunomodulatory or biologic therapy in patients with quiescent IBD, and (4) a need for careful observation of elderly (>60 years old) and IBD patients receiving corticosteroid treatment during the COVID-19 pandemic.

DOI PubMed

Concomitant use of an immunomodulator with ustekinumab as an induction therapy for Crohn's disease: A systematic review and meta-analysis

Takeo Yoshihara, Shinichiro Shinzaki, Takahiro Amano, Hideki Iijima, Tetsuo Takehara, Nagamu Inoue, Motoi Uchino, Motohiro Esaki, Taku Kobayashi, Masayuki Saruta, Ken Sugimoto, Shiro Nakamura, Keisuke Hata, Fumihito Hirai, Sakiko Hiraoka, Toshimitsu Fujii, Minoru Matsuura, Katsuyoshi Matsuoka, Kenji Watanabe, Hiroshi Nakase, Mamoru Watanabe

Journal of Gastroenterology and Hepatology (Australia) 36 ( 7 ) 1744 - 1753 2021

Background and aim: Ustekinumab (UST), a fully humanized monoclonal antibody against the p40 subunit of interleukin-12/23, is effective for the treatment of Crohn's disease (CD). The benefit of concomitant use of an immunomodulator (IM) with UST, however, is unclear. This study aimed to provide a systematic review and meta-analysis comparing the efficacy and safety of concomitant use of an IM with UST as an induction therapy for CD patients. Methods: A systematic literature search was performed using PubMed/MEDLINE, the Cochrane Library, and the Japana Centra Revuo Medicina from inception to October 31, 2019. The main outcome measure was achievement of clinical efficacy (remission, response, and clinical benefit) at 6–12 weeks. The quality of the included studies was assessed using the risk of bias in non-randomized studies of interventions (ROBINS-I) tools. The fixed-effects model was used to calculate the pooled odds ratios. Results: From 189 yielded articles, six including a total of 1507 patients were considered in this meta-analysis. Concomitant use of an IM with UST was significantly effective than UST monotherapy as an induction therapy (pooled odds ratio in the fixed-effects model: 1.35, 95% confidence interval [1.06–1.71], P = 0.015). The heterogeneity among studies was low (I2 = 2.6%). No statistical comparisons of the occurrence of adverse events between UST monotherapy and concomitant use of an IM with UST were performed. Conclusion: The efficacy of concomitant use of an IM with UST as an induction therapy for CD was significantly superior to that of monotherapy with UST.

DOI PubMed

[A case of mediastinal pancreatic pseudocyst diagnosed and treated successfully by endoscopic procedure].

Tomoya Nakamura, Yoshiharu Masaki, Yujiro Kawakami, Keisuke Ishigami, Ayako Murota, Masayo Motoya, Hiroshi Nakase

Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology 118 ( 6 ) 578 - 585 2021 [Domestic journal]

A 60-year-old man was admitted for investigation of a mediastinal cystic lesion. During endoscopic retrograde pancreatography, the contrast medium leaked from the head of the main pancreatic duct, and the cystic fluid collected with endoscopic ultrasonography (EUS) -guided aspiration showed high levels of pancreatic enzymes. Therefore, we diagnosed mediastinal pancreatic pseudocyst. The pseudocyst shrank as a result of EUS-guided drainage, and an endoscopic nasopancreatic drainage tube was then placed to close the fistula of the pancreatic duct. This case suggests that endoscopic procedures could be useful for the diagnosis and treatment of mediastinal pancreatic pseudocyst. We review 48 case reports of mediastinal pancreatic pseudocyst and discuss the usefulness of endoscopic procedures for diagnosis and treatment.

DOI PubMed

A case of hepatitis b virus and hepatitis c virus co-infection that achieved sustained virological response 12 following treatment with glecaprevir hydrate/pibrentasvir for 3 days

Yasunao Numata, Shigeru Sasaki, Noriyuki Akutsu, Takehiro Hirano, Kohei Wagatsuma, Yujiro Kawakami, Keisuke Ishigami, Hiroshi Nakase

Acta Hepatologica Japonica ( Japan Society of Hepatology ) 62 ( 9 ) 578 - 584 2021

An 82-year-old female patient who was co-infected with hepatitis B virus (HBV) and hepatitis C virus (HCV) was regularly followed at our institution. The patient was taking clarithromycin because of comorbid nontuberculous mycobacteriosis (NTM) lung disease. Since chronic liver damage has possibly progressed, the patient was treated with direct-acting antiviral (DAA). Soon after taking DAA, severe pruritus appeared, and the patient stopped it in 3 days. However, HCV RNA level decreased to an undetectable level 2 weeks after the start of the treatment and achieved sustained virological response (SVR) 12. Two factors were considered for the success of DAA treatment in a short period in this case. One factor was that the immune response for HCV elimination was easily generated due to the patient’s high immunological activity caused by the effects of co-existing NTM lung disease and co-infection with HBV. The other reason is that the blood level of DAA was high because of the concomitant drug.

DOI

【大腸鋸歯状病変の新展開】分類不能鋸歯状病変を由来としたTraditional serrated adenomaの癌化症例

山川司, 吉井新二, 市原真, 大和田紗恵, 柴田泰洋, 風間友江, 平山大輔, 久保俊之, 能正勝彦, 須藤豪太, 山本英一郎, 鈴木拓, 山野泰穂, 仲瀬裕志

胃と腸 ( (株)医学書院 ) 55 ( 13 ) 1631 - 1638 2020.12

＜文献概要＞患者は40歳代,女性.血便を主訴に近医を受診し,下部消化管内視鏡検査にて上部直腸(Ra)に径約35mmのLST-GMを認めた.本病変は辺縁に平坦部分を伴い複数の分葉構造を呈し,拡大所見では平坦部分は鋸歯状構造を伴ったII型様pitで構成されていたが,既存の分類には合致しない鋸歯状病変と考えられた.病変の大部分を占める中心の隆起部ではIV型pitを主体としcytological dysplasiaを疑った.病理組織像では平坦部の表層部分にわずかに鋸歯状構造は認めるが,深部はうねった管状腺管で腺腫様であり,免疫染色Ki-67では陽性細胞が散在し腺腫や既存の鋸歯状病変にも当てはまらない組織像であった.一方,隆起部では鋸歯状変化を呈するTSA様の領域と,絨毛状の形態をとりtubulovillous adenomaと考えられる領域が混在していた.また,隆起部の粘膜深部に細胞異型,構造異型が強く,腺管が密に増殖した領域があり,同部位でp53,Ki-67がびまん性の陽性を示しtub1相当の腺癌(Tis)と診断した.遺伝子解析では平坦部,隆起部いずれもKRAS変異陽性(G13D)で一連の病変と考えられた.本症例は内視鏡所見や免疫染色,遺伝子解析結果から既存の分類に当てはまらない鋸歯状病変を基盤として発育進展した病変と考え,ここに報告する.

Successful treatment with endoscopic transpapillary drainage for gallbladder perforation associated with steroid treatment for interstitial pneumonia (with video).

Yujiro Kawakami, Kazuya Suzuki, Masakazu Akahonai, Takakazu Miyake, Masahiro Taniguchi, Hiroshi Nakase

JGH open : an open access journal of gastroenterology and hepatology 4 ( 6 ) 1233 - 1235 2020.12 [International journal]

This case report highlights the clinical efficacy of endoscopic transpapillary drainage for gallbladder perforation in a high-risk surgical patient with a history of steroid treatment for interstitial pneumonia. The usefulness of endoscopic transpapillary gallbladder drainage in high-risk surgical patients with acute cholecystitis has not been established. In difficult cases of emergent surgery, such as described here, endoscopic transpapillary drainage is a promising method to manage gallbladder perforation and acute cholecystitis recurrence.

DOI PubMed

Autophagy and Autophagy-Related Diseases: A Review.

Tadashi Ichimiya, Tsukasa Yamakawa, Takehiro Hirano, Yoshihiro Yokoyama, Yuki Hayashi, Daisuke Hirayama, Kohei Wagatsuma, Takao Itoi, Hiroshi Nakase

International journal of molecular sciences 21 ( 23 ) 2020.11 [International journal]

Autophagy refers to the process involving the decomposition of intracellular components via lysosomes. Autophagy plays an important role in maintaining and regulating cell homeostasis by degrading intracellular components and providing degradation products to cells. In vivo, autophagy has been shown to be involved in the starvation response, intracellular quality control, early development, and cell differentiation. Recent studies have revealed that autophagy dysfunction is implicated in neurodegenerative diseases and tumorigenesis. In addition to the discovery of certain disease-causing autophagy-related mutations and elucidation of the pathogenesis of conditions resulting from the abnormal degradation of selective autophagy substrates, the activation of autophagy is essential for prolonging life and suppressing aging. This article provides a comprehensive review of the role of autophagy in health, physiological function, and autophagy-related disease.

DOI PubMed

Haemorrhagic exfoliative oesophagitis associated with nasogastric tube placement.

Gota Sudo, Akira Goto, Takashi Fujisawa, Hiroshi Nakase

BMJ case reports 13 ( 11 ) 2020.11 [International journal]

A 92-year-old man hospitalised for cerebral infarction developed haematemesis. The patient was taking low-dose aspirin and apixaban for his cerebral infarction and non-valvular atrial fibrillation. His enteral nutrition was administrated through nasogastric tube. Upper endoscopy revealed active bleeding from a protruded lesion in the upper oesophagus. The lesion was removed by washing with a water jet, followed by successful endoscopic haemostasis. Histopathological examination revealed degenerated squamous epithelium without specific findings; the diagnosis was exfoliative oesophagitis. In our case, mechanical mucosal injury caused by nasogastric tube placement may result in exfoliative oesophagitis. In addition, the use of low-dose aspirin with apixaban may have contributed to the bleeding. We then performed a wire-guided nasogastric tube placement under fluoroscopy. No further bleeding was observed, but the patient died of sepsis 1 month later. This case highlights the importance of a risk assessment and management of oesophageal complications associated with nasogastric tube placement.

DOI PubMed

【拡大内視鏡を極める】拡大・超拡大内視鏡診断を極める Pit pattern診断を極める

山野泰穂, 吉井新二, 久保俊之, 柴田泰洋, 齋藤潤信, 松下弘雄, 吉川健二郎, 仲瀬裕志

Intestine ( (株)日本メディカルセンター ) 24 ( 4 ) 337 - 346 2020.11

＜文献概要＞拡大内視鏡,pit pattern診断は近年における内視鏡診断学を大きく発展させた.pit pattern診断は一般的になりつつあるが,単純な分類型に当てはめる診断法では通用しない.その理由はpit pattern分類は大腸上皮性腫瘍性病変(腺腫,癌)において成立しており,それ以外の病変まで網羅していないこと,腺腫・癌においてもpit patternには亜型が存在すること,病理学の概念が変わることで対応しきれないことなどが挙げられる.しかし拡大内視鏡における観察の仕方,pit patternの理論や病態が拡大所見へ及ぼす影響などを理解することで極めることができると考える.

Long-term clinical effectiveness of ustekinumab in patients with Crohn’s disease: A retrospective cohort study

Takahiro Ito, Atsuo Maemoto, Takehiko Katsurada, Hiroki Tanaka, Satoshi Motoya, Nobuhiro Ueno, Mikihiro Fujiya, Toshifumi Ashida, Daisuke Hirayama, Hiroshi Nakase

Crohn's and Colitis 360 2 ( 4 ) 1 - 9 2020.10

Background: This study clarifies the long-term effectiveness of ustekinumab based on real-life data from Japanese Crohn’s disease (CD) patients. Methods: A total of 137 patients were included, and 124 patients (90.5%) were exposed to anti-tumor necrosis factor-α agents. Results: The clinical remission rate at week 52 was 32.4% in moderate to severely active CD patients. The achievement of clinical remission for 8 weeks after ustekinumab therapy induction was associated with clinical remission at week 52. Ustekinumab persistence rate at week 104 was 81.4%. Conclusion: Ustekinumab is effective and persistent in CD patients with the previous treatment history of several biologics.

DOI

Exploratory study of the effectiveness of granulocyte and monocyte adsorptive apheresis before initiation of steroids in patients with active ulcerative colitis (EXPECT study): A multicenter prospective clinical trial

Kazuki Kakimoto, Minoru Matsuura, Takumi Fukuchi, Hitoshi Hongo, Tsuguhiro Kimura, Nobuo Aoyama, Yorihide Okuda, Kazuki Aomatsu, Noriko Kamata, Yoko Yokoyama, Chiemi Mizuno, Takuya Inoue, Takako Miyazaki, Shiro Nakamura, Kazuhide Higuchi, Hiroshi Nakase

Crohn's and Colitis 360 ( Oxford University Press ) 2 ( 4 ) 2020.10

Background: Granulocyte and monocyte adsorptive apheresis (GMA) has been used for therapy of steroid-dependent/refractory ulcerative colitis (UC). The aim of this study was to investigate the effectiveness of GMA in UC patients not receiving steroids. Methods: We conducted a single-arm, open-label, and multicenter prospective clinical trial. UC patients who had insufficient responses to 5-aminosalicylic acid received GMA twice a week for 5 weeks. Results: The response rate of all patients was 58.2% (39/67). Of the 39 patients who achieved a response, 74.4% achieved endoscopically confirmed mucosal healing. Conclusions: GMA shows effectiveness in inducing remission in UC patients not receiving steroid.

DOI

術後再発し、進展が早かった肝内胆管粘液癌における遺伝子異常

柾木喜晴, 足立靖, 石上敬介, 室田文子, 阿久津典之, 久保俊之, 岩田徳和, 本谷雅代, 佐々木茂, 遠藤高夫, 石井良文, 佐々木泰史, 仲瀬裕志

日本癌治療学会学術集会抄録集 ( (一社)日本癌治療学会 ) 58回 O23 - 3 2020.10

皮膚様食道扁平上皮癌の1例

久保俊之, 足立靖, 中村浩子, 菊地剛史, 中村正弘, 見田裕章, 安達靖代, 岩田徳和, 吉田幸成, 伴紀宏, 石井良文, 高橋宏明, 仲瀬裕志, 遠藤高夫

日本消化器病学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 127回 49 - 49 2020.10

分類不能鋸歯状病変を伴ったtraditional serrated adenoma癌化症例

山川司, 吉井新二, 市原真, 秋田浩太朗, 大和田紗恵, 横山佳浩, 柴田泰洋, 風間友江, 赤保内正和, 久保俊之, 仲地耕平, 能正勝彦, 山下健太郎, 須藤豪太, 山本英一郎, 鈴木拓, 山野泰穂, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 62 ( Suppl.2 ) 2150 - 2150 2020.10

分類不能鋸歯状病変を伴ったtraditional serrated adenoma癌化症例

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 62 ( Suppl.2 ) 2150 - 2150 2020.10

早期大腸がん浸潤先進部の分子解析

須藤豪太, 山本英一郎, 青木敬則, 高澤啓, 新沼猛, 久保俊之, 萬顕, 北嶋洋志, 甲斐正広, 小山内誠, 仲瀬裕志, 鈴木拓

日本癌学会総会記事 ( (一社)日本癌学会 ) 79回 PJ14 - 8 2020.10

AEBP1の発現上昇は大腸がんの腫瘍血管新生を促進する

山本英一郎, 萬顕, 新沼猛, 北嶋洋志, 須藤豪太, 甲斐正広, 高野賢一, 仲瀬裕志, 鈴木拓

日本癌学会総会記事 ( (一社)日本癌学会 ) 79回 OJ14 - 5 2020.10

当科における高齢者切除不能膵癌に対する化学療法の現状と治療効果

大和田紗恵, 室田文子, 平野雄大, 我妻康平, 川上裕次郎, 石上敬介, 柾木喜晴, 阿久津典之, 本谷雅代, 佐々木茂, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 117 ( 臨増大会 ) A724 - A724 2020.10

集学的治療により3年生存した胆嚢混合型腺神経内分泌癌(MiNEN)の1例

秋田浩太朗, 本谷雅代, 我妻康平, 大和田紗恵, 平野雄大, 川上裕次郎, 柾木喜晴, 石上敬介, 伊東文子, 阿久津典之, 佐々木茂, 木村康利, 竹政伊知朗, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 127回・121回 39 - 39 2020.10

治療困難肝内結石に対するSpyGlass DSを用いた胆道鏡下治療

瀧澤歩, 川上裕次郎, 平野雄大, 我妻康平, 沼田泰尚, 石上敬介, 柾木喜晴, 室田文子, 阿久津典之, 本谷雅代, 佐々木茂, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 62 ( Suppl.2 ) 2135 - 2135 2020.10

IGF2と肝臓がん罹患リスク-a nested case-control study

足立靖, 野島正寛, 森満, 久保俊之, 仲瀬裕志, 遠藤高夫, 林櫻松, 若井建志, 玉腰暁子

日本癌学会総会記事 ( (一社)日本癌学会 ) 79回 OE24 - 3 2020.10

膵癌におけるcirculating tumor DNA(ctDNA)前向き観察研究

室田文子, 本谷雅代, 木村康利, 吉田真誠, 平野雄大, 川上裕次郎, 柾木喜晴, 佐々木茂, Fabio Pittella-Silva, 竹政伊知朗, 中村祐輔, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 127回・121回 35 - 35 2020.10

非切除急性胆嚢炎に対する内視鏡的胆嚢ドレナージ-EGBS対EUS-GBDの後ろ向き比較研究-

川上裕次郎, 鈴木一也, 谷口正浩, 大久保陽介, 平野雄大, 越前栄次朗, 我妻康平, 石上敬介, 柾木喜晴, 室田文子, 菅野伸一, 若杉英樹, 本谷雅代, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 62 ( Suppl.2 ) 2116 - 2116 2020.10

治療困難肝内結石に対するSpyGlass DSを用いた胆道鏡下治療

瀧澤歩, 川上裕次郎, 平野雄大, 我妻康平, 沼田泰尚, 石上敬介, 柾木喜晴, 室田文子, 本谷雅代, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 127回・121回 29 - 29 2020.10

胆道癌の術前進展度診断における、胆道鏡の有用性に関する検討

柾木喜晴, 平野雄大, 我妻康平, 沼田泰尚, 川上裕次郎, 石上敬介, 室田文子, 本谷雅代, 木村康利, 仲瀬裕志

当科における高齢者切除不能膵癌に対する化学療法の現状およびその治療効果

大和田紗恵, 室田文子, 平野雄大, 我妻康平, 川上裕次郎, 沼田泰尚, 石上敬介, 柾木喜晴, 阿久津典之, 本谷雅代, 佐々木茂, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 127回・121回 69 - 69 2020.10

Infliximabによる維持療法中に血管炎を発症したCrohn病の1例

横山涼太, 山下健太郎, 吉井新二, 風間友江, 大和田紗恵, 山川司, 平山大輔, 山野泰穂, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 127回・121回 37 - 37 2020.10

家族性大腸ポリポーシス症例に発生した多発胃癌の2例

大和田紗恵, 吉井新二, 瀧澤歩, 山川司, 風間友江, 平山大輔, 能正勝彦, 山野泰穂, 仲瀬裕志, 山下健太郎

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 127回・121回 52 - 52 2020.10

チオプリン製剤投与中のIBD患者における赤血球中6-TGN濃度と白血球分画についての検討

中村友哉, 横山佳浩, 高田夢実, 大和田紗恵, 山川司, 風間友江, 赤保内正和, 仲地耕平, 能正勝彦, 吉井新二, 山下健太郎, 山野泰穂, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 117 ( 臨増大会 ) A754 - A754 2020.10

悪性胆道狭窄における術前胆管ドレナージ不全についての検討

平野雄大, 柾木喜晴, 我妻康平, 川上裕次郎, 石上敬介, 室田文子, 本谷雅代, 木村康利, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 127回・121回 40 - 40 2020.10

非切除急性胆嚢炎に対するEGBSとEUS-GBDの治療成績の検討

川上裕次郎, 鈴木一也, 大久保陽介, 平野雄大, 越前栄次朗, 我妻康平, 石上敬介, 柾木喜晴, 室田文子, 菅野伸一, 若杉英樹, 本谷雅代, 仲瀬裕志

OATP機能異常が疑われたクラリスロマイシン投与後の高ビリルビン血症の1例

山本智香, 石上敬介, 阿久津典之, 沼田泰尚, 平野雄大, 我妻康平, 川上裕次郎, 柾木喜晴, 室田文子, 本谷雅代, 佐々木茂, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 127回・121回 36 - 36 2020.10

Intestinal cancer in patients with Crohn's disease: A systematic review and meta‐analysis

Journal of Gastroenterology and Hepatology ( Wiley ) 2020.09

DOI

COVID-19パンデミック状況下における炎症性腸疾患の管理に関する専門家の意見JAPAN IBD COVID-19 TASKFORCE 厚生労働科学研究費補助金(難治性疾患政策研究事業)難治性炎症性腸管障害に関する調査研究班

仲瀬裕志, 松本主之, 松浦稔, 飯島英樹, 松岡克善, 大宮直木, 石原俊治, 平井郁仁, 我妻康平, 横山佳浩, 久松理一

日本消化管学会雑誌 ( (一社)日本消化管学会 ) 4 ( 1 ) 15 - 24 2020.09

Coronavirus disease 2019(COVID-19)にともなう消化器症状ならびにCOVID-19パンデミック状況下での、炎症性腸疾患(IBD)患者に対しての、日常診療上の重要なポイントを解説する。現時点では、(1)IBD患者のCOVID-19リスクは、一般の方と比べて高くない、(2)原則としてIBD疾患活動性の制御が優先される、(3)寛解状態のIBD患者において、免疫調節薬や生物学的製剤治療を中止する必要はない、(4)ステロイド投与中患者、高齢IBD患者(60歳以上)では、COVID-19による入院、ICU管理、人工呼吸器使用率が高いといえる。(著者抄録)

Author's reply: acute serologic autoimmune hepatitis in the post-partum period.

Noriyuki Akutsu, Keisuke Ishigami, Hiroshi Nakase

Clinical journal of gastroenterology 13 ( 4 ) 634 - 634 2020.08 [Refereed] [Domestic journal]

DOI PubMed

横行結腸に発生したcytological dysplasiaを伴う分類困難な鋸歯状病変の1例

秋田浩太朗, 山野泰穂, 柴田泰洋, 久保俊之, 吉井新二, 横山佳浩, 風間友江, 三橋慧, 能正勝彦, 山下健太郎, 須藤豪太, 山本英一郎, 鈴木拓, 寺井琴美, 辻脇光洋, 長谷川匡, 永塚真, 菅井有, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 62 ( Suppl.1 ) 1265 - 1265 2020.08

SSA/P由来が示唆された横行結腸SM癌の一例

久保俊之, 山野泰穂, 中村友哉, 柴田泰洋, 山川司, 風間友江, 赤保内正和, 吉井新二, 山下健太郎, 須藤豪太, 山本英一郎, 鈴木拓, 永塚真, 菅井有, 杉田真太朗, 長谷川匡, 遠藤高夫, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 62 ( Suppl.1 ) 1327 - 1327 2020.08

Superficially serrated adenoma(SuSA)の発がんが観察された微小大腸癌の1例

柴田泰洋, 山野泰穂, 久保俊之, 吉井新二, 山下健太郎, 須藤豪太, 山本英一郎, 鈴木拓, 寺井琴美, 長谷川匡, 永塚真, 菅井有, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 62 ( Suppl.1 ) 1265 - 1265 2020.08

Arteriovenous malformation in pancreas mimicking hypervascular tumor.

Keisuke Ishigami, Tomoya Sakuma, Masato Saito, Yujiro Kawakami, Yoshiharu Masaki, Ayako Murota, Masayo Motoya, Yasutoshi Kimura, Hiroshi Nakase

JGH open : an open access journal of gastroenterology and hepatology 4 ( 4 ) 773 - 774 2020.08 [International journal]

Arteriovenous malformation (AVM) is defined as a disease that causes blood flow abnormality due to anastomoses of the arteries and veins. AVM can occur in any gastrointestinal tract, but pancreatic AVM (P-AVM) is very rare. Previous reports demonstrated that contrast-enhanced CT (CECT) typically showed abnormal vascular network in pancreas. We present a 58-year old man with a history of acute pancreatitis. He was referred to our hospital for examination of pancreatic mass. CECT showed a round-shaped hypervascular lesion with a diameter of 8 mm in the head of the pancreas. Selective angiography showed vascular network and early visualization of superior mesenteric vein. We finally diagnosed this case as P-AVM. He underwent duodenum preserving pancreatic head resection. Histological findings confirmed the preoperative diagnosis of P-AVM.

DOI PubMed

術後再建腸管に対するショートタイプダブルバルーン内視鏡を用いたERCP関連手技の治療成績

川上裕次郎, 柾木喜晴, 平野雄大, 我妻康平, 石上敬介, 伊東文子, 阿久津典之, 本谷雅代, 佐々木茂, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 62 ( Suppl.1 ) 1307 - 1307 2020.08

悪性胆道狭窄における術前胆道ドレナージ不全についての検討

平野雄大, 柾木喜晴, 我妻康平, 川上裕次郎, 石上敬介, 室田文子, 本谷雅代, 木村康利, 仲瀬裕志

胆道 ( (一社)日本胆道学会 ) 34 ( 3 ) 490 - 490 2020.08

Non traumatic tubeを用いた大腸内視鏡観察法の工夫

吉井新二, 山野泰穂, 仲瀬裕志, 柴田泰洋, 久保俊之, 山下健太郎, 能正勝彦

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 62 ( Suppl.1 ) 1279 - 1279 2020.08

Motion capture技術を用いた大腸内視鏡挿入手技の客観的評価の試み

山野泰穂, 久保俊之, 仲瀬裕志, 白田智洋, 我妻康平, 風間友江, 上野あかり, 中村友哉, 大和田紗英, 柴田泰洋, 山川司, 赤保内正和, 仲地耕平, 吉井新二, 山下健太郎

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 62 ( Suppl.1 ) 1230 - 1230 2020.08

胆道癌の術前進展度診断における、胆道鏡の有用性に関する検討

柾木喜晴, 平野雄大, 我妻康平, 川上裕次郎, 石上敬介, 室田文子, 本谷雅代, 木村康利, 仲瀬裕志

胆道 ( (一社)日本胆道学会 ) 34 ( 3 ) 500 - 500 2020.08

Interactive Web-based Graphs of Coronavirus Disease 2019 Cases and Deaths per Population by Country.

Masashi Idogawa, Shoichiro Tange, Hiroshi Nakase, Takashi Tokino

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 71 ( 15 ) 902 - 903 2020.07 [Refereed] [International journal]

DOI PubMed

Long-Term Follow-Up of Targeted Biopsy Yield (LOFTY Study) in Ulcerative Colitis Surveillance Colonoscopy.

Keisuke Hata, Soichiro Ishihara, Yoichi Ajioka, Keiichi Mitsuyama, Kenji Watanabe, Hiroyuki Hanai, Reiko Kunisaki, Hiroshi Nakase, Keiji Matsuda, Ryuichi Iwakiri, Nobuyuki Hida, Shinji Tanaka, Yoshiaki Takeuchi, Masaru Shinozaki, Noriyuki Ogata, Kentaro Moriichi, Fumihito Hirai, Kenichi Sugihara, Tadakazu Hisamatsu, Yasuo Suzuki, Mamoru Watanabe, Toshifumi Hibi

Journal of clinical medicine 9 ( 7 ) 2020.07 [Refereed] [International journal]

We previously performed a randomized controlled trial (RCT) comparing targeted and random biopsy in neoplasia detection in patients with ulcerative colitis (UC), which showed the short-term effectiveness of targeted biopsy with one-time colonoscopy. In this retrospective cohort study, we investigated the long-term effectiveness of targeted biopsy in tertiary care hospitals, using the follow-up data from patients with UC for ≥ 8 years who had enrolled in the initial RCT. The primary outcome was death from colorectal cancer (CRC). Secondary outcomes were advanced neoplasia (CRC or high-grade dysplasia) and colectomy due to neoplasia after the RCT. We compared these outcomes between target and random groups. Data on 195 of the 221 patients (88.2%) enrolled in the previous RCT were collected from 28 institutions between 2008 and 2019. No patients died of CRC in either group, with a median 8.8-year follow-up demonstrating a robustness for targeted biopsy in terms of CRC death prevention. Advanced neoplasia was detected in four and three patients in the target and random groups, respectively. Colectomy was required due to neoplasia in three patients in each group. The chance of developing CRC in patients with a negative colonoscopy was low, and the targeted biopsy appeared effective in this population. Conversely, patients found with low-grade dysplasia at initial RCT have 10-fold higher risk of progression to high-grade dysplasia and/or CRC. Ten extracolonic malignancies were observed during the follow-up, resulting in four deaths. Panchromoendoscopy was used only in 4.6% and targeted biopsy was only performed in 59.1% of colonoscopies. We recommend targeted biopsy rather than > 33 random biopsies in real-world settings under adequate observation by specialists.

DOI PubMed

The shining DIAMOND for evidence-based treatment strategies for Crohn's disease.

Hiroshi Nakase, Takayuki Matsumoto, Kenji Watanabe, Tadakazu Hisamatsu

Journal of gastroenterology 2020.07 [Refereed] [Domestic journal]

Anti-tumor necrosis factor (TNF)-α antibodies are effective therapeutic agents to treat inflammatory bowel disease (IBD). In the biologic era, the development of immunogenicity has been a critical issue for secondary loss of response. The superiority of anti-TNF therapy in combination with immunomodulators (IMs) is well-established for infliximab (IFX) but less evident for adalimumab (ADA). To clarify the contribution of thiopurines to ADA-treated patients with Crohn's disease (CD), the deep remission of immunomodulator and adalimumab combination therapy for Crohn's disease (DIAMOND) studies provided the first randomized comparison of efficacy between ADA monotherapy and ADA with thiopurine. The results of the DIAMOND and DIAMOND2 studies revealed the appropriate ADA therapeutic strategy for immunosuppressant-naïve patients with active CD based on therapeutic drug monitoring, endoscopic findings and clinical issues regarding the use of thiopurines.

DOI PubMed

Gastrointestinal: Abdominal aortic aneurysm caused symptoms mimicking superior mesenteric artery syndrome.

G Sudo, H Takagi, S Nakahara, A Goto, Y Hinoda, H Nakase

Journal of gastroenterology and hepatology 2020.07 [International journal]

DOI PubMed

Comparison of dissection speed during colorectal ESD between the novel Multiloop (M-loop) traction method and ESD methods without traction.

Yuichiro Suzuki, Tokuma Tanuma, Masanori Nojima, Gota Sudo, Yuki Murakami, Tatsuya Ishii, Masakazu Akahonai, Yosuke Kobayashi, Hidetaka Hamamoto, Hironori Aoki, Taku Harada, Akio Katanuma, Hiroshi Nakase

Endoscopy international open 8 ( 7 ) E840-E847 2020.07 [Refereed] [International journal]

Background and study aims We previously reported on a novel traction method called Multiloop (M-loop) for faster colorectal endoscopic submucosal dissection (ESD). In this study, we retrospectively compared the difference in submucosal dissection time (SDT), and submucosal dissection speed (SDS) between groups of patients who were treated using traction with the M-loop method, and with non-traction methods of colorectal ESD. Patients and methods We reviewed and timed duration of colorectal ESD by the non-traction method from videos recorded between June 2016 and December 2017. From January 2018 onward, we used the M-loop method during all colorectal ESDs and timed it until August 2018. Outcomes of colorectal ESD with the M-loop method and non-traction methods were compared. The study involved two experts and eight non-experts and was carried out at a tertiary endoscopic center in Japan. Results The study included 50 patients who treated with the M-loop method and 115 patients treated with the non-traction method. Submucosal dissection time (SDT) was not significantly different (M-loop group, 42.1 ± 4.2 min, non-traction ESD group, 51.9 ± 3.3 min) ( P = 0.098), but submucosal dissection speed (SDS) was significantly greater (M-loop group, 28.0 ± 2.9 mm 2 /min, non-traction ESD group, 19.9 ± 2.0 mm 2 /min) ( P = 0.0014) in the M-loop method group. Multivariate analysis showed that the M-loop method increased SDS by odds ratio of 1.46 ( P = 0.001) when compared to the non-traction ESD method. A significant difference was also observed for SDT and SDS when the two methods were compared after propensity score matching ( P = 0.001). No differences in unfavorable outcomes were observed. Conclusions The M-loop method improved SDS compared to non-traction methods of ESD. The method is an effective tool to assist colorectal ESD.

DOI PubMed

Lynch症候群に合併した多発微小大腸癌の1例

柴田泰洋, 山野泰穂, 久保俊之, 吉井新二, 山下健太郎, 須藤豪太, 山本英一郎, 鈴木拓, 寺井琴美, 長谷川匡, 永塚真, 菅井有, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 117 ( 臨増総会 ) A319 - A319 2020.07

Lynch症候群に合併した多発微小大腸癌の1例

柴田泰洋, 山野泰穂, 久保俊之, 吉井新二, 山下健太郎, 須藤豪太, 山本英一郎, 鈴木拓, 寺井琴美, 長谷川匡, 永塚真, 菅井有, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 117 ( 臨増総会 ) A319 - A319 2020.07

新規大腸がん間質関連遺伝子の同定とがん微小環境における機能の解明

須藤豪太, 山本英一郎, 三橋慧, 久保俊之, 山野泰穂, 鈴木拓, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 117 ( 臨増総会 ) A318 - A318 2020.07

胃蜂窩織炎を併発したNASH肝硬変の1剖検例

岩田徳和, 田中克典, 矢花剛, 小関至, 菊地剛史, 見田裕章, 安達靖代, 吉田幸成, 足立靖, 加藤康夫, 遠藤高夫, 阿久津典之, 佐々木茂, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 117 ( 臨増総会 ) A385 - A385 2020.07

当科における切除不能・再発胆道癌に対するGemcitabine/cisplatin/S-1(GCS)併用療法の経験

本谷雅代, 柾木喜晴, 川上裕次郎, 石上敬介, 伊東文子, 阿久津典之, 佐々木茂, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 117 ( 臨増総会 ) A392 - A392 2020.07

対照的な経過を辿った膵動静脈奇形の2例

高田夢実, 石上敬介, 平野雄大, 川上裕次郎, 柾木喜晴, 室田文子, 本谷雅代, 山口洋志, 今村将史, 木村康利, 岡俊州, 金戸宏行, 竹政伊知朗, 仲瀬裕志

膵臓 ( (一社)日本膵臓学会 ) 35 ( 3 ) A461 - A461 2020.07

IPMNの術前診断におけるSpyGlass DSの有用性

川上裕次郎, 本谷雅代, 平野雄大, 我妻康平, 石上敬介, 柾木喜晴, 室田文子, 佐々木茂, 山口洋志, 今村将史, 木村康利, 竹政伊知朗, 仲瀬裕志

膵臓 ( (一社)日本膵臓学会 ) 35 ( 3 ) A355 - A355 2020.07

穿刺針の太さによるEUS-FNBの診断率の差異

柾木喜晴, 平野雄大, 川上裕次郎, 石上敬介, 室田文子, 本谷雅代, 佐々木茂, 仲瀬裕志

膵臓 ( (一社)日本膵臓学会 ) 35 ( 3 ) A380 - A380 2020.07

CYP3A5 Genotype as a Potential Pharmacodynamic Biomarker for Tacrolimus Therapy in Ulcerative Colitis in Japanese Patients.

Yuki Yamamoto, Hiroshi Nakase, Minoru Matsuura, Shihoko Maruyama, Satohiro Masuda

International journal of molecular sciences 21 ( 12 ) 2020.06 [Refereed] [International journal]

Tacrolimus has been used to induce remission in patients with steroid-refractory ulcerative colitis. It poses a problem of large individual differences in dosage necessary to attain target blood concentration and, often, this leads to drug inefficacy. We examined the difference in mRNA expression levels of ATP binding cassette transporter B1 (ABCB1) between inflamed and non-inflamed tissues, and the influence of CYP3A5 genotype on tacrolimus therapy. The mRNA expression of CYP3A4 in colonic mucosa and that of cytochrome p450 3A5 (CYP3A5) and ABCB1 in inflamed and non-inflamed areas were examined in 14 subjects. The mRNA expression levels of CYP3A5 were higher than that of CYP3A4. The mRNA expression of ABCB1 was lower in the inflamed than in the non-inflamed mucosa, despite that of CYP3A5 mRNA level being not significantly changed. Hence, the deterioration of the disease is related to the reduction of the barrier in the inflamed mucosa. The relationship between CYP3A5 genotype and blood concentration, dose, and concentration/dose (C/D) ratio of tacrolimus in 15 subjects was studied. The tacrolimus dose to maintain equivalent blood concentrations was lower in CYP3A5*3/*3 than in CYP3A5*1 carriers, and the C/D ratio was significantly higher in the latter. Thus, CYP3A5 polymorphism information played a role in determining the initial dose of tacrolimus. Furthermore, since the effect of tacrolimus appears earlier in CYP3A5*3/*3 than in CYP3A5*1/*1 and *1/*3, it seems necessary to change the evaluation time of therapeutic effect by CYP3A5 genotype. Additionally, the relationship between CYP3A5 genotype and C/D ratio of tacrolimus in colonic mucosa was investigated in 10 subjects. Tacrolimus concentration in the mucosa was two-fold higher in CYP3A5*3/*3 than in CYP3A5*1 carriers, although no significant difference in tacrolimus-blood levels was observed. Therefore, the local concentration of tacrolimus affected by CYP3A5 polymorphism might be related to its therapeutic effect.

DOI PubMed

Double small bowel cancers leading to the diagnosis of Lynch syndrome with germline MSH6 mutation in an elderly patient.

Sae Ohwada, Kentaro Yamashita, Tomoe Kazama, Kei Mitsuhashi, Akiko Ichiyanagi, Kohei Nakachi, Hiro-O Yamano, Takayuki Nobuoka, Tatsuya Ito, Wataru Sasao, Hiroshi Nakase

Clinical journal of gastroenterology 2020.06 [Refereed] [Domestic journal]

A female patient in her 80s was referred to our hospital because of an ileal tumor identified by capsule endoscopy. FDG-PET suggested double intestinal tumors not only in the ileum but also in the jejunum. The patient has cancer past history including sigmoid colon, rectum, and endometrium, and also had cancer family history fulfilling the revised Amsterdam criteria. Double balloon enteroscopy disclosed two ulcerated tumors in the jejunum and the ileum. Biopsy was diagnosed as adenocarcinoma pathologically, and microsatellite instability-high (MSI-H) genetically. Surgical resection was performed, and the jejunal and the ileal tumors were tubular (T2N0M0) and mucinous adenocarcinoma (T4N0M0), respectively. Germline mutation analysis revealed a pathogenic splice-site mutation in MSH6.

DOI PubMed

Sigmoid colon tumor with G-nas mutation presenting unique morphology.

Gota Sudo, Hironori Aoki, Yuko Omori, Hiromu Suzuki, Hiroshi Nakase

Gastrointestinal endoscopy 92 ( 5 ) 1133 - 1135 2020.06 [Refereed] [International journal]

DOI PubMed

【無痛大腸内視鏡挿入法-technique & device】総論軸保持短縮法の基本

山野泰穂, 吉井新二, 仲瀬裕志

Intestine ( (株)日本メディカルセンター ) 24 ( 2 ) 99 - 104 2020.06

＜文献概要＞大腸は柔軟性・伸縮性に富み,かつ複雑であるばかりではなく個人差もあり,多彩な形状を示す管腔臓器である.この大腸にスコープを挿入する方法として軸保持短縮法がある.その内容はストラテジー(戦略)とタクティクス(戦術)に分けて考えると理解しやすい.ストラテジーとは結腸,直腸に5ヶ所の固定点を想定し,これらを直線で結ぶ経路を軸と称し,これになぞらえるように腸管およびスコープを修正し挿入していくことで腸管が過伸展することなく安全,無痛性に挿入できるとした全体構想である.タクティクスとは実際の局面でどのように操作するべきなのかの実践であるが,スコープ軸を保持するように操作することがスコープ動作を掌握するうえで重要である.また腸管はさまざまな形状を示すため,スコープ軸は時に一つとは限らず,これらの軸を最終的には固定点を結んだ軸に一致させることを,机上および実際のUPD画像を通じて解説した.

Intestinal epithelial cell-derived IL-15 determines local maintenance and maturation of intra-epithelial lymphocytes in the intestine.

Yuanbo Zhu, Guangwei Cui, Eiji Miyauchi, Yuki Nakanishi, Hisa Mukohira, Akihiro Shimba, Shinya Abe, Shizue Tani-Ichi, Takahiro Hara, Hiroshi Nakase, Tsutomu Chiba, Atsuko Sehara-Fujisawa, Hiroshi Seno, Hiroshi Ohno, Koichi Ikuta

International immunology 32 ( 5 ) 307 - 319 2020.05 [Refereed] [International journal]

Interleukin-15 (IL-15) is a cytokine critical for maintenance of intestinal intra-epithelial lymphocytes (IELs), especially CD8αα + IELs (CD8αα IELs). In the intestine, IL-15 is produced by intestinal epithelial cells (IECs), blood vascular endothelial cells (BECs) and hematopoietic cells. However, the precise role of intestinal IL-15 on IELs is still unknown. To address the question, we generated two kinds of IL-15 conditional knockout (IL-15cKO) mice: villin-Cre (Vil-Cre) and Tie2-Cre IL-15cKO mice. IEC-derived IL-15 was specifically deleted in Vil-Cre IL-15cKO mice, whereas IL-15 produced by BECs and hematopoietic cells was deleted in Tie2-Cre IL-15cKO mice. The cell number and frequency of CD8αα IELs and NK IELs were significantly reduced in Vil-Cre IL-15cKO mice. By contrast, CD8αα IELs were unchanged in Tie2-Cre IL-15cKO mice, indicating that IL-15 produced by BECs and hematopoietic cells is dispensable for CD8αα IELs. Expression of an anti-apoptotic factor, Bcl-2, was decreased, whereas Fas expression was increased in CD8αα IELs of Vil-Cre IL-15cKO mice. Forced expression of Bcl-2 by a Bcl-2 transgene partially restored CD8αα IELs in Vil-Cre IL-15cKO mice, suggesting that some IL-15 signal other than Bcl-2 is required for maintenance of CD8αα IELs. Furthermore, granzyme B production was reduced, whereas PD-1 expression was increased in CD8αα IELs of Vil-Cre IL-15cKO mice. These results collectively suggested that IEC-derived IL-15 is essential for homeostasis of IELs by promoting their survival and functional maturation.

DOI PubMed

Immunological Mechanisms in Inflammation-Associated Colon Carcinogenesis.

Takehiro Hirano, Daisuke Hirayama, Kohei Wagatsuma, Tsukasa Yamakawa, Yoshihiro Yokoyama, Hiroshi Nakase

International journal of molecular sciences 21 ( 9 ) 2020.04 [Refereed] [International journal]

Patients with chronic inflammatory bowel diseases are at an increased risk of developing colitis-associated cancer (CAC). Chronic inflammation positively correlates with tumorigenesis. Similarly, the cumulative rate of incidence of developing CAC increases with prolonged colon inflammation. Immune signaling pathways, such as nuclear factor (NF)-κB, prostaglandin E2 (PGE2)/cyclooxygenase-2 (COX-2), interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3), and IL-23/T helper 17 cell (Th17), have been shown to promote CAC tumorigenesis. In addition, gut microbiota contributes to the development and progression of CAC. This review summarizes the signaling pathways involved in the pathogenesis following colon inflammation to understand the underlying molecular mechanisms in CAC tumorigenesis.

DOI PubMed

Treatment of inflammatory bowel disease from the immunological perspective.

Hiroshi Nakase

Immunological medicine 1 - 8 2020.04 [Refereed] [International journal]

Since 1950, the number of patients with inflammatory bowel disease (IBD) in Japan has been increasing. Recent research data indicate that the pathophysiology of IBD involves abnormalities in disease susceptibility genes, environmental factors and intestinal bacteria. The elucidation of the mechanism of IBD has facilitated therapeutic development based on basic research data. In particular, the emergence of biologics has brought about a paradigm shift in the treatment of IBD. However, there are still IBD patients who are refractory to these biologics. IBD pathophysiology is extremely complex. Therefore, to address these clinical issues, further clinical and basic data are required. The bottom line of IBD drug therapy is still to use the most of recent treatments. Therefore, the physicians should be familiar with the modes of action (MOA) of the available drugs.

DOI PubMed

A Rare Cause of Ileus in a Middle-Aged Japanese Woman.

Tomoya Iida, Yoshiaki Arimura, Hiroshi Nakase

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 18 ( 4 ) e43 2020.04 [Refereed] [International journal]

DOI PubMed

大腸がんにおけるAEBP1の発現上昇は腫瘍血管新生を促進する

鈴木拓, 萬顕, 山本英一郎, 新沼猛, 北嶋洋志, 甲斐正広, 仲瀬裕志

日本臨床分子医学会学術総会プログラム・抄録集 ( 日本臨床分子医学会 ) 57回 63 - 63 2020.04

Current Diagnostic and Therapeutic Approaches to Cytomegalovirus Infections in Ulcerative Colitis Patients Based on Clinical and Basic Research Data.

Yoshihiro Yokoyama, Tsukasa Yamakawa, Takehiro Hirano, Tomoe Kazama, Daisuke Hirayama, Kohei Wagatsuma, Hiroshi Nakase

International journal of molecular sciences 21 ( 7 ) 2020.03 [Refereed] [International journal]

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus (the human herpesvirus 5) and an opportunistic pathogen that primarily infects HIV-positive and other immuno-compromised patients. Retrospective studies in the field of inflammatory bowel disease (IBD) have suggested a relationship between a concomitant colonic HCMV infection and poor outcomes in patients with an ulcerative colitis (UC) due to the presence of HCMV in surgical specimens of patients with a toxic megacolon or a steroid-resistant UC. Therefore, gastroenterologists have focused on the contribution of HCMV infections in the exacerbation of UC. Numerous studies have addressed the benefits of treating colonic HCMV reactivation in UC using an antiviral treatment. However, its clinical relevance remains uncertain as only a few prospective studies have assessed the direct relationship between clinical outcomes and the viral load of HCMV in colonic tissues. HCMV reactivation can be triggered by inflammation according to fundamental research studies. Thus, optimal control of intestinal inflammation is essential for preventing an HCMV reactivation in the intestinal mucosa. Indeed, several reports have indicated the effectiveness of an anti-tumor necrosis factor-alpha (TNFα) treatment in patients with an active UC and concomitant HCMV infections. In this review, we describe the mechanism of HCMV reactivation in UC cases and discuss the current issues regarding diagnosis and treatment of HCMV infections in UC patients.

DOI PubMed

Recanalization of an obstructive pancreaticojejunal anastomosis with direct visualization by using antegrade peroral pancreatoscopy.

Yujiro Kawakami, Shinsuke Koshita, Yoshihide Kanno, Takahisa Ogawa, Toji Murabayashi, Hiroshi Nakase, Kei Ito

Endoscopy 2020.03 [Refereed] [International journal]

DOI PubMed

New paradigm of B-cell biology regarding the elucidation of a new mechanism of tissue fibrosis in IgG4-related disease.

Hiroshi Nakase, Keisuke Ishigami

The Journal of allergy and clinical immunology 145 ( 3 ) 785 - 787 2020.03 [Refereed] [International journal]

DOI PubMed

p53-induced ARVCF modulates the splicing landscape and supports the tumor suppressive function of p53.

Natsumi Suzuki, Masashi Idogawa, Shoichiro Tange, Tomoko Ohashi, Yasushi Sasaki, Hiroshi Nakase, Takashi Tokino

Oncogene 39 ( 10 ) 2202 - 2211 2020.03 [Refereed] [International journal]

p53 is one of the most important tumor suppressor genes, and the exploration of p53-target genes is important for elucidation of its functional mechanisms. In this study, we identified Armadillo Repeat gene deleted in Velo-Cardio-Facial syndrome (ARVCF) as a direct target of p53 through ChIP-sequencing analysis. Activated p53 protein was found to bind to two distinct sites in the ARVCF gene, resulting in induction of ARVCF expression at both the mRNA and protein levels. We revealed that the knockdown of ARVCF inhibited p53-induced apoptosis. Interestingly, ARVCF interacted with hnRNPH2, which is involved in pre-mRNA splicing, and ARVCF knockdown induced dynamic changes in alternative splicing patterns. These results suggest that p53-induced ARVCF indirectly, but not directly, regulates p53 target selectivity through splicing alterations of specific genes. Thus, we demonstrated that the induction of ARVCF expression contributed to the tumor suppressive function of p53. Recently, it has been reported that many tumors have thousands of alternative splicing events that are not detectable in normal samples. ARVCF may play a role in alternative splicing events in cancer and may provide clues to explore novel approaches for cancer diagnosis and therapy.

DOI PubMed

次世代シーケンサーによる遺伝子解析を行い得た、肝内胆管粘液癌の一剖検例

柾木喜晴, 川上裕次郎, 石上敬介, 伊東文子, 阿久津典之, 本谷雅代, 佐々木茂, 足立靖, 佐々木泰史, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 126回・120回 41 - 41 2020.03

消化器がん内視鏡診断・治療の最前線大腸腫瘍性病変に対するTranslational researchの確立を目指した内視鏡診療

赤保内正和, 吉井新二, 鈴木拓, 山野泰穂, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 126回・120回 34 - 34 2020.03

大腸癌の内視鏡Up-to-date 大腸ESD後潰瘍および穿孔部の縫縮テクニック

吉井新二, 山野泰穂, 仲瀬裕志

大腸がんperspective ( (株)メディカルレビュー社 ) 4 ( 4 ) 332 - 334 2020.03

今だから聞きます、胆石をどうしていますか? 治療困難肝内結石に対するSpyGlass DSを用いた胆道鏡下治療

川上裕次郎, 本谷雅代, 大和田紗恵, 平野雄大, 我妻康平, 石上敬介, 柾木喜晴, 伊東文子, 阿久津典之, 佐々木茂, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 126回・120回 32 - 32 2020.03

Timing of indocyanine green injection prior to laparoscopic colorectal surgery for tumor localization: a prospective case series.

Tetsuta Satoyoshi, Kenji Okita, Masayuki Ishii, Atsushi Hamabe, Akihiro Usui, Emi Akizuki, Koichi Okuya, Toshihiko Nishidate, Hiroo Yamano, Hiroshi Nakase, Ichiro Takemasa

Surgical endoscopy 35 ( 2 ) 763 - 769 2020.02 [Refereed] [International journal]

BACKGROUND: Accurate identification of tumor sites during laparoscopic colorectal surgery helps to optimize oncological clearance. We aimed to assess the timing of the local injection preoperatively and clarify the usefulness and limitation of tumor site marking using indocyanine green (ICG) fluorescence imaging. METHODS: Consecutive patients who underwent primary colorectal cancer surgery from September 2017 to January 2019 were included. Preoperatively, lower endoscopy was used to inject the ICG solution into the submucosal layer near the tumor. During laparoscopic surgery, ICG fluorescence marking as the tumor site marking was detected using a laparoscopic near-infrared camera system. The detection rate and factors associated with successful intraoperative ICG fluorescence visualization including the interval between local injection and surgery were evaluated. RESULTS: One hundred sixty-five patients were enrolled. Using the laparoscopic near-infrared system, the intraoperative detection rates of ICG marking were 100% for ICG injection within 6 days preoperatively, 60% for injection between 7 and 9 days preoperatively, and 0% for injection earlier than 10 days preoperatively. There were no complications associated with ICG marking. Additionally, this method did not disturb the progress of the surgical procedure because injected ICG in the submucosal layer did not cause any tissue inflammation, and if ICG spilled into the serosa, it was invisible by white light. CONCLUSION: Advantages of ICG fluorescence tumor site marking were high visibility of infrared imaging during laparoscopic colorectal surgery and minimal adverse events of surgery. One of the most important findings regarding practical use was a rapid decrease in fluorescence marking visibility if one week passed from the time of ICG local injection.

DOI PubMed

Development of anti-centromere antibody-positive autoimmune hepatitis after childbirth.

Mitsunobu Saito, Noriyuki Akutsu, Yasunao Numata, Keisuke Ishigami, Shigeru Sasaki, Hiroshi Nakase

Clinical journal of gastroenterology 13 ( 5 ) 855 - 859 2020.01 [Refereed] [Domestic journal]

This is the first case involving the development of anti-centromere antibody (ACA)-positive autoimmune hepatitis (AIH) after childbirth that triggered nailfold bleeding. A 32-year-old woman visited a dermatologist presenting with nailfold bleeding 6 months after the delivery of her second baby. Blood tests revealed liver dysfunction, and she was admitted to our hospital. Tests for hepatitis virus, antinuclear antibody, and anti-mitochondrial antibody were negative. She had no history of alcohol consumption or oral medication. Because of nailfold bleeding, we performed tests for ACA, anti-Scl-70 antibody, anti-RNA polymerase III antibody, and anti-U1 RNP antibodies; only ACA was positive. A liver biopsy was performed for the diagnosis of liver dysfunction. Histological examination of the liver biopsy specimen showed moderate infiltration of inflammatory cells, interface hepatitis, bridging fibrosis, and bile duct injury. The AIH international score was 17, and thus, we diagnosed AIH. Oral prednisolone (PSL) 0.6 mg/day/body weight was initiated. Two weeks post-treatment, the liver enzyme levels normalized and the nailfold bleeding disappeared. In case of nailfold bleeding complicated with liver dysfunction post-childbirth, ACA-positive AIH should be considered as a differential diagnosis.

DOI PubMed

Optimizing the Use of Current Treatments and Emerging Therapeutic Approaches to Achieve Therapeutic Success in Patients with Inflammatory Bowel Disease.

Hiroshi Nakase

Gut and liver 14 ( 1 ) 7 - 19 2020.01 [Refereed] [International journal]

The current goal of inflammatory bowel disease (IBD) treatment is a symptom-free everyday life accompanied by mucosal healing with minimal use of corticosteroids. Recent therapeutic advances, particularly, the emergence of anti-tumor necrosis factor (anti-TNF) antibodies, have changed the natural history of IBD. Additionally, these advances also led to the emergence of the therapeutic concept of the "treat to target" strategy. With the development of new drugs and clinical trials, not only biologics but also small molecules have been applied to clinical practice to better individualize and optimize therapy. However, if newer drugs, including anti-TNF therapies, are recommended for all patients diagnosed with IBD, a significant number of patients will be overtreated. The basic goal of IBD treatment is still to make the best use of conventional treatments based on IBD pathophysiology. Thus, physicians should be familiar with the modes of action of the available drugs. In this review, the author discusses the existing data for many approved drugs and provide insights for optimizing current treatments for the management of patients with IBD in the era of biologics.

DOI PubMed

Automatic, computer-aided determination of endoscopic and histological inflammation in patients with mild to moderate ulcerative colitis based on red density.

Peter Bossuyt, Hiroshi Nakase, Séverine Vermeire, Gert de Hertogh, Tom Eelbode, Marc Ferrante, Tadashi Hasegawa, Hilde Willekens, Yousuke Ikemoto, Takao Makino, Raf Bisschops

Gut 2020.01 [Refereed] [International journal]

BACKGROUND: The objective evaluation of endoscopic disease activity is key in ulcerative colitis (UC). A composite of endoscopic and histological factors is the goal in UC treatment. We aimed to develop an operator-independent computer-based tool to determine UC activity based on endoscopic images. METHODS: First, we built a computer algorithm using data from 29 consecutive patients with UC and 6 healthy controls (construction cohort). The algorithm (red density: RD) was based on the red channel of the red-green-blue pixel values and pattern recognition from endoscopic images. The algorithm was refined in sequential steps to optimise correlation with endoscopic and histological disease activity. In a second phase, the operating properties were tested in patients with UC flares requiring treatment escalation. To validate the algorithm, we tested the correlation between RD score and clinical, endoscopic and histological features in a validation cohort. RESULTS: We constructed the algorithm based on the integration of pixel colour data from the redness colour map along with vascular pattern detection. These data were linked with Robarts histological index (RHI) in a multiple regression analysis. In the construction cohort, RD correlated with RHI (r=0.74, p<0.0001), Mayo endoscopic subscores (r=0.76, p<0.0001) and UC Endoscopic Index of Severity scores (r=0.74, p<0.0001). The RD sensitivity to change had a standardised effect size of 1.16. In the validation set, RD correlated with RHI (r=0.65, p=0.00002). CONCLUSIONS: RD provides an objective computer-based score that accurately assesses disease activity in UC. In a validation study, RD correlated with endoscopic and histological disease activity.

DOI PubMed

Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis.

Nobuyuki Kakiuchi, Kenichi Yoshida, Motoi Uchino, Takako Kihara, Kotaro Akaki, Yoshikage Inoue, Kenji Kawada, Satoshi Nagayama, Akira Yokoyama, Shuji Yamamoto, Minoru Matsuura, Takahiro Horimatsu, Tomonori Hirano, Norihiro Goto, Yasuhide Takeuchi, Yotaro Ochi, Yusuke Shiozawa, Yasunori Kogure, Yosaku Watatani, Yoichi Fujii, Soo Ki Kim, Ayana Kon, Keisuke Kataoka, Tetsuichi Yoshizato, Masahiro M Nakagawa, Akinori Yoda, Yasuhito Nanya, Hideki Makishima, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Masashi Sanada, Eiji Sugihara, Taka-Aki Sato, Takashi Maruyama, Hiroyuki Miyoshi, Makoto Mark Taketo, Jun Oishi, Ryosaku Inagaki, Yutaka Ueda, Shinya Okamoto, Hideaki Okajima, Yoshiharu Sakai, Takaki Sakurai, Hironori Haga, Seiichi Hirota, Hiroki Ikeuchi, Hiroshi Nakase, Hiroyuki Marusawa, Tsutomu Chiba, Osamu Takeuchi, Satoru Miyano, Hiroshi Seno, Seishi Ogawa

Nature 577 ( 7789 ) 260 - 265 2020.01 [Refereed] [International journal]

Chronic inflammation is accompanied by recurring cycles of tissue destruction and repair and is associated with an increased risk of cancer1-3. However, how such cycles affect the clonal composition of tissues, particularly in terms of cancer development, remains unknown. Here we show that in patients with ulcerative colitis, the inflamed intestine undergoes widespread remodelling by pervasive clones, many of which are positively selected by acquiring mutations that commonly involve the NFKBIZ, TRAF3IP2, ZC3H12A, PIGR and HNRNPF genes and are implicated in the downregulation of IL-17 and other pro-inflammatory signals. Mutational profiles vary substantially between colitis-associated cancer and non-dysplastic tissues in ulcerative colitis, which indicates that there are distinct mechanisms of positive selection in both tissues. In particular, mutations in NFKBIZ are highly prevalent in the epithelium of patients with ulcerative colitis but rarely found in both sporadic and colitis-associated cancer, indicating that NFKBIZ-mutant cells are selected against during colorectal carcinogenesis. In further support of this negative selection, we found that tumour formation was significantly attenuated in Nfkbiz-mutant mice and cell competition was compromised by disruption of NFKBIZ in human colorectal cancer cells. Our results highlight common and discrete mechanisms of clonal selection in inflammatory tissues, which reveal unexpected cancer vulnerabilities that could potentially be exploited for therapeutics in colorectal cancer.

DOI PubMed

A novel endoscopic imaging system for quantitative evaluation of colonic mucosal inflammation in patients with quiescent ulcerative colitis.

Yusuke Honzawa, Minoru Matsuura, Hirokazu Higuchi, Takaki Sakurai, Hiroshi Seno, Hiroshi Nakase

Endoscopy international open 8 ( 1 ) E41-E49 2020.01 [Refereed] [International journal]

Background and study aims Mucosal healing (MH) is associated with clinical outcome in ulcerative colitis (UC) patients. In most clinical trials, a Mayo endoscopic subscore (MES) of 0 or 1 is defined as MH. However, several recent studies have reported that clinical outcome is different between UC patients with MES 0 and those with MES 1. In addition, the MES is subjective and may differ among endoscopists. Therefore, a repeatable and objective scoring system is required to distinguish MES 0 from MES 1, even in clinically quiescent UC. Here, we assessed the usefulness of new image-enhancing endoscopic technology, the i-scan TE-c, to quantitatively evaluate colonic inflammation in patients with quiescent UC. Methods We retrospectively reviewed the data from 52 UC patients in clinical remission who had undergone routine colonoscopy with standard white light. The white-light images were reassessed using the new system, and the degree of colonic mucosal inflammation was quantified according to the MAGIC (Mucosal Analysis of Inflammatory Gravity by i-scan TE-c Image) score. We used the i-scan TE-c system to investigate the association among the MAGIC score, MES, and histologic activity (Geboes score). Results The MAGIC score was significantly higher in the MES 1 group than in the MES 0 group ( P = 0.0034). The MAGIC score significantly correlated with the Geboes score ( P = 0.015). Conclusions Our novel image-enhancing endoscopic system was useful for objective and quantitative evaluation of MH in patients with quiescent UC. Further clinical studies using this imaging system are required to confirm its clinical benefit for the management of UC patients.

DOI PubMed

Multiloop as a novel traction method in accelerating colorectal endoscopic submucosal dissection.

Yuichiro Suzuki, Tokuma Tanuma, Masanori Nojima, Gota Sudo, Masakazu Akahonai, Hidetaka Hamamoto, Hironori Aoki, Taku Harada, Akio Katanuma, Hiroshi Nakase

Gastrointestinal endoscopy 91 ( 1 ) 185 - 190 2020.01 [Refereed] [International journal]

BACKGROUND AND AIMS: Traction methods have been reported to speed up endoscopic submucosal dissection (ESD). We used the multiloop (M-loop) method as a traction method for colorectal ESD and recorded the submucosal dissection time (SDT) and submucosal dissection speed (SDS). METHODS: From January to August 2018, we used the M-loop method for colorectal ESD procedures and timed the duration and recorded the outcomes. Two experts and eight nonexperts performed the procedures, which were carried out at a tertiary endoscopic center in Japan. RESULTS: A total of 50 patients were treated by colorectal ESD using the M-loop method. The mean SDT was 42.1 ± 4.16 minutes and the mean SDS was 28.0 ± 2.89 mm2/minutes. The mean SDS was 38.9 ± 6.9 mm2/minutes for experts and 25.3 ± 3.1 mm2/minutes for nonexperts. En bloc resection was achieved in 100% of cases. There were 3 adverse events and unfavorable outcomes. CONCLUSIONS: Traction by the M-loop method improved SDS in colorectal ESD. The method can be an effective tool to assist colorectal ESD. Further evaluation of the usefulness of the M-loop method is required in direct comparison with conventional ESD.

DOI PubMed

Down-regulation of RalGTPase-Activating Protein Promotes Colitis-Associated Cancer via NLRP3 Inflammasome Activation.

Tomoya Iida, Daisuke Hirayama, Naoki Minami, Minoru Matsuura, Kohei Wagatsuma, Kentaro Kawakami, Kanna Nagaishi, Masanori Nojima, Hiroki Ikeuchi, Seiichi Hirota, Ryutaro Shirakawa, Hisanori Horiuchi, Hiroshi Nakase

Cellular and molecular gastroenterology and hepatology ( Elsevier BV ) 9 ( 2 ) 277 - 293 2020 [Refereed] [International journal]

BACKGROUND & AIMS: Ral guanosine triphosphatase-activating protein α2 (RalGAPα2) is the major catalytic subunit of the negative regulators of the small guanosine triphosphatase Ral, a member of the Ras subfamily. Ral regulates tumorigenesis and invasion/metastasis of some cancers; however, the role of Ral in colitis-associated cancer (CAC) has not been investigated. We aimed to elucidate the role of Ral in the mechanism of CAC. METHODS: We used wild-type (WT) mice and RalGAPα2 knockout (KO) mice that showed Ral activation, and bone marrow chimeric mice were generated as follows: WT to WT, WT to RalGAPα2 KO, RalGAPα2 KO to WT, and RalGAPα2 KO to RalGAPα2 KO mice. CAC was induced in these mice by intraperitoneal injection of azoxymethane followed by dextran sulfate sodium intake. Intestinal epithelial cells were isolated from colon tissues, and we performed complementary DNA microarray analysis. Cytokine expression in normal colon tissues and CAC was analyzed by quantitative polymerase chain reaction. RESULTS: Bone marrow chimeric mice showed that immune cell function between WT mice and RalGAPα2 KO mice was not significantly different in the CAC mechanism. RalGAPα2 KO mice had a significantly larger tumor number and size and a significantly higher proportion of tumors invading the submucosa than WT mice. Higher expression levels of matrix metalloproteinase-9 and matrix metalloproteinase-13 were observed in RalGAPα2 KO mice than in WT mice. The expression levels of interleukin 1β, NLRP3, apoptosis associated speck-like protein containing a CARD, and caspase-1 were apparently increased in the tumors of RalGAPα2 KO mice compared with WT mice. NLRP3 inhibitor reduced the number of invasive tumors. CONCLUSIONS: Ral activation participates in the mechanism of CAC development via NLRP3 inflammasome activation.

DOI PubMed

Current clinical issue of skin lesions in patients with inflammatory bowel disease.

Tomoya Iida, Tokimasa Hida, Minoru Matsuura, Hisashi Uhara, Hiroshi Nakase

Clinical journal of gastroenterology 12 ( 6 ) 501 - 510 2019.12 [Refereed] [Domestic journal]

Inflammatory bowel disease (IBD) is associated with a number of extraintestinal complications, including skin lesions. Most reports have shown that skin lesions are found in 10-15% of IBD cases, although this depends on the definition of skin lesions. The representative skin lesions in patients with IBD are erythema nodosum, pyoderma gangrenosum, Sweet's syndrome, and so on. These lesions are often associated with IBD progression, and intestinal lesions in particular require appropriate treatment. Recently, another clinical issue regarding skin lesions in patients with IBD, a so-called paradoxical reaction, during the treatment with anti-tumor necrosis factor (TNF)-α agents has emerged. These reactions are termed paradoxical reactions because the skin lesions sometimes resemble psoriasis, although the anti-TNF-α agents have been historically used to treat psoriasis. Paradoxical reactions are reportedly found in approximately 5-10% of patients using anti-TNF-α agents and are no longer rare. Now that the use of biologics is at its culmination, reports regarding paradoxical reactions are predicted to increase in number; thus, we must recognize skin lesions with IBD patients including this type of adverse events and manage them appropriately while consulting with dermatologists.

DOI PubMed

Brunner's Gland Hamartoma Arising From the Pyloric Ring.

Gota Sudo, Toshihisa Kobayashi, Hiroshi Nakase

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 17 ( 13 ) e155 2019.12 [Refereed] [International journal]

DOI PubMed

肝細胞癌におけるBRD4阻害の抗腫瘍効果メカニズムの解析(Analysis of the anti-tumor mechanism of BRD4 inhibition in hepatocellular carcinoma)

佐々木基, 北嶋洋志, 新沼猛, 若杉英樹, 石黒一也, 萬顕, 須藤豪太, 畠平知, 阿久津典之, 山本英一郎, 甲斐正広, 佐々木茂, 仲瀬裕志, 鈴木拓

札幌医学雑誌 ( 札幌医科大学 ) 88 ( 1-6 ) 21 - 35 2019.12

BRD4を含むBETファミリー蛋白質はアセチル化ヒストンのリーダー蛋白質であり、転写調節において重要な役割を担っている。BRD4阻害剤は様々な悪性腫瘍において抗腫瘍効果を示す事が報告されている。今回我々は、肝細胞癌におけるBRD4阻害の抗腫瘍効果メカニズムの解明を目的とした。まずBRD4阻害剤JQ1の抗腫瘍効果を9種類の肝癌細胞株を用いて検証した結果、増殖抑制、細胞周期停止、アポトーシスの誘導が認められた。次に我々は、JQ1が遺伝子発現に与える影響をマイクロアレイによって解析した。その結果、JQ1が細胞周期やアポトーシス関連遺伝子に強い影響を与えること、そしてBCAT1、DDR1、GDF15、FANCD2、SENP1、TYRO3など複数の肝細胞癌関連遺伝子の発現を抑制することを見いだした。これらの遺伝子のプロモーター領域へのBRD4結合が確認されたことから、これらは肝細胞癌におけるBRD4の標的遺伝子と考えられた。今回の結果から、BRD4阻害剤は複数の癌関連遺伝子を抑制することで、肝細胞癌に対する抗腫瘍効果を示すと考えられた。(著者抄録)

Sessile serrated adenoma/polyp showed rapid malignant transformation in the final 13 months.

Sadahiro Amemori, Hiro-O Yamano, Yoshihito Tanaka, Kenjiro Yoshikawa, Hiro-O Matsushita, Ryo Takagi, Eiji Harada, Yuko Yoshida, Kazunori Tsuda, Bunichiro Kato, Eri Tamura, Makoto Eizuka, Tamotsu Sugai, Yasushi Adachi, Eiichiro Yamamoto, Hiromu Suzuki, Hiroshi Nakase

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 32 ( 6 ) 979 - 983 2019.11 [Refereed] [International journal]

Based on the concept of the adenoma-carcinoma sequence, most colorectal cancers are considered to arise from conventional adenomas. However, recent studies suggested that a subset of colorectal cancers develop through the serrated neoplastic pathway. It has also been documented that serrated polyps can rapidly transform into invasive cancers even when they are small in size. We now describe a case of a sessile serrated adenoma/polyp which had been followed up for 4 years but eventually showed rapid transformation into an advanced cancer accompanied by a remarkable morphological change within only 13 months. Retrospective genetic and epigenetic analyses showed microsatellite instability, CpG island methylator phenotype-positive, and BRAF mutation in the lesion, suggesting the tumor had developed through the serrated neoplastic pathway. This case may provide valuable information about the natural history of sessile serrated adenoma/polyps which eventually progress to advanced cancers.

DOI PubMed

Therapeutic Efficacy and Adverse Events of Tacrolimus in Patients with Crohn's Disease: Systematic Review and Meta-Analysis.

Tomoya Iida, Masanori Nojima, Hiroshi Nakase

Digestive diseases and sciences 64 ( 10 ) 2945 - 2954 2019.10 [Refereed] [International journal]

BACKGROUND: Only a few randomized controlled trials (RCTs) and some uncontrolled trials have reported the efficacy and adverse events (AEs) of tacrolimus (Tac) in patients with refractory Crohn's disease (CD). The aim of this study was to undertake a systematic review and meta-analysis of the therapeutic efficacy and AEs of Tac in patients with CD. METHODS: We investigated studies reporting the therapeutic efficacy of Tac in patients with CD from 1950 until December 2017. Study subjects were categorized into three groups: systemic administration of Tac for patients with luminal CD (Group 1); systemic administration of Tac for patients with perianal CD (Group 2); and topical administration of Tac for patients with localized CD (Group 3). The primary endpoint of this study was the remission rate. Secondary endpoints were partial response rate, factors related to remission, and the incidence of AEs. RESULTS: The remission rate of Group 1, 2, and 3 was 37.1, 32.0, and 22.7%, respectively. The partial response rate of those was 42.3, 42.9, and 44.3%, respectively. In addition, the incidence of AEs of those was 50.9, 65.5, and 40.0%, respectively. No life-threatening AEs were observed in any study. CONCLUSION: This systematic review and meta-analysis demonstrated that Tac therapy was effective for subpopulation of CD patients and that the incidence of AEs was tolerable. Therefore, Tac therapy should be considered an option for patients with CD. However, there have been few well-designed RCTs on this subject and further studies are required.

DOI PubMed

Withdrawal of thiopurines in Crohn's disease treated with scheduled adalimumab maintenance: a prospective randomised clinical trial (DIAMOND2).

Tadakazu Hisamatsu, Shingo Kato, Reiko Kunisaki, Minoru Matsuura, Masakazu Nagahori, Satoshi Motoya, Motohiro Esaki, Norimasa Fukata, Satoko Inoue, Takeshi Sugaya, Hirotake Sakuraba, Fumihito Hirai, Kenji Watanabe, Takanori Kanai, Makoto Naganuma, Hiroshi Nakase, Yasuo Suzuki, Mamoru Watanabe, Toshifumi Hibi, Masanori Nojima, Takayuki Matsumoto

Journal of gastroenterology 54 ( 10 ) 860 - 870 2019.10 [Refereed] [Domestic journal]

BACKGROUND: The risk:benefit ratio of concomitant use of thiopurines with scheduled adalimumab (ADA) maintenance therapy for Crohn's disease is controversial. The aim of this study is to identify the influence of withdrawal of thiopurines in patients in remission with combination therapy in an open-label, randomised, controlled trial (DIAMOND2; UMIN000009596). METHODS: Patients in corticosteroid-free clinical remission (CFCR) for ≥ 6 months with ADA (40 mg, s.c., every other week) scheduled maintenance combined with thiopurines were randomised into two groups, "continue" (Con) or "discontinue" (Dis) group of thiopurines, whereas all other patients kept receiving scheduled ADA maintenance therapy for 52 weeks. The primary endpoint was the proportion of patients in CFCR at week 52. Secondary endpoints were endoscopic remission (ER), trough levels of ADA in serum, and safety. RESULTS: Fifty patients were randomised to Con or Dis groups. Characteristics of patients were not significantly different between the groups. CFCR and ER prevalence at week 52 were not significantly different between groups (log rank, P = 0.704, P = 1.000, respectively). Trough levels of ADA were not significantly different between groups (P = 0.515). The proportion of patients with AAA positivity at week 52 was not significantly different (P = 0.437). ER at week 0 was involved in ER and triple remission at week 52. No serious adverse effects were observed in either group. CONCLUSION: Continuation of thiopurines > 6 months offers no clear benefit over scheduled ADA monotherapy. CFCR, ER, and ADA trough level at week 52 were not significantly different between groups. ER at week 0 may be involved in better long-term clinical outcomes.

DOI PubMed

ペプシノゲンIIと低分化混在早期胃癌の関連

三橋慧, 上野あかり, 斎藤潤信, 守谷洋, 柴田泰洋, 風間友江, 須藤豪太, 五十嵐央祥, 久保俊之, 山本英一郎, 能正勝彦, 山下健太郎, 山野泰穂, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 61 ( Suppl.2 ) 2151 - 2151 2019.10

新規治療薬時代におけるクローン病患者のビタミンK栄養状態

辻秀美, 幣憲一郎, 青未空, 桑原晶子, 長嶋一昭, 山田聡, 松浦稔, 仲瀬裕志, 田中清, 稲垣暢也

日本病態栄養学会誌 ( (一社)日本病態栄養学会 ) 22 ( 4 ) 253 - 257 2019.10

我々は以前、クローン病(CD)患者において血中ビタミンK(VK)濃度が顕著に低下し、原因として脂質摂取制限による吸収障害が疑われることを報告した。近年薬物治療の進歩を承けて、脂質摂取制限が緩和されたため、血中VK関連指標を再調査した。VK摂取中央値は目安量を上回っていたが、肝臓および骨におけるVK不足の指標である血清PIVKA-II及びucOC異常高値者の割合は高く、VK不足が示唆された。VK摂取量は血清PIVKA-II・ucOCと相関せず、脂質摂取量がPIVKA-IIと有意な負の相関を示した。血清PIVKA-II濃度は、小腸切除群で有意に高値を示し、血清ucOC濃度に有意差は見られなかった。VK必要量は肝臓より骨で多く、CD患者ではVK不足者の割合は依然として高く、特に小腸切除群では吸収面積減少に加え腸肝循環の障害により、肝臓に必要な量すらVKが供給されていない可能性が示唆された。(著者抄録)

自己免疫性膵炎(AIP)におけるEUS-FNAの病理学的診断能の検討

本谷雅代, 柾木喜春, 石上敬介, 伊東文子, 阿久津典之, 仲地耕平, 佐々木茂, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 61 ( Suppl.2 ) 2184 - 2184 2019.10

Concerns and Side Effects of Azathioprine During Adalimumab Induction and Maintenance Therapy for Japanese Patients With Crohn's Disease: A Subanalysis of a Prospective Randomised Clinical Trial [DIAMOND Study].

Tadakazu Hisamatsu, Takayuki Matsumoto, Kenji Watanabe, Hiroshi Nakase, Satoshi Motoya, Naoki Yoshimura, Tetsuya Ishida, Shingo Kato, Tomoo Nakagawa, Motohiro Esaki, Masakazu Nagahori, Toshiyuki Matsui, Yuji Naito, Takanori Kanai, Yasuo Suzuki, Masanori Nojima, Mamoru Watanabe, Toshifumi Hibi

Journal of Crohn's & colitis 13 ( 9 ) 1097 - 1104 2019.09 [Refereed] [International journal]

BACKGROUND: Combining a thiopurine with the human anti-tumour necrosis factor-α monoclonal antibody adalimumab for Crohn's disease [CD] treatment is controversial with regard to efficacy and safety. By conducting a subanalysis of a multicentre, randomised, prospective, open-label trial [the DIAMOND study, UMIN registration number 000005146], we studied the risk of discontinuation of thiopurine in combination with adalimumab. METHODS: In the preceding DIAMOND study, we analysed the: [i] timing and reasons for dropout in the monotherapy group and combination group; [ii] risk factors for dropout in the combination group. RESULTS: There was no significant difference in the dropout rate up to Week 52 between the monotherapy group and combination group [p = 0.325]. The main reason for study dropout was active CD in the monotherapy group, whereas it was adverse effects in the combination group [Fisher's exact test, p <0.001]. Kaplan-Meier analyses revealed significantly earlier dropout in the combination group [log-rank test, p = 0.001]. Multivariable analysis revealed low body weight to be a risk for dropout due to adverse effects in the combination group. CONCLUSIONS: Combination of azathioprine with adalimumab resulted in dropout in the early stage of the study due to side effects of azathioprine, in comparison with late dropout due to active CD in the adalimumab monotherapy group.

DOI PubMed

MEFV Gene-Related Enterocolitis Account for Some Cases Diagnosed as Inflammatory Bowel Disease Unclassified.

Daisuke Saito, Noritaka Hibi, Ryo Ozaki, Oki Kikuchi, Taro Sato, Sotaro Tokunaga, Shintaro Minowa, Osamu Ikezaki, Tatsuya Mitsui, Miki Miura, Akihito Sakuraba, Mari Hayashida, Jun Miyoshi, Minoru Matsuura, Hiroshi Nakase, Tadakazu Hisamatsu

Digestion 1 - 9 2019.09 [Refereed] [International journal]

BACKGROUND AND AIMS: Familial mediterranean fever (FMF), an autoinflammatory disease, is characterized by periodic fever and serositis. An MEFV gene mutation has been identified as the cause of FMF. Recently, patients with MEFV gene mutations and chronic gastrointestinal mucosal inflammation mimicking inflammatory bowel disease (IBD) have been reported. In this retrospective study, we analyzed the clinical characteristics of patients with IBD unclassified (IBDU) with MEFV gene mutations. METHODS: MEFV gene analysis was performed on 8 patients with IBDU among 710 patients with IBD who had been treated at Kyorin University Hospital from April 2016 to December 2018. Clinical manifestations, endoscopic findings, and serological markers were also analyzed. RESULTS: The average of the 8 patients with IBDU (3 men, 5 women) was 32.7 ± 6.4 years (range 26-76 years). Their symptoms comprised diarrhea (n = 8, 100%), hematochezia (n = 3, 37.5%), abdominal pain (n = 3, 37.5%), high fever (n = 2, 16.5%), and other periodic symptoms (n = 2, 16.5%). MEFV gene mutation was confirmed in 4/8 of these patients. Colonoscopy showed various mucosal lesions, rectal sparing, right side dominant colitis, pseudopolyposis, and granular protrusions. Colchicine was administered to 5 of the 8 patients (4 with and 1 without MEFV mutation) who were resistant to conventional treatment for ulcerative colitis. Clinical and endoscopic improvement was observed in all of 5 patients treated with colchicine. CONCLUSIONS: Some patients diagnosed as having IBDU have enterocolitis related to MEFV gene mutation and respond to colchicine therapy.

DOI PubMed

Gastric Hamartomatous Inverted Polyp Causing Ball Valve Syndrome.

Gota Sudo, Tokuma Tanuma, Hiroshi Nakase

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 17 ( 10 ) e119-e120 2019.09 [Refereed] [International journal]

DOI PubMed

Interleukin 5-producing ST2+ memory Th2 cells in IgG4-related dacryoadenitis and sialadenitis.

Motohisa Yamamoto, Ken-Ichi Takano, Ryuta Kamekura, Satsuki Aochi, Chisako Suzuki, Shingo Ichimiya, Hiroshi Nakase, Tetsuo Himi, Hiroki Takahashi

Modern rheumatology 29 ( 5 ) 856 - 860 2019.09 [Refereed] [International journal]

Objectives: Immunoglobulin (Ig) G4-related disease (IgG4-RD) is often complicated by allergic disorders. This study was conducted to investigate the mechanism of type 2 helper T-inflammation (Th2-inflammation) in IgG4-related dacryoadenitis and sialadenitis (IgG4-DS). Methods: We separated and analyzed the proportion of growth stimulation expressed gene 2 (ST2)+ memory Th2 cells among the peripheral blood mononuclear cells by flow cytometry in cases with IgG4-DS and healthy individuals. Finally, we identified the role of ST2+ memory Th2 cells in the involved tissues. Results: The proportion of circulating ST2+ memory Th2 cells was much higher in the patients with IgG4-DS than in the healthy controls. Abundant infiltration of ST2+ memory Th2 cells was detected in the involved salivary glands and lymph nodes, and these cells produced interleukin-5. Conclusion: We demonstrated that there is an increase of interleukin-5 producing ST2+ memory Th2 cells in the involved tissues in IgG4-DS. This subset of cells is considered to be an important player in inducing the inflammatory Th2 environment characteristic of IgG4-DS.

DOI PubMed

多発性骨髄腫における新規エピジェネティック併用療法の開発(Development of a new combinational epigenetic therapy of multiple myeloma)

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 ) 78回 P - 2241 2019.09

SMOC1の大腸腫瘍診断マーカーとしての臨床的有用性の検討(Clinical usefulness of SMOC1 as a diagnostic marker of colorectal precancerous lesions)

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, 小山内誠, 仲瀬裕志, 菅井有, 鈴木拓

日本癌学会総会記事 ( 日本癌学会 ) 78回 P - 1323 2019.09

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

須藤豪太, 山本英一郎, 萬顕, 新沼猛, 杉本亮, 北嶋洋志, 久保俊之, 畠中柚衣, 甲斐正広, 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 ) 78回 P - 3102 2019.09

正常大腸粘膜のヒストン修飾異常とCIMP大腸腫瘍の発がんリスクの関連(Repressive histone mark in normal colon is associated with the risk of CRC with CpG island methylator phenotype)

山本英一郎, 須藤豪太, 久保俊之, 萬顕, 原田拓, 青木敬則, 北嶋洋志, 新沼猛, 甲斐正広, 菅井有, 仲瀬裕志, 鈴木拓

日本癌学会総会記事 ( 日本癌学会 ) 78回 J - 2035 2019.09

術後早期に腹腔内播種再発をきたしたnon-invasive IPMCの一例

中村友哉, 柾木喜晴, 大和田紗恵, 平野雄大, 川上裕次郎, 石上敬介, 伊東文子, 阿久津典之, 本谷雅代, 佐々木茂, 今村将史, 木村康利, 竹政伊知朗, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 125回・119回 39 - 39 2019.09

肝血管腫として11年間経過観察中に診断された混合型肝癌の1例

平野雄大, 阿久津典之, 大和田紗恵, 柾木喜晴, 石上敬介, 伊東文子, 本谷雅代, 佐々木茂, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 125回・119回 58 - 58 2019.09

消化器内視鏡治療におけるトラブルシューティング当科におけるEST後出血の現状と対処法

柾木喜晴, 本谷雅代, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 125回・119回 54 - 54 2019.09

Diversity of Gut Microbiota Affecting Serum Level of Undercarboxylated Osteocalcin in Patients with Crohn's Disease.

Kohei Wagatsuma, Satoshi Yamada, Misora Ao, Minoru Matsuura, Hidemi Tsuji, Tomoya Iida, Kentaro Miyamoto, Kentaro Oka, Motomichi Takahashi, Kiyoshi Tanaka, Hiroshi Nakase

Nutrients ( MDPI AG ) 11 ( 7 ) 1541 - 1541 2019.07 [Refereed] [International journal]

Several reports have indicated a possible link between decreasing plasma levels of vitamin K and bone mineral density. It has been suggested that intestinal bacteria contribute to maintenance of vitamin K. Several factors are involved in the reduction of vitamin K in patients with Crohn's disease (CD). We aimed to assess the relationship between gut microbiota and alternative indicators of vitamin K deficiency in patients with CD. We collected the feces of 26 patients with clinically inactive CD. We extracted 16S rRNA from the intestinal bacteria in the feces and amplified it by polymerase chain reaction. The generated polymerase chain reaction product was analyzed using a 16S metagenomic approach by Illumina Miseq platform. Serum undercarboxylated osteocalcin concentration was used as an alternative indicator of vitamin K deficiency. There was a significant negative correlation between serum undercarboxylated osteocalcin and mean Chao1 index in cases of low activity. The diversity of the gut microbiota was significantly lower, and Ruminococcaceae and Lachnospiraceae were significantly decreased in the vitamin K-deficient group in comparison to the vitamin K-normal group. Taken together, these data suggested the significance of investigating the gut microbiota even in patients with clinically inactive CD for improving patients' vitamin K status.

DOI PubMed

The Etiology of Pancreatic Manifestations in Patients with Inflammatory Bowel Disease.

Tomoya Iida, Kohei Wagatsuma, Daisuke Hirayama, Yoshihiro Yokoyama, Hiroshi Nakase

Journal of clinical medicine 8 ( 7 ) 2019.06 [Refereed] [International journal]

Inflammatory bowel disease (IBD) is an idiopathic chronic and recurrent condition that comprises Crohn's disease and ulcerative colitis. A pancreatic lesion is one of the extraintestinal lesions in patients with IBD. Acute pancreatitis is the representative manifestation, and various causes of pancreatitis have been reported, including those involving adverse effects of drug therapies such as 5-aminosalicylic acid and thiopurines, gall stones, gastrointestinal lesions on the duodenum, iatrogenic harm accompanying endoscopic procedures such as balloon endoscopy, and autoimmunity. Of these potential causes, autoimmune pancreatitis (AIP) is a relatively newly recognized disease and is being increasingly diagnosed in IBD. AIP cases can be divided into type 1 cases involving lymphocytes and IgG4-positive plasma cells, and type 2 cases primarily involving neutrophils; the majority of AIP cases complicating IBD are type 2. The association between IBD and chronic pancreatitis, exocrine pancreatic insufficiency, pancreatic cancer, etc. has also been suggested; however, studies with high-quality level evidence are limited, and much remains unknown. In this review, we provide an overview of the etiology of pancreatic manifestation in patients with IBD.

DOI PubMed

膵癌に対するGemcitabine+nab-Paclitaxel療法・FOLFIRINOX療法における原発巣縮小効果

仲地耕平, 本谷雅代, 阿久津典之, 石上敬介, 伊東文子, 柾木喜晴, 佐々木茂, 金戸宏之, 矢和田敦, 岡俊洲, 仲瀬裕志

膵臓 ( (一社)日本膵臓学会 ) 34 ( 3 ) A160 - A160 2019.06

UHRF1 depletion and HDAC inhibition reactivate epigenetically silenced genes in colorectal cancer cells.

Takeshi Niinuma, Hiroshi Kitajima, Masahiro Kai, Eiichiro Yamamoto, Akira Yorozu, Kazuya Ishiguro, Hajime Sasaki, Gota Sudo, Mutsumi Toyota, Tomo Hatahira, Reo Maruyama, Takashi Tokino, Hiroshi Nakase, Tamotsu Sugai, Hiromu Suzuki

Clinical epigenetics 11 ( 1 ) 70 - 70 2019.05 [Refereed] [International journal]

BACKGROUND: Ubiquitin-like protein containing PHD and RING finger domains 1 (UHRF1) is a major regulator of epigenetic mechanisms and is overexpressed in various human malignancies. In this study, we examined the involvement of UHRF1 in aberrant DNA methylation and gene silencing in colorectal cancer (CRC). RESULTS: CRC cell lines were transiently transfected with siRNAs targeting UHRF1, after which DNA methylation was analyzed using dot blots, bisulfite pyrosequencing, and Infinium HumanMethylation450 BeadChip assays. Gene expression was analyzed using RT-PCR and gene expression microarrays. Depletion of UHRF1 rapidly induced genome-wide DNA demethylation in CRC cells. Infinium BeadChip assays and bisulfite pyrosequencing revealed significant demethylation across entire genomic regions, including CpG islands, gene bodies, intergenic regions, and repetitive elements. Despite the substantial demethylation, however, UHRF1 depletion only minimally reversed CpG island hypermethylation-associated gene silencing. By contrast, the combination of UHRF1 depletion and histone deacetylase (HDAC) inhibition reactivated the silenced genes and strongly suppressed CRC cell proliferation. The combination of UHRF1 depletion and HDAC inhibition also induced marked changes in the gene expression profiles such that cell cycle-related genes were strikingly downregulated. CONCLUSIONS: Our results suggest that (i) maintenance of DNA methylation in CRC cells is highly dependent on UHRF1; (ii) UHRF1 depletion rapidly induces DNA demethylation, though it is insufficient to fully reactivate the silenced genes; and (iii) dual targeting of UHRF1 and HDAC may be an effective new therapeutic strategy.

DOI PubMed

Chronic intestinal pseudo-obstruction due to al amyloidosis: a case report and literature review.

Tomoya Iida, Daisuke Hirayama, Gota Sudo, Kei Mitsuhashi, Hisayoshi Igarashi, Kentaro Yamashita, Hiroo Yamano, Hiroshi Nakase

Clinical journal of gastroenterology 12 ( 2 ) 176 - 181 2019.04 [Refereed] [Domestic journal]

A 59-year-old woman presented to our hospital with a 6-month history of nausea, weight loss, and abdominal distension. Physical examination revealed abdominal distension without tenderness, and edema, numbness, and multiple peripheral neuropathy in the limbs. Blood test results showed anemia, hypoproteinemia, and hypoalbuminemia. Immunoelectrophoresis detected kappa-type Bence-Jones protein in both the serum and urine. Bone marrow examination did not reveal an increase of plasma cells. Computed tomography showed intestinal distension and retention of intestinal contents. No obstructive intestinal lesions were observed. Lower gastrointestinal endoscopy showed a decrease in the vascular visibility of the rectal mucosa. Histological findings showed amyloid deposition, which was positive for amyloid light-chain (AL) κ. Thus, she was diagnosed with chronic intestinal pseudo-obstruction (CIPO) due to gastrointestinal and neurological involvement of AL amyloidosis. Her abdominal symptoms were gradually improved by the insertion of an ileus tube and medication. Although we recommended chemotherapy for stopping her disease progression, she did not want to receive it. She died 1 year later because of her pneumonia. We should keep in mind that amyloidosis is an important cause of CIPO. Histopathological examination by endoscopic biopsy is required for exact diagnosis and appropriate treatment for CIPO due to amyloidosis.

DOI PubMed

Pedunculated Upper Esophageal Adenocarcinoma in Lynch Syndrome.

Hajime Sasaki, Kentaro Yamashita, Hiroshi Nakase

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 17 ( 5 ) A20 2019.04 [Refereed] [International journal]

DOI PubMed

Gastric Xanthomas and Fundic Gland Polyps as Endoscopic Risk Indicators of Gastric Cancer.

Kentaro Yamashita, Ryo Suzuki, Toshiyuki Kubo, Kei Onodera, Tomoya Iida, Mayuko Saito, Yoshiaki Arimura, Takao Endo, Masanori Nojima, Hiroshi Nakase

Gut and liver 13 ( 4 ) 409 - 414 2019.03 [Refereed] [International journal]

Background/Aims: Fundic gland polyps (FGPs), hyperplastic polyps (HPs), and xanthomas (XTs) are common benign gastric lesions that can be diagnosed by endoscopic appearance alone in most cases. The aim of this study was to evaluate associations between gastric cancer and these benign lesions. Methods: Two expert endoscopists reviewed a series of gastroscopy images. FGPs, HPs, and XTs were diagnosed by endoscopic appearance, whereas all gastric cancers were confirmed pathologically. Results: Of the 1,227 patients reviewed, 114 (9.3%) had a concurrent or past history of gastric cancer. The overall prevalences of FGPs, HPs and XTs were 9.4%, 6.3% and 14.2%, respectively. HPs and XTs coexisted in 1.6% of patients, whereas other combinations were rarer. XTs were observed in 39.3% and 11.5% of patients with and without gastric cancer, respectively (p<0.001). In contrast, no gastric cancer patients had FGPs, whereas 10.4% of patients without cancer had FGPs (p<0.001). The prevalence of HPs was similar between the two groups (8.8% and 6.0% of patients with and without cancer, respectively, p=0.29). Multivariate and Mantel-Haenszel analyses demonstrated that XTs were positively associated and FGPs were negatively associated with gastric cancer. Conclusions: XTs and FGPs might be useful as endoscopic risk indicators for monitoring gastric cancer.

DOI PubMed

Tumor recognition of peanut agglutinin-immobilized fluorescent nanospheres in biopsied human tissues.

Hironori Kumagai, Kosuke Yamada, Kanako Nakai, Tokio Kitamura, Kohta Mohri, Masami Ukawa, Takumi Tomono, Takaaki Eguchi, Testuya Yoshizaki, Takumi Fukuchi, Takuya Yoshino, Minoru Matsuura, Etsuo Tobita, Wellington Pham, Hiroshi Nakase, Shinji Sakuma

European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V ( Elsevier ) 136 29 - 37 2019.03 [Refereed] [International journal]

We are investigating an imaging agent for early detection of colorectal cancer. The agent, named the nanobeacon, is coumarin 6-encapsulated polystyrene nanospheres whose surfaces are covered with poly(N-vinylacetamide) and peanut agglutinin that reduces non-specific interactions with the normal mucosa and exhibits high affinity for terminal sugars of the Thomsen-Friedenreich antigen, which is expressed cancer-specifically on the mucosa, respectively. We expect that cancer can be diagnosed by detecting illumination of intracolonically administered nanobeacon on the mucosal surface. In the present study, biopsied human tissues were used to evaluate the potential use of the nanobeacon in the clinic. Prior to the clinical study, diagnostic capabilities of the nanobeacon for detection of colorectal cancer were validated using 20 production batches whose characteristics were fine-tuned chemically for the purpose. Ex vivo imaging studies on 66 normal and 69 cancer tissues removed from the colons of normal and orthotopic mouse models of human colorectal cancer, respectively, demonstrated that the nanobeacon detected colorectal cancer with excellent capabilities whose rates of true and false positives were 91% and 5%, respectively. In the clinical study, normal and tumor tissues on the large intestinal mucosa were biopsied endoscopically from 11 patients with colorectal tumors. Histological evaluation revealed that 9 patients suffered from cancer and the rest had adenoma. Mean fluorescence intensities of tumor tissues treated with the nanobeacon were significantly higher than those of the corresponding normal tissues. Correlation of magnitude relation of the intensity in individuals was observed in cancer patients with a high probability (89%); however, the probability reduced to 50% in adenoma patients. There was a reasonable likelihood for diagnosis of colorectal cancer by the nanobeacon applied to the mucosa of the large intestine.

DOI PubMed

当初潰瘍性大腸炎と診断された家族性地中海熱の一例

柴田泰洋, 山下健太郎, 上野あかり, 斎藤潤信, 守谷洋, 風間友江, 須藤豪太, 三橋慧, 能正勝彦, 山野泰穂, 菊地剛史, 遠藤高夫, 仲瀬裕志

日本消化器病学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 124回 80 - 80 2019.03

術前診断が困難であった低異型度分化型胃癌(超高分化型胃癌)の2例

風間友江, 上野あかり, 柴田泰洋, 須藤豪太, 五十嵐央祥, 久保俊之, 三橋慧, 能正勝彦, 山下健太郎, 山野泰穂, 市原真, 杉田真太朗, 長谷川匡, 信岡隆幸, 竹政伊知朗, 仲瀬裕志

日本消化器病学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 124回 67 - 67 2019.03

Infliximab投与中に血管炎を併発したクローン病の一例

上野あかり, 山下健太郎, 仲瀬裕志, 山野泰穂, 三橋慧, 須藤豪太, 五十嵐央祥, 風間友江, 柴田泰洋

日本消化器病学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 124回 51 - 51 2019.03

化学療法終了24ヵ月後に発症したde novo B型肝炎の一例

齋藤潤信, 阿久津典之, 谷口正浩, 守谷洋, 石上敬介, 柾木喜晴, 伊東文子, 仲地耕平, 本谷雅代, 佐々木茂, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 124回・118回 48 - 48 2019.03

術前に原発性卵巣癌との鑑別が困難であった膵尾部癌卵巣転移の1切除例

守谷洋, 伊東文子, 柾木喜晴, 石上敬介, 阿久津典之, 仲地耕平, 本谷雅代, 佐々木茂, 木村康利, 仲瀬裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 ) 124回・118回 70 - 70 2019.03

OPeNing the Epithelial Barrier: Osteopontin Preserves Gut Barrier Function During Intestinal Inflammation.

Hiroshi Nakase

Digestive diseases and sciences 64 ( 2 ) 294 - 296 2019.02 [Refereed] [International journal]

DOI PubMed

Influence of Pharmaceutical Formulation on the Mucosal Concentration of 5-Aminosalicylic Acid and N-Acetylmesalamine in Japanese Patients with Ulcerative Colitis.

Yuki Yamamoto, Satohiro Masuda, Hiroshi Nakase, Minoru Matsuura, Shihoko Maruyama, Tadakazu Hisamatsu, Yasuo Suzuki, Kazuo Matsubara

Biological & pharmaceutical bulletin 42 ( 1 ) 81 - 86 2019.01 [Refereed] [Domestic journal]

The efficacy of 5-aminosalicylic acid (5-ASA) as the first-line therapy for ulcerative colitis (UC) is determined by the extent of drug delivery to the inflamed region. Moreover, differences among the various formulations influence delivery of the drug. In this study, we examined the clinical significance of colonic mucosal concentrations of 5-ASA and N-acetylmesalamine (Ac-5-ASA) in UC patients receiving a pH-dependent or time-dependent release formulation of 5-ASA. The subjects were 67 patients with UC who were treated with a pH-dependent or time-dependent formulation of 5-ASA between December 2011 and April 2014. A retrospective observational analysis of clinical outcomes was performed using the clinical activity index (CAI) obtained on the day of biopsy. Colonic mucosal concentrations of 5-ASA and Ac-5-ASA in biopsy samples were measured by LC-tandem mass spectrometry/mass spectrometry. Patients who were treated with the pH-dependent formulation had higher colon mucosal concentrations of 5-ASA than those who were treated with the time-dependent formulation. Additionally, 5-ASA concentration was significantly higher in patients with CAI scores ≤3. A higher concentration of Ac-5-ASA was achieved with the time-dependent formulation than with the pH-dependent formulation. Furthermore, patients with CAI scores ≤3 had higher concentrations of 5-ASA than those with CAI scores ≥4. The colonic mucosal concentration of 5-ASA in patients with UC is influenced by the pharmaceutical formulation and the remission status of UC.

DOI PubMed

DOT1L inhibition blocks multiple myeloma cell proliferation by suppressing IRF4-MYC signaling.

Kazuya Ishiguro, Hiroshi Kitajima, Takeshi Niinuma, Tadao Ishida, Reo Maruyama, Hiroshi Ikeda, Toshiaki Hayashi, Hajime Sasaki, Hideki Wakasugi, Koyo Nishiyama, Tetsuya Shindo, Eiichiro Yamamoto, Masahiro Kai, Yasushi Sasaki, Takashi Tokino, Hiroshi Nakase, Hiromu Suzuki

Haematologica 104 ( 1 ) 155 - 165 2019.01 [Refereed] [International journal]

Epigenetic alterations play an important role in the pathogenesis in multiple myeloma, but their biological and clinical relevance is not fully understood. Here, we show that DOT1L, which catalyzes methylation of histone H3 lysine 79, is required for myeloma cell survival. DOT1L expression levels were higher in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma than in normal plasma cells. Treatment with a DOT1L inhibitor induced cell cycle arrest and apoptosis in myeloma cells, and strongly suppressed cell proliferation in vitro The anti-myeloma effect of DOT1L inhibition was confirmed in a mouse xenograft model. Chromatin immunoprecipitation-sequencing and microarray analysis revealed that DOT1L inhibition downregulated histone H3 lysine 79 dimethylation and expression of IRF4-MYC signaling genes in myeloma cells. In addition, DOT1L inhibition upregulated genes associated with immune responses and interferon signaling. Myeloma cells with histone modifier mutations or lower IRF4/MYC expression were less sensitive to DOT1L inhibition, but with prolonged treatment, anti-proliferative effects were achieved in these cells. Our data suggest that DOT1L plays an essential role in the development of multiple myeloma and that DOT1L inhibition may provide new therapies for myeloma treatment.

DOI PubMed

Multiloop method for traction during colorectal endoscopic submucosal dissection.

Gota Sudo, Tokuma Tanuma, Yuichiro Suzuki, Hiroshi Nakase

VideoGIE : an official video journal of the American Society for Gastrointestinal Endoscopy 4 ( 1 ) 11 - 13 2019.01 [Refereed] [International journal]

DOI PubMed

Integrated Analysis of the Endoscopic, Pathological and Molecular Characteristics of Colorectal Tumorigenesis.

Hiromu Suzuki, Eiichiro Yamamoto, Hiro-O Yamano, Hiroshi Nakase, Tamotsu Sugai

Digestion 99 ( 1 ) 33 - 38 2019 [Refereed] [International journal]

BACKGROUND: Colorectal cancers (CRCs) develop through the accumulation of genetic and epigenetic alterations of oncogenes and tumor suppressor genes. In addition to the well-characterized adenoma-carcinoma sequence, the serrated neoplasia pathway is now recognized as an alternative pathway for CRC development. SUMMARY: Through analysis of the colonoscopic, pathological, and molecular features of colorectal tumors, we identified a novel microsurface structure characteristic of serrated lesions. The Type II-Open (Type II-O) pit pattern is highly specific to sessile serrated adenoma/polyps (SSA/Ps), and Type-II-O-positive tumors frequently exhibit v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation and 5'-C-phosphate-G-3' (CpG) island hypermethylation. By screening DNA methylation associated with the development of serrated lesions, we detected methylation of secreted protein acidic and rich in cysteine (SPARC)-related modular calcium binding 1 (SMOC1) in traditional serrated adenomas (TSAs). Epigenetic silencing of SMOC1 is prevalent among TSAs but it is rarely observed in SSA/Ps, which suggests SMOC1 could be a useful diagnostic marker of serrated lesions. We also searched for epigenetic alterations associated with the growth pattern of colorectal tumors and found that methylation of neurotensin receptor 1 is associated with lateral and non-invasive tumor growth. Key Message: Through the summarized studies, we have been able to identify novel morphological and molecular features that could contribute to a better understanding of colorectal tumors and to improved clinical diagnosis.

DOI PubMed

Prognostic Effect of Long Noncoding RNA NEAT1 Expression Depends on p53 Mutation Status in Cancer.

Masashi Idogawa, Hiroshi Nakase, Yasushi Sasaki, Takashi Tokino

Journal of oncology 2019 4368068 - 4368068 2019 [Refereed] [International journal]

Recently, many studies have revealed that long noncoding RNAs (lncRNAs) play important roles in various biological and pathological processes. Our previous study reported that lncRNA NEAT1 is a direct transcriptional target of p53. NEAT1 is an essential component of paraspeckles, which have recently been identified as a novel type of nuclear compartment. Although our previous findings indicate that NEAT1 induction contributes to the tumor-suppressor function of p53, the role of NEAT1 in cancer is still controversial. In this study, we comprehensively analyzed the relationship between NEAT1 expression and p53 mutation status. Interestingly, survival analysis based on NEAT1 expression in several cancer tissues revealed that the p53 wild-type group with high NEAT1 expression had a good prognosis, while poor prognosis or no correlation between NEAT1 expression and survival was observed in the p53-mutated group. These results demonstrate that the tumor-suppressive effect of NEAT1 depends on p53 function and is consistent with our previous report showing that NEAT1 supports the tumor-suppressive function of p53. Specifically, NEAT1 seems to play a tumor-suppressive role only in the presence of wild-type p53. These results provide important clues to the roles of NEAT1 in cancer.

DOI PubMed

The Incidence and Risk Factors of Venous Thromboembolism in Patients with Inflammatory Bowel Disease: A Prospective Multicenter Cohort Study.

Katsuyoshi Ando, Mikihiro Fujiya, Yoshiki Nomura, Yuhei Inaba, Yuya Sugiyama, Yu Kobayashi, Takuya Iwama, Masami Ijiri, Keitaro Takahashi, Nobuhiro Ueno, Shin Kashima, Kentaro Moriichi, Hiroki Tanabe, Yusuke Mizukami, Kazumi Akasaka, Satoshi Fujii, Satoshi Yamada, Hiroshi Nakase, Toshikatsu Okumura

Digestion 100 ( 4 ) 229 - 237 2019 [Refereed] [International journal]

BACKGROUND: Venous thromboembolism (VTE) has been shown to be more frequent in inflammatory bowel disease (IBD) than in the general population in Western studies. However, the actual state of VTE in Asian IBD remains poorly understood. AIMS: To reveal the incidence of VTE in IBD patients in Japan. METHODS: Eighty-five patients admitted to 3 gastroenterology centers were registered from 2013 to 2018. The incidence of VTE in patients with IBD (n = 42) was prospectively compared to that among patients with other digestive diseases (n = 43). The presence of VTE was surveyed using contrast-enhanced computed tomography and/or ultrasonography at admission and at 1-2 weeks after admission. The patient characteristics and laboratory data of IBD patients with or without VTE were compared to determine the risk factors for VTE. RESULTS: The incidence of VTE with IBD was 16.7%, which was significantly more frequent than with other digestive diseases (2.3%; p = 0.0296). In IBD patients, VTE was detected in 6 of 22 patients with ulcerative colitis (27.2%) but in only 1 of 20 patients with Crohn's disease (5.0%). VTE was diagnosed at admission in 4 IBD patients and 2 weeks after admission in 3 IBD patients. The risk factors of VTE in IBD were the presence of an indwelling central venous catheter, a low level of total protein, a low activated partial thromboplastin time, and a high level of fibrinogen degradation products. CONCLUSION: VTE was frequently detected in Japanese IBD patients both at and after admission. Adequate screening and prophylaxis for VTE is deemed necessary in IBD.

DOI PubMed

Molecular biology of colorectal cancer -mechanism of tumorigenesis and molecular subtypes-

Hiromu Suzuki, Eiichiro Yamamoto, Hiroshi Nakase

Journal of Japanese Society of Gastroenterology ( Japanese Society of Gastroenterology ) 116 ( 11 ) 859 - 866 2019

DOI PubMed

Impact of Autophagy of Innate Immune Cells on Inflammatory Bowel Disease.

Tomoya Iida, Yoshihiro Yokoyama, Kohei Wagatsuma, Daisuke Hirayama, Hiroshi Nakase

Cells 8 ( 1 ) 2018.12 [Refereed] [International journal]

Autophagy, an intracellular degradation mechanism, has many immunological functions and is a constitutive process necessary for maintaining cellular homeostasis and organ structure. One of the functions of autophagy is to control the innate immune response. Many studies conducted in recent years have revealed the contribution of autophagy to the innate immune response, and relationships between this process and various diseases have been reported. Inflammatory bowel disease is an intractable disorder with unknown etiology; however, immunological abnormalities in the intestines are known to be involved in the pathology of inflammatory bowel disease, as is dysfunction of autophagy. In Crohn's disease, many associations with autophagy-related genes, such as ATG16L1, IRGM, NOD2, and others, have been reported. Abnormalities in the ATG16L1 gene, in particular, have been reported to cause autophagic dysfunction, resulting in enhanced production of inflammatory cytokines by macrophages as well as abnormal function of Paneth cells, which are important in intestinal innate immunity. In this review, we provide an overview of the autophagy mechanism in innate immune cells in inflammatory bowel disease.

DOI PubMed

Ectopic relapse of IgG4-related disease presenting as IgG4-related sclerosing cholecystitis: A case report and review of literature.

Keisuke Ishigami, Masahiro Shitani, Yasutoshi Kimura, Tadashi Hasegawa, Yoshiharu Masaki, Ayako Ito, Noriyuki Akutsu, Motohisa Yamamoto, Masayo Motoya, Shigeru Sasaki, Hiroki Takahashi, Ichiro Takemasa, Hiroshi Nakase

Medicine 97 ( 52 ) e13868 2018.12 [Refereed] [International journal]

RATIONALE: Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a chronic inflammatory disorder characterized by high levels of serum IgG4, swollen organs with fibrosis and abundant infiltration of IgG4-positive plasmacytes. PATIENT CONCERNS: An 82-year-old male visited our hospital for an evaluation of a pancreatic enlargement and a bilateral submandibular adenopathy. Further investigation revealed elevation of serum IgG4 and bilateral lacrimal submandibular adenopathy. We diagnosed him with IgG4-related disease (IgG4-RD) and started administration of corticosteroid (CS) therapy. Both pancreatic enlargement and adenopathy rapidly improved; however, there was a new occurrence of diffuse wall thickening of the gallbladder during CS treatment. DIAGNOSIS: Radiological examination revealed diffuse wall thickening of the gallbladder, and its inner layer was smooth and homogenous. These findings suggested an inflammatory change, but the possibility of malignancy could not be excluded. INTERVENTIONS: The patient underwent laparoscopic cholecystectomy for a pathological diagnosis. OUTCOMES: Histological examination revealed a transmural infiltration of IgG4 positive plasma cells and dense fibrosis. The patient was pathologically diagnosed with IgG4 related cholecystitis presenting as an ectopic relapse. LESSONS: There are 2 major types of IgG4-related cholecystitis, a diffuse wall thickening type and a mass formation type. It is sometimes difficult to differentiate IgG4-related cholecystitis with gallbladder cancer.Corticosteroid (CS) is effective for induction of remission; however, we sometimes encounter disease relapse after reduction of CS dose. We should be mindful that some patients may relapse with new organ involvements even if the primary site and serum IgG4 level are well controlled.

DOI PubMed

Surface microstructures are associated with mutational intratumoral heterogeneity in colorectal tumors.

Taku Harada, Eiichiro Yamamoto, Hiro-O Yamano, Hironori Aoki, Hiro-O Matsushita, Kenjiro Yoshikawa, Ryo Takagi, Eiji Harada, Yoshihito Tanaka, Yuko Yoshida, Makoto Eizuka, Akira Yorozu, Gota Sudo, Hiroshi Kitajima, Takeshi Niinuma, Masahiro Kai, Yasushi Sasaki, Takashi Tokino, Tamotsu Sugai, Hiroshi Nakase, Hiromu Suzuki

Journal of gastroenterology 53 ( 12 ) 1241 - 1252 2018.12 [Refereed] [Domestic journal]

BACKGROUND: Recent studies revealed that colorectal tumors are composed of genetically diverse subclones. We aimed to clarify whether the surface microstructures of colorectal tumors are associated with genetic intratumoral heterogeneity (ITH). METHODS: The surface microstructures (pit patterns) of colorectal tumors were observed using magnifying endoscopy, and biopsy specimens were obtained from respective areas when tumors exhibited multiple pit patterns. A total of 711 specimens from 477 colorectal tumors were analyzed for BRAF, KRAS and TP53 mutations using pyrosequencing and direct sequencing. A panel of cancer-related genes was analyzed through targeted sequencing in 7 tumors. RESULTS: Colorectal tumors with multiple pit patterns exhibited more advanced pit patterns and higher frequencies of KRAS and/or TP53 mutations than tumors with a single pit pattern. In tumors with multiple pit patterns, mutations were observed as public (common to all areas) or private (specific to certain areas), and private KRAS and/or TP53 mutations were often variable and unrelated to the pit pattern grade. Notably, invasive CRCs frequently exhibited public TP53 mutations, even in adenomatous areas, which is indicative of their early malignant potential. Targeted sequencing revealed additional public and private mutations in tumors with multiple pit patterns, indicating their single clonal origin. CONCLUSIONS: Our results suggest intratumoral pit pattern variation does not simply reflect the process of colorectal tumor evolution, but instead represents genetically diverse subclones, and this diversity may be associated with malignant potential.

DOI PubMed

Development of oral drug delivery systems with probiotic bacteria in the future

Kohei Wagatsuma, Yoshihiro Yokoyama, Hiroshi Nakase

Drug Delivery System ( Japan Society of Drug Delivery System ) 33 ( 5 ) 414 - 421 2018.11

Inflammatory bowel disease (IBD) commonly occurs in young people, and the number of IBD patients is still increasing in Japan. Regarding the treatment of IBD, glucocorticosteroids (CSs), immunosuppressants, and biologics are used for the purpose of controlling excessive immune response. Although the therapeutic effect of CSs has been established, physicians always concern about adverse events related to long-term use of CSs. Additionally, treatment with anti-inflammatory cytokines has been expected, however, the efficacy of their systemic administration is not necessarily expected because of their short half-life. Drug delivery system (DDS) can in principle provide enhanced efficacy and/ or reduced toxicity of drugs. Until now, there have been various reports of therapeutic effects of DDS with genetically modified intestinal bacteria, that can produce anti-inflammatory substances, on IBD models. Previously, DDS with genetically modified intestinal bacteria producing interleukin-10 had been focused. Recently, reports on DSS with genetically modified intestinal bacteria producing proteins and other cytokines except IL-10 are increasing. On the other hand, further studies will be required to elucidate how kinds of intestinal bacteria and anti-inflammatory substances affect therapeutic efficacy in ameliorating intestinal inflammation. Additionally, to assess the safety of treatment with these DDS and the risk influencing environment will be necessary before clinical application.

DOI

Current status and issues of drug delivery system for regulating mucosal immune system of the gastrointestinal tract

Minoru Matsuura, Hiroshi Nakase

Drug Delivery System ( Japan Society of Drug Delivery System ) 33 ( 5 ) 406 - 413 2018.11

Current advances in the treatment of inflammatory bowel disease (IBD) are mainly due to improvement in selectivity or specificity of therapeutic target molecules and mechanisms of action. However, it is not necessarily sufficient from the viewpoint of selective target to gastrointestinal tracts. Development of drug delivery system targeted to the gastrointestinal tract using biodegradable microspheres, which could carry and sustained release various materials such as corticosteroids, anti-inflammatory cytokines and growth factors would be expected to contribute to future therapeutic strategy for inflammatory bowel disease.

DOI

Stage classification of IgG4-related dacryoadenitis and sialadenitis by the serum cytokine environment.

Motohisa Yamamoto, Kenichi Takano, Ryuta Kamekura, Chisako Suzuki, Shingo Ichimiya, Tetsuo Himi, Hiroshi Nakase, Hiroki Takahashi

Modern rheumatology 28 ( 6 ) 1004 - 1008 2018.11 [Refereed] [International journal]

OBJECTIVES: Patients with immunoglobulin-G4 related disease (IgG4-RD) diagnosed according to the comprehensive diagnostic criteria (CDC) show varied therapeutic responses and prognoses. We assumed that there are clinical stages in IgG4-RD and have verified it using serum cytokine levels in the groups classified by lesion distribution. METHODS: Definite IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) cases were divided according to the CDC for IgG4-RD into 11 cases with focal type and 30 cases with systemic type. The levels of serum interleukin (IL)-4, IL-5, IL-6, IL-10, IL-13, IL-15, IL-21, interferon (IFN)-α, IFN-γ, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β1, and monocyte chemotactic protein (MCP)-1 were measured in healthy controls, allergic patients, probable IgG4-RD cases, and focal and systemic type cases. The cytokine environment was analyzed in each group. The 52 definite IgG4-RD cases were next classified into four groups with cluster analysis in terms of therapeutic responses and prognosis. The relationships between each cytokine level and therapeutic responses were also analyzed. RESULTS: Both serum IL-5 and IFN-α concentrations were very low in healthy controls, but they increased in the allergic cases, probable cases, and focal and systemic type cases. The level of serum IL-5 was significantly higher in definite cases than in healthy controls. The serum IL-5 level was also significantly increased in the groups with a poor prognosis than in the good prognosis group. CONCLUSION: These results suggest that there are clinical stages in IgG4-RD, and serum IL-5 play roles in the pathogenesis of IgG4-RD.

DOI PubMed

Dysregulation of miRNA in chronic hepatitis B is associated with hepatocellular carcinoma risk after nucleos(t)ide analogue treatment.

Hideki Wakasugi, Hideaki Takahashi, Takeshi Niinuma, Hiroshi Kitajima, Ritsuko Oikawa, Naoki Matsumoto, Yuko Takeba, Takehito Otsubo, Masayuki Takagi, Yasushi Ariizumi, Michihiro Suzuki, Chiaki Okuse, Shogo Iwabuchi, Masayuki Nakano, Noriyuki Akutsu, Jong-Hon Kang, Takeshi Matsui, Norie Yamada, Hajime Sasaki, Eiichiro Yamamoto, Masahiro Kai, Yasushi Sasaki, Shigeru Sasaki, Yasuhito Tanaka, Hiroshi Yotsuyanagi, Takeya Tsutsumi, Hiroyuki Yamamoto, Takashi Tokino, Hiroshi Nakase, Hiromu Suzuki, Fumio Itoh

Cancer letters 434 91 - 100 2018.10 [Refereed] [International journal]

Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC). Nucleos(t)ide analogue (NA) therapy effectively reduces the incidence of HCC, but it does not completely prevent the disease. Here, we show that dysregulation of microRNAs (miRNAs) is involved in post-NA HCC development. We divided chronic hepatitis B (CHB) patients who received NA therapy into two groups: 1) those who did not develop HCC during the follow-up period after NA therapy (no-HCC group) and 2) those who did (HCC group). miRNA expression profiles were significantly altered in CHB tissues as compared to normal liver, and the HCC group showed greater alteration than the no-HCC group. NA treatment restored the miRNA expression profiles to near-normal in the no-HCC group, but it was less effective in the HCC group. A number of miRNAs implicated in HCC, including miR-101, miR-140, miR-152, miR-199a-3p, and let-7g, were downregulated in CHB. Moreover, we identified CDK7 and TACC2 as novel target genes of miR-199a-3p. Our results suggest that altered miRNA expression in CHB contributes to HCC development, and that improvement of miRNA expression after NA treatment is associated with reduced HCC risk.

DOI PubMed

Usefulness of fecal calprotectin by monoclonal antibody testing in adult Japanese with inflammatory bowel diseases: a prospective multicenter study.

Shiro Nakamura, Hirotsugu Imaeda, Hiroki Nishikawa, Masaki Iimuro, Minoru Matsuura, Hideo Oka, Junsuke Oku, Takako Miyazaki, Hirohito Honda, Kenji Watanabe, Hiroshi Nakase, Akira Andoh

Intestinal research 16 ( 4 ) 554 - 562 2018.10 [Refereed] [International journal]

Background/Aims: Noninvasive objective monitoring is advantageous for optimizing treatment strategies in patients inflammatory bowel disease (IBD). Fecal calprotectin (FCP) is superior to traditional biomarkers in terms of assessing the activity in patients with IBD. However, there are the differences among several FCP assays in the dynamics of FCP. In this prospective multicenter trial, we investigated the usefulness of fecal FCP measurements in adult Japanese patients with IBD by reliable enzyme immunoassay using a monoclonal antibody. Methods: We assessed the relationship between FCP levels and disease or endoscopic activity in patients with ulcerative colitis (UC, n=64) or Crohn's disease (CD, n=46) compared with healthy controls (HCs, n=64). Results: FCP levels in UC patients strongly correlated with the Disease Activity Index (rs=0.676, P<0.0001) and Mayo endoscopic subscore (MES; rs=0.677, P<0.0001). FCP levels were significantly higher even in patients with inactive UC or CD compared with HCs (P=0.0068, P<0.0001). The optimal cutoff value between MES 1 and 2 exhibited higher sensitivity (94.1%). FCP levels were significantly higher in active UC patients than in inactive patients (P<0.001), except those with proctitis. The Crohn's Disease Activity Index tended to correlate with the FCP level (rs=0.283, P=0.0565). Conclusions: Our testing method using a monoclonal antibody for FCP was well-validated and differentiated IBD patients from HCs. FCP may be a useful biomarker for objective assessment of disease activity in adult Japanese IBD patients, especially those with UC.

DOI PubMed

当院におけるBR-A膵癌とUR-LA膵癌の臨床的差異の検討

柾木喜晴, 本谷雅代, 風間友江, 沼田泰尚, 志谷真啓, 阿久津典之, 佐々木茂, 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 ) A798 - A798 2018.10

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]

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]

DOI PubMed

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]

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.

DOI PubMed

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]

DOI PubMed

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]

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.

DOI PubMed

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]

DOI PubMed

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]

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]

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.

DOI PubMed

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]

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.

DOI PubMed

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]

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.

DOI PubMed

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]

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.

DOI PubMed

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]

DOI PubMed

Can Trainees Safely Perform Endoscopic Treatments for Common Bile Duct Stones? A Single-center Retrospective Study.

Tomoya Iida, Hiroyuki Kaneto, Kohei Wagatsuma, Hajime Sasaki, Yumiko Naganawa, Suguru Nakagaki, Shuji Satoh, Haruo Shimizu, Hiroshi Nakase

Internal medicine (Tokyo, Japan) 57 ( 7 ) 923 - 928 2018.04 [Refereed] [Domestic journal]

Objective There are no reports on whether or not trainees can safely carry out endoscopic procedures for the removal of common bile duct (CBD) stones. The aim of this study was to investigate the efficacy and safety of endoscopic treatments for CBD stones by trainees. Methods Endoscopic retrograde cholangiopancreatography (ERCP) was performed in 1,016 consecutive patients at our institution during the 6-year study period. The endoscopically treated patients with CBD stones were included in this study. Physicians who had experienced ≥300 ERCP procedures were defined as experts, while those who had experienced <300 procedures were defined as trainees. The trainees were replaced by an expert when they could not achieve the established criteria. Patients were divided into the following three groups to retrospectively examine the patients' backgrounds, details of endoscopic treatments, and intra-/post-operative complications: Group A, completed by trainees under supervision of an expert; B, treated by an expert who switched in for a trainee in the middle of the procedure; and C, completed by an expert. Results A total of 325 patients with CBD stones underwent endoscopic treatments. The number included in Groups A, B, and C was 176, 102, and 47, respectively. The bile duct catheter insertion successes rates for Groups A, B, and C were 99.0%, 97.1%, and 100% (p=0.09), and the complete stone removal rates were 94.2%, 94.8%, and 100%, respectively (p=0.07), showing no significant difference among the three groups. Furthermore, the frequency of intra-/post-operative complications was not significantly different among the three groups (p=0.48, p=0.12, respectively). Conclusion This study showed that trainees could safely perform endoscopic procedures in accordance with our facility's criteria during ERCP.

DOI PubMed

Predicting outcomes to optimize disease management in inflammatory bowel disease in Japan: their differences and similarities to Western countries.

Taku Kobayashi, Tadakazu Hisamatsu, Yasuo Suzuki, Haruhiko Ogata, Akira Andoh, Toshimitsu Araki, Ryota Hokari, Hideki Iijima, Hiroki Ikeuchi, Yoh Ishiguro, Shingo Kato, Reiko Kunisaki, Takayuki Matsumoto, Satoshi Motoya, Masakazu Nagahori, Shiro Nakamura, Hiroshi Nakase, Tomoyuki Tsujikawa, Makoto Sasaki, Kaoru Yokoyama, Naoki Yoshimura, Kenji Watanabe, Miiko Katafuchi, Mamoru Watanabe, Toshifumi Hibi

Intestinal research 16 ( 2 ) 168 - 177 2018.04 [Refereed] [International journal]

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease of the gastrointestinal tract, with increasing prevalence worldwide. IBD Ahead is an international educational program that aims to explore questions commonly raised by clinicians about various areas of IBD care and to consolidate available published evidence and expert opinion into a consensus for the optimization of IBD management. Given differences in the epidemiology, clinical and genetic characteristics, management, and prognosis of IBD between patients in Japan and the rest of the world, this statement was formulated as the result of literature reviews and discussions among Japanese experts as part of the IBD Ahead program to consolidate statements of factors for disease prognosis in IBD. Evidence levels were assigned to summary statements in the following categories: disease progression in CD and UC; surgery, hospitalization, intestinal failure, and permanent stoma in CD; acute severe UC; colectomy in UC; and colorectal carcinoma and dysplasia in IBD. The goal is that this statement can aid in the optimization of the treatment strategy for Japanese patients with IBD and help identify high-risk patients that require early intervention, to provide a better long-term prognosis in these patients.

DOI PubMed

Clinical and Pharmacokinetic Factors Associated With Adalimumab-Induced Mucosal Healing in Patients With Crohn's Disease.

Kenji Watanabe, Takayuki Matsumoto, Tadakazu Hisamatsu, Hiroshi Nakase, Satoshi Motoya, Naoki Yoshimura, Tetsuya Ishida, Shingo Kato, Tomoo Nakagawa, Motohiro Esaki, Masakazu Nagahori, Toshiyuki Matsui, Yuji Naito, Takanori Kanai, Yasuo Suzuki, Masanori Nojima, Mamoru Watanabe, Toshifumi Hibi

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 16 ( 4 ) 542 - 549 2018.04 [Refereed] [International journal]

BACKGROUND & AIMS: We previously reported results from a prospective randomized controlled trial comparing the efficacy of adalimumab monotherapy versus combination with azathioprine for patients with Crohn's disease (CD) who were naive to biologics and thiopurines. We performed a subanalysis of data from this study to evaluate factors associated with endoscopic response and mucosal healing in study participants. METHODS: We compared simple endoscopic scores for CD between patients with moderate to severe active CD randomly assigned groups that received adalimumab monotherapy (n = 85) or adalimumab in combination with azathioprine (n = 91), from June 2011 to June 2014 in Japan. We evaluated associations of simple endoscopic scores for CD with clinical factors and trough levels of adalimumab. Ultimately, 135 patients at Week 26 and 139 patients at Week 52 from 44 referral sites were analyzed for the present investigation. RESULTS: The odds for endoscopic response were significantly higher in the combination group than in the monotherapy group at Week 26 (odds ratio [OR], 2.12; 95% confidence interval [CI], 1.04-4.32) but not at Week 52 (OR, 1.50; 95% CI, 0.77-2.94). The odds of mucosal healing did not differ significantly between groups at Weeks 26 or 52. Simple endoscopic scores for CD at Week 0 was significantly associated with mucosal healing at Week 26 (OR, 0.80; 95% CI, 0.72-0.90) and at Week 52 (OR, 0.91; 95% CI, 0.84-0.99). Higher adalimumab trough level at Week 26 associated with mucosal healing at Week 52 (OR, 1.34; 95% CI, 1.14-1.58; P for trend = .001) and was significantly higher in patients with endoscopic response than in patients without endoscopic response at Weeks 26 and 52 (P < .001). CONCLUSIONS: In a post hoc analysis of data from a randomized controlled trial of patients with moderate to severe CD, we found that adalimumab in combination with azathioprine increased trough levels of adalimumab. Higher trough levels of adalimumab associated with endoscopic response and mucosal healing at Weeks 26 and 52. UMIN registration No: 000005146.

DOI PubMed

胆管癌の術前診断におけるSpyGlassDSの有用性

柾木喜晴, 志谷真啓, 我妻康平, 沼田泰尚, 阿久津典之, 本谷雅代, 佐々木茂, 木村康利, 武政伊知朗, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 60 ( Suppl.1 ) 668 - 668 2018.04

当院におけるステロイド投与によるB型肝炎再活性化への対応の現状と再活性化例の検討

沼田泰尚, 佐々木基, 石上敬介, 若杉英樹, 阿久津典之, 佐々木茂, 仲瀬裕志

肝臓 ( (一社)日本肝臓学会 ) 59 ( Suppl.1 ) A323 - A323 2018.04

Efficacy of Endoscopic Balloon Dilation for Small Bowel Strictures in Patients With Crohn's Disease: A Nationwide, Multi-centre, Open-label, Prospective Cohort Study.

Fumihito Hirai, Akira Andoh, Fumiaki Ueno, Kenji Watanabe, Naoki Ohmiya, Hiroshi Nakase, Shingo Kato, Motohiro Esaki, Yutaka Endo, Hironori Yamamoto, Toshiyuki Matsui, Mitsuo Iida, Toshifumi Hibi, Mamoru Watanabe, Yasuo Suzuki, Takayuki Matsumoto

Journal of Crohn's & colitis 12 ( 4 ) 394 - 401 2018.03 [Refereed] [International journal]

Background and Aims: Endoscopic balloon dilation [EBD] is an alternative to surgery for Crohn's strictures. However, there have been no prospective studies of EBD for small bowel strictures in patients with Crohn's disease [CD]. The aim of this study was to clarify the efficacy and safety of EBD using balloon-assisted enteroscopy for small bowel strictures in CD. Methods: This was a nationwide, multi-centre, open-label, prospective cohort study. The subjects were CD patients with at least one symptom [abdominal pain, abdominal bloating, nausea] attributable to small bowel stricture. The primary endpoint related to short-term outcomes was the level of improvement of symptoms evaluated using a 10-cm visual analogue scale [VAS]. Cases in which VAS scores for all symptoms improved 4 weeks after EBD compared with baseline were considered to have short-term symptomatic improvement. Factors related to short-term treatment outcomes and safety were investigated as secondary endpoints. Results: A total of 112 patients were enrolled. Seventeen were later excluded because they did not meet the criteria, and the analysis was conducted with the remaining 95 patients. Of these 95 patients, procedure failure occurred in six [6.3%], and short-term symptomatic improvement was achieved in 66 patients [69.5%]. Adverse events were seen in five patients [5%] and all of these improved with conservative treatment. A large dilation diameter of the balloon was a factor contributing to the success of EBD. Conclusions: EBD using balloon-assisted enteroscopy for small bowel strictures in CD patients was shown to be an effective and safe procedure. Clinical trial registry: UMIN000005946.

DOI PubMed

Elevation of Plasmin-α2-plasmin Inhibitor Complex Predicts the Diagnosis of Systemic AL Amyloidosis in Patients with Monoclonal Protein.

Kazuya Ishiguro, Toshiaki Hayashi, Yoshihiro Yokoyama, Yuka Aoki, Kei Onodera, Hiroshi Ikeda, Tadao Ishida, Hiroshi Nakase

Internal medicine (Tokyo, Japan) 57 ( 6 ) 783 - 788 2018.03 [Refereed] [Domestic journal]

Objective The complication of systemic immunoglobulin light chain (AL) amyloidosis in patients with monoclonal immunoglobulin affects the prognosis, but amyloid deposition in tissues is sometimes difficult to detect due to bleeding tendencies and preferential distributions. However, fibrinolysis is known to be exacerbated in patients with systemic AL amyloidosis specifically. We therefore explored new biomarkers for predicting a diagnosis of systemic AL amyloidosis focusing on coagulation and fibrinolysis markers. Methods We reviewed the clinical features and treatment outcomes of patients with serum monoclonal protein, including primary systemic AL amyloidosis and multiple myeloma (MM), treated at our hospital between January 2008 and December 2014. Results Among several biomarkers, only the serum level of plasmin-α2-plasmin inhibitor complex (PIC) in patients with systemic AL amyloidosis (n=26) at the diagnosis was significantly higher than in patients with MM without AL amyloidosis (n=26) (mean±standard deviation, 3.69±2.82 μg/mL vs. 1.23±0.97 μg/mL, p<0.01). The cut-off for predicting a diagnosis of systemic AL amyloidosis in patients with serum monoclonal protein was 1.72 μg/mL with 84.6% sensitivity and 80.8% specificity. Hepatic involvement resulted in a significantly higher PIC level than no involvement in patients with systemic AL amyloidosis. The serum PIC level was also associated with the hematological response of systemic AL amyloidosis. Conclusion PIC is a useful biomarker for the diagnosis and management of patients with systemic AL amyloidosis.

DOI PubMed

Predicting therapeutic response in IgG4-related disease based on cluster analysis.

Motohisa Yamamoto, Ken-Ichi Takano, Ryuta Kamekura, Chisako Suzuki, Tetsuya Tabeya, Rieko Murakami, Saho Honda, Masaya Mukai, Masanori Nojima, Shingo Ichimiya, Tetsuo Himi, Hiroshi Nakase, Hiroki Takahashi

Immunological medicine 41 ( 1 ) 30 - 33 2018.03 [Refereed] [International journal]

To bring the clinical practice of immunoglobulin (Ig)G4-related disease (IgG4-RD) close to personalized medicine, we classified the patient groups and clarified the therapeutic responses of each group. A total of 147 patients enrolled in our registry were classified into four groups by cluster analysis with the software. The therapeutic responses and prognosis of each group were examined. The cluster analysis classified the subjects into four groups: Cluster 1, patients who presented with prominent hypergammaglobulinemia, elevated levels of serum IgG4, and hypocomplementemia; Cluster 2, patients who presented with eosinophilia, elevated concentrations of serum IgG, IgG4, and IgE, and in whom CRP tended to be positive; Cluster 3, patients with younger onset and serum levels of IgG, IgG4, and IgE and peripheral eosinophil counts lower than the other clusters; and Cluster 4, patients with elder onset and low peripheral eosinophil counts. The amounts of glucocorticoid for maintenance treatment were from 5 to 7 mg/d in all groups, but the amounts were significantly greater in Cluster 1 (patients with hypergammaglobulinemia, elevated levels of serum IgG4, and hypocomplementemia) than in Cluster 4 (elder onset patients, relatively low concentrations of peripheral eosinophils). With regard to the use of immunosuppressants and the relapse rate, there were high frequencies in Cluster 1 and Cluster 3 (younger onset patients who presented with mild elevations of serum IgG and IgG4). On the other hand, Cluster 4 showed a low rate of relapse and often could discontinue steroids. The present results suggest that personalized medicine could be provided in IgG4-RD by classifying patients based on their clinical features.

DOI PubMed

Systemic amyloidosis with gastrointestinal involvement: Diagnosis from endoscopic and histological views.

Tomoya Iida, Hiroo Yamano, Hiroshi Nakase

Journal of gastroenterology and hepatology 33 ( 3 ) 583 - 590 2018.03 [Refereed] [International journal]

Amyloid tends to deposit in the gastrointestinal tract, which, being easily accessible, is often the target organ for a pathological diagnostic examination. Although a mucosal biopsy is necessary for a definitive diagnosis and several studies have reported positive results for each possible biopsy site, there remain many unclear features in various aspects. This review focuses on the current literature to determine a better understanding of the diagnosis from endoscopic and histological views in patients with systemic amyloidosis with gastrointestinal involvement. A literature search was performed using PubMed to identify relevant studies; linked references were also reviewed. Endoscopic findings vary based on the organ and the depositing amyloids. A fine granular appearance or polypoid protrusions are likely to occur in the duodenum. AL, Aβ2M, and ATTR amyloids are likely to deposit submucosally, while AA amyloid is easily deposited in the superficial layer of the mucous membrane. Furthermore, it is necessary to consider the collection of biopsy specimens from the duodenum, which has high positive biopsy rates. However, the difference in the positive biopsy rates depends on whether endoscopic findings are available or whether the appropriate number has not been fully elucidated. A duodenal biopsy is strongly recommended to confirm the deposition of amyloid in patients with systemic amyloidosis having gastrointestinal involvement. Because amyloidosis is a disease with a poor prognosis, early diagnosis and treatment are required; gastroenterologists and endoscopists play important roles.

DOI PubMed

Evidence-based clinical practice guidelines for inflammatory bowel disease.

Katsuyoshi Matsuoka, Taku Kobayashi, Fumiaki Ueno, Toshiyuki Matsui, Fumihito Hirai, Nagamu Inoue, Jun Kato, Kenji Kobayashi, Kiyonori Kobayashi, Kazutaka Koganei, Reiko Kunisaki, Satoshi Motoya, Masakazu Nagahori, Hiroshi Nakase, Fumio Omata, Masayuki Saruta, Toshiaki Watanabe, Toshiaki Tanaka, Takanori Kanai, Yoshinori Noguchi, Ken-Ichi Takahashi, Kenji Watanabe, Toshifumi Hibi, Yasuo Suzuki, Mamoru Watanabe, Kentaro Sugano, Tooru Shimosegawa

Journal of gastroenterology 53 ( 3 ) 305 - 353 2018.03 [Refereed] [Domestic journal]

Inflammatory bowel disease (IBD) is a chronic disorder involving mainly the intestinal tract, but possibly other gastrointestinal and extraintestinal organs. Although etiology is still uncertain, recent knowledge in pathogenesis has accumulated, and novel diagnostic and therapeutic modalities have become available for clinical use. Therefore, the previous guidelines were urged to be updated. In 2016, the Japanese Society of Gastroenterology revised the previous versions of evidence-based clinical practice guidelines for ulcerative colitis (UC) and Crohn's disease (CD) in Japanese. A total of 59 clinical questions for 9 categories (1. clinical features of IBD; 2. diagnosis; 3. general consideration in treatment; 4. therapeutic interventions for IBD; 5. treatment of UC; 6. treatment of CD; 7. extraintestinal complications; 8. cancer surveillance; 9. IBD in special situation) were selected, and a literature search was performed for the clinical questions with use of the MEDLINE, Cochrane, and Igaku Chuo Zasshi databases. The guidelines were developed with the basic concept of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Recommendations were made using Delphi rounds. This English version was produced and edited based on the existing updated guidelines in Japanese.

DOI PubMed

術前CTにおける右肝動脈周囲の脂肪織濃度上昇所見に関する検討

志谷真啓, 風間友江, 我妻康平, 柾木喜晴, 阿久津典之, 本谷雅代, 佐々木茂, 山口洋志, 永山稔, 今村将史, 木村康利, 水口徹, 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 ( 臨増総会 ) A391 - A391 2018.03

A case of a rectal stricture related to ischemic proctitis following rupture of an aortic aneurysm.

Tomoya Iida, Yosuke Ohkubo, Toshiyuki Kubo, Kentaro Yamashita, Kei Onodera, Eiichiro Yamamoto, Katsuhiko Nosho, Toshiro Ito, Hiroo Yamano, Hiroshi Nakase

Endoscopy international open 6 ( 2 ) E186-E189 2018.02 [Refereed] [International journal]

Background and study aims Ischemic proctitis is a rare disease and comprises 2 % to 5 % of cases of ischemic colitis, because the rectum has abundant blood supply and rich collaterals. Herein, we report a case of a 73-year-old male patient with a pronounced rectal stricture caused by ischemic proctitis resulting from an abdominal aortic rupture and treated by endoscopic balloon dilation therapy. To date, only 3 cases of rectal stricture related to ischemic proctitis including our case have been reported, and this is the first case of rectal stricture related to ischemic proctitis, which was successfully treated by endoscopic balloon dilation.

DOI PubMed

Epigenetic silencing of SMOC1 in traditional serrated adenoma and colorectal cancer.

Hironori Aoki, Eiichiro Yamamoto, Akira Takasawa, Takeshi Niinuma, Hiro-O Yamano, Taku Harada, Hiro-O Matsushita, Kenjiro Yoshikawa, Ryo Takagi, Eiji Harada, Yoshihito Tanaka, Yuko Yoshida, Tomoyuki Aoyama, Makoto Eizuka, Akira Yorozu, Hiroshi Kitajima, Masahiro Kai, Norimasa Sawada, Tamotsu Sugai, Hiroshi Nakase, Hiromu Suzuki

Oncotarget 9 ( 4 ) 4707 - 4721 2018.01 [Refereed] [International journal]

Colorectal sessile serrated adenoma/polyps (SSA/Ps) are well-known precursors of colorectal cancer (CRC) characterized by BRAF mutation and microsatellite instability. By contrast, the molecular characteristics of traditional serrated adenoma (TSAs) are not fully understood. We analyzed genome-wide DNA methylation in TSAs having both protruding and flat components. We identified 11 genes, including SMOC1, methylation of which progressively increased during the development of TSAs. SMOC1 was prevalently methylated in TSAs, but was rarely methylated in SSA/Ps (p < 0.001). RT-PCR and immunohistochemistry revealed that SMOC1 was expressed in normal colon and SSA/Ps, but its expression was decreased in TSAs. Ectopic expression of SMOC1 suppressed proliferation, colony formation and in vivo tumor formation by CRC cells. Analysis of colorectal lesions (n = 847) revealed that SMOC1 is frequently methylated in TSAs, high-grade adenomas and CRCs. Among these, SMOC1 methylation was strongly associated with KRAS mutation and CpG island methylator phenotype (CIMP)-low. These results demonstrate that epigenetic silencing of SMOC1 is associated with TSA development but is rarely observed in SSA/Ps. SMOC1 expression could thus be a diagnostic marker of serrated lesions, and SMOC1 methylation could play a role in neoplastic pathways in TSAs and conventional adenomas.

DOI PubMed

Identification of genomic alterations in oral squamous cell carcinomas using amplicon-based whole-exome sequencing

Sasaki Yasushi, Tamura Miyuki, Nakagaki Takafumi, Koyama Ryota, Idogawa Masashi, Ogi Kazuhiro, Hiratsuka Hiroyoshi, Nakase Hiroshi, Tokino Takashi

CANCER SCIENCE 109 990 2018.01 [Refereed]

Clinicopathological comparison between acute gastrointestinal-graft-versus-host disease and infectious colitis in patients after hematopoietic stem cell transplantation.

Sae Ohwada, Tomoya Iida, Daisuke Hirayama, Gota Sudo, Toshiyuki Kubo, Masanori Nojima, Kentaro Yamashita, Hiroo Yamano, Hiroshi Nakase

PloS one 13 ( 7 ) e0200627 2018 [Refereed] [International journal]

The aim of this study is to elucidate the differences of the clinicopathological characteristics between acute gastrointestinal (GI)-graft-versus-host disease (GVHD) and infectious colitis (IC) after hematopoietic stem cell transplantation (HSCT). Of the 282 patients who underwent HSCT at our institution between January 1991 and December 2015, we could investigate 182 patients in detail. Of the 182 patients, we selected those who underwent colonoscopy and were diagnosed with acute GI-GVHD or IC after HSCT. Patients' backgrounds, colonoscopic findings, and pathological findings were retrospectively analyzed. There were 30 patients who had colonoscopy performed and diagnosed with acute GI-GVHD or IC after HSCT. Of the 30 patients, 20 had acute GI-GVHD and 10 had IC. All the cases of acute GI-GVHD were diagnosed by endoscopic biopsy and 4 of the IC patients had Clostridium difficile associated colitis. In the IC group, the period from the transplantation up to diagnosis was significantly shorter than acute GI-GVHD group (10.0 days vs. 43.2 days, p = 0.03). In the acute GI-GVHD group, tortoiseshell-like mucosal patterns were significantly more common than the IC group (70% vs. 0%, p < 0.001). Furthermore, there were some cases presenting normal mucosal appearance despite the diagnosis with acute GI-GVHD by pathological findings. Clinically, we should consider IC when abdominal symptoms appeared in the early period after HSCT. Endoscopically, tortoiseshell-like mucosal pattern was a characteristic feature of acute GI-GVHD. In addition, it is essential to perform mucosal biopsy for diagnose of acute GI-GVHD even in patients showing the normal mucosal appearance.

DOI PubMed

Efficacy and safety of endoscopic procedures for common bile duct stones in patients aged 85 years or older: A retrospective study.

Tomoya Iida, Hiroyuki Kaneto, Kohei Wagatsuma, Hajime Sasaki, Yumiko Naganawa, Suguru Nakagaki, Shuji Satoh, Haruo Shimizu, Hiroshi Nakase

PloS one 13 ( 1 ) e0190665 2018 [Refereed] [International journal]

The Endoscopic procedures for common bile duct (CBD) stones are reportedly safe in the elderly patients. However, the definition of the elderly is different in each report. If the elderly are defined as people aged 85 years or older, data on the effectiveness and safety of endoscopic retrograde cholangiopancreatography (ERCP) for CBD stones are limited. This study investigated the efficacy and safety of endoscopic procedures for CBD stones in patients aged 85 years or older. 1,016 consecutive ERCP procedures were performed at our institution from January 2009 to December 2014. Of these, 235 cases with CBD stones were finally analyzed. Group A patients were younger than 85 years and Group B patients were 85 years or older. Patient background, details of endoscopic therapy, complications, and related factors were retrospectively reviewed for 185 cases in Group A, and 50 cases in Group B. Patients in Group B showed high rates of dementia and cerebrovascular disorders and larger CBD stones and diameters, in comparison with patients in Group A. The complete removal rate of bile duct stones was slightly higher in Group A. However, there was no difference between the two groups in recurrence rate of CBD stones, complication and mortality rates, and length and cost of hospitalization. Despite some differences between the two groups, endoscopic procedures for CBD stones in patients aged 85 years or older can be performed effectively and safely without increasing medical costs.

DOI PubMed

The Phagocytic Function of Macrophage-Enforcing Innate Immunity and Tissue Homeostasis.

Daisuke Hirayama, Tomoya Iida, Hiroshi Nakase

International journal of molecular sciences 19 ( 1 ) 2017.12 [Refereed] [International journal]

Macrophages are effector cells of the innate immune system that phagocytose bacteria and secrete both pro-inflammatory and antimicrobial mediators. In addition, macrophages play an important role in eliminating diseased and damaged cells through their programmed cell death. Generally, macrophages ingest and degrade dead cells, debris, tumor cells, and foreign materials. They promote homeostasis by responding to internal and external changes within the body, not only as phagocytes, but also through trophic, regulatory, and repair functions. Recent studies demonstrated that macrophages differentiate from hematopoietic stem cell-derived monocytes and embryonic yolk sac macrophages. The latter mainly give rise to tissue macrophages. Macrophages exist in all vertebrate tissues and have dual functions in host protection and tissue injury, which are maintained at a fine balance. Tissue macrophages have heterogeneous phenotypes in different tissue environments. In this review, we focused on the phagocytic function of macrophage-enforcing innate immunity and tissue homeostasis for a better understanding of the role of tissue macrophages in several pathological conditions.

DOI PubMed

Is Osteopontin a Friend or Foe of Cell Apoptosis in Inflammatory Gastrointestinal and Liver Diseases?

Tomoya Iida, Kohei Wagatsuma, Daisuke Hirayama, Hiroshi Nakase

International journal of molecular sciences 19 ( 1 ) 2017.12 [Refereed] [International journal]

Osteopontin (OPN) is involved in a variety of biological processes, including bone remodeling, innate immunity, acute and chronic inflammation, and cancer. The expression of OPN occurs in various tissues and cells, including intestinal epithelial cells and immune cells such as macrophages, dendritic cells, and T lymphocytes. OPN plays an important role in the efficient development of T helper 1 immune responses and cell survival by inhibiting apoptosis. The association of OPN with apoptosis has been investigated. In this review, we described the role of OPN in inflammatory gastrointestinal and liver diseases, focusing on the association of OPN with apoptosis. OPN changes its association with apoptosis depending on the type of disease and the phase of disease activity, acting as a promoter or a suppressor of inflammation and inflammatory carcinogenesis. It is essential that the roles of OPN in those diseases are elucidated, and treatments based on its mechanism are developed.

DOI PubMed

Editorial: therapeutic drug monitoring for anti-TNF agents—has it all been said? Author's reply

H. Nakase

Alimentary Pharmacology and Therapeutics ( Blackwell Publishing Ltd ) 46 ( 11-12 ) 1114 - 1115 2017.12 [Refereed]

DOI PubMed

Endoscopic and molecular characterization of colorectal sessile serrated adenoma/polyps with cytologic dysplasia.

Yoshihito Tanaka, Hiro-O Yamano, Eiichiro Yamamoto, Hiro-O Matushita, Hironori Aoki, Kenjiro Yoshikawa, Ryo Takagi, Eiji Harada, Michiko Nakaoka, Yuko Yoshida, Makoto Eizuka, Tamotsu Sugai, Hiromu Suzuki, Hiroshi Nakase

Gastrointestinal endoscopy ( MOSBY-ELSEVIER ) 86 ( 6 ) 1131 - 1138 2017.12 [Refereed] [International journal]

BACKGROUND AND AIMS: Sessile serrated adenoma/polyps (SSA/Ps), which are precursor lesions of colorectal cancer (CRC) with BRAF mutation and the CpG island methylator phenotype (CIMP), develop cytologic dysplasia (CD) during the progression of colorectal tumorigenesis. In the present study we aimed to clarify the endoscopic and molecular signatures of SSA/Ps, with and without CD. METHODS: A series of 208 serrated lesions, including 41 hyperplastic polyps, 90 SSA/Ps, 33 SSA/Ps with CD, and 44 traditional serrated adenomas, were observed and resected using magnifying endoscopy. BRAF and KRAS mutations and methylation of CIMP markers (MINT1, MINT2, MINT12, MINT31, and p16) were analyzed through pyrosequencing. Molecular alterations were then compared with endoscopic and pathologic characteristics. RESULTS: Among SSA/Ps without CD, the Type II-Open pit pattern (Type II-O), BRAF mutation, and CIMP were tightly associated with a proximal colon location. SSA/Ps in the distal colon infrequently exhibited Type II-O and CIMP. By contrast, most SSA/Ps with CD showed Type II-O plus adenomatous pit patterns (Type III or IV), BRAF mutation, and CIMP, irrespective of their locations. CONCLUSIONS: Our results suggest that the Type II-O plus III/IV pit pattern is a common feature of SSA/Ps with CD in both the proximal and distal colon and that this pit pattern is a hallmark of serrated lesions at high risk of developing into CRCs.

DOI PubMed

Significance of measurement of serum trough level and anti-drug antibody of adalimumab as personalised pharmacokinetics in patients with Crohn's disease: a subanalysis of the DIAMOND trial

H. Nakase, S. Motoya, T. Matsumoto, K. Watanabe, T. Hisamatsu, N. Yoshimura, T. Ishida, S. Kato, T. Nakagawa, M. Esaki, M. Nagahori, T. Matsui, Y. Naito, T. Kanai, Y. Suzuki, M. Nojima, M. Watanabe, T. Hibi, DIAMOND study group, Akira Andoh, Toshifumi Ashida, Katsuya Endo, Yutaka Endo, Motohiro Esaki, Hiroshi Fujita, Mikihiro Fujiya, Ken Haruma, Toshifumi Hibi, Sakiko Hiraoka, Ichiro Hirata, Tadakazu Hisamatsu, Yutaka Honda, Hideki Iijima, Bunei Iizuka, Kentaro Ikeya, Takuya Inoue, Shuji Inoue, Tetsuya Ishida, Yo Ishiguro, Shunji Ishihara, Hiroaki Ito, Ryuichi Iwakiri, Takashi Kagaya, Takanori Kanai, Hiroshi Kashida, Shingo Kato, Jun Kato, Takehiko Katsurada, Fukunori Kinjyo, Kiyonori Kobayashi, Mayumi Kodama, Reiko Kunisaki, Koichi Kurahara, Takafumi Kurokami, Lee Kyouwon, Koichiro Matsuda, Kazuhiro Matsueda, Toshiyuki Matsui, Takayuki Matsumoto, Keiichi Mitsuyama, Yuji Mizokami, Satoshi Motoya, Yuji Naito, Tomoo Nakagawa, Shiro Nakamura, Hiroshi Nakase, Masanori Nojima, Masafumi Nomura, Atsuhiro Ogawa, Kazuichi Okazaki, Kazuaki Otsuka, Hirotake Sakuraba, Masayuki Saruta, Makoto Sasaki, Takayuki Shirai, Tomoaki Suga, Kazuhito Sugimura, Toshiro Sugiyama, Yasuo Suzuki, Fuminao Takeshima, Hiroyuki Tamaki, Shinji Tanaka, Satoshi Tanida, Keiichi Tominaga, Taku Tomizawa, Kenji Watanabe, Mamoru Watanabe, Shojiro Yamamoto, Masaki Yamashita, Atsushi Yoshida, Naoki Yoshimura

Alimentary Pharmacology and Therapeutics ( Blackwell Publishing Ltd ) 46 ( 9 ) 873 - 882 2017.11 [Refereed]

Background: Significance of monitoring adalimumab trough levels and anti-adalimumab antibodies (AAA) for disease outcome in Crohn's disease (CD) patients remained unclear. Aim: To evaluate the association of adalimumab trough levels and AAA at week 26 with clinical remission at week 52, the effect of azathiopurine on AAA and factors influencing trough levels in CD patients in the DIAMOND trial. Methods: We performed this study using adalimumab trough levels, AAA at week 26 and 6-thioguanine nucleotide (TGN) in red blood cells at week 12. A multiple regression model and receiver operating analysis was performed to identify factors influencing adalimumab trough levels and AAA, and adalimumab thresholds for predicting disease activity. Results: There was a significant difference of adalimumab trough level at week 26 between patients with disease remission and without at week 52 (7.7 ± 3.3 μg/mL vs 5.4 ± 4.3 μg/mL: P < .001). Adalimumab trough level of 5.0 μg/mL yielded optimal sensitivity and specificity for remission prediction (80.2% and 55.6%, respectively). AAA development at week 26 significantly affected remission at week 52 (P =.021), which was strongly associated with adalimumab trough levels. Female gender and increasing body weight were independently associated with low adalimumab trough levels, and female gender was associated with AAA development. A cut-off 6TGN level of > 222.5 p mol/8 ×108 RBCs yielded sensitivity (100%) and specificity (60.6%) for AAA negativity. Conclusion: Adalimumab trough levels and AAA occurrence were significantly associated with clinical remission. Higher 6TGN affected AAA negativity. The combination therapy is beneficial in some relevant aspects for CD patients. (UMIN Registration No. 000005146).

DOI PubMed

Downregulation of miR-186 is associated with metastatic recurrence of gastrointestinal stromal tumors.

Takeshi Niinuma, Masahiro Kai, Hiroshi Kitajima, Eiichiro Yamamoto, Taku Harada, Reo Maruyama, Takayuki Nobuoka, Toshirou Nishida, Tatsuo Kanda, Tadashi Hasegawa, Takashi Tokino, Tamotsu Sugai, Yasuhisa Shinomura, Hiroshi Nakase, Hiromu Suzuki

Oncology letters ( SPANDIDOS PUBL LTD ) 14 ( 5 ) 5703 - 5710 2017.11 [Refereed] [International journal]

Although dysregulation of microRNAs (miRNAs/miRs) is a common feature of human malignancies, its involvement in gastrointestinal stromal tumors (GISTs) is not fully understood. The present study aimed to identify the miRNAs that perform a role in GIST metastasis. miRNA expression profiles from a series of 32 primary GISTs were analyzed using microarrays, and miR-186 was observed to be downregulated in tumors exhibiting metastatic recurrence. Reverse transcription-quantitative polymerase chain reaction analysis of an independent cohort of 100 primary GISTs revealed that low miR-186 expression is associated with metastatic recurrence and a poor prognosis. Inhibition of miR-186 in GIST-T1 cells promoted cell migration. Gene expression microarray analysis demonstrated that miR-186 inhibition upregulated a set of genes implicated in cancer metastasis, including insulin-like growth factor-binding protein 3, AKT serine/threonine kinase 2, hepatocyte growth factor receptor, CXC chemokine receptor 4 and epidermal growth factor-containing fibulin-like extracellular matrix protein 1. These results suggest that the downregulation of miR-186 is involved in the metastatic recurrence of GISTs, and that miR-186 levels could potentially be a predictive biomarker for clinical outcome.

DOI PubMed

Tricho-hepato-enteric syndrome with novel SKIV2L gene mutations: A case report.

Eitaro Hiejima, Takahiro Yasumi, Hiroshi Nakase, Minoru Matsuura, Yusuke Honzawa, Hirokazu Higuchi, Ikuo Okafuji, Tohru Yorifuji, Takayuki Tanaka, Kazushi Izawa, Tomoki Kawai, Ryuta Nishikomori, Toshio Heike

Medicine ( LIPPINCOTT WILLIAMS & WILKINS ) 96 ( 46 ) e8601 2017.11 [Refereed] [International journal]

RATIONALE: Tricho-hepato-enteric syndrome (THES) is a rare disorder caused by mutations in the TTC37 or SKIV2L genes and characterized by chronic diarrhea, liver disease, hair abnormalities, and high mortality in early childhood due to severe infection or liver cirrhosis. PATIENT CONCERNS: The patient is the second child of three siblings born to non-consanguineous healthy Japanese parents. She had intrauterine growth retardation and was delivered at 33 weeks of gestation due to placental abruption. She presented with watery diarrhea, elevated levels of liver enzymes, multiple episodes of recurrent bacterial infection, and mild mental retardation. She had facial dysmorphism, including prominent forehead and hypertelorism, and had woolly hair without trichorrhexis nodosa. DIAGNOSIS: Clinical features led to consideration of THES. Novel compound heterozygous nonsense mutations, c.1420G>T (p.Q474*) and c.3262G>T (p.E1088*), in the SKIV2L gene were identified in the patient, and decreased levels of SKIV2L protein expression were revealed by flow cytometry and confirmed by western blot analysis using patient peripheral blood mononuclear cells (PBMCs). INTERVENTIONS: Total parenteral nutrition was required from day 30 to day 100. Trimethoprim-sulfamethoxazole prophylaxis was started at the age of 7 years after multiple episodes of bacterial pneumonia and otitis media. OUTCOMES: Chronic diarrhea persisted for more than 10 years, but the symptoms gradually improved with age. At the age of 13 years, she started a normal diet in combination with oral nutritional supplementation and her height and weight were just below the 3rd percentile for healthy individuals. She developed secondary sex characteristics, and menarche occurred at the age of 12 years. Facial dysmorphism, including prominent forehead and hypertelorism, and woolly hair without trichorrhexis nodosa became noticeable as she matured. LESSONS: Physicians must be aware of THES when they encounter a patient with infantile diarrhea, hair abnormalities, immune deficiency, mental retardation, and liver disease. Moreover, flow cytometric detection of SKIV2L protein in PBMCs may facilitate early diagnosis.

DOI PubMed

Cutting Edge: A Critical Role of Lesional T Follicular Helper Cells in the Pathogenesis of IgG4-Related Disease.

Ryuta Kamekura, Kenichi Takano, Motohisa Yamamoto, Koji Kawata, Katsunori Shigehara, Sumito Jitsukawa, Tomonori Nagaya, Fumie Ito, Akinori Sato, Noriko Ogasawara, Chieko Tsubomatsu, Hiroki Takahashi, Hiroshi Nakase, Tetsuo Himi, Shingo Ichimiya

Journal of immunology (Baltimore, Md. : 1950) ( AMER ASSOC IMMUNOLOGISTS ) 199 ( 8 ) 2624 - 2629 2017.10 [Refereed] [International journal]

IgG4-related disease (IgG4-RD) is a newly recognized systemic chronic fibroinflammatory disease. However, the pathogenesis of IgG4-RD remains unknown. To determine the pathophysiologic features of IgG4-RD, we examined T follicular helper (Tfh) cells in lesions and blood from patients with IgG4-RD. Patients with IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) showed increased infiltration of Tfh cells highly expressing programmed death 1 and ICOS in submandibular glands. Tfh cells from IgG4-DS submandibular glands had higher expression of B cell lymphoma 6 and a greater capacity to help B cells produce IgG4 than did tonsillar Tfh cells. We also found that the percentage of programmed death 1hi circulating Tfh cells in IgG4-DS patients was higher than that in healthy volunteers and was well correlated with clinical parameters. Our findings indicate that anomalous Tfh cells in tissue lesions of IgG4-RD have features distinct from those in lymphoid counterparts or blood and potentially regulate local IgG4 production in IgG4-RD.

DOI PubMed

Author's Reply.

Tomoya Iida, Hiroyuki Kaneto, Hiroshi Nakase

Intestinal research 15 ( 4 ) 554 - 554 2017.10 [Refereed] [International journal]

DOI PubMed

ヒストンメチル化酵素DOT1Lは多発性骨髄腫の治療標的となりうる

石黒一也, 佐々木基, 若杉英樹, 北嶋洋志, 新沼猛, 丸山玲緒, 甲斐正広, 池田博, 石田禎夫, 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 ) 76回 P - 2244 2017.09

口腔扁平上皮癌の全エクソン解析

佐々木泰史, 田村みゆき, 中垣貴文, 小山良太, 井戸川雅史, 荻和弘, 平塚博義, 仲瀬裕志, 時野隆至

日本癌学会総会記事 ( (一社)日本癌学会 ) 76回 P - 3044 2017.09

Endoscopic removal of an impacted barolith at the sigmoid colon: a rare case report.

Tomoya Iida, Takehiro Hirano, Kei Onodera, Toshiyuki Kubo, Kentaro Yamashita, Hiroo Yamano, Hiroshi Nakase

Clinical journal of gastroenterology 10 ( 4 ) 361 - 363 2017.08 [Refereed] [Domestic journal]

A 45-year-old woman visited our hospital complaining of abdominal pain 1 week after undergoing an annual medical checkup. Her vital signs and blood test results were normal, but tenderness was found in the lower abdomen. A high-density round structure found at the midline of the lower abdomen on an abdominal radiograph was thought to be an accumulation of barium (a barolith) from upper gastrointestinal barium radiography. Two liters of an oral gastrointestinal cleaning agent was administered, but defecation did not occur. Lower gastrointestinal endoscopy revealed that the barolith was impacted at the sigmoid colon. We unsuccessfully attempted to move it using a pressurized water jet and forceps, but it was too large to be captured by the net. Therefore, we broke it down using a snare. After a successful endoscopic procedure, 120 mL of a glycerin enema solution was injected through the forceps opening, causing the barolith to be excreted. There is only one similar case of successful endoscopic treatment of a barolith in the literature.

DOI PubMed

Epigenetic silencing of diacylglycerol kinase gamma in colorectal cancer.

Masahiro Kai, Eiichiro Yamamoto, Akiko Sato, Hiro-O Yamano, Takeshi Niinuma, Hiroshi Kitajima, Taku Harada, Hironori Aoki, Reo Maruyama, Mutsumi Toyota, Tomo Hatahira, Hiroshi Nakase, Tamotsu Sugai, Toshiharu Yamashita, Minoru Toyota, Hiromu Suzuki

Molecular carcinogenesis ( WILEY ) 56 ( 7 ) 1743 - 1752 2017.07 [Refereed] [International journal]

Diacylglycerol kinases (DGKs) are important regulators of cell signaling and have been implicated in human malignancies. Whether epigenetic alterations are involved in the dysregulation of DGKs in cancer is unknown, however. We therefore analyzed methylation of the promoter CpG islands of DGK genes in colorectal cancer (CRC) cell lines. We found that DGKG, which encodes DGKγ, was hypermethylated in all CRC cell lines tested (n = 9), but was not methylated in normal colonic tissue. Correspondingly, DGKG expression was suppressed in CRC cell lines but not in normal colonic tissue, and was restored in CRC cells by treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-dC). DGKG methylation was frequently observed in primary CRCs (73/141, 51.8%) and was positively associated with KRAS and BRAF mutations and with the CpG island methylator phenotype (CIMP). DGKG methylation was also frequently detected in colorectal adenomas (89 of 177, 50.3%), which suggests it is an early event during colorectal tumorigenesis. Ectopic expression of wild-type DGKγ did not suppress CRC cell proliferation, but did suppress cell migration and invasion. Notably, both constitutively active and kinase-dead DGKγ mutants exerted inhibitory effects on CRC cell proliferation, migration and invasion, and the wild-type and mutant forms of DGKγ all suppressed Rac1 activity in CRC cells. These data suggest DGKG may play a tumor suppressor role in CRC.

DOI PubMed

Long non-coding RNA NEAT1 is a transcriptional target of p53 and modulates p53-induced transactivation and tumor-suppressor function.

Masashi Idogawa, Tomoko Ohashi, Yasushi Sasaki, Hiroshi Nakase, Takashi Tokino

International journal of cancer 140 ( 12 ) 2785 - 2791 2017.06 [Refereed] [International journal]

p53 is one of the most important tumor suppressor genes, and the direct transcriptional targets of p53 must be explored to elucidate its functional mechanisms. Thus far, the p53 targets that have been primarily studied are protein-coding genes. Our previous study revealed that several long non-coding RNAs (lncRNAs) are direct transcriptional targets of p53, and knockdown of specific lncRNAs modulates p53-induced apoptosis. In this study, analysis of next-generation chromatin immunoprecipitation-sequencing (ChIP-seq) data for p53 revealed that the lncRNA NEAT1 is a direct transcriptional target of p53. The suppression of NEAT1 induction by p53 attenuates the inhibitory effect of p53 on cancer cell growth and also modulates gene transactivation, including that of many lncRNAs. Furthermore, low expression of NEAT1 is related to poor prognosis in several cancers. These results indicate that the induction of NEAT1 expression contributes to the tumor-suppressor function of p53 and suggest that p53 and NEAT1 constitute a transcriptional network contributing to various biological functions and tumor suppression.

DOI PubMed

Insulin-like growth factor-1, IGF binding protein-3, and the risk of esophageal cancer in a nested case-control study.

Yasushi Adachi, Masanori Nojima, Mitsuru Mori, Kentaro Yamashita, Hiro-O Yamano, Hiroshi Nakase, Takao Endo, Kenji Wakai, Kiyomi Sakata, Akiko Tamakoshi

World journal of gastroenterology 23 ( 19 ) 3488 - 3495 2017.05 [Refereed] [International journal]

AIM: To assess the relationship between serum levels of insulin-like growth factor-1 (IGF1)/IGF-binding protein-3 (IGFBP3) and the risk of esophageal carcinoma. METHODS: We assessed the relationship between the serum levels of these molecules and the risk of esophageal cancer in a prospective, nested case-control study of participants from the Japan Collaborative Cohort Study. A baseline survey was conducted from 1988 to 1990. Of the 110585 enrolled participants, 35% donated blood samples. Those who had been diagnosed with esophageal cancer were considered cases for nested case-control studies. A conditional logistic model was used to estimate odds ratios for the incidence of esophageal cancer associated with serum IGF1 and IGFBP3 levels. RESULTS: Thirty-one cases and 86 controls were eligible for the present assessment. The molar ratio of IGF1/IGFBP3, which represents the free and active form of IGF1, was not correlated with the risk of esophageal carcinoma. A higher molar difference between IGFBP3 and IGF1, which estimates the free form of IGFBP3, was associated with a decreased risk of esophageal carcinoma (P = 0.0146), and people in the highest tertile had the lowest risk (OR = 0.107, 95%CI: 0.017-0.669). After adjustment for body mass index, tobacco use, and alcohol intake, the molar difference of IGFBP3-IGF1 was inversely correlated with the risk of esophageal carcinoma (P = 0.0150). CONCLUSION: The free form of IGFBP3, which is estimated by this molar difference, may be inversely associated with esophageal cancer incidence.

DOI PubMed

自己免疫性膵炎に対する診療の現状と長期予後当科における自己免疫性膵炎を含むIgG4関連疾患の検討

本谷雅代, 山本元久, 志谷真啓, 佐々木基, 阿久津典之, 佐々木茂, 高橋裕樹, 仲瀬裕志

膵臓 ( (一社)日本膵臓学会 ) 32 ( 3 ) 356 - 356 2017.05

Osteopontin attenuates acute gastrointestinal graft-versus-host disease by preventing apoptosis of intestinal epithelial cells.

Kentaro Kawakami, Naoki Minami, Minoru Matsuura, Tomoya Iida, Takahiko Toyonaga, Kanna Nagaishi, Yoshiaki Arimura, Mineko Fujimiya, Toshimitsu Uede, Hiroshi Nakase

Biochemical and biophysical research communications ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 485 ( 2 ) 468 - 475 2017.04 [Refereed] [International journal]

BACKGROUND AND AIMS: Acute graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation, which often targets gastrointestinal (GI) tract. Osteopontin (OPN) plays an important physiological role in the efficient development of Th1 immune responses and cell survival by inhibiting apoptosis. The role of OPN in acute GI-GVHD is poorly understood. In the present study, we investigated the role of OPN in donor T cells in the pathogenicity of acute GI-GVHD. METHODS: OPN knockout (KO) mice and C57BL/6 (B6) mice were used as donors, and (C57BL/6 × DBA/2) F1 (BDF1) mice were used as allograft recipients. Mice with acute GI-GVHD were divided into three groups: the control group (BDF1→BDF1), B6 group (B6→BDF1), and OPN-KO group (OPN-KO→BDF1). Bone marrow cells and spleen cells from donors were transplanted to lethally irradiated recipients. Clinical GVHD scores were assessed daily. Recipients were euthanized on day 7 after transplantation, and colons and small intestines were collected for various analyses. RESULTS: The clinical GVHD score in the OPN-KO group was significantly increased compared with the B6 and control groups. We observed a difference in the severity of colonic GVHD between the OPN-KO group and B6 group, but not small intestinal-GVHD between these groups. Interferon-γ, Tumor necrosis factor-α, Interleukin-17A, and Interleukin-18 gene expression in the OPN-KO group was differed between the colon and small intestine. Flow cytometric analysis revealed that the fluorescence intensity of splenic and colonic CD8 T cells expressing Fas Ligand was increased in the OPN-KO group compared with the B6 group. CONCLUSION: We demonstrated that the importance of OPN in T cells in the onset of acute GI-GVHD involves regulating apoptosis of the intestinal cell via the Fas-Fas Ligand pathway.

DOI PubMed

MicroRNA-196b is an independent prognostic biomarker in patients with pancreatic cancer.

Shinichi Kanno, Katsuhiko Nosho, Keisuke Ishigami, Itaru Yamamoto, Hideyuki Koide, Hiroyoshi Kurihara, Kei Mitsuhashi, Masahiro Shitani, Masayo Motoya, Shigeru Sasaki, Tokuma Tanuma, Hiroyuki Maguchi, Tadashi Hasegawa, Yasutoshi Kimura, Ichiro Takemasa, Yasuhisa Shinomura, Hiroshi Nakase

Carcinogenesis ( OXFORD UNIV PRESS ) 38 ( 4 ) 425 - 431 2017.04 [Refereed] [International journal]

Pancreatic cancer is a highly aggressive malignancy, with <50% patients surviving beyond 6 months after the diagnosis, and thus, there is an urgent need to explore new diagnostic and therapeutic approaches for this disease. Therefore, we conducted microRNA (miRNA) array analysis to detect miRNA molecules potentially associated with pancreatic cancer malignancy. To assess the identified miRNAs, we performed quantitative reverse transcription-PCR on 248 pancreatic ductal adenocarcinomas (UICC stage II). We also examined miRNA expression [microRNA-21 (miR-21) and microRNA-31 (miR-31)] and epigenetic alterations, including CpG island methylator phenotype (CIMP), potentially associated with the identified miRNAs. For functional analysis, we conducted proliferation and invasion assays using a pancreatic cancer cell line. miRNA array analysis revealed that microRNA-196b (miR-196b) was the most up-regulated miRNA in pancreatic cancer tissues compared with normal pancreatic duct cells. High miR-196b expression was associated with miR-21 (P = 0.0025) and miR-31 (P = 0.0001) expression. It was also related to poor prognosis in the multivariate analysis using overall survival (hazard ratio: 1.66; 95% confidence interval: 1.09-2.54; P = 0.019). Functional analysis demonstrated that miR-196b inhibitor decreased cell proliferation and that miR-196b mimic promoted cancer cell invasion. In conclusion, a significant association of high miR-196b expression with poor prognosis was observed in pancreatic cancer. Our data also revealed that miR-196b played an oncogenic role and that the transfection of the miR-196b inhibitor had an anti-tumour effect in the pancreatic cancer cell line. These results suggest that miR-196b is a promising diagnostic biomarker and therapeutic target in pancreatic cancer.

DOI PubMed

Clinical outcomes of sigmoid colon volvulus: identification of the factors associated with successful endoscopic detorsion.

Tomoya Iida, Suguru Nakagaki, Shuji Satoh, Haruo Shimizu, Hiroyuki Kaneto, Hiroshi Nakase

Intestinal research 15 ( 2 ) 215 - 220 2017.04 [Refereed] [International journal]

BACKGROUND/AIMS: Although multiple treatment options exist for the management of sigmoid colon volvulus, no study has examined the factors associated with successful endoscopic detorsion. This study aimed to examine the clinical course of patients with sigmoid colon volvulus and to identify factors related to successful endoscopic detorsion. METHODS: This study included 30 cases (21 patients) of sigmoid volvulus from among 545 cases of intestinal obstruction at a single center. We retrospectively examined the clinical course and the factors associated with the possibility of endoscopic detorsion of sigmoid colon volvulus. RESULTS: The rate of laxative use among the study participants was 76.2%; the rate of comorbid neuropsychiatric disorders was 61.9%; and 57.1% of patients had a history of open abdominal surgery. All patients were initially treated with endoscopic detorsion, and this procedure had a 61.9% success rate. The recurrence rate after detorsion was as high as 46.2%, but detorsion during revision endoscopy was possible in all cases. Statistical analysis revealed that the absence of abdominal tenderness (P=0.027), the use of laxatives (P=0.027), and a history of open abdominal surgery (P=0.032) were factors predictive of successful endoscopic detorsion. CONCLUSIONS: The results of our study are consistent with previous reports with respect to the success rate of endoscopic detorsion, the subsequent recurrence rate, and the proportion of patients requiring surgical treatment. In addition, we identified the absence of abdominal tenderness, the use of laxatives, and history of open abdominal surgery as factors predicting successful endoscopic detorsion of sigmoid colon volvulus.

DOI PubMed

膵癌と腫瘤形成性膵炎の鑑別にContrast-enhanced harmonic EUS(CH-EUS)は有用か

三宅高和, 志谷真啓, 大和田紗恵, 大久保陽介, 平野雄大, 佐々木基, 若杉英樹, 阿久津典之, 本谷雅代, 佐々木茂, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 59 ( Suppl.1 ) 1038 - 1038 2017.04

EZH2 expression is a prognostic biomarker in patients with colorectal cancer treated with anti-EGFR therapeutics.

Itaru Yamamoto, Katsuhiko Nosho, Shinichi Kanno, Hisayoshi Igarashi, Hiroyoshi Kurihara, Keisuke Ishigami, Kazuya Ishiguro, Kei Mitsuhashi, Reo Maruyama, Hideyuki Koide, Hiroyuki Okuda, Tadashi Hasegawa, Yasutaka Sukawa, Kenji Okita, Ichiro Takemasa, Hiroyuki Yamamoto, Yasuhisa Shinomura, Hiroshi Nakase

Oncotarget 8 ( 11 ) 17810 - 17818 2017.03 [Refereed] [International journal]

The polycomb group protein enhancer of zeste homolog 2 (EZH2) is a methyltransferase that suppresses microRNA-31 (miR-31) in various human malignancies including colorectal cancer. We recently suggested that miR-31 regulates the signaling pathway downstream of epidermal growth factor receptor (EGFR) in colorectal cancer. Therefore, we conducted this study for assessing the relationship between EZH2 expression and clinical outcomes in patients with colorectal cancer treated with anti-EGFR therapeutics. We immunohistochemically evaluated EZH2 expression and assessed miR-31 and gene mutations [KRAS (codon 61/146), NRAS (codon 12/13/61), and BRAF (codon 600)] in 109 patients with colorectal cancer harboring KRAS (codon 12/13) wild-type. We also evaluated the progression-free survival (PFS) and overall survival (OS). In the result, low EZH2 expression was significantly associated with shorter PFS (log-rank test: P = 0.023) and OS (P = 0.036) in patients with colorectal cancer. In the low-miR-31-expression group and the KRAS (codon 61/146), NRAS, and BRAF wild-type groups, a significantly shorter PFS (P = 0.022, P = 0.039, P = 0.021, and P = 0.036, respectively) was observed in the EZH2 low-expression groups than in the high-expression groups. In the multivariate analysis, low EZH2 expression was associated with a shorter PFS (P = 0.046), independent of the mutational status and miR-31. In conclusion, EZH2 expression was associated with survival in patients with colorectal cancer who were treated with anti-EGFR therapeutics. Moreover, low EZH2 expression was independently associated with shorter PFS in patients with cancer, suggesting that EZH2 expression is a useful additional prognostic biomarker for anti-EGFR therapy.

DOI PubMed

5-Aminosalicylic acid.

Tomoya Iida, Kei Onodera, Hiroshi Nakase

Nihon rinsho. Japanese journal of clinical medicine 75 ( 3 ) 392 - 397 2017.03 [Refereed] [Domestic journal]

Despite the emergence of new biological therapies that aim for mucosal healing as a new therapeutic target, the importance of 5-ASA formulations in the standard treatment for inflammatory bowel diseases, particularly ulcerative colitis, remains unchanged. With a growing number of patients suffering from inflammatory bowel diseases in Japan, general physicians are also increasingly prescribing 5-ASA formulations. In order to obtain the maximum efficacy of 5-ASA formulations when treating inflammatory bowel diseases, it is essential that the dosage and administration are appropriate.

PubMed

当科におけるC型慢性肝疾患に対するDAAsの現状

平野雄大, 阿久津典之, 若杉英樹, 高木秀安, 安達雄哉, 大和田紗恵, 大久保陽介, 三宅高和, 飯田智哉, 佐々木基, 志谷真啓, 本谷雅代, 佐々木茂, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 114 ( 臨増総会 ) A364 - A364 2017.03

Role of Small GTPase Ral in the Mechanism of Colitis-associated Cancer

Tomoya Iida, Naoki Minami, Kentaro Kawakami, Hiroki Ikeuchi, Seiichi Hirotak, Ryutaro Shirakawa, Hisanori Horiuchi, Hiroshi Nakase

INFLAMMATORY BOWEL DISEASES ( LIPPINCOTT WILLIAMS & WILKINS ) 23 S81 - S82 2017.02 [Refereed]

S状結腸原発内分泌細胞癌の一剖検例

吉田幸成, 石井良文, 佐々木泰史, 菊地剛史, 秋野公臣, 檜森亮吾, 青木敬則, 見田裕章, 安達靖代, 中村正弘, 足立靖, 加藤康夫, 川上賢太郎, 仲瀬裕志, 遠藤高夫

日本大腸肛門病学会雑誌 ( (一社)日本大腸肛門病学会 ) 70 ( 2 ) 89 - 89 2017.02

Maternal and fetal outcomes in pregnant Japanese women with inflammatory bowel disease: our experience with a series of 23 cases.

Naoki Minami, Minoru Matsuura, Yorimitsu Koshikawa, Satoshi Yamada, Yusuke Honzawa, Shuji Yamamoto, Hiroshi Nakase

Intestinal research 15 ( 1 ) 90 - 96 2017.01 [Refereed] [International journal]

BACKGROUND/AIMS: Our physicians work to expand the possibilities to treat female patients with inflammatory bowel disease (IBD) who wish to become pregnant. Although many drugs, including 5-aminosalicylate (5-ASA), corticosteroids, immunomodulators, and biologics, are used safely during pregnancy, few reports have described the therapeutic regimen throughout pregnancy and the management of patients who relapse during pregnancy precisely. The aim of this study was to assess the management of patients with IBD during pregnancy. METHODS: We identified 19 patients (five with Crohn's disease and 14 with ulcerative colitis [UC]) who became pregnant with a total of 23 pregnancies between May 2005 and May 2015 by reviewing the medical records of Kyoto University Hospital. The following data were collected: the maternal variables, the IBD treatment type, the disease activity, the pregnancy outcome, and the mode of delivery. RESULTS: Among the 19 patients, 18 had become pregnant after being diagnosed with IBD, while one had developed UC newly after pregnancy. Throughout the gestation, all patients were treated with probiotics, 5-ASA, prednisolone, cytapheresis, or infliximab. The relapse rate during pregnancy was 21.7% (5/23 cases). The five patients who experienced a relapse were able to pursue their pregnancy after intensification of their treatments. There were no adverse fetal or neonatal problems, except in one case that required an emergency Caesarean section because of placental dysfunction and in which a very low-birth-weight infant was born preterm. CONCLUSIONS: Our present data confirmed that even if the disease flares up during pregnancy, good pregnancy outcomes can be achieved with an optimal intensification of the patient's treatment.

DOI PubMed

High prevalence of vitamin B-12 insufficiency in patients with Crohn's disease

Misora Ao, Hidemi Tsuji, Kenichiro Shide, Yuki Kosaka, Akari Noda, Nobuya Inagaki, Hiroshi Nakase, Kiyoshi Tanaka

ASIA PACIFIC JOURNAL OF CLINICAL NUTRITION ( H E C PRESS, HEALTHY EATING CLUB PTY LTD ) 26 ( 6 ) 1076 - 1081 2017 [Refereed]

Background and Objectives: In Crohn's disease (CD), belonging to inflammatory bowel disease, the small intestine is involved in most cases. Most frequently affected is the distal ileum, where vitamin B-12 is specifically absorbed. Therefore, malabsorption of vitamin B-12 is quite likely to occur in patients with CD. In this study, we have studied the vitamin B-12 status in CD patients. Methods and Study Design: Forty eight patients with CD were evaluated for their food intake, and circulating concentrations of vitamin B-12, folic acid, and homocysteine (Hcy) as a sensitive marker for the insufficiency of these vitamins and a risk factor of atherosclerosis. Results: Plasma Hcy concentration was significantly correlated with serum vitamin B-12 concentration alone, and 60.4 % of the subjects had hyperhomocysteinemia. Receiver Operating Characteristics (ROC) analysis showed that serum concentration of vitamin B-12, but not folic acid, predicted hyperhomocysteinemia. Their intake of vitamin B-12 was much higher than the Japanese RDA, but not correlated with blood concentrations of vitamin B-12 or Hcy, probably due to malabsorption. Conclusions: Vitamin B-12 insufficiency and hyperhomocysteinemia were highly prevalent in CD patients. Recently, the significance of extra-intestinal complications of CD has been increasingly recognized, and our finding is likely to be of clinical importance.

DOI

Evaluation of a novel fluorescent nanobeacon for targeted imaging of Thomsen-Friedenreich associated colorectal cancer.

Hiroshi Nakase, Shinji Sakuma, Takumi Fukuchi, Takuya Yoshino, Kohta Mohri, Kohei Miyata, Hironori Kumagai, Ken-Ichiro Hiwatari, Kazufumi Tsubaki, Tetsuya Ikejima, Etsuo Tobita, Meiying Zhu, Kevin J Wilson, Kay Washington, John C Gore, Wellington Pham

International journal of nanomedicine ( DOVE MEDICAL PRESS LTD ) 12 1747 - 1755 2017 [Refereed] [International journal]

The Thomsen-Friedenreich (TF) antigen represents a prognostic biomarker of colorectal carcinoma. Here, using a nanobeacon, the surface of which was fabricated with peanut agglutinin as TF-binding molecules, we demonstrate that the nanobeacon is able to detect TF antigen in frozen and freshly biopsied polyps using fluorescence microscopy. Our results provide important clues about how to detect aberrant colonic tissues in the most timely fashion. Given the versatile application method for this topical nanobeacon, the protocol used in this work is amenable to clinical colonoscopy. Moreover, the prospects of clinical translation of this technology are evident.

DOI PubMed

DNA and Histone Methylation in Colon Cancer: Its Biological Impact and Clinical Implications

Hiromu Suzuki, Eiichiro Yamamoto, Hiroshi Nakase, Tamotsu Sugai

Cancer Drug Discovery and Development ( Humana Press Inc. ) ( 9783319597843 ) 461 - 487 2017

Colorectal cancers (CRCs) are thought to arise through accumulation of genetic and epigenetic alterations. CRC genomes exhibit dual-faceted DNA methylation abnormality, global hypomethylation with CpG island hypermethylation, and CRCs are classified into two groups based on whether their genomes exhibit microsatellite instability (MSI) or chromosomal instability (CIN). In addition, a subset of CRCs is characterized by concurrent hypermethylation of multiple CpG islands, known as the CpG island methylator phenotype (CIMP). Genomic instability and epigenetic alterations are tightly linked, and CRCs with MSI largely overlap CIMP-positive tumors, while CIN is associated with global DNA hypomethylation. Dysregulation of histone methylation and altered expression of histone modifying enzymes are also commonly observed in CRC, indicating their critical roles in CRC development. Evidence now suggests that DNA and histone methylation could potentially serve as biomarkers useful for CRC diagnosis, risk assessment and prediction of therapeutic effects and prognosis. Although many studies examining clinical applications are still at an early phase, it is anticipated that further investigation will lead to improved prevention and management of CRC.

DOI

Heparin bridge therapy and post-polypectomy bleeding.

Toshiyuki Kubo, Kentaro Yamashita, Kei Onodera, Tomoya Iida, Yoshiaki Arimura, Masanori Nojima, Hiroshi Nakase

World journal of gastroenterology ( BAISHIDENG PUBLISHING GROUP INC ) 22 ( 45 ) 10009 - 10014 2016.12 [Refereed] [International journal]

AIM: To identify risk factors for post-polypectomy bleeding (PPB), focusing on antithrombotic agents. METHODS: This was a case-control study based on medical records at a single center. PPB was defined as bleeding that occurred 6 h to 10 d after colonoscopic polypectomy and required endoscopic hemostasis. As risk factors for PPB, patient-related factors including anticoagulants, antiplatelets and heparin bridge therapy as well as polyp- and procedure-related factors were evaluated. All colonoscopic hot polypectomies, endoscopic mucosal resections and endoscopic submucosal dissections performed between January 2011 and December 2014 were reviewed. RESULTS: PPB occurred in 29 (3.7%) of 788 polypectomies performed during the study period. Antiplatelet or anticoagulant agents were prescribed for 210 (26.6%) patients and were ceased before polypectomy except for aspirin and cilostazol in 19 cases. Bridging therapy using intravenous unfractionated heparin was adopted for 73 patients. The univariate analysis revealed that anticoagulants, heparin bridge, and anticoagulants plus heparin bridge were significantly associated with PPB (P < 0.0001) whereas antiplatelets and antiplatelets plus heparin were not. None of the other factors including age, gender, location, size, shape, number of resected polyps, prophylactic clipping and resection method were correlated with PPB. The multivariate analysis demonstrated that anticoagulants and anticoagulants plus heparin bridge therapy were significant risk factors for PPB (P < 0.0001). Of the 29 PPB cases, 4 required transfusions and none required surgery. A thromboembolic event occurred in a patient who took anticoagulant. CONCLUSION: Patients taking anticoagulants have an increased risk of PPB, even if the anticoagulants are interrupted before polypectomy. Heparin-bridge therapy might be responsible for the increased PPB in patients taking anticoagulants.

DOI PubMed

Adalimumab Monotherapy and a Combination with Azathioprine for Crohn's Disease: A Prospective, Randomized Trial.

Takayuki Matsumoto, Satoshi Motoya, Kenji Watanabe, Tadakazu Hisamatsu, Hiroshi Nakase, Naoki Yoshimura, Tetsuya Ishida, Shingo Kato, Tomoo Nakagawa, Motohiro Esaki, Masakazu Nagahori, Toshiyuki Matsui, Yuji Naito, Takanori Kanai, Yasuo Suzuki, Masanori Nojima, Mamoru Watanabe, Toshifumi Hibi

Journal of Crohn's & colitis 10 ( 11 ) 1259 - 1266 2016.11 [Refereed] [International journal]

BACKGROUND AND AIMS: The efficacy of azathioprine for Crohn's disease under adalimumab treatment remains obscure. METHODS: In an open-labelled prospective study, we evaluated the efficacy of adalimumab with and without azathioprine in patients with active Crohn's disease, who were naïve to biologics and thiopurines. The patients were randomly assigned to subcutaneous administration of adalimumab [monotherapy group] or to exactly the same schedule of adalimumab with azathioprine [25-100mg daily] [combination group] for 52 Weeks. The primary endpoint was clinical remission at WWeek 26. We also evaluated the score for simple endoscopic severity of Crohn's disease before the therapy and at WWeeks 26 and 52. RESULTS: A total of 176 patients were randomized to either the monotherapy group [n = 85] or to the combination group [n = 91]. Eighteen patients [21.2%] from the monotherapy group and 7 patients [7.7%] from the combination group withdrew owing to active disease, and 15 patients [16.5%] from the combination group and 1 patient [1.2%] from the monotherapy group withdrew due to side effects of the medications. Non-responder imputation analysis revealed that the remission rate at WWeek 26 did not differ between the monotherapy group and the combination group [71.8% vs 68.1%; OR 0.84, p = 0.63]. The rate of endoscopic improvement at WWeek 26 was significantly higher in the combination group [84.2%, n = 57] than in the monotherapy group [63.8%, n = 58] [p = 0.019]. CONCLUSION: The clinical efficacy of a combination of adalimumab and azathioprine at WWeek 26 did not differ from that of adalimumab monotherapy in patients with Crohn's disease naïve to both medications.

DOI PubMed

CD68 on rat macrophages binds tightly to S100A8 and S100A9 and helps to regulate the cells' immune functions.

Kohki Okada, Satoshi Arai, Hiroshi Itoh, Souichi Adachi, Masahiko Hayashida, Hiroshi Nakase, Masaki Ikemoto

Journal of leukocyte biology ( FEDERATION AMER SOC EXP BIOL ) 100 ( 5 ) 1093 - 1104 2016.11 [Refereed] [International journal]

S100A8 and S100A9 (S100 proteins) are regulators of immune cells of myeloid origin. Whereas S100 proteins are found at high concentrations in such cells, their immunologic roles remain unclear. We focused on cluster of differentiation 68 (CD68). The aim of this study is to investigate whether CD68 binds to extracellular S100A8 and/or S100A9 and subsequently participates in the regulation of the cells' immune functions. ELISA and affinity chromatography showed that both recombinant rat S100A8 (r-S100A8) and r-S100A9 bound to r-CD68, but not to r-CD14. Flow cytometry clearly showed evidences supporting above the 2 results. As analyzed by flow cytometry, a less amount of r-S100A8 or r-S100A9 bound to the macrophages treated with some deglycosylation enzymes. In an in vitro assay, the expression levels of S100A8 and S100A9 were significantly suppressed after the macrophages had been treated with an anti-CD68 antibody (ED1). As stimulated macrophages with r-S100A9, the expression of IL-1β mRNA in macrophages, which were treated with anti-TLR4 or -RAGE antibodies, was significantly suppressed. r-S100A8 up-regulated IL-6 and IL-10 mRNAs, while r-S100A9 did TNF-α and IL-6 mRNAs, although these regulations were not statistically significant. Small interfering CD68 also significantly suppressed activation of macrophages through an autocrine pathway by r-S100A8 or r-S100A9. In macrophages stimulated with LPS, fluorescent immunologic staining showed that most CD68 colocalized with S100A8 or S100A9 and that the levels of all 3 molecules were markedly increased. In conclusion, CD68 on macrophages binds to S100A8 and S100A9 and thereby, plays a role in the regulation of the cells' immune functions.

DOI PubMed

Lipocalin 2 prevents intestinal inflammation by enhancing phagocytic bacterial clearance in macrophages.

Takahiko Toyonaga, Minoru Matsuura, Kiyoshi Mori, Yusuke Honzawa, Naoki Minami, Satoshi Yamada, Taku Kobayashi, Toshifumi Hibi, Hiroshi Nakase

Scientific reports 6 35014 - 35014 2016.10 [Refereed] [International journal]

Lipocalin 2 (Lcn2), also called neutrophil gelatinase B-associated lipocalin (NGAL), is an anti-microbial peptide originally identified in neutrophil granules. Although Lcn2/NGAL expression is increased in the inflamed intestinal tissues of patients with inflammatory bowel disease, the role of Lcn2/NGAL in the development of intestinal inflammation remains unclear. Here we investigated the role of Lcn2/NGAL in intestinal inflammation using a spontaneous mouse colitis model, interleukin-10 knock out (IL-10 KO) mice. Lcn2 expression in the colonic tissues of IL-10 KO mice increased with the development of colitis. Lcn2/IL-10 double-KO mice showed a more rapid onset and development of colitis compared to IL-10 KO mice. Lcn2 enhanced phagocytic bacterial clearance in macrophages in vitro after infection with Escherichia coli. Transfer of Lcn2-repleted macrophages prevented the development of colitis in Lcn2/IL-10 double-KO mice in vivo. Our findings revealed that Lcn2 prevents the development of intestinal inflammation. One crucial factor seems to be the enhancement of phagocytic bacterial clearance in macrophages by Lcn2.

DOI PubMed

Targeting cytomegalovirus during ulcerative colitis flare-ups.

Hiroshi Nakase, Kei Onodera

Expert review of gastroenterology & hepatology 10 ( 10 ) 1119 - 1125 2016.10 [Refereed] [International journal]

INTRODUCTION: Human cytomegalovirus (CMV) is a common cause of opportunistic infection leading to severe and fatal disease in immune-compromised individuals. In inflammatory bowel disease patients, particularly those with ulcerative colitis (UC), CMV is often reactivated because these patients are frequently treated with immunosuppressive agents. Many reports have described the relationship between CMV reactivation and UC exacerbation, however, a therapeutic strategy for CMV infection in UC patients has not been established. Area covered: This review highlights therapeutic strategies for UC patients with CMV infection. Recent findings have suggested a benefit from antiviral therapy in patients with histologically proven CMV colitis and/or a high colonic CMV load as determined by quantitative PCR. Expert commentary: To decide who requires antiviral therapies and when we start antiviral therapies, prospective studies of large numbers of UC patients with CMV infection are needed. However, we should know that the bottom-line therapy for UC patients with CMV infection is to optimally control mucosal inflammation.

DOI PubMed

Erratum: Treatment of inflammatory bowel disease in Asia: the results of a multinational web-based survey in the 2nd Asian Organization for Crohn's and Colitis (AOCC) meeting in Seoul.

Hiroshi Nakase, Bora Keum, Byong Duk Ye, Soo Jung Park, Hoon Sup Koo, Chang Soo Eun

Intestinal research 14 ( 4 ) 381 - 381 2016.10 [Refereed] [International journal]

PubMed

多発性骨髄腫に有効なヒストンメチル化阻害薬の探索

石黒一也, 北嶋洋志, 新沼猛, 丸山玲緒, 甲斐正広, 西山廣陽, 進藤哲哉, 池田博, 石田禎夫, 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 ) 75回 P - 2096 2016.10

自己免疫性膵炎におけるEUS-FNAの役割穿刺針の検討

本谷雅代, 榮浪洋介, 若杉英樹, 志谷真啓, 阿久津典之, 佐々木茂, 仲瀬裕志

Gastroenterological Endoscopy ( (一社)日本消化器内視鏡学会 ) 58 ( Suppl.2 ) 1972 - 1972 2016.10

ラット大腸3次元培養における間葉系幹細胞のニッチ作用

川上賢太郎, 一色裕之, 有村佳昭, 小野寺馨, 永石歓和, 山下健太郎, 藤宮峯子, 仲瀬裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 113 ( 臨増大会 ) A758 - A758 2016.09

Diagnostic accuracy of endoscopic features of pediatric acute gastrointestinal graft-versus-host disease.

Eitaro Hiejima, Hiroshi Nakase, Minoru Matsuura, Yusuke Honzawa, Hirokazu Higuchi, Satoshi Saida, Katsutsugu Umeda, Hidefumi Hiramatsu, Souichi Adachi, Kazushi Izawa, Tomoki Kawai, Takahiro Yasumi, Ryuta Nishikomori, Toshio Heike

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 28 ( 5 ) 548 - 55 2016.07 [Refereed] [International journal]

BACKGROUND AND AIM: Acute gastrointestinal graft-versus-host disease (GI-GVHD) is a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). There are very few studies on specific endoscopic findings in pediatric acute GI-GVHD. The aim of this retrospective case-control study was to elucidate the characteristic endoscopic findings in pediatric acute GI-GVHD that improve the diagnostic accuracy of endoscopy. METHODS: All consecutive patients under 18 years of age who underwent allogeneic HSCT in Kyoto University Hospital from May 2003 to October 2014 were identified retrospectively. Patients who underwent GI endoscopy as a result of sustained GI symptoms were identified. Intestinal villous patterns were evaluated by magnification endoscopy with the water-immersion technique. The patients were diagnosed with acute GI-GVHD and non-GVHD on the basis of biopsy histology. Endoscopic findings of the two groups were compared. RESULTS: Of the 171 patients who underwent HSCT, 30 underwent GI endoscopy. Of these, 17 and nine were diagnosed with acute GI-GVHD and non-GVHD, respectively. Compared with non-GVHD, acute GI-GVHD was associated significantly more often with short blunt villi in the duodenum (P = 0.013), variable defect villi and short blunt villi in the ileum (P = 0.009 and 0.035, respectively), and edema, erosion, and tortoiseshell-like mucosae in the colon (P = 0.017, 0.023, and 0.017, respectively). CONCLUSION: Pediatric acute GI-GVHD was associated with several characteristic features on magnifying endoscopy with the water-immersion technique. These features will be useful for endoscopic diagnosis of pediatric acute GI-GVHD.

DOI PubMed

Treatment of inflammatory bowel disease in Asia: the results of a multinational web-based survey in the 2(nd) Asian Organization of Crohn's and Colitis (AOCC) meeting in Seoul.

Hiroshi Nakase, Bora Keum, Byoung Duk Ye, Soo Jung Park, Hoon Sup Koo, Chang Soo Eun

Intestinal research 14 ( 3 ) 231 - 9 2016.07 [Refereed] [International journal]

BACKGROUND/AIMS: Inflammatory bowel disease (IBD) management guidelines have been released from Western countries, but no adequate data on the application of these guidelines in Asian countries and no surveys on the treatment of IBD in real practice exist. Since there is a growing need for a customized consensus for IBD treatment in Asian countries, Asian Organization of Crohn's and Colitis performed a multinational survey of medical doctors who treat IBD patients in Asian countries. METHODS: A questionnaire was developed between August 2013 and November 2013. It was composed of 4 domains: personal information, IBD diagnosis, IBD treatment, and quality of IBD care. Upon completion of the questionnaire, a web-based survey was conducted between 17 March 2014 and 12 May 2014. RESULTS: In total, 353 medical doctors treating IBD from ten Asian countries responded to the survey. This survey data suggested a difference in available medical treatments (budesonide, tacrolimus) among Asian countries. Therapeutic strategies regarding refractory IBD (acute severe ulcerative colitis [UC] refractory to intravenous steroids and refractory Crohn's disease [CD]) and active UC were coincident, however, induction therapies for mild to moderate inflammatory small bowel CD are different among Asian countries. CONCLUSIONS: This survey demonstrated that current therapeutic approaches and clinical management of IBD vary among Asian countries. Based on these results and discussions, we hope that optimal management guidelines for Asian IBD patients will be developed.

DOI PubMed

Retrospective Analysis of Growth Speed of 54 Lesions of Colitis-associated Colorectal Neoplasia.

Kazutomo Yamasaki, Toshiyuki Matsui, Takashi Hisabe, Yutaka Yano, Fumihito Hirai, Tsuyoshi Morokuma, Yasushi Iwao, Takayuki Matsumoto, Hidehisa Ohi, Akira Andoh, Motohiro Esaki, Kunihiko Aoyagi, Akira Sugita, Hiroshi Nakase, Mikihiro Fujiya, Daijiro Higashi, Kitaro Futami

Anticancer research ( INT INST ANTICANCER RESEARCH ) 36 ( 7 ) 3731 - 40 2016.07 [Refereed] [International journal]

AIM: This study used a multicenter questionnaire survey to evaluate the morphology and progression of the initial lesion in cases of colitis-associated colorectal neoplasia (CRN). PATIENTS AND METHODS: Endoscopic images of lesions that had been definitively diagnosed as CRN by pathological examination were retrospectively reviewed. RESULTS: This resulted in the identification of 54 initial lesions in 49 patients. The 54 initial lesions fell into the following categories: 22 endoscopically visible localized lesions consisting of 18 elevated lesions and 4 depressed lesions, as well as 32 lesions that were not endoscopically visible as localized and consisted of 20 active-phase mucosal lesions and 12 remission-phase mucosal lesions. Nineteen of the lesions eventually became advanced cancers, while 35 lesions eventually became early-stage cancers. The final lesions were 40 elevated lesions, 5 flat or depressed lesions and 9 stenotic lesions. The form of growth of the advanced cancers was progressive stenosis or increased elevation. For approximately 69% of the early-stage cancers, the growth form was increasing elevation or development of elevation. For 73.6% of the advanced cancers, the initial lesion underwent rapid growth and became advanced cancer within 3 years; they accounted for 25.9% of the total cancers. Approximately 40% of the initial lesions of CRN were endoscopically visible as localized lesions, while approximately 60% were judged to be inflammatory mucosal lesions. CONCLUSION: It will be necessary to proactively take biopsy inflammatory mucosal lesions in order to discover tumors early and periodic surveillance should be performed with the knowledge that tumors may grow very quickly.

PubMed

Effects of Granulocyte and Monocyte Adsorptive Apheresis in Renal Transplantation Recipients with Concomitant Cytomegalovirus Infection

T. Naganuma, Y. Takemoto, T. Iwai, N. Kuwabara, J. Uchida, T. Nakatani, K. Kitamura, A. Masuda, K. Ohmori, M. Matsuura, H. Nakase

Transplantation Proceedings ( Elsevier USA ) 48 ( 3 ) 929 - 932 2016.04 [Refereed]

Background Granulocyte and monocyte adsorptive apheresis (GMAA) is widely used as a treatment for active ulcerative colitis (UC) in Japan. Much attention has been paid to the possibility of GMAA for the treatment and control of cytomegalovirus (CMV) reactivation in patients with refractory UC and concomitant CMV infection. In this study, the effects of the combination of GMAA and antiviral therapy were examined in renal transplant recipients with concomitant CMV infection. Methods Combination therapy of GMAA and antiviral drugs was performed 9 times in 7 renal transplant recipients with concomitant CMV infection. Four of the cases were positive for CMV-IgG, and 3 were negative. The clinical presentation of CMV infection was viremia in 6 cases and disease (CMV retinitis) in 1 case. CMV infection was diagnosed by using an antigenemia assay (C7-HRP). GMAA session was performed once, and the duration of the session was 120 min. Immediately after the GMAA session, ganciclovir was administered at 5 mg/kg/body weight. CMV infection was monitored based on C7-HRP and CMV-DNA in the peripheral blood samples. Results All cases became negative for C7-HRP and CMV-DNA within 21 days (median, 14 days range, 3-21 days) and 17 days (median, 6 days range, 3-17 days), respectively, after starting the combination therapy. No side effects of GMAA were observed. Conclusions This case series found that GMAA in combination with antiviral drugs may shorten the duration of treatment against CMV infection in renal transplant recipients. Further studies in a larger number of patients are required to confirm these results.

DOI PubMed

Cytomegalovirus Colitis, Cytomegalovirus Hepatitis and Systemic Cytomegalovirus Infection: Common Features and Differences.

Hiroshi Nakase, Hans Herfarth

Inflammatory intestinal diseases 1 ( 1 ) 15 - 23 2016.04 [Refereed] [International journal]

Cytomegalovirus (CMV) is a ubiquitous human herpes virus, which, after often asymptomatic primary infection, establishes a lifelong latent infection that can periodically be reactivated in both immunocompetent and immunosuppressed carriers. Whereas the diagnostic approach in case of a suspicion of CMV reactivation is well defined, the indication for antiviral therapy can often only be made in the context of an extent of organ involvement, the immune status, and comorbidities of the patient. This article reviews the epidemiology, diagnosis, and therapy of CMV reactivation with a focus on inflammatory bowel diseases and potentially different diagnostic and therapeutic approaches in Asia and the Western world.

PubMed

Exon skipping causes atypical phenotypes associated with a loss-of-function mutation in FLNA by restoring its protein function.

Hirotsugu Oda, Tatsuhiro Sato, Shinji Kunishima, Kenji Nakagawa, Kazushi Izawa, Eitaro Hiejima, Tomoki Kawai, Takahiro Yasumi, Hiraku Doi, Kenji Katamura, Hironao Numabe, Shinya Okamoto, Hiroshi Nakase, Atsushi Hijikata, Osamu Ohara, Hidenori Suzuki, Hiroko Morisaki, Takayuki Morisaki, Hiroyuki Nunoi, Seisuke Hattori, Ryuta Nishikomori, Toshio Heike

European journal of human genetics : EJHG ( NATURE PUBLISHING GROUP ) 24 ( 3 ) 408 - 14 2016.03 [Refereed] [International journal]

Loss-of-function mutations in filamin A (FLNA) cause an X-linked dominant disorder with multiple organ involvement. Affected females present with periventricular nodular heterotopia (PVNH), cardiovascular complications, thrombocytopenia and Ehlers-Danlos syndrome. These mutations are typically lethal to males, and rare male survivors suffer from failure to thrive, PVNH, and severe cardiovascular and gastrointestinal complications. Here we report two surviving male siblings with a loss-of-function mutation in FLNA. They presented with multiple complications, including valvulopathy, intestinal malrotation and chronic intestinal pseudo-obstruction (CIPO). However, these siblings had atypical clinical courses, such as a lack of PVNH and a spontaneous improvement of CIPO. Trio-based whole-exome sequencing revealed a 4-bp deletion in exon 40 that was predicted to cause a lethal premature protein truncation. However, molecular investigations revealed that the mutation induced in-frame skipping of the mutated exon, which led to the translation of a mutant FLNA missing an internal region of 41 amino acids. Functional analyses of the mutant protein suggested that its binding affinity to integrin, as well as its capacity to induce focal adhesions, were comparable to those of the wild-type protein. These results suggested that exon skipping of FLNA partially restored its protein function, which could contribute to amelioration of the siblings' clinical courses. This study expands the diversity of the phenotypes associated with loss-of-function mutations in FLNA.

DOI PubMed

Ileal follicular lymphoma with atypical endoscopic findings.

Satoshi Yamada, Yorimitsu Koshikawa, Naoki Minami, Yusuke Honzawa, Minoru Matsuura, Hiroshi Nakase

Endoscopy international open 4 ( 3 ) E323-5 - 5 2016.03 [Refereed] [International journal]

A 72-year-old woman presented with symptomatic anemia without abdominal symptoms. She had no history of abdominal surgery or use of non-steroidal anti-inflammatory drugs. Enhanced computed tomography of the abdomen revealed swelling of multiple intraperitoneal lymph nodes and a high density of mesenteric adipose tissue. Fluorodeoxyglucose (FDG-) positron emission tomography showed high FDG accumulation at the intraperitoneal lymph nodes. Double-balloon enteroscopy detected severe stenosis with an annular ulcer in the lower ileum. She was diagnosed with ileal follicular lymphoma based on histologic examination and fluorescence in situ hybridization analysis of the biopsy specimen. The ileal ulcer was successfully treated by chemotherapy with rituximab and bendamustine for 1 year. We strongly recommend consideration of gastrointestinal follicular lymphoma in the differential diagnosis of annular ulcers in the small intestine.

DOI PubMed

Efficacy of probiotic treatment with Bifidobacterium longum 536 for induction of remission in active ulcerative colitis: A randomized, double-blinded, placebo-controlled multicenter trial.

Hiroyuki Tamaki, Hiroshi Nakase, Satoko Inoue, Chiharu Kawanami, Toshinao Itani, Masaya Ohana, Toshihiro Kusaka, Suguru Uose, Hiroshi Hisatsune, Masahide Tojo, Teruyo Noda, Souichi Arasawa, Masako Izuta, Atsushi Kubo, Chikara Ogawa, Toshihiro Matsunaka, Mitsushige Shibatouge

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society ( WILEY-BLACKWELL ) 28 ( 1 ) 67 - 74 2016.01 [Refereed] [International journal]

BACKGROUND AND AIM: We conducted a randomized, double-blinded, placebo-controlled trial to investigate the efficacy of Bifidobacterium longum 536 (BB536) supplementation for induction of remission in Japanese patients with active ulcerative colitis (UC). METHODS: Fifty-six patients with mild to moderate UC were enrolled. Three patients had pancolitis, 36 had left-sided colitis, and 17 had proctitis. Patients were randomly treated with 2-3 × 10(11) freeze-dried viable BB536 (28 patients) or placebo (28 patients) for 8 weeks. RESULTS: In total, 63% of patients receiving BB536 showed clinical remission (UC disease activity index [UCDAI] ≤2) at week 8 compared to 52% of those receiving placebo (P = 0.395). We observed a significant decrease of UCDAI scores (3.8 ± 0.4 at baseline to 2.6 ± 0.4 at week 8) in the BB536 group (P < 0.01), whereas there was no significant decrease in the placebo group (P = 0.88). There was also a significant decrease in the Rachmilewitz endoscopic index (EI) and the Mayo subscore at week 8 in the BB536 group, whereas there was no significant decrease in the placebo group. A single patient in the BB536 group complained of a mild side-effect, but no other adverse effects were observed. CONCLUSION: Supplementation with BB536 was well tolerated and reduced UCDAI scores, EI and Mayo subscores after 8 weeks in Japanese patients with mild to moderately active UC.

DOI PubMed

Ischemic enteritis with intestinal stenosis.

Yorimitsu Koshikawa, Hiroshi Nakase, Minoru Matsuura, Takuya Yoshino, Yusuke Honzawa, Naoki Minami, Satoshi Yamada, Yumiko Yasuhara, Shigehiko Fujii, Toshihiro Kusaka, Dai Manaka, Hiroyuki Kokuryu

Intestinal research 14 ( 1 ) 89 - 95 2016.01 [Refereed] [International journal]

A 75-year-old man was admitted to our hospital with sudden onset of vomiting and abdominal distension. The patient was taking medication for arrhythmia. Computed tomography showed stenosis of the ileum and a small bowel dilatation on the oral side from the region of stenosis. A transnasal ileus tube was placed. Enteroclysis using contrast medium revealed an approximately 6-cm afferent tubular stenosis 10 cm from the terminal ileum and thumbprinting in the proximal bowel. Transanal double-balloon enteroscopy showed a circumferential shallow ulcer with a smooth margin and edema of the surrounding mucosa. The stenosis was so extensive that we could not perform endoscopic balloon dilation therapy. During hospitalization, the patient's nutritional status deteriorated. In response, we surgically resected the region of stenosis. Histologic examination revealed disappearance of the mucosal layer and transmural ulceration with marked fibrosis, especially in the submucosal layer. Hemosiderin staining revealed sideroferous cells in the submucosal layers. Based on the pathologic findings, the patient was diagnosed with ischemic enteritis. The patient's postoperative course was uneventful.

DOI PubMed

The development of drug delivery system for regulating mucosal immune system for future therapy of inflammatory bowel disease

Hiroshi Nakase, Tomoya Iida, Kei Onodera

Drug Delivery System ( Japan Society of Drug Delivery System ) 31 ( 3 ) 194 - 200 2016 [Refereed]

DOI

TET1 Depletion Induces Aberrant CpG Methylation in Colorectal Cancer Cells.

Masahiro Kai, Takeshi Niinuma, Hiroshi Kitajima, Eiichiro Yamamoto, Taku Harada, Hironori Aoki, Reo Maruyama, Mutsumi Toyota, Yasushi Sasaki, Tamotsu Sugai, Takashi Tokino, Hiroshi Nakase, Hiromu Suzuki

PloS one ( PUBLIC LIBRARY SCIENCE ) 11 ( 12 ) e0168281 2016 [Refereed] [International journal]

Aberrant DNA methylation is commonly observed in colorectal cancer (CRC), but the underlying mechanism is not fully understood. 5-hydroxymethylcytosine levels and TET1 expression are both reduced in CRC, while epigenetic silencing of TET1 is reportedly associated with the CpG island methylator phenotype. In the present study, we aimed to clarify the relationship between loss of TET1 and aberrant DNA methylation in CRC. Stable TET1 knockdown clones were established using Colo320DM cells, which express high levels of TET1, and HCT116 cells, which express TET1 at a level similar to that in normal colonic tissue. Infinium HumanMethylation450 BeadChip assays revealed increased levels of 5-methylcytosine at more than 10,000 CpG sites in TET1-depleted Colo320DM cells. Changes in DNA methylation were observed at various positions within the genome, including promoters, gene bodies and intergenic regions, and the altered methylation affected expression of a subset of genes. By contrast, TET1 knockdown did not significantly affect DNA methylation in HCT116 cells. However, TET1 depletion was associated with attenuated effects of 5-aza-2'-deoxycytidine on gene expression profiles in both cell lines. These results suggest that loss of TET1 may induce aberrant DNA methylation and may attenuate the effect of 5-aza-2'-deoxycytidine in CRC cells.

DOI PubMed

Risk factors for developing colorectal cancer in Japanese patients with ulcerative colitis: a retrospective observational study-CAPITAL (Cohort and Practice for IBD total management in Kyoto-Shiga Links) study I.

Takuya Yoshino, Hiroshi Nakase, Tomohisa Takagi, Shigeki Bamba, Yusuke Okuyama, Takuji Kawamura, Teruki Oki, Hirozumi Obata, Chiharu Kawanami, Shinji Katsushima, Toshihiro Kusaka, Tomoyuki Tsujikawa, Yuji Naito, Akira Andoh, Takafumi Kogawa

BMJ open gastroenterology 3 ( 1 ) e000122 2016 [Refereed] [International journal]

BACKGROUND AND AIMS: Patients with ulcerative colitis (UC) are at risk for developing colorectal cancer (CRC), despite the development of new therapeutic agents. Stratification of the individual UC-patient's risk would be helpful to validate the risk factors for CRC. The aim of this study was to evaluate the risk factors for the development of CRC in a large cohort of patients with UC. METHODS: Data were obtained from 12 hospitals in the Kyoto-Shiga region during 2003-2013. We performed a retrospective cohort study of 2137 patients with UC. RESULTS: In total, 60 lesions of CRC were detected in 43 (2.0%) of 2137 patients. 30 of the 43 patients were male. The median age was 53 years. The median duration of disease was 13 years, and 67.4% of these patients had a disease duration >10 years. Of the 43 patients, 34 (79.1%) had extensive colitis. Primary sclerosing cholangitis was detected in 2 patients (4.7%). The median corticosteroids (CS) dose was 6.4 g, and 4 patients were treated with a total of more than 10 g of CS. 18 of these patients underwent more than 1 year CS treatment. Of all 60 CRC lesions, 43 (71.7%) were located in the distal colon and 35 (58.3%) were of the superficial type. Moreover, the stage of CRC was stage 0 or I in 55.8% of the 43 patients with CRC. Multivariate analysis suggested that extensive colitis could be a risk factor for the development of advanced CRC in patients with UC. CONCLUSIONS: Our findings indicated that male, extensive colitis, long-term duration of UC and family history of CRC, but not concomitant primary sclerosing cholangitis, are important factors for predicting CRC in Japanese patients with UC. Moreover, long-standing extensive colitis might contribute to the progression of CRC. Further studies are required to establish CRC surveillance in Japanese patients with UC.

PubMed

Association of colorectal carcinogenesis pathway with life style and intestinal microbiome based on the genome and epigenome abnormalities.

Katsuhiko Nosho, Yasutaka Sukawa, Hiroshi Nakase

Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology 113 ( 11 ) 1878 - 1886 2016 [Refereed] [Domestic journal]

PubMed

Reply: To PMID 25946569.

Eitaro Hiejima, Hiroshi Nakase, Toshio Heike

Inflammatory bowel diseases 21 ( 12 ) E30-1 - 1 2015.12 [Refereed] [International journal]

DOI PubMed

An open-label prospective randomized multicenter study of intensive versus weekly granulocyte and monocyte apheresis in active crohn's disease.

Naoki Yoshimura, Yoko Yokoyama, Katsuyoshi Matsuoka, Hiroki Takahashi, Ryuichi Iwakiri, Takayuki Yamamoto, Tomoo Nakagawa, Takumi Fukuchi, Satoshi Motoya, Reiko Kunisaki, Shingo Kato, Fumihito Hirai, Yoh Ishiguro, Satoshi Tanida, Sakiko Hiraoka, Keiichi Mitsuyama, Shunji Ishihara, Shinji Tanaka, Michiro Otaka, Taro Osada, Takashi Kagaya, Yasuo Suzuki, Hiroshi Nakase, Hiroyuki Hanai, Kenji Watanabe, Nobuhito Kashiwagi, Toshifumi Hibi

BMC gastroenterology ( BIOMED CENTRAL LTD ) 15 163 - 163 2015.11 [Refereed] [International journal]

BACKGROUND: Granulocyte and monocyte adsorptive apheresis (GMA) has shown efficacy in patients with active Crohn's disease (CD). However, with routine weekly therapy, it may take several weeks to achieve remission. This study was performed to assess clinical efficacy and safety of intensive GMA in patients with active CD. METHODS: In an open-label, prospective, randomized multicentre setting, 104 patients with CD activity index (CDAI) of 200 to 450 received intensive GMA, at two sessions per week (n = 55) or one session per week (n = 49). Clinical remission was defined as a CDAI score <150. Patients in each arm could receive up to 10 GMA sessions. However, GMA treatment could be discontinued when CDAI decreased to <150 (clinical remission level). RESULTS: Of the 104 patients, 99 were available for efficacy evaluation as per protocol, 45 in the weekly GMA group, and 54 in the intensive GMA group. Remission was achieved in 16 of 45 patients (35.6 %) in the weekly GMA and in 19 of 54 (35.2 %) in the intensive GMA (NS). Further, the mean time to remission was 35.4 ± 5.3 days in the weekly GMA and 21.7 ± 2.7 days in the intensive GMA (P = 0.0373). Elevated leucocytes and erythrocyte sedimentation rate were significantly improved by intensive GMA, from 8005/μL to 6950/μL (P = 0.0461) and from 54.5 mm/hr to 30.0 mm/hr (P = 0.0059), respectively. In both arms, GMA was well tolerated and was without safety concern. CONCLUSIONS: In this study, with respect to remission rate, intensive GMA was not superior to weekly GMA, but the time to remission was significantly shorter in the former without increasing the incidence of side effects. UMIN registration # 000003666.

DOI PubMed

Efficacy and Safety of Long-Term Thiopurine Maintenance Treatment in Japanese Patients With Ulcerative Colitis.

Satoshi Yamada, Takuya Yoshino, Minoru Matsuura, Masamichi Kimura, Yorimitsu Koshikawa, Naoki Minami, Takahiko Toyonaga, Yusuke Honzawa, Hiroshi Nakase

Intestinal research 13 ( 3 ) 250 - 8 2015.07 [Refereed] [International journal]

BACKGROUND/AIMS: The long-term clinical outcomes of patients with bio-naive ulcerative colitis (UC) who maintain remission with thiopurine are unclear. The aim of this study was to assess the long-term efficacy and safety of maintenance treatment with thiopurine in UC patients. METHODS: This was a retrospective observational cohort analysis conducted at a single center. Between December 1998 and August 2013, 59 of 87 patients with bio-naive UC who achieved remission after induction with treatments other than biologics were enrolled. Remission maintenance with thiopurine was defined as no concomitant treatment needed other than 5-aminosalicylate without relapse. We assessed the remission-maintenance rate, mucosal healing rate, colectomy-free rate, and treatment safety in UC patients who received thiopurine as maintenance treatment. RESULTS: The 84-month cumulative remission-maintenance and colectomy-free survival rates in the UC patients who were receiving maintenance treatment with thiopurine and 5-aminosalicylate were 43.9% and 88.0%, respectively. Of the 38 patients who underwent colonoscopy during thiopurine maintenance treatment, 23 (60.5%) achieved mucosal healing. Of the 59 patients who achieved clinical remission with thiopurine, 6 patients (10.2%) discontinued the thiopurine therapy because of adverse events. CONCLUSIONS: Our study demonstrates the long-term efficacy and safety of thiopurine treatment in patients with bio-naive UC.

DOI PubMed

Efficacy of Thiopurines in Biologic-Naive Japanese Patients With Crohn's Disease: A Single-Center Experience.

Takuya Yoshino, Minoru Matsuura, Naoki Minami, Satoshi Yamada, Yusuke Honzawa, Masamichi Kimura, Yorimitsu Koshikawa, Ali Madian, Takahiko Toyonaga, Hiroshi Nakase

Intestinal research 13 ( 3 ) 266 - 73 2015.07 [Refereed] [International journal]

BACKGROUND/AIMS: Early use of biologics in patients with Crohn's disease (CD) improves quality of life. However, the effects of the early use of immunomodulators on long-term outcomes remain unclear. This study aimed to evaluate the effects of immunomodulators in patients with CD. METHODS: Between January 2004 and December 2011, 47 biologic-naive CD patients treated with thiopurines alone for remission maintenance were analyzed. The patients were classified into 2 groups depending on the presence or absence of digestive complications. We evaluated the efficacy of and predictive factors for thiopurine use for remission maintenance. RESULTS: The cumulative relapse rates at 24 and 60 months were 13.7% and 35.4%, respectively. Regarding patient characteristics, there was a significant difference in patient history of surgery between the non-relapse and relapse groups (P=0.021). The cumulative relapse rate was lower in patients without a history of surgery than in those with such a history (27.2% and 52.9% at 60.0 months, respectively). Multivariate analysis suggested that the prevalence of stricturing and penetrating complications is an independent factor for relapse. The cumulative relapse rate in patients without a history of surgery was significantly lower in the non-stricturing and non-penetrating group than in the stricturing and penetrating group (11.8% at 85.0 months vs. 58.5% at 69.0 months; P=0.036). CONCLUSIONS: Thiopurine use might be beneficial for the long-term maintenance of remission in biologic-naive Crohn's disease patients without digestive complications and a history of surgery.

DOI PubMed

Reduced Numbers and Proapoptotic Features of Mucosal-associated Invariant T Cells as a Characteristic Finding in Patients with Inflammatory Bowel Disease.

Eitaro Hiejima, Tomoki Kawai, Hiroshi Nakase, Tatsuaki Tsuruyama, Takeshi Morimoto, Takahiro Yasumi, Takashi Taga, Hirokazu Kanegane, Masayuki Hori, Katsuyuki Ohmori, Takeshi Higuchi, Minoru Matsuura, Takuya Yoshino, Hiroki Ikeuchi, Kenji Kawada, Yoshiharu Sakai, Mina T Kitazume, Tadakazu Hisamatsu, Tsutomu Chiba, Ryuta Nishikomori, Toshio Heike

Inflammatory bowel diseases ( LIPPINCOTT WILLIAMS & WILKINS ) 21 ( 7 ) 1529 - 40 2015.07 [Refereed] [International journal]

BACKGROUND: Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in the homeostasis of mucosal immunity; however, their role in inflammatory bowel disease (IBD) is unclear. METHODS: Flow cytometry was used to enumerate peripheral blood MAIT cells in 88 patients with ulcerative colitis (UC), 68 with Crohn's disease (CD), and in 57 healthy controls. Immunohistochemistry identified MAIT cells in intestinal tissue samples from patients with UC (n = 5) and CD (n = 10), and in control colon (n = 5) and small intestine (n = 9) samples. In addition, expression of activated caspases by MAIT cells in the peripheral blood of 14 patients with UC and 15 patients with CD, and 16 healthy controls was examined. RESULTS: Peripheral blood analysis revealed that patients with IBD had significantly fewer MAIT cells than healthy controls (P < 0.0001). The number of MAIT cells in the inflamed intestinal mucosae of patients with UC and CD was also lower than that in control mucosae (P = 0.0079 and 0.041, respectively). The number of activated caspase-expressing MAIT cells in the peripheral blood of patients with UC and CD was higher than that in healthy controls (P = 0.0061 and 0.0075, respectively), suggesting that the reduced MAIT cell numbers in IBD are associated with an increased level of apoptosis among these cells. CONCLUSIONS: The number of MAIT cells in the peripheral blood and inflamed mucosae of patients with UC and CD was lower than that in non-IBD controls. Also, MAIT cells from patients with IBD exhibited proapoptotic features. These data suggest the pathological involvement and the potential for therapeutic manipulation of these cells in patients with IBD.

DOI PubMed

Reduced Numbers and Proapoptotic Features of Mucosal-associated Invariant T Cells as a Characteristic Finding in Patients with Inflammatory Bowel Disease.

Inflamm. Bowel Dis. 21 ( 7 ) 1529 - 1540 2015.07 [Refereed]

Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in the homeostasis of mucosal immunity; however, their role in inflammatory bowel disease (IBD) is unclear.
Flow cytometry was used to enumerate peripheral blood MAIT cells in 88 patients with ulcerative colitis (UC), 68 with Crohn's disease (CD), and in 57 healthy controls. Immunohistochemistry identified MAIT cells in intestinal tissue samples from patients with UC (n = 5) and CD (n = 10), and in control colon (n = 5) and small intestine (n = 9) samples. In addition, expression of activated caspases by MAIT cells in the peripheral blood of 14 patients with UC and 15 patients with CD, and 16 healthy controls was examined.
Peripheral blood analysis revealed that patients with IBD had significantly fewer MAIT cells than healthy controls (P < 0.0001). The number of MAIT cells in the inflamed intestinal mucosae of patients with UC and CD was also lower than that in control mucosae (P = 0.0079 and 0.041, respectively). The number of activated caspase-expressing MAIT cells in the peripheral blood of patients with UC and CD was higher than that in healthy controls (P = 0.0061 and 0.0075, respectively), suggestin

DOI PubMed

Factors associated with treatment outcome, and long-term prognosis of patients with ulcerative colitis undergoing selective depletion of myeloid lineage leucocytes: a prospective multicenter study.

Yoko Yokoyama, Kenji Watanabe, Hiroaki Ito, Masakazu Nishishita, Koji Sawada, Yusuke Okuyama, Kazuichi Okazaki, Hisao Fujii, Hiroshi Nakase, Tsutomu Masuda, Ken Fukunaga, Akira Andoh, Shiro Nakamura

Cytotherapy ( ELSEVIER SCI LTD ) 17 ( 5 ) 680 - 8 2015.05 [Refereed] [International journal]

BACKGROUND: Patients with ulcerative colitis (UC) have elevated/activated myeloid lineage leucocytes and may respond favorably to adsorptive granulocyte/monocyte apheresis (GMA). However, there are patients who respond well to GMA, and patients who do not benefit. Therefore, predictive factors of GMA efficacy need to be defined. METHODS: In a prospective multicenter setting, 200 UC patients at 32 institutes received one GMA session per week over 10 weeks. Patients who achieved remission were followed for 12 months. The Clinical Activity Index (CAI) ≤3 meant remission, and response meant CAI decreased by ≥3. Quality of life was evaluated by the Inflammatory Bowel Disease Questionnaire (IBDQ). RESULTS: After final GMA, remission, response and no response rates were 67.0%, 15.0% and 18%, respectively. The remission group had a significant decrease in myeloid leucocytes and platelets. Corticosteroid dose decreased (P < 0.001); 49 of 97 patients on corticosteroids became steroid-free. Baseline CAI was lower in the remission group versus non-remission (P < 0.01), whereas IBDQ was higher in the remission group versus non-remission (P < 0.05). After 12 months, 52 of 134 patients had maintained remission. Disease duration was longer in the relapsed group versus maintained remission group (P = 0.041). Male gender, first UC episode and corticosteroid responder were significant factors for maintaining remission, whereas corticosteroid dependent UC was associating with relapse. DISCUSSION: Selective myeloid leucocyte depletion was effective for remission induction and improving patients' quality of life. Baseline demographics such as disease activity level, duration and corticosteroid dependency appear to predict response to GMA. Additionally, patients with a first UC episode who were drug naive responded well to GMA and achieved a favorable long-term disease course by avoiding pharmacologics from an early stage of their inflammatory bowel disease. These findings should help to end unnecessary use of medical resources by targeting GMA to patients who may respond well.

DOI PubMed

Usefulness of Adalimumab for Treating a Case of Intestinal Behçet's Disease With Trisomy 8 Myelodysplastic Syndrome.

Masamichi Kimura, Yoshihisa Tsuji, Masako Iwai, Masahiro Inagaki, Ali Madian, Takuya Yoshino, Minoru Matsuura, Hiroshi Nakase

Intestinal research 13 ( 2 ) 166 - 9 2015.04 [Refereed] [International journal]

Behçet's disease (BD) is a systemic vasculitis, while myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematologic disorders characterized by ineffective hematopoiesis. Some studies suggest a relationship between MDS and BD, especially intestinal BD, and trisomy 8 seems to play an important role in both diseases. There are several reports on patients with BD comorbid with MDS involving trisomy 8 that frequently have intestinal lesions refractory to conventional medical therapies. Tumor necrosis factor (TNF)-α is strongly involved in the pathophysiology of several autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and BD. In addition, TNF-α plays an important role in the pathophysiology of MDS by inhibiting normal hematopoiesis and inducing the programmed cell death of normal total bone marrow cells and normal CD34+ cells. Recent clinical reports demonstrate the favorable effect of TNF-α antagonists in patients with refractory intestinal BD and in those with MDS. We present the case of a patient with intestinal BD and MDS involving trisomy 8 who was successfully treated with adalimumab.

DOI PubMed

Autocrine pathways involving S100A8 and/or S100A9 that are postulated to regulate the immunological functions of macrophages in rats.

Kohki Okada, Satoshi Arai, Hiroshi Nakase, Hisashi Kohno, Fumihiko Nakamura, Mayu Takeda, Yoshinobu Toda, Hiroshi Itoh, Souichi Adachi, Masaki Ikemoto

Biochemical and biophysical research communications ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 456 ( 1 ) 415 - 20 2015.01 [Refereed] [International journal]

The development of ulcerative colitis (UC) is closely associated with abnormally functioning macrophages. Rat S100A8 (r-S100A8) and r-S100A9 (S100 proteins) is abundantly expressed in immune cells of myeloid origin, macrophages; however, it remains unclear why r-S100A9 is dominantly expressed in the macrophages of UC rats (UCR). The purpose of this study was to verify the immunological roles of S100 proteins in UCR. We observed the distribution of S100 protein-positive macrophages in the large colons of UCR using a fluorescent immunological staining method, so that S100 protein-positive macrophages were restricted to the rectal tissues of the UCR, and that the mRNA levels of r-S100A8 and r-S100A9 were up-regulated by stimulation with recombinant rat S100A8 (rr-S100A8) alone and rr-S100A9 alone, respectively. When the changes in the mRNA levels of r-S100A8 and r-S100A9 in macrophages were examined in in vitro study by PCR and real-time PCR, the mRNA levels of anti-inflammatory and inflammatory cytokines increased selectively after stimulation with rr-S100A8 alone and rr-S100A9 alone, respectively. These results suggest that autocrine signal transduction pathways involving S100 proteins regulate the immunological functions of macrophages to maintain homeostasis in the gastrointestinal tract. This may be depended on expression balance of S100 proteins in macrophages. It is strongly suggested that in UCR the immune functions of macrophages are regulated in a complex manner by r-S100A8 and/or r-S100A9 through undefined autocrine pathways on the cells.

DOI PubMed

Osteopontin Deficiency Accelerates Spontaneous Colitis in Mice with Disrupted Gut Microbiota and Macrophage Phagocytic Activity.

Takahiko Toyonaga, Hiroshi Nakase, Satoru Ueno, Minoru Matsuura, Takuya Yoshino, Yusuke Honzawa, Ayako Itou, Kazuyoshi Namba, Naoki Minami, Satoshi Yamada, Yorimitsu Koshikawa, Toshimitsu Uede, Tsutomu Chiba, Kazuichi Okazaki

PloS one 10 ( 8 ) e0135552 2015 [Refereed] [International journal]

BACKGROUND: Osteopontin (OPN) is a multifunctional protein expressed in a variety of tissues and cells. Recent studies revealed increased OPN expression in the inflamed intestinal tissues of patients with inflammatory bowel disease (IBD). The role of OPN in the pathophysiology of IBD, however, remains unclear. AIMS: To investigate the role of OPN in the development of intestinal inflammation using a murine model of IBD, interleukin-10 knock out (IL-10 KO) mice. METHODS: We compared the development of colitis between IL-10 KO and OPN/IL-10 double KO (DKO) mice. OPN expression in the colonic tissues of IL-10 KO mice was examined by fluorescence in situ hybridization (FISH) analysis. Enteric microbiota were compared between IL-10 KO and OPN/IL-10 DKO mice by terminal restriction fragment length polymorphism analysis. The effect of OPN on macrophage phagocytic function was evaluated by phagocytosis assay. RESULTS: OPN/IL-10 DKO mice had an accelerated onset of colitis compared to IL-10 KO mice. FISH analysis revealed enhanced OPN synthesis in the colonic epithelial cells of IL-10 KO mice. OPN/IL-10 DKO mice had a distinctly different enteric bacterial profile with a significantly lower abundance of Clostridium subcluster XIVa and a greater abundance of Clostridium cluster XVIII compared to IL-10 KO mice. Intracellular OPN deletion in macrophages impaired phagocytosis of fluorescence particle-conjugated Escherichia coli in vitro. Exogenous OPN enhanced phagocytosis by OPN-deleted macrophages when administered at doses of 1 to 100 ng/ml, but not 1000 ng/ml. CONCLUSIONS: OPN deficiency accelerated the spontaneous development of colitis in mice with disrupted gut microbiota and macrophage phagocytic activity.

DOI PubMed

Tacrolimus or infliximab for severe ulcerative colitis: short-term and long-term data from a retrospective observational study.

Naoki Minami, Takuya Yoshino, Minoru Matsuura, Yorimitsu Koshikawa, Satoshi Yamada, Takahiko Toyonaga, Ali Madian, Yusuke Honzawa, Hiroshi Nakase

BMJ open gastroenterology 2 ( 1 ) e000021 2015 [Refereed] [International journal]

OBJECTIVE: Treatment of severe ulcerative colitis (UC) is challenging. Although the efficacy of tacrolimus (TAC) and infliximab (IFX) have been evaluated in patients with severe UC, the safety and efficacy levels of sequential therapies (TAC→IFX/IFX→TAC) in these patients remain unclear. The aim of this study was to assess short-term and long-term outcomes in patients with severe UC treated with TAC and IFX. METHODS: From October 2001 to February 2014, 29 patients with consecutive severe UC treated with TAC or IFX were retrospectively evaluated. Median follow-up duration was 27 months (range 0.5-118 months). The primary end point was short-term outcomes at 8 weeks after induction of TAC (TAC group, n=22) or IFX (IFX group, n=7). The secondary end point included long-term outcomes and colectomy-free survival. The clinical response was evaluated based on a partial Mayo score. RESULTS: The clinical remission (CR) rate at 8 weeks in the TAC and IFX groups was 63.6% and 71.4%, respectively. In 13 of the 29 patients (10 in the TAC group, 3 in the IFX group), sequential therapies were used in their clinical courses. In 9 of these 13 patients (6 in the TAC group, 3 in the IFX group), CR was achieved and maintained by sequential therapies. Overall cumulative colectomy-free survival was 79.3% at 118 months. CONCLUSIONS: TAC and IFX had similar effects on remission induction in patients with severely active UC. Sequential therapies could rescue patients with UC who failed initial treatment with TAC or IFX. In clinical practice, sequential therapies might be deliberately performed.

DOI PubMed

Involvement of interleukin-17A-induced expression of heat shock protein 47 in intestinal fibrosis in Crohn's disease.

Yusuke Honzawa, Hiroshi Nakase, Masahiro Shiokawa, Takuya Yoshino, Hirotsugu Imaeda, Minoru Matsuura, Yuzo Kodama, Hiroki Ikeuchi, Akira Andoh, Yoshiharu Sakai, Kazuhiro Nagata, Tsutomu Chiba

Gut ( BMJ PUBLISHING GROUP ) 63 ( 12 ) 1902 - 12 2014.12 [Refereed] [International journal]

OBJECTIVE: Intestinal fibrosis is a clinically important issue in Crohn's disease (CD). Heat shock protein (HSP) 47 is a collagen-specific molecular chaperone involved in fibrotic diseases. The molecular mechanisms of HSP47 induction in intestinal fibrosis related to CD, however, remain unclear. Here we investigated the role of interleukin (IL)-17A-induced HSP47 expression in intestinal fibrosis in CD. DESIGN: Expressions of HSP47 and IL-17A in the intestinal tissues of patients with IBD were determined. HSP47 and collagen I expressions were assessed in intestinal subepithelial myofibroblasts (ISEMFs) isolated from patients with IBD and CCD-18Co cells treated with IL-17A. We examined the role of HSP47 in IL-17A-induced collagen I expression by administration of short hairpin RNA (shRNA) to HSP47 and investigated signalling pathways of IL-17A-induced HSP47 expression using specific inhibitors in CCD-18Co cells. RESULTS: Gene expressions of HSP47 and IL-17A were significantly elevated in the intestinal tissues of patients with active CD. Immunohistochemistry revealed HSP47 was expressed in α-smooth muscle actin (α-SMA)-positive cells and the number of HSP47-positive cells was significantly increased in the intestinal tissues of patients with active CD. IL-17A enhanced HSP47 and collagen I expressions in ISEMFs and CCD-18Co cells. Knockdown of HSP47 in these cells resulted in the inhibition of IL-17A-induced collagen I expression, and analysis of IL-17A signalling pathways revealed the involvement of c-Jun N-terminal kinase in IL-17A-induced HSP47 expression. CONCLUSIONS: IL-17A-induced HSP47 expression is involved in collagen I expression in ISEMFs, which might contribute to intestinal fibrosis in CD.

DOI PubMed

A randomized clinical trial of mesalazine suppository: The usefulness and problems of central review of evaluations of colonic mucosal findings.

Kiyonori Kobayashi, Fumihito Hirai, Makoto Naganuma, Kenji Watanabe, Takafumi Ando, Hiroshi Nakase, Katsuyoshi Matsuoka, Mamoru Watanabe

J Crohns Colitis 8 ( 11 ) 1444 - 1453 2014.11 [Refereed]

DOI PubMed

A randomized clinical trial of mesalazine suppository: the usefulness and problems of central review of evaluations of colonic mucosal findings.

Kiyonori Kobayashi, Fumihito Hirai, Makoto Naganuma, Kenji Watanabe, Takafumi Ando, Hiroshi Nakase, Katsuyoshi Matsuoka, Mamoru Watanabe

Journal of Crohn's & colitis ( ELSEVIER SCIENCE BV ) 8 ( 11 ) 1444 - 53 2014.11 [Refereed] [International journal]

BACKGROUND: The methods of evaluating endoscopic mucosal findings and the definition of mucosal healing in inflammatory bowel disease have not been standardized. AIM: To examine a third-party central review of colonic mucosal evaluations. METHODS: A double-blind, placebo-controlled, parallel-group trial was performed for 4weeks, which involved continuous administration of a 1-g mesalazine suppository to 129 patients with mild to moderate ulcerative colitis and active rectal inflammatory findings. Mucosal findings were evaluated by using a 4-grade score (0, 1, 2, 3). Reviews by attending physicians were considered the primary evaluations. Concurrently, a central review committee of 7 gastroenterologists served as the third party. RESULTS: The endoscopic remission induction rate from the attending physicians' evaluations was 82.8% in the mesalazine suppository group and 31.1% in the placebo suppository group, whereas the respective rates from the central review committee were 90.6% and 59.0%. However, there was a difference of 27.9 percentage points between the remission induction rates of the placebo group found by the two groups of raters. Differences in the evaluations of mucosal finding scores were also found among the third-party reviewers. CONCLUSIONS: The evaluations of the attending physicians were consistent with those of the central review committee in showing the effectiveness of mesalazine suppository through the index of mucosal healing. However, differences were observed among the raters in their evaluations of mucosal finding scores. Therefore, standardizing evaluation criteria and improving review methods for mucosal findings would enable the more effective use of third-party central reviews in clinical drug trials.

DOI PubMed

Role in calcineurin inhibitors for inflammatory bowel disease in the biologics era: when and how to use.

Hiroshi Nakase, Takuya Yoshino, Minoru Matsuura

Inflammatory bowel diseases ( LIPPINCOTT WILLIAMS & WILKINS ) 20 ( 11 ) 2151 - 6 2014.11 [Refereed] [International journal]

Ulcerative colitis and Crohn's disease, which is the 2 major forms of inflammatory bowel disease, are chronic relapsing and remitting inflammatory disorder of the gastrointestinal tract. During the last 30 years, the therapy for patients with refractory inflammatory bowel diseases is still challenging despite the fact that morbidity and mortality rates have been obviously reduced. The conventional management with corticosteroids has been modified by the introduction of calcineurin inhibitors and biologics. In this review, we focus on role in calcineurin inhibitors for patients with inflammatory bowel disease in the currently clinical practice.

DOI PubMed

感染性腸炎の診断と治療潰瘍性大腸炎に合併するサイトメガロウイルス再活性化症例の予後の検討

長沼誠, 仲瀬裕志, 鈴木康夫

日本大腸肛門病学会雑誌 ( (一社)日本大腸肛門病学会 ) 67 ( 9 ) 605 - 605 2014.09

Education and Imaging. Gastroenterology: mesenteric lymphoma with chylous ascites.

Soichi Arasawa, Hiroshi Nakase, Naoki Minami

Journal of gastroenterology and hepatology ( WILEY-BLACKWELL ) 29 ( 8 ) 1570 - 1570 2014.08 [Refereed] [International journal]

DOI PubMed

Therapeutic effect of intensive granulocyte and monocyte adsorption apheresis combined with thiopurines for steroid- and biologics-naïve Japanese patients with early-diagnosed Crohn's disease.

Takumi Fukuchi, Hiroshi Nakase, Satoshi Ubukata, Minoru Matsuura, Takuya Yoshino, Takahiko Toyonaga, Keiji Shimazu, Hideaki Koga, Hiroshi Yamashita, Dai Ito, Kiyoshi Ashida

BMC gastroenterology ( BIOMED CENTRAL LTD ) 13 124 - 124 2014.07 [Refereed] [International journal]

BACKGROUND: Early induction with biologics can reduce complications in patients with Crohn's disease (CD) and improve their quality of life. The safety of biologics, however, is uncertain. Granulocyte and monocyte adsorptive apheresis (GMAA) is a natural biologic therapy that selectively removes granulocytes and monocytes/macrophages and has few severe adverse effects. The effects of GMAA on patients with early-diagnosed CD are unclear. We investigated the effects of GMAA combined with thiopurines on patients with early-diagnosed CD. METHODS: Twenty-two corticosteroid- and biologic-naïve patients with active early-diagnosed CD were treated with intensive GMAA (twice per week) combined with thiopurines administration. Active early-diagnosed CD was defined as follows: (i) within 2years after diagnosis of CD, (ii) with no history of both surgical treatment and endoscopic dilation therapy, and (iii) Crohn's Disease Activity Index (CDAI) was higher than 200. We investigated the ratios of clinical remission defined as CDAI was less than or equal to 150 at 2, 4, 6 and 52weeks and mucosal healing defined as a Simplified Endoscopic Activity Score for Crohn's Disease (SES-CD) as 0 at 6 and 52weeks. Adverse events were recorded at each visit. RESULTS: The ratios of clinical remission at 2, 4, and 6 weeks were 6 of 22 (27.2%), 12 of 22 (54.5%), and 17 of 22 (77.2%), respectively. At 52 weeks, 18 of 21 patients (81.8%) were in clinical remission. The ratios of mucosal healing at 6 and 52 weeks were 5 of 22 (22.7%) and 11 of 22 (50%), respectively. The difference in the mucosal healing ratio was significant between 6 and 52 weeks (p = 0.044). No serious adverse effects were observed during this study. CONCLUSIONS: Combination therapy with intensive GMAA and thiopurines administration rapidly induced high remission in patients with active early-diagnosed CD without serious adverse effect. Mucosal healing was observed in 50.0% of enrolled patients. This combination therapy might be a rational option for patients with early-diagnosed CD.

DOI PubMed

Pulmonary Mycobacterium avium Infection in a Patient with Crohn's Disease under Azathioprine Treatment.

Tomonori Hirano, Minoru Matsuura, Hiroshi Nakase

Case reports in gastroenterology 8 ( 2 ) 182 - 5 2014.05 [Refereed] [International journal]

Anti-tumor necrosis factor alpha therapy is known as a risk factor of non-tuberculous mycobacteria (NTM) infection. However, there are few reports of NTM infection under treatment with thiopurine agents. We herein report a first case of pulmonary infection caused by Mycobacterium avium complex (MAC) in a patient with Crohn's disease under treatment with thiopurine. After starting antibiotics therapy for NTM including clarithromycin, rifampicin, ethambutol and streptomycin, MAC infection was well controlled, and she kept clinical remission even without azathioprine. In conclusion, our case emphasizes the importance of considering NTM infection in respiratory complications of inflammatory bowel disease patients under immunosuppressive therapies.

DOI PubMed

Long-term efficacy of infliximab for refractory ulcerative colitis: results from a single center experience.

Satoshi Yamada, Takuya Yoshino, Minoru Matsuura, Naoki Minami, Takahiko Toyonaga, Yusuke Honzawa, Yoshihisa Tsuji, Hiroshi Nakase

BMC gastroenterology ( BIOMED CENTRAL LTD ) 14 80 - 80 2014.04 [Refereed] [International journal]

BACKGROUND: The long-term efficacy of infliximab (IFX) for patients with refractory ulcerative colitis (UC) is unclear. The aim of this study was to assess the long-term outcomes of IFX treatment in patients with refractory UC. METHODS: Thirty-three patients with refractory UC who received IFX treatment at Kyoto University Hospital between 2003 and 2013 were retrospectively evaluated. IFX intensification was defined as a dose escalation (up to 10 mg/kg) and/or shorter intervals between infusions (every 4-6 weeks). RESULTS: Of the 33 patients who received scheduled infusions of IFX, 24 (72.7%) achieved clinical remission within 8 weeks after initiating IFX treatment. Of these 24 responders, 17 (70.8%) experienced a relapse of UC and required IFX intensification, and 16 (66.7%) eventually maintained clinical remission with IFX treatment, including IFX intensification. Of the 33 patients, 6 (18.2%) underwent colectomy during IFX treatment. Multivariate regression analysis showed that a serum C-reactive protein (CRP) concentration <5 mg/L two weeks after starting IFX was a predictor of a positive clinical response to IFX induction therapy. No severe adverse events occurred in UC patients treated with IFX. CONCLUSION: IFX intensification was necessary for long-term maintenance of remission and to prevent colectomy in patients with refractory UC.

DOI PubMed

Unique endoscopic findings of colitis-associated colorectal cancer in a patient with ulcerative colitis and Lynch syndrome.

Naoki Minami, Takuya Yoshino, Hiroshi Nakase

Journal of Crohn's & colitis ( ELSEVIER SCIENCE BV ) 8 ( 4 ) 336 - 7 2014.04 [Refereed] [International journal]

DOI PubMed

Efficacy and safety of granulocyte and monocyte adsorption apheresis for ulcerative colitis: a meta-analysis.

Takuya Yoshino, Hiroshi Nakase, Naoki Minami, Satoshi Yamada, Minoru Matsuura, Shujiro Yazumi, Tsutomu Chiba

Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver ( ELSEVIER SCIENCE INC ) 46 ( 3 ) 219 - 26 2014.03 [Refereed] [International journal]

BACKGROUND: Safe and effective treatments are required for patients with ulcerative colitis. It was suggested that granulocyte and monocyte adsorption apheresis might play an important role for ulcerative colitis. Therefore, a meta-analysis was performed. METHODS: Medline and the Cochrane controlled trials register were used to identify randomized controlled trials comparing granulocyte and monocyte adsorption apheresis with corticosteroids, and comparing intensive with conventional apheresis in patients with ulcerative colitis. RESULTS: Nine randomized trials were eligible for inclusion criteria. According to pooled data, granulocyte and monocyte adsorption apheresis is effective for inducing clinical remission in patients with ulcerative colitis compared with corticosteroids (odds ratio, 2.23; 95% confidence interval: 1.38-3.60). However, the efficacy of granulocyte and monocyte adsorption apheresis was not dependent on the number of apheresis sessions. The intensive apheresis (≥2 sessions per week) is more effective for inducing clinical remission than weekly apheresis (odds ratio, 2.10; 95% confidence interval: 1.12-3.93). The rate of adverse events by apheresis was significantly lower than that by corticosteroids (odds ratio, 0.24; 95% confidence interval: 0.15-0.37). CONCLUSION: Our meta-analysis reveals that intensive granulocyte and monocyte adsorption apheresis is a safe and effective treatment with higher rates of clinical remission and response for ulcerative colitis compared with corticosteroids.

DOI PubMed

Diagnosis and treatment of ulcerative colitis with cytomegalovirus infection: importance of controlling mucosal inflammation to prevent cytomegalovirus reactivation.

Hiroshi Nakase, Yusuke Honzawa, Takahiko Toyonaga, Satoshi Yamada, Naoki Minami, Takuya Yoshino, Minoru Matsuura

Intestinal research 12 ( 1 ) 5 - 11 2014.01 [Refereed] [International journal]

Human cytomegalovirus (HCMV) is a member of the herpesvirus family. HCMV infection persists throughout the host lifespan in a latent state following primary infection. The ability of HCMV to escape control by the host immune system and its resulting reactivation suggests the importance of ongoing immune surveillance in the prevention of HCMV reactivation. HCMV is a common cause of opportunistic infection that causes severe and fatal disease in immune-compromised individuals. In inflammatory bowel disease patients, particularly those with ulcerative colitis (UC), HCMV is often reactivated because these patients are frequently treated with immunosuppressive agents. This reactivation exacerbates colitis. Additionally, HCMV infection can induce severe colitis, even in patients with UC who have never been treated with immunosuppressive agents. However, the role of HCMV in colonic inflammation in patients with UC remains unclear. Here, we present previous and current clinical data on the diagnosis and treatment of HCMV infection in UC. Additionally, our experimental data from a newly established mouse model mimicking UC with concomitant CMV infection clearly demonstrate that inflammation could result in the exacerbation of UC disease activity with induction of HCMV reactivation. In summary, optimal control of colonic inflammation should be achieved in UC patients who are refractory to conventional immunosuppressive therapies and are positive for HCMV.

DOI PubMed

Use of capsule endoscopy in patients with Crohn's disease in Japan: A multicenter survey

Motohiro Esaki, Takayuki Matsumoto, Kenji Watanabe, Tetsuo Arakawa, Yuji Naito, Minoru Matsuura, Hiroshi Nakase, Toshifumi Hibi, Takayuki Matsumoto, Sadaharu Nouda, Kazuhide Higuchi, Naoki Ohmiya, Hidemi Goto, Sei Kurokawa, Satoshi Motoya, Mamoru Watanabe

Journal of Gastroenterology and Hepatology (Australia) 29 ( 1 ) 96 - 101 2014.01 [Refereed]

Background and Aim: Until the approval of patency capsule, capsule endoscopy (CE) has not been routinely applied for the diagnosis of Crohn's disease (CD) in Japan. We aimed to survey current situation of CE use for patients with CD in Japan. Methods: The nationwide survey of 40 Japanese institutions identified 94 patients with established CD (eCD) and 80 patients with suspected CD (sCD), who were examined by CE. Types and positive rates of mucosal injury under CE and capsule retention rate were investigated. In sCD, final diagnosis after CE was also analyzed. Results: Patients with eCD comprised 82 patients of ileitis or ileocolitis type, while 12 patients had CD of colitis type. CE identified mucosal injuries in 83 of 94 patients. Eight of 12 patients with eCD of colitis type had ileal lesions under CE, thereby being reclassified as ileocolitis type. In patients with sCD, CE detected mucosal injuries in 58 patients. Linear ulceration and cobblestone appearance were depicted in 22 and 3 patients, respectively, thereby resulting in established diagnosis of CD in 23 patients. Mucosal lesion was not found in 22 patients with sCD, who were diagnosed as not having CD. Capsule retention rate was not statistically different between patients with eCD and those with sCD (7.4% vs 6.3%, P=1.0). Conclusions: CE is useful for the evaluation of small bowel mucosal injuries in Japanese patients with sCD and eCD. Possible intestinal stricture needs to be carefully evaluated before CE even in patients with sCD. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

DOI PubMed

Use of capsule endoscopy in patients with Crohn's disease in Japan: a multicenter survey.

Journal of gastroenterology and hepatology ( WILEY-BLACKWELL ) 29 ( 1 ) 96 - 101 2014.01 [Refereed] [International journal]

BACKGROUND AND AIM: Until the approval of patency capsule, capsule endoscopy (CE) has not been routinely applied for the diagnosis of Crohn's disease (CD) in Japan. We aimed to survey current situation of CE use for patients with CD in Japan. METHODS: The nationwide survey of 40 Japanese institutions identified 94 patients with established CD (eCD) and 80 patients with suspected CD (sCD), who were examined by CE. Types and positive rates of mucosal injury under CE and capsule retention rate were investigated. In sCD, final diagnosis after CE was also analyzed. RESULTS: Patients with eCD comprised 82 patients of ileitis or ileocolitis type, while 12 patients had CD of colitis type. CE identified mucosal injuries in 83 of 94 patients. Eight of 12 patients with eCD of colitis type had ileal lesions under CE, thereby being reclassified as ileocolitis type. In patients with sCD, CE detected mucosal injuries in 58 patients. Linear ulceration and cobblestone appearance were depicted in 22 and 3 patients, respectively, thereby resulting in established diagnosis of CD in 23 patients. Mucosal lesion was not found in 22 patients with sCD, who were diagnosed as not having CD. Capsule retention rate was not statistically different between patients with eCD and those with sCD (7.4% vs 6.3%, P = 1.0). CONCLUSIONS: CE is useful for the evaluation of small bowel mucosal injuries in Japanese patients with sCD and eCD. Possible intestinal stricture needs to be carefully evaluated before CE even in patients with sCD.

DOI PubMed

Development and function of cortical thymic epithelial cells.

Kensuke Takada, Izumi Ohigashi, Michiyuki Kasai, Hiroshi Nakase, Yousuke Takahama

Current topics in microbiology and immunology 373 1 - 17 2014 [Refereed] [International journal]

The thymic cortex provides a microenvironment that supports the generation and T cell antigen receptor (TCR)-mediated selection of CD4(+)CD8(+)TCRαβ(+) thymocytes. Cortical thymic epithelial cells (cTECs) are the essential component that forms the architecture of the thymic cortex and induces the generation as well as the selection of newly generated T cells. Here we summarize current knowledge on the development, function, and heterogeneity of cTECs, focusing on the expression and function of β5t, a cTEC-specific subunit of the thymoproteasome.

DOI PubMed

Bifid tail of the pancreas with localized acute pancreatitis.

Sho Koyasu, Hiroyoshi Isoda, Hiroshi Nakase, Yuzo Kodama, Tsutomu Chiba, Kaori Togashi

Magnetic resonance in medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine ( JPN SOC MAGNETIC RESONANCE IN MEDICINE ) 12 ( 4 ) 315 - 8 2013.12 [Refereed] [Domestic journal]

Bifid tail of the pancreas is an extremely rare developmental anomaly, and its clinical importance is not well known. We report the case of a 28-year-old man with acute pancreatitis limited to one side of a bifid tail with no otherwise detectable parenchymal edema on magnetic resonance (MR) imaging. Neither was there evidence of other anatomical ductal abnormalities that could have contributed to the patient's pancreatitis. To the best of our knowledge, this is the first report to suggest that bifid tail of the pancreas might cause acute pancreatitis.

DOI PubMed

Tacrolimus therapy for patients with ulcerative colitis

Hiroshi Nakase

Journal of Japanese Society of Gastroenterology 110 ( 11 ) 1916 - 1921 2013.11 [Refereed]

DOI PubMed

Effect of intensive granulocyte and monocyte adsorptive apheresis in patients with ulcerative colitis positive for cytomegalovirus.

Takumi Fukuchi, Hiroshi Nakase, Minoru Matsuura, Takuya Yoshino, Takahiko Toyonaga, Katsuyuki Ohmori, Satoshi Ubukata, Aya Ueda, Takaaki Eguchi, Hiroshi Yamashita, Dai Ito, Kiyoshi Ashida

Journal of Crohn's & colitis ( ELSEVIER SCIENCE BV ) 7 ( 10 ) 803 - 11 2013.11 [Refereed] [International journal]

BACKGROUND AND AIM: Cytomegalovirus (CMV) exacerbates ulcerative colitis (UC) refractory to immunosuppressive therapies. The conditions under which CMV reactivation occurs in patients with UC, however, is unclear. In addition, the diagnostic and treatment strategies for UC positive for CMV have not been established. Granulocyte and monocyte adsorptive apheresis (GMAA) is natural biological therapy for UC in which the granulocytes/macrophages producing inflammatory cytokines are removed. We investigated the rate of colonic CMV reactivation and the efficacy of GMAA in active UC patients positive for CMV without concomitant corticosteroid (CS) therapy. METHODS: Fifty-one active UC patients without concomitant CS therapy were enrolled. Colonic CMV reactivation was examined by real-time polymerase chain reaction (PCR) using biopsy specimen and/or histological examination. All patients were treated with intensive GMAA (twice per week). Rates of clinical remission and mucosal healing were compared between UC patients positive and negative for CMV. RESULTS: Of 51 patients, 15 (29.4%) were diagnosed as CMV positive. The clinical remission rates following intensive GMAA did not differ between UC patients positive and negative for CMV (73.3% vs 69.4%, p=0.781). Proportion of patients achieving mucosal healing was also similar between these two groups. CMV-DNA became negative in all UC patients positive for CMV who achieved clinical remission 1 week after completion of intensive GMAA. CONCLUSIONS: Intestinal inflammation might trigger CMV reactivation in a subpopulation of active UC patients without CS treatment. GMAA could be a promising option for active UC positive for CMV.

DOI PubMed CiNii

Human CD1c⁺ myeloid dendritic cells acquire a high level of retinoic acid-producing capacity in response to vitamin D₃.

Takayuki Sato, Toshio Kitawaki, Haruyuki Fujita, Makoto Iwata, Tomonori Iyoda, Kayo Inaba, Toshiaki Ohteki, Suguru Hasegawa, Kenji Kawada, Yoshiharu Sakai, Hiroki Ikeuchi, Hiroshi Nakase, Akira Niwa, Akifumi Takaori-Kondo, Norimitsu Kadowaki

Journal of immunology (Baltimore, Md. : 1950) 191 ( 6 ) 3152 - 60 2013.09 [Refereed] [International journal]

All-trans-retinoic acid (RA) plays a critical role in maintaining immune homeostasis. Mouse intestinal CD103⁺ dendritic cells (DCs) produce a high level of RA by highly expressing retinal dehydrogenase (RALDH)2, an enzyme that converts retinal to RA, and induce gut-homing T cells. However, it has not been identified which subset of human DCs produce a high level of RA. In this study, we show that CD1c⁺ blood myeloid DCs (mDCs) but not CD141(high) mDCs or plasmacytoid DCs exhibited a high level of RALDH2 mRNA and aldehyde dehydrogenase (ALDH) activity in an RA- and p38-dependent manner when stimulated with 1α,25-dihydroxyvitamin D₃ (VD₃) in the presence of GM-CSF. The ALDH activity was abrogated by TLR ligands or TNF. CD103⁻ rather than CD103⁺ human mesenteric lymph node mDCs gained ALDH activity in response to VD₃. Furthermore, unlike in humans, mouse conventional DCs in the spleen and mesenteric lymph nodes gained ALDH activity in response to GM-CSF alone. RALDH2(high) CD1c⁺ mDCs stimulated naive CD4⁺ T cells to express gut-homing molecules and to produce Th2 cytokines in an RA-dependent manner. This study suggests that CD1c⁺ mDCs are a major human DC subset that produces RA in response to VD₃ in the steady state. The "vitamin D-CD1c⁺mDC-RA" axis may constitute an important immune component for maintaining tissue homeostasis in humans.

DOI PubMed

Prior use of immunomodulatory drugs improves the clinical outcome of endoscopic balloon dilation for intestinal stricture in patients with Crohn's disease.

Yusuke Honzawa, Hiroshi Nakase, Minoru Matsuura, Hirokazu Higuchi, Takahiko Toyonaga, Kayoko Matsumura, Takuya Yoshino, Kazuichi Okazaki, Tsutomu Chiba

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society ( WILEY-BLACKWELL ) 25 ( 5 ) 535 - 43 2013.09 [Refereed] [International journal]

BACKGROUND: Endoscopic balloon dilation is a promising procedure to improve symptoms of intestinal stricture in patients with Crohn's disease (CD). However, the long-term efficacy of endoscopic balloon dilation combined with immunomodulatory drugs remains unclear. The aim of the present study is to investigate whether prior use of immunomodulatory drugs affects the clinical outcome of endoscopic balloon dilation for intestinal stricture in CD. PATIENTS AND METHODS: Between January 2004 and December 2011, 83 dilations were carried out in 25 patients with CD. Median follow-up period was 46 months. Patients were categorized into two groups based on their medications at the first endoscopic balloon dilation: early immunomodulatory drug-induction group (early IM-induction group) in which patients were already treated with immunomodulatory drugs before the dilation; and post-immunomodulatory drug-induction group (post-IM-induction group) in which patients were not yet treated withimmunomodulatory drugs before dilation. We compared the long-term cumulative non-surgical rate and the mean number of dilation procedures per patient between early and post-IM-induction groups to clarify the influence of prior use of immunomodulatory drugs on the clinical outcome of endoscopic balloon dilation. RESULTS: There was a significant difference in the mean number of dilation procedures per patient between the early IM-induction and post-IM-induction groups (P = 0.04), although no significant difference in the cumulative non-surgical rate was observed between the two groups (P = 0.14). CONCLUSION: Prior use of immunomodulatory drugs may improve the clinical outcome of endoscopic balloon dilation for intestinal stricture in CD.

DOI PubMed J-GLOBAL

Heparan sulfate on intestinal epithelial cells plays a critical role in intestinal crypt homeostasis via Wnt/β-catenin signaling.

Shuji Yamamoto, Hiroshi Nakase, Minoru Matsuura, Yusuke Honzawa, Kayoko Matsumura, Norimitsu Uza, Yu Yamaguchi, Emiko Mizoguchi, Tsutomu Chiba

American journal of physiology. Gastrointestinal and liver physiology 305 ( 3 ) G241-9 2013.08 [Refereed] [International journal]

Heparan sulfate (HS), a constituent of HS proteoglycans (HSPGs), is a linear polysaccharide present on the cell surface. HSPGs modulate functions of several growth factors and signaling molecules. We examined whether small intestinal epithelial HS plays some roles in crypt homeostasis using intestinal epithelium cell (IEC)-specific HS-deficient C57Bl/6 mice. Survival rate after total body irradiation was significantly reduced in HS-deficient mice due to profound intestinal injury. HS-deficient IECs exhibited Wnt/β-catenin pathway disruption, decreased levels of β-catenin nuclear localization, and reduced expression of Wnt target genes, including Lgr5 during crypt regeneration. Moreover, epithelial HS increased Wnt binding affinity of IECs, promoted phosphorylation of Wnt coreceptor LRP6, and enhanced Wnt/β-catenin signaling following ex vivo stimulation with Wnt3a, whereas activation of canonical Wnt signaling following direct inhibition of glycogen synthase kinase-3β by lithium chloride was similar between HS-deficient and wild-type mice. Thus HS influences the binding affinity of IECs to Wnt, thereby promoting activation of canonical Wnt signaling and facilitating regeneration of small intestinal crypts after epithelial injury.

DOI PubMed

Establishment of a novel mouse model of ulcerative colitis with concomitant cytomegalovirus infection: in vivo identification of cytomegalovirus persistent infected cells.

Kayoko Matsumura, Hiroshi Nakase, Isao Kosugi, Yusuke Honzawa, Takuya Yoshino, Minoru Matsuura, Hideya Kawasaki, Yoshifumi Arai, Toshihide Iwashita, Takashi Nagasawa, Tsutomu Chiba

Inflammatory bowel diseases ( LIPPINCOTT WILLIAMS & WILKINS ) 19 ( 9 ) 1951 - 63 2013.08 [Refereed] [International journal]

BACKGROUND: Human cytomegalovirus (HCMV) infection is considered to be an exacerbating factor in patients with ulcerative colitis (UC). However, the pathogenicity of HCMV in the exacerbation of UC remains unclear. The lack of a model mimicking UC with HCMV infection has posed a challenge for research into the pathogenic mechanism of HCMV in flare of UC. Therefore, the aim of our study was to establish a new mouse model of UC with HCMV infection. METHODS: We established latent murine CMV (MCMV) infection in T-cell receptor α knockout (TCR-α KO) mice at an early age by adjustment of viral dose. Next, we performed immunohistochemical analysis in various organs of infected adult TCR-α KO mice to prove the correlation between MCMV infection and development of colitis. We then assessed colitis histologically and cytokine expression in the colon of infected and uninfected TCR-α KO mice. Finally, the types of MCMV-infected cells in the inflamed colon were examined by immunohistochemical analysis. RESULTS: MCMV antigen-positive cells reappeared predominantly in the inflamed colon of TCR-α KO mice. Severe colitis developed in the infected TCR-α KO mice compared with uninfected mice, and Th1/Th17 and Th2 responses were strongly induced. MCMV-infected cells were mainly perivascular stromal cells including pericytes, expressing platelet-derived growth factor receptor-beta (PDGFR-β) and CXC chemokine ligand 12 (CXCL12). CONCLUSIONS: In this study, we established, to our knowledge, the first mouse model of UC with HCMV infection. This model is an excellent tool for clarifying the detailed pathogenicity of HCMV in the exacerbation of UC and developing new treatment strategy for active UC with HCMV infection.

DOI PubMed

IL-7 produced by thymic epithelial cells plays a major role in the development of thymocytes and TCRγδ+ intraepithelial lymphocytes.

Soichiro Shitara, Takahiro Hara, Bingfei Liang, Keisuke Wagatsuma, Saulius Zuklys, Georg A Holländer, Hiroshi Nakase, Tsutomu Chiba, Shizue Tani-ichi, Koichi Ikuta

Journal of immunology (Baltimore, Md. : 1950) ( AMER ASSOC IMMUNOLOGISTS ) 190 ( 12 ) 6173 - 9 2013.06 [Refereed] [International journal]

IL-7 is a cytokine essential for T cell development and survival. However, the local function of IL-7 produced by thymic epithelial cells (TECs) is poorly understood. To address this question, we generated IL-7-floxed mice and crossed them with FoxN1 promoter-driven Cre (FoxN1-Cre) mice to establish knockout mice conditionally deficient for the expression of IL-7 by TECs. We found that αβ and γδ T cells were significantly reduced in the thymus of IL-7(f/f) FoxN1-Cre mice. Proportion of mature single-positive thymocytes was increased. In lymph nodes and the spleen, the numbers of T cells were partially restored in IL-7(f/f) FoxN1-Cre mice. In addition, γδ T cells were absent from the fetal thymus and epidermis of IL-7(f/f) FoxN1-Cre mice. Furthermore, TCRγδ(+) intraepithelial lymphocytes (IELs) were significantly decreased in the small intestines of IL-7(f/f) FoxN1-Cre mice. To evaluate the function of IL-7 produced in the intestine, we crossed the IL-7(f/f) mice with villin promoter-driven Cre (Vil-Cre) mice to obtain the mice deficient in IL-7 production from intestinal epithelial cells. We observed that αβ and γδ IELs of IL-7(f/f) Vil-Cre mice were comparable to control mice. Collectively, our results suggest that TEC-derived IL-7 plays a major role in proliferation, survival, and maturation of thymocytes and is indispensable for γδ T cell development. This study also demonstrates that IL-7 produced in the thymus is essential for the development of γδ IELs and indicates the thymic origin of γδ IELs.

DOI PubMed

Erratum: The challenge of acute rejection in intestinal transplantation (Pediatric Surgery International (2012) 28 (855-859) DOI: 10.1007/s00383-012- 3110-x)

E. Y. Yoshitoshi, A. Yoshizawa, E. Ogawa, M. Kaneshiro, N. Takada, S. Okamoto, Y. Fujimoto, S. Sakamoto, S. Masuda, M. Matsuura, H. Nakase, T. Chiba, T. Tsuruyama, H. Haga, S. Uemoto

Pediatric Surgery International 29 ( 6 ) 663 2013.06 [Refereed]

DOI

Effect of infliximab on inflammatory bowel disease with Takayasu arteritis: case series and review of the literature.

Naoki Minami, Hiroshi Nakase, Takuya Yoshino, Satoshi Yamada, Takahiko Toyonaga, Yusuke Honzawa, Minoru Matsuura, Tsutomu Chiba

Clinical journal of gastroenterology 6 ( 3 ) 226 - 30 2013.06 [Refereed] [Domestic journal]

Takayasu arteritis (TA) and inflammatory bowel disease (IBD) are chronic inflammatory disorders. The mechanisms underlying these diseases are not precisely known, but tumor necrosis factor alpha (TNF-α) is considered to have an important role in the pathophysiology of both TA and IBD. Simultaneous occurrence of both TA and IBD is rare. Our first case was a 42-year-old woman with TA and inflammatory bowel disease unclassified. The patient was refractory to treatment with an immunomodulator, and infliximab (IFX) was started. After starting IFX, clinical remission was achieved and maintained for 2 years. The second case was a 34-year-old woman with TA accompanied by Crohn's disease. Because her abdominal symptoms relapsed despite treatment with an immunomodulator, IFX was started. Both diseases were well controlled for 2 years by scheduled maintenance therapy with IFX. Relapse of the TA required increased doses of IFX at shorter intervals, which relieved her symptoms. Overall, we identified nine cases for which IFX was effective, including our 2 cases. They may demonstrate the efficacy of IFX for IBD with TA and emphasize the role of TNF-α in the pathophysiology.

DOI PubMed

Histology of intestinal allografts: lymphocyte apoptosis and phagocytosis of lymphocytic apoptotic bodies are diagnostic findings of acute rejection in addition to crypt apoptosis.

Tatsuaki Tsuruyama, Shinya Okamoto, Yasuhiro Fujimoto, Atsushi Yoshizawa, Elena Yoshitoshi, Hiroto Egawa, Hiroshi Nakase, Wulamujiang Aini, Masashi Miyao, Keiji Tamaki, Hirohiko Yamabe, Hironori Haga, Shinji Uemoto

The American journal of surgical pathology 37 ( 2 ) 178 - 84 2013.02 [Refereed] [International journal]

Acute rejection of a small-bowel transplant is often difficult to diagnose due to complicated immune responses. The present study aimed to elucidate the specific immune responses involved in intestinal transplant rejection. We correlated immunohistologic findings with an increase in crypt apoptosis, which has been commonly accepted as a criterion for the diagnosis of acute cellular rejection (ACR). Of 8 patients who received an intestinal allograft at Kyoto University Hospital, biopsy specimens from 7 patients were assessed immunohistologically with antibodies against 20 types of lymphocytic antigens including CD3, CD4, CD8, CD79a, CD20, IgG, and T-cell receptor, along with assessment of the patients' clinical courses. It was revealed that, in addition to apoptotic crypts, T-lymphocyte apoptosis and phagocytosis of apoptotic bodies in the lamina propria of villi were findings of ACR; both were observed in all cases. Immunostaining of the Fas ligand, one of the apoptosis-inducing molecules, was useful for the identification of the apoptotic bodies in the lamina propria of villi. Apoptotic body phagocytosis may be a surrogate diagnostic finding of grafts undergoing ACR.

DOI PubMed J-GLOBAL

Refractoriness of intestinal Behçet's disease with myelodysplastic syndrome involving trisomy 8 to medical therapies - our case experience and review of the literature.

Takahiko Toyonaga, Hiroshi Nakase, Minoru Matsuura, Naoki Minami, Satoshi Yamada, Yusuke Honzawa, Norimasa Hukata, Takuya Yoshino, Tsutomu Chiba, Kazuichi Okazaki

Digestion ( KARGER ) 88 ( 4 ) 217 - 21 2013 [Refereed] [International journal]

BACKGROUND/AIMS: Gastrointestinal lesions of Behçet's disease (BD) are often refractory to medical therapy and sometimes result in serious comorbidities such as gastrointestinal perforation and massive bleeding. There are several reports of patients with BD comorbid with myelodysplastic syndrome (MDS) involving trisomy 8 that frequently have intestinal lesions refractory to conventional medical therapy. Little is known about the efficacy of infliximab (IFX) for these intestinal lesions. METHODS: We present 2 cases of intestinal BD with MDS involving trisomy 8 who did not respond to IFX, and review previous reports of BD with MDS involving trisomy 8 concerning their responsiveness to conventional medical therapy. RESULTS: Among 31 previously reported cases that received medical treatment for BD, 19 (61.3%) showed temporary improvement of the BD symptoms, 9 (29.0%) deteriorated, and 3 (9.7%) showed no change. All of the 9 cases that showed deterioration had intestinal lesions. Our 2 cases failed to respond to IFX, resulting in a poor prognosis. CONCLUSIONS: IFX might not be effective for improving intestinal BD comorbid with MDS involving trisomy 8. Trisomy 8 is associated with the BD prognosis and refractoriness to conventional medical therapy.

DOI PubMed

Mediterranean mimicker.

Soichi Arasawa, Hiroshi Nakase, Yoshinao Ozaki, Norimitsu Uza, Minoru Matsuura, Tsutomu Chiba

Lancet (London, England) ( ELSEVIER SCIENCE INC ) 380 ( 9858 ) 2052 - 2052 2012.12 [Refereed] [International journal]

DOI PubMed

Gastric ulcer and gastroenteritis caused by Epstein-Barr virus during immunosuppressive therapy for a child with systemic juvenile idiopathic arthritis.

Eitaro Hiejima, Takahiro Yasumi, Hirohito Kubota, Katsuyuki Ohmori, Koichi Ohshima, Ryuta Nishikomori, Hiroshi Nakase, Tsutomu Chiba, Toshio Heike

Rheumatology (Oxford, England) ( OXFORD UNIV PRESS ) 51 ( 11 ) 2107 - 9 2012.11 [Refereed] [International journal]

DOI PubMed

Letter: mucosal PCR for cytomegalovirus in refractory ulcerative colitis

T. Yoshino, H. Nakase, M. Matsuura

ALIMENTARY PHARMACOLOGY & THERAPEUTICS ( WILEY-BLACKWELL ) 36 ( 8 ) 811 - 812 2012.10 [Refereed]

DOI

Esophageal foreign body causing sustained stridor in an infant.

Eitaro Hiejima, Hiroshi Nakase, Shinji Uemoto, Toshio Heike

Clinical journal of gastroenterology 5 ( 2 ) 146 - 9 2012.04 [Refereed] [Domestic journal]

The patient was an 8-month-old boy with a 2-month history of stridor. Initially, he had been diagnosed with bronchitis and/or asthma and treated with antibiotics, a β-antagonist and a leukotriene antagonist, but his symptoms were not relieved. An enhanced computed tomography scan showed a gas filled mass and tracheal compression above the level of the aortic arch, and barium swallow revealed an approximately 3 cm mass with irregular surface. Endoscopic examination showed a yellow foreign body (FB) with surrounding granulation tissue. The FB was removed surgically. Postoperative bronchoscopy showed improvement of tracheal compression. The patient had an uneventful recovery with disappearance of his stridor.

DOI PubMed

The role of Hes genes in intestinal development, homeostasis and tumor formation.

Taro Ueo, Itaru Imayoshi, Taeko Kobayashi, Toshiyuki Ohtsuka, Hiroshi Seno, Hiroshi Nakase, Tsutomu Chiba, Ryoichiro Kageyama

Development (Cambridge, England) ( COMPANY OF BIOLOGISTS LTD ) 139 ( 6 ) 1071 - 82 2012.03 [Refereed] [International journal]

Notch signaling regulates intestinal development, homeostasis and tumorigenesis, but its precise downstream mechanism remains largely unknown. Here we found that inactivation of the Notch effectors Hes1, Hes3 and Hes5, but not Hes1 alone, led to reduced cell proliferation, increased secretory cell formation and altered intestinal structures in adult mice. However, in Apc mutation-induced intestinal tumors, inactivation of Hes1 alone was sufficient for reducing tumor cell proliferation and inducing differentiation of tumor cells into all types of intestinal epithelial cells, but without affecting the homeostasis of normal crypts owing to genetic redundancy. These results indicated that Hes genes cooperatively regulate intestinal development and homeostasis and raised the possibility that Hes1 is a promising target to induce the differentiation of tumor cells.

DOI PubMed

Targeting activation-induced cytidine deaminase prevents colon cancer development despite persistent colonic inflammation

A. Takai, H. Marusawa, Y. Minaki, T. Watanabe, H. Nakase, K. Kinoshita, G. Tsujimoto, T. Chiba

ONCOGENE ( NATURE PUBLISHING GROUP ) 31 ( 13 ) 1733 - 1742 2012.03 [Refereed]

Inflammatory bowel disease (IBD) is an important etiologic factor in the development of colorectal cancer. However, the mechanism underlying carcinogenesis through chronic inflammation is still unknown. Activation-induced cytidine deaminase (AID) is induced by the inflammation and involved in various human carcinogenesis via its mutagenic activity. In the current study, we investigated whether the inflammation/AID axis plays an integral role in the development of colitis-associated cancers. Inflammation in the cecum was more severe than that in other colonic regions, and endogenous AID expression was enhanced most prominently in the inflamed cecal mucosa of interleukin (IL)-10(-/-) mice. Blockade of tumor necrosis factor (TNF)-alpha and IL-12 significantly suppressed AID expression. Although proinflammatory cytokine expression was comparable between IL-10(-/-) AID(+/+) and IL-10(-/-) AID(-/-) mice, sequencing analyses revealed a significantly lower incidence of somatic mutations in Trp53 gene in the colonic mucosa of IL-10(-/-) AID(-/-) than IL-10(-/-) AID(+/+) mice. Colon cancers spontaneously developed in the cecum in 6 of 22 (27.2%) IL-10(-/-) AID(+/+) mice. In contrast, none of the IL-10(-/-) AID(-/-) mice developed cancers except only one case of neoplasia in the distal colon. These findings suggest that the proinflammatory cytokine-induced aberrant production of AID links colonic inflammation to an enhanced genetic susceptibility to oncogenic mutagenesis. Targeting AID could be a novel strategy to prevent colitis-associated colon carcinogenesis irrespective of ongoing colonic inflammation. Oncogene (2012) 31, 1733-1742; doi:10.1038/onc.2011.352; published online 15 August 2011

DOI PubMed

Successful treatment with infliximab for inflammatory colitis in a patient with X-linked anhidrotic ectodermal dysplasia with immunodeficiency.

Tomoyuki Mizukami, Megumi Obara, Ryuta Nishikomori, Tomoki Kawai, Yoshihiro Tahara, Naoki Sameshima, Kousuke Marutsuka, Hiroshi Nakase, Nobuhiro Kimura, Toshio Heike, Hiroyuki Nunoi

Journal of clinical immunology ( SPRINGER/PLENUM PUBLISHERS ) 32 ( 1 ) 39 - 49 2012.02 [Refereed] [International journal]

X-linked anhidrotic ectodermal dysplasia with immunodeficiency (X-EDA-ID) is caused by hypomorphic mutations in the gene encoding nuclear factor-κB essential modulator protein (NEMO). Patients are susceptibile to diverse pathogens due to insufficient cytokine and frequently show severe chronic colitis. An 11-year-old boy with X-EDA-ID was hospitalized with autoimmune symptoms and severe chronic colitis which had been refractory to immunosuppressive drugs. Since tumor necrosis factor (TNF) α is responsible for the pathogenesis of NEMO colitis according to intestinal NEMO and additional TNFR1 knockout mice studies, and high levels of TNFα-producing mononuclear cells were detected in the patient due to the unexpected gene reversion mosaicism of NEMO, an anti-TNFα monoclonal antibody was administered to ameliorate his abdominal symptoms. Repeated administrations improved his colonoscopic findings as well as his dry skin along with a reduction of TNFα-expressing T cells. These findings suggest TNF blockade therapy is of value for refractory NEMO colitis with gene reversion.

DOI PubMed J-GLOBAL

[Effect of immunosuppressants on inflammatory bowel disease: tacrolimus and cyclosporine].

Hiroshi Nakase, Minoru Matsuura, Tsutomu Chiba

Nihon rinsho. Japanese journal of clinical medicine 70 Suppl 1 324 - 8 2012.02 [Refereed] [Domestic journal]

PubMed

Technology of drug delivery system for gastroenterologists

Hiroshi Nakase, Minoru Matsuura

Drug Delivery System 27 ( 4 ) 267 - 274 2012 [Refereed]

Many gastroenterologists have performed various treatments on several diseases such as inflammatory diseases and neoplastic diseases. Therefore, in the field of Gastroenterology, drug delivery system (DDS) is absolutely required for avoidance of drug-induced side effects. Development of DDS with polymeric materials such as biodegradable microspheres, etc., which could carry drugs and cytokines to targeted gastrointestinal tracts and liver, would contribute to future therapeutic strategy for gastrointestinal diseases. © 2012, THE JAPAN SOCIETY OF DRUG DELIVERY SYSTEM. All rights reserved.

DOI

SR-PSOX/CXCL16 plays a critical role in the progression of colonic inflammation.

Norimitsu Uza, Hiroshi Nakase, Shuji Yamamoto, Takuya Yoshino, Yasuhiro Takeda, Satoru Ueno, Satoko Inoue, Sakae Mikami, Minoru Matsuura, Takeshi Shimaoka, Noriaki Kume, Manabu Minami, Shin Yonehara, Hiroki Ikeuchi, Tsutomu Chiba

Gut ( B M J PUBLISHING GROUP ) 60 ( 11 ) 1494 - 505 2011.11 [Refereed] [International journal]

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is initiated and perpetuated by a dysregulated immune response to unknown environmental antigens such as luminal bacteria in genetically susceptible hosts. SR-PSOX/CXCL16, a scavenger receptor that binds phosphatidylserine and oxidised lipoprotein, has both phagocytic activity and chemotactic properties. The aim of this study was to investigate the role of SR-PSOX/CXCL16 in patients with IBD and experimental murine colitis. METHODS: The serum levels of SR-PSOX/CXCL16 were measured in patients with IBD. The roles of SR-PSOX/CXCL16 in phagocytosis of bacterial components and cytokine production by macrophages from wild-type (WT) and SR-PSOX/CXCL16 knockout (KO) mice were assessed. Colitis was induced by administering dextran sulfate sodium (DSS) to WT and SR-PSOX/CXCL16 KO mice. Colonic inflammation was analysed by clinical, histological and immunological parameters. Finally, the effect of a monoclonal antibody (mAb) to SR-PSOX/CXCL16 on DSS-induced colitis and trinitrobenzene sulfonic acid-induced colitis models was evaluated. RESULTS: Serum levels of SR-PSOX/CXCL16 correlated significantly with the disease activity of patients with IBD. Ex vivo experiments showed that SR-PSOX/CXCL16 was involved in both phagocytosis of bacterial antigens and the T helper 1 immune response through the production of interleukin 12 and interferon γ. In vivo murine experiments demonstrated the upregulated gene expression of SR-PSOX/CXCL16 in inflamed colonic tissues and the predominant expression of SR-PSOX/CXCL16 on macrophages. SR-PSOX/CXCL16 KO mice were less susceptible to colonic inflammation than were their WT littermates. Administration of SR-PSOX/CXCL16 mAb ameliorated the condition in the two different experimental colitis models. CONCLUSIONS: SR-PSOX/CXCL16 plays a critical role in colonic inflammation and could be a potential therapeutic target for patients with IBD.

DOI PubMed CiNii

Involvement of mycobacterium avium subspecies paratuberculosis in TNF-α production from macrophage: possible link between MAP and immune response in Crohn's disease.

Hiroshi Nakase, Hiroyuki Tamaki, Minoru Matsuura, Tsutomu Chiba, Kazuichi Okazaki

Inflammatory bowel diseases ( WILEY-BLACKWELL ) 17 ( 11 ) E140-2 - E142 2011.11 [Refereed] [International journal]

DOI PubMed

Importance of CXCL16 as a biomarker for granulocytapheresis in patients with Crohn's disease.

Hiroshi Nakase, Norimitsu Uza, Minoru Matsuura, Tsutomu Chiba

Inflammatory bowel diseases ( WILEY-BLACKWELL ) 17 ( 10 ) 2211 - 2 2011.10 [Refereed] [International journal]

DOI PubMed

Rapid induction of mucosal healing by intensive granulocyte and monocyte adsorptive aphaeresis in active ulcerative colitis patients without concomitant corticosteroid therapy

T. Fukuchi, H. Nakase, D. Ito, H. Yamashita, M. Matsuura, Y. Nagatani, H. Koga, K. Senda, T. Eguchi, S. Ubukata, S. Kawaguchi, A. Ueda, T. Tanaka, R. Ohashi, M. Otzuka, K. Ashida

ALIMENTARY PHARMACOLOGY & THERAPEUTICS ( WILEY-BLACKWELL ) 34 ( 5 ) 583 - 585 2011.09 [Refereed]

DOI

Tacrolimus therapy as an alternative to thiopurines for maintaining remission in patients with refractory ulcerative colitis.

Shuji Yamamoto, Hiroshi Nakase, Minoru Matsuura, Satohiro Masuda, Ken-ichi Inui, Tsutomu Chiba

Journal of clinical gastroenterology ( LIPPINCOTT WILLIAMS & WILKINS ) 45 ( 6 ) 526 - 30 2011.07 [Refereed] [International journal]

BACKGROUND: Although the efficacy of tacrolimus for inducing remission of refractory ulcerative colitis (UC) is established, its efficacy for maintaining remission of UC has not been evaluated. AIM: The aim of this study was to evaluate the efficacy of tacrolimus compared with thiopurines for maintaining remission in patients with refractory UC. METHODS: Twenty-four UC patients treated with tacrolimus and 34 treated with thiopurines to maintain remission were enrolled as the tacrolimus group and the thiopurine group, respectively. In the tacrolimus group, 82.8% of the patients were treated with tacrolimus for induction of the remission, whereas 70% of the patients in the thiopurine group were induced remission with either corticosteroid or cytapheresis. Proportions of patients who kept steroid-free remission between the tacrolimus and the thiopurine groups were compared. Maintenance of remission using tacrolimus or thiopurines was defined as no need for other therapies other than aminosalicylates without relapse for at least 3 months. Secondarily, to determine whether the response to thiopurines affects the long-term efficacy of tacrolimus maintenance therapy, the overall cumulative relapse-free survival based on the Kaplan-Meier method was estimated in thiopurine-naive or thiopurine-intolerant patients and thiopurine-refractory ones in the tacrolimus group. RESULTS: Remission was successfully maintained in 17 patients (70.8%) of the tacrolimus group, and 28 patients (82.4%) of the thiopurine group. The overall cumulative relapse-free survival of thiopurine-naive or thiopurine-intolerant patients in the tacrolimus group was similar to that in the thiopurine group, and significantly higher than that of thiopurine-refractory patients in the tacrolimus group. CONCLUSION: Maintenance therapy with tacrolimus for patients with UC could be considered an alternative to thiopurine therapy.

DOI PubMed

Tacrolimus suppresses IL-12/IL23 p40 in Crohn's disease and heals fistulae refractory to anti-TNF-alpha therapy

H. Nakase, M. Matsuura, N. Uza, T. Chiba

ALIMENTARY PHARMACOLOGY & THERAPEUTICS ( WILEY-BLACKWELL ) 33 ( 8 ) 979 - 980 2011.04 [Refereed]

DOI

Ectopic pancreas at the jejunum.

Yasuhiro Takeda, Hiroshi Nakase, Tsutomu Chiba

Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 43 ( 3 ) e6 2011.03 [Refereed] [International journal]

DOI PubMed

Potential role of granulocyte/monocyte adsorptive apheresis for ulcerative colitis with concomitant CMV infection

H. Nakase, M. Matsuura, T. Chiba

ALIMENTARY PHARMACOLOGY & THERAPEUTICS ( WILEY-BLACKWELL ) 33 ( 4 ) 497 - 498 2011.02 [Refereed]

DOI

Positive finding of colonic polymerase chain reaction for cytomegalovirus DNA is not false positive but a warning for treating patients with ulcerative colitis refractory to immunosuppressive therapies.

Hiroshi Nakase, Takuya Yoshino, Kayoko Matumura, Yusuke Honzawa, Shuji Yamamoto, Minoru Matsuura, Tsutomu Chiba

Inflammatory bowel diseases 17 ( 2 ) E13-4 2011.02 [Refereed] [International journal]

DOI PubMed

Clinical significance of serum diamine oxidase activity in inflammatory bowel disease: Importance of evaluation of small intestinal permeability.

Yusuke Honzawa, Hiroshi Nakase, Minoru Matsuura, Tsutomu Chiba

Inflammatory bowel diseases 17 ( 2 ) E23-5 2011.02 [Refereed] [International journal]

DOI PubMed

Tacrolimus: rescue therapy or experimental drug for severe ulcerative colitis?

H. Nakase, S. Yamamoto, M. Matsuura, T. Chiba

ALIMENTARY PHARMACOLOGY & THERAPEUTICS ( WILEY-BLACKWELL PUBLISHING, INC ) 33 ( 3 ) 413 - 414 2011.02 [Refereed]

DOI

Role of heat shock protein 47 in intestinal fibrosis of experimental colitis.

Hiroshi Kitamura, Shuji Yamamoto, Hiroshi Nakase, Minoru Matsuura, Yusuke Honzawa, Kayoko Matsumura, Yasuhiro Takeda, Norimitsu Uza, Kazuhiro Nagata, Tsutomu Chiba

Biochemical and biophysical research communications ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 404 ( 2 ) 599 - 604 2011.01 [Refereed] [International journal]

BACKGROUND AND AIMS: Intestinal fibrosis is a clinically important issue of inflammatory bowel disease (IBD). It is unclear whether or not heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, plays a critical role in intestinal fibrosis. The aim of this study is to investigate the role of HSP47 in intestinal fibrosis of murine colitis. METHODS: HSP47 expression and localization were evaluated in interleukin-10 knockout (IL-10KO) and wild-type (WT, C57BL/6) mice by immunohistochemistry. Expression of HSP47 and transforming growth factor-β1 (TGF-β1) in colonic tissue was measured. In vitro studies were conducted in NIH/3T3 cells and primary culture of myofibroblasts separated from colonic tissue of IL-10KO (PMF KO) and WT mice (PMF WT) with stimulation of several cytokines. We evaluated the inhibitory effect of administration of small interfering RNA (siRNA) targeting HSP47 on intestinal fibrosis in IL-10KO mice in vivo. RESULTS: Immunohistochemistry revealed HSP47 positive cells were observed in the mesenchymal and submucosal area of both WT and IL-10 KO mice. Gene expressions of HSP47 and TGF-β1 were significantly higher in IL-10KO mice than in WT mice and correlated with the severity of inflammation. In vitro experiments with NIH3T3 cells, TGF-β1 only induced HSP47 gene expression. There was a significant difference of HSP47 gene expression between PMF KO and PMF WT. Administration of siRNA targeting HSP47 remarkably reduced collagen deposition in colonic tissue of IL-10KO mice. CONCLUSIONS: Our results indicate that HSP47 plays an essential role in intestinal fibrosis of IL-10KO mice, and may be a potential target for intestinal fibrosis associated with IBD.

DOI PubMed J-GLOBAL

[Non-epithelial tumors of the small intestine].

Hiroshi Nakase, Shuji Yamamoto, Minoru Matsuura, Tsutomu Chiba

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 100 ( 1 ) 113 - 8 2011.01 [Refereed] [Domestic journal]

PubMed

Effect and safety of granulocyte-monocyte adsorption apheresis for patients with ulcerative colitis positive for cytomegalovirus in comparison with immunosuppressants.

Takuya Yoshino, Hiroshi Nakase, Minoru Matsuura, Kayoko Matsumura, Yusuke Honzawa, Takumi Fukuchi, Kenji Watanabe, Mitsuyuki Murano, Tomoyuki Tsujikawa, Ken Fukunaga, Takayuki Matsumoto, Tsutomu Chiba

Digestion ( KARGER ) 84 ( 1 ) 3 - 9 2011 [Refereed] [International journal]

BACKGROUND: Cytomegalovirus (CMV) infection exacerbates ulcerative colitis (UC) refractory to immunosuppressive therapies (IMT). However, the underlying UC remained active in some UC patients, despite the fact that CMV-DNA in colonic mucosa became negative after antiviral therapy. Therefore, new therapeutic strategies for UC patients concomitant with CMV infection in mucosa are required. AIMS: The aim of this study was to evaluate the effect and safety of granulocyte-monocyte adsorption apheresis (GMA) in UC patients positive for CMV infection after antiviral therapy. METHODS: From October 2003 to December 2008, 64 patients with UC refractory to IMT, including steroids and immunomodulators, were enrolled in this retrospective, observational, multicenter study, which was reviewed and approved by the Institutional Review Board of Kyoto University. CMV infection was investigated by 3 methods (histologic examination, CMV antigenemia, and polymerase chain reaction). We investigated the clinical outcomes of GMA and IMT after 2 weeks of treatment with ganciclovir. RESULTS: Thirty-one (48.4%) of 64 patients with UC refractory to IMT were positive for CMV. Of the 31 patients, 4 (12.9%) underwent colectomy. Twenty-seven patients (87.1%) underwent antiviral therapy. Of those 27 patients, 7 achieved remission following antiviral therapy alone. Of the remaining 20 patients who did not achieve remission despite the disappearance of CMV-DNA, 11 and 9 patients were treated with additional GMA (GMA group) and IMT (IMT group), respectively. Of 11 patients (GMA group), 9 achieved remission and 2 underwent colectomy. Out of the remaining 9 patients (IMT group), 4 achieved remission and 5 underwent colectomy. CMV-DNA was not detected in 11 patients after GMA, but it was detected again in all 5 patients of the IMT group who underwent colectomy. The total colectomy rate in UC patients positive for CMV was 35.5% (11/31). In addition, colectomy-free survival in the CMV relapse (+) group was estimated to be 12.9% at 65 months, while that in the CMV relapse (-) group was estimated to be 100% at 60 months. CONCLUSION: The colectomy ratio tends to be high in refractory UC patients with recurrent CMV reactivation or infection. Therefore, GMA might be a safe and effective treatment for UC patients positive for CMV because it does not induce CMV reactivation.

DOI PubMed

Patients with crohn\\'s disease have hypovitaminosis D and K, which is independent of general malnutrition

A. Kuwabara, N. Tsugawa, M. Kamao, H. Nakase, T. Chiba, T. Okano, K. Tanaka

Vitamin D: Nutrition, Side Effects and Supplements 155 - 164 2011 [Refereed]

Immunosuppressive effects of tacrolimus on macrophages ameliorate experimental colitis.

Takuya Yoshino, Hiroshi Nakase, Yusuke Honzawa, Kayoko Matsumura, Shuuji Yamamoto, Yasuhiro Takeda, Satoru Ueno, Norimitsu Uza, Satohiro Masuda, Kenichi Inui, Tsutomu Chiba

Inflammatory bowel diseases ( JOHN WILEY & SONS INC ) 16 ( 12 ) 2022 - 33 2010.12 [Refereed] [International journal]

BACKGROUND: Tacrolimus is a novel immunomodulator for inflammatory bowel diseases. Immunosuppressive effects of tacrolimus on T cells are well known; however, the effects of tacrolimus on macrophages remain unclear. The aim of this study was to investigate the effects of tacrolimus on activated macrophages and to examine its efficacy in murine colitis models. METHODS: Proinflammatory cytokine production from lipopolysaccharide (LPS)-stimulated peritoneal macrophages of IL-10-knockout (KO) mice with and without tacrolimus was measured. We investigated the effects of tacrolimus on nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and caspase activation in macrophages and the induction of apoptosis in macrophages in vitro and examined the in vivo apoptotic effect of tacrolimus on colonic macrophages in IL-10-KO mice. We evaluated the effect of the rectal administration of tacrolimus on colonic inflammation in IL-10-KO mice and dextran sulfate sodium (DSS)-induced colitis in CB.17/SCID mice. RESULTS: Proinflammatory cytokine production from tacrolimus-treated macrophages was significantly lower than that from untreated cells. Tacrolimus suppressed LPS-induced activation of both NF-κB and MAPK in macrophages and induced apoptosis of macrophages via activation of caspases 3 and 9. Rectal administration of tacrolimus evoked apoptosis of colonic macrophages in IL-10-KO mice. Moreover, the rectal administration of tacrolimus ameliorated colitis in IL-10-KO mice and DSS-induced colitis in CB.17/SCID mice. Gene expression of inflammatory cytokines in colonic mucosa was significantly lower in tacrolimus-treated mice than in untreated mice. CONCLUSIONS: Tacrolimus suppresses the function of activated macrophages and promotes their apoptosis, which may lead to the amelioration of colonic inflammation.

DOI PubMed

Heat shock protein 47 can be a new target molecule for intestinal fibrosis related to inflammatory bowel disease.

Yusuke Honzawa, Hiroshi Nakase, Yasuhiro Takeda, Kazuhiro Nagata, Tsutomu Chiba

Inflammatory bowel diseases ( JOHN WILEY & SONS INC ) 16 ( 12 ) 2004 - 6 2010.12 [Refereed] [International journal]

DOI PubMed

The therapy in experimental colitis by microspheres with incorporating cyclosporine A

深田憲将, 内田一茂, 大宮美香, 松下光伸, 仲瀬裕志, 千葉勉, 田畑泰彦, 岡崎和一

Gastroenterology ( 科学評論社 ) 51 ( 4 ) 336 - 340 2010.10 [Refereed]

CiNii

Successful Endoscopic Dilation Treatment of Small Intestinal Stricture Occurring during Chemotherapy for Malignant Lymphoma.

Yusuke Honzawa, Masahiko Kondo, Takanobu Hayakumo, Minoru Matsuura, Hiroshi Nakase

Case reports in gastroenterology 4 ( 3 ) 323 - 329 2010.09 [Refereed] [International journal]

We report a stricture occurring during chemotherapy for malignant lymphoma that was successfully treated by endoscopic balloon dilation. The patient was diagnosed with stage IV malignant lymphoma by esophagogastroduodenoscopy and computed tomography scans. She complained of nausea and vomiting after undergoing the second cycle of chemotherapy. A small intestinal series through an ileus tube showed severe stricture of the ileum. Endoscopic balloon dilation was successfully performed with single-balloon endoscopy. After the procedure, her symptoms subsided and did not recur even 8 months after endoscopic dilation therapy.

DOI PubMed

Cytomegalovirus affects clinical outcome of infliximab in ulcerative colitis refractory to tacrolimus

H. Nakase, S. Yamamoto, M. Matsuura, Y. Honzawa, T. Chiba

ALIMENTARY PHARMACOLOGY & THERAPEUTICS ( WILEY-BLACKWELL ) 32 ( 3 ) 510 - 511 2010.08 [Refereed]

DOI

Pedunculated cavernous hemangioma mimicking inflammatory fibroid polyp in a patient with ulcerative colitis

K. Ueda, H. Nakase, H. Yaku, Y. Honzawa, T. Chiba

ENDOSCOPY ( GEORG THIEME VERLAG KG ) 42 ( SUPPL. 2 ) E162 - E162 2010.07 [Refereed]

DOI PubMed

Modulation of Th1/Th2 balance by infliximab rescues postoperative occurrence of small-intestinal inflammation associated with ulcerative colitis.

Reiko Akitake, Hiroshi Nakase, Masashi Tamaoki, Satoru Ueno, Sakae Mikami, Tsutomu Chiba

Digestive diseases and sciences ( SPRINGER ) 55 ( 6 ) 1781 - 4 2010.06 [Refereed] [International journal]

DOI PubMed CiNii J-GLOBAL

Effect of EP4 agonist (ONO-4819CD) for patients with mild to moderate ulcerative colitis refractory to 5-aminosalicylates: a randomized phase II, placebo-controlled trial.

Hiroshi Nakase, Yoshihide Fujiyama, Nobuhide Oshitani, Toru Oga, Kimiko Nonomura, Toshiyuki Matsuoka, Yoshiyasu Esaki, Toshinori Murayama, Satoshi Teramukai, Tsutomu Chiba, Shuh Narumiya

Inflammatory bowel diseases ( JOHN WILEY & SONS INC ) 16 ( 5 ) 731 - 3 2010.05 [Refereed] [International journal]

DOI PubMed

Low prevalence of CMV infection in patients with Crohn's disease in comparison with ulcerative colitis: effect of different immune response on prevalence of CMV infection.

Hiroshi Nakase, Takuya Yoshino, Yusuke Honzawa, Tsutomu Chiba

Digestive diseases and sciences ( SPRINGER ) 55 ( 5 ) 1498 - 9 2010.05 [Refereed] [International journal]

DOI PubMed

Efficacy and safety of infliximab as rescue therapy for ulcerative colitis refractory to tacrolimus.

Shuji Yamamoto, Hiroshi Nakase, Minoru Matsuura, Yusuke Honzawa, Satohiro Masuda, Ken-ichi Inui, Tsutomu Chiba

Journal of gastroenterology and hepatology ( WILEY-BLACKWELL ) 25 ( 5 ) 886 - 91 2010.05 [Refereed] [International journal]

BACKGROUND AND AIM: Little is known about the efficacy and safety of infliximab for ulcerative colitis refractory to tacrolimus. The aim of this study was to evaluate the efficacy and safety of infliximab in the induction of remission in ulcerative colitis patients with persistent symptoms despite tacrolimus therapy. METHODS: We report a retrospective, observational, single-center case series of 12 consecutively enrolled patients with ulcerative colitis refractory to tacrolimus that received infliximab therapy for the induction of remission. Eight patients received a single infusion of infliximab, and four received two or more infusions. Median follow-up duration was 16.0 months (range, 1.6-41.4 months). The clinical response was evaluated based on a modified Truelove-Witts severity index. RESULTS: Six patients (50.0%) achieved clinical remission within 30 days. Overall cumulative colectomy-free survival was estimated to be 58.3% at 41.4 months. Adverse events included an elevation of liver enzymes (1/12; 8.3%) and a mild infusion reaction (1/12; 8.3%). No mortality occurred. CONCLUSIONS: Infliximab can induce remission in patients with ulcerative colitis who do not tolerate or respond to tacrolimus therapy.

DOI PubMed

Sustained abdominal discomfort in a 57-year-old woman. Idiopathic mesenteric phlebosclerosis.

Hisayo Nishiura, Hiroshi Nakase, Tsutomu Chiba

Gut ( B M J PUBLISHING GROUP ) 59 ( 5 ) 578, 594 - + 2010.05 [Refereed] [International journal]

DOI PubMed

Gastrointestinal follicular lymphoma: review of the literature.

Shuji Yamamoto, Hiroshi Nakase, Kouhei Yamashita, Minoru Matsuura, Mariko Takada, Chiharu Kawanami, Tsutomu Chiba

Journal of gastroenterology ( SPRINGER TOKYO ) 45 ( 4 ) 370 - 88 2010.04 [Refereed] [Domestic journal]

Gastrointestinal follicular lymphoma (GI-FL) is a relatively rare disease, accounting for only 1%-3.6% of gastrointestinal non-Hodgkin's lymphoma. Although the duodenum and terminal ileum are considered to be the most common sites of origin, the development of wireless capsule endoscopy and double-balloon enteroscopy has increased the detection of GI-FL in every part of the small intestine. Approximately 70% of patients with GI-FL are estimated to have multiple lesions throughout the entire gastrointestinal tract. FL is a low-grade lymphoma that usually develops very slowly. If the lymphoma causes no symptoms, immediate treatment may not be necessary. Standard therapy has not yet been established for GI-FL, but chemotherapy, radiotherapy, monoclonal antibody therapy, or a combination of these therapies, is sometimes performed based on the therapeutic regimens for nodal FL. Regimens including conventional chemotherapy with rituximab, which achieve high response rates in nodal FL, are commonly used for GI-FL. The long-term clinical outcome of GI-FL is unclear. The results of a few series on the long-term outcomes of patients with GI-FL treated with conventional therapy indicate a median relapse-free time ranging from 31 to 45 months. On the other hand, in patients with GI-FL who were followed without treatment, the median time to disease progression was 37.5 months. Thus, whether to initiate aggressive therapy or whether to continue watchful waiting in patients with GI-FL is a critically important decision. Ongoing research on biomarkers to guide individualized GI-FL therapy may provide invaluable information that will lead to the establishment of a standard therapeutic regimen.

DOI PubMed CiNii

TNF-alpha is an important pathogenic factor contributing to reactivation of cytomegalovirus in inflamed mucosa of colon in patients with ulcerative colitis: lesson from clinical experience.

Hiroshi Nakase, Tsutomu Chiba

Inflammatory bowel diseases ( JOHN WILEY & SONS INC ) 16 ( 4 ) 550 - 1 2010.04 [Refereed] [International journal]

DOI PubMed

Heat shock protein 47 is a new candidate molecule as anti-fibrotic treatment of Crohn's disease

H. Nakase, Y. Honzawa, T. Chiba

ALIMENTARY PHARMACOLOGY & THERAPEUTICS ( WILEY-BLACKWELL PUBLISHING, INC ) 31 ( 8 ) 927 - 927 2010.04 [Refereed]

DOI

Oral tacrolimus (FK 506) in refractory paediatric ulcerative colitis: authors' reply

S. Yamamoto, H. Nakase, T. Chiba

ALIMENTARY PHARMACOLOGY & THERAPEUTICS ( WILEY-BLACKWELL PUBLISHING, INC ) 31 ( 6 ) 677 - 678 2010.03 [Refereed]

DOI

Efficacy of oral tacrolimus on intestinal Behcet's disease.

Kayoko Matsumura, Hiroshi Nakase, Tsutomu Chiba

Inflammatory bowel diseases ( JOHN WILEY & SONS INC ) 16 ( 2 ) 188 - 9 2010.02 [Refereed] [International journal]

DOI PubMed

Development of oral drug delivery system with cyclosporine in experimental colitis.

Fukata n, Uchida K, Kusuda T, Koyabu M, Fukui T, Matsushita M, Nishio A, Nakase H, Chiba T, Tabata Y, Okazaki K

Digestive disease week 2010（2010.5.3 New Orleans） ( W B SAUNDERS CO-ELSEVIER INC ) 138 ( 5 ) S413 - S414 2010 [Refereed]

An open-label prospective randomized multicenter study shows very rapid remission of ulcerative colitis by intensive granulocyte and monocyte adsorptive apheresis as compared with routine weekly treatment.

Atsushi Sakuraba, Satoshi Motoya, Kenji Watanabe, Masakazu Nishishita, Kazunari Kanke, Toshiyuki Matsui, Yasuo Suzuki, Tadayuki Oshima, Reiko Kunisaki, Takayuki Matsumoto, Hiroyuki Hanai, Ken Fukunaga, Naoki Yoshimura, Toshimi Chiba, Shinsuke Funakoshi, Nobuo Aoyama, Akira Andoh, Hiroshi Nakase, Yohei Mizuta, Ryoichi Suzuki, Taiji Akamatsu, Masahiro Iizuka, Toshifumi Ashida, Toshifumi Hibi

The American journal of gastroenterology ( NATURE PUBLISHING GROUP ) 104 ( 12 ) 2990 - 5 2009.12 [Refereed] [International journal]

OBJECTIVES: Granulocyte and monocyte adsorptive apheresis (GMA) has shown efficacy in patients with active ulcerative colitis (UC). However, with routine weekly treatment, it may take several weeks to achieve remission, and to date, the efficacy of a more frequent treatment schedule remains unknown. The aim of this study was to assess the clinical efficacy and safety of intensive GMA treatment in patients with active UC. METHODS: This was an open-label, prospective, randomized multicenter study to compare an intensive, two GMA sessions per week, with the routine, one GMA session per week. A total of 163 patients with mild-to-moderately active UC were randomly assigned to routine weekly treatment or intensive treatment. The maximum number of sessions of GMA permitted was 10. However, when patients achieved remission, GMA was discontinued. Remission rate at the end of the study, time to remission, and adverse events were assessed in both groups. RESULTS: Of the 163 patients, 149 were available for efficacy analysis as per protocol, 76 were in weekly GMA, and 73 were in intensive GMA. At the end of the study period, clinical remission was achieved in 41 of 76 patients (54.0%) in weekly GMA and in 52 of 73 patients (71.2%) in intensive GMA (P=0.029). The mean time to remission was 28.1+/-16.9 days in the weekly GMA treatment group and 14.9+/-9.5 days in the intensive GMA group (P<0.0001). Intensive GMA was well tolerated without GMA-related serious adverse side effects. CONCLUSIONS: Intensive GMA in patients with active UC seems to be more efficacious than weekly treatment, and significantly reduced the patients' morbidity time without increasing the incidence of side effects.

DOI PubMed

Acute Epstein-Barr virus infection presenting as severe gastroenteritis without infectious mononucleosis-like manifestations.

Mikio Fujiwara, Shin'ichi Miyamoto, Kouta Iguchi, Toshihiro Matsunaka, Hiromi Sakashita, Tatsuaki Tsuruyama, Hirokazu Kanegane, Hiroyuki Marusawa, Hiroshi Nakase, Tsutomu Chiba

Clinical journal of gastroenterology 2 ( 6 ) 398 - 403 2009.12 [Refereed] [Domestic journal]

Primary Epstein-Barr virus (EBV) infection is usually a self-limiting disease. Although it is sometimes accompanied by severe complications such as thrombocytopenia, hemolytic anemia, and splenic rupture, predominantly gastrointestinal complications are rarely reported. We studied an unusual case of primary EBV infection associated with severe hemorrhagic gastroenteritis. EBV infection was confirmed in the biopsy specimen by demonstrating the presence of EBV DNA by polymerase chain reaction, and of EBV-encoded small RNA (EBER)-positive cells by in-situ hybridization. Our patient was suspected of having primary EBV infection from the serological findings-EBV-viral capsid antigen IgM (+) and EBV nuclear antigen (-)-but he did not show typical clinical features of infectious mononucleosis such as lymph node swelling, pharyngitis, liver dysfunction, and splenomegaly. A definite diagnosis of primary EBV infection was made using biopsy specimens by demonstrating the presence of EBV DNA and EBER-positive cells.

DOI PubMed

Upregulation of T-bet and tight junction molecules by Bifidobactrium longum improves colonic inflammation of ulcerative colitis.

Yasuhiro Takeda, Hiroshi Nakase, Kazuyoshi Namba, Satoko Inoue, Satoru Ueno, Norimitsu Uza, Tsutomu Chiba

Inflammatory bowel diseases ( JOHN WILEY & SONS INC ) 15 ( 11 ) 1617 - 8 2009.11 [Refereed] [International journal]

DOI PubMed

Role of double-balloon endoscopy in the diagnosis of small-bowel tumors: the first Japanese multicenter study.

Keigo Mitsui, Shu Tanaka, Hironori Yamamoto, Tsuyoshi Kobayashi, Akihito Ehara, Tomonori Yano, Hidemi Goto, Hiroshi Nakase, Shinji Tanaka, Toshiyuki Matsui, Mitsuo Iida, Kentaro Sugano, Choitsu Sakamoto

Gastrointestinal endoscopy ( MOSBY-ELSEVIER ) 70 ( 3 ) 498 - 504 2009.09 [Refereed] [International journal]

BACKGROUND: The early diagnosis of small-bowel tumors (SBT) was a difficult task until the advent of capsule endoscopy (CE) and double-balloon endoscopy (DBE) allowed access to the disease site. However, although CE and DBE have greatly simplified the task, DBE studies have yet to provide sufficient data on the diagnosis and outcome of patients with SBTs. OBJECTIVE: To determine the efficacy of DBE examination in the detection and diagnosis of SBT. DESIGN: A retrospective analysis of cross-sectional case series. SETTING: Seven major medical centers in Japan. PATIENTS: The first 1035 consecutive DBE cases at these major Japanese centers since the introduction of DBE. MAIN OUTCOME MEASUREMENTS: The percentage of subjects with SBT and a diagnosis of SBT, their indications for DBE, and diagnostic and therapeutic DBE procedures carried out for SBT. RESULTS: SBTs were identified in 144 of 1035 subjects (13.9%) who underwent DBE between September 2000 and December 2005. For subjects with SBT, the most common indication for DBE was the suspected presence of a SBT (61/144 [42.4%]). For subjects without SBT, the most common indication was obscure GI bleeding (OGIB) (419/891 [47.0%]). Malignant lymphoma and GI stromal tumor (GIST) were the most frequent (31/144 [21.5%]) and the second-most frequent SBTs (27/144 [18.8%]), respectively, in this database. We also performed 85 biopsies and 45 therapeutic procedures for the evaluation and treatment of SBTs in 144 patients. Although complications were encountered in 5.3% of cases (14/266 sessions), none of these were life threatening in the present study. CONCLUSION: DBE proved a valuable tool for the detection and diagnosis of SBTs, especially when tumors were suspected. Biopsies and therapeutic procedures were also possible in most of these patients, which directed our management of the disease.

DOI PubMed

Modulation of the Th1/Th2 balance by infliximab improves hyperthyroidism associated with a flare-up of ulcerative colitis.

Kayoko Matsumura, Hiroshi Nakase, Shuji Yamamoto, Takuya Yoshino, Yasuhiro Takeda, Katsuhiro Kasahara, Satoru Ueno, Norimitsu Uza, Tsutomu Chiba

Inflammatory bowel diseases ( JOHN WILEY & SONS INC ) 15 ( 7 ) 967 - 8 2009.07 [Refereed] [International journal]

DOI PubMed

Alteration of CXCR4 expression and Th1/Th2 balance of peripheral CD4-positive T cells can be a biomarker for leukocytapheresis therapy for patients with refractory ulcerative colitis.

Hiroshi Nakase, Sakae Mikami, Tsutomu Chiba

Inflammatory bowel diseases ( JOHN WILEY & SONS INC ) 15 ( 7 ) 963 - 4 2009.07 [Refereed] [International journal]

DOI PubMed

High prevalence of vitamin K and D deficiency and decreased BMD in inflammatory bowel disease

A. Kuwabara, K. Tanaka, N. Tsugawa, H. Nakase, H. Tsuji, K. Shide, M. Kamao, T. Chiba, N. Inagaki, T. Okano, S. Kido

OSTEOPOROSIS INTERNATIONAL ( SPRINGER LONDON LTD ) 20 ( 6 ) 935 - 942 2009.06 [Refereed]

Vitamin K and D deficiency and decreased bone mineral density (BMD) were highly prevalent in patients with inflammatory bowel disease (IBD), especially Crohn's disease (CD). Dietary intakes of these vitamins, however, were above the Japanese adequate intakes in IBD patients, suggesting that malabsorption is the basis for hypovitaminosis K and D and decreased BMD. We have studied the possible involvement of vitamin K and D deficiency in the pathogenesis of decreased BMD in IBD. Seventy patients with IBD were evaluated for their BMD; plasma levels of vitamin K; phylloquinone (PK), menaquinone-7 (MK-7), and 25OH-D; serum PTH, protein induced by vitamin K absence (PIVKA-II), and undercarboxylated osteocalcin (ucOC) levels; and their food intake. Compared with ulcerative colitis (UC) patients, CD patients had significantly lower plasma vitamin K and 25OH-D concentrations; significantly higher serum levels of PTH, PIVKA-II, and ucOC; and significantly lower BMD scores at almost all measurement sites. More IBD patients were vitamin K deficient in bone than in liver. Multiple regression analyses revealed that low plasma concentrations of vitamin K and 25OH-D were independent risk factors for low BMD and that they were associated with the patients' fat intake, but not with their intake of these vitamins. IBD patients have high prevalence of decreased BMD and vitamin K and D deficiency probably caused by malabsorption of these vitamins.

DOI PubMed

Clinical challenges and images in GI. Image 1. Relapsing polychondritis.

Shuji Yamamoto, Hiroshi Nakase, Mariko Takada

Gastroenterology 136 ( 7 ) 2064, 2415 2009.06 [Refereed] [International journal]

DOI PubMed

Massive jejunal bleeding due to Heyde syndrome successfully treated with double balloon endoscopy.

Sakiko Ohta, Tomohiro Watanabe, Shuko Morita, Satoru Ueno, Yoshihisa Tsuji, Hiroshi Nakase, Tsutomu Chiba

Clinical journal of gastroenterology 2 ( 3 ) 187 - 189 2009.06 [Refereed] [Domestic journal]

There is a well-documented relationship between aortic valve stenosis and recurrent gastrointestinal bleeding from angiodysplasia in elderly patients, called Heyde syndrome. We report a case of Heyde syndrome with massive jejunal bleeding. Capsule endoscopy showed bleeding from jejunal angiodysplasia. Spurting bleeding from jejunal angiodysplasia was identified and treated by double balloon endoscopy. No gastrointestinal bleeding was seen after the endoscopic treatment and aortic valve replacement was performed. This case suggests that capsule endoscopy and double balloon endoscopy were very useful for the diagnosis and treatment of small intestinal bleeding due to Heyde syndrome.

DOI PubMed

Clinical challenges and images in GI. Image 4. Transplant-associated thrombotic microangiopathy of the colon accompanied by graft-versus-host disease.

Shuji Yamamoto, Hiroshi Nakase, Tsutomu Chiba, Kouhei Yamashita, Masafumi Ito

Gastroenterology 136 ( 7 ) 2067, 2418 2009.06 [Refereed] [International journal]

DOI PubMed

Combination of Endoscopic Resection and Heat Ablation Is a Promising Endoscopic Therapy for Adenoma-Like Dysplastic Lesion in Chronic Ulcerative Colitis.

Kayoko Matsumura, Hiroshi Nakase, Tsutomu Chiba

Case reports in gastroenterology 3 ( 1 ) 121 - 124 2009.04 [Refereed] [International journal]

In January 2007, a 74-year-old male was admitted to our hospital for treatment of an adenoma-like dysplastic lesion (ALM). He had a four-year history of ulcerative colitis. Endoscopic findings revealed that a protruded lesion with an approximate size of 3 cm at the splenic flexure was surrounded by pseudopolyps. Lifting of the tumor was poor despite injection of normal saline around it. Therefore, the combination of endoscopic resection and heat ablation therapy with argon plasma coagulation was performed. Histopathological examination of the resected specimen showed tubular adenoma with high-grade atypia. Endoscopic examination 15 months after this treatment revealed no occurrence of ALM. Whether or not there is a possibility of local recurrence after ablation therapy in addition to endoscopic resection performed in this case remains unclear. However, this endoscopic therapy is a promising option for ALM in chronic ulcerative colitis.

PubMed

The effect of proteasome inhibitor MG132 on experimental inflammatory bowel disease

S. Inoue, H. Nakase, M. Matsuura, S. Mikami, S. Ueno, N. Uza, T. Chiba

CLINICAL AND EXPERIMENTAL IMMUNOLOGY ( WILEY-BLACKWELL PUBLISHING, INC ) 156 ( 1 ) 172 - 182 2009.04 [Refereed]

Immunoproteasome up-regulation enhances the processing of nuclear factor-kappa B (NF-kappa B) and degradation of I kappa B alpha, which correlates with increased amounts of NF-kappa B in the various cells. Aberrant activation of NF-kappa B is involved in the pathogenesis of inflammatory bowel disease (IBD). The aim of this study was to elucidate the effect of proteasome inhibitor MG132 on experimental IBD. We investigated the effects of MG132 on intestinal inflammation and epithelial regeneration in both interleukin-10-deficient (IL-10(-/-)) mice and mice with dextran sulphate sodium (DSS)-induced colitis. Body weight, histological findings and tumour necrosis factor (TNF)-alpha mRNA expression, epithelial cell proliferation and NF-kappa B p65 activity in colonic tissues were examined. The effects of MG132 on cell proliferation, migration and multiple drug resistance 1 (MDR1) gene expression were determined in vitro. MG132 ameliorated intestinal inflammation of IL-10(-/-) mice by decreasing TNF-alpha mRNA expression in the colonic tissues, which was associated with suppression of NF-kappa B activation, and reduced significantly the number of Ki-67-positive intestinal epithelial cells. On the other hand, MG132 did not reduce intestinal inflammation in mice with DSS-induced colitis, and delayed significantly the recovery of body weight and epithelial regeneration. MG132 also suppressed significantly epithelial cell proliferation, cell migration and MDR1 gene expression in vitro. Proteasome inhibition reduces T cell-mediated intestinal inflammation, but may interrupt both epithelial regeneration and barrier function of colonic mucosa. Optimal use of proteasome inhibitor should be kept in mind when we consider its clinical application for patients with IBD.

DOI PubMed

Involvement of lupus enteritis in a patient with lupus cystitis and nephritis.

Reiko Akitake, Hiroshi Nakase, Satoru Ueno, Shinichi Miyamoto, Noriyuki Iehara, Tsutomu Chiba

Digestion ( KARGER ) 80 ( 3 ) 160 - 4 2009 [Refereed] [International journal]

We present the case of a patient with lupus enteritis accompanied by both lupus cystitis and lupus nephritis without a history of systemic lupus erythematosus. The patient had a 2-month history of diarrhea and pollakiuria and was admitted to our hospital. Physical examination showed abdominal tenderness. Laboratory data revealed reductions in both total protein and albumin, elevated serum creatinine levels, and elevated antinuclear and anti-Smith antibodies. Urinalysis revealed proteinuria. Stool and urine cultures were negative. Abdominal computed tomography revealed diffuse edematous wall thickening, dilatation of the small intestine suggesting paralytic ileus, and irregular wall thickening of the urinary bladder. Histological results of the cystic and renal biopsies revealed interstitial cystitis and membranous nephropathy which were suggestive of lupus cystitis and lupus nephritis, respectively. The patient's gastrointestinal symptoms were finally diagnosed as resulting from lupus enteritis. After initiating 30 mg oral prednisolone daily, the diarrhea and pollakiuria subsided, and renal function became normal. Lupus enteritis should always be considered in the differential diagnosis when patients complaining of chronic diarrhea of unknown etiology are encountered.

DOI PubMed

Simultaneous occurrence of inflammatory bowel disease and myelodysplastic syndrome due to chromosomal abnormalities in bone marrow cells.

Fumiyasu Nakamura, Tomohiro Watanabe, Kimiko Hori, Yoshiaki Ohara, Kouhei Yamashita, Yoshihisa Tsuji, Yoshihide Ueda, Sakae Mikami, Hiroshi Nakase, Tsutomu Chiba

Digestion ( KARGER ) 79 ( 4 ) 215 - 9 2009 [Refereed] [International journal]

BACKGROUND/AIMS: Although chromosomal abnormalities in bone marrow (BM) cells, such as trisomy 8, are risk factors for the development of inflammatory bowel diseases (IBD) as well as myelodysplastic syndrome (MDS), the mechanisms of how these cytogenetic abnormalities cause intestinal inflammation are poorly understood. METHODS AND RESULTS: A 55-year-old man with a 3-month history of watery diarrhea, fever and abdominal pain was admitted. Blood examinations revealed pancytopenia. Pathological analysis and endoscopic images of the entire colon led to the diagnosis of IBD of unclassified type. BM examination showed that the pancytopenia was due to MDS and that his BM cells had dual chromosomal abnormalities: 47, XY, +1, der(1;7)(q10;p10), +8. Immunological studies using peripheral blood monocytes from this patient revealed that the dual chromosomal abnormalities of BM cells led to the development of colitogenic monocytes producing a large amount of pro-inflammatory cytokines and showing resistance to apoptosis upon stimulation with microbial antigens. CONCLUSION: An abnormal karyotype of BM cells is not only responsible for the development of MDS, but also for IBD in this case.

DOI PubMed

ドラッグデリバリーシステムの将来展望とは？

岡崎和一, 深田憲将, 大宮美香, 内田一茂, 松下光伸, 仲瀬裕志, 千葉勉, 田畑泰彦

分子消化器病．6（2）: 151－55（2009） 2009 [Refereed]

[The involvement of cytomegalovirus infection in the patient with intestinal Behçet's disease].

Sakae Mikami, Hiroshi Nakase, Tsutomu Chiba

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 97 ( 12 ) 3056 - 9 2008.12 [Refereed] [Domestic journal]

PubMed

Blockade of CXCL12/CXCR4 axis ameliorates murine experimental colitis.

Sakae Mikami, Hiroshi Nakase, Shuji Yamamoto, Yasuhiro Takeda, Takuya Yoshino, Katushiro Kasahara, Satoru Ueno, Norimitsu Uza, Shinya Oishi, Nobutaka Fujii, Takashi Nagasawa, Tsutomu Chiba

The Journal of pharmacology and experimental therapeutics ( AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS ) 327 ( 2 ) 383 - 92 2008.11 [Refereed] [International journal]

Recent studies indicate that the CXCL12/CXCR4 interaction is involved in several inflammatory conditions. However, it is unclear whether this interaction has a role in the pathophysiology of inflammatory bowel disease (IBD). We investigated the significance of this interaction in patients with IBD and in mice with dextran sulfate sodium (DSS)-induced colitis and the effect of a CXCR4 antagonist on experimental colitis. First, we measured CXCR4 expression on peripheral T cells in patients with IBD. Furthermore, we investigated CXCR4 expression on leukocytes and CXCL12 expression in the colonic tissue of mice with DSS-induced colitis, and we evaluated the effects of a CXCR4 antagonist on DSS-induced colitis and colonic inflammation of interleukin (IL)-10 knockout (KO) mice. Colonic inflammation was assessed both clinically and histologically. Cytokine production from mesenteric lymph node cells was also examined. CXCR4 expression on peripheral T cells was significantly higher in patients with active ulcerative colitis (UC) compared with normal controls, and CXCR4 expression levels of UC patients correlated with disease activity. Both CXCR4 expression on leukocytes and CXCL12 expression in colonic tissue were significantly increased in mice with DSS-induced colitis. Administration of a CXCR4 antagonist ameliorated colonic inflammation in DSS-induced colitis and IL-10 KO mice. CXCR4 antagonist reduced tumor necrosis factor-alpha and interferon-gamma production from mesenteric lymph node cells, whereas it did not affect IL-10 production. The percentage of mesenteric Foxp3+CD25+ T cells in DSS-induced colitis was not affected by CXCR4 antagonist. These results suggest that blockade of this chemokine axis might have potential as a therapeutic target for the treatment of IBD.

DOI PubMed

Long-term effect of tacrolimus therapy in patients with refractory ulcerative colitis

S. Yamamoto, H. Nakase, S. Mikami, S. Inoue, T. Yoshino, Y. Takeda, K. Kasahara, S. Ueno, N. Uza, H. Kitamura, H. Tamaki, M. Matsuura, K. Inui, T. Chiba

ALIMENTARY PHARMACOLOGY & THERAPEUTICS ( WILEY-BLACKWELL ) 28 ( 5 ) 589 - 597 2008.09 [Refereed]

BAckground Little is known about long-term outcome of tacrolimus therapy for ulcerative colitis. Aim To evaluate long-term efficacy and safety of tacrolimus in Japanese patients with refractory ulcerative colitis. Methods Twenty-seven patients with UC refractory to conventional therapy were administered tacrolimus with trough whole-blood levels of 10-15 ng/mL to induce remission and 5-10 ng/mL to maintain remission. Median treatment duration was 11 months (1-39 months) and median follow-up duration was 17 months (2-65 months). Evaluation of the clinical response was based on a modified Truelove-Witts severity index (MTWSI). Results Tacrolimus produced a clinical response in 21 patients (77.8%), and remission was achieved in 19 of these 21 (70.4%) within 30 days. Overall cumulative colectomy-free survival was estimated as 62.3% at 65 months. In 18 of 19 patients treated with corticosteroids at the initiation of tacrolimus therapy, corticosteroids were discontinued or tapered. Adverse events were tremor (25.9%), renal function impairment (18.5%), infectious disease (14.8%), hot flashes (11.1%), hyperkalaemia (7.4%), headache (7.4%), epigastralgia (7.4%) and nausea (3.7%). No mortality occurred. Conclusions Long-term administration of tacrolimus appears to be an effective and well-tolerated treatment for Japanese patients with refractory ulcerative colitis.

DOI

Activation-induced cytidine deaminase links between inflammation and the development of colitis-associated colorectal cancers.

Yoko Endo, Hiroyuki Marusawa, Tadayuki Kou, Hiroshi Nakase, Shigehiko Fujii, Takahiro Fujimori, Kazuo Kinoshita, Tasuku Honjo, Tsutomu Chiba

Gastroenterology ( W B SAUNDERS CO-ELSEVIER INC ) 135 ( 3 ) 889 - 98 2008.09 [Refereed] [International journal]

BACKGROUND & AIMS: Activation-induced cytidine deaminase (AID) was originally identified as an inducer of somatic hypermutations in the immunoglobulin gene. We recently revealed that ectopic AID expression serves as a link between the cellular editing machinery and high mutation frequencies, leading to human cancer development. In the current study, we investigated whether AID might contribute to the development of colitis-associated colorectal cancers. METHODS: The expression and regulation of AID in association with proinflammatory cytokine stimulation were investigated in cultured colonic cells. Genotoxic activity of AID in colonic cells was analyzed using retroviral system. Immunohistochemistry for AID was carried out on various human colonic tissues specimens. RESULTS: Tumor necrosis factor-alpha induced aberrant AID expression via IkappaB kinase-dependent nuclear factor (NF)-kappaB-signaling pathways in human colonic epithelial cells. Moreover, AID expression was also induced in response to the T helper cell 2-driven cytokines interleukin-4 and interleukin-13, which are activated in human inflammatory bowel disease. Aberrant activation of AID in colonic cells preferentially induced genetic mutations in the TP53 gene, whereas there were no nucleotide alterations of the APC gene. Immunohistochemistry revealed enhanced expression of endogenous AID protein not only in the inflamed colonic mucosa of ulcerative colitis patients but also in tumor lesions of colitis-associated colorectal cancers. CONCLUSIONS: Our findings indicate that proinflammatory cytokine-mediated aberrant expression of AID in colonic epithelial cells is a genotoxic factor linking inflammation, somatic mutations, and colorectal cancer development.

DOI PubMed

Clinical features of Japanese patients with colonic angiodysplasia.

Satoru Ueno, Hiroshi Nakase, Katsuhiro Kasahara, Norimitsu Uza, Hiroshi Kitamura, Satoko Inoue, Sakae Mikami, Minoru Matsuura, Tsutomu Chiba

Journal of gastroenterology and hepatology ( BLACKWELL PUBLISHING ) 23 ( 8 Pt 2 ) e363-6 - E366 2008.08 [Refereed] [International journal]

BACKGROUND AND AIM: With improvements in endoscopic resolution, angiodysplasia (AGD) has become an increasingly recognized disorder. The aim of this study was to describe the clinical features of Japanese patients with colonic AGD and compare them to the clinical features of Western patients. METHODS: Retrospective analyses were performed in all patients who had undergone colonoscopical examination from March 2003 to October 2005 at the Kyoto University Hospital. Four independent literature searches were performed to document the characteristics of colonic AGD in Western countries. The characteristics of 41 Japanese patients diagnosed as having colonic AGD were compared with those of Western patients. RESULTS: The incidence of colonic AGD increased with age, and the most prevalent underlying disease in patients with colonic AGD was cardiovascular disease (56.1%). These tendencies were similar in the Japanese and Western data. Colonic AGD in Japanese patients was predominantly located in the left colon (41.7%), whereas in Western patients, it was mainly located in the right colon (54%-81.9%). The percentage of colonic AGD with a size of more than 5 mm or elevated type detected in Japanese patients was significantly higher than that in Western patients. CONCLUSION: The characteristics of Japanese patients with colonic AGD were similar to those of Western patients, except for its localization, size, and type.

DOI PubMed

[Ischemic enteritis].

Hiroshi Nakase

Nihon rinsho. Japanese journal of clinical medicine 66 ( 7 ) 1330 - 4 2008.07 [Refereed] [Domestic journal]

Ischemic enteritis is a rare disease, but its mortality is high, whether it is caused by anatomic occlusion of the mesenteric macrovasculature or pathophysiologic vasospasm at the microvascular level. Despite advances in the management of the critical ill patient, a large proportion of the patients recognized with this diagnosis succumb acutely to their condition. Lesser degrees of mesenteric ischemia (particularly, in small intestine), even when not manifest overtly as the classic clinical syndrome, may contribute to the development of systemic sepsis and the multiple organ failure syndrome, which leads to death. Therefore, the understanding, recognition, and proper management of mesenteric vascular insufficiency has become very important.

PubMed

Importance of diagnosis of concomitant cytomegalovirus infection in patients with intestinal Behçet's disease.

Takuya Yoshino, Hiroshi Nakase, Sakae Mikami, Mikako Nio, Satoru Ueno, Norimitsu Uza, Katsuyuki Ohmori, Toshiaki Manabe, Tsutomu Chiba

Inflammatory bowel diseases ( JOHN WILEY & SONS INC ) 14 ( 6 ) 877 - 8 2008.06 [Refereed] [International journal]

DOI PubMed

Possible link between ulcerative colitis and in situ adenocarcinoma of an appendiceal mucocele: importance of inflammation in the appendiceal orifice related to UC.

Yasuhiro Takeda, Hiroshi Nakase, Sakae Mikami, Tateaki Inoue, Seizi Satou, Yoshiharu Sakai, Tsutomu Chiba

Inflammatory bowel diseases ( JOHN WILEY & SONS INC ) 14 ( 6 ) 873 - 4 2008.06 [Refereed] [International journal]

DOI PubMed

Repeated administration of ghrelin to patients with functional dyspepsia: its effects on food intake and appetite

Takashi Akamizu, Hiroshi Iwakura, Hiroyuki Ariyasu, Hiroshi Hosoda, Toshinori Murayama, Masayuki Yokode, Satoshi Teramukai, Hiroshi Seno, Tsutomu Chiba, Shunichi Noma, Yoshikatsu Nakai, Mikhiko Fukunaga, Yoshihide Nakai, Kenji Kangawa

EUROPEAN JOURNAL OF ENDOCRINOLOGY ( BIO SCIENTIFICA LTD ) 158 ( 4 ) 491 - 498 2008.04 [Refereed]

Background: Ghrelin plays a major role in the regulation of food intake (FI), which makes it a strong candidate for the treatment of anorexia. Objective: We attempted to evaluate the clinical response to repeated ghrelin administration in patients with anorexia caused by functional disorders, such as functional dyspepsia (FD). Subjects and methods: Subjects included in this study were those who 1) were diagnosed with functional anorexia, including FD and other eating disorders with the exception of anorexia nervosa; 2) were lean (body mass index (BMI) < 22 kg/m(2)); and 3) exhibited decreased FI. Subjects received an i.v. infusion of ghrelin (3 mu g/kg) for 30 min twice a day (before breakfast and dinner) for 2 weeks. We investigated the effects of ghrelin administration on FI, appetite, hormones, and metabolic parameters. Results: Six patients with FD were enrolled in this study. Ghrelin administration tended to increase daily FI in comparison with levels before and after completion of treatment, but this difference that was the primary endpoint of this study did not reach statistical significance (P=0.084). Hunger sensation was significantly elevated at the end of drip infusion (P < 0.0001). No severe adverse effects were observed. Conclusions: These results suggest that ghrelin administration is safe and that this treatment has stimulatory effects on appetite in patients with FD. Further studies are necessary to confirm the efficacy of ghrelin treatment for anorexia-related disorders.

DOI PubMed

Systematic review: cytomegalovirus infection in inflammatory bowel disease.

Hiroshi Nakase, Kayoko Matsumura, Takuya Yoshino, Tsutomu Chiba

Journal of gastroenterology ( SPRINGER TOKYO ) 43 ( 10 ) 735 - 40 2008 [Refereed] [Domestic journal]

DOI PubMed CiNii

Prevalence of non-steroidal anti-inflammatory drug-induced enteropathy determined by double-balloon endoscopy: a Japanese multicenter study.

Takayuki Matsumoto, Tetsuji Kudo, Motohiro Esaki, Tomonori Yano, Hironori Yamamoto, Choitsu Sakamoto, Hidemi Goto, Hiroshi Nakase, Shinji Tanaka, Toshiyuki Matsui, Kentaro Sugano, Mitsuo Iida

Scandinavian journal of gastroenterology ( TAYLOR & FRANCIS AS ) 43 ( 4 ) 490 - 6 2008 [Refereed] [International journal]

OBJECTIVE: Capsule endoscopy has shown that non-steroidal anti-inflammatory drugs (NSAIDs) can damage the small intestine. The aim of this study was to determine the prevalence of NSAIDs enteropathy in subjects indicated for double-balloon endoscopy (DBE). MATERIAL AND METHODS: The Japanese Study Group for Double-Balloon Endoscopy (JSG-DBE) established a database for the practical use of DBE in the Japanese population during a 2-year period from 2004 to 2005. Using this database, we identified subjects who had been taking NSAIDs within a month prior to DBE (NSAIDs group) and those free from NSAIDs use (control group). The clinical background and DBE findings were compared between the two groups. RESULTS: Among 1035 patients registered in the JSG-DBE database, 61 subjects were classified as the NSAIDs group and 600 served as the control group. Patients in the NSAIDs group were older (62+/-18 versus 51+/-19 years, p<0.0001) and gastrointestinal bleeding was a more frequent indication for DBE (79% versus 44%, p<0.001) compared with in the control group. Non-specific mucosal breaks were detected by DBE in 31 patients in the NSAIDs group (51%) and 29 patients in the control group (5%, p <0.0001). Aspirin was less frequently prescribed and cardiovascular disease was a less frequent indication for NSAIDs use in patients with mucosal breaks than in those without breaks. CONCLUSIONS: In the cases indicated for enteroscopy, NSAIDs enteropathy occurred in half of the patients taking NSAIDs. Aspirin seems to be less harmful to the small intestine than other NSAIDs.

DOI PubMed

The effect of medical treatment on patients with fistulizing Crohn's disease: a retrospective study.

Norimitsu Uza, Hiroshi Nakase, Satoru Ueno, Satoko Inoue, Sakae Mikami, Hiroyuki Tamaki, Minoru Matsuura, Tsutomu Chiba

Internal medicine (Tokyo, Japan) ( JAPAN SOC INTERNAL MEDICINE ) 47 ( 4 ) 193 - 9 2008 [Refereed] [Domestic journal]

BACKGROUND: Fistulas are a major complication of Crohn's disease (CD), but the treatment strategy for fistulizing Crohn's disease is controversial. The aim of this study is to analyze the efficacy of medical therapy for fistulizing Crohn's disease. METHODS: Therapeutic regimens and clinical outcome of medical therapy were evaluated in 10 patients with fistulizing Crohn's disease (6 with external fistulas, 4 with internal fistulas). Complete response was defined as fistula closure with complete arrest of drainage in cases of external fistula, and disappearance of the fistula demonstrated by imaging studies in cases of internal fistula. Clinical remission was defined as a Crohn's disease activity index of less than 150 points. RESULTS: Complete responses were observed in all 6 patients with external fistulas (4 patients treated with a combination of antibiotics and immunomodulators, and 2 also treated with infliximab). In contrast, fistula closure was observed in only 1 of 4 patients with internal fistulas. Clinical remission of CD was achieved in all patients with external fistulas, whereas there was no significant difference in the CD activity index before and after medical therapy in patients with internal fistulas. CONCLUSIONS: External fistulas were more responsive to medical therapy than internal fistulas in patients with CD. Combined treatment with antibiotics and immunomodulators might be a suitable initial therapy for CD patients with external fistulas, and infliximab can be used as an additional therapy in cases refractory to this combination therapy. However, randomized controlled studies will be required to investigate what kinds of therapies are optimal for CD patients with fistulas.

DOI PubMed CiNii

The effect of tacrolimus (FK-506) on Japanese patients with refractory Crohn's disease.

Hiroyuki Tamaki, Hiroshi Nakase, Minoru Matsuura, Satoko Inoue, Sakae Mikami, Satoru Ueno, Norimitsu Uza, Hiroshi Kitamura, Katsuhiro Kasahara, Tsutomu Chiba

Journal of gastroenterology ( SPRINGER TOKYO ) 43 ( 10 ) 774 - 9 2008 [Refereed] [Domestic journal]

BACKGROUND: Recent evidence indicates that intravenous or oral therapy with tacrolimus (FK-506) is effective in treating patients with Crohn's disease. We evaluated the usefulness of tacrolimus therapy for Japanese patients with refractory Crohn's disease. METHODS: Fourteen adult Japanese patients with Crohn's disease that was refractory to conventional therapies, including prednisolone (n = 5), azathioprine (n = 6), and infliximab (n = 5), were enrolled. Treatment with tacrolimus was started orally or intravenously and aimed for serum trough levels of 10-15 ng/ml. After the patients achieved clinical improvement, tacrolimus maintenance therapy was administered to maintain the trough level at 5-10 ng/ml. RESULTS: All patients achieved remission or significant improvement 40 days after starting tacrolimus treatment. By 120 days after the start of therapy, 9 (64%) patients achieved remission, 2 patients (14%) achieved significant improvement, and only 3 patients (21%) relapsed. The relapsed patients were treated with infliximab therapy and achieved remission. Steroids were discontinued by the 5 patients who had taken steroids before the study began. Adverse effects of tacrolimus included a temporary increase in serum creatinine concentration (n = 1, 7%), hyperkalemia (n = 1, 7%), and tremor (n = 1, 7%). CONCLUSIONS: Tacrolimus therapy is effective and well tolerated in patients with Crohn's disease that is refractory to conventional therapies.

DOI PubMed CiNii J-GLOBAL

Adminstration of PEG-Interferon to a Patient with Ulcerative Colitis and Chronic Hepatitis C Correlated with Reduced Colonic Inflammation and Reversal of Peripheral Th1/Th2 Ratios.

Katsuhiro Kasahara, Hiroshi Nakase, Norimitsu Uza, Satoru Ueno, Minoru Matsuura, Sakae Mikami, Satoko Inoue, Tsutomu Chiba

Case reports in gastroenterology 1 ( 1 ) 157 - 61 2007.12 [Refereed] [International journal]

A 42-year-old man with chronic hepatitis C and ulcerative colitis (UC) was referred to our hospital in August 2004 because of bloody diarrhea. He was clinically and endoscopically diagnosed with flare of UC. After informed consent had been obtained, he was treated with PEG-IFN-α-2a. Four weeks after initiation of PEG-IFN therapy, his abdominal symptoms gradually subsided. Intracellular cytokine assay revealed that the ratio of T-helper (Th) 1 (IFN-?)/Th 2 (IL-4) increased after IFN therapy. Three months after starting IFN therapy, colonoscopy revealed a normal mucosal pattern. He was uneventfully treated with PEG-IFN-α-2a for one year. When last seen in November 2006, he was still in remission of UC. Our intracellular cytokine data suggested that alteration of Th1/Th2 cytokine balance by IFN is one possible mechanisms of reducing intestinal inflammation in patients with UC. In this regard, IFN therapy could be useful for some patients with UC refractory to other conventional therapies.

DOI PubMed

Usefulness of quantitative real-time PCR assay for early detection of cytomegalovirus infection in patients with ulcerative colitis refractory to immunosuppressive therapies.

Takuya Yoshino, Hiroshi Nakase, Satoru Ueno, Norimitsu Uza, Satoko Inoue, Sakae Mikami, Minoru Matsuura, Katsuyuki Ohmori, Takaki Sakurai, Satoshi Nagayama, Suguru Hasegawa, Yoshiharu Sakai, Tsutomu Chiba

Inflammatory bowel diseases ( JOHN WILEY & SONS INC ) 13 ( 12 ) 1516 - 21 2007.12 [Refereed] [International journal]

BACKGROUND: Studies suggest that cytomegalovirus (CMV) infection exacerbates ulcerative colitis (UC) refractory to immunosuppressive therapies. Early and accurate diagnosis of CMV infection is important for the treatment of UC. We evaluated the usefulness of quantitative real-time polymerase chain reaction (PCR) for detecting CMV infection in inflamed colonic mucosa of patients with UC refractory to immunosuppressive therapies. METHODS: From 2003 to 2006, 30 patients (mean age: 41 +/- 18 years; 14 men, 16 women) with UC refractory to immunosuppressive therapies were enrolled in the study. We evaluated CMV infection by CMV antigenemia, histologic examination, and quantitative real-time PCR for CMV using colonic mucosa and investigated the clinical outcomes of antiviral therapy. RESULTS: CMV-DNA was detected only in the inflamed colonic mucosa in 17 (56.7%) of 30 patients. Of the 17 CMV-DNA-positive patients, 4 were positive for CMV antigenemia or inclusion bodies on histologic examination; of the 13 CMV-DNA-negative patients none was positive for CMV antigenemia or inclusion bodies. Of the 17 CMV-DNA-positive patients, 12 (70.6%) were treated with ganciclovir for 2 weeks and 10 patients went into remission. Two other patients required colectomy after antiviral therapy. In contrast, of the 13 CMV-DNA-negative patients 12 (92.3%) achieved remission after intensifying their immunosuppressive therapies. CONCLUSIONS: Quantitative real-time PCR assay for detecting CMV-DNA is useful for early, accurate diagnosis of CMV infection in patients with UC refractory to immunosuppressive therapies, enabling prompt and appropriate treatment.

DOI PubMed

Follicular lymphoma with small intestinal involvement detected by double-balloon enteroscopy.

Shuji Yamamoto, Hiroshi Nakase, Chiharu Kawanami

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association ( ELSEVIER SCIENCE INC ) 5 ( 11 ) A24 - XXIV 2007.11 [Refereed] [International journal]

DOI PubMed

DXA法による炎症性腸疾患(IBD)患者の体組成の評価およびその背景因子

桑原晶子, 幣憲一郎, 小川蓉子, 岸本正実, 辻秀美, 仲瀬裕志, 千葉勉, 稲垣暢也, 田中清, 木戸詔子

日本病態栄養学会誌 ( (一社)日本病態栄養学会 ) 10 ( 4 ) 512 - 512 2007.11

Cross-primed CD8+ cytotoxic T cells induce severe Helicobacter-associated gastritis in the absence of CD4+ T cells.

Toshiro Fukui, Akiyoshi Nishio, Kazuichi Okazaki, Katsuhiro Kasahara, Kazuyuki Saga, Junya Tanaka, Norimitsu Uza, Satoru Ueno, Masahiro Kido, Shinya Ohashi, Masanori Asada, Hiroshi Nakase, Norihiko Watanabe, Tsutomu Chiba

Helicobacter ( WILEY ) 12 ( 5 ) 486 - 97 2007.10 [Refereed] [International journal]

BACKGROUND: Although previous studies have reported important roles of CD4(+) type 1-helper T cells and regulatory T cells in Helicobacter-associated gastritis, the significance of CD8(+) cytotoxic T cells remains unknown. To study the roles of CD8(+) T cells, we examined the immune response in the gastric mucosa of Helicobacter felis-infected major histocompatibility complex (MHC) class II-deficient (II(-/-)) mice, which lack CD4(+) T cells. MATERIALS AND METHODS: Stomachs from H. felis-infected wild-type and infected MHC II(-/-) mice were examined histologically and immunohistochemically. Gastric acidity and serum levels of anti-H. felis antibodies were measured. The expression of pro-inflammatory and anti-inflammatory cytokine, Fas-ligand, perforin, and Foxp3 genes in the gastric mucosa was investigated. RESULTS: H. felis-infected MHC II(-/-) mice developed severe gastritis, accompanied by marked infiltration of CD8(+) cells. At 1 and 2 months after inoculation, mucosal inflammation and atrophy were more severe in MHC II(-/-) mice, although gastritis had reached similar advanced stages at 3 months after inoculation. There was little infiltration of CD4(+) cells, and no Foxp3-positive cells were detected in the gastric mucosa of the infected MHC II(-/-) mice. The expression of the interleukin-1beta and Fas-ligand genes was up regulated, but that of Foxp3 was down regulated in the infected MHC II(-/-) mice. Serum levels of anti-H. felis antibodies were lower in the infected MHC II(-/-) mice, despite severe gastritis. CONCLUSIONS: The present study suggests that cross-primed CD8(+) cytotoxic T cells can induce severe H.-associated gastritis in the absence of CD4(+) helper T cells and that Foxp3-positive cells may have an important role in the control of gastric inflammation.

DOI PubMed

Clinical Challenges and Images in GI. Unique gastrointestinal involvement in a patient with Henoch-Schonlein purpura.

Taro Ueo, Hiroshi Nakase, Tsutomu Chiba

Gastroenterology 133 ( 4 ) 1076, 1395 2007.10 [Refereed] [International journal]

DOI PubMed

Diagnosis and treatment of obscure GI bleeding with double balloon endoscopy.

Hiroshi Nakase, Minoru Matsuura, Sakae Mikami, Tsutomu Chiba

Gastrointestinal endoscopy ( MOSBY-ELSEVIER ) 66 ( 3 Suppl ) S78-81 - S81 2007.09 [Refereed] [International journal]

DOI PubMed

Ileal polyposis caused by follicular lymphoma.

Minoru Matsuura, Hiroshi Nakase, Naomi Mochizuki

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 5 ( 8 ) e30 2007.08 [Refereed] [International journal]

DOI PubMed

Gastrointestinal: Ileal ulcers induced by non-steroidal anti-inflammatory drugs

M. Matsuura, H. Nakase, F. Nakamura, Y. Ueda, S. Mikami, T. Yoshino, S. Ueno, N. Uza, T. Chiba

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY ( BLACKWELL PUBLISHING ) 22 ( 8 ) 1346 - 1346 2007.08 [Refereed]

DOI PubMed

Open label trial of clarithromycin therapy in Japanese patients with Crohn's disease.

Satoko Inoue, Hiroshi Nakase, Minoru Matsuura, Satoru Ueno, Norimitsu Uza, Hiroshi Kitamura, Sakae Mikami, Hiroyuki Tamaki, Katsuhiro Kasahara, Tsutomu Chiba

Journal of gastroenterology and hepatology ( BLACKWELL PUBLISHING ) 22 ( 7 ) 984 - 8 2007.07 [Refereed] [International journal]

BACKGROUND AND AIM: The pathogenesis of Crohn's disease is unclear, but many studies suggest that luminal bacteria play an important role in chronic intestinal inflammation in patients with this condition. Clarithromycin is a macrolide antibiotic with immunomodulatory activity. The aim of this study was to evaluate the effect of clarithromycin therapy in Japanese patients with Crohn's disease. METHODS: Fourteen patients with active Crohn's disease (12 with ileocolonic, one with colonic, one with small bowel type) were treated with oral clarithromycin 200 mg twice daily for 4 weeks. Patients who showed a clinical response within 4 weeks continued the therapy for up to 24 weeks. Four patients also received azathioprine. Clinical activity was assessed with the Crohn's Disease Activity Index (CDAI) at entry and at 4, 12, and 24 weeks after starting clarithromycin. RESULTS: The mean CDAI score at entry was 343.5. Within 4 weeks, eight (57.1%) of the 14 patients showed clinical improvement, and five (35.7%) of the eight patients achieved remission. All of those eight patients continued clarithromycin therapy after 4 weeks, and six (42.9%) were in clinical remission at 12 weeks. Of the 14 total patients, four (28.6%) continued clarithromycin for more than 24 weeks, and have remained in remission. Patients who received azathioprine concomitantly had a better response to clarithromycin therapy. No severe side-effects were observed during the study period. CONCLUSIONS: This open label study showed encouraging results of clarithromycin therapy in Japanese patients with active Crohn's disease.

DOI PubMed

Involvement of cytomegalovirus infection in the ileal lesions of the patient with Behçet's disease.

Sakae Mikami, Hiroshi Nakase, Satoru Ueno, Minoru Matsuura, Takaki Sakurai, Tsutomu Chiba

Inflammatory bowel diseases ( JOHN WILEY & SONS INC ) 13 ( 6 ) 802 - 3 2007.06 [Refereed] [International journal]

DOI PubMed

Gastrointestinal: Pneumatosis of the ascending colon

S. Mikami, H. Nakase, T. Sakurai, T. Chiba, S. Shimizu

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY ( BLACKWELL PUBLISHING ) 22 ( 5 ) 760 - 760 2007.05 [Refereed]

DOI PubMed

Localized cytomegalovirus reactivation after radiotherapy for high-grade gastric lymphoma.

Kazuyuki Saga, Toshiro Fukui, Yoko Kato, Toshiki Komeda, Hiroshi Nakase, Norihiko Watanabe, Akiyoshi Nishio, Tsutomu Chiba

Gastrointestinal endoscopy ( MOSBY-ELSEVIER ) 65 ( 3 ) 545 - 7 2007.03 [Refereed] [International journal]

DOI PubMed

Hepatobiliary and pancreatic: Hemosuccus pancreaticus

J. Maruyama, H. Nakase, T. Chiba

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY ( BLACKWELL PUBLISHING ) 22 ( 3 ) 446 - 446 2007.03 [Refereed]

DOI

Importance of early detection of cytomegalovirus infection in refractory inflammatory bowel disease.

Hiroshi Nakase, Takuya Yoshino, Satoru Ueno, Norimitsu Uza, Sakae Mikami, Minoru Matsuura, Tsutomu Chiba

Inflammatory bowel diseases ( JOHN WILEY & SONS INC ) 13 ( 3 ) 364 - 364 2007.03 [Refereed] [International journal]

DOI PubMed

尿中γ-カルボキシグルタミン酸(Gla)の意義に関する研究炎症性腸疾患(IBD)患者における骨量低下との関係

桑原晶子, 辻秀美, 幣憲一郎, 仲瀬裕志, 千葉勉, 岡野登志夫, 姫野雅子, 田中清, 木戸詔子

日本病態栄養学会誌 ( (一社)日本病態栄養学会 ) 10 ( 1 ) 37 - 44 2007.03

炎症性腸疾患(IBD)患者の尿中γ-カルボキシグルタミン酸(Gla)、骨量、血液および尿中の既知の骨吸収マーカーを測定することにより骨減少の実態を明らかにし、尿中Glaの骨代謝マーカーおよびビタミンK栄養状態の指標としての有用性について検討した。炎症性腸疾患患者のうち、ビタミンK製剤と骨吸収抑制剤服用者を除く76例を対象とした。栄養の指標として血清総タンパク、アルブミン、総コレステロール、貧血の指標として赤血球数とヘモグロビン、炎症の指標としてC反応性タンパクと白血球数の測定値を用いた。IBD患者では.尿中Gla高値を示す者がクローン病患者で38%、潰瘍性大腸炎患者で21%存在し、尿中DPDと弱い正の相関が見られた。また、尿中Glaは血清ビタミンKレベルとも正の相関が得られた。

A case of ileal heterotopic pancreas with repeated melena.

Yoko Endo, Shujiro Yazumi, Yuto Kimura, Norimitsu Uza, Minoru Matsuura, Yuzo Kodama, Hiroshi Nakase, Tsutomu Chiba

Gastrointestinal endoscopy ( MOSBY-ELSEVIER ) 65 ( 1 ) 156 - 7 2007.01 [Refereed] [International journal]

DOI PubMed

A CASE OF HEMORRHAGIC VASCULAR ECTASIA OF THE SMALL INTESTINE, DIAGNOSED AND TREATED BY A COMBINATION OF CAPSULE ENDOSCOPY AND DOUBLE BALLOON ENDOSCOPY

OKITA Kenji, MIYAMOTO Shinichi, KUSAKA Toshihiro, NAKASE Hiroshi, MATSUURA Minoru, MIZUTA Kazuhiko, NISHIO Akiyoshi, CHIBA Tsutomu

Gastroenterological Endoscopy 49 ( 2 ) 190 - 194 2007 [Refereed]

DOI CiNii J-GLOBAL

Rescue therapy with tacrolimus for a patient with severe ulcerative colitis refractory to combination leukocytapheresis and high-dose corticosteroid therapy.

Hiroshi Nakase, Sakae Mikami, Minoru Matsuura, Satoru Ueno, Norimitsu Uza, Satoko Inoue, Hiroshi Kitamura, Katsuhiro Kasahara, Takuya Yoshino, Yasuhiro Takeda, Tsutomu Chiba

Internal medicine (Tokyo, Japan) ( JAPAN SOC INTERNAL MEDICINE ) 46 ( 11 ) 717 - 20 2007 [Refereed] [Domestic journal]

A19-year-old man complaining of severe diarrhea and hematochezia was admitted to our hospital. Endoscopic findings and laboratory data revealed that he had ulcerative colitis (UC). Despite combination therapy with high-dose corticosteroids and intensive granulocytapheresis, his condition did not improve. Therefore, we initiated tacrolimus therapy. Intravenous administration of tacrolimus with a trough level of 10 to 15 ng/ml relieved his abdominal symptoms within 1 week. The patient experienced no UC relapse 1 year after treatment with oral tacrolimus. Tacrolimus is a promising therapy for patients with UC refractory to the combination of high-dose corticosteroids and leukocytapheresis.

DOI PubMed CiNii

Magnified endoscopic view of primary follicular lymphoma at the duodenal papilla.

Hiroshi Nakase, Minoru Matsuura, Sakae Mikami, Tsutomu Chiba

Internal medicine (Tokyo, Japan) ( JAPAN SOC INTERNAL MEDICINE ) 46 ( 3 ) 141 - 2 2007 [Refereed] [Domestic journal]

DOI PubMed CiNii

Hepatobiliary and pancreatic: Hemosuccus pancreaticus

J. Maruyama, H. Nakase, T. Chiba

Journal of Gastroenterology and Hepatology (Australia) ( Blackwell Publishing ) 22 ( 3 ) 446 2007 [Refereed]

DOI PubMed

Identification of a novel autoantibody against pancreatic secretory trypsin inhibitor in patients with autoimmune pancreatitis

Asada Masanori, Nishio Akiyoshi, Uchida Kazushige, Kido Masahiro, Ueno Satoru, Uza Norimitsu, Kiriya Keiichi, Inoue Satoko, Kitamura Hiroshi, Ohashi Shinya, Tamaki Hiroyuki, Fukui Toshiro, Matsuura Minoru, Kawasaki Kimio, Nishi Toshiki, Watanabe Norihiko, Nakase Hiroshi, Chiba Tsutomu, Okazaki Kazuichi

Suizo ( Japan Pancreas Society ) 22 ( 1 ) 82 - 84 2007

CiNii

Caecal cancer associated with longstanding Crohn's disease.

Norimitsu Uza, Hiroshi Nakase, Yasuhide Kuwabara, Shigehiko Fujii, Tsutomu Chiba

Lancet (London, England) ( LANCET LTD ) 368 ( 9549 ) 1842 - 1842 2006.11 [Refereed] [International journal]

DOI PubMed

炎症性腸疾患(IBD)患者における脂質摂取制限が患者QOLに及ぼす影響

辻秀美, 幣憲一郎, 桑原晶子, 近藤歌奈, 吉田朋美, 姫野雅子, 小川蓉子, 仲瀬裕志, 木戸詔子, 田中清, 稲垣暢也

日本病態栄養学会誌 ( (一社)日本病態栄養学会 ) 9 ( 4 ) 444 - 444 2006.11

炎症性腸疾患(IBD)患者の骨量改善への影響因子の検討尿中Glaと血中脂溶性ビタミンについて

桑原晶子, 幣憲一郎, 小川蓉子, 姫野雅子, 辻秀美, 仲瀬裕志, 千葉勉, 田中清, 岡野登志夫, 木戸詔子

日本病態栄養学会誌 ( (一社)日本病態栄養学会 ) 9 ( 4 ) 531 - 531 2006.11

Human thioredoxin-1 ameliorates experimental murine colitis in association with suppressed macrophage inhibitory factor production.

Hiroyuki Tamaki, Hajime Nakamura, Akiyoshi Nishio, Hiroshi Nakase, Satoru Ueno, Norimitsu Uza, Masahiro Kido, Satoko Inoue, Sakae Mikami, Masanori Asada, Keiichi Kiriya, Hiroshi Kitamura, Shinya Ohashi, Toshiro Fukui, Kimio Kawasaki, Minoru Matsuura, Yasuyuki Ishii, Kazuichi Okazaki, Junji Yodoi, Tsutomu Chiba

Gastroenterology ( W B SAUNDERS CO-ELSEVIER INC ) 131 ( 4 ) 1110 - 21 2006.10 [Refereed] [International journal]

BACKGROUND & AIMS: Thioredoxin-1 (TRX) is a small multifunctional protein with antioxidative and redox-regulating functions. In this study, we investigated the significance of TRX in patients with inflammatory bowel disease (IBD) and the ability and mechanism to ameliorate experimental colitis. METHODS: Serum TRX and macrophage migration inhibitory factor (MIF) levels were measured in patients with IBD. The effects of TRX were evaluated in a dextran sulfate sodium (DSS)-induced colitis model by comparing TRX-overexpressing transgenic (TRX-TG) and control mice. We further evaluated the effect of recombinant human TRX (rhTRX) administration on DSS-induced colitis and colonic inflammation of interleukin (IL)-10 knockout (IL-10 KO) mice. Colonic inflammation was examined clinically and histologically. Proinflammatory cytokine levels were examined in colonic tissues, and MIF levels were measured in colonic tissues and sera in mice. The effect of TRX on MIF production was also analyzed in vitro. RESULTS: Serum TRX and MIF levels were significantly higher in patients with IBD than normal controls, and TRX levels correlated with disease activity. TRX significantly ameliorated DSS-induced colitis and colonic inflammation of IL-10 KO mice. Increase of tumor necrosis factor-alpha and interferon-gamma in colonic tissues was significantly suppressed in TRX-TG mice compared with wild-type mice. MIF levels in colonic tissues and sera were significantly lower in TRX-TG mice than in wild-type mice, irrespective of DSS administration. Anti-TRX treatment exacerbated DSS-induced colitis. In vitro studies demonstrated that rhTRX suppressed MIF production in human monocyte cells. CONCLUSIONS: TRX might have a potential as a novel therapeutic agent for the treatment of IBD.

DOI PubMed

Clinical challenges and images in GI. Meckel's diverticulum with an enterolith.

Norimitsu Uza, Hiroshi Nakase, Tsutomu Chiba

Gastroenterology 131 ( 2 ) 351, 690 2006.08 [Refereed] [International journal]

PubMed

Identification of a novel autoantibody against pancreatic secretory trypsin inhibitor in patients with autoimmune pancreatitis.

Masanori Asada, Akiyoshi Nishio, Kazushige Uchida, Masahiro Kido, Satoru Ueno, Norimitsu Uza, Keiichi Kiriya, Satoko Inoue, Hiroshi Kitamura, Shinya Ohashi, Hiroyuki Tamaki, Toshiro Fukui, Minoru Matsuura, Kimio Kawasaki, Toshiki Nishi, Norihiko Watanabe, Hiroshi Nakase, Tsutomu Chiba, Kazuichi Okazaki

Pancreas ( LIPPINCOTT WILLIAMS & WILKINS ) 33 ( 1 ) 20 - 6 2006.07 [Refereed] [International journal]

OBJECTIVES: Although autoimmune pancreatitis (AIP) has been recently recognized as a new disease entity of chronic pancreatitis, the clinical diagnosis of the disease remains disputed. Autoantibodies against carbonic anhydrase II and lactoferrin are detected in most patients with AIP, but not in about 10%. We undertook this study to determine whether additional autoantibodies are present in the serum level of AIP patients. METHODS: We recruited 26 patients with AIP for the study. For comparison, we also recruited 53 patients with various pancreatic diseases and 12 healthy subjects. We immunoscreened human pancreatic cDNA library using patients' sera. Positive clones were analyzed by DNA sequencing and were constructed into a pGEX-4T-1 expression vector. The recombinant proteins were used as antigens in enzyme-linked immunosorbent assay to screen the subjects' sera for autoantibodies. RESULTS: We cloned a cDNA encoding the pancreatic secretory trypsin inhibitor (PSTI). Among 26 patients with AIP, autoantibodies against PSTI were significantly positive in 11 (42.3%) by western blotting and in 8 (30.8%) by enzyme-linked immunosorbent assay, respectively. However, none of control subjects was positive for anti-PSTI antibodies. CONCLUSIONS: These findings suggest that PSTI may be related to the pathogenesis of AIP, and autoantibodies against PSTI can be a useful diagnostic marker for the disease.

DOI PubMed

Cytomegalovirus infection in patients with ulcerative colitis diagnosed by quantitative real-time PCR analysis.

Tadayuki Kou, Hiroshi Nakase, Hiroyuki Tamaki, Toyoichiro Kudo, Akiyoshi Nishio, Tsutomu Chiba

Digestive diseases and sciences ( SPRINGER ) 51 ( 6 ) 1052 - 5 2006.06 [Refereed] [International journal]

DOI PubMed

Gastric mucosal hyperplasia via upregulation of gastrin induced by persistent activation of gastric innate immunity in major histocompatibility complex class II deficient mice

T Fukui, A Nishio, K Okazaki, N Uza, S Ueno, M Kido, S Inoue, H Kitamura, K Kiriya, S Ohashi, M Asada, H Tamaki, M Matsuura, K Kawasaki, K Suzuki, K Uchida, H Fukui, H Nakase, N Watanabe, T Chiba

GUT ( B M J PUBLISHING GROUP ) 55 ( 5 ) 607 - 615 2006.05 [Refereed]

Background and aim: Major histocompatibility complex class II deficient (A alpha(o/o)) mice have decreased CD4(+) T cells, making them immunologically similar to patients with acquired immunodeficiency syndrome (AIDS). Both patients with AIDS and A alpha(o/o) mice have hypertrophic gastric folds. To clarify the mechanism of gastric mucosal hyperplasia, we investigated the pathophysiology and the role of the innate immunity in the stomach of A alpha(o/o) mice. Methods: Stomachs from 1-6 month old A alpha(o/o) mice, kept under specific pathogen free conditions, were examined at 1 month intervals histologically and immunohistochemically. Gene expression of proinflammatory cytokines, Toll-like receptors (TLRs), cyclooxygenase (COX)-2, and myeloperoxidase (MPO) activity in the gastric mucosa was investigated. Serum gastrin levels and gastric acidity were measured. Bacterial culture of the stomach was performed. To clarify the roles of hypergastrinaemia in the gastric mucosa, a gastrin receptor antagonist ( AG041R) was administered. Results: A alpha(o/o) mice had a diffusely thick corpus mucosa with infiltration of CD11b(+) granulocytes and macrophages. Anti-Ki67 staining demonstrated expansion of the proliferating neck zone. Gene expression of interleukin 1 beta, interferon gamma, TLR-2, TLR-4, and COX-2 were upregulated, and MPO activity was increased. Only a small amount of non-pathogenic bacteria was detected in the stomach. Serum gastrin levels and Reg-I alpha positive cells in the gastric mucosa increased, despite normal gastric acidity. After treatment with AG041R, gastric mucosal thickness was significantly reduced. Conclusion: Persistent activation of innate immunity in the stomach induced gastric mucosal hyperplasia through upregulation of gastrin synthesis in A alpha(o/o) mice, suggesting a pathophysiology similar to the gastric changes in patients with AIDS.

DOI PubMed

Protective roles of redox-active protein thioredoxin-1 for severe acute pancreatitis.

Shinya Ohashi, Akiyoshi Nishio, Hajime Nakamura, Masahiro Kido, Satoru Ueno, Norimitsu Uza, Satoko Inoue, Hiroshi Kitamura, Keiichi Kiriya, Masanori Asada, Hiroyuki Tamaki, Minoru Matsuura, Kimio Kawasaki, Toshiro Fukui, Norihiko Watanabe, Hiroshi Nakase, Junji Yodoi, Kazuichi Okazaki, Tsutomu Chiba

American journal of physiology. Gastrointestinal and liver physiology ( AMER PHYSIOLOGICAL SOC ) 290 ( 4 ) G772-81 - G781 2006.04 [Refereed] [International journal]

Severe acute pancreatitis is a disease with high mortality, and infiltration of inflammatory cells and reactive oxygen species have a crucial role in the pathophysiology of this disease. Thioredoxin-1 (TRX-1) is an endogenous redox-active multifunctional protein with antioxidant and anti-inflammatory effects. TRX-1 is induced in various inflammatory conditions and shows cytoprotective effects. The aim of the present study was to clarify the protective roles of TRX-1 in the host defense mechanism against severe acute pancreatitis. Experimental acute pancreatitis was induced by intraperitoneal administration of cerulein, a CCK analog, and aggravated by lipopolysaccharide injection in transgenic mice overexpressing human TRX-1 (hTRX-1) and control C57BL/6 mice. Transgenic overexpression of hTRX-1 strikingly attenuated the severity of experimental acute pancreatitis. TRX-1 overexpression suppressed neutrophil infiltration as determined by myeloperoxidase activity, oxidative stress as determined by malondialdehyde concentration, and cytoplasmic degradation of inhibitor of kappaB-alpha, thereby suppressing proinflammatory cytokines, tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6; a neutrophil chemoattractant, keratinocyte-derived chemokine; and inducible nitric oxide synthase in the pancreas. Administration of recombinant hTRX-1 also suppressed neutrophil infiltration, reduced the inflammation of the pancreas and the lung, and improved the mortality rate. The present study suggests that TRX-1 has potent antioxidant and anti-inflammatory actions in experimental acute pancreatitis and might be a new therapeutic strategy to improve the prognosis of severe acute pancreatitis.

DOI PubMed

Solitary rectal ulcer syndrome associated with ulcerative colitis.

Norimitsu Uza, Hiroshi Nakase, Kazuhiko Nishimura, Shunichi Yoshida, Kenji Kawabata, Tsutomu Chiba

Gastrointestinal endoscopy ( MOSBY-ELSEVIER ) 63 ( 2 ) 355 - 6 2006.02 [Refereed] [International journal]

DOI PubMed

Specific antibodies against recombinant protein of insertion element 900 of Mycobacterium avium subspecies paratuberculosis in Japanese patients with Crohn's disease.

Hiroshi Nakase, Akiyoshi Nishio, Hiroyuki Tamaki, Minoru Matsuura, Masanori Asada, Tsutomu Chiba, Kazuichi Okazaki

Inflammatory bowel diseases ( LIPPINCOTT WILLIAMS & WILKINS ) 12 ( 1 ) 62 - 9 2006.01 [Refereed] [International journal]

BACKGROUND: Mycobacterial avium subspecies paratuberculosis (MAP) infection has been hypothesized as an etiological factor of Crohn's disease (CD). However, the involvement of MAP in the pathophysiology of CD is controversial. The aim of this study is to investigate whether MAP is involved in the pathogenesis of CD with the glutathione S-transferase fusion recombinant protein encoding a portion of insertion element (IS) 900 (IS900-GST), which is specific for MAP. METHODS: Serum samples from the patients with CD (n = 50), ulcerative colitis (n = 40), colonic tuberculosis (n = 20), and non-IBD controls (n = 44), were applied for solid-phase enzyme-linked immunosorbent assay (ELISA) to detect antibodies against MAP and Saccharomyces cerevisiae. IS900-GST, which was made by the pGST-4T-2 vector inserted with polymerase chain reaction-amplified IS900DNA, was used as an antigen of MAP. Moreover, we studied the relationship between antibodies against IS900-GST and clinical characteristics. RESULTS: ELISA showed that the serum level of immunoglobulin G and immunoglobulin A antibodies against IS900-GST (anti-IS900) in patients with CD were significantly higher than those with ulcerative colitis, colonic tuberculosis, and control subjects. The levels of anti-IS900 tended to be higher in CD patients with small intestinal involvement than with colonic involvement alone. Anti-IS900 in patients with penetrating- and stricture-type CD was significantly higher than with inflammatory-type CD. Furthermore, a negative correlation was found between the titer of anti-IS900 and disease duration. Anti-IS900 was not associated with surgical treatment nor was it associated with the use of immunosuppressants. No significant correlation was observed between the serum levels of anti-IS900 and anti-S cerevisiae antibody. CONCLUSIONS: This is the first demonstration of the ELISA system of detecting antibodies against IS900 in IBD patients. MAP could be involved in the pathophysiology of Japanese patients with CD.

DOI PubMed

Diffuse hepatoid adenocarcinoma in the peritoneal cavity.

Hiroshi Kitamura, Kazuki Ikeda, Toyohiko Honda, Tetsuro Ogino, Hiroshi Nakase, Tsutomu Chiba

Internal medicine (Tokyo, Japan) ( JAPAN SOC INTERNAL MEDICINE ) 45 ( 19 ) 1087 - 91 2006 [Refereed] [Domestic journal]

Hepatoid adenocarcinoma (HAC) is a rare tumor that occurs mostly in the gastrointestinal tract. We encountered a 68-year-old man suffering from HAC with severe ascites. The serum and ascitic alpha-fetoprotein (AFP) levels were markedly high. Computed tomography (CT) revealed that multiple nodular lesions were disseminated only in the peritoneal cavity. Based on laparoscopic and histological findings, this tumor was diagnosed as diffuse HAC which was developed primarily in the peritoneum. Despite treatments with appropriate chemotherapy, he died six months after diagnosis. According to literature updates, this is the first documented case of diffuse HAC which developed in the peritoneum.

DOI PubMed CiNii

Gluten sensitivity in Japanese patients with adult-onset cerebellar ataxia.

Masafumi Ihara, Fumi Makino, Hideyuki Sawada, Takahiro Mezaki, Kotaro Mizutani, Hiroshi Nakase, Makoto Matsui, Hidekazu Tomimoto, Shun Shimohama

Internal medicine (Tokyo, Japan) ( JAPAN SOC INTERNAL MEDICINE ) 45 ( 3 ) 135 - 40 2006 [Refereed] [Domestic journal]

OBJECTIVE: Gluten sensitivity is associated with multiple neurological abnormalities including gluten ataxia, motor neuron disease-like neuropathy, small fiber type neuropathy, cognitive impairment, and even parkinsonism. We investigated whether or not gluten sensitivity is involved in Japanese patients with idiopathic cerebellar ataxia with extracerebellar presentation. PATIENTS OR MATERIALS: Fourteen patients with idiopathic cerebellar ataxia with extracerebellar presentation (autonomic instability, parkinsonism, or pyramidal dysfunction in varying combinations) were screened for anti-gliadin antibodies (AGA) to analyze for the presence or absence of gluten sensitivity. Patients with typical MR findings of multiple system atrophy of the cerebellar type were excluded. As disease controls without cerebellar ataxia, 9 patients with Parkinson's disease and 18 patients with amyotrophic lateral sclerosis were screened for AGA. Forty-seven normal controls were also screened for AGA. RESULTS: We found a high prevalence of AGA in 5 (36%) of 14 cerebellar ataxia patients, but in only 1 (4%) of 27 disease controls without cerebellar ataxia (odds ratio, 14.4; 95% CI, 1.41147; p<0.05) and in only 1 (2%) of 47 normal controls (odds ratio, 25.6; 95% CI, 2.66246; p<0.001). Among the cerebellar ataxia patients, atypical features such as sensorimotor neuropathy and/or mild cognitive impairment were more prevalent in the AGA-positive group (60%) than in the AGA-negative group (0%). In one of the ataxic patients with AGA, a gluten-free diet had positive effects on neurological symptoms and nutritional status. CONCLUSION: Gluten sensitivity is involved in at least some of the unexplained neurological symptoms of Japanese patients with adult-onset, sporadic cerebellar ataxia.

DOI PubMed CiNii

A case of collagenous colitis (microscopic colitis) with a long time follow up

S. Mikami, H. Nakase, T. Sakuria, H. Sawami, T. Chiba

Gastroenterological Endoscopy 48 ( 11 ) 2645 - 2650 2006 [Refereed]

DOI

Rectal carcinoid tumor mimicking colonic adenomatous lesion.

Hiroshi Nakase, Minoru Matsuura, Norimitsu Uza, Satoru Ueno, Akiyoshi Nishio, Tsutomu Chiba

Gastrointestinal endoscopy ( MOSBY, INC ) 62 ( 6 ) 976 - 7 2005.12 [Refereed] [International journal]

DOI PubMed

IBD患者における骨減少と尿中Glaとの相関性

桑原晶子, 幣憲一郎, 姫野雅子, 辻秀美, 仲瀬裕志, 千葉勉, 田中清, 木戸詔子

日本病態栄養学会誌 ( (一社)日本病態栄養学会 ) 8 ( 4 ) 390 - 390 2005.11

炎症性腸疾患(IBD)患者における骨減少及び脂溶性ビタミン欠乏症(第2報)

辻秀美, 幣憲一郎, 奥野梓, 土屋恵美, 姫野雅子, 桑原晶子, 仲瀬裕志, 千葉勉, 木戸詔子, 田中清

日本病態栄養学会誌 ( (一社)日本病態栄養学会 ) 8 ( 4 ) 390 - 390 2005.11

Possible role of REG I alpha protein in ulcerative colitis and colitic cancer

A Sekikawa, H Fukui, S Fujii, A Nanakin, N Kanda, Y Uenoyama, T Sawabu, H Hisatsune, T Kusaka, S Ueno, H Nakase, H Seno, T Fujimori, T Chiba

GUT ( B M J PUBLISHING GROUP ) 54 ( 10 ) 1437 - 1444 2005.10 [Refereed]

Background and aims: Although regenerating gene (REG) I alpha protein may be involved in the inflammation and carcinogenesis in the gastrointestinal tract, its pathophysiological role in ulcerative colitis (UC) and the resulting colitic cancer remains unclear. We investigated expression of the REG I alpha gene and its protein in UC and colitic cancer tissues. We examined whether cytokines are responsible for REG I alpha gene expression and whether REG I alpha protein has a trophic and/or an antiapoptotic effect on colon cancer cells. Methods: Expression of REG Ia mRNA and its gene product in UC tissues was analysed by real time reverse transcription-polymerase chain reaction and immunohistochemistry, respectively. The effects of cytokines on REG I alpha promoter activity were examined in LoVo cells by luciferase reporter assay. The effects of REG I alpha protein on growth and H2O2 induced apoptosis were examined in LoVo cells by MTT and TUNEL assays, respectively. Results: REG I alpha protein was strongly expressed in inflamed epithelium and in dysplasias and cancerous lesions in UC tissues. The level of REG Ia mRNA expression in UC tissues correlated significantly with severity of inflammation and disease duration. REG Ia promoter activity was enhanced by stimulation with interferon gamma or interleukin 6. REG I alpha protein promoted cell growth and conferred resistance to H2O2 induced apoptosis in LoVo cells. REG I alpha protein promoted Akt phosphorylation and enhanced Bcl-xL and Bcl-2 expression in LoVo cells. Conclusions: The REG I alpha gene is inducible by cytokines and its gene product may function as a mitogenic and/or an antiapoptotic factor in the UC-colitic cancer sequence.

DOI PubMed

Cecal ameboma.

Minoru Matsuura, Hiroshi Nakase, Takahiro Fujimori, Kazuo Mizuma, Yoshiyasu Tsuda, Tsutomu Chiba

Gastrointestinal endoscopy ( MOSBY, INC ) 62 ( 3 ) 442 - 3 2005.09 [Refereed] [International journal]

DOI PubMed

Helicobacter felis-induced gastritis was suppressed in mice overexpressing thioredoxin-1.

Kimio Kawasaki, Akiyoshi Nishio, Hajime Nakamura, Kazushige Uchida, Toshiro Fukui, Masaya Ohana, Hazuki Yoshizawa, Shinya Ohashi, Hiroyuki Tamaki, Minoru Matsuura, Masanori Asada, Toshiki Nishi, Hiroshi Nakase, Shinya Toyokuni, Wenrui Liu, Junji Yodoi, Kazuichi Okazaki, Tsutomu Chiba

Laboratory investigation; a journal of technical methods and pathology ( NATURE PUBLISHING GROUP ) 85 ( 9 ) 1104 - 17 2005.09 [Refereed] [International journal]

Thioredoxin-1 (TRX-1) is a redox-active protein involved in scavenging reactive oxygen species and regulating redox-sensitive transcription factors. TRX-1 is induced in various inflammatory conditions and shows cytoprotective action. We investigated the roles of TRX-1 in the host defense mechanism against Helicobacter felis (H. felis) infection. Transgenic (TG) mice overexpressing human TRX-1 and wild-type (WT) mice were orally inoculated with H. felis. After 2 months, histology, oxidative damage, and gene expression of several cytokines, including macrophage inflammatory protein-2 (MIP-2), a murine equivalent to interleukin (IL)-8, in the gastric mucosa were investigated. Furthermore, the effects of TRX-1 on oxidative stress and neutrophil migration were studied both in vivo and in vitro. The gastric mucosa was thickened in H. felis-infected WT mice, but not in infected TRX-1-TG mice. Histologically, all H. felis-infected WT mice developed moderate-to-severe gastritis, whereas the development of gastritis was significantly suppressed in infected TRX-1-TG mice. Oxidative damage markers, 8-hydroxy-2'-deoxyguanosine and malondialdehyde, increased in the stomach of infected WT mice, but not TRX-1-TG mice. Upregulation of IL-1beta and tumor necrosis factor-alpha gene expression in H. felis-infected TRX-1-TG mice was significantly lower than in WT mice. However, upregulation of MIP-2 and IL-7 was not different between the two groups. TRX-1 suppressed oxidative cytotoxicity and DNA damage, and inhibited neutrophil migration both in vivo and in vitro. The present study suggests that overexpression of TRX-1 suppresses H. felis-induced gastritis by inhibiting chemotaxis of neutrophils and reducing oxidative stress.

DOI PubMed

Usefulness of famotidine in functional dyspepsia patient treatment: comparison among prokinetic, acid suppression and antianxiety therapies

H Seno, H Nakase, T Chiba

ALIMENTARY PHARMACOLOGY & THERAPEUTICS ( BLACKWELL PUBLISHING ) 21 ( 2 ) 32 - 36 2005.06 [Refereed]

Background: The treatment of functional dyspepsia is controversial. Aim: The purpose of this paper is to clarify the initial effect of prokinetic, acid suppression and antianxiety treatment for functional dyspepsia patients. Patients and methods: Sixty-four functional dyspepsia patients without Helicobacter pylori infection were randomly assigned to 15 mg/day of mosapride, 40 mg/day of famotidine, or 30 mg/day of tandospirone during an 8-week treatment. Individual functional dyspepsia symptoms were evaluated with 4 cm visual analogue scale before and at 2, 4 and 8 weeks after treatment. Results: Among 64 enrolled patients, 62 completed the study. Within 2 weeks, visual analogue scale score in the mosapride-treated group decreased from 2.29 +/- 0.14 to 1.57 +/- 0.2 0; in the famotidine from 2.04 +/- 0.16 to 1.09 +/- 0.12 (mean +/- S.E.). Therefore, there were significant improvements of functional dyspepsia symptoms in mosapride-and famotidine-treated patients (P < 0.01). Furthermore, famotidine was significantly more effective than mosapride (P < 0.05). On the contrary. visual analogue scale score in the tandospirone therapy was 2.23 +/- 0.20 and 2.13 +/- 0.22 before and at 2 weeks, respectively. without any significant improvement. Conclusions: A treatment regimen of famotidine at 40 mg/day had a significant favourable effect on the clinical outcome in functional dyspepsia patients.

DOI PubMed

Usefulness of famotidine in functional dyspepsia patient treatment: Comparison among prokinetic, acid suppression and antianxiety therapies

H. Seno, H. Nakase, T. Chiba

Alimentary Pharmacology and Therapeutics, Supplement 21 ( 2 ) 32 - 36 2005.06 [Refereed]

Background: The treatment of functional dyspepsia is controversial. Aim: The purpose of this paper is to clarify the initial effect of prokinetic, acid suppression and antianxiety treatment for functional dyspepsia patients. Patients and methods: Sixty-four functional dyspepsia patients without Helicobacter pylori infection were randomly assigned to 15 mg/day of mosapride, 40 mg/day of famotidine, or 30 mg/day of tandospirone during an 8-week treatment. Individual functional dyspepsia symptoms were evaluated with 4 cm visual analogue scale before and at 2, 4 and 8 weeks after treatment. Results: Among 64 enrolled patients, 62 completed the study. Within 2 weeks, visual analogue scale score in the mosapride-treated group decreased from 2.29 ± 0.14 to 1.57 ± 0.20 in the famotidine from 2.04 ± 0.16 to 1.09 ± 0.12 (mean ± S.E.). Therefore, there were significant improvements of functional dyspepsia symptoms in mosapride- and famotidine-treated patients (P < 0.01). Furthermore, famotidine was significantly more effective than mosapride (P < 0.05). On the contrary, visual analogue scale score in the tandospirone therapy was 2.23 ± 0.20 and 2.13 ± 0.22 before and at 2 weeks, respectively, without any significant improvement. Conclusions: A treatment regimen of famotidine at 40 mg/day had a significant favourable effect on the clinical outcome in functional dyspepsia patients. © 2005 Blackwell Publishing Ltd.

PubMed

[Etiopathogenesis and aggravating factors in ulcerative colitis].

Satoko Inoue, Hiroshi Nakase, Tsutomu Chiba

Nihon rinsho. Japanese journal of clinical medicine 63 ( 5 ) 757 - 62 2005.05 [Refereed] [Domestic journal]

Ulcerative colitis (UC) is a chronic inflammatory disease limited to the colon. Although the pathogenesis of inflammatory bowel disease (IBD) remains unclear, several studies have suggested that the onset and development of IBD require the interaction between genetic susceptibility, stimulation by luminal bacterial antigens and adjuvants, and episodic environmental triggers which break the mucosal barrier. There are many reports that experimental enterocolitis in animals does not occur in a sterile (germ free) environment and is prevented by antibiotics therapy. Moreover, patients with UC exhibit pathological immune responses to many commensal enteric bacterial species. Recent data showed that certain probiotic species decrease relapse of UC. These findings suggest that the most possible cause of UC is associated with chronic intestinal inflammation which is induced and perpetuated by non-pathogenic bacteria in genetically susceptible hosts.

PubMed

Therapeutic effects of rectal administration of basic fibroblast growth factor on experimental murine colitis.

Minoru Matsuura, Kazuichi Okazaki, Akiyoshi Nishio, Hiroshi Nakase, Hiroyuki Tamaki, Kazushige Uchida, Toshiki Nishi, Masanori Asada, Kimio Kawasaki, Toshiro Fukui, Hazuki Yoshizawa, Shinya Ohashi, Satoko Inoue, Chiharu Kawanami, Hiroshi Hiai, Yasuhiko Tabata, Tsutomu Chiba

Gastroenterology ( W B SAUNDERS CO ) 128 ( 4 ) 975 - 86 2005.04 [Refereed] [International journal]

BACKGROUND & AIMS: Basic fibroblast growth factor (bFGF) is a promising therapeutic agent for various diseases. It remains unclear, however, whether bFGF is effective for the treatment of inflammatory bowel disease. The aim of this study was to examine the efficacy of bFGF on 2 experimental murine colitis models and to investigate its molecular mechanisms. METHODS: We evaluated the effects of human recombinant bFGF (hrbFGF) on mice with dextran sulfate sodium (DSS)-induced colitis and mice with trinitrobenzene sulfonic acid (TNBS)-induced colitis as well as normal mice. Body weight, survival rate, and histologic findings of the colonic tissues were examined. Gene expression of tumor necrosis factor (TNF)-alpha, cyclooxygenase (COX)-2, transforming growth factor (TGF)-beta, mucin 2 (MUC2), intestinal trefoil factor (ITF), and vascular endothelial growth factor (VEGF) in the colonic tissues was determined. The proliferation activity of hrbFGF on the colonic epithelium was evaluated by immunohistochemistry. RESULTS: Rectal administration of hrbFGF ameliorated DSS-induced colitis in a dose-dependent manner. Gene expression of TNF-alpha was significantly reduced in the colonic tissues of mice with DSS-induced colitis treated with hrbFGF, whereas MUC2 and ITF messenger RNA expression was up-regulated. Rectal administration of hrbFGF significantly improved the survival rate of mice with TNBS-induced colitis and partially ameliorated colitis. hrbFGF significantly increased the number of Ki-67-positive cells in the colonic epithelium of normal mice, and up-regulated the gene expression of COX-2, TGF-beta, MUC2, ITF, and VEGF in the colonic tissues. CONCLUSIONS: Rectal administration of bFGF might be a promising option for the treatment of inflammatory bowel disease.

DOI PubMed

Refractory enterovesical and duodenocolic fistulas in Crohn's disease successfully managed with tacrolimus.

Akihisa Fukuda, Hiroshi Nakase, Hiroshi Seno, Motoshige Nabeshima, Mitsutaka Sawada, Tsutomu Chiba

Journal of gastroenterology ( SPRINGER TOKYO ) 40 ( 4 ) 433 - 5 2005.04 [Refereed] [Domestic journal]

DOI PubMed CiNii J-GLOBAL

A case of autoimmune pancreatitis associated with sclerosing cholangitis, retroperitoneal fibrosis and Sjögren's syndrome.

Toshiro Fukui, Kazuichi Okazaki, Hazuki Yoshizawa, Shinya Ohashi, Hiroyuki Tamaki, Kimio Kawasaki, Minoru Matsuura, Masanori Asada, Hiroshi Nakase, Yasuaki Nakashima, Akiyoshi Nishio, Tsutomu Chiba

Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] ( KARGER ) 5 ( 1 ) 86 - 91 2005 [Refereed] [International journal]

We report a very rare case of autoimmune pancreatitis (AIP) associated with sclerosing cholangitis, retroperitoneal fibrosis and Sjögren's syndrome. The patient had an enlarged pancreas, and autoantibodies were detected in the serum. Serum IgG and IgG4 concentrations were also elevated. Endoscopic retrograde cholangiopancreatography revealed an irregular narrowing of the main pancreatic duct from the head to the body and sclerotic change in the intrapancreatic common bile duct, which later extended to the intrahepatic bile ducts. In addition, histological examination of the liver revealed lymphocytic sclerosis around the bile ducts, similar to the histology in the pancreas of AIP. Retroperitoneal tumors were diagnosed as retroperitoneal fibrosis by histological examination. Serological and functional abnormalities suggestive of Sjögren's syndrome were detected, and histological findings of the lip were compatible with Sjögren's syndrome. Immunohistochemistry of each lesion disclosed that most of the infiltrating lymphocytes were T cells with similar levels of both CD4+ and CD8+ cells. Moreover, some of the infiltrating plasma cells were positive for anti-IgG4 monoclonal antibody. These diseases were dramatically improved by steroid therapy. Although the pathophysiology of AIP is still unclear, the present case suggests a common pathophysiological mechanism for AIP, sclerosing cholangitis, retroperitoneal fibrosis and Sjögren's syndrome.

DOI PubMed

Protective roles of redox-active protein thioredoxin-1 for severe acute pancreatitis.

Ohashi S, Nishio A, Nakamura H, Kido M, Ueno S, Uza N, Inoue S, Kitamura H, Kiriya K, Asada M, Tamaki H, Matsuura M, Kawasaki K, Fukui T, Watanabe N, Nakase H, Yodoi J, Okazaki K, Chiba T

Am J Physiol Gastrointest Liver Physiol. Dec 1, 2005. 2005 [Refereed]

Metastatic thyroid lymphoma.

Masanobu Katayama, Hiroshi Nakase, Kenji Kanaji, Tadashi Matsumura, Tsutomu Chiba, Akira Tanaka

Gastrointestinal endoscopy ( MOSBY, INC ) 60 ( 4 ) 605 - 6 2004.10 [Refereed] [International journal]

DOI PubMed

実験的急性膵炎モデルにおけるチオレドキシンの防御作用についての検討

大橋真也, 西尾彰功, 井上聡子, 北村浩, 桐谷景一, 吉澤はづき, 浅田全範, 玉置敬之, 松浦稔, 川崎公男, 福井寿朗, 仲瀬裕志, 中村肇, 千葉勉

日本消化器病学会雑誌 ( (一財)日本消化器病学会 ) 101 ( 臨増大会 ) A856 - A856 2004.09

Characteristics of gastric B-cell lymphoma of mucosa-associated lymphoid tissue type involving multiple organs.

Masahiro Iwano, Kazuichi Okazaki, Kazushige Uchida, Hiroshi Nakase, Masaya Ohana, Yumi Matsushima, Hiroshi Inagaki, Tsutomu Chiba

Journal of gastroenterology ( SPRINGER TOKYO ) 39 ( 8 ) 739 - 46 2004.08 [Refereed] [Domestic journal]

BACKGROUND: Mucosa-associated lymphoid tissue (MALT) lymphoma involving multiple organs is not well characterized. METHODS: To obtain a better understanding of gastric MALT lymphoma with multiple organ involvement, we compared Helicobacter pylori infection status; response to eradication therapy; prevalence of genetic abnormality, including t(11;18)(q21;q21); and clonality of tumor cells between patients with gastric MALT lymphoma with and without multiple organ involvement. RESULTS: Of 54 patients with only gastric involvement, 51 were positive for H. pylori (94.4%), whereas only 3 of 9 patients with multiple organ involvement had the infection (33.3%). Among those who received eradication therapy, the remission rate in patients with only gastric involvement was significantly higher than that in patients with multiple organ involvement (71.4% vs 33.3%; P < 0.05). The positive rate of API2-MALT1 fusion transcripts was significantly greater in patients with multiple lesions with either single or multiple organ involvement than in those with a single gastric lesion (71.4% vs 12.5%; P < 0.05), but 2 of 2 patients with multiple gastric lesions had the fusion transcripts. Of 5 patients with multiple organ involvement tested for clonality of the CDR3 region, distinct clones were detected in lymphoma lesions in different organs in 3 patients, whereas the identical clone was present in the different lesions in the remaining 2 patients. CONCLUSIONS: Gastric MALT lymphoma with multiple organ involvement is often associated with API2-MALT1 fusion transcripts. Moreover, H. pylori infection is rare in patients with multiple organ involvement as compared to those with only gastric involvement. Patients with gastric MALT lymphoma with multiple organ involvement who are positive for H. pylori are resistant to eradication therapy.

DOI PubMed CiNii

Environmental pollutant tributyltin promotes Th2 polarization and exacerbates airway inflammation.

Takuma Kato, Ryuichi Uchikawa, Minoru Yamada, Naoki Arizono, Saeko Oikawa, Shosuke Kawanishi, Akiyoshi Nishio, Hiroshi Nakase, Kagemasa Kuribayashi

European journal of immunology ( WILEY-V C H VERLAG GMBH ) 34 ( 5 ) 1312 - 21 2004.05 [Refereed] [International journal]

It has been shown that a relatively high dose of tributyltin (TBT), which is recognized as a particularly notable environmental pollutant, exerts immunotoxic effects such as thymic atrophy via induction of T cell apoptosis. However, the effect of low doses of TBT on the immune responses remains unknown. Here we show that environmentally relevant doses of TBT promoted strong Th2 polarization via suppression and augmentation of Th1 and Th2 development, respectively, from naive CD4(+) T cells primed with anti-CD3 and splenic antigen-presenting cells (APC). TBT-induced Th2 polarization was indirect, working through APC via suppression of IL-12 production by macrophages/DC and the augmentation of IL-10 production by B cells. Th2 polarization was also induced in mice treated with TBT and immunized with OVA or infected with Nippostrongylus brasiliensis. Furthermore, airway inflammation in mice sensitized and challenged with OVA was exacerbated by the administration of TBT with concomitant augmentation of Th2-type immunity. Our results highlight the fact that an important environmental pollutant TBT may present significant risk for the induction of allergic diseases via promotion of Th2 polarization.

DOI PubMed J-GLOBAL

Inhibitory effects of Helicobacter pylori infection on murine autoimmune gastritis

M Ohana, K Okazaki, C Oshima, K Kawasaki, T Fukui, H Tamaki, M Matsuura, M Asada, T Nishi, K Uchida, S Uose, H Nakase, M Iwano, Y Matsushima, H Hiai, T Chiba

GUT ( BRITISH MED JOURNAL PUBL GROUP ) 52 ( 8 ) 1102 - 1110 2003.08 [Refereed]

Background and aim: Long term Helicobacter pylori infection leads to atrophic gastritis but the relation between H pylori infection and autoimmune related atrophic gastritis (AIG) remains unclear. We studied the effects of H pylori infection on the pathophysiology of AIG in mice. Materials and methods: BALB/ c nu/nu mice (n=40) with or without H pylori infection received splenocytes from neonatally thymectomised mice to induce AIG. Half of the mice were orally infected with H pylori prior to AIG induction. Histological findings, and local and systemic immune responses were serially evaluated. Results: Two and six months after transfer, parietal cells in uninfected mice were depleted while those in infected mice were well preserved. The degree of gland atrophy (p<0.01), hyperplasia (p<0.01), gastric pH (p<0.05), and serum gastrin levels of infected mice were significantly lower than those of uninfected mice. Serum antiparietal cell antibody levels gradually decreased in infected mice, and were significantly lower than those of uninfected mice at six months (p<0.05). Real time polymerase chain reaction studies revealed significantly higher interleukin 4 (p<0.05) and transforming growth factor β (p<0.05) gene expression in the gastric mucosa in infected mice than in uninfected mice at both two and six months after AIG induction. Conclusions: H pylori infection inhibited the development of AIG in mice. Th2-type immune responses and transforming growth factor beta in the gastric microenvironment might be involved in the inhibitory effects of H pylori infection on the development of AIG, in which Th1-type responses have an important role.

DOI PubMed

Involvement of myeloid dendritic cells in the development of gastric secondary lymphoid follicles in Helicobacter pylori-infected neonatally thymectomized BALB/c mice.

Toshiki Nishi, Kazuichi Okazaki, Kimio Kawasaki, Toshiro Fukui, Hiroyuki Tamaki, Minoru Matsuura, Masanori Asada, Tomohiro Watanabe, Kazushige Uchida, Norihiko Watanabe, Hiroshi Nakase, Masaya Ohana, Hiroshi Hiai, Tsutomu Chiba

Infection and immunity ( AMER SOC MICROBIOLOGY ) 71 ( 4 ) 2153 - 62 2003.04 [Refereed] [International journal]

We previously described an animal model of Helicobacter pylori-induced follicular gastritis in neonatally thymectomized (nTx) mice. However, it is still not clear whether antigen-presenting dendritic cells (DCs) in the stomach have a role in the development of secondary follicles in H. pylori-infected nTx mice. We investigated the distribution of DC subsets using this model and examined their roles. To identify lymphoid and myeloid DCs, sections were stained with anti-CD11c (pan-DC marker) in combination with anti-CD8alpha (lymphoid DC marker) or anti-CD11b (myeloid DC marker) and were examined with a confocal microscope. Expression of macrophage inflammatory protein 3alpha (MIP-3alpha), which chemoattracts immature DCs, was analyzed by real-time PCR and immunohistochemistry. Follicular dendritic cells (FDCs) were stained with anti-SKY28 antibodies. In noninfected nTx mice, a few myeloid and lymphoid DCs were observed in the bottom portion of the lamina propria, whereas in H. pylori-infected nTx mice, there was an increased influx of myeloid DCs throughout the lamina propria. FDC staining was also observed in the stomachs of members of the infected group. MIP-3alpha gene expression was upregulated in the infected nTx group, and the immunohistochemistry analysis revealed MIP-3alpha-positive epithelial cells. These data suggest that H. pylori infection upregulates MIP-3alpha gene expression in gastric epithelial cells and induces an influx of myeloid DCs in the lamina propria of the gastric mucosa in nTx mice. Myeloid DCs and FDCs might contribute to the development of gastric secondary lymphoid follicles in H. pylori-infected nTx mice.

DOI PubMed

Biodegradable microspheres targeting mucosal immune-regulating cells: new approach for treatment of inflammatory bowel disease.

Hiroshi Nakase, Kazuichi Okazaki, Yasuhiko Tabata, Tsutomu Chiba

Journal of gastroenterology ( SPRINGER-VERLAG TOKYO ) 38 Suppl 15 59 - 62 2003.03 [Refereed] [Domestic journal]

Several studies have indicated that active monocytes, such as macrophages and T cells, play an important role in the pathogenesis of chronic human inflammatory bowel disease (IBD), although the etiology remains unclear. Manipulation of these cells appears essential for the treatment of patients with IBD. Recently, considerable attention has been paid to the use of polymer microspheres for the sustained release of various drugs and the targeting of therapeutic agents to their site of action. It was reported that biodegradable poly-D,L-lactic acid (PDLLA) microspheres can be efficiently taken up by macrophages and M cells. We evaluated the effect of a new drug delivery system targeting microfold cells and macrophages with PDLLA microspheres and gelatin microspheres (GM) on colitis models. In the first experiment, colitis was induced in Balb/c mice by 5% dextran sodium sulfate, and microspheres containing dexamethsone (Decadrone, Dx; Dx microspheres) were orally administered to these mice. Serum levels of Dx did not reach a detectable level after administration of Dx microspheres. The tissue distribution of microspheres containing 125I-Dx in inflamed colon was significantly higher than that in other organs. The histological score, myeloperoxidase activity, and nitric oxide production of mice treated with Dx microspheres were significantly lower than in those treated with Dx alone. Gene expression of proinflammatory cytokines was remarkably downregulated in mice treated with Dx microspheres compared to Dx alone. Next, we investigated the effect of elimination of resident macrophages using microspheres containing dichloromethylene diphosphonate (DMDP) on IL-10 knockout mice. We administered DMDP microspheres to IL-10 KO mice rectally and assessed whether this reagent could reduce the number of local Mac-1-positive cells in the intestine and suppress the development of colitis in IL-10 KO mice. DMDP microspheres reduced the numbers of resident macrophages in the colon of IL-10 KO mice but did not reduce the percentage of Mac-1-positive cells in the spleen, peritoneal cavity, or mesenteric lymph nodes. Depletion of intestinal macrophages significantly suppressed development of chronic colitis in IL-10 KO mice, however. Third, we developed gelatin microspheres containing IL-10, which can be released sustainedly to a local site without losing bioactivity. We administered these microspheres to IL-10 KO mice rectally to investigate whether this treatment can ameliorate colitis. Colonic inflammation in mice treated with GM-IL-10 is remarkably reduced compared to those treated with IL-10 alone. Moreover, expression of CD 40 on Mac-1-positive cells treated with GM-IL-10 is decreased more notably than in mice treated with IL-10 alone. These data suggest that a drug delivery system using these microspheres containing immunomodulatory agents may be a therapeutic approach to human IBD.

PubMed

Elimination of local macrophages in intestine prevents chronic colitis in interleukin-10-deficient mice.

Norihiko Watanabe, Koichi Ikuta, Kazuichi Okazaki, Hiroshi Nakase, Yasuhiko Tabata, Minoru Matsuura, Hiroyuki Tamaki, Chiharu Kawanami, Tasuku Honjo, Tsutomu Chiba

Digestive diseases and sciences ( KLUWER ACADEMIC/PLENUM PUBL ) 48 ( 2 ) 408 - 14 2003.02 [Refereed] [International journal]

Uncontrolled activation of T cells and macrophages is involved in the development of inflammatory bowel disease (IBD). However, the precise role of intestinal macrophages for development of IBD is till unclear. To investigate the role of local macrophages for development of IBD, we developed poly-D, L-lactic acid microspheres containing dichloromethylene diphosphonate, which was specifically taken up by macrophages and depleted them, and then the animal model for human IBD was treated with this reagent. We have shown that rectal administration of the microspheres reduced the numbers of resident macrophages in the intestinal lymphoid follicles of interleukin-10-deficient mice. Importantly, depletion of intestinal macrophages was associated with suppression of development of chronic colitis. These results suggest that local macrophages in the intestine play a critical role in the development of chronic colitis in an animal model for IBD. Our study implies that elimination of resident macrophages in the intestine may become a therapeutic approach to IBD.

DOI PubMed

Hepatobiliary and pancreatic: Primary rabdomyosarcoma of the liver

H Nakase, K Okazaki, M Matsuura, T Chiba

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY ( WILEY-BLACKWELL ) 18 ( 1 ) 105 - 105 2003.01 [Refereed]

DOI

Comparison of histological analysis and endosonographic features in esophageal granular cell tumors

Shujiro Yazumi, Rei Takahashi, Toru Kajiyama, Hiroshi Nakase, Norihiko Watanabe, Masaya Ohana, Shigemi Matsumoto, Hiroshi Seno, Mitsutaka Sawada, Kazushige Uchida, Motoshige Nabeshima, Kazuichi Okazaki, Tsutomu Chiba

Digestive Endoscopy 15 ( 4 ) 284 - 288 2003 [Refereed]

Background: The increased use of esophagogastroduodenoscopy has revealed the esophagus to be a common site of occurrence of granular cell tumors (GCT). To clarify the endosonographic features of esophageal GCT, we compared endosonographic findings and histopathological analysis of resected specimens of esophageal GCT and submucosal leiomyomas. Methods: We enrolled a total number of 18 consecutive patients with esophageal submucosal tumors. They were preoperatively examined using 15 MHz or 20 MHz probe endoscopic ultrasonography. The endosonographic findings were retrospectively compared with hisopathological findings of the resected specimens. Results: Five GCT and 13 submucosal leiomyomas were diagnosed histologically as well as endosonographically. Pathological analysis revealed that the dispropotional mixture of tumor cells, fibrosis and muscularis mucosa within the GCT would be endosonographically visualized as a heterogeneous hypoechoic mass. Moreover, the laterally scattered tumor cells, together with adjacent thickened muscularis mucosa, are reflected by the unclear margin of the tumor by endoscopic ultrasonography. In contrast, in the submucosal leiomyomas, tumor cells and fibrosis were uniformly mixed and the margin of the tumor was clearly demarcated. These histological findings would be endosonographically recognized as a homogeneously hypoechoic mass with a clearly demarcated border. Conclusion: A high-frequency probe endoscopic ultrasonography is useful for differentiating esophageal GCT from submucosal leiomyomas. Considering the histological characteristics, esophageal GCT should be resected with adequate tumor-free margin when endoscopic treatment is applied.

DOI CiNii J-GLOBAL

Intestinal drug delivery systems with biodegradable microspheres targeting mucosal immune-regulating cells for chronic inflammatory colitis.

Kazuichi Okazaki, Hiroshi Nakase, Norihiko Watanabe, Yasuhiko Tabata, Yoshito Ikada, Tsutomu Chiba

Journal of gastroenterology ( SPRINGER-VERLAG TOKYO ) 37 Suppl 14 ( SUPPL. 14 ) 44 - 52 2002.11 [Refereed] [Domestic journal]

We developed two kinds of delivery systems targeting mucosal immune regulating cells with poly (D,L-lactic acid) microspheres containing dexamethasone and dichloromethylene diphosphonate, and gelatine microspheres containing interleukin-10. To estimate the efficacy of these drug delivery systems, we studied the effects on experimental colitis induced by dextran sodium sulfate, 2,4,6-trinitrobenzene sulfonic acid, and interleukin-10-deficient mice. Intestinal administration of these microspheres significantly improved colitis with decreased histological score, myeloperoxidase activity, and nitric oxide production compared with mice treated with free agents. Gene expressions of tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma were down-regulated in treated animals. Serum Dx, IL-10 levels, and systemic macrophages were unchanged after treatment. Our findings suggest that local macrophages in the intestine play a critical role in the initiation of chronic colitis in the animal model of inflammatory bowel disease (IBD). Intestinal drug delivery systems with biodegradable microspheres targeting mucosal immune-regulating cells may become a therapeutic approach to human IBD.

PubMed CiNii

A novel human fibroblast growth factor treats experimental intestinal inflammation.

Michael Jeffers, William F McDonald, Rajeev A Chillakuru, Meijia Yang, Hiroshi Nakase, Lisa L Deegler, Elizabeth D Sylander, Beth Rittman, Alison Bendele, R Balfour Sartor, Henri S Lichenstein

Gastroenterology ( W B SAUNDERS CO ) 123 ( 4 ) 1151 - 62 2002.10 [Refereed] [International journal]

BACKGROUND & AIMS: We recently identified a novel member of the human fibroblast growth factor (FGF) family of signaling molecules, designated FGF-20. In the present study, we examined the activity of this protein in 2 animal models of acute intestinal inflammation and in mechanistic studies in vitro. METHODS: In vivo experiments consisted of a murine dextran sulfate sodium (DSS) model of colitis and a rat indomethacin model of small intestinal ulceration/inflammation. Cell growth, restitution, gene expression (cyclooxygenase-2 [COX-2] and intestinal trefoil factor [ITF]), and prostaglandin E2 (PGE2) levels were examined in vitro. RESULTS: In the DSS-colitis model, prophylactic administration of FGF-20 significantly reduced the severity and extent of mucosal damage as indicated by a 55%-93% reduction in luminal blood loss, distal colonic edema, histologic inflammation, and epithelial cell loss relative to animals administered vehicle control. No toxicity was noted during administration of FGF-20 to normal controls. In addition, therapeutic administration of FGF-20 enhanced survival in this model. In the indomethacin-small bowel ulceration/inflammation model, administration of FGF-20 reduced small intestinal weight gain, necrosis, inflammation, and weight loss (36%-53% relative to vehicle control). In vitro studies demonstrated that FGF-20 stimulates growth, restitution, mRNA expression of COX-2 and ITF, and PGE2 levels in human intestinal epithelial cells and enhances the growth of human intestinal fibroblasts. CONCLUSIONS: FGF-20, having demonstrated therapeutic activity in 2 experimental models of intestinal inflammation, represents a promising new candidate for the treatment of human inflammatory bowel disease.

DOI PubMed

The "scarf-ring sign" of ball valve syndrome.

Shujiro Yazumi, Hiroshi Nakase, Yumi Matsushima, Tsutomu Chiba, Isao Shirahase, Shinsuke Yoshizaki, Shinitchi Mise

Gastrointestinal endoscopy ( MOSBY, INC ) 55 ( 4 ) 560 - 560 2002.04 [Refereed] [International journal]

DOI PubMed

New cytokine delivery system using gelatin microspheres containing interleukin-10 for experimental inflammatory bowel disease.

Hiroshi Nakase, Kazuichi Okazaki, Yasuhiko Tabata, Makoto Ozeki, Norihiko Watanabe, Masaya Ohana, Suguru Uose, Kazushige Uchida, Toshiki Nishi, Minoru Mastuura, Hiroyuki Tamaki, Toshiyuki Itoh, Chiharu Kawanami, Tsutomu Chiba

The Journal of pharmacology and experimental therapeutics ( AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS ) 301 ( 1 ) 59 - 65 2002.04 [Refereed] [International journal]

Interleukin (IL)-10 is an anti-inflammatory cytokine that suppresses the T helper 1 immune response and down-regulates macrophages and monocytes. The therapeutic effect of systemic administration of IL-10 for patients with inflammatory bowel disease, however, has not been satisfactory. We examined whether rectal administration of gelatin microspheres (GM) containing IL-10 (GM-IL-10) prevents colitis in IL-10-deficient (IL-10(-/-)) mice. GM-IL-10 and IL-10 alone were administered rectally. The colon was examined macroscopically and microscopically. IL-12 mRNA expression and CD40 expression in Mac-1-positive cells were also examined. Macroscopic and microscopic examination revealed marked improvement of colitis in IL-10(-/-) mice treated with GM-IL-10. mRNA expression of IL-12 in Mac-1-positive cells in GM-IL-10-treated mice was significantly decreased compared with that in the mice treated with IL-10 alone. Additionally, CD40 expression in Mac-1-positive cells in GM-IL-10-treated mice was decreased more prominently than in mice treated with IL-10 alone. The therapeutic effects of GM-IL-10 were associated with decreased expression of IL-12 mRNA and down-regulation of CD40 expression in Mac-1-positive cells. GM-IL-10 might be useful for treatment of patients with inflammatory bowel disease.

DOI PubMed

The possible involvement of micro-organisms other than Helicobacter pylori in the development of rectal MALT lymphoma in H-pylori-negative patients

H Nakase, K Okazaki, M Ohana, K Ikeda, K Uchida, S Uose, T Itoh, M Iwano, N Watanabe, S Yazumi, C Kawanami, F Inoue, T Chiba

ENDOSCOPY ( GEORG THIEME VERLAG KG ) 34 ( 4 ) 343 - 346 2002.04 [Refereed]

It remains unclear whether lymphoma of the mucosa-associated lymphoid tissue (MALT) in the extragastric organs is related to Helicobacter pylori infection or not. This report describes three patients with rectal MALT lymphoma negative for H. pylori infection, all of whom showed disease regression after being treated with antibiotics. One patient had MALT lymphoma in both the descending colon and the rectum; the other two patients had rectal disease only. None of the patients had chronic gastritis which was detectable either endoscopically or histologically and H. pylori infection was completely ruled out by various methods, including a urease breath test. These patients received antibiotic therapy. In all the patients, regression of MALT lymphoma was observed endoscopically and histologically, and polymerase chain reaction revealed that a previously observed rearranged band of immunoglobulin heavy chain had also disappeared after antibiotic treatment. These cases therefore suggest involvement of micro-organisms other than H. pylori in the development of rectal MALT lymphoma.

DOI PubMed

Experimental immune-mediated pancreatitis in neonatally thymectomized mice immunized with carbonic anhydrase II and lactoferrin.

Kazushige Uchida, Kazuichi Okazaki, Toshiki Nishi, Suguru Uose, Hiroshi Nakase, Masaya Ohana, Yumi Matsushima, Katsuyuki Omori, Tsutomu Chiba

Laboratory investigation; a journal of technical methods and pathology ( LIPPINCOTT WILLIAMS & WILKINS ) 82 ( 4 ) 411 - 24 2002.04 [Refereed] [International journal]

We previously reported that autoantibodies against carbonic anhydrase II and lactoferrin are frequently identified in patients with autoimmune-related pancreatitis. To clarify the role of carbonic anhydrase II and lactoferrin, we created animal models of autoimmune pancreatitis by immunizing neonatally thymectomized mice with carbonic anhydrase II and lactoferrin and also by transferring immunized spleen cells to nude mice. Neonatally thymectomized BALB/c mice were immunized with carbonic anhydrase II or lactoferrin followed by three booster injections (n = 10 in each group). We transferred whole, CD4+, or CD8+ spleen cells prepared from immunized neonatally thymectomized mice to nude mice (n = 5 in each group). Gene expression of IFN-gamma and IL-4 was investigated using semiquantitative reverse transcription-polymerase chain reaction. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling staining was used to examine apoptosis. In immunized neonatally thymectomized mice, the prevalence of inflammation was significantly higher in the pancreas. Inflammation was present in all mice receiving whole or CD4+ cells. There was no change in any of the mice receiving CD8+ cells or nonimmunized spleen cells. Carbonic anhydrase II or lactoferrin-immunized mice had apoptotic duct cells or acinar cells, respectively. Expression of the IFN-gamma gene was up-regulated in each group. Similar findings were observed in the salivary glands and liver. An immunologic mechanism against carbonic anhydrase II or lactoferrin is involved in the pathogenesis of these pancreatitis models, in which the effector cells are Th1-type CD4+ T cells.

PubMed

Diffuse colon cancer with tumor thrombus in the portal vein.

Hiroshi Nakase, Chiharu Kawanami, Toshiyuki Itoh, Kazuichi Okazaki, Tsutomu Chiba, Toshinao Itani, Jun Mimura, Toshihiko Kawasaki, Hideshi Komori

Gastrointestinal endoscopy ( MOSBY, INC ) 55 ( 2 ) 239 - 40 2002.02 [Refereed] [International journal]

DOI PubMed

Rectal leiomyoma with fibromuscular obliteration mimicking adematous lesion

H. Nakase, M. Ide, S. Yazumi, N. Watanabe, T. Itoh, M. Matsuura, C. Kawanami, K. Okazaki, T. Chiba

Endoscopy 34 ( 3 ) 241 2002 [Refereed]

DOI PubMed

Immunological and molecular analysis of B lymphocytes in low-grade MALT lymphoma of the stomach. Are there any useful markers for predicting outcome after Helicobacter pylori eradication?

Yumi Matsushima, Yoshikazu Kinoshita, Hirokazu Fukui, Toru Maekawa, Shujiro Yazumi, Akihiko Okada, Hiroshi Nakase, Chiharu Kawanami, Masahiro Iwano, Kimio Hashimoto, Zenju Takeda, Kazuichi Okazaki, Tsutomu Chiba

Journal of gastroenterology ( SPRINGER-VERLAG TOKYO ) 37 ( 6 ) 428 - 33 2002 [Refereed] [Domestic journal]

BACKGROUND: Although Helicobacter pylori eradication is effective in treating low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma, the condition in some patients deteriorates even after the eradication. Therefore, it is important to predict the disease outcome before starting H. pylori eradication. We investigated the usefulness of flow cytometry, quantifying CD19- and CD20-positive B lymphocytes in MALT lymphoma tissue, for predicting the disease outcome after H. pylori eradication. METHODS: Tissue specimens from 14 patients with H. pylori-positive low-grade gastric MALT lymphoma were examined by histology, Southern blotting, and flow cytometry before therapy. Serum levels of soluble interleukin (IL)-2 receptor were also measured. The relationship between the data and the prognosis after H. pylori eradication was analyzed. RESULTS: Remission occurred in 10 of the 14 patients. The condition in the 4 remaining patients deteriorated even after H. pylori eradication. The percentages of CD19- and CD20-positive cells in MALT lymphoma tissue from the patients in remission were both significantly lower than those in the tissue from patients not in remission. Indeed, 4 of the 5 patients in whom both CD19- and CD20-positive cells accounted for more than 50% of the total number of lymphocytes had gastrectomy, whereas all patients in whom both CD19- and CD20-positive cells accounted for less than 50% of the total number of lymphocytes achieved remission. Although immunoglobulin gene rearrangement was present in all patients operated on, there were also 6 patients whose MALT lymphoma was ameliorated in spite of the presence of gene rearrangement. The serum level of soluble IL-2 receptor was in the normal range in all patients tested. CONCLUSIONS: Analysis of mature B-cell markers in MALT lymphoma tissue is more useful than the examination of immunoglobulin gene rearrangement or serum levels of soluble IL-2 receptor in predicting the outcome of low-grade gastric MALT lymphoma after H. pylori eradication.

DOI PubMed CiNii J-GLOBAL

新しいdrug delivery systemによる大腸炎治療－マイクロスフェアーを用いた治療方法の開発－．

仲瀬裕志, 松浦稔, 玉置敬之, 河南智晴, 千葉勉, 田畑泰彦

炎症と免疫 10 71 - 76 2002

Rectal immunization with antigen-containing microspheres induces stronger Th2 responses than oral immunization: a new method for vaccination

H Nakase, K Okazaki, Y Tabata, K Uchida, S Uose, M Ohana, T Nishi, T Watanabe, M Matsuura, H Hisatsune, K Matsumura, T Itoh, C Kawanami, T Chiba

VACCINE ( ELSEVIER SCI LTD ) 20 ( 3-4 ) 377 - 384 2001.11 [Refereed]

The rectum as an effective site for induction of systemic and local immunity has received little attention. Rectal immunization with microspheres-containing ovalbumin (MS-OVA) was tested for its ability to elicit systemic and mucosal immune responses. Rectal immunization with MS-OVA enhanced both Th2 dominant OVA-specific IgG levels in the serum and OVA-specific IgA levels in fecal extracts more prominently than did oral immunization. Cytokine analysis of CD4(+) T cells indicated a predominant induction of Th2-type responses compared to Th1-type responses following rectal immunization compared to oral immunization. These results demonstrate that rectal immunization with microspheres could be an effective new vaccination method. (C) 2001 Elsevier Science Ltd. All rights reserved.

DOI PubMed

Therapeutic effects on intestinal Behcet's disease of an intravenous drug delivery system using dexamethasone incorporated in lipid emulsion

H Nakase, K Okazaki, C Kawanami, K Uchida, M Ohana, S Uose, T Nishi, T Itoh, A Okano, A Nishio, H Takakuwa, T Chiba

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY ( BLACKWELL PUBLISHING ASIA ) 16 ( 11 ) 1306 - 1308 2001.11 [Refereed]

Recurrent intestinal ulcer is a frequent problem in the management of Behcet's disease. However, no standard therapy for intestinal Behect's disease has been established. We report two patients with intestinal Behcet disease and recurrent ileal ulcers who were treated successfuly with a lipid emulsion of dexamethasone. In one patient, the cecal ulcer did not relapse after the intravenous administration initiation of a lipid emulsion of dexamethasone once a week, despite the discontinuation of prednisolone. In the other patient, the cecal ulcer showed a healing tendency, and oral administration of prednisolone was reduced from 40 to 15 mg/day after intravenous administration of a lipid emulsion of dexamethasone. Both patients experienced no complications associated with the administration of the emulsion. These results suggest that an intravenous drug delivery system using a lipid emulsion of dexamethasone is useful for treatment of intestinal Behcet's disease. (C) 2001 Blackwell Science Asia Pry Ltd.

DOI PubMed

Successful treatment with steroids of upper gastrointestinal acute graft vs. host disease after hematopoietic stem cell transplantation

T Nishi, K Okazaki, S Fujii, K Uchida, S Uose, H Nakase, M Ohana, T Nishihara, T Chiba

ENDOSCOPY ( GEORG THIEME VERLAG KG ) 33 ( 11 ) 985 - 987 2001.11 [Refereed]

A 39-year-old man with acute myeloid leukemia underwent completely matched related hematopoietic stem cell transplantation. On post-transplantation day 83 he was diagnosed as having upper gastrointestinal graft-versus-host disease (GVHD) by endoscopic examination and pathological examination of endoscopic biopsy specimens, and daily administration of 60 mg of water-soluble prednisolone and 50 mg of cyclosporine was started. After steroid therapy, the symptoms of upper gastrointestinal GVHD disappeared completely and endoscopic findings dramatically improved.

DOI PubMed

Analysis of cytokines in the early development of gastric secondary lymphoid follicles in Helicobacter pylori-infected BALB/c mice with neonatal thymectomy

K Uchida, K Okazaki, A Debrecceni, T Nishi, H Iwano, M Inai, S Uose, H Nakase, M Ohana, C Oshima, Y Matsushima, C Kawanami, H Hiai, T Masuda, T Chiba

INFECTION AND IMMUNITY ( AMER SOC MICROBIOLOGY ) 69 ( 11 ) 6749 - 6754 2001.11 [Refereed]

Immunological interaction between the host and Helicobacter pylori seems to play a critical role in follicular formation in gastric mucosa. We reported H. pylori-induced follicular gastritis model using neonatally thymectomized mice. In this study, we investigated the involvement of various cytokines in this model. BALB/c mice were thymectomized on the third day after birth (nTx). At 6 weeks old, these mice were orally infected with H. pylori. Histological studies showed that follicular formation occurred from 8 weeks after the infection and that most of the infiltrating lymphocytes were CD4(+) and B cells. Neutrophils increased transiently at I week after the infection. Gamma interferon, interleukin-7 (IL-7), and IL-7 receptor were expressed in the stomach of the nTx mice irrespective of the infection. In contrast, expressions of the tumor necrosis factor alpha, IL-4 and lymphotoxin-a. genes were remarkably upregulated by the infection. Our findings suggest that follicular formation may require cooperative involvement of a Th2-type immune response, tumor necrosis factor alpha and lymphotoxin-a in addition to the Th1-type immune response in H. pylori-induced gastritis in nTx mice.

DOI PubMed

Substrate recognition mechanism of carboxypeptidase Y

H Nakase, S Murata, H Ueno, R Hayashi

BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY ( TAYLOR & FRANCIS LTD ) 65 ( 11 ) 2465 - 2471 2001.11 [Refereed]

To clarify the substrate-recognition mechanism of carboxypeptidase Y, Fmoc-(Glu)(n)Ala-OH (n=1 to 6), Fmoc-(Glu)(n)Ala-NH2 (1 to 5), and Fmoc-Lys(GIU)(3)Ala-NH2 were synthesized, and kinetic parameters for these substrates were measured. K-m for Fmoc-peptides significantly decreased as peptide length increased from n =1 to n=5 with only slight changes in k(cat). K-m for Fmoc-(Glu)(5,6)Ala-OH were almost the same as one for protein substrates described previously (Nakase et al., Bull. Chem. Soc. Jpn., 73, 2587-2590). These results show that the enzyme has six subsites (S-1' and S-1-S-5)Each subsite affinity calculated from the K-m revealed subsite properties, and from the differences of subsite affinity between pH 6.5 and 5.0, the residues in each subsite were predicted. For Fmoc-peptide amide substrates, the priorities of amidase and carboxamide peptidase activities were dependent on the substrate. It is likely that the interactions between side chains of peptide and subsites compensate for the lack of P-1'-S-1' interaction, so the amidase activity prevailed for Fmoc-(Glu)(3,5)Ala-NH2. These results suggest that these subsites contribute extensively to substrate recognition rather than a hydrogen bond network.

DOI PubMed CiNii

Recent concept and diagnostic evaluation of graft-versus-host disease

OKAZAKI K., NISHI T., WATANABE N., MATSUURA M., NAKASE H., KAWANAMI C., CHIBA T.

The Japanese journal of proctology ( The Japan Society of Coloproctology ) 54 ( 10 ) 965 - 969 2001.10

Organ transplantation, especially allogeneic bone marrow transplantation, has been established and is increasing. Graft-versus-host disease (GVHD), which often involves the skin, liver, and GI tract, is one of the most common complications of transplantation. Clinical symptoms and skin biopsy usually make the diagnosis of GI GVHD. However, GI symptoms of GVHD are nonspecific, such as nausea, vomiting, diarrhea, GI bleeding, and abdominal pain. Although it is difficult because of few endoscopic and histological findings, specific endoscopic findings, such as sloughing of the mucosa and apoptosis, are very useful to make a diagnosis of GVHD. In this review, we discuss the current concept and diagnostic evaluation for GI GVHD.

DOI CiNii

Successful treatment of severe acute pancreatitis by the combination therapy of continuous arterial infusion of a protease inhibitor and continuous hemofiltration

H Nakase, T Itani, J Mimura, T Kawasaki, H Komori, K Okazaki, T Chiba

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY ( BLACKWELL PUBLISHING ASIA ) 16 ( 8 ) 944 - 945 2001.08 [Refereed]

DOI

A critical role for IL-713 signaling in the development of Helicobacter felis-induced gastritis in mice

M Ohana, K Okazaki, C Oshima, D Andra's, T Nishi, K Uchida, S Uose, H Nakase, Y Matsushima, T Chiba

GASTROENTEROLOGY ( W B SAUNDERS CO ) 121 ( 2 ) 329 - 336 2001.08 [Refereed]

Background & Aims: Interleukin (IL)-7 is a critical cytokine in the development of T and B cells and is involved in gastrointestinal pathophysiology. The aim of this study was to investigate the involvement of IL-7 receptor (IL-7R) signaling in Helicobacter-induced gastritis. Methods: C57BL/6 mice (n = 40) were inoculated with H. felis. Twenty mice were injected intraperitoneally with neutralizing IL-7R antibody (A7R34) every seventh day for 3 months. Histology, serum anti-H. felis antibody, and gene expression of IL-7, IL-7R, and proinflammatory cytokines in the gastric mucosa were evaluated. Results: Seventeen of 20 (85%) infected mice without A7R34 developed severe atrophic gastritis, whereas there was no gastritis in A7R34-treated infected mice. There was no difference in the serum levels of anti-H. felis antibody between the 2 groups. IL-7, IL-7R, IL-1 alpha, tumor necrosis factor alpha, and interferon gamma messenger RNA expressions were up-regulated in control infected mice, whereas only IL-7 messenger RNA was up-regulated in A7R34-treated infected mice. Immunohistochemistry indicated positive cytoplasmic staining of IL-7 in the gastric epithelial cells. Conclusions: These data suggest a critical role for IL-7 receptor signaling in the development of Helicobacter-induced gastritis in mice.

DOI PubMed

Isolated metastatic gastric cancer to the colon: A unique endoscopic appearance

H Nakase, S Yazumi, C Kawanami, K Okazaki, T Chiba, S Yoshizaki, S Mise

GASTROINTESTINAL ENDOSCOPY ( MOSBY, INC ) 54 ( 1 ) 76 - 76 2001.07 [Refereed]

An oral drug delivery system targeting immune-regulating cells ameliorates mucosal injury in trinitrobenzene sulfonic acid-induced colitis

H Nakase, K Okazaki, Y Tabata, S Uose, M Ohana, K Uchida, T Nishi, A Debreceni, T Itoh, C Kawanami, M Iwano, Y Ikada, T Chiba

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS ( AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS ) 297 ( 3 ) 1122 - 1128 2001.06 [Refereed]

Control of immune-regulating cells in the colonic mucosa is important in the treatment of patients with inflammatory bowel disease (IBD). The aim of study was to examine the therapeutic effect of dexamethasone (DX) microspheres on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats, a model for human Crohn's disease. DX microspheres and DX alone were administered orally to rats with TNBS-induced colitis. The macroscopic score. histological score, myeloperoxidase (MPO) activity, nitric oxide (NO) production, and gene expressions of proinflammatory cytokines, cyclooxygenase (COX)-1, and COX-2 in the colonic tissue were determined. Proliferating cell nuclear antigen (PCNA) staining and expression of nuclear transcription factor (NF)-kappaB in colonic tissues were also investigated. Macroscopic score, histological score, MPO activity, and NO production in rats treated with DX microspheres were significantly lower than in those treated with DX alone. The gene expression of proinflammatory cytokines and COX-2 in rats treated with DX microspheres was down-regulated, compared with that in rats treated with DX alone. The number of PCNA-positive cells in the DX microsphere group was larger than in the group treated with DX alone. DX microspheres suppressed NF-kappaB activation in TNBS-induced colitis more strongly than DX alone. Oral administration of DX microspheres appears to ameliorate mucosal injury in TNBS-induced colitis, This drug delivery system could be an ideal therapy for human IBD.

PubMed J-GLOBAL

Budd-Chiari syndrome and extrahepatic portal obstruction associated with congenital antithrombin III deficiency

H Nakase, T Kawasaki, T Itani, J Mimura, H Komori, K Okazaki, T Chiba

JOURNAL OF GASTROENTEROLOGY ( SPRINGER-VERLAG ) 36 ( 5 ) 341 - 345 2001.05 [Refereed]

We report a patient with Budd-Chiari syndrome (BCS) and extrahepatic portal obstruction (EHO) associated with congenital antithrombin (AT) III deficiency. A 35-year-old man was admitted to Nishi Kobe Medical Center for evaluation of abnormal intrahepatic veins. By various imaging modalities, BCS and EHO were diagnosed. Laboratory data revealed parallel decreases in activity and antigen concentration of AT III despite normal liver function. Taken together, the etiology of both BCS and EHO was considered to be thrombosis, associated with congenital AT III deficiency. Two years after beginning warfarin therapy, the patient has no symptoms and his liver function remains normal. Anticoagulant therapy is considered useful for preventing progression of the disease.

DOI CiNii J-GLOBAL

mRNA expression of cytokines and chemokines in the normal gastric surface mucous epithelial cell line GSM06 during bacterial infection with Helicobacter felis

A Debreceni, K Okazaki, Y Matsushima, M Ohana, H Nakase, K Uchida, S Uose, T Chiba

JOURNAL OF PHYSIOLOGY-PARIS ( EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER ) 95 ( 1-6 ) 461 - 467 2001.01 [Refereed]

Background and aim: A group of the proinflammatory and chemotactic cytokines (chemokines) has been considered as an important factor in the pathomechanism of different bacterial diseases, among them the common Helicobacter pylori infection. Experimental results obtained with gastric biopsy samples of H. pylori positive patients, and with H. pylori infected tumor originated gastric cell lines indicated that these cytokines have essential roles in the development and maintenance of the immune response and inflammation of the gastric mucosa during H. pylori infection. Although the mRNA expression was shown in these biopsy samples and cell lines, it is not yet proved that the normal gastric mucosal epithelial cells themselves express these cytokines. The establishment of a gastric surface mucous cell line with non-tumor origin (GSM06), and the usage of Helicobacter felis as a model of the classic H. pylori infection gave us the possibility to check this question. Materials and methods: in this study GSM06 cells were infected with different numbers (10(5), 10(6), 10(7), 10(8), 10(9) bacterium/ml medium) of H.felis for two different time periods (2, 4 h). Cells treated with medium only were used as control. Then the mRNA expression of the following cytokines was measured by RT-PCR method in the GSM06 cells: proinflammatory cytokine IL1-beta, and chemokine RANTES, eotaxin, MCP-1, MIP1-alpha and MIP1-beta. Results: we found that neither mRNA of the investigated cytokines was expressed constitutively, however the GSM06 cells expressed the mRNA of each cytokine during H. felis infection. Conclusion: our results prove that normal gastric surface mucous epithelial cells express immunologically active peptides during H.felis infection. We may suppose that the epithelial cells of the gastric mucosa contribute to the immune response and inflammation by expressing proinflammatory (IL1-beta) and chemotactic (RANTES, eotaxin, MCP-1, MIP1-alpha and beta) cytokines during H. pylori infection in human. (C) 2001 Elsevier Science Ltd. All rights reserved.

DOI PubMed

粘膜免疫の分子機構とその破綻－Drug Delivery Systemを応用した炎症性腸疾患治療法の開発．

仲瀬裕志, 千葉勉, 田畑泰彦

医学のあゆみ 199 119 - 123 2001

Effects of Helicobacter pylori infection on Zollinger-Ellison syndrome

T Watanabe, Y Matsushima, H Nakase, M Iwano, R Hosotani, M Imamura, Y Kinoshita, T Chiba

JOURNAL OF GASTROENTEROLOGY ( SPRINGER-VERLAG ) 35 ( 10 ) 735 - 741 2000.10 [Refereed]

Both Zollinger-Ellison syndrome (ZES) and Helicobacterpylori infection are major etiologic factors for peptic ulcer. The aim of this study was to investigate the effect of H. pylori infection on ZES with special reference to acid secretion. Sixteen patients with ZES were selected (median age, 59 years; range, 39-66 years; M/F, 9/7), and H. pylori status, ulcer location, gastric acid secretion, serum pepsinogen (PG) I and II concentrations, and PG I/II ratio were determined. The seroprevalence of H. pylori infection was 50%, whereas active H. pylori infection was seen in only 25% of the patients. Thirteen patients had duodenal ulcer (DU), 1 had gastric ulcer (GU), and 2 had both GU and DU. DU was seen in both H. pylori-positive and H. pylori-negative patients, whereas GU was found only in H. pylori-positive patients. Both basal and maximal acid outputs were significantly lower in H. pylori-positive patients than in H. pylori-negative patients (P < 0.05). Moreover, both serum PG I and the PG I/II ratio were significantly lower in H, pylori-positive patients than in H. pylori-negative patients. These results indicate that ZES is an independent risk factor for DU, but H. pylori infection may play some role in the development of GU in ZES. In patients with ZES, N. pylori infection may reduce both hypersecretion from parietal cells and PG I secretion from chief cells, and hyperacidity of the stomach in ZES may have eradicated H. pylori in some patients.

DOI PubMed CiNii

A patient with improvement of ulcerative colitis after appendectomy

K Okazaki, H Onodera, N Watanabe, H Nakase, S Uose, M Matsushita, C Kawanami, M Imamura, T Chiba

GASTROENTEROLOGY ( W B SAUNDERS CO ) 119 ( 2 ) 502 - 506 2000.08 [Refereed]

Recently, several retrospective studies have shown an inverse association between appendectomy and development of ulcerative colitis. We describe a 21-year-old man with distal ulcerative colitis and appendiceal involvement. The patient passed bloody stools continually during the 3 years before admission. Macroscopic and microscopic findings showed chronic moderate inflammation of the appendix and rectum. The ratio of CD4 to CD8 lymphocytes isolated from rectal and appendiceal mucosa was increased (4.3 and 3.8, respectively) compared with controls (n = 11; 1.0 in the rectum and 1.4 in the appendix). Clinical symptoms and colonoscopic and microscopic findings improved significantly after appendectomy. In addition, the amount of interferon gamma secreted from rectal lymphocytes was reduced to 83 pg/mL after surgery (before appendectomy, 254 pg/mL). However, interleukin 4 production was below detectable levels both before and after appendectomy. These findings suggest that appendectomy resulted in altered T-helper (Th)1/Th2 balance in this patient. In the 3 years since surgery, the patient has been in good condition without recurrence of symptoms. This is the first report demonstrating therapeutic benefit of appendectomy in a patient with ulcerative colitis and potential mechanistic relationship.

DOI PubMed

Autoimmune-related pancreatitis is associated with autoantibodies and a Th1/Th2-type cellular immune response

K Okazaki, K Uchida, M Ohana, H Nakase, S Uose, M Inai, Y Matsushima, K Katamura, K Ohmori, T Chiba

GASTROENTEROLOGY ( W B SAUNDERS CO ) 118 ( 3 ) 573 - 581 2000.03 [Refereed]

Background & Aims: Although autoimmunity may be involved in some cases of pancreatitis, the mechanism is still unknown. To clarify this, we studied serum autoantibodies, subsets of lymphocytes, and the Th1/ Th2 balance of cellular immune responses in patients with autoimmune-related pancreatitis (AIP), Methods: Seventeen patients with AIP (8 men and 9 women; age, 53.2 +/- 13.0 years) were studied. Autoantibodies including antilactoferrin (ALF) or carbonic anhydrase II antibody (ACA-II) were examined using the enzyme-linked immunosorbent assay (ELISA) or the indirect fluorescein antibody method. Intracellular cytokines (interferon gamma and interleukin 4) and subtypes of peripheral blood lymphocytes were examined by flow cytometry and ELISA, Results: More than one autoantibody was observed in all 17 patients. Serum antinuclear antibody was detected in 13 of 17 patients, ALF antibody in 13, ACA-II antibody in 10, rheumatoid factor in 5; and anti-smooth muscle antibody in 3, but antimitochondrial antibody in none. The serum levels of ACA-II and LF antibody were not correlated. HLA-DR(+)CD8(+) and HL4-DR(+)CD4(+) cells were significantly increased in peripheral blood (P < 0.05). CD4(+) cells producing interferon gamma and the secreted levels were significantly increased compared with those in controls (P < 0.05), but interleukin 4 was not increased. Conclusions: An autoimmune mechanism against CA-II or LF, and Th1-type immune response, may be involved in AIP.

DOI PubMed

Endoscopic resection of small inflammatory fibroid polyp of the colon

H Nakase, J Mimura, T Kawasaki, T Itani, H Komori, K Hashimoto, K Okazaki, T Chiba

INTERNAL MEDICINE ( JAPAN SOC INTERNAL MEDICINE ) 39 ( 1 ) 25 - 27 2000.01 [Refereed]

DOI CiNii

Development of an oral drug delivery system targeting immune-regulating cells in experimental inflammatory bowel disease: A new therapeutic strategy

H Nakase, K Okazaki, Y Tabata, S Uose, M Ohana, K Uchida, Y Matsushima, C Kawanami, C Oshima, Y Ikada, T Chiba

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS ( AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS ) 292 ( 1 ) 15 - 21 2000.01 [Refereed]

Several studies have indicated the involvement of macrophages and dendritic cells in active inflammatory bowel disease (IBD). Manipulation of these cells is considered a very important therapeutic strategy for patients with IBD. We evaluated the effect of a new drug delivery system targeting microfold cells and macrophages with poly( DL-lactic acid) microspheres containing dexamethasone (Dx). Colitis was induced in BALB/c mice by 5% dextran sodium sulfate. Dx microspheres (n = 10) and only Dx (n = 10) were orally administered to dextran sodium sulfate-treated mice. Thereafter, serum levels and tissue distributions of Dx were investigated. To estimate the efficacy of this drug delivery system, we measured the histological score, myeloperoxidase activity and nitric oxide production, and gene expressions of tumor necrosis factor-alpha, interleukin-1 beta, and interferon-gamma in the colonic tissue. Serum Dx levels were not increased after oral administration of Dx microspheres. The tissue distribution of microspheres containing I-125-labeled Dx in inflamed colon was significantly higher than in other organs. The histological score, myeloperoxidase activity, and nitric oxide production of the group treated with Dx microspheres were significantly lower than of those treated with Dx alone. Gene expressions of tumor necrosis factor-alpha, interleukin-1 beta, and interferon-gamma were down-regulated in mice treated with Dx microspheres. Microspheres containing glucocorticoids such as Dx, which target microfold cells and macrophages, can facilitate mucosal repair in experimental colitis and could be an ideal agent for treatment of human IBD.

PubMed J-GLOBAL

Ｍ細胞の機能と病態へのかかわり．

仲瀬裕志, 伊藤俊之, 河南智晴, 岡崎和一

G.I. Research 8 29 - 35 2000

炎症性腸疾患および腫瘍性疾患の鑑別のポイント．

仲瀬裕志

Medical Practice 17 639 - 644 2000

特集「炎症性腸疾患の病態と治療戦略」炎症性腸疾患におけるTh1/Th2バランスと治療

仲瀬裕志, 河南智晴, 岡崎和一

Pharma Medica 19 61 - 65 2000

Relationship between asthma and gastro-oesophageal reflux: Significance of endoscopic grade of reflux oesophagitis in adult asthmatics

H Nakase, T Itani, J Mimura, T Kawasaki, H Komori, H Tomioka, T Chiba

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY ( BLACKWELL SCIENCE ASIA ) 14 ( 7 ) 715 - 722 1999.07 [Refereed]

Background: The association between asthma and gastro-oesophageal reflux disease (GERD) is well known. The aim of this study was to elucidate the causal relationship between reflux oesophagitis (RE) and asthma. Methods: Seventy-two adult asthmatics were examined regarding their GERD symptoms, and each underwent an endoscopic examination. According to the Los Angeles classification, we divided the patients into three groups: group 1 (n = 52), no mucosal break; group 2 (n = 15), RE corresponding to grades A or B; group 3 (n = 5), RE corresponding to grades C or D. The asthmatics in groups 2 and 3 received anti-reflux treatment for their GERD for 8 weeks. Their morning and evening peak expiratory flow rates (PEFR), daily variability of the PEER and daily use of an inhalation bronchodilator were compared before and after this treatment. Results: The percentage of severe asthma and postprandial exacerbation of asthma in group 3 were significantly higher than those in the other two groups. In contrast, the number of eosinophiles and the serum level of immunoglobulin E in group 3 were significantly lower than those in the other two groups. After the antireflux treatment, significant improvements of both PEER and daily use of the inhalation bronchodilator were observed only in group 3. Conclusions: The endoscopic severity of RE is associated with the characteristics of adult asthmatics and the treatment of severe RE improved the asthmatics' condition. (C) 1999 Blackwell Science Asia Pty Ltd.

DOI

Gastric ulcer formation after the Hanshin-Awaji earthquake: A case study of Helicobacter pylori infection and stress-induced gastric ulcers

Y Matsushima, N Aoyama, H Fukuda, Y Kinoshita, A Todo, S Himeno, S Fujimoto, M Kasuga, H Nakase, T Chiba

HELICOBACTER ( BLACKWELL SCIENCE INC ) 4 ( 2 ) 94 - 99 1999.06 [Refereed]

Background. Both Helicobacter pylori (H. pylori) infection and various stresses are known to induce peptic ulcer disease of the upper gastrointestinal tract. However, the pathogenetic relationship between the two factors has not yet been clarified. We conducted a case-control study to examine whether H. pylori infection played a role in the development of gastric ulcer (GU) induced by life-event stresses that were experienced after the Hanshin-Awaji earthquake. Materials and Methods. Serum samples from patients in the devastated area who developed GUs during the 2 months following the Hanshin-Awaji earthquake and those from GU patients in the same area during the corresponding period of the previous year, and from gender-, age- and institute-matched ulcer-free controls were tested for the presence of the H. pylori Ige antibody. Results. A significant association between H. pylori infection and the development of GU in uninjured patients was observed in all sets [matched odds ratio (OR) 3.23, 95% confidence interval: 1.95-5.35]. Moreover, the prevalence of H. pylori infection in patients who developed GUs after the earthquake was not different from that for GU patients in the previous year. In contrast, there was no association between H. pylori infection and the development of GU in the physically injured patients after the earthquake. Conclusions. H. pylori infection may play an important role in the development of GUs that are induced by emotional life-event stresses.

DOI

Acute pancreatitis secondary to 5-aminosalicylic acid therapy in a patient with ulcerative colitis

E Adachi, K Okazaki, Y Matsushima, H Seno, K Uchida, H Nakase, C Kawanami, T Nakamura, T Chiba

INTERNATIONAL JOURNAL OF PANCREATOLOGY ( HUMANA PRESS INC ) 25 ( 3 ) 217 - 221 1999.06 [Refereed]

Therapy with oral 5-aminosalicylic acid (5-ASA) for ulcerative colitis has been reported to be effective and safe. We describe a case of biochemically proven mild acute pancreatitis occurring after 9 d of oral 5-ASA therapy for ulcerative colitis. A hypersensitivity mechanism seemed to be involved in the development of pancreatitis probably owing to erratic systemic absorption of the drug. We suggest clinical and biochemical monitoring for early diagnosis of pancreatitis in patients with ulcerative colitis receiving 5-ASA administration. This is the first report of acute pancreatitis developed by oral 5-ASA therapy for the treatment of ulcerative colitis in the literature of Japan.

PubMed

Colonic ulceration caused by administration of loxoprofen sodium

H Nakase, T Itani, J Mimura, T Kawasaki, H Komori, K Hashimoto, T Chiba

INTERNAL MEDICINE ( JAPAN SOC INTERNAL MEDICINE ) 38 ( 3 ) 249 - 251 1999.03 [Refereed]

A 54-year-old female with chronic headache was admitted to our hospital because of hematochezia. She had routinely taken loxoprofen sodium because of severe headache, Emergent colonoscopic examination revealed ulceration of the cecum, After administration of loxoprofen sodium was discontinued and administration of sulfasalazine was initiated, her intestinal bleeding subsided, Two months after discontinuation of loxoprofen sodium, the colonoscopic examination revealed scar formation at the site of cecal ulceration. In this case, it was conceivable that the administration of loxoprofen sodium might have induced colonic ulceration.

DOI CiNii

Bronchial Asthma and Reflux Esophagitis a Clinical Study on 106 Cases with Bronchial Asthma

H. Tomioka, T. Itani, H. Nakase

Japanese Journal of Chest Diseases 58 ( 11 ) 834 - 835 1999 [Refereed]

気管支喘息と胃食道逆流症－喘息患者に対する逆流症治療の意義．

仲瀬裕志, 千葉勉

消化器科 28 350 - 353 1999

Power Doppler imaging of hepatic tumours: Differential diagnosis between hepatocellular carcinoma and metastatic adenocarcinoma

T Kawasaki, T Itani, H Nakase, J Mimura, H Komori, K Sugimoto

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY ( BLACKWELL SCIENCE ) 13 ( 11 ) 1152 - 1160 1998.11 [Refereed]

We evaluated the usefulness of power Doppler imaging in the differential diagnosis between hepatocellular carcinoma and metastatic adenocarcinoma. Forty-seven patients with hepatocellular carcinoma and 18 patients with metastatic adenocarcinoma were evaluated using power Doppler imaging. The colour signals of hepatic rumours were graded as follows: 1, colour signals only in the marginal area; 2, small dot or dotted line colour signals within the rumours; 3, continuous solid line colour signals within the rumours. The grade 3 colour signals were classified in the following three patterns; winding line pattern, stretched line pattern and mixed pattern. The colour signals of hepatocellular carcinoma were grade 1 in seven patients, grade 2 in 11 and grade 3 in 29. The colour signals of metastatic adenocarcinoma were grade 1 in three patients and grade 3 in 15. Of the 29 hepatocellular carcinoma patients with a grade 3 signal, 26 patients had winding line patterns and three had mixed patterns. Of the 15 metastatic adenocarcinoma patients with a grade 3 signal, 12 patients had stretched line patterns and three had mixed patterns. In conclusion, power Doppler imaging is useful in the differential diagnosis between hepatocellular carcinoma and metastatic adenocarcinoma to evaluate the colour signal pattern within the tumour.

DOI

Transient protein-losing enteropathy associated with cytomegalovirus infection in a noncompromised host: A case report

H Nakase, T Itani, J Mimura, R Takeuchi, T Kawasaki, H Komori, K Hashimoto, T Chiba

AMERICAN JOURNAL OF GASTROENTEROLOGY ( ELSEVIER SCIENCE INC ) 93 ( 6 ) 1005 - 1006 1998.06 [Refereed]

DOI

③消化管大腸

仲瀬裕志, 千葉勉

認定医・専門医のための内科学レビュー ’98 －最新主要文献と解説－ 84 - 89 1998

気管支喘息患者における逆流性食道炎の評価

仲瀬裕志

薬理と治療 26 ( 5 ) 679 - 682 1998

CiNii

Evaluation of GERD in bronchial asthmatic patients

H. Nakase

Japanese Pharmacology and Therapeutics 26 ( 5 ) 33 - 36 1998 [Refereed]

経腸栄養法における合併症と対策

仲瀬裕志

臨床栄養 91 35 - 41 1997

Analysis of the usefulness of power Doppler imaging in diagnosing acute appendicitis

H. Uchida, T. Okuno, T. Kawasaki, F. Maenishi, S. Azuma, R. Horikawa, Y. Sakakibara, K. Noborio, H. Komori, J. Mimura, T. Itani, H. Nakase

Journal of Medical Ultrasonics 24 ( 4 ) 19 - 25 1997 [Refereed]

私の治療法－クローン病の治療法/その1.

仲瀬裕志

臨床科学 34 547 - 550 1997

便秘の分類と治療

仲瀬裕志

内科診療Q＆A － 678 - 679 1997

Endoscopic variceal ligation versus endoscopic injection sclerotherapy: Comparison of hepatic and renal function

H Nakase, T Kawasaki, H Komori, N Sakatani, S Sawai, T Chiba

AMERICAN JOURNAL OF GASTROENTEROLOGY ( WILLIAMS & WILKINS ) 91 ( 10 ) 2170 - 2173 1996.10 [Refereed]

Objectives: The aim of the present study was to compare the safety of endoscopic variceal ligation (EVL) and endoscopic injection sclerotherapy (EIS) in terms of liver and kidney functions in patients with liver cirrhosis. Methods: Forty-four patients admitted to Takatsuki General Hospital between February 1991 and March 1993 with esophageal varices due to liver cirrhosis were randomly assigned to receive either EVL or EIS, Serum levels of AST, ALT, total bilirubin (T-bil), direct bilirubin (D-bil), prothrombin time (PT), hepaplastin test (HPT), antithrombin III (ATIII), creatinine (Cr), and blood urea nitrogen (BUN) were measured before and 24 h, 3 days, 7 days, and 14 days after both forms of therapy. Results: Significant elevations of serum T-bil, serum D-bil, and serum ALT and AST levels were observed in the EIS group but not in the EVL group. No significant increases of serum PT, HPT, ATIII, BUN, or Cr levels were observed after treatment in either group, Conclusion: EVL should be considered a first choice therapy for eradicating esophageal varices.

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