Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Ihara Eikichi Last modified date:2023.04.10

Associate Professor / Department of Gastroenterology and Metabolism , Graduate School of Medical Sciences, Kyushu University / Department of Clinical Medicine / Faculty of Medical Sciences

1. Shin-Ichiro Fukuda, Kaoru Ichida, Yusuke Kitagawa, Kayoko Nakano, Chaen Tomohito, Daisuke Yoshimura, Toshiaki Ochiai, Eikichi Ihara, Yoshihiro Ogawa, An adult case of congenital duodenal diaphragm that was successfully treated by endoscopic resection using a grasping-type scissor forceps., DEN open, 10.1002/deo2.93, 2, 1, e93, 2022.04, Congenital duodenal diaphragm (CDD) is a rare disease that is usually diagnosed in the neonatal period; however, it is sometimes diagnosed later in the adult period. A 39-year-old woman was referred to our hospital due to tarry stool and anemia. Emergent esophagogastroduodenoscopy (EGD) revealed an obstructing membranous structure with a small orifice in the second portion of the duodenum, together with dilatation of the bulbar part. The membranous structure was accompanied by a Dieulafoy-like vessel on the backside, which was considered to have caused tarry stool and anemia. The Dieulafoy-like vessel was successfully treated by endoscopic hemostasis. Based on the computed tomographic gastrography and barium duodenography findings, it was diagnosed as CDD. Later, endoscopic resection of the diaphragm was conducted by an endoscopic submucosal dissection (ESD)-based procedure, with the use of an electrosurgical grasping-type scissor forceps (ClutchCutter [CC]). There were no procedure-related complications. The definite diagnosis of CDD was made based on the observation of typical structures in a pathological examination. This is the first case report of adult CDD that was successfully treated by endoscopic resection using ESD-based techniques with a CC..
2. Takayuki Nasu, Mitsuru Esaki, Yoshihisa Shoguchi, Xiaopeng Bai, Yosuke Minoda, Haruei Ogino, Eikichi Ihara, Application of intralesional traction assistance with traction wire to endoscopic submucosal dissection for colorectal neoplasms., Endoscopy, 10.1055/a-1809-4967, 2022.04.
3. Mitsuru Esaki, Eikichi Ihara, Misato Esaki, Kei Nishioka, Yusuke Kimura, Yoshitaka Hata, Hirotaka Tsuru, Masafumi Wada, Yosuke Minoda, Xiaopeng Bai, Yoshihisa Shoguchi, Takayuki Nasu, Shuzaburo Nagatomo, Kazumasa Muta, Haruei Ogino, Yoshihiro Ogawa, Comparisons of outcomes between ProKnife injection endoscopic submucosal dissection and conventional endoscopic submucosal dissection for large gastric lesions in ex vivo porcine model study: A randomized controlled trial., DEN open, 10.1002/deo2.91, 2, 1, e91, 2022.04, Objective: To compare treatment outcomes between injection endoscopic submucosal dissection using ProKnife (P-ESD) and conventional ESD (C-ESD) for gastric lesions. Methods: In this randomized controlled trial, we compared treatment outcomes of P-ESD and C-ESD for simulated gastric lesions ≥3 cm in resected porcine stomachs. Predictive factors associated with ESD difficulties were investigated using logistic regression analysis. Results: Seventy lesions were screened; however, two lesions were excluded. A total of 12 endoscopists performed 68 ESDs: 34 P-ESDs and 34 C-ESDs. The ESD procedure time of P-ESD (36.3 [28.4-46.8] min) was significantly shorter than that of C-ESD (46 [36.4-64.6] min; p = 0.0014). The technical success rates did not differ between the P-ESD and C-ESD groups (en bloc resection rate, 100% in both groups; complete resection rate, 94.1% and 85.3%, respectively; p = 0.23). The number of injections during P-ESD (7.5 [6-10] times) was significantly higher than during C-ESD (4 [3-5] times; p
4. Mitsuru Esaki, Shun Yamakawa, Ryoji Ichijima, Sho Suzuki, Chika Kusano, Hisatomo Ikehara, Yosuke Minoda, Eikichi Ihara, Takuji Gotoda, Self-completion method of endoscopic submucosal dissection using the Endosaber for treating colorectal neoplasms (with video)., Scientific reports, 10.1038/s41598-022-09792-8, 12, 1, 5821-5821, 2022.04, Endoscopic submucosal dissection (ESD) is effective for the treatment of colorectal neoplasms. We have developed a self-completion ESD (S-ESD) using Endosaber without requiring additional instruments or assistance. This prospective cohort study was conducted to investigate the feasibility of S-ESD for colorectal neoplasms. Patients with colorectal neoplasms measuring 20-40 mm in size were enrolled. A single operator, without assistance, performed ESD using only the Endosaber. The primary outcome was the success rate of S-ESD. Secondary outcomes included procedure time, the rates of en bloc, complete, and curative resection, and complication rates, including the incidence of perforation and delayed bleeding. In total, 15 patients with 15 lesions were enrolled. The median size of the resected lesions was 28 mm (interquartile range 25-29 mm). S-ESD success rate of 100% was achieved. The median procedure time was 44 min (29.5-53.5 min). We observed en bloc, complete, and curative resection rates of 100%, 93.3%, and 86.7%, respectively, and a complication rate of 6.7% (perforation: 0%, delayed bleeding: 6.7%). S-ESD for colorectal neoplasms was successfully performed with favorable treatment outcomes and low complication rates. S-ESD reduces the number of devices and extent of assistance, making S-ESD a simple and cost-effective procedure..
5. Mitsuru Esaki, Eikichi Ihara, Hiroyuki Fujii, Yorinobu Sumida, Kazuhiro Haraguchi, Shunsuke Takahashi, Tsutomu Iwasa, Kayoko Nakano, Masafumi Wada, Shinichi Somada, Yosuke Minoda, Haruei Ogino, Koshiro Tagawa, Yoshihiro Ogawa, Comparison of the procedure time differences between hybrid endoscopic submucosal dissection and conventional endoscopic submucosal dissection in patients with early gastric neoplasms: a study protocol for a multi-center randomized controlled trial (Hybrid-G trial)., Trials, 10.1186/s13063-022-06099-x, 23, 1, 166-166, 2022.02, BACKGROUND: Endoscopic submucosal dissection (ESD) is widely accepted as a local treatment for gastrointestinal tract tumors. As a simplified endoscopic procedure, hybrid ESD (H-ESD) has been performed for colorectal neoplasms in recent times. However, whether H-ESD is superior to conventional ESD (C-ESD) for patients with early gastric neoplasms (EGN) remains unclear. In this trial, we will compare the treatment outcomes of H-ESD and C-ESD. We hypothesize that the procedure time for H-ESD is shorter than that for C-ESD. METHODS: This is an investigator-initiated, multi-center, prospective, randomized, open-label, parallel-group trial to be conducted beginning in August 2020 at nine institutions in Japan. We will determine if H-ESD is superior to C-ESD in terms of procedure time in patients with EGN diagnosed as macroscopically intramucosal (T1a) differentiated carcinoma ≤ 20 mm in diameter without ulcerative findings according to current Japanese gastric cancer treatment guidelines. A total of 82 patients will be recruited and randomly assigned to either the C-ESD or the H-ESD group. The primary outcome is ESD procedure time. Secondary outcomes include mucosal incision, time and speed of submucosal dissection, en bloc resection, complete resection, curability, adverse events related to the ESD procedure, extent of dissection before snaring, volume of injection solution, number and time of hemostasis, thickness of the submucosal layer in the resected specimen, and handover to another operator. The stated sample size was determined based on the primary outcome. According to a previous report comparing the procedure times of C-ESD and H-ESD, we hypothesized that H-ESD would provide a 0.2 reduction in logarithmically concerted procedure time (-37%). We estimated that a total of 82 participants were needed to reach a power of 80% for a t-test with a significance level of 0.05 and considering a 10% dropout. DISCUSSION: This trial will provide high-quality data on the benefits and risks of H-ESD for EGN patients. The results of this study could lead to improved outcomes in patients with EGN undergoing ESD. The results will be presented at national and international meetings and published in peer-reviewed journals. TRIAL REGISTRATION: UMIN-CTR UMIN000041244 . Registered on July 29, 2020..
6. Katsuhiko Iwakiri, Yasuhiro Fujiwara, Noriaki Manabe, Eikichi Ihara, Shiko Kuribayashi, Junichi Akiyama, Takashi Kondo, Hiroshi Yamashita, Norihisa Ishimura, Yuichi Kitasako, Katsunori Iijima, Tomoyuki Koike, Nobuo Omura, Tsutomu Nomura, Osamu Kawamura, Shuichi Ohara, Soji Ozawa, Yoshikazu Kinoshita, Satoshi Mochida, Nobuyuki Enomoto, Tooru Shimosegawa, Kazuhiko Koike, Evidence-based clinical practice guidelines for gastroesophageal reflux disease 2021., Journal of gastroenterology, 10.1007/s00535-022-01861-z, 2022.02, In Japan, with the increasing prevalence of gastroesophageal reflux disease (GERD) and growing public interest, the Japanese Society of Gastroenterology issued Evidence-based Clinical Practice Guidelines for GERD (1st edition) in 2009 and a revised 2nd edition in 2015. A number of studies on GERD were subsequently conducted in Japan and abroad, and vonoprazan, a potassium-competitive acid blocker (P-CAB), became available for the first time in Japan in February 2015. The revised 3rd edition (Japanese edition), which incorporates new findings and information, was published in April 2021. These guidelines are summarized herein, particularly sections related to the treatment of GERD. The important clinical issues addressed in the present revision are (i) the introduction of treatment algorithms that classify GERD into reflux esophagitis and non-erosive reflux disease, (ii) the clarification of treatment algorithms based on to the severity of reflux esophagitis, and (iii) the positioning of vonoprazan in the treatment for GERD. The present guidelines propose vonoprazan as the initial/maintenance treatment for severe reflux esophagitis. They also recommend vonoprazan or PPI as an initial treatment for mild reflux esophagitis and recommended PPI and proposed vonoprazan as maintenance treatment. These updated guidelines offer the best clinical strategies for GERD patients in Japan and hope that they will be of global use for the diagnosis and treatment for GERD..
7. Taisuke Sasaki, Kenichi Kohashi, Shinichiro Kawatoko, Eikichi Ihara, Eiji Oki, Masafumi Nakamura, Yoshihiro Ogawa, Yoshinao Oda, Tumor progression by epithelial-mesenchymal transition in ARID1A- and SMARCA4-aberrant solid-type poorly differentiated gastric adenocarcinoma., Virchows Archiv : an international journal of pathology, 10.1007/s00428-021-03261-9, 2022.01, Solid-type poorly differentiated adenocarcinoma (PDA) of the stomach is frequently associated with microsatellite instability (MSI) and aberrations of the SWI/SNF chromatin remodeling complex. Previous studies showed that aberrant ARID1A and SMARCA4 expression induces mesenchymal transition. We analyzed 51 primary-site cases and 209 metastatic lymph nodes among solid-type PDA for the expression of SWI/SNF complex subunits (ARID1A, SMARCA4, SMARCB1, SMARCC2) and epithelial-mesenchymal transition (EMT) markers (E-cadherin, β-catenin, Snail). We also analyzed 40 cases of non-solid-type PDA as a stage-matched control group. Aberrant expression of ARID1A (39%) and SMARCA4 (49%) was more common in solid-type PDA than in non-solid-type PDA (ARID1A, P = 0.0049; SMARCA4, P 
8. Eikichi Ihara, Haruei Ogino, Kazumasa Muta, Shohei Hamada, Masafumi Wada, Yoshitaka Hata, Hiroko Ikeda, Xiaopeng Bai, Yosuke Minoda, Mitsuru Esaki, Yoshimasa Tanaka, Takatoshi Chinen, Yoshihiro Ogawa, The treatment effects of acotiamide in esophagogastric outflow obstruction: a prospective longitudinal observational study., Esophagus : official journal of the Japan Esophageal Society, 10.1007/s10388-021-00887-1, 2021.10, OBJECTIVES: We have found that an altered lower esophageal sphincter (LES) accommodation response is an underlying cause of esophagogastric junction outflow obstruction (EGJOO). The objective of this study was to examine the treatment effect of acotiamide, a prokinetic agent which improves impaired gastric accommodation in functional dyspepsia, in patients with EGJOO. METHODS: A prospective observational longitudinal study was conducted between October 2014 and March 2020. Acotiamide (100 mg, 3 times a day) was administered to 25 patients with EGJOO for 4 weeks. High-resolution manometry (HRM) was performed just before and after 4 weeks of treatment. RESULTS: As the primary outcome, the extent of integrated relaxation pressure (IRP) after treatment (14.6, 12.1-22.0 mmHg) was significantly lower than that before treatment (19.4, 17.1-27.4 mmHg). The extent of LES accommodation index after treatment (32.7, 21.0-40.0 mmHg) was also significantly lower than that before treatment (39.3, 31.2-50.2 mmHg). Acotiamide normalized the IRP (
9. Akito Ohkubo, Takashi Osoegawa, Naohiko Harada, Yoichiro Iboshi, Yorinobu Sumida, Makoto Nakamuta, Eiichi Suematsu, Hiroyuki Kobayashi, Eikichi Ihara, A Rare Case of Rheumatoid Arthritis with Tocilizumab-induced Intestinal Mucosal Injury., Internal medicine (Tokyo, Japan), 10.2169/internalmedicine.8031-21, 2021.09, Intestinal mucosal injury that develops as a complication of tocilizumab (TCZ) is usually associated with diverticulosis. We herein report a rare case of TCZ-induced intestinal mucosal injury in the absence of diverticulosis. A 74-year-old woman suffering from rheumatoid arthritis started taking TCZ. Six months later, she complained of hematochezia and abdominal pain. Colonoscopy revealed multiple ulcers spreading from the cecum to the transverse colon but no diverticulosis. These lesions were cured at three months after the discontinuation of TCZ. We should consider TCZ as a risk factor for intestinal mucosal injury, even if patients have no history of intestinal disease associated with diverticulosis..
10. Yoshihiro Otsuka, Xiaopeng Bai, Yoshimasa Tanaka, Eikichi Ihara, Takatoshi Chinen, Haruei Ogino, Yoshihiro Ogawa, Involvement of interstitial cells of Cajal in nicotinic acetylcholine receptor-induced relaxation of the porcine lower esophageal sphincter., European journal of pharmacology, 10.1016/j.ejphar.2021.174491, 910, 174491-174491, 2021.09, The interstitial cells of Cajal (ICCs) play an important role in coordinated gastrointestinal motility. The present study aimed to elucidate whether or how ICCs are involved in the lower esophageal sphincter (LES) relaxation induced by stimulation of the nicotinic acetylcholine receptor. The application of 1,1-dimethyl-4-phenyl-piperazinium (DMPP; a nicotinic acetylcholine receptor agonist) induced a transient relaxation in the circular smooth muscle of the porcine LES. DMPP-induced relaxation was abolished by not only 1 μM tetrodotoxin but also the inhibition of ICC activity by pretreatment with 100 μM carbenoxolone (a gap junction inhibitor), pretreatment with 100 μM CaCCinh-A01 (an anoctamin-1 blocker acting as a calcium-activated chloride channel inhibitor), and pretreatment with Cl--free solution. However, pretreatment with 100 μM Nω-nitro-L-arginine methyl ester had little effect on DMPP-induced relaxation. Furthermore, DMPP-induced relaxation was inhibited by pretreatment with 1 mM suramin, a purinergic P2 receptor antagonist, but not by 1 μM VIP (6-28), a vasoactive intestinal peptide (VIP) receptor antagonist. Stimulation of the purinergic P2 receptor with adenosine triphosphate (ATP) induced relaxation, which was abolished by the inhibition of ICC activity by pretreatment with CaCCinh-A01. In conclusion, membrane hyperpolarization of the ICCs via the activation of anoctamin-1 plays a central role in DMPP-induced relaxation. ATP may be a neurotransmitter for inhibitory enteric neurons, which stimulate the ICCs. The ICCs act as the interface of neurotransmission of nicotinic acetylcholine receptor in order to induce LES relaxation..
11. Yosuke Minoda, Shuzaburo Nagatomo, Nao Fujimori, Kei Nishioka, Shotaro Kakehashi, Katsuhito Teramatsu, Yu Takamatsu, Haruei Ogino, Eikichi Ihara, Usefulness of a gel immersion-assisted EUS-guided fine-needle aspiration/biopsy for ampullary lesions (with videos)., Endoscopic ultrasound, 10.4103/EUS-D-21-00043, 2021.09.
12. Mitsuru Esaki, Yosuke Minoda, Eikichi Ihara, In Living Color: Linked Color Imaging for the Detection of Early Gastric Cancer., Digestive diseases and sciences, 10.1007/s10620-021-07235-4, 2021.08.
13. Kei Nishioka, Haruei Ogino, Takatoshi Chinen, Eikichi Ihara, Yoshimasa Tanaka, Kazuhiko Nakamura, Yoshihiro Ogawa, Mucosal IL23A expression predicts the response to Ustekinumab in inflammatory bowel disease., Journal of gastroenterology, 10.1007/s00535-021-01819-7, 2021.08, BACKGROUND: Biologics against tumor necrosis factor-α (TNF) and the p40 subunit of interleukin (IL)-12 and IL-23 are increasingly used in inflammatory bowel disease (IBD) treatment. However, information on response prediction to these agents is limited. Thus, we aimed to identify factors for IBD treatment response prediction. METHODS: We conducted a retrospective study in 33 IBD subjects for anti-TNF and a prospective study of 23 IBD and 11 non-IBD subjects for ustekinumab (UST). Mucosal biopsy specimens were obtained before treatment with biologics. The expression of 18 immune-related genes encoding representative cytokines and transcription factors was analyzed by quantitative polymerase chain reaction. RESULTS: There was no difference between the treatment-resistant and -sensitive groups with regard to clinical characteristics. A higher expression of oncostatin M (OSM) and its receptor OSMR in the intestinal mucosa was most strongly associated with anti-TNF resistance, whereas lower IL23A expression was most strongly associated with UST resistance. In addition to the absolute expression levels of genes, concordant or discordant expression patterns of particular gene sets were associated with treatment sensitivity and resistance. CONCLUSIONS: The association of anti-TNF resistance and mucosal OSM and OSMR expression was consistent with the results of a previous study in a European cohort. Our observation that IBD subjects with higher mucosal IL23A expression were more likely to achieve remission by UST has not been previously reported. The response to biologics may thus be predicted in IBD patients through the analysis of mucosal gene expression levels and patterns..
14. Mitsuru Esaki, Eikichi Ihara, Takuji Gotoda, Endoscopic instruments and techniques in endoscopic submucosal dissection for early gastric cancer., Expert review of gastroenterology & hepatology, 10.1080/17474124.2021.1924056, 1-12, 2021.07, Introduction: Endoscopic submucosal dissection (ESD) is a less invasive local treatment for early gastric cancer (EGC).Areas covered: Japanese guidelines have recently expanded the endoscopic treatment indications for EGC. ESD is sometimes performed for lesions with a relative indication that has not previously been considered for ESD. ESD procedures are technically difficult, especially for larger and more invasive lesions. Complete resection and accurate histological assessment of EGC lesions are essential to evaluate endoscopic curability. Various endoscopic instruments, including three types of endoscopic knives and specific hemostatic forceps, have been developed, and endoscopic techniques, including the traction method, have been modified to simplify the procedure.Expert opinion: An insulated-tip knife with large tissue contact allows us to perform faster incisions, while a needle-type knife with minimal tissue contact allows us to perform precise incisions. Furthermore, a scissor-type knife with grasping tissues allows us to perform more secure incision. The traction method enables the operator to proceed with submucosal dissection procedures. In cases with small lesions, snaring can be used, as well as knife dissection. Understanding the features of each endoscopic instrument and technique is essential because appropriate selection and usage contribute to successful and safe ESD procedures..
15. Yuichiro Nishihara, Haruei Ogino, Masaru Tanaka, Eikichi Ihara, Keita Fukaura, Kei Nishioka, Takatoshi Chinen, Yoshimasa Tanaka, Jiro Nakayama, Dongchon Kang, Yoshihiro Ogawa, Mucosa-associated gut microbiota reflects clinical course of ulcerative colitis., Scientific reports, 10.1038/s41598-021-92870-0, 11, 1, 13743-13743, 2021.07, This longitudinal study was designed to elucidate whether gut microbiota is associated with relapse and treatment response in ulcerative colitis (UC) patients. Fifty-one patients with UC were enrolled between 2012 and 2017, and followed up through 2020. Colon mucosal biopsy were obtained at enrollment, and 16S ribosomal RNA sequencing was performed using extracted RNA. Of the 51 patients, 24 were in remission and 27 had active UC at enrollment. Of the 24 patients in remission, 17 maintained remission and 7 developed relapse during follow-up. The 7 patients with relapse showed lower diversity, with a lower proportion of Clostridiales (p = 0.0043), and a higher proportion of Bacteroides (p = 0.047) at enrollment than those without relapse. The 27 patients with active UC were classified into response (n = 6), refractory (n = 13), and non-response (n = 8) groups according to their treatment response in 6 months. The refractory and non-response groups showed lower diversity with a lower proportion of Prevotella (p = 0.048 and 0.043) at enrollment than the response group. This study is the first demonstration that reduced diversity and particular microbes are associated with the later clinical course of relapse events and treatment response in UC..
16. Shohei Hamada, Eikichi Ihara, Kazumasa Muta, Masafumi Wada, Yoshitaka Hata, Hiroko Ikeda, Yoshimasa Tanaka, Haruei Ogino, Takatoshi Chinen, Yoshihiro Ogawa, Onigiri esophagography as a screening test for esophageal motility disorders., Journal of neurogastroenterology and motility, 10.5056/jnm20138, 2021.07, Background/Aims: No screening test for esophageal motility disorder (EMD) has been established, the objective of this study is to examine the potential usefulness of our newly developed "Onigiri esophagography" combined with an obstruction level (OL) classification system in screening for EMD. Methods: A total of 102 patients with suspected EMDs who underwent both high-resolution manometry (HRM) and Onigiri esophagography between April 2017 and January 2019 were examined. The EMD diagnosis was performed based on the Chicago classification version 3.0 by HRM. Onigiri esophagography was performed using a liquid medium (barium sulfate) followed by a solid medium, which consisted of an Onigiri (a Japanese rice ball) with barium powder. The extent of medium obstruction was assessed by the OL classification, which was defined in a stepwise fashion from OL0 (no obstruction) to OL4 (severe obstruction). Results: Thirty-two percent of the patients with OL0 (32.3%), OL1 (50.0%), OL2 (88.0%), OL3 (100.0%), and OL4 (100.0%) were diagnosed EMDs by HRM. The area under the curve, as determined by a receiver operating characteristic analysis, for the OL classification was 0.86. Using the cutoff value of OL1, the sensitivity and specificity were 87.3% and 61.3%, respectively, while using a cutoff value of OL2, the sensitivity and specificity were 73.2% and 90.3%, respectively. Conclusion: In conclusion, Onigiri esophagography combined with the OL classification system can be used as a screening test for EMDs with a cutoff value of OL1..
17. Yosuke Minoda, Yuichi Hisamatsu, Eikichi Ihara, Usefulness of preoperative site marking with an indocyanine green fluorescent clip for gastrointestinal stromal tumor., Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, 10.1111/den.13978, 33, 5, e95-e96, 2021.07.
18. Mitsuru Esaki, Eikichi Ihara, Norikazu Hashimoto, Shuichi Abe, Chihoko Aratono, Noriko Shiga, Yorinobu Sumida, Hiroyuki Fujii, Kazuhiro Haraguchi, Shunsuke Takahashi, Tsutomu Iwasa, Kayoko Nakano, Masafumi Wada, Shinichi Somada, Kei Nishioka, Yosuke Minoda, Haruei Ogino, Yoshihiro Ogawa, Efficacy of hybrid endoscopic submucosal dissection with SOUTEN in gastric lesions: An ex vivo porcine model basic study., World journal of gastrointestinal surgery, 10.4240/wjgs.v13.i6.563, 13, 6, 563-573, 2021.06, BACKGROUND: Hybrid endoscopic submucosal dissection (ESD) that comprises mucosal incision and partial submucosal dissection followed by snaring in a planned manner, has been developed for endoscopic resection of gastrointestinal neoplasms to overcome the technical barrier of ESD. Although the superiority of hybrid ESD with SOUTEN, a single multifunctional device, over conventional ESD has been indicated, the actual effect of snaring itself remains unclear since SOUTEN could be applied to hybrid ESD group, but not to the conventional ESD group, due to ethical issue in clinical practice. AIM: To determine whether and how hybrid ESD was superior to conventional ESD in the endoscopic treatment of gastric lesions in an ex vivo porcine model basic study. METHODS: Sixteen endoscopists participated in this basic study in August 2020 at Kyushu University, performing 32 procedures each for hybrid ESD and conventional ESD. Mock lesions (10-15 mm, diameter) were created in the porcine stomach. The primary outcome was total procedure time and secondary outcomes were en bloc or complete resection, perforation, procedure time/speed for both, mucosal incision, and submucosal dissection. Factors associated with difficulty in ESD including longer procedure time, incomplete resection, and perforation, were also investigated. Categorical and continuous data were analyzed using the chi-square test or Fisher's exact test and the Mann-Whitney U test, respectively. RESULTS: The median total procedure time of hybrid ESD was significantly shorter than that of conventional ESD (median: 8.3 min vs 16.2 min, P
19. Shuzaburo Nagatomo, Yosuke Minoda, Eikichi Ihara, Double scope recovery technique to manage procedure-related trouble during wire trimming with a Loop cutter., Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, 10.1111/den.13954, 33, 4, e83-e84, 2021.05.
20. Ogino, Haruei; Fukaura, Keita; Iboshi, Yoichiro; Nagamatsu, Yousuke; Okuno, Hiroaki; Nishioka, Kei; Nishihara, Yuichiro; Tanaka, Yoshimasa; Chinen, Takatoshi; Ihara, Eikich; Ogawa, Yoshihiro, Role of the IL-23-T-bet/GATA3 Axis for the Pathogenesis of Ulcerative Colitis, INFLAMMATION, 10.1007/s10753-020-01358-y, 44, 2, 592-603, 2021.04.
21. Mitsuru Esaki, Ryosuke Maehara, Shuzaburo Nagatomo, Kei Nishioka, Yosuke Minoda, Haruei Ogino, Eikichi Ihara, Application of traction-method to hybrid endoscopic submucosal dissection for gastrointestinal tumors., Endoscopy, 10.1055/a-1422-2902, 2021.04.
22. Kazumasa Muta, Eikichi Ihara, Shohei Hamada, Hiroko Ikeda, Masafumi Wada, Yoshitaka Hata, Xiaopeng Bai, Yuichiro Nishihara, Yoshimasa Tanaka, Haruei Ogino, Yoshihiro Ogawa, Physiological and pathological roles of the accommodation response in lower esophageal sphincter relaxation during wet swallows., Scientific reports, 10.1038/s41598-021-87052-x, 11, 1, 7898-7898, 2021.04, The preparatory accommodation response of lower esophageal sphincter (LES) before swallowing is one of the mechanisms involved in LES relaxation during wet swallows, however, the physiological and/or pathological roles of LES accommodation remain to be determined in humans. To address this problem, we conducted a prospective observational study of 38 patients with normal high-resolution manometry (HRM) and 23 patients with idiopathic esophagogastric junction outflow obstruction (EGJOO) to assess dry and wet swallows. The LES accommodation measurement was proposed for practical use in evaluating the LES accommodation response. Although swallow-induced LES relaxation was observed in both dry and wet swallows, LES accommodation (6.4, 3.1-11.1 mmHg) was only observed in wet swallows. The extent of LES accommodation was impaired in idiopathic EGJOO (0.6, - 0.6-6 mmHg), and the LES accommodation measurement of patients with idiopathic EGJOO (36.8, 29.5-44.3 mmHg) was significantly higher in comparison to those with normal HRM (23.8, 18-28.6 mmHg). Successful LES relaxation in wet swallowing can be achieved by LES accommodation in combination with swallow-induced LES relaxation. Impaired LES accommodation is characteristic of idiopathic EGJOO. In addition to the IRP value, the LES accommodation measurement may be useful for evaluating the LES relaxation function in clinical practice..
23. Esaki M, Horii T, Ichijima R, Wada M, Sakisaka S, Abe S, Tomoeda N, Kitagawa Y, Nishioka K, Minoda Y, Tsuruta S, Suzuki S, Akiho H, Ihara E, Ogawa Y, Gotoda T., Assistant skill in gastric endoscopic submucosal dissection using a clutch cutter, WORLD JOURNAL OF GASTROINTESTINAL SURGERY, 10.4240/wjgs.v13.i2.116, 13, 2, 116-126, 2021.02.
24. Esaki, Mitsuru; Minoda, Yosuke; Wada, Masafumi; Sakisaka, Seiichiro; Tsuruta, Shinichi; Hosokawa, Taizo; Matsuguchi, Takahiro; Ichijima, Ryoji; Suzuki, Sho; Tamura, Yu; Iwao, Aya; Yamakawa, Shun; Irie, Akira; Ihara, Eikichi; Ogawa, Yoshihiro, Self-Completion Method of Endoscopic Submucosal Dissection Using Endosaber without Any Other Device or Assistance: An ex vivo Porcine Model Study, DIGESTION, 10.1159/000502771, 102, 2, 139-146, 2021.02.
25. Hamada, Shohei; Ihara, Eikichi; Ikeda, Hiroko; Muta, Kazumasa; Ogino, Haruei; Chinen, Takatoshi; Tanaka, Yoshimasa; Ogawa, Yoshihiro, Clinical Characterization of Vonoprazan-Refractory Gastroesophageal Reflux Disease, DIGESTION, 10.1159/000503340, 102, 2, 197-204, 2021.02.
26. Okuno, Hiroaki; Ogino, Haruei; Ihara, Eikichi; Nishioka, Kei; Tanaka, Yoshimasa; Chinen, Takatoshi; Kohjima, Motoyuki; Oono, Takamasa; Tanaka, Masatake; Goya, Takeshi; Fujimori, Nao; Iboshi, Yoichiro; Gotoda, Takuji; Ogawa, Yoshihiro, Discriminant equation using mucosally expressed cytokines and transcription factor for making definite diagnosis of inflammatory bowel disease unclassified, BMC GASTROENTEROLOGY, 10.1186/s12876-021-01656-1, 21, 1, 2021.02.
27. Fujimori, Nao; Osoegawa, Takashi; Aso, Akira; Itaba, Soichi; Minoda, Yosuke; Murakami, Masatoshi; Matsumoto, Kazuhide; Teramatsu, Katsuhito; Takamatsu, Yu; Takaoka, Takehiro; Oono, Takamasa; Ihara, Eikichi; Yoshizumi, Tomoharu; Ohtsuka, Takao; Nakamura, Masafumi; Ogawa, Yoshihiro, Efficacy of Early Endoscopic Ultrasound-Guided Transluminal Drainage for Postoperative Pancreatic Fistula, CANADIAN JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 10.1155/2021/6691705, 2021, 2021.01.
28. Minoda, Yosuke; Ihara, Eikichi; Komori, Keishi; Ogino, Haruei; Otsuka, Yoshihiro; Chinen, Takatoshi; Tsuda, Yasuo; Ando, Koji; Yamamoto, Hidetaka; Ogawa, Yoshihiro, Efficacy of endoscopic ultrasound with artificial intelligence for the diagnosis of gastrointestinal stromal tumors, JOURNAL OF GASTROENTEROLOGY, 10.1007/s00535-020-01725-4, 55, 12, 1119-1126, 2020.12.
29. Esaki, Mitsuru; Haraguchi, Kazuhiro; Akahoshi, Kazuya; Tomoeda, Naru; Aso, Akira; Itaba, Soichi; Ogino, Haruei; Kitagawa, Yusuke; Fujii, Hiroyuki; Nakamura, Kazuhiko; Kubokawa, Masaru; Harada, Naohiko; Minoda, Yosuke; Suzuki, Sho; Ihara, Eikichi; Ogawa, Yoshihiro, Endoscopic mucosal resection vs endoscopic submucosal dissection for superficial non-ampullary duodenal tumors, WORLD JOURNAL OF GASTROINTESTINAL ONCOLOGY, 10.4251/wjgo.v12.i8.918, 12, 8, 918-930, 2020.08.
30. Shunya Nakane, Akihiro Mukaino, Eikichi Ihara, Yoshihiro Ogawa, Autoimmune gastrointestinal dysmotility: the interface between clinical immunology and neurogastroenterology., Immunological medicine, 10.1080/25785826.2020.1797319, 1-12, 2020.07, Autoimmune gastrointestinal dysmotility (AGID), an idiopathic or paraneoplastic phenomenon, is a clinical form of limited autoimmune dysautonomia. The symptoms of AGID and gastrointestinal manifestations in patients with autoimmune rheumatic diseases are overlapping. Antineuronal autoantibodies are often detected in patients with AGID. Autoantibodies play a key role in GI dysmotility; however, whether they cause neuronal destruction is unknown. Hence, the connection between the presence of these autoantibodies and the specific interference in synaptic transmission in the plexus ganglia of the enteric nervous system has to be determined. The treatment options for AGID are not well-defined. However, theoretically, immunomodulatory therapies have been shown to be effective and are therefore used as the first line of treatment. Nonetheless, diverse combined immunomodulatory therapies should be considered for intractable cases of AGID. We recommend comprehensive autoimmune evaluation and cancer screening for clinical diagnosis of AGID. Univocal diagnostic criteria, treatment protocols, and outcome definitions for AGID are required for prompt diagnosis and treatment and appropriate management of immunotherapy, which will circumvent the need for surgeries and improve patient outcome. In conclusion, AGID, a disease at the interface of clinical immunology and neurogastroenterology, requires further investigations and warrants cooperation among specialists, especially clinical immunologists, gastroenterologists, and neurologists..
31. Hiroaki Okuno, Haruei Ogino, Eikichi Ihara, Kei Nishioka, Yoichiro Iboshi, Takatoshi Chinen, Toshiaki Ochiai, Hirotada Akiho, Kazuhiko Nakamura, Takuji Gotoda, Yoshihiro Ogawa, Interleukin-1β as a Predictor of Glucocorticoid Response in Ulcerative Colitis., Digestion, 10.1159/000507435, 1-11, 2020.05, BACKGROUND/AIM: Currently, there are no established biomarkers to differentiate between glucocorticoid (GC)-resistant and GC-sensitive ulcerative colitis (UC); however, interleukin (IL)-1β could be one such candidate biomarker. The aim of this study was to investigate whether mucosally expressed IL-1β could predict the response to GC in patients with UC. METHODS: A total of 27 mucosal tissue samples from 10 patients with GC-resistant UC (GC-resistant group), 9 patients with GC-sensitive UC (GC-sensitive group), and 8 control patients (control group) were analyzed by qRT-PCR for the expression of IL-1β, GC receptor α (GRα), GRβ, and other inflammatory mediators. Rachmilewitz endoscopic index (REI) between the GC-resistant and GC-sensitive groups was matched to avoid any potential influence of inflammation. RESULTS: The REI did not significantly differ between the GC-resistant and GC-sensitive groups. Mucosally expressed IL-1β levels in the GC-resistant group were significantly higher than those in the GC-sensitive group. However, there were no significant differences in the expression levels of GRα, GRβ, and other inflammatory mediators between the 2 groups. We could distinguish between the GC-resistant and GC-sensitive groups with a sensitivity of 90.0% and specificity of 77.8% based on mucosally expressed IL-1β. CONCLUSIONS: Mucosally expressed IL-1β can be used as a predictor of GC response in patients with UC..
32. Yosuke Minoda, Eikichi Ihara, Haruei Ogino, Keishi Komori, Yoshihiro Otsuka, Hiroko Ikeda, Mitsuru Esaki, Takatoshi Chinen, Takahiro Matsuguchi, Shunsuke Takahashi, Noriko Shiga, Rie Yoshimura, Yoshihiro Ogawa, The Efficacy and Safety of a Promising Single-Channel Endoscopic Closure Technique for Endoscopic Treatment-Related Artificial Ulcers: A Pilot Study., Gastrointestinal tumors, 10.1159/000503994, 7, 1-2, 21-29, 2020.04, Background/Aims: It is important to appropriately manage patients with procedure-related artificial mucosal ulcers or procedure-related complications. Many endoscopic closure techniques have been reported; however, they often require the use of special devices. We developed a single-channel endoscopic closure technique (SCCT) that can be performed with conventional devices. In the present study, we describe the technique and evaluate its efficacy. Methods: Twenty-five consecutive patients who underwent endoscopic treatment and whose artificial ulcer was closed using the SCCT were enrolled in this study. The technical success rate, number of clips for closure, procedure time, complication rate on the day of the procedure, clinical success rates on days 1 and 5, and incidence of severe stenosis of the gastrointestinal (GI) tract at 2 months after the procedure were evaluated. Results: The median ulcer diameter was 20 mm. The tumor locations were the stomach (n = 19), jejunum (n = 1), and colon (n = 5). The technical success rate was 100% (25/25), and the rate of incomplete closure was 0% (0/25). Eight clips were needed on average. The median procedure time was 18 min (range 5-49 min). The complication rate was 0% (25/25). The clinical success rates on days 1 and 5 were 100% (19/19) and 100% (9/9), respectively. No patients presented stenosis as a late complication at 2 months after the procedure (0/25). Conclusion: The SCCT could be applied in the treatment of artificial ulcers in several parts of the GI tract with a high clinical success rate and no complications. The SCCT appears to be a good option for closing artificial mucosal ulcers..
33. Mitsuru Esaki, Yasuyo Hayashi, Hisatomo Ikehara, Eikichi Ihara, Toshiki Horii, Yu Tamura, Ryoji Ichijima, Shun Yamakawa, Akira Irie, Hitoshi Shibuya, Sho Suzuki, Chika Kusano, Yosuke Minoda, Hirotada Akiho, Yoshihiro Ogawa, Takuji Gotoda, The effect of scissor-type versus non-scissor-type knives on the technical outcomes in endoscopic submucosal dissection for superficial esophageal cancer: a multi-center retrospective study., Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus, 10.1093/dote/doz077, 33, 4, 2020.04, The Clutch Cutter was invented as a scissor-type knife for endoscopic submucosal dissection (ESD) of gastrointestinal neoplasms. ESD with the scissor-type knife (ESD-S) may be considered a technically easier procedure than ESD with non-scissor-type knives (ESD-NS). Therefore, this study aimed to compare the technical outcomes of ESD-S with those of ESD-NS for superficial esophageal cancer. This was a multicenter retrospective study. Patients with superficial esophageal cancer treated with ESD between October 2015 and March 2018 at three hospitals were retrospectively reviewed. The ESD-S group had 48 patients and the ESD-NS group had 114 patients. A propensity score matching analysis was performed to compensate for the confounding bias between both groups. Multivariate analyses and propensity score matching were used to adjust for age, sex, the tumor size, tumor location, tumor depth, degree of tumor circumference, operator level, usage of the traction method, and the sedation method. The primary outcome was the procedure time of the ESD. Secondary outcomes were the rate of en-bloc/complete resection and the rate of complications including perforation, delayed bleeding, and stricture. Propensity score matching analysis provided 36 matched pairs. Median procedure time in the ESD-S group was significantly shorter than that in the ESD-NS group (44.0 min vs. 66.5 min, P = 0.020). In addition, the treatment outcomes were similar in both groups (en-bloc resection: 100% vs. 97.2%, P = 1; complete resection: 88.9% vs. 86.1%, P = 1; curative resection: 80.6% vs. 77.8%, P = 1; perforation: 0% vs. 5.6%, P = 0.49; delayed bleeding: 0% in both groups; stricture: 2.8% vs. 8.3%, P = 0.61). ESD-S was associated with a shorter procedure time than ESD-NS, without an increase in the incidence of complications. Therefore, the scissor-type knife should be considered as an endo-knife for ESD of superficial esophageal cancers..
34. Naohiko Harada, Manami Hirowatari, Eikichi Ihara, Etsuko Ishihara, Mitsuko Inoue, Tomoya Miyamura, Makoto Nakamuta, A Case of Suspicious Allergic Reaction to Peracetic Acid Following Endoscopy., Clinical endoscopy, 10.5946/ce.2019.129, 2020.03, A 43-year-old man with rheumatic arthritis was admitted to our hospital for symptoms of cough, left chest pain, and left elbow pain, and further examination revealed an elevated level of C-reactive protein. On day 2 after admission, he underwent esophagogastroduodenoscopy. On the morning of day 7, he developed a high fever of 39.7°C, several hours after bronchoscopy. On day 13, he underwent colonoscopy. Five minutes after the colonoscopy, he developed a high fever of 39.9°C, accompanied by stridor, indicating a decrease in arterial oxygen saturation level. An intradermal test for peracetic acid which was used for cleaning flexible endoscopy was positive. We suspect that he suffered from an allergic reaction to peracetic acid following the flexible endoscopy. This is the first case reported on suspicious allergic reaction to peracetic acid following a flexible endoscopy procedure..
35. Shinichi Tsuruta, Kenichi Kohashi, Yuichi Yamada, Minako Fujiwara, Yutaka Koga, Eikichi Ihara, Yoshihiro Ogawa, Eiji Oki, Masafumi Nakamura, Yoshinao Oda, Solid-type poorly differentiated adenocarcinoma of the stomach: Deficiency of mismatch repair and SWI/SNF complex., Cancer science, 10.1111/cas.14301, 111, 3, 1008-1019, 2020.03, ARID1A, one of the subunits in SWI/SNF chromatin remodeling complex, is frequently mutated in gastric cancers with microsatellite instability (MSI). The most frequent MSI in solid-type poorly differentiated adenocarcinoma (PDA) has been reported, but the SWI/SNF complex status in solid-type PDA is still largely unknown. We retrospectively analyzed 54 cases of solid-type PDA for the expressions of mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), SWI/SNF complex subunits (ARID1A, INI1, BRG1, BRM, BAF155, and BAF170) and EBER, and mutations in KRAS and BRAF. We analyzed 40 cases of another histological type of gastric cancer as a control group. The solid-type PDAs showed coexisting glandular components (76%), MMR deficiency (39%), and complete/partial loss of ARID1A (31%/7%), INI1 (4%/4%), BRG1 (48%/30%), BRM (33%/33%), BAF155 (13%/41%), and BAF170 (6%/2%), EBER positivity (4%), KRAS mutation (2%), and BRAF mutation (2%). Compared to the control group, MMR deficiency and losses of ARID1A, BRG1, BRM, and BAF155 were significantly frequent in solid-type PDAs. Mismatch repair deficiency was associated with the losses of ARID1A, BRG1, and BAF155 in solid-type PDAs. In the MMR-deficient group, solid components showed significantly more frequent losses of ARID1A, BRG1, BRM, and BAF155 compared to glandular components (P = .0268, P = .0181, P = .0224, and P = .0071, respectively). In the MMR-proficient group, solid components showed significantly more frequent loss of BRG1 compared to glandular components (P = .012). In conclusion, solid-type PDAs showed frequent losses of MMR proteins and the SWI/SNF complex. We suggest that loss of the SWI/SNF complex could induce a morphological shift from differentiated-type adenocarcinoma to solid-type PDA..
36. Nao Fujimori, Yosuke Minoda, Masatoshi Murakami, Yuta Suehiro, Takamasa Oono, Eikichi Ihara, Yoshihiro Ogawa, Endoscopic removal of a lumen-apposing metal stent that migrated into the walled-off necrosis during the first drainage procedure, ENDOSCOPY, 10.1055/a-0992-8900, 52, 2, E51-E52, 2020.02.
37. Mitsuru Esaki, Yosuke Minoda, Eikichi Ihara, Seiichiro Sakisaka, Shinichi Tsuruta, Taizo Hosokawa, Masafumi Wada, Yoshitaka Hata, Sho Suzuki, Aya Iwao, Shun Yamakawa, Akira Irie, Hirotada Akiho, Yoshihiro Ogawa, Efficacy of traction, using a clip-with-thread, for esophageal endoscopic submucosal dissection for esophageal lesions with fibrosis in an ex vivo pig training model., The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology, 10.5152/tjg.2020.19207, 31, 1, 58-64, 2020.01, BACKGROUND/AIMS: Endoscopic submucosal dissection (ESD) of recurrent esophageal carcinoma is technically difficult to perform due to submucosal fibrosis that develops after definitive chemoradiation therapy. Therefore, our aim was to evaluate the usefulness of clip-with-thread traction for ESD of esophageal lesions with submucosal fibrosis. MATERIALS AND METHODS: Four endoscopists excised 16 lesions by ESD in an ex vivo pig training model. Mock lesions (30 mm in diameter) were created, including a 10-mm area of submucosal fibrosis in the center of each lesion. Each endoscopist performed two ESDs with traction (ESD-T) and two without traction (ESD-N). The primary outcome was the time required for submucosal dissection. Secondary outcomes were the rate of en bloc (complete) resection and perforation during the procedure, and the total amount of solution injected. RESULTS: All esophageal ESDs were completed. The median dissection time was significantly shorter for the ESD-T group (median 12.5 min, interquartile range 10.2-14.5) when comparing to the ESD-N group (median 18.0 min, interquartile range 14.6-19.2) (P=0.040). The en bloc resection rate was 100% in both groups, with a rate of complete resection of 87.5% and a rate of perforation of 37.5% for both groups. The median amount of solution injected was not significantly different between the ESD-T (18.0 ml) and ESD-N (20.5 ml) groups (P=0.526). CONCLUSION: Clip-with-thread traction improved the performance of ESD for lesions with submucosal fibrosis. However, the method might not reduce the risk of perforation, which remains an important clinical issue to resolve..
38. Yosuke Minoda, Takatoshi Chinen, Takashi Osoegawa, Soichi Itaba, Kazuhiro Haraguchi, Hirotada Akiho, Akira Aso, Yorinobu Sumida, Keishi Komori, Haruei Ogino, Eikichi Ihara, Yoshihiro Ogawa, Superiority of mucosal incision-assisted biopsy over ultrasound-guided fine needle aspiration biopsy in diagnosing small gastric subepithelial lesions: A propensity score matching analysis, BMC Gastroenterology, 10.1186/s12876-020-1170-2, 20, 1, 19-19, 2020.01, © 2020 The Author(s). Background: Gastric subepithelial lesions, including gastrointestinal stromal tumors, are often found during routine gastroscopy. While endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) has been the gold standard for diagnosing gastric subepithelial lesions, alternative open biopsy procedures, such as mucosal incision-assisted biopsy (MIAB) has been reported useful. The aim of this study is to evaluate the efficacy of MIAB for the diagnosis of gastric SELs compared with EUS-FNAB. Methods: We retrospectively analyzed medical records of 177 consecutive patients with gastric SELs who underwent either MIAB or EUS-FNAB at five hospitals in Japan between January 2010 and January 2018. Diagnostic yield, procedural time, and adverse event rates for the two procedures were evaluated before and after propensity-score matching. Results: No major procedure-related adverse events were observed in either group. Both procedures yielded highly-accurate diagnoses once large enough samples were obtained; however, such successful sampling was more often accomplished by MIAB than by EUS-FNAB, especially for small SELs. As a result, MIAB provided better diagnostic yields for SELs smaller than 20-mm diameter. The diagnostic yields of both procedures were comparable for SELs larger than 20-mm diameter; however, MIAB required significantly longer procedural time (approximately 13 min) compared with EUS-FNAB. Conclusions: Although MIAB required longer procedural time, it outperformed EUS-FNAB when diagnosing gastric SELs smaller than 20-mm diameter..
39. Keishi Komori, Eikichi Ihara, Yosuke Minoda, Haruei Ogino, Taisuke Sasaki, Minako Fujiwara, Yoshinao Oda, Yoshihiro Ogawa, The Altered Mucosal Barrier Function in the Duodenum Plays a Role in the Pathogenesis of Functional Dyspepsia, Digestive Diseases and Sciences, 10.1007/s10620-019-5470-8, 64, 11, 3228-3239, 2019.11, © 2019, Springer Science+Business Media, LLC, part of Springer Nature. Background: An altered gastrointestinal barrier function is reportedly associated with the pathogenesis of functional dyspepsia (FD); however, the pathogenesis of FD has not yet been fully elucidated. Aims: The objective of the present study was to determine whether the mucosal barrier function is impaired in patients with FD and to investigate the mechanisms underlying FD. Methods: The present study included patients with FD (FD group, n = 24), non-FD patients with abdominal symptoms (symptomatic control group, n = 14), and patients with no abdominal symptoms (asymptomatic control group, n = 20). The groups were compared regarding the mucosal electrical impedance (MI) values of the stomach and duodenum, which were measured using a tissue conductance meter during esophagogastroduodenoscopy. Results: There were no significant differences between the three groups in the MI of the stomach. In contrast, the duodenal MI of the FD group (17.8 ± 4.3 Ω) was significantly lower than those of the symptomatic control group (27.2 ± 6.4 Ω, p
40. Kazuya Akahoshi, Yuki Shiratsuchi, Masafumi Oya, Hidenobu Koga, Masaru Kubokawa, Naotaka Nakama, Kazuaki Akahoshi, Eikichi Ihara, Endoscopic submucosal dissection with a grasping-type scissors for early colorectal epithelial neoplasms: a large single-center experience, VideoGIE, 10.1016/j.vgie.2019.05.003, 4, 10, 486-492, 2019.10, © 2019 American Society for Gastrointestinal Endoscopy Background and aims: The Clutch Cutter (CC) can grasp, pull, coagulate, and incise targeted tissue with the use of electrosurgical current. It was developed as a biopsy technique to reduce the technical difficulty of endoscopic submucosal dissection (ESD) with knives. The aim of this study was to evaluate the efficacy and safety of ESD using the CC (ESD-CC) for early colorectal epithelial neoplasms (ECENs). Methods: In this prospective study, we enrolled 437 consecutive patients with a diagnosis of ECEN between January 2009 and January 2018. They all satisfied the Japanese colorectal cancer treatment guidelines for ESD; namely, confirmation by preliminary endoscopy, EUS, and endoscopic biopsy. The CC was used for all steps of ESD (mucosal incision, submucosal dissection, and hemostatic treatment); therapeutic efficacy and safety were assessed. Results: The en bloc resection rate was 99.3% (434/437), and the R0 resection rate was 87.0% (380/437). The mean operating time was 88.3 minutes. Perforation occurred in 10 cases (2.3%) and was managed with conservative medical treatment. Post-ESD-CC bleeding occurred in 10 cases (2.3%) and was successfully treated by endoscopic hemostatic treatment. Conclusions: ESD-CC is a technically efficient, safe, and easy method for resecting ECEN..
41. Yosuke Minoda, Haruei Ogino, Takatoshi Chinen, Eikichi Ihara, Kazuhiro Haraguchi, Hirotada Akiho, Nobuyoshi Takizawa, Akira Aso, Yosuke Tomita, Mitsuru Esaki, Keishi Komori, Yoshihiro Otsuka, Tsutomu Iwasa, Yoshihiro Ogawa, Objective validity of the Japan Narrow-Band Imaging Expert Team classification system for the differential diagnosis of colorectal polyps, Digestive Endoscopy, 10.1111/den.13393, 31, 5, 544-551, 2019.09, © 2019 Japan Gastroenterological Endoscopy Society Background and Aim: The Japan Narrow-Band Imaging (NBI) Expert Team (JNET) classification is a recently proposed NBI magnifying endoscopy-based classification system for colorectal tumors. Although the usefulness of this system has been reported by JNET experts, its objective validity remains unclear. We tested its validity and usefulness for the diagnosis of colorectal polyps by including colonoscopy experts and non-experts as test participants. Methods: Forty NBI images of polyps of various JNET types were shown to 22 doctors (11 experts and 11 non-gastrointestinal [GI] trainees) who had not examined the patients. The doctors diagnosed the polyps based solely on the surface and vessel patterns in the magnified images and the JNET classification system. Concordance rates of their diagnoses with the pathological findings of the polyps were determined, and the results for experts and non-GI trainees were compared. Results: Both for colonoscopy experts and non-GI trainees, the JNET classification system was particularly useful for classifying polyps as benign or malignant. Although the accuracy rates for classifying polyps into each JNET type varied among colonoscopy experts, those who were familiar with the JNET classification system were able to diagnose polyps with approximately 90% accuracy. Common mistakes were attributable to misunderstandings of the wording in the JNET classification chart and lack of proper training. Conclusion: The JNET classification system is a practical approach for the diagnosis of colorectal polyps. Training is required even for experienced colonoscopists to adopt the system properly. Common pitfalls must be shared among colonoscopists to improve the accuracy of the diagnosis..
42. Xiaopeng Bai, Eikichi Ihara, Yoshihihro Otsuka, Shinichi Tsuruta, Katsuya Hirano, Yoshimasa Tanaka, Haruei Ogino, Mayumi Hirano, Takatoshi Chinen, Hirotada Akiho, Kazuhiko Nakamura, Yoshinao Oda, Yoshihiro Ogawa, Involvement of different receptor subtypes in prostaglandin E2-induced contraction and relaxation in the lower esophageal sphincter and esophageal body, European Journal of Pharmacology, 10.1016/j.ejphar.2019.172405, 857, 172405-172405, 2019.08, © 2019 Elsevier B.V. Prostaglandin E2 (PGE2) plays a role in the pathogenesis of gastro-esophageal reflux disease (GERD). There are 4 subtypes of PGE2, PGE2 receptor 1, 2, 3 and 4 (EP 1–4). In GERD patents, PGE2, EP2 and EP4 are upregulated. However, the effects of PGE2 on esophageal motility remain elusive. We examined how PGE2 regulates motility in the porcine circular smooth muscle of the lower esophageal sphincter (LES), and the circular and longitudinal smooth muscle of the esophagus body in organ bath. PGE2 induced tonic relaxation in the LES and circular smooth muscle, but transient contraction in longitudinal smooth muscle. The relaxation of the LES and circular smooth muscle was similar in pattern and mechanism, but was much larger in the LES. The relaxation was completely blocked by a voltage-gated K+ channel blocker or 40 mM K+ depolarization, indicating the involvement of K+ channel. Longitudinal smooth muscle contraction was completely blocked by an L-type Ca2+ channel blocker, showing the contribution of Ca2+ movement. The involvement of the EP receptor in motility was examined with selective receptor agonists and antagonists. Activation of EP2 and EP4 caused relaxation in the LES and circular smooth muscle. Compatible with PGE2, EP2 and EP4 agonists caused more significant relaxation in the LES than in circular smooth muscle. EP1 contributed to the longitudinal smooth muscle contraction. The different effects of PGE2 in the LES, circular and longitudinal smooth muscle contributes to esophageal motility, their impairment might increase the amount and frequency of esophageal reflux..
43. Takashi Osoegawa, Yosuke Minoda, Eikichi Ihara, Keishi Komori, Akira Aso, Ayako Goto, Soichi Itaba, Haruei Ogino, Kazuhiko Nakamura, Naohiko Harada, Kosuke Makihara, Shinichi Tsuruta, Hidetaka Yamamoto, Yoshihiro Ogawa, Mucosal incision-assisted biopsy versus endoscopic ultrasound-guided fine-needle aspiration with a rapid on-site evaluation for gastric subepithelial lesions: A randomized cross-over study, Digestive Endoscopy, 10.1111/den.13367, 31, 4, 413-421, 2019.07, © 2019 Japan Gastroenterological Endoscopy Society Objectives: This study aimed to compare the diagnostic yield of mucosal incision-assisted biopsy (MIAB) and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) with a rapid on-site evaluation (ROSE) for gastric subepithelial lesions (SEL) suspected of being gastrointestinal stromal tumors (GIST) with an intraluminal growth pattern. Methods: This was a prospective randomized, cross-over multicenter study. The primary outcome was the diagnostic yield of EUS-FNA and MIAB. The secondary outcomes were the technical success rate, complication rate, procedure time and biopsy frequency. Results: A total of 47 patients were randomized to the MIAB group (n = 23) and EUS-FNA group (n = 24). There was no significant difference in the diagnostic yield of MIAB and EUS-FNA (91.3% vs 70.8%, P = 0.0746). The complication rates of MIAB and EUS-FNA did not differ to a statistically significant extent. The mean procedure time in the MIAB group was significantly longer than that in the EUS-FNA group (34 vs 26 min, P = 0.0011). Conclusions: The diagnostic yield of MIAB was satisfactorily as high as EUS-FNA with ROSE for gastric SEL with an intraluminal growth pattern..
44. Shinichi Tsuruta, Yoshihiro Ohishi, Minako Fujiwara, Eikichi Ihara, Yoshihiro Ogawa, Eiji Oki, Masafumi Nakamura, Yoshinao Oda, Gastric hepatoid adenocarcinomas are a genetically heterogenous group; most tumors show chromosomal instability, but MSI tumors do exist, Human Pathology, 10.1016/j.humpath.2019.03.006, 88, 27-38, 2019.06, © 2019 The Cancer Genome Atlas Research Network classified gastric adenocarcinoma into four molecular subtypes: (1) Epstein-Barr virus–positive (EBV), (2) microsatellite-instable (MSI), (3) chromosomal instable (CIN), and (4) genomically stable (GS). The molecular subtypes of gastric hepatoid adenocarcinomas are still largely unknown. We analyzed 52 hepatoid adenocarcinomas for the expression of surrogate markers of molecular subtypes (MLH1, p53, and EBER in situ hybridization) and some biomarkers (p21, p16, Rb, cyclin D1, cyclin E, β-catenin, Bcl-2, IMP3, ARID1A and HER2), and mutations of TP53, CTNNB1, KRAS, and BRAF. We analyzed 36 solid-type poorly differentiated adenocarcinomas as a control group. Hepatoid adenocarcinomas were categorized as follows: EBV group (EBER-positive), no cases (0%); MSI group (MLH1 loss), three cases (6%); “CIN or GS” (CIN/GS) group (EBER-negative, MLH1 retained), 49 cases (94%). In the CIN/GS group, most of the tumors (59%) had either p53 overexpression or TP53 mutation and a coexisting tubular intestinal-type adenocarcinoma component (90%), suggesting that most hepatoid adenocarcinomas should be categorized as a true CIN group. Hepatoid adenocarcinomas showed relatively frequent expressions of HER2 (score 3+/2+: 21%/19%). Hepatoid adenocarcinomas showed shorter survival, more frequent overexpressions of p16 (67%) and IMP3 (98%) than the control group. None of hepatoid adenocarcinomas had KRAS or CTNNB1 mutations except for one case each, and no hepatoid adenocarcinomas had BRAF mutation. In conclusion, gastric hepatoid adenocarcinomas are a genetically heterogenous group. Most hepatoid adenocarcinomas are “CIN,” but a small number of hepatoid adenocarcinomas with MSI do exist. Hepatoid adenocarcinomas are characterized by overexpressions of p16 and IMP3..
45. Keita Fukaura, Yoichiro Iboshi, Haruei Ogino, Eikichi Ihara, Kazuhiko Nakamura, Yuichiro Nishihara, Kei Nishioka, Takatoshi Chinen, Tsutomu Iwasa, Akira Aso, Ayako Goto, Kazuhiro Haraguchi, Hirotada Akiho, Naohiko Harada, Yoshihiro Ogawa, Mucosal Profiles of Immune Molecules Related to T Helper and Regulatory T Cells Predict Future Relapse in Patients with Quiescent Ulcerative Colitis, Inflammatory bowel diseases, 10.1093/ibd/izy395, 25, 6, 1019-1027, 2019.05, Background: T helper (Th)- and regulatory T (Treg) cell-related immune molecules are implicated in ulcerative colitis (UC). However, the association between their mucosal expression during remission and the subsequent clinical course of UC is unknown. Methods: The expression of cytokines and transcription factors related to Th1, Th2, Th17, and Treg in endoscopic mucosal biopsy specimens from 40 UC patients in clinical remission and 9 controls was measured by quantitative polymerase chain reaction. The relationship between their expression patterns, as stratified by Mayo Endoscopic Subscore (MES), and any future relapse was evaluated by univariate and multivariate analyses. Results: Six of 40 patients (baseline MES 0/1/2, 22/14/4) experienced a relapse during the study period (median, 37 months). At baseline, even in the MES0 patients, the interleukin (IL)-17A of the patients was significantly upregulated in comparison with controls (P = 0.0351). Future relapse was associated with a higher baseline expression of IL-17A, IL-17F, and IL-21 in MES0/1, and the upregulation of IL-17F and IL-21 remained statistically significant when limited to MES0 patients. Kaplan-Meier analysis revealed that as a single marker, a higher IL-21 level best grouped patients with an increased risk of relapse (P = 0.0042). Furthermore, a multivariate model that consisted of IL-21 and T-bet showed an even greater value (P = 0.0001). Conclusions: The profiles of Th/Treg-related gene expression in the colonic mucosa are altered, even during clinical and endoscopic remission of UC, with a detectable Th17-predominant profile predicting future relapse. This association might represent latent immune dysregulation during disease quiescence and has the potential to be utilized to improve patient care..
46. Takaaki Fujimoto, Yasuhisa Mori, Yohei Nakashima, Takao Ohtsuka, So Nakamura, Yoshitaka Gotoh, Kenjiro Date, Yoshihiko Sadakari, Kohei Nakata, Yoshihiro Miyasaka, Takashi Osoegawa, Akira Aso, Eikichi Ihara, Kazuhiko Nakamura, Yoshihiro Ogawa, Shuji Shimizu, Masafumi Nakamura, Endoscopic retrograde cholangiopancreatography in patients with surgically altered gastrointestinal anatomy
A retrospective study, International Surgery, 10.9738/INTSURG-D-17-00137.1, 103, 3-4, 184-190, 2019.01, Objective: The aim of this study was to evaluate the difficulty of endoscopic retrograde cholangiopancreatography (ERCP) procedures when performed in patients with different types of surgically altered gastrointestinal (GI) anatomies. Summary of background data: Clinical data of 102 consecutive patients with surgically altered GI anatomy who underwent ERCP using a double-balloon enteroscope or a regular gastroendoscope between January 2008 and March 2015 were retrospectively reviewed. Methods: The success rate of reaching the destination, the time until reaching the destination, the success rate of the procedures, and complications were assessed for each type of altered GI anatomy using a double-balloon enteroscope and a regular gastroendoscope. Results: A total of 180 ERCP procedures were performed. The total success rate of reaching the destination was 91% (164 of 180), and that of treatment was 88% (144 of 164). The success rate of reaching the destination in patients with Roux-en-Y hepaticojejunostomy (HJ þ R-Y) was significantly lower than that of the other types of reconstruction. The time until reaching the destination was significantly longer in patients after R-Y reconstruction (gastrectomy or HJ) than that after Billroth-II gastrectomy or pancreatoduodenectomy. GI perforation occurred in 2 patients after R-Y reconstruction (1 patient after gastrectomy, and 1 patient after HJ). However, no other complications, such as severe pancreatitis, bleeding, or air embolism, were observed. Conclusions: ERCP for patients with surgically altered GI anatomy is feasible. Improvement of the success rate of reaching the destination in patients after HJ þ R-Y and prevention of perforation in those with R-Y reconstruction are necessary..
47. Akihiro Mukaino, Hitomi Minami, Hajime Isomoto, Hitomi Hamamoto, Eikichi Ihara, Yasuhiro Maeda, Osamu Higuchi, Tohru Okanishi, Yohei Kokudo, Kazushi Deguchi, Fumisato Sasaki, Toshihito Ueki, Ken ya Murata, Takeshi Yoshida, Mistuyo Kinjo, Yoshihiro Ogawa, Akio Ido, Hidenori Matsuo, Kazuhiko Nakao, Shunya Nakane, Anti-ganglionic AChR antibodies in Japanese patients with motility disorders, Journal of Gastroenterology, 10.1007/s00535-018-1477-8, 53, 12, 1227-1240, 2018.12, © 2018, Japanese Society of Gastroenterology. Background: The existence of several autoantibodies suggests an autoimmune basis for gastrointestinal (GI) dysmotility. Whether GI motility disorders are features of autoimmune autonomic ganglionopathy (AAG) or are related to circulating anti-ganglionic acetylcholine receptor (gAChR) antibodies (Abs) is not known. The aim of this study was to determine the associations between autonomic dysfunction, anti-gAChR Abs, and clinical features in patients with GI motility disorders including achalasia and chronic intestinal pseudo-obstruction (CIPO). Methods: First study: retrospective cohort study and laboratory investigation. Samples from 123 patients with seropositive AAG were obtained between 2012 and 2017. Second study: prospective study. Samples from 28 patients with achalasia and 14 patients with CIPO were obtained between 2014 and 2016, and 2013 and 2017, respectively. In the first study, we analyzed clinical profiles of seropositive AAG patients. In the second study, we compared clinical profiles, autonomic symptoms, and results of antibody screening between seropositive, seronegative achalasia, and CIPO groups. Results: In the first study, we identified 10 patients (8.1%) who presented with achalasia, or gastroparesis, or paralytic ileus. In the second study, we detected anti-gAChR Abs in 21.4% of the achalasia patients, and in 50.0% of the CIPO patients. Although patients with achalasia and CIPO demonstrated widespread autonomic dysfunction, bladder dysfunction was observed in the seropositive patients with CIPO as a prominent clinical characteristic of dysautonomia. Conclusions: These results demonstrate a significant prevalence of anti-gAChR antibodies in patients with achalasia and CIPO. Anti-gAChR Abs might mediate autonomic dysfunction, contributing to autoimmune mechanisms underlying these GI motility disorders..
48. Yasuyo Hayashi, Mitsuru Esaki, Sho Suzuki, Eikichi Ihara, Azusa Yokoyama, Seiichiro Sakisaka, Taizo Hosokawa, Yoshimasa Tanaka, Takahiro Mizutani, Shinichi Tsuruta, Aya Iwao, Shun Yamakawa, Akira Irie, Yosuke Minoda, Yoshitaka Hata, Haruei Ogino, Hirotada Akiho, Yoshihiro Ogawa, Clutch Cutter knife efficacy in endoscopic submucosal dissection for early gastric neoplasms, World Journal of Gastrointestinal Oncology, 10.4251/wjgo.v10.i12.487, 10, 12, 487-495, 2018.12, © The Author(s) 2018. AIM To compare the outcomes of endoscopic submucosal dissection (ESD) for gastric neoplasms using Clutch Cutter (ESD-C) or other knives (ESD-O). METHODS This was a single-center retrospective study. Gastric neoplasms treated by ESD between April 2016 and October 2017 at Kitakyushu Municipal Medical Center were reviewed. Multivariate analyses and propensity score matching were used to reduce biases. Covariates included factors that might affect outcomes of ESD, including age, sex, underlying disease, anti-thrombotic drugs use, tumor location, tumor position, tumor size, tumor depth, tumor morphology, tumor histology, ulcer (scar), and operator skill. The treatment outcomes were compared among two groups. The primary outcome was ESD procedure time. Secondary outcomes were en bloc, complete, and curative resection rates, and adverse events rates including perforation and delayed bleeding. RESULTS A total of 155 patients were included in this study; 44 pairs were created by propensity score matching. Background characteristics were quite similar among two groups after matching. Procedure time was significantly shorter for ESD-C (median; 49 min) than for ESD-O (median; 88.5 min) (P
49. Yosuke Minoda, Keishi Komori, Ryoko Naruo, Tsutomu Iwasa, Haruei Ogino, Eikichi Ihara, Yoshihiro Ogawa, Recovery technique using a double scope to rescue failed primary endoscopic ligation, ENDOSCOPY, 10.1055/a-0631-7760, 50, 9, E244-E245, 2018.09.
50. Takao Sato, Kazuya Akahoshi, Naru Tomoeda, Norikatsu Kinoshita, Masaru Kubokawa, Kentaro Yodoe, Yuka Hiraki, Masafumi Oya, Hidetaka Yamamoto, Eikichi Ihara, Leiomyosarcoma of the stomach treated by endoscopic submucosal dissection, Clinical Journal of Gastroenterology, 10.1007/s12328-018-0838-4, 11, 4, 291-296, 2018.08, © 2018, Japanese Society of Gastroenterology. There have been no reports of primary leiomyosarcoma of the stomach treated by endoscopic submucosal dissection (ESD). We report an extremely rare case of gastric leiomyosarcoma that was successfully treated by ESD. An asymptomatic 74-year-old female underwent esophagogastroduodenoscopy for screening in December 2013. A centrally depressed submucosal tumor 10 mm in diameter was detected at the posterior wall of the upper gastric body. Follow-up esophagogastroduodenoscopy conducted 5 months later showed that the tumor diameter had increased to 15 mm. Endoscopic ultrasound revealed a hypoechoic mass located in the second to the middle of the third layer. Endoscopic ultrasound-guided fine-needle aspiration demonstrated a myogenic tumor. The tumor was completely resected by ESD without complications. Immunohistopathological diagnosis of the resected specimen was gastric leiomyosarcoma derived from the muscularis mucosae, with negative lateral and vertical margins. No local recurrence or metastasis has been detected at 36 months after ESD. This is the first report of gastric leiomyosarcoma treated by ESD in the English language literature..
51. Keita Fukaura, Eikichi Ihara, Haruei Ogino, Yoichiro Iboshi, Kazumasa Muta, Bai Xiaopeng, Shohei Hamada, Yoshitaka Hata, Tsutomu Iwasa, Akira Aso, Kazuhiko Nakamura, Yoshihiro Ogawa, Mucosally Expressed Cytokines are Associated with the Esophageal Motility Function, Digestion, 10.1159/000487708, 98, 2, 95-103, 2018.08, © 2018 S. Karger AG, Basel. Copyright: All rights, or by any information storage and retrieval system, without permission in writing from the publisher. Background and Aim: Although basic research has shown that certain cytokines affect gastrointestinal motility, the clinical evidence is lacking. The objective of this study was to explore the association between mucosally expressed cytokines and the esophageal motility function in humans. Methods: We enrolled a total of 57 patients with suspected esophageal motility disorders (EMDs) who underwent high-resolution manometry. Results: The diagnoses of the patients were as follows: normal esophageal motility (n = 25), ineffective esophageal motility (n = 5), esophagogastric junction outflow obstruction (EGJOO; n = 10), distal esophageal spasm (n = 5), achalasia (n = 10), absent contractility (n = 1), and jackhammer esophagus (n = 1). The expression of tumor necrosis factor (TNF)-α in the esophagogastric junction (EGJ) was significantly higher in EGJOO (14.6, 14.0-15.8, n = 10) than in normal esophageal motility (13.3, 12.8-14.1, n = 25); however, there was no difference in the expression of TNF-α between achalasia (13.4, 13.0-14.1, n = 10) and normal esophageal motility (13.3, 12.8-14.1, n = 25). EGJOO was discriminated from achalasia/normal by a linear discriminant analysis (AUC = 0.917). A multivariable regression analysis revealed that interleukin (IL)-13 and IL-23A were predictive of the distal contractile integral, whereas TNF-α and IL-6 were predictive of the basal EGJ pressure. Conclusions: The esophageal motility was associated with mucosally expressed cytokines in humans; these cytokines could be useful targets for the diagnosis and treatment of EMDs..
52. Tetsuyuki Miyazaki, Shinichi Aishima, Minoru Fujino, Keigo Ozono, Yuichiro Kubo, Yasuhiro Ushijima, Takashi Osoegawa, Eikichi Ihara, Itou Tetsuhide, Takao Ohtsuka, Masafumi Nakamura, Yoshinao Oda, Neuroendocrine tumor of the pancreas with rhabdoid feature, Virchows Archiv, 10.1007/s00428-018-2398-x, 473, 2, 247-252, 2018.08, © 2018, The Author(s). Imaging of a 53-year-old Japanese man revealed two tumors in the liver and a tumor in the head of the pancreas with a swelling lymph node. A needle biopsy for the liver tumors was performed, revealing a neuroendocrine tumor. Enucleation, lymphadenectomy, and partial hepatectomy were performed. The microscopic examination identified many tumor cells with intracytoplasmic inclusions arranged in a nested, cord, or tubular fashion. The intracytoplasmic inclusions displayed densely eosinophilic globules and displaced the nuclei toward the periphery, which constitutes “rhabdoid” features. The tumor cells were positive for synaptophysin and weakly positive for NCAM, but negative for chromogranin A. Epithelial markers (AE1/AE3 and CAM5.2) accentuated intracytoplasmic globules. Pancreatic neuroendocrine tumors with rhabdoid features are very rare. Generally, rhabdoid features are aggressive and dedifferentiated characteristics of various types of tumor. Pancreatic neuroendocrine tumors containing rhabdoid cells tend to display extrapancreatic spread at the time of presentation, although some of these tumors with rhabdoid features are not always associated with aggressive behavior..
53. Mitsuru Esaki, Sho Suzuki, Yasuyo Hayashi, Azusa Yokoyama, Shuichi Abe, Taizo Hosokawa, Shinichi Tsuruta, Yosuke Minoda, Yoshitaka Hata, Haruei Ogino, Hirotada Akiho, Eikichi Ihara, Yoshihiro Ogawa, Propensity score-matching analysis to compare clinical outcomes of endoscopic submucosal dissection for early gastric cancer in the postoperative and non-operative stomachs, BMC Gastroenterology, 10.1186/s12876-018-0855-2, 18, 1, 125-125, 2018.08, © 2018 The Author(s). Background: Endoscopic submucosal dissection (ESD) of the postoperative stomach (ESD-P) for early gastric cancer (EGC) is considered a technically difficult procedure. However, it is difficult to compare the outcomes of ESD-P and ESD of the non-operative stomach (ESD-N) because their baseline characteristics are different. Therefore, we aimed to compare the technical outcomes of ESD-P with those of ESD-N using a propensity score-matching analysis to compensate for the differences. Methods: The chart records of 1046 patients with EGC who were treated with ESD between January 2004 and July 2016 at Kitakyushu Municipal Medical Center in Japan were reviewed in this retrospective study. Multivariate analyses and propensity score-matching were performed for age, sex, lesion location, lesion size, tumor invasion, tumor size, ulcer (scar), and operator skill. The primary outcome was procedure time. Secondary outcomes were percentages of en bloc, complete, and curative resections, and percentages of adverse events, which were evaluated between the two groups. Results: Forty-one patients were in the ESD-P group and 1005 patients were in the ESD-N group. Propensity score-matching created 41 matched pairs. According to the adjusted comparisons, ESD-P required a significantly longer procedure time (85 min vs 51 min, p
54. Tsutomu Iwasa, Ryu Nakadate, Shinya Onogi, Yasuharu Okamoto, Jumpei Arata, Susumu Oguri, Haruei Ogino, Eikichi Ihara, Kenoki Ohuchida, Tomohiko Akahoshi, Tetsuo Ikeda, Yoshihiro Ogawa, Makoto Hashizume, A new robotic-assisted flexible endoscope with single-hand control: endoscopic submucosal dissection in the ex vivo porcine stomach, Surgical Endoscopy, 10.1007/s00464-018-6188-y, 32, 7, 3386-3392, 2018.07, © 2018, Springer Science+Business Media, LLC, part of Springer Nature. Background: Difficulties in endoscopic operations and therapeutic procedures seem to occur due to the complexity of operating the endoscope dial as well as difficulty in performing synchronized movements with both hands. We developed a prototype robotic-assisted flexible endoscope that can be controlled with a single hand in order to simplify the operation of the endoscope. The aim of this study was to confirm the operability of the robotic-assisted flexible endoscope (RAFE) by performing endoscopic submucosal dissection (ESD). Methods: Study 1: ESD was performed manually or with RAFE by an expert endoscopist in ex vivo porcine stomachs; six operations manually and six were performed with RAFE. The procedure time per unit circumferential length/area was calculated, and the results were statistically analyzed. Study 2: We evaluated how smoothly a non-endoscopist can move a RAFE compared to a manual endoscope by assessing the designated movement of the endoscope. Results: Study 1: En bloc resection was achieved by ESD using the RAFE. The procedure time was gradually shortened with increasing experience, and the procedure time of ESD performed with the RAFE was not significantly different from that of ESD performed with a manual endoscope. Study 2: The time for the designated movement of the endoscope was significantly shorter with a RAFE than that with a manual endoscope as for a non-endoscopist. Conclusions: The RAFE that we developed enabled an expert endoscopist to perform the ESD procedure without any problems and allowed a non-endoscopist to control the endoscope more easily and quickly than a manual endoscope. The RAFE is expected to undergo further development..
55. Xiaopeng Bai, Eikichi Ihara, Katsuya Hirano, Yoshimasa Tanaka, Kayoko Nakano, Satomi Kita, Takahiro Iwamoto, Haruei Ogino, Mayumi Hirano, Yoshinao Oda, Kazuhiko Nakamura, Yoshihiro Ogawa, Endogenous Hydrogen Sulfide Contributes to Tone Generation in Porcine Lower Esophageal Sphincter Via Na+/Ca2+ Exchanger, Cellular and Molecular Gastroenterology and Hepatology, 10.1016/j.jcmgh.2017.11.004, 5, 3, 209-221, 2018.03, © 2018 The Authors Background and Aims: Hydrogen sulfide (H2S) is a major physiologic gastrotransmitter. Its role in the regulation of the lower esophageal sphincter (LES) function remains unknown. The present study addresses this question. Methods: Isometric contraction was monitored in circular smooth muscle strips of porcine LES. Changes in cytosolic Ca2+ concentration ([Ca2+]i) and force were simultaneously monitored in fura-2-loaded strips with front-surface fluorometry. The contribution of endogenous H2S to LES contractility was investigated by examining the effects of inhibitors of H2S-generating enzymes, including cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase, on the LES function. Results: Porcine LES strips myogenically maintained a tetrodotoxin-resistant basal tone. Application of AOA (cystathionine-β-synthase inhibitor) or L-aspartic acid (L-Asp; 3-mercaptopyruvate sulfurtransferase inhibitor) but not DL-PAG (cystathionine-γ-lyase inhibitor), decreased this basal tone. The relaxant effects of AOA and L-Asp were additive. Maximum relaxation was obtained by combination of 1 mM AOA and 3 mM L-Asp. Immunohistochemical analyses revealed that cystathionine-β-synthase and 3-mercaptopyruvate sulfurtransferase, but not cystathionine-γ-lyase, were expressed in porcine LES. AOA+L-Asp–induced relaxation was accompanied by a decrease in [Ca2+]i and inversely correlated with the extracellular Na+ concentration ([Na+]o) (25-137.4 mM), indicating involvement of an Na+/Ca2+ exchanger. The reduction in the basal [Ca2+]i level by AOA was significantly augmented in the antral smooth muscle sheets of Na+/Ca2+ exchanger transgenic mice compared with wild-type mice. Conclusions: Endogenous H2S regulates the LES myogenic tone by maintaining the basal [Ca2+]i via Na+/Ca2+ exchanger. H2S-generating enzymes may be a potential therapeutic target for esophageal motility disorders, such as achalasia..
56. Mitsuru Esaki, Sho Suzuki, Yasuyo Hayashi, Azusa Yokoyama, Shuichi Abe, Taizo Hosokawa, Haruei Ogino, Hirotada Akiho, Eikichi Ihara, Yoshihiro Ogawa, Splash M-knife versus Flush Knife BT in the technical outcomes of endoscopic submucosal dissection for early gastric cancer: A propensity score matching analysis, BMC Gastroenterology, 10.1186/s12876-018-0763-5, 18, 1, 35-35, 2018.02, © 2018 The Author(s). Background: Endoscopic submucosal dissection (ESD) is a standard treatment for early gastric cancer. A new multi-functional ESD device was developed to achieve complete ESD with a single device. A metal plate attached to its distal sheath achieves better hemostasis during the procedure than the other needle-knife device, Flush Knife BT®, that has been conventionally used. The aim of this study was to compare the technical outcomes of ESD for early gastric cancer using the Splash M-Knife® with those using the Flush Knife BT. Methods: We conducted a retrospective review of the case records of 149 patients with early gastric cancer treated with ESD using the needle-type ESD knives between January 2012 and August 2016 at Kitakyushu Municipal Medical Center. Lesions treated with ESD using the Splash M-knife (ESD-M) and the Flush Knife BT (ESD-F) were compared. Multivariate analyses and propensity score matching were used to compensate for the differences in age, gender, underlying disease, antithrombotic drug use, lesion location, lesion position, macroscopic type, tumor size, presence of ulceration, operator level and types of electrosurgical unit used. The primary endpoint was the requirement to use hemostatic forceps in the two groups. The secondary endpoints of procedure time, en bloc and complete resection rates, and adverse events rates were evaluated for the two groups. Results: There were 73 patients in the ESD-M group, and 76 patients in the ESD-F group. Propensity score matching analysis created 45 matched pairs. Adjusted comparisons between the two groups showed a significantly lower usage rate of hemostatic forceps in the ESD-M group than in the ESD-F group (6.7% vs 84.4%, p
57. Kayoko Nakano, Hidetaka Yamamoto, Minako Fujiwara, Yutaka Koga, Shinichi Tsuruta, Eikichi Ihara, Eiji Oki, Masafumi Nakamura, Yoshihiro Ogawa, Yoshinao Oda, Clinicopathologic and molecular characteristics of synchronous colorectal carcinoma with mismatch repair deficiency, American Journal of Surgical Pathology, 10.1097/PAS.0000000000000947, 42, 2, 172-182, 2018.01, S.
58. Yoshihiro Otsuka, Kazuya Akahoshi, Kayoko Yasunaga, Masaru Kubokawa, Junya Gibo, Shigeki Osada, Kayo Tokumaru, Kazuaki Miyamoto, Takao Sato, Yuki Shiratsuchi, Masafumi Oya, Hidenobu Koga, Eikichi Ihara, Kazuhiko Nakamura, Clinical outcomes of Clutch Cutter endoscopic submucosal dissection for older patients with early gastric cancer, World Journal of Gastrointestinal Oncology, 10.4251/wjgo.v9.i10.416, 9, 10, 416-422, 2017.10, © The Author(s) 2017. AIM To evaluate the clinical outcome of endoscopic subSubmitmucosal dissection using the Clutch Cutter (ESDCC) in older patients. METHODS We reviewed 232 consecutive patients with early gastric cancer who underwent ESDCC between June 2010 and February 2014 at Aso Iizuka Hospital. We divided patients into two groups according to age: Older patients ( > 80 years, n = 64) and non-older patients (= 80 years, n = 168). We retrospectively compared the prevalence rates of pre-existing comorbidities, anticoagulant therapy, en bloc resection, mean duration of hospitalization, incidence of ESDCC-related complications, change in performance status (PS) before and after ESDCC, and financial cost of admission. RESULTS The older group comprised 64 patients with a mean age of 84.1 years, and the non-older group comprised 168 patients with a mean age of 69.5 years. Older patients had significantly more pre-existing comorbidities than did non-older patients, specifically heart disease (P
59. Kazuya Akahoshi, Masaru Kubokawa, Junya Gibo, Shigeki Osada, Kayo Tokumaru, Eriko Yamaguchi, Hiroko Ikeda, Takao Sato, Kazuaki Miyamoto, Yusuke Kimura, Yuki Shiratsuchi, Kazuaki Akahoshi, Masafumi Oya, Hidenobu Koga, Eikichi Ihara, Kazuhiko Nakamura, Endoscopic submucosal dissection of gastric adenomas using the clutch cutter., World journal of gastrointestinal endoscopy, 10.4253/wjge.v9.i7.334, 9, 7, 334-340, 2017.07, AIM: To evaluate the efficacy and safety of endoscopic submucosal dissection (ESD) using the clutch cutter (CC) (ESD-CC) for gastric adenoma (GA). METHODS: From June 2007 to August 2015, 122 consecutive patients with histological diagnoses of GA from specimens resected by ESD-CC were enrolled in this prospective study. The CC was used for all ESD steps (marking, mucosal incision, submucosal dissection, and hemostatic treatment), and its therapeutic efficacy and safety were assessed. RESULTS: Both the en-bloc resection rate and the R0 resection rate were 100% (122/122). The mean surgical time was 77.4 min, but the time varied significantly according to tumor size and location. No patients suffered perforation. Post-ESD-CC bleeding occurred in six cases (4.9%) that were successfully resolved by endoscopic hemostatic treatment. CONCLUSION: ESD-CC is a technically efficient, safe, and easy method for resecting GA..
60. Yoichiro Iboshi, Kazuhiko Nakamura, Keita Fukaura, Tsutomu Iwasa, Haruei Ogino, Yorinobu Sumida, Eikichi Ihara, Hirotada Akiho, Naohiko Harada, Makoto Nakamuta, Increased IL-17A/IL-17F expression ratio represents the key mucosal T helper/regulatory cell-related gene signature paralleling disease activity in ulcerative colitis, Journal of Gastroenterology, 10.1007/s00535-016-1221-1, 52, 3, 315-326, 2017.03, © 2016, Japanese Society of Gastroenterology. Background: T helper (Th) and regulatory T (Treg) cell-related cytokines are implicated in inflammatory bowel diseases, including ulcerative colitis (UC). While these cytokines are generally upregulated in inflamed mucosae, the key cytokine profile explaining disease severity has not been determined. Methods: The Rachmilewitz endoscopic index (REI) was assessed in 61 UC patients undergoing colonoscopy. Biopsies obtained from inflamed (REI 3–12) and noninflamed (REI 0–2) areas were analyzed by quantitative PCR for expression of mRNAs encoding cytokines and transcription factors related to Th1 (TNF-α, IFN-γ, IL-12p35, IL-12p40, and T-bet), Th2 (IL-4, IL-13, IL-33, and GATA3), Th17 (IL-17A, IL-17F, IL-21, IL-22, IL-23p19, IL-6, and RORC), Th9 (IL-9, IRF4, and PU.1), and Treg (TGF-β and Foxp3). Expression patterns associated with higher REI were determined by univariate and multivariate analyses. Results: Despite general upregulation, none of these mRNAs showed univariate correlation with REI in inflamed samples. Multiple regression analysis, however, found that joint expression of IL-17A, IL-17F, IL-21, RORC, and TGF-β was significantly predictive of REI (P 
61. Bai Xiaopeng, Yoshimasa Tanaka, Eikichi Ihara, Katsuya Hirano, Kayoko Nakano, Mayumi Hirano, Yoshinao Oda, Kazuhiko Nakamura, Trypsin induces biphasic muscle contraction and relaxation via transient receptor potential vanilloid 1 and neurokinin receptors 1/2 in porcine esophageal body, European Journal of Pharmacology, 10.1016/j.ejphar.2017.01.004, 797, 65-74, 2017.01.
62. Eikichi Ihara, Kazumasa Muta, Keita Fukaura, Kazuhiko Nakamura, Diagnosis and Treatment Strategy of Achalasia Subtypes and Esophagogastric Junction Outflow Obstruction Based on High-Resolution Manometry, Digestion, 10.1159/000452354, 95, 1, 29-35, 2017.01, © 2016 S. Karger AG, Basel. Background: Based on Chicago Classification version 3.0, the disorders of esophagogastric junction outflow obstruction (EGJOO) include achalasia (types I, II and III) and EGJOO. Although no curative treatments are currently available for the treatment of the disorders of EGJOO, medical treatments, endoscopic pneumatic dilation (PD), laparoscopic Heller myotomy (LHM), and per-oral endoscopic myotomy (POEM) are usually the sought-after modes of treatment. Since the etiology and pathogenesis might vary depending on the types of EGJOO disorders, treatment strategies should be considered based on those subtypes. Summary: Based on the accumulated evidences, the treatment strategies of our institution are as follows: effects of medical treatments on achalasia are limited. Either PD or LHM/POEM can be considered a first-line in achalasia type I, according to the patient's wish. PD and POEM can be considered first-line in achalasia types II and III, respectively. Conversely, In EGJOO, medical treatments including drugs like acotiamide and/or diltiazem can be tested as a first-line, and PD and POEM will be considered second and third-line treatments, respectively. Key Messages: The classification of subtypes based on high-resolution manometry will help us consider which treatment option can be selected as a first-line treatment depending upon the subtypes of disorders of EGJOO. Acotiamide has the potential to cure patients with EGJOO..
63. Kazuya Akahoshi, Masaru Kubokawa, Junya Gibo, Shigeki Osada, Kayo Tokumaru, Yuki Shiratsuchi, Masafumi Oya, Eikichi Ihara, Kazuhiko Nakamura, Endoscopic resection using the Clutch Cutter and a detachable snare for large pedunculated colonic polyps, Endoscopy, 10.1055/s-0042-116023, 49, 1, 54-58, 2017.01, Background and study aims Endoscopic snare polypectomy with prophylactic detachable snare of large pedunculated colonic polyps (PCPs) is technically demanding. To facilitate removal of such polyps, we developed endoscopic resection using the Clutch Cutter and a detachable snare (ERCCDS). This study aimed to evaluate the efficacy and safety of the procedure. Patients and methods From April 2010 to July 2015, 14 consecutive patients who had PCPs with head > 10 mm, stalk width > 5 mm, and stalk length > 10 mm were enrolled in this single-center prospective uncontrolled study. They were treated using ERCCDS by a single endoscopist. The efficacy and safety were assessed using a database prospectively formatted from the medical records. Results The Clutch Cutter was able to cut the distal side of the stalk an adequate distance from the detachable snare under good visual control. R0 resections were obtained in all lesions. There were no immediate or delayed complications. Conclusions ERCCDS appears to be a safe, easy, and technically efficient method for large PCPs, although larger studies are needed to compare ERCCDS and standard resection..
64. Keishi Komori, Masaru Kubokawa, Eikichi Ihara, Kazuya Akahoshi, Kazuhiko Nakamura, Kenta Motomura, Akihide Masumoto, Prognostic factors associated with mortality in patients with gastric fundal variceal bleeding, World Journal of Gastroenterology, 10.3748/wjg.v23.i3.496, 23, 3, 496-504, 2017.01, © 2017 Baishideng Publishing Group Inc. All rights reserved. AIM: To determine the prognostic factors associated with mortality in patients with gastric fundal variceal (GFV) bleeding. METHODS: In total, 42 patients were endoscopically diagnosed with GFV bleeding from January 2000 to March 2014. We retrospectively reviewed the patients' medical records and assessed their history, etiology of liver cirrhosis, disease conditions, treatment options for GFV bleeding, medications administered before and after onset of GFV bleeding, blood test results (hemoglobin, albumin, and bilirubin concentrations), and imaging results (including computed tomography and abdominal ultrasonography). We also assessed the prognostic factors associated with short-term mortality (up to 90 d) and long-term mortality in all patients. RESULTS: Multivariate analysis showed that prophylactic administration of antibiotics was an independent prognostic factor associated with decreases in short-term mortality (OR = 0.08, 95%CI: 0.01-0.52) and long-term mortality (OR = 0.27, 95%CI: 0.08-0.91) in patients with GFV bleeding. In contrast, concurrent hepatocellular carcinoma (HCC) and regular use of proton pump inhibitors (PPI) were independent prognostic factors associated with increases in short-term mortality (HCC: OR = 15.4, 95%CI: 2.08-114.75; PPI: OR = 12.76, 95%CI: 2.13-76.52) and long-term mortality (HCC: OR = 7.89, 95%CI: 1.98-31.58; PPI: OR = 10.91, 95%CI: 2.86-41.65) in patients with GFV bleeding. The long-term overall survival rate was significantly lower in patients who regularly used PPI than in those who did not use PPI (P = 0.0074). CONCLUSION: Administration of antibiotics is associated with decreased short- and long-term mortality, while concurrent HCC and regular PPI administration are associated with increased short- and long-term mortality..
65. Kazuhiko Nakamura, Eikichi Ihara, Hirotada Akiho, Kazuya Akahoshi, Naohiko Harada, Toshiaki Ochiai, Norimoto Nakamura, Haruei Ogino, Tsutomu Iwasa, Akira Aso, Yoichiro Iboshi, Ryoichi Takayanagi, Limited effect of rebamipide in addition to proton pump inhibitor (PPI) in the treatment of post-endoscopic submucosal dissection gastric ulcers: A randomized controlled trial comparing ppi plus rebamipide combination therapy with PPI monotherapy, Gut and Liver, 10.5009/gnl15486, 10, 6, 917-924, 2016.11, Background/Aims: The ability of endoscopic submucosal dissection (ESD) to resect large early gastric cancers (EGCs) results in the need to treat large artificial gastric ulcers. This study assessed whether the combination therapy of rebamipide plus a proton pump inhibitor (PPI) offered benefits over PPI monotherapy. Methods: In this prospective, randomized, multicenter, open-label, and comparative study, patients who had undergone ESD for EGC or gastric adenoma were randomized into groups receiving either rabeprazole monotherapy (10 mg/day, n=64) or a combination of rabeprazole plus rebamipide (300 mg/day, n=66). The Scar stage (S stage) ratio after treatment was compared, and factors independently associated with ulcer healing were identified by using multivariate analyses. Results: The S stage rates at 4 and 8 weeks were similar in the two groups, even in the subgroups of patients with large amounts of tissue resected and regardless of CYP2C19 genotype. Independent factors for ulcer healing were circumferential location of the tumor and resected tissue size; the type of treatment did not affect ulcer healing. Conclusions: Combination therapy with rebamipide and PPI had limited benefits compared with PPI monotherapy in the treatment of post-ESD gastric ulcer (UMIN Clinical Trials Registry, UMIN000007435)..
66. Kazumasa Muta, Eikichi Ihara, Keita Fukaura, Osamu Tsuchida, Toshiaki Ochiai, Kazuhiko Nakamura, Effects of Acotiamide on the Esophageal Motility Function in Patients with Esophageal Motility Disorders: A Pilot Study, Digestion, 10.1159/000447010, 94, 1, 9-16, 2016.08, © 2016 S. Karger AG, Basel. Background and Aim: Acotiamide is a newly developed prokinetic drug that is clinically used to treat functional dyspepsia (FD). The objective of this study was to assess the therapeutic effects of acotiamide in patients with esophageal motility disorders (EMDs). Methods: Twenty-nine patients with both symptoms of FD and symptoms suspicious of EMDs were enrolled. Esophageal motility function was evaluated by high-resolution manometry before and after 2 weeks administration of acotiamide (100 mg) 3 times per day. Results: Twenty-nine patients were diagnosed with achalasia (n = 4), esophagogastric junction outflow obstruction (EGJOO) (n = 6), absent peristalsis (n = 2), distal esophageal spasm (n = 4), frequently failed peristalsis (n = 7), weak peristalsis (n = 2) and 4 of them were found to be normal. An analysis in all 29 patients showed that acotiamide had no effects on based on distal contractile integral (DCI), basal lower esophageal sphincter (LES) pressure, or integrated relaxation pressure (IRP). Subgroup analysis, however, showed that acotiamide dramatically reduced IRP, from 19.5 (15.1-30.8) to 12.1 (5.6-16.4) mm Hg, and DCI, from 2,517.9 (1,451.0-8,385.0) to 1,872.5 (812.3-5,225.3) mm Hg·cm·s, in the 6 patients with EGJOO. Conclusions: Acotiamide potentially normalized impaired LES relaxation in patients with EGJOO, while having no effects on normal esophageal motility patterns. Acotiamide may be a promising treatment for EGJOO..
67. Yoshimasa Tanaka, Eikichi Ihara, Kazuhiko Nakamura, Kazumasa Muta, Keita Fukaura, Koji Mukai, Xiaopeng Bai, Ryoichi Takayanagi, Clinical characteristics associated with esophageal motility function, Journal of Gastroenterology and Hepatology (Australia), 10.1111/jgh.13262, 31, 6, 1133-1140, 2016.06, © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd. Background and Aim:: Esophageal motility disorders (EMDs) affect coordinated esophageal contractility. Recent developments in high-resolution manometry have improved diagnosis of EMDs; however, the etiology of EMDs remains to be determined. This study aimed to determine which clinical characteristics are associated with esophageal motility. Methods:: From May 2013 to July 2014, 97 patients (54 women, 43 men; age, 16-89years) with suspected EMDs were assessed by high-resolution manometry in Kyushu University Hospital. Esophageal motility was evaluated by measuring the distal contractile integral (DCI), basal lower esophageal sphincter pressure, and integrated relaxation pressure (IRP). Data on age, gender, body mass index (BMI), Brinkman Index, and blood tests were retrospectively collected and analyzed. Results:: Fifty patients were diagnosed as normal, nine with achalasia, twelve with esophagogastric junction outflow obstruction, four with distal esophageal spasm, one with jackhammer esophagus, six with absent peristalsis, ten with frequent failed peristalsis, and five with weak peristalsis. The median DCI was 1229.0mmHg-s-cm, the median basal lower esophageal sphincter pressure was 25.3mmHg, and the median IRP was 9.6mmHg. Patients with major motility disorders were excluded from analysis. By multivariate regression analysis, BMI (P=0.029) and total cholesterol (P=0.023) were negatively associated with DCI, while BMI (P=0.007) was negatively associated with IRP and glucose (P=0.044) was positively associated with IRP. Conclusions:: Both BMI and total cholesterol could be highly predictive factors for esophageal body contractility, while BMI and glucose could be predictive factors for lower esophageal sphincter contractile function..
68. Keishi Komori, Kazuhiko Nakamura, Eikichi Ihara, tsutomu iwasa, Minako Hirahashi, Yoshinao Oda, Ryoichi Takayanagi, Endoscopic Submucosal Dissection is Feasible for Very Elderly Patients with Early Gastric Cancer
Comparison of Short-Term and Long-Term Outcomes in Very Elderly and Non-Elderly Patients, Fukuoka igaku zasshi = Hukuoka acta medica, 107, 4, 72-81, 2016.04.
69. Kazuhiko Nakamura, Mikako Osada, Ayako Goto, Tsutomu Iwasa, Shunsuke Takahashi, Nobuyoshi Takizawa, Kazuya Akahoshi, Toshiaki Ochiai, Norimoto Nakamura, Hirotada Akiho, Soichi Itaba, Naohiko Harada, Moritomo Iju, Munehiro Tanaka, Hiroaki Kubo, Shinichi Somada, Eikichi Ihara, Yoshinao Oda, Tetsuhide Ito, Ryoichi Takayanagi, Short- and long-term outcomes of endoscopic resection of rectal neuroendocrine tumours: Analyses according to the WHO 2010 classification, Scandinavian Journal of Gastroenterology, 10.3109/00365521.2015.1107752, 51, 4, 448-455, 2016.04, © 2015 Taylor & Francis. Objective Although the World Health Organisation (WHO) defined a novel classification of gastroenteropancreatic neuroendocrine tumours (NETs) in 2010, indications for endoscopic resection of rectal NETs in the guidelines were based on evidence accumulated for carcinoid tumours defined by a previous classification. This study was designed to clarify indications for endoscopic resection of rectal NETs corresponding to the new WHO classifications. Material and methods One hundred-seventy rectal NETs resected endoscopically from April 2001 to March 2012 were histologically re-classified according to the WHO 2010 criteria. The clinicopathological features of these lesions were analysed, and the short- and long-term outcomes of endoscopic resection were evaluated. Results Of the 170 rectal NETs, 166 were histopathologically diagnosed as NET G1 and four as NET G2. Thirty-eight tumours (22.4%) were positive for lymphovascular invasion, a percentage higher than expected. Although the curative resection rate was low (65.3%), en bloc (98.8%) and complete (85.9%) resection rates were high. Modified endoscopic mucosal resection (88.0%) and endoscopic submucosal dissection (92.2%) resulted in significantly higher complete resection rates than conventional endoscopic mucosal resection (36.4%). No patient experienced tumour recurrence, despite the low curative resection rate. Conclusion Despite the low curative resection rate, prognosis after endoscopic resection of rectal NETs was excellent. Prospective large-scale, long-term studies are required to determine whether NET G2 and tumours >1 cm should be included in the indication for endoscopic resection and whether tumours with lymphovascular invasion can be followed up without additional surgery..
70. 小森 圭司, 中村 和彦, 伊原 栄吉, 岩佐 勉, 平橋 美奈子, 小田 義直, 高柳 涼一, 超高齢者における内視鏡的粘膜下層剥離術は早期胃癌に適した治療である 非高齢者との短期成績と長期成績の比較による検討(Endoscopic Submucosal Dissection is Feasible for Very Elderly Patients with Early Gastric Cancer: Comparison of Short-Term and Long-Term Outcomes in Very Elderly and Non-Elderly Patients), 福岡医学雑誌, 107, 4, 72-81, 2016.04, 【背景】内視鏡的粘膜下層剥離術は早期胃癌治療のスタンダードとなっている。しかしながら、80歳以上の超高齢者に適した治療であるかはいまだ明らかではない。【方法】ガイドライン絶対適応内病変と適応拡大病変と診断した89名の患者106症例を65歳以下のNE群、80歳以上のVE群とし両群の比較検討を行った。ガイドラインを満たさない18症例は適応外病変と定義した。【結果】一括完全切除率はVEとNE両群で良好であり、統計学的有意差は認めなかった。NE群と比較してVE群に虚血性心疾患の併存症と抗血栓薬の使用が多かったが、内視鏡的粘膜下層剥離術における合併症に有意差は認めなかった。適応外病変の患者18症例のうち7症例が超高齢者であり、うち2名が追加外科切除をうけ、残る5名は経過観察とした。すべての群で局所再発、遠隔転移、胃癌関連死は認めなかった。【結論】早期胃癌に対する内視鏡的粘膜下層剥離術の短期及び長期成績は超高齢者において非高齢者と同様に良好であった。(著者抄録).
71. Kazuhiko Nakamura, Kuniomi Honda, Kazuya Akahoshi, Eikichi Ihara, Hiroshi Matsuzaka, Yorinobu Sumida, Daisuke Yoshimura, Hirotada Akiho, Yasuaki Motomura, Tsutomu Iwasa, Keishi Komori, Yoshiharu Chijiiwa, Naohiko Harada, Toshiaki Ochiai, Masafumi Oya, Yoshinao Oda, Ryoichi Takayanagi, Suitability of the expanded indication criteria for the treatment of early gastric cancer by endoscopic submucosal dissection: Japanese multicenter large-scale retrospective analysis of short- and long-term outcomes, Scandinavian Journal of Gastroenterology, 10.3109/00365521.2014.940377, 50, 4, 413-422, 2015.04, © Informa Healthcare Objective. The criteria for endoscopic resection for early gastric cancer include absolute and expanded indications. Consensus already exists for the absolute indications. However, the suitability of the expanded indications must be validated by long-term outcome analyses since such lesions have only recently become resectable with the development of endoscopic submucosal dissection. The aim of this study is to clarify the suitability of the expanded indications for the treatment of early gastric cancer with endoscopic submucosal dissection. Materials and methods. The medical records of 1161 patients with early gastric cancers (1332 lesions) treated by endoscopic submucosal dissection and meeting the criteria for absolute or expanded indications without additional treatment with gastrectomy were divided into absolute indication group or expanded indication group. Results. Complete resection rates were 96.4% and 93.4% in absolute and expanded indication groups, respectively, with no significant differences between the groups. Delayed bleeding rates were significantly higher in the expanded indication group, whereas all cases were successfully managed conservatively. The 5-year overall survival and recurrence-free rates were 93.7%/99.77% and 90.49%/98.90% in the absolute and the expanded indication groups, respectively, with no significant differences between the groups for either measure. Multivariate analyses revealed that affected horizontal margin and tumor location were independent predictive factors for recurrence. Conclusion. The expanded indication group showed excellent post-endoscopic submucosal dissection short-term and long-term outcomes compared with the absolute indications group, demonstrating that expanded indications are suitable for endoscopic submucosal dissection for early gastric cancer..
72. Yoshimasa Tanaka, Eikichi Ihara, Katsuya Hirano, Shunsuke Takahashi, Mayumi Hirano, Kazuhiko Nakamura, Hirotada Akiho, Yoshinao Oda, Ryoichi Takayanagi, Trypsin-induced biphasic regulation of tone in the porcine lower esophageal sphincter, European Journal of Pharmacology, 10.1016/j.ejphar.2015.02.008, 752, 97-105, 2015.04, © 2015 Elsevier B.V. All rights reserved. The lower esophageal sphincter (LES) plays an important role in coordinated esophageal motility. The present study aimed to elucidate how trypsin affects LES contractility. Porcine LES circular smooth muscle strips were prepared. Contractile responses to trypsin were assessed. Trypsin (300 nM) induced a transient contraction. At concentrations of 1 μM or higher, trypsin induced biphasic responses, consisting of a transient contraction followed by a transient relaxation. Pretreatment with either 1 μM tetrodotoxin or carbenoxolone had no effect on these responses. In contrast, trypsin-induced responses were completely blocked by pretreatment with the serine protease inhibitor. Pretreatment with 10 μM FSLLRY-NH2, a PAR2 antagonist, significantly inhibited trypsin-induced biphasic responses. Trypsin (1 μM)-induced contractions were partially inhibited by pretreatment with 10 μM Y-27632. In addition, trypsin (10 μM)-induced relaxation was partially inhibited by pretreatment with 10 μM Y-27632, 10 μM PD98059 or 10 μM SB203580. Trypsin-induced relaxation was abolished by increasing the extracellular K+ concentration to 40 mM, but not by pretreatment with l-arginine methyl ester. Furthermore, trypsin-induced relaxation was partially inhibited by pretreatment with 10 μM glibenclamide or 1 μM 4-aminopyridine. Trypsin causes biphasic regulation of LES tone by directly acting on smooth muscle. Rho-associated protein kinase (ROK) is involved in trypsin-induced contraction, whereas ROK, ERK1/2, p38MAPK, and membrane hyperpolarization are involved in relaxation. The regulation of LES tone by trypsin may play a role in esophageal motility..
73. Yohei Tokita, Hirotada Akiho, Kazuhiko Nakamura, Eikichi Ihara, Masahiro Yamamoto, Contraction of gut smooth muscle cells assessed by fluorescence imaging, Journal of Pharmacological Sciences, 10.1016/j.jphs.2015.02.002, 127, 3, 344-351, 2015.01.
74. Keishi Komori, Kazuya Akahoshi, Masaru Kubokawa, Yasuaki Motomura, Masafumi Oya, Eikichi Ihara, Kazuhiko Nakamura, Endoscopic submucosal dissection for rectal carcinoid tumour using the Clutch Cutter, ANZ Journal of Surgery, 10.1111/ans.12643, 84, 11, 847-851, 2014.11, © 2014 Royal Australasian College of Surgeons. Background: To reduce the risk of complications related to endoscopic submucosal dissection (ESD) using knives, we developed the Clutch Cutter (CC), which can grasp and incise the target tissue similarly to biopsy techniques using an electrosurgical current. The aim of this study was to evaluate the efficacy and safety of ESD using the CC for removal of rectal carcinoid tumours. Methods: Between December 2009 and December 2011, we prospectively enrolled seven patients (seven lesions) on 7 different days. Patients were endoscopically diagnosed with rectal subepithelial lesions (upper rectum, n = 3; lower rectum, n = 4) within the level 3 layer and without lymph node involvement, with the diagnosis confirmed by preliminary endoscopy, endoscopic ultrasound and endoscopic biopsies. ESD using the CC was performed in all cases, and the therapeutic efficacy, safety and tumour recurrence were assessed. Results: All lesions were treated easily and safely, and there were no inadvertent incisions. En bloc resection was obtained in all cases, and histologic tumour-free lateral/basal margins were obtained in six of the seven patients. No delayed haemorrhage, perforation or tumour recurrence occurred. Conclusion: ESD using the CC appears to be an easy, safe and technically efficient method for resecting rectal carcinoid tumour..
75. Yoichiro Iboshi, Kazuhiko Nakamura, Eikichi Ihara, Tsutomu Iwasa, Hirotada Akiho, Naohiko Harada, Makoto Nakamuta, Ryoichi Takayanagi, Multigene analysis unveils distinctive expression profiles of helper T-cell-related genes in the intestinal mucosa that discriminate between ulcerative colitis and Crohn's disease, Inflammatory Bowel Diseases, 10.1097/MIB.0000000000000028, 20, 6, 967-977, 2014.06, Background: Although the involvement of helper T (Th) and regulatory T (Treg) cell-related immune molecules in pathogenesis of inflammatory bowel disease (IBD) is widely accepted, no discriminatory mucosal expression profiles of these molecules between ulcerative colitis (UC) and Crohn's disease (CD) have been clarified. Methods: Mucosal expression of 17 cytokines and transcription factors related to Th1, Th2, Th17, and Treg were measured by quantitative PCR in endoscopic biopsies from inflamed (40 from UC [UCI] and 20 from CD [CDI]) and noninflamed (47, 22, and 25 from UC, CD, and controls, respectively) colon or ileum. The discriminatory power of these markers to differentiate between the 2 diseases was evaluated by linear discriminant analysis and, unsupervised, principal component analysis. Results: By univariate analysis, many targets were markedly increased in inflamed versus noninflamed areas. However, marker expression was almost comparable between UCI and CDI, with the largest difference in UCI-predominant interleukin (IL) 21 and IL-13 with area under the receiver operating characteristic curve (AUC) values of 0.704 and 0.664, respectively. In contrast, combinations of 2 to 7 markers improved UCI versus CDI discrimination with AUC = 0.875 to 0.975. Among these, a 5-maker set (interferon-g, IL-12 p35, T-bet, GATA3, and IL-21) demonstrated an AUC of 0.949 and a misclassification rate of 8.3%. Principal component analysis also markedly separated UCI and CDI. Conclusions: Inflamed mucosae from UC and CD could be discriminated with high accuracy using combinations of Th cell-related markers. Multigene analysis, possibly reflecting the underlying pathogenesis, is expected to be useful for diagnosis, monitoring and further defining distinctive characteristics in inflammatory bowel disease. Copyright © 2014 Crohn's & Colitis Foundation of America, Inc..
76. Hirotada Akiho, Yohei Tokita, Kazuhiko Nakamura, Kazuko Satoh, Mitsue Nishiyama, Naoko Tsuchiya, Kazuaki Tsuchiya, Katsuya Ohbuchi, Yoichiro Iwakura, Eikichi Ihara, Ryoichi Takayanagi, Masahiro Yamamoto, Involvement of interleukin-17A-induced hypercontractility of intestinal smooth muscle cells in persistent gut motor dysfunction, PLoS ONE, 10.1371/journal.pone.0092960, 9, 5, e92960, 2014.05, Background and Aim: The etiology of post-inflammatory gastrointestinal (GI) motility dysfunction, after resolution of acute symptoms of inflammatory bowel diseases (IBD) and intestinal infection, is largely unknown, however, a possible involvement of T cells is suggested. Methods: Using the mouse model of T cell activation-induced enteritis, we investigated whether enhancement of smooth muscle cell (SMC) contraction by interleukin (IL)-17A is involved in postinflammatory GI hypermotility. Results: Activation of CD3 induces temporal enteritis with GI hypomotility in the midst of, and hypermotility after resolution of, intestinal inflammation. Prolonged upregulation of IL-17A was prominent and IL-17A injection directly enhanced GI transit and contractility of intestinal strips. Postinflammatory hypermotility was not observed in IL-17A-deficient mice. Incubation of a muscle strip and SMCs with IL-17A in vitro resulted in enhanced contractility with increased phosphorylation of Ser19 in myosin light chain 2 (p-MLC), a surrogate marker as well as a critical mechanistic factor of SMC contractility. Using primary cultured murine and human intestinal SMCs, IκBζ- and p38 mitogen-activated protein kinase (p38MAPK)-mediated downregulation of the regulator of G protein signaling 4 (RGS4), which suppresses muscarinic signaling of contraction by promoting inactivation/desensitization of Gαq/11 protein, has been suggested to be involved in IL-17A-induced hypercontractility. The opposite effect of L-1β was mediated by IκBζ and c-jun N-terminal kinase (JNK) activation. Conclusions: We propose and discuss the possible involvement of IL-17A and its downstream signaling cascade in SMCs in diarrheal hypermotility in various GI disorders. © 2014 Akiho et al..
77. Akira Aso, Hisato Igarashi, Noriaki Matsui, Eikichi Ihara, Takehiro Takaoka, Takashi Osoegawa, Yusuke Niina, Takamasa Oono, Kazuya Akahoshi, Kazuhiko Nakamura, Tetsuhide Ito, Ryoichi Takayanagi, Large area of walled-off pancreatic necrosis successfully treated by endoscopic necrosectomy using a grasping-type scissors forceps, Digestive Endoscopy, 10.1111/den.12134, 26, 3, 474-477, 2014.05, Endoscopic necrosectomy (EN) for walled-off pancreatic necrosis (WOPN) is less invasive than surgical treatment and has become the first choice for pancreatic abscess. EN is usually carried out with several devices including snares, baskets, and grasping forceps. Occasionally, we have encountered cases in which EN has not been satisfactorily carried out, and there is pressure for further innovation in EN. Here, we describe a case of a large area of WOPN that was successfully treated by EN with endoscopic submucosal dissection and associated techniques, which facilitated removal of necrotic tissues. A 60-year-old man was referred to our hospital for WOPN as a complication of necrotizing pancreatitis. As a result of his complicating conditions including ischemic heart disease, uncontrollable arrhythmia, chronic renalfailure, and persistent pleural effusion, he was deemed a poor surgical candidate. Although EN with conventional devices was carried out for five sessions, we could not remove the dense and massive necrotic tissues. At the sixth EN session, the Clutch Cutter device (Fujifilm, Tokyo, Japan) was used to remove the necrotic tissues, without major complications. This is believed to be the first report of EN using the Clutch Cutter for successful treatment of WOPN. © 2013 Japan Gastroenterological Endoscopy Society..
78. Akira Aso, Eikichi Ihara, Takashi Osoegawa, Kazuhiko Nakamura, Soichi Itaba, Hisato Igarashi, Tetsuhide Ito, Shinichi Aishima, Yoshinao Oda, Masao Tanaka, Ryoichi Takayanagi, Key endoscopic ultrasound features of pancreatic ductal adenocarcinoma smaller than 20 mm, Scandinavian Journal of Gastroenterology, 10.3109/00365521.2013.878745, 49, 3, 332-338, 2014.03, Background and study aims. Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis compared with other solid pancreatic tumors. Diagnosis of PDAC in the earliest possible stage is important to improve the prognosis. Although endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has been the gold-standard modality for diagnosing pancreatic lesions, its diagnostic yield is not satisfactory for pancreatic tumors smaller than 20 mm. The purpose of this study was to determine the EUS findings that are useful for differentiating PDAC from other solid pancreatic tumors when the lesions are smaller than 20 mm. Patients and methods. We performed a retrospective review of 126 patients with pancreatic tumors smaller than 20 mm who had undergone EUS. According to the final pathological diagnoses, they were categorized into either the PDAC or non-PDAC group. We, then, compared the EUS findings between the two groups. Results. Among the 126 patients, we diagnosed PDAC in 75 patients and non-PDAC in the remaining patients, including neuroendocrine tumor in 43 patients, intraductal papillary mucinous carcinoma in 3 patients, solid pseudopapillary neoplasm in 2 patients, and inflammatory pseudotumor in 3 patients. Of all EUS findings, three factors were significantly indicative of PDAC: an irregular tumor edge, main pancreatic duct dilation, and tumor location in the pancreatic head. The predicted probability for PDAC was 80%, 92.6%, and 74.1%, respectively. Conclusions. EUS could be a useful modality for differentiating PDAC from other solid pancreatic tumors, when the diagnostic yield of EUS-FNA is unsatisfactory, even for lesions smaller than 20 mm. © 2014 Informa Healthcare..
79. Dysregulation of T helper reaction in inflammatory bowel disease.
80. Soichi Itaba, Kazuhiko Nakamura, Akira Aso, Shoji Tokunaga, Hirotada Akiho, Eikichi Ihara, Yoichiro Iboshi, Tsutomu Iwasa, Kazuya Akahoshi, Tetsuhide Ito, Ryoichi Takayanagi, Prospective, randomized, double-blind, placebo-controlled trial of ulinastatin for prevention of hyperenzymemia after double balloon endoscopy via the antegrade approach, Digestive Endoscopy, 10.1111/den.12014, 25, 4, 421-427, 2013.07, Background Double balloon endoscopy (DBE) allows the entire small intestine to be viewed using a combination of antegrade and retrograde approaches. Acute pancreatitis is a serious complication of antegrade DBE with no effective prophylactic treatment currently available. Ulinastatin has been shown to be effective for the prevention of pancreatitis following endoscopic retrograde cholangiopancreatography. We therefore assessed the efficacy of ulinastatin for hyperenzymemia after antegrade DBE. Patients and methods Forty-four patients were enrolled in this prospective, randomized, double-blind, placebo-controlled trial. Patients in the ulinastatin group received 150 000 U ulinastatin by i.v. drip infusion for 2 h from the start of the procedure. Serum concentrations of pancreatic amylase and lipase were measured before and 3 and 18 h after antegrade DBE. Results The study was terminated after interim analysis. Of the 44 patients, 23 were randomized to ulinastatin and 21 to placebo.The groups were similar with regard to sex ratio, age, type of endoscope, insertion time, total procedure time, number of endoscope pull-back procedures, and baseline pancreaticamylase and lipase concentrations. Post-DBE hyperenzymemia was observed in 35.0% and 47.8% of patients in the placebo and ulinastatin groups, respectively. The higher frequency of hyperenzymemia in the ulinastatin group was unexpected, but the difference was not statistically significant. One patient in the placebo group (5.0%) and none in the ulinastatin group experienced acute pancreatitis, but the difference was not statistically significant. Conclusion The results of this trial suggest that ulinastatin does not prevent hyperenzymemia following antegrade DBE. © 2012 The Authors..
81. Eikichi Ihara, Hiroshi Matsuzaka, Kuniomi Honda, Yoshitaka Hata, Yorinobu Sumida, Hirotada Akiho, Tadashi Misawa, Satoshi Toyoshima, Yoshiharu Chijiiwa, Kazuhiko Nakamura, Ryoichi Takayanagi, Mucosal-incision assisted biopsy for suspected gastric gastrointestinal stromal tumors., World journal of gastrointestinal endoscopy, 10.4253/wjge.v5.i4.191, 5, 4, 191-6, 2013.04, To evaluate the diagnostic yield of the procedure, mucosal-incision assisted biopsy (MIAB), for the histological diagnosis of gastric gastrointestinal stromal tumor (GIST), we performed a retrospective review of the 27 patients with suspected gastric GIST who underwent MIAB in our hospitals. Tissue samples obtained by MIAB were sufficient to make a histological diagnosis (diagnostic MIAB) in 23 out of the 27 patients, where the lesions had intraluminal growth patterns. Alternatively, the samples were insufficient (non-diagnostic MIAB) in remaining 4 patients, three of whom had gastric submucosal tumor with extraluminal growth patterns. Although endoscopic ultrasound and fine needle aspiration is the gold standard for obtaining tissue specimens for histological and cytological analysis of suspected gastric GISTs, MIAB can be used as an alternative method for obtaining biopsy specimens of lesions with an intraluminal growth pattern..
82. Aso A, Ihara E, Kubo H, Osoegawa T, Oono T, Nakamura K, Ito T, Kakeji Y, Mikako O, Yamamoto H, Oishi T, Oishi Y, Hachitanda Y, Takayanagi R, Gastric gastrointestinal stromal tumor smaller than 20 mm with liver metastasis., Clinical journal of gastroenterology, 10.1007/s12328-012-0351-0, 6, 1, 29-32, 2013.02.
83. Takashi Osoegawa, Yasuaki Motomura, Kazuya Akahoshi, Naomi Higuchi, Yoshimasa Tanaka, T Hisano, Soichi Itaba, Junya Gibo, Y Yamada, Masaru Kubokawa, Yorinobu Sumida, Hirotada Akiho, Eikichi Ihara, Kazuhiko Nakamura, Improved techniques for double-balloon-enteroscopy-assisted endoscopic retrograde cholangiopancreatography., World J Gastroenterol , 18, 6843-6849, 2012.12.
84. Kazuhiko Nakamura, Kazuya Akahoshi, Toshiaki Ochiai, Keishi Komori, Kazuhiro Haraguchi, Munehiro Tanaka, Norimoto Nakamura, Yoshimasa Tanaka, Kana Kakigao, Haruei Ogino, Eikichi Ihara, Hirotada Akiho, Yasuaki Motomura, Teppei Kabemura, Naohiko Harada, Yoshiharu Chijiiwa, Tetsuhide Ito, Ryoichi Takayanagi, Characteristics of hemorrhagic peptic ulcers in patients receiving antithrombotic/nonsteroidal antiinflammatory drug therapy, Gut and Liver, 10.5009/gnl.2012.6.4.423, 6, 4, 423-426, 2012.10, Background/Aims: Antithrombotic/nonsteroidal antiinflammatory drug (NSAID) therapies increase the incidence of upper gastrointestinal bleeding. The features of hemorrhagic peptic ulcer disease in patients receiving antithrombotic/NSAID therapies were investigated. Methods: We investigated the medical records of 485 consecutive patients who underwent esophagogastroduodenoscopy and were diagnosed with hemorrhagic gastroduodenal ulcers. The patients treated with antithrombotic agents/NSAIDs were categorized as the antithrombotic therapy (AT) group (n=213). The patients who were not treated with antithrombotics/NSAIDs were categorized as the control (C) group (n=263). The clinical characteristics were compared between the groups. Results: The patients in the AT group were significantly older than those in the C group (p
85. Tsutomu Iwasa, Haruei Ogino, Kazuhiko Nakamura, Eikichi Ihara, Hirotada Akiho, Ryoichi Takayanagi, Feeding administration of daikenchuto suppresses colitis induced by naive CD4+ T cell transfer into SCID mice, Digestive Diseases and Sciences, 10.1007/s10620-012-2218-0, 57, 10, 2571-2579, 2012.10, Background and Aims Daikenchuto, a traditional Japanese herbal medicine, suppresses bacterial translocation by improvement of gastrointestinal motility and blood flow. As Daikenchuto reportedly reduces gastrointestinal inflammatory activity by these mechanisms, we analyzed whether Daikenchuto suppresses experimental colitis and reduces inflammatory cytokine expression in a mouse model. Methods Colitis was induced by transfer of naive CD4+ T cells of BALB/c mice into SCID mice, and mice were given either control or 2.7 % Daikenchuto-containing feed. We investigated body weight, clinical symptoms, histological changes, and Th1- and Th17-cytokine expression. Cytokine mRNA expression was analyzed using real-time RT-PCR. The ratio of IL-17+ and IFN-c+ CD4+ T cells were analyzed by flow cytometry. Results Daikenchuto delayed the development of colitis and significantly reduced the histological inflammation scores. Analyses of cytokine mRNA revealed that Th17 cytokines were significantly decreased in colons of mice that received Daikenchuto. Absolute numbers of IL-17+ or IFN-c+ CD4+ T cells per colon were less in mice receiving Daikenchuto than in mice that received control feed, as both groups received naive CD4+ T cells to induce colitis. Conclusions We demonstrated that feeding administration of Daikenchuto suppresses colitis induced by naive CD4+ T cell transfer into SCID mice. Daikenchuto may show clinical benefit in the treatment of human inflammatory bowel disease and further studies are warranted. © 2012 Springer Science+Business Media, LLC..
86. Shinichi Somada, Hiromi Muta, Kazuhiko Nakamura, Xun Sun, Kuniomi Honda, Eikichi Ihara, Hirotada Akiho, Ryoichi Takayanagi, Yasunobu Yoshikai, Eckhard R. Podack, Kenzaburo Tani, CD30 ligand/CD30 interaction is involved in pathogenesis of inflammatory bowel disease, Digestive Diseases and Sciences, 10.1007/s10620-012-2129-0, 57, 8, 2031-2037, 2012.08, Background and Aims Although CD30 has long been recognized as an important marker in many lymphomas of diverse origin, and as an activation molecule on B and T cells, its primary function has remained obscure. Soluble CD30 (sCD30) is released from CD30 on the cell membrane by enzymatic cleavage. This study investigated the role of CD30 ligand (CD30L)/CD30 signals in intestinal mucosal damage. Methods Serum sCD30 in patients with ulcerative colitis (UC) and Crohn's disease (CD) and healthy individuals was assessed. A model of enteritis induced by anti-CD3 monoclonal antibody injection was studied in wild-type mice and in CD30L knockout mice. Results Increased sCD30 was observed in UC and CD patients, and the level was correlated with disease activity in both conditions. In a murine model of enteritis, histological intestinal damage was significantly reduced in CD30L knockout mice with decreased Th1 and Th17 cytokine levels. Moreover, blocking of CD30L/CD30 signals by CD30-immunoglobulin (CD30-Ig) resulted in reduced inflammation. Conclusions Increased sCD30 expression correlating with disease activity suggested that CD30L/CD30 signals play an important role in pathogenesis of UC and CD. CD30L/CD30 pathway acts as an accelerator of enteritis in a murine disease model. Successful blockade of enteritis by CD30-Ig suggests a potential tool for future therapy of inflammatory bowel diseases. © Springer Science+Business Media, LLC 2012..
87. Yoshimasa Tanaka, Yasuaki Motomura, Kazuya Akahoshi, Risa Iwao, Keishi Komori, Naotaka Nakama, Takashi Osoegawa, Soichi Itaba, Masaru Kubokawa, Terumasa Hisano, Eikichi Ihara, Kazuhiko Nakamura, Ryoichi Takayanagi, Predictive factors for colonic diverticular rebleeding: A retrospective analysis of the clinical and colonoscopic features of 111 patients, Gut and Liver, 10.5009/gnl.2012.6.3.334, 6, 3, 334-338, 2012.07, Background/Aims: Colonic diverticular bleeding can stop spontaneously or be stopped by endoscopic hemostasis. We analyzed the clinical and colonoscopic features of patients with colonic diverticular bleeding to establish the predictive factors for rebleeding. Methods: A total of 111 patients (median age, 72 years) with colonic diverticular bleeding in Aso Iizuka Hospital between April 2007 and July 2010 were enrolled. Age, sex, body mass index (BMI), comorbidity, medication, location of bleeding, colonoscopic findings and hemostatic methods were analyzed retrospectively from the hospital records. Results: The most common sites of bleeding were the ascending (39.6%) and sigmoid (29.7%) colon. Overt rebleeding occurred in 30 patients (27.0%). Spontaneous hemostasis was seen in 81 patients (73.0%), and endoscopic hemostatic treatment was performed in 30 patients. The BMI in the patients with colonic diverticular rebleeding was significantly higher than in patients without rebleeding. Colonoscopic findings of actively bleeding or nonbleeding visible vessels in the responsible diverticula were more frequent in the group with rebleeding. Conclusions: A higher BMI and colonoscopic findings of actively bleeding or nonbleeding visible vessels can be used as predictive factors for colonic diverticular rebleeding. Patients with such findings should be carefully followed up after hemostasis of the initial colonic diverticular bleeding..
88. Noriaki Matsui, Kazuya Akahoshi, Kazuhiko Nakamura, Eikichi Ihara, Hiroto Kita, Endoscopic submucosal dissection for removal of superficial gastrointestinal neoplasms: A technical review., World journal of gastrointestinal endoscopy, 10.4253/wjge.v4.i4.123, 4, 4, 123-36, 2012.04, Endoscopic submucosal dissection (ESD) is now the most common endoscopic treatment in Japan for intramucosal gastrointestinal neoplasms (non-metastatic). ESD is an invasive endoscopic surgical procedure, requiring extensive knowledge, skill, and specialized equipment. ESD starts with evaluation of the lesion, as accurate assessment of the depth and margin of the lesion is essential. The devices and strategies used in ESD vary, depending on the nature of the lesion. Prior to the procedure, the operator must be knowledgeable about the treatment strategy(ies), the device(s) to use, the electrocautery machine settings, the substances to inject, and other aspects. In addition, the operator must be able to manage complications, should they arise, including immediate recognition of the complication(s) and its treatment. Finally, in case the ESD treatment is not successful, the operator should be prepared to apply alternative treatments. Thus, adequate knowledge and training are essential to successfully perform ESD..
89. Kazuhiko Nakamura, Tetsuhide Ito, Kazuhiro Kotoh, Eikichi Ihara, Haruei Ogino, Tsutomu Iwasa, Yoshimasa Tanaka, Yoichiro Iboshi, Ryoichi Takayanagi, Hepatopancreatobiliary manifestations of inflammatory bowel disease, Clinical Journal of Gastroenterology, 10.1007/s12328-011-0282-1, 5, 1, 1-8, 2012.02, Inflammatory bowel disease (IBD) is frequently associated with extraintestinal manifestations such as hepatopancreatobiliary manifestations (HPBMs), which include primary sclerosing cholangitis (PSC), pancreatitis, and cholelithiasis. PSC is correlated with IBD, particularly ulcerative colitis (UC); 70-80% of PSC patients in Western countries and 20-30% in Japan have comorbid UC. Therefore, patients diagnosed with PSC should be screened for UC by total colonoscopy. While symptoms of PSC-associated UC are usually milder than PSC-negative UC, these patients have a higher risk of colorectal cancer, particularly in the proximal colon. Therefore, regular colonoscopy surveillance is required regardless of UC symptoms. Administration of 5-aminosalicylic acid or ursodeoxycholic acid may prevent colorectal cancer and cholangiocarcinoma. While PSC is diagnosed by diffuse multifocal strictures on cholangiography, it must be carefully differentiated from immunoglobulin G4 (IgG4)-associated cholangitis, which shows a similar cholangiogram but requires different treatment. When PSC is suspected despite a normal cholangiogram, the patient may have small-duct PSC, which requires a liver biopsy. IBD patients have a high incidence of acute and chronic pancreatitis. Most cases are induced by cholelithiasis or medication, although some patients may have autoimmune pancreatitis (AIP), most commonly type 2 without elevation of serum IgG4. AIP should be accurately identified based on characteristic image findings, because AIP responds well to corticosteroids. Crohn's disease is frequently associated with gallstones, and several risk factors are indicated. HPBMs may influence the management of IBD, therefore, accurate diagnosis and an appropriate therapeutic strategy are important, as treatment depends upon the type of HPBM. © 2011 Springer..
90. Ihara E, Chappellaz M, Turner SR, MacDonald JA, Contribution of Protein kinase C and CPI-17 signaling pathways to hypercontractility in murine experimental colitis. , Neurogastroenterol Motil, 24, e15-26, 2012.01.
91. Kenji Kanayama, Kazuhiko Nakamura, Haruei Ogino, Yorinobu Sumida, Eikichi Ihara, Hirotada Akiho, Ryoichi Takayanagi, Th1 responses are more susceptible to infliximab-mediated immunosuppression than Th17 responses, Digestive Diseases and Sciences, 10.1007/s10620-011-1780-1, 56, 12, 3525-3533, 2011.12, Background Treatment with infliximab, a chimeric antitumor necrosis factor (TNF)-α antibody, is highly efficient in patients with inflammatory bowel disease (IBD). It neutralizes soluble TNF-α and induces the apoptosis of transmembrane TNF-α-positive macrophages and T cells in the gut. Recently, T helper (Th)17, as well as Th1, responses have been implicated in the pathogenesis of IBD. Aims To clarify the effects of infliximab on Th1 and Th17 responses in vitro. Methods Naive CD4 + T cells isolated from the peripheral blood of healthy volunteers were stimulated under Th1- or Th17-inducing conditions in the presence of 10 μg/ml of infliximab or control immunoglobulin (Ig)G1. The concentrations of interferon (IFN)-c, interleukin (IL)-17, and TNF-α in the culture supernatants were determined by enzyme-linked immunosorbent assay (ELISA). Th1 and Th17 cells were immunostained with infliximab or control IgG1 and transmembrane TNF-α-positive cells were analyzed by flow cytometry. Annexin V staining and terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) assays were conducted in order to analyze the percentage of apoptotic cells. Results Both Th1 and Th17 cells expressed soluble and transmembrane TNF-α abundantly. Although infliximab suppressed IFN-γ secretion by Th1 cells and IL-17 secretion by Th17 cells, the level of the former was more profound than the latter. Infliximab increased annexin V- and TUNEL-positive apoptotic cells under Th1-inducing conditions, but not under Th17-inducing conditions. Conclusions Infliximab suppressed Th1 and Th17 differentiation in vitro; however, IFN-γ production by Th1 cells was more profoundly suppressed than IL-17 secretion by Th17 cells. Th1 responses were more susceptible to infliximab-mediated apoptosis than Th17 responses. Our results clarify a new mechanism of action of infliximab. © Springer Science+Business Media, LLC 2011..
92. Hirotada Akiho, Eikichi Ihara, Yasuaki Motomura, Kazuhiko Nakamura, Cytokine-induced alterations of gastrointestinal motility in gastrointestinal disorders., World journal of gastrointestinal pathophysiology, 2, 5, 72-81, 2011.10, Inflammation and immune activation in the gut are usually accompanied by alteration of gastrointestinal (GI) motility. In infection, changes in motor function have been linked to host defense by enhancing the expulsion of the infectious agents. In this review, we describe the evidence for inflammation and immune activation in GI infection, inflammatory bowel disease, ileus, achalasia, eosinophilic esophagitis, microscopic colitis, celiac disease, pseudo-obstruction and functional GI disorders. We also describe the possible mechanisms by which inflammation and immune activation in the gut affect GI motility. GI motility disorder is a broad spectrum disturbance of GI physiology. Although several systems including central nerves, enteric nerves, interstitial cells of Cajal and smooth muscles contribute to a coordinated regulation of GI motility, smooth muscle probably plays the most important role. Thus, we focus on the relationship between activation of cytokines induced by adaptive immune response and alteration of GI smooth muscle contractility. Accumulated evidence has shown that Th1 and Th2 cytokines cause hypocontractility and hypercontractility of inflamed intestinal smooth muscle. Th1 cytokines downregulate CPI-17 and L-type Ca(2+) channels and upregulate regulators of G protein signaling 4, which contributes to hypocontractility of inflamed intestinal smooth muscle. Conversely, Th2 cytokines cause hypercontractilty via signal transducer and activator of transcription 6 or mitogen-activated protein kinase signaling pathways. Th1 and Th2 cytokines have opposing effects on intestinal smooth muscle contraction via 5-hydroxytryptamine signaling. Understanding the immunological basis of altered GI motor function could lead to new therapeutic strategies for GI functional and inflammatory disorders..
93. Eikichi Ihara, Hirotada Akiho, Kazuhiko Nakamura, Sara R Turner, Justin A Macdonald, MAPKs represent novel therapeutic targets for gastrointestinal motility disorders., World journal of gastrointestinal pathophysiology, 10.4291/wjgp.v2.i2.19, 2, 2, 19-25, 2011.04, The number of patients suffering from symptoms associated with gastrointestinal (GI) motility disorders is on the rise. GI motility disorders are accompanied by alteration of gastrointestinal smooth muscle functions. Currently available drugs, which can directly affect gastrointestinal smooth muscle and restore altered smooth muscle contractility to normal, are not satisfactory for treating patients with GI motility disorders. We have recently shown that ERK1/2 and p38MAPK signaling pathways play an important role in the contractile response not only of normal intestinal smooth muscle but also of inflamed intestinal smooth muscle. Here we discuss the possibility that ERK1/2 and p38MAPK signaling pathways represent ideal targets for generation of novel therapeutics for patients with GI motility disorders..
94. Haruei Ogino, Kazuhiko Nakamura, Eikichi Ihara, Hirotada Akiho, Ryoichi Takayanagi, CD4+CD25+ regulatory T cells suppress Th17-responses in an experimental colitis model, Digestive Diseases and Sciences, 10.1007/s10620-010-1286-2, 56, 2, 376-386, 2011.02, Background: After the recent discovery of Th17 cells, it was proposed that Th17 responses are involved in the pathogenesis of inflammatory bowel diseases (IBD). CD4+CD25+ regulatory T cells (Treg) are considered to be an attractive tool for the treatment of IBD. Here, we investigated whether Treg are capable of suppressing Th17-mediated colitis. Methods: Naive CD4 + T cells were transferred into SCID mice with or without Treg. In some experiments, Treg were transferred into recipient mice with established colitis. Mice treated with Treg were injected with an anti-transforming growth factor (TGF)-β mAb or control IgG. Clinical symptoms of colitis, histological changes and cytokine expressions were investigated. Results: SCID mice transferred with naive CD4+ T cells developed chronic colitis with significant increases in Th1 and Th17 cytokine expressions in the colon. When Treg were co-transferred with naive CD4+ T cells, development of colitis was prevented, and Th17 cytokine expressions were markedly reduced. Similarly, when Treg were transferred into mice with established colitis, the colitis was significantly ameliorated in association with dramatic reductions in Th17 cytokine expressions. Injection of anti-TGF-β mAb abolished the Treg-mediated suppression with significant elevations in Th17 cytokine productions. Conclusion: This adoptive transfer model of colitis was associated with augmented Th1 and Th17 responses, and Treg were capable of suppressing colonic inflammation by downregulating Th17 responses as well as Th1 responses via TGF-β. Consequently, Treg transfer therapy is expected to be efficacious for IBD even if Th17 is involved in the pathogenesis. © 2010 Springer Science+Business Media, LLC..
95. Ogino H, Nakamura K, Ihara E, Akiho H, Takayanagi R, CD4+CD25+ Regulatory T Cells Suppress Th17-Responses in an Experimental Colitis Model. , Dig Dis Sci , 57, 497-500, 2011.01.
96. Hirotada Akiho, Eikichi Ihara, Kazuhiko Nakamura, Low-grade inflammation plays a pivotal role in gastrointestinal dysfunction in irritable bowel syndrome., World journal of gastrointestinal pathophysiology, 10.4291/wjgp.v1.i3.97, 1, 3, 97-105, 2010.08, The pathogenesis of irritable bowel syndrome (IBS) is considered to be multifactorial and includes psychosocial factors, visceral hypersensitivity, infection, microbiota and immune activation. It is becoming increasingly clear that low-grade inflammation is present in IBS patients and a number of biomarkers have emerged. This review describes the evidence for low-grade inflammation in IBS and explores its mechanism with particular focus on gastrointestinal motor dysfunction. Understanding of the immunological basis of the altered gastrointestinal motor function in IBS may lead to new therapeutic strategies for IBS..
97. Hirota, SA, Fines K, Ng J, Traboulsi D, Lee J, Ihara E, Li Y, Willmore WG, Chung D, Scully MM. Louie T, Medicot S, Lejeune M, Chadee K, Armstrong G, Colagan SP, Muruve DA, Macdonald JA, Beck PL, Hypoxia-inducible factor signaling provides protection in Clostridium difficile-induced intestinal injury. , Gastroenterology, 139, 259-269, 2010.07.
98. P. L. Beck, E. Ihara, S. A. Hirota, J. A. MacDonald, D. Meng, N. N. Nanthakumar, D. K. Podolsky, R. J. Xavier, Exploring the interplay of barrier function and leukocyte recruitment in intestinal inflammation by targeting fucosyltransferase VII and trefoil factor 3, American Journal of Physiology - Gastrointestinal and Liver Physiology, 10.1152/ajpgi.00228.2009, 299, 1, G43-53, 2010.07, Intestinal mucosal integrity is dependent on epithelial function and a regulated immune response to injury. Fucosyltransferase VII (Fuc-TVII) is an essential enzyme required for the expression of the functional ligand for E- and P-selectin. Trefoil factor 3 (TFF3) is involved in both protecting the intestinal epithelium against injury as well as aiding in wound repair following injury. The aim of the present study was to assess the interplay between barrier function and leukocyte recruitment in intestinal inflammation. More specifically, we aimed to examine how targeted disruption of Fuc-TVII either in wild-type or TFF3-/- mice would alter their susceptibility to colonic injury. TFF3 and Fuc-TVII double-knockout mice (TFF3/Fuc-TVII-/- mice) were generated by mating TFF3-/- and Fuc-TVII-/- mice. Colitis was induced by administration of dextran sodium sulfate (DSS) (2.5% wt/vol) in the drinking water. Changes in baseline body weight, diarrhea, and fecal blood were assessed daily. Upon euthanasia, extents of colonic inflammation were assessed macroscopically, microscopically, and through quantification of myeloperoxidase (MPO) activity. Colonic lymphocyte subpopulations were assessed at 6 days after administration of DSS by flow cytometry and immunohistochemistry. No baseline intestinal inflammation was found in TFF3/Fuc-TVII-/-, TFF3-/-, Fuc-TVII -/-, or wild-type mice. Loss of Fuc-TVII resulted in a reduction in disease severity whereas TFF3-/- mice were markedly more susceptible to DSS-induced colitis. Remarkably, the loss of Fuc-TVII in TFF3-/- mice markedly decreased the severity of DSS-induced colitis as evidenced by reduced weight loss, diarrhea, decreased colonic MPO levels and improved survival. Furthermore, the loss of TFF3 resulted in increased severity of spontaneous colitis in IL-2/β-microglobulin-deficient mice. These studies highlight the importance of the interplay between factors involved in the innate immune response, mucosal barrier function, and genes involved in regulating leukocyte recruitment and other aspects of the immune response. Copyright © 2010 the American Physiological Society..
99. Simon A. Hirota, Kyla Fines, Jeffrey Ng, Danya Traboulsi, Josh Lee, Eikichi Ihara, Yan Li, William G. Willmore, Daniel Chung, Melanie M. Scully, Thomas Louie, Shaun Medlicott, Manigandan Lejeune, Kris Chadee, Glen Armstrong, Sean P. Colgan, Daniel A. Muruve, Justin A. MacDonald, Paul L. Beck, Hypoxia-Inducible Factor Signaling Provides Protection in Clostridium difficile-Induced Intestinal Injury, Gastroenterology, 10.1053/j.gastro.2010.03.045, 139, 1, 259-69, 2010.07, Background & Aims: Clostridium difficile is the leading cause of nosocomial infectious diarrhea. Antibiotic resistance and increased virulence of strains have increased the number of C difficile-related deaths worldwide. The innate host response mechanisms to C difficile are not resolved; we propose that hypoxia-inducible factor (HIF-1) has an innate, protective role in C difficile colitis. We studied the impact of C difficile toxins on the regulation of HIF-1 and evaluated the role of HIF-1α in C difficile-mediated injury/inflammation. Methods: We assessed HIF-1α mRNA and protein levels and DNA binding in human mucosal biopsy samples and Caco-2 cells following exposure to C difficile toxins. We used the mouse ileal loop model of C difficile toxin-induced intestinal injury. Mice with targeted deletion of HIF-1α in the intestinal epithelium were used to assess the effects of HIF-1α signaling in response to C difficile toxin. Results: Mucosal biopsy specimens and Caco-2 cells exposed to C difficile toxin had a significant increase in HIF-1α transcription and protein levels. Toxin-induced DNA binding was also observed in Caco-2 cells. Toxin-induced HIF-1α accumulation was attenuated by nitric oxide synthase inhibitors. In vivo deletion of intestinal epithelial HIF-1α resulted in more severe, toxin-induced intestinal injury and inflammation. In contrast, stabilization of HIF-1α with dimethyloxallyl glycine attenuated toxin-induced injury and inflammation. This was associated with induction of HIF-1-regulated protective factors (such as vascular endothelial growth factor-α, CD73, and intestinal trefoil factor) and down-regulation of proinflammatory molecules such as tumor necrosis factor and Cxcl1. Conclusions: HIF-1α protects the intestinal mucosa from C difficile toxins. The innate protective actions of HIF-1α in response to C difficile toxins be developed as therapeutics for C difficile-associated disease. © 2010 AGA Institute..
100. Eikichi Ihara, Lori Moffat, Meredith A. Borman, Jennifer E. Amon, Michael P. Walsh, Justin A. MacDonald, Ca2+-independent contraction of longitudinal ileal smooth muscle is potentiated by a zipper-interacting protein kinase pseudosubstrate peptide, American Journal of Physiology - Gastrointestinal and Liver Physiology, 10.1152/ajpgi.00112.2009, 297, 2, G361-70-70, 2009.08, As a regulator of smooth muscle contraction, zipper-interacting protein kinase (ZIPK) can directly phosphorylate the myosin regulatory light chains (LC20) and produce contractile force. Synthetic peptides (SM-1 and AV25) derived from the autoinhibitory region of smooth muscle myosin light chain kinase can inhibit ZIPK activity in vitro. Paradoxically, treatment of Tritonskinned ileal smooth muscle strips with AV25, but not SM-1, potentiated Ca2+-independent, microcystin- and ZIPK-induced contractions. The AV25-induced potentiation was limited to ileal and colonic smooth muscles and was not observed in rat caudal artery. Thus the potentiation of Ca 2+-independent contractions by AV25 appeared to be mediated by a mechanism unique to intestinal smooth muscle. AV25 treatment elicited increased phosphorylation of LC20 (both Ser-19 and Thr-18) and myosin phosphatase-targeting subunit (MYPT1, inhibitory Thr-697 site), suggesting involvement of a Ca2+-independent LC20 kinase with coincident inhibition of myosin phosphatase. The phosphorylation of the inhibitor of myosin phosphatase, CPI-17, was not affected. The AV25-induced potentiation was abolished by pretreatment with staurosporine, a broad-specificity kinase inhibitor, but specific inhibitors of Rho-associated kinase, PKC, and MAPK pathways had no effect. When a dominant-negative ZIPK [kinase-dead ZIPK(1-320)-D161A] was added to skinned ileal smooth muscle, the potentiation of microcystin-induced contraction by AV25 was blocked. Furthermore, pretreatment of skinned ileal muscle with SM-1 abolished AV25-induced potentiation. We conclude, therefore, that, even though AV25 is an in vitro inhibitor of ZIPK, activation of the ZIPK pathway occurs following application of AV25 to permeabilized ileal smooth muscle. Finally, we propose a mechanism whereby conformational changes in the pseudosubstrate region of ZIPK permit augmentation of ZIPK activity toward LC20 and MYPT1 in situ. AV25 or molecules based on its structure could be used in therapeutic situations to induce contractility in diseases of the gastrointestinal tract associated with hypomotility. Copyright © 2009 the American Physiological Society..
101. Ihara E, Beck PL, Chappellaz M, Wong J, Medlicott SA and MacDonald JA, Mitogen-activated protein kinase pathways conribute to hypercontractility and increased Ca2+-sensitization in murine experimental colitis. , Mol Pharmacol, 75, 1031-1041, 2009.07.
102. Eikichi Ihara, Paul L. Beck, Mona Chappellaz, Josee Wong, Shaun A. Medlicott, Justin A. MacDonald, Mitogen-activated protein kinase pathways contribute to hypercontractility and increased Ca2+ sensitization in murine experimental colitis, Molecular Pharmacology, 10.1124/mol.108.049858, 75, 5, 1031-1040, 2009.05, Inflammatory bowel disease (IBD) is associated with intestinal smooth muscle dysfunction. Many smooth muscle contractile events are associated with alterations in Ca2+-sensitizing pathways. The aim of the present study was to assess the effect of colitis on Ca2+ sensitization and the signaling pathways responsible for contractile dysfunction in murine experimental colitis. Colitis was induced in BALB/c mice by providing 5% dextran sulfate sodium (DSS) in drinking water for 7 days. Contractile responses of colonic circular smooth muscle strips to 118 mM K+ and carbachol (CCh) were assessed. DSS induced a TH2 colitis [increased interleukin (IL)-4 and IL-6] with no changes in TH1 cytokines. Animals exposed to DSS had increased CCh-induced contraction (3.5-fold) and CCh-induced Ca 2+-sensitization (2.2-fold) responses in intact and α-toxin permeabilized colonic smooth muscle, respectively. The contributions of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) to CCh-induced contractions were significantly increased during colitis. Ca2+-independent contraction induced by microcystin was potentiated (1.5-fold) in mice with colitis. ERK and p38MAPK (but not Rho-associated kinase) contributed to this potentiation. ERK1/2 and p38MAPK expression were increased in the muscularis propria of colonic tissue from both DSS-treated mice and patients with IBD (ulcerative colitis ≫ Crohn's disease). Murine TH2 colitis resulted in colonic smooth muscle hypercontractility with increased Ca2+ sensitization. Both ERK and p38MAPK pathways contributed to this contractile dysfunction, and expression of these molecules was altered in patients with IBD. Copyright © 2009 The American Society for Pharmacology and Experimental Therapeutics..
103. Eikichi Ihara, Lori Moffat, Janina Ostrander, Michael P. Walsh, Justin A. MacDonald, Characterization of protein kinase pathways responsible for Ca2+ sensitization in rat ileal longitudinal smooth muscle, American Journal of Physiology - Gastrointestinal and Liver Physiology, 10.1152/ajpgi.00214.2007, 293, 4, G699-710-710, 2007.10, We investigated the protein kinases responsible for myosin regulatory light chain (LC20) phosphorylation and regulation of myosin light chain phosphatase (MLCP) activity during microcystin (phosphatase inhibitor)-induced contraction at low Ca2+ concentrations of rat ileal smooth muscle stretched in the longitudinal axis. Application of 1 μM microcystin induced LC20 diphosphorylation and contraction of β-escin-permeabilized rat ileal smooth muscle at pCa 9. The PKC inhibitor GF-109203x, the MEK inhibitor PD-98059, and the p38 MAPK inhibitor SB-203580 significantly reduced this contraction. These inhibitory effects were abolished when the microcystin concentration was increased to 10 μM, indicating that application of these kinase inhibitors generated an increase in MLCP activity. GF-109203x and PD-98059, but not SB-203580, significantly decreased the phosphorylation level of the myosin-targeting subunit of MLCP, MYPT1, at Thr-697 (rat sequence) during microcystin-induced contraction at pCa 9. On the other hand, SB-203580, but not GF-109203x or PD-98059, significantly reduced the phosphorylation level of the PKC-potentiated phosphatase inhibitor of 17 kDa (CPI-17). A zipper-interacting protein kinase (ZIPK) inhibitor (SM1 peptide) and a Rho-associated kinase inhibitor (Y-27632) had little effect on microcystin-induced contraction at pCa 9. In conclusion, PKC, ERK1/2, and p38 MAPK pathways facilitate microcystin-induced contraction at low Ca2+ concentrations by contributing to the inhibition of MLCP activity either through phosphorylation of MYPT1 or CPI-17 [probably mediated by integrin-linked kinase (ILK)]. ILK and not ZIPK is likely to be the protein kinase responsible for LC20 diphosphorylation during microcystin-induced contraction of rat ileal smooth muscle at pCa 9, similar to its recently described role in vascular smooth muscle. The negative regulation of MLCP by PKC and MAPKs during microcystin-induced contraction at pCa 9, which is not observed in vascular smooth muscle, may be unique to phasic smooth muscle. Copyright © 2007 the American Physiological Society..
104. Eikichi Ihara, Elena Edwards, Meredith A. Borman, David P. Wilson, Michael P. Walsh, Justin A. MacDonald, Inhibition of zipper-interacting protein kinase function in smooth muscle by a myosin light chain kinase pseudosubstrate peptide, American Journal of Physiology - Cell Physiology, 10.1152/ajpcell.00434.2006, 292, 5, C1951-9-9, 2007.05, As a regulator of smooth muscle contractility, zipper-interacting protein kinase (ZIPK) appears to phosphorylate the regulatory myosin light chain (RLC20), directly or indirectly, at Ser19 and Thr18 in a Ca2+- independent manner. The calmodulin-binding and autoinhibitory domain of myosin light chain kinase (MLCK) shares similarity to a sequence found in ZIPK. This similarity in sequence prompted an investigation of the SM1 peptide, which is derived from the autoinhibitory region of MLCK, as a potential inhibitor of ZIPK. In vitro studies showed that SM1 is a competitive inhibitor of a constitutively active 32-kDa form of ZIPK with an apparent Ki value of 3.4 μM. Experiments confirmed that the SM1 peptide is also active against full-length ZIPK. In addition, ZIPK autophosphorylation was reduced by SM1. ZIPK activity is independent of calmodulin; however, calmodulin suppressed the in vitro inhibitory potential of SM1, likely as a result of nonspecific binding of the peptide to calmodulin. Treatment of ileal smooth muscle with exogenous ZIPK was accompanied by an increase in RLC20 diphosphorylation, distinguishing between ZIPK [and integrin-linked kinase (ILK)] and MLCK actions. Administration of SM1 suppressed steady-state muscle tension developed by the addition of exogenous ZIPK to Triton-skinned rat ileal muscle strips with or without calmodulin depletion by trifluoperazine. The decrease in contractile force was associated with decreases in both RLC20 mono- and diphosphorylation. In summary, we present the SM1 peptide as a novel inhibitor of ZIPK. We also conclude that the SM1 peptide, which has no effect on ILK, can be used to distinguish between ZIPK and ILK effects in smooth muscle tissues. Copyright © 2007 the American Physiological Society..
105. Eikichi Ihara, Justin A. MacDonald, The regulation of smooth muscle contractility by zipper-interacting protein kinase, Canadian Journal of Physiology and Pharmacology, 10.1139/Y06-103, 85, 1, 79-87, 2007.01, Smooth muscle contractility is mainly regulated by phosphorylation of the 20 kDa myosin light chains (LC20), a process that is controlled by the opposing activities of myosin light chain kinase (MLCK) and myosin light chain phosphatase (MLCP). Recently, intensive research has revealed that various protein kinase networks including Rho-kinase, integrin-linked kinase, zipper-interacting protein kinase (ZIPK), and protein kinase C (PKC) are involved in the regulation of LC20 phosphorylation and have important roles in modulating smooth muscle contractile responses to Ca2+ (i.e., Ca2+ sensitization and Ca2+ desensitization). Here, we review the general background and structure of ZIPK and summarize our current understanding of its involvement in a number of cell processes including cell death (apoptosis), cell motility, and smooth muscle contraction. ZIPK has been found to induce the diphosphorylation of LC20 at Ser-19 and Thr-18 in a Ca2+-independent manner and to regulate MLCP activity directly through its phosphorylation of the myosin-targeting subunit of MLCP or indirectly through its phosphorylation of the PKC-potentiated inhibitory protein of MLCP. Future investigations of ZIPK function in smooth muscle will undoubtably focus on determining the mechanisms that regulate its cellular activity, including the identification of upstream signaling pathways, the characterization of autoinhibitory domains and regulatory phosphorylation sites, and the development of specific inhibitor compounds. © 2007 NRC..
106. Katsuya Hirano, Eikichi Ihara, Mayumi Hirano, Junji Nishimura, Hajime Nawata, Hideo Kanaide, Facilitation of proteasomal degradation of p27Kip1 by N-terminal cleavage and their sequence requirements, FEBS Letters, 10.1016/j.febslet.2004.08.014, 574, 1-3, 111-115, 2004.09, The sequence requirement for N-terminal cleavage and the proteasomal degradation of p27Kip1 and their relationship was investigated. Residues 5-8 were required for the cleavage and the mutation of S10 to E inhibited the cleavage. The C-terminal PEST sequence was necessary for the degradation and residue R165 was found to play an important role in the degradation. The inhibition of the cleavage by deleting residues 5-8 inhibited the degradation, while the fragment mimicking the cleavage product accelerated the degradation. Both the cleavage and degradation demonstrated a similar sensitivity toward proteasome inhibitors and ATP depletion. These two processes are thus suggested to be tightly linked and sequential. © 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved..
107. Kuniomi Honda, Eikichi Ihara, Toshiaki Ochiai, Masahiro Matsumoto, Hiroyuki Matsuda, Akihiko Nakashima, Naohiko Harada, Teppei Kabemura, Lymphangioma of small intestine, Gastrointestinal Endoscopy, 10.1067/S0016-5107(03)01876-5, 58, 4, 574-575, 2003.10.
108. A case of Hereditary Hemorrhasic Telangiectasia (Rendu-Osler-Weber disease) with gastric hemorrhagic lesions successfully treated by Algon plasma coagulation
A 47-year-old man was admitted to our hospital with the chief complaint of frequent nasal bleeding. Several telangiectatic lesions were observed both on his skin and on his oral mucosa. His father had not only similarly experienced frequent nasal bleeding but also had similar skin lesions as those demonstrated by the patient. We, therefore, made a diagnosis of Hereditary Hemorrhagic Telangiectasia (Rendu-Osler-Weber disease: ROW disease). Upper gastrointestinal endoscopy revealed a number of hemorrhagic telangiectasia lesions throughout the stomach which are considered to cause chronic anemia. Argon plasma coagulation was used to treat the hemorrhagic telangiectasia, with which resulted in an improvement of his anemia. He also demonstrated a couple of pulmonary arteriovenus malformations (p-AVM) and multiple hepatic hemangiomatous lesions associated with ROW disease. Since he also suffered from exartional dyspnea with hypoxia due to p-AVM, embolization with platinum coils was performed to treat the p-AVM. The argon plasma coagulation method is considered to be an effective treatment for gastric lesions in ROW disease..
109. Kiichiro Beppu, Takashi Morisaki, Hisashi Matsunaga, Akihiko Uchiyama, Eikichi Ihara, Katsuya Hirano, Hideo Kanaide, Masao Tanaka, Mitsuo Katano, Inhibition of interferon-γ-activated nuclear factor-κB by cyclosporin A: A possible mechanism for synergistic induction of apoptosis by interferon-γ and cyclosporin A in gastric carcinoma cells, Biochemical and Biophysical Research Communications, 10.1016/S0006-291X(03)00853-2, 305, 4, 797-805, 2003.06, We previously reported synergistic induction of apoptosis by IFN-γ plus either cyclosporin A (CsA) or tacrolimus (FK506) in gastric carcinoma cells. In this study, we aimed to elucidate the mechanism for this synergistic induction of apoptosis. IFN-γ plus CsA synergistically induced caspase-3 mediated apoptosis in gastric carcinoma cells. Although IFN-γ induced activation of signal transducer and activator of transcription1 (STAT1) and expression of interferon regulatory factor-1 (IRF-1) mRNA, IFN-γ alone was not able to induce caspase-3 activation and apoptosis. When gastric carcinoma cells were treated with cyclohexamide, a protein synthesis inhibitor, following IFN-γ pretreatment, caspase-3 was activated, and apoptosis was markedly induced. These findings suggest the existence of IFN-γ-induced anti-apoptotic pathway and we evaluated the effect of IFN-γ and CsA on calcium-sensitive nuclear factor-κB (NF-κB) activation. IFN-γ increased intracellular calcium ion concentration ([Ca2+]i) consisting of a spike and a sustained phase, and the latter was completely abrogated by CsA. Activation of NF-κB occurred in response to IFN-γ, and which was markedly inhibited by either CsA or FK506. NF-κB decoy also enhanced the cytotoxic effect of IFN-γ. These results suggest that IFN-γ may simultaneously induce the STAT1-mediated apoptotic pathway and the anti-apoptotic pathway through calcium-activated NF-κB and that inhibition of the latter by CsA may result in dominance of the apoptosis-inducing pathway. © 2003 Elsevier Science (USA). All rights reserved..
110. Ihara E, Hirano K, Hirano M, Nishimura J, Nawata H, Kanaide H, Mechanism of down-regulation of L-type Ca2+ channel in the proliferating smooth muscle cells of rat aorta. , J Cell Biochem, 10.1002/jcb.10295, 87, 2, 242-251, 2002.07.
111. Eikichi Ihara, Dmitry N. Derkach, Katsuya Hirano, Junji Nishimura, Hajime Nawata, Hideo Kanaide, Ca2+ influx in the endothelial cells is required for the bradykinin-induced endothelium-dependent contraction in the porcine interlobar renal artery, Journal of Physiology, 10.1111/j.1469-7793.2001.t01-1-00701.x, 534, 3, 701-711, 2001.08, 1. To determine the mechanism of bradykinin-induced production of endothelium-derived contracting factors, we monitored the changes in cytosolic Ca2+ concentration ([Ca2+]i) in in situ endothelial cells in porcine aortic valvular strips and the changes in [Ca2+]i of smooth muscle cells and force in porcine interlobar renal arterial strips using front-surface fluorometry of fura-2. 2. In the presence of Nω-nitro-L-arginine methyl ester, bradykinin caused an endothelium-dependent transient elevation of [Ca2+]i and contraction in smooth muscle in the interlobar renal artery. This contraction was completely inhibited by a prostaglandin H2/thromboxane A2 receptor antagonist. 3. In the absence of extracellular Ca2+, bradykinin failed to induce contraction. However, replenishing extracellular Ca2+ to 0.75 mM and higher induced an instantaneous contraction. However, replenishing Ca2+ per se did not induce any contraction in the absence of bradykinin. Pretreatment with either 10-5 M 1-(β-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenethyl)-1H-imidazole hydrochloride (SKF96365) or 0.2 mM Ni2+ abolished the contraction induced by bradykinin in the presence of extracellular Ca2+. 4. Treatment with 10-5 M indomethacin completely inhibited the contractile response induced by Ca2+ replenishment, regardless of the timing of its application, before or after the application of bradykinin. 5. In endothelial cells in the valvular strips, bradykinin caused a transient [Ca2+]i elevation in the presence of 1.25 mM extracellular Ca2+, but [Ca2+]i returned to the resting level within 10 min. Neither 10-5 M SKF96365 nor 0.2mM Ni2+ had any effect on the peak [Ca2+]i elevation, but decreased [Ca2+]i in the declining phase. In the absence of extracellular Ca2+, bradykinin induced a transient [Ca2+]i elevation to a level similar to that seen in the presence of 1.25 mM extracellular Ca2+. However, [Ca2+]i then rapidly returned to the prestimulation level within 5 min. Subsequent Ca2+ replenishment to 0.75 mM and higher in the presence of bradykinin elevated [Ca2+]i to significantly higher levels than the resting level seen in the media containing 1.25 mM Ca2+. 6. In conclusion, Ca2+ influx in the endothelial cells is essential for bradykinin to induce endothelium-dependent contraction in the porcine interlobar renal artery..
112. Ihara E, Hirano K, Derkach DN, Nishimura J, Nawata H, Kanaide H, The mechanism of bradykinin-induced endothelium-dependent contraction and relaxation in the porcine interlobar renal artery. , Br J Pharmacol, 10.1038/sj.bjp.0703141, 129, 5, 943-952, 2000.07.
113. Derkach DN, Ihara E, Hirano K, Nishimura J, Takahashi S, Kanaide H, Thrombin causes endothelium-dependent biphasic regulation of vascular tone in the porcine renal interlobar artery. , Br J Pharmacol 2000;131, 10.1038/sj.bjp.0703737, 131, 8, 1635-1642, 2000.07.
114. Morisaki T, Matsunaga H, Beppu K, Ihara E, Hirano K, Kanaide H, Mori M, Katano M, A combination of cyclosporin-A (CsA) and interferon-gamma (INF-γ) induces apoptosis in human gastric carcinoma cells. , Anticancer Res, 20, 5B, 3363-3373, 2000.07.
115. Ihara E, Hirano K, Nishimura J, Nawata H, Kanaide H, Thapsigargin-induced endothelium-dependent triphasic regulation of vascular tone in the porcine renal artery. , Br J Pharmacol, 10.1038/sj.bjp.0702821, 128, 3, 689-699, 1999.07.