研究者詳細 - 金井　隆典

論文 - 金井　隆典

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Management of perforation related to endoscopic submucosal dissection for superficial duodenal epithelial tumors

Fukuhara S., Kato M., Iwasaki E., Sasaki M., Tsutsumi K., Kiguchi Y., Akimoto T., Takatori Y., Nakayama A., Maehata T., Minami K., Ogata H., Kanai T., Yahagi N.

Gastrointestinal Endoscopy （Gastrointestinal Endoscopy） 91 （ 5 ） 1129 - 1137 2019年

ISSN 00165107

© 2019 American Society for Gastrointestinal Endoscopy Background and Aims: Endoscopic submucosal dissection (ESD) is being performed more frequently as a local treatment for superficial duodenal epithelial tumors (SDETs). However, ESD for SDETs is technically difficult because of specific anatomic features that increase the risk of perforation and often require surgery. This study was performed to evaluate the management of ESD-related perforation in patients with SDETs. Methods: Patients who underwent ESD for SDETs from July 2010 to December 2018 were studied. We collected data on complete closure, insertion of endoscopic nasobiliary and pancreatic duct drainage (ENBPD) tubes, and additional interventions. We also evaluated clinical outcomes, including the fasting period, hospital stay, and maximum serum C-reactive protein level. Results: ESD was completed in 264 patients with SDETs. Perforation was observed in 36 patients, including 4 patients with delayed perforation. Among 32 patients with intraoperative perforation, complete closure was achieved in 13 patients. Compared with patients without complete closure, the fasting period and hospital stay were significantly shorter and the maximum serum C-reactive protein level was significantly lower in patients with complete closure, which were equivalent to those in patients without perforation. In patients without complete closure for mucosal defect, no additional interventions were required when an ENBPD tube was inserted, whereas 2 patients without ENBPD tube insertion underwent additional interventions such as percutaneous drainage and a surgical operation. Conclusions: Perforation associated with ESD for SDETs required complex conservative management with complete closure or insertion of an ENBPD tube.

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Late-onset visceral varicella-zoster virus infection presented as acute liver failure after allogeneic hematopoietic stem cell transplantation

Kikuchi T., Arai M., Koda Y., Kato J., Shimizu T., Katano H., Fujii-Nishimura Y., Sakamoto M., Ebinuma H., Nakamoto N., Kanai T., Okamoto S., Mori T.

Transplant Infectious Disease （Transplant Infectious Disease） 21 （ 4 ） 2019年

ISSN 13982273

© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Although much less common than localized zoster, initial presentation of varicella-zoster virus (VZV) as visceral infection can occur especially after allogeneic hematopoietic stem cell transplantation (HSCT). We herein report a case of post-transplant visceral VZV infection presenting as fatal acute liver failure. It developed 4 years after allogeneic HSCT when a long-term prophylactic anti-VZV agent administration was discontinued. VZV should be listed as a causative pathogen of acute liver failure even years after allogeneic HSCT. Indication for, and duration of anti-VZV prophylaxis should be further investigated.

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Indigo naturalis is effective even in treatment-refractory patients with ulcerative colitis: a post hoc analysis from the INDIGO study

Naganuma M., Sugimoto S., Fukuda T., Mitsuyama K., Kobayashi T., Yoshimura N., Ohi H., Tanaka S., Andoh A., Ohmiya N., Saigusa K., Yamamoto T., Morohoshi Y., Ichikawa H., Matsuoka K., Hisamatsu T., Watanabe K., Mizuno S., Abe T., Suzuki Y., Kanai T., Naganuma M., Nakazato Y., Teratani T., Ogata H., Iwao Y., Yamasaki H., Toyonaga T., Nakano M., Hibi T., Sameshima Y., Hayashi R., Ueno Y., Bamba S., Watanabe M., Nakazawa A., Koike Y., Imai J., Shimoyama T., Takeuchi K., Nagasaka M., Kitano A., Ashizuka S., Inatsu H., Onodera K., Nakase H., Kitamura K., Ikeya K., Hanai H., Watanabe C., Hokari R., Hirai F., Naito Y., Hoshi N., Kinjo F., Ishiguro Y., Sasaki M., Matsumoto T., Sano F., Roberts R., Suda W., Hattori M., Fukuda S., Hirayama A.

Journal of Gastroenterology （Journal of Gastroenterology） 55 （ 2 ） 169 - 180 2019年

ISSN 09441174

© 2019, Japanese Society of Gastroenterology. Background: We recently reported the efficacy of indigo naturalis (IN) in patients with active ulcerative colitis (UC) in a randomized controlled trial (INDIGO study). However, few studies have been conducted to investigate whether IN is effective even in treatment-refractory cases, such as in those with steroid dependency and anti-TNF refractoriness. Methods: In the INDIGO study, 86 patients with active UC were randomly assigned to an IN group (0.5–2.0 g daily) or placebo group. The rate of clinical response (CR), mucosal healing (MH), and change in fecal calprotectin (FCP) levels was compared between refractory [patients with steroid-dependent disease, previous use of anti-TNF-α, and concomitant use of immunomodulators (IM)] and non-refractory patients. We also analyzed factors predicting CR and MH at week 8. Results: The rates of CR of IN group were significantly higher than placebo group, even in patients with steroid-dependent disease (p < 0.001), previous use of anti-TNF-α (p = 0.002), and concomitant use of IM (p = 0.013). The rates of MH in IN group were significantly higher than in placebo group in patients with steroid-dependent disease (p = 0.009). In the IN group, median FCP levels, at week 8, were significantly lower than baseline in patients with steroid-dependent disease and patients with the previous use of anti-TNF-α (p < 0.001, respectively). Multivariate analysis indicated that the previous use of anti-TNF-α was not a predictive factor for CR and MH at week 8. Conclusions: In a sub-analysis of data from a randomized placebo-controlled trial, we found that IN may be useful even in patients with steroid-dependent disease and patients with the previous use of anti-TNF-α.

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Impact of electrical pulse cut mode during endoscopic papillectomy: Pilot randomized clinical trial

Iwasaki E., Minami K., Itoi T., Yamamoto K., Tsuji S., Sofuni A., Tsuchiya T., Tanaka R., Tonozuka R., Machida Y., Takimoto Y., Tamagawa H., Katayama T., Kawasaki S., Seino T., Horibe M., Fukuhara S., Kitago M., Ogata H., Kanai T.

Digestive Endoscopy （Digestive Endoscopy） 32 （ 1 ） 127 - 135 2019年

ISSN 09155635

© 2019 Japan Gastroenterological Endoscopy Society Objective: Endoscopic papillectomy is increasingly being used for ampullary adenoma treatment. However, it remains challenging despite increased safety with treatment advances. The ideal power output and electrosurgical current mode for mucosal resection are not established. We aimed to identify the ideal electrical pulse for use during resection. Methods: This pilot randomized, single-blind, prospective, multicenter trial, recruited patients with ampullary adenomas and conventional anatomy who were scheduled to undergo endoscopic papillectomy. Endoscopic treatment was performed using a standardized algorithm and patients were randomized for endoscopic papillectomy with Endocut or Autocut. The primary outcome was the incidence of delayed bleeding. Incidence of procedure-related pancreatitis, successful complete resection, pathological findings, and other adverse events were secondary endpoints. Results: Sixty patients were enrolled over a 2-year period. The incidences of delayed bleeding (13.3% vs. 16.7%, P = 1.00) and pancreatitis (27% vs. 30%, P = 0.77) were similar between both groups. The rate of crush artifacts was higher in the Endocut than in the Autocut group (27% vs. 3.3%, P = 0.03). Immediate bleeding when resecting tumors greater than 14 mm in diameter was more common in the Autocut than in the Endocut group (88% vs. 46%, P = 0.04). Conclusions: The Autocut and Endocut modes have similar efficacy and safety for endoscopic papillectomy. The Endocut mode may prevent immediate bleeding in cases with large tumor sizes, although it causes more frequent crush artifacts. Registry and the registration number: The Japanese UMIN Clinical Trials Registry (UMIN-CTR: 000021382).

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How I do it: Endoscopic diagnosis for superficial non-ampullary duodenal epithelial tumors

Nakayama A., Kato M., Takatori Y., Shimoda M., Mizutani M., Tsutsumi K., Kiguchi Y., Akimoto T., Sasaki M., Mutaguchi M., Takabayashi K., Maehata T., Ochiai Y., Kanai T., Yahagi N.

Digestive Endoscopy （Digestive Endoscopy） 32 （ 3 ） 417 - 424 2019年

ISSN 09155635

© 2019 Japan Gastroenterological Endoscopy Society There are no reports on detailed endoscopic diagnosis of superficial non-ampullary duodenal epithelial tumors (SNADET) except for relatively small case series. Herein, we conducted a prospective observational study to investigate the relationship between endoscopic findings and histopathological diagnosis of SNADET. A total of 163 SNADET diagnosed using magnified endoscopic examination with image-enhanced endoscopy (IEE-ME) were prospectively registered in this study. We investigated location, size, macroscopic type, color, and IEE-ME findings including surface structure (closed- or open-loop) and presence of white opaque substance (WOS) in SNADET. We analyzed association between these findings and histopathological diagnosis of SNADET based on the Vienna classification (VCL) using logistic regression analysis. In univariate analysis, lesion size, superficial structure, and WOS deposition showed statistical significance, and the oral side of the lesion location showed statistical tendency for association with VCL C4/5. In multivariate analysis, lesion size (odds ratio [OR], 2.92; 95% CI, 1.94–4.39; P < 0.05) and negative WOS (OR, 5.59; 95% CI, 1.72–18.1; P < 0.05) were significantly associated with VCL C4/5 lesions. Superficial structures with a closed-loop pattern on the surface showed statistical tendency for predicting VCL C4/5 lesions (OR, 2.15; 95% CI, 0.86–5.37; P = 0.10). Based on these findings, we concluded that negative WOS by IEE-ME and lesion size were independent predictors of VCL C4/5 SNADET. These factors may help us to understand of pathophysiology of SNADET and to select appropriate therapeutic strategies.

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Feasibility study comparing underwater endoscopic mucosal resection and conventional endoscopic mucosal resection for superficial non-ampullary duodenal epithelial tumor < 20 mm

Kiguchi Y., Kato M., Nakayama A., Sasaki M., Mizutani M., Tsutsumi K., Akimoto T., Takatori Y., Mutaguchi M., Takabayashi K., Ochiai Y., Maehata T., Kanai T., Yahagi N.

Digestive Endoscopy （Digestive Endoscopy） 32 （ 5 ） 753 - 760 2019年

ISSN 09155635

© 2019 Japan Gastroenterological Endoscopy Society Background and Aim: Underwater endoscopic mucosal resection (UEMR) has been reported as an alternative to conventional EMR for superficial non-ampullary duodenal epithelial tumors (SNADET). However, the detailed outcomes are unclear. This study aimed to compare the clinical outcomes between UEMR and EMR for SNADET <20 mm. Patients and methods: This is a retrospective observational study using a prospective maintained database. From November 2017 to December 2018, 104 consecutive cases of attempted UEMR for SNADET <20 mm were prospectively allocated. A total of 240 cases of attempted EMR were chosen as historical controls. We compared technical success rate, defined as the resection rate without conversion to ESD; en bloc resection rate; R0 resection rate; and adverse event rate. Next, multivariate analyses were constructed to identify predictors of conversion to ESD, piecemeal resection, and RX or R1 (RX/R1) resection. Results: Technical success rate of UEMR was significantly higher than that of EMR (87% and 70%, P < 0.01). En bloc resection and R0 resection rates of UEMR were significantly lower than those of EMR (en bloc resection: 87% vs 96%, P < 0.01; R0 resection: 67% vs 80%, P = 0.05). Concerning adverse events, there were no significant differences. In multivariate analyses, attempted EMR, lesion size and depressed type were independent predictors of conversion to ESD. Attempted UEMR was an independent predictor of piecemeal resection and RX/R1 resection. Conclusion: The present study indicated that UEMR could be a feasible endoscopic resection method for SNADET (UMIN000025442).

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Electric endocut and autocut resection for endoscopic papillectomy: A systematic review

Minami K., Iwasaki E., Fukuhara S., Horibe M., Seino T., Kawasaki S., Katayama T., Takimoto Y., Tamagawa H., MacHida Y., Kanai T., Itoi T.

Internal Medicine （Internal Medicine） 58 （ 19 ） 2767 - 2772 2019年

ISSN 09182918

© 2019 The Japanese Society of Internal Medicine. Objective Risks of bleeding and pancreatitis after mucosal resection using the purecut/autocut and blendcut/ endocut modes for endoscopic papillectomy have not been fully clarified. Thus, a systematic review on electrosurgical cutting modes for endoscopic papillectomy was conducted focusing on the types and incidence of adverse events. Methods We searched the PubMed and Cochrane library for cases of endoscopic papillectomy recorded as of April 2017. Studies reporting the methods of electrically excising a tumor in the duodenal papilla and the number of adverse events were extracted. Studies were collected and examined separately based on the electrosurgical cutting mode, and the incidence rate for each adverse event was summarized. Results A total of 159 relevant articles were found; among them, 20 studies were included and 139 excluded. Five studies analyzed endoscopic papillectomy with the purecut/autocut mode and 16 with the blendcut/ endocut mode. Only one study investigated both modes (purecut and endocut). With the purecut/autocut mode, the incidence of bleeding was 2.8-50%, and that of pancreatitis was 0-50% (mean: 12.8%). With the blendcut/endocut mode, the incidence of bleeding was 0-42.3%, and that of pancreatitis was 0%-17.9% (mean: 9.5%). Conclusion Both methods had high adverse event rates for endoscopic papillectomy. Thus, a standard method of endoscopic papillectomy, including the electrosurgical cutting mode, needs to be established.

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Current knowledge of irritable bowel syndrome-treatment

Masaoka T., Kanai T.

Journal of Japanese Society of Gastroenterology （Journal of Japanese Society of Gastroenterology） 116 （ 7 ） 570 - 575 2019年

ISSN 04466586

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10-Year Trends in Helicobacter pylori Eradication Rates by Sitafloxacin-Based Third-Line Rescue Therapy

Mori H., Suzuki H., Matsuzaki J., Masaoka T., Kanai T.

Digestion （Digestion） 101 （ 5 ） 644 - 650 2019年

ISSN 00122823

© 2019 S. Karger AG, Basel. All rights reserved. Background/Aims: Sitafloxacin (STFX)-containing regimens were shown to be useful options for third-line Helicobacter pylori eradication therapy. It is reported that resistance to quinolone is also increasing globally. Therefore, we conducted an analysis of the current efficacy of a 10-day-STFX-containing third-line rescue therapy and the changes of antibiotic resistance to H. pylori compared to 2 historical controls. Methods: Patients in whom eradication treatment using both first-and second-line triple therapies failed were enrolled from 2014 to 2015. The minimum inhibitory concentrations of STFX, clarithromycin (CLR), amoxicillin (AMX), metronidazole (MTZ) and the gyrA mutation status of the H. pylori strains were determined before treatment. After that, the patients received a 10-day triple therapy containing esomeprazole (20 mg, b.i.d.), AMX (500 mg, q.i.d.) and STFX (100 mg, b.i.d.; 10-day EAS). The eradication rate and the rate of antibiotic resistance to H. pylori were compared with 2 previous reports about STFX-containing third-line rescue therapies in 2009-2011 and 2012-2013. To explore the association between the eradication rates of regimens containing STFX, AMX and proton pump inhibitors and the location of gyrA mutation or AMX resistance, a meta-analysis was attempted. Results: The overall eradication rates, the eradication rate for gyrA mutation negative-and positive-strains were 81.6% (31/38), 94.7% (18/19) and 68.4% (13/19) respectively. These rates were not significantly different from 2 previous reports. The resistant rates to STFX, CLR, AMX, MTZ and the rate of presence of mutation in gyrA were 50.0, 81.6, 36.8, 78.9 and 50.0%, respectively, which was also not significantly different from 2 previous reports. A meta-analysis showed that the relative risk of the eradication failure is significantly lower in gyrA mutation negative strains compared to gyrA mutation positive strains, and that the relative risk of the eradication failure is significantly lower in gyrA mutation at D91 compared to gyrA mutation at N87 (p < 0.001 and p = 0.022, respectively). Moreover, a meta-analysis showed that the relative risk of the eradication failure is significantly lower in AMX-sensitive strains compared to AMX-resistant ones. Conclusion: Changes in the rate of antibiotic resistance to H. pylori were not observed from 2009 to 2015. The status of gyrA mutation is a superior marker for predicting successful eradication in STFX/AMX-containing triple regimen as a third-line rescue therapy.

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Inhibiting xCT improves 5-fluorouracil resistance of gastric cancer induced by CD44 variant 9 expression

Miyoshi S., Tsugawa H., Matsuzaki J., Hirata K., Mori H., Saya H., Kanai T., Suzuki H.

Anticancer Research （Anticancer Research） 38 （ 11 ） 6163 - 6170 2018年11月

ISSN 02507005

© 2018 International Institute of Anticancer Research.All right reserved. Background/Aim: Cancer stem cells (CSCs) play a critical role in resistance to chemotherapy. CD44 is a cell surface marker of CSCs. CD44 variant 9 (CD44v9) interacts with a cystine-glutamate antiporter (xCT) and is an unfavorable predictive factor in gastric cancer. We investigated the impact of CD44v9 expression on 5-fluorouracil (5-FU) resistance and the efficacy of the xCT inhibitor, sulfasalazine (SASP), in improving drug resistance. Materials and Methods: The human gastric cancer cell line MKN28 was transfected with pRc/CMV plasmids encoding human CD44 or CD44v9, which were used for in vitro and in vivo experiments. Results: CD44v9 expression results in 5-FU resistance by increasing intracellular glutathione and suppressing the drug-induced production of reactive oxygen species (ROS). SASP improved the drug sensitivity of CD44v9-expressing cells. Conclusion: Inhibition of xCT improved the clinical efficacy of chemotherapy against gastric cancer. CD44v9 expression can be a novel biomarker to predict resistance against 5-FU in gastric cancer.

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Pethidine dose and female sex as risk factors for nausea after esophagogastroduodenoscopy

Nishizawa T., Suzuki H., Arita M., Kataoka Y., Fukagawa K., Ohki D., Hata K., Uraoka T., Kanai T., Yahagi N., Toyoshima O.

Journal of Clinical Biochemistry and Nutrition （Journal of Clinical Biochemistry and Nutrition） 63 （ 3 ） 230 - 232 2018年11月

ISSN 09120009

© 2018 JCBN. Nausea and vomiting after esophagogastroduodenoscopy have not been studied in detail. The aim of this study was to evaluate the risk factors for post-endoscopic nausea. We performed a case-control study at the Toyoshima Endoscopy Clinic. Eighteen patients with post-endoscopic nausea and 190 controls without post-endoscopic nausea were analyzed. We conducted univariate and multivariate logistic regression analyses with respect to patient age; sex; body height; body weight; the use of psychotropic drugs as baseline medications; and the dosing amounts of midazolam, pethidine, flumazenil and naloxone. On univariate analysis, post-endoscopic nausea was significantly related with patient age (odds ratio = 0.946); female sex (odds ratio = 10.85); body weight (odds ratio = 0.975); and the dose per kg body weight of pethidine (odds ratio = 53.03), naloxone (odds ratio = 1.676), and flumazenil (odds ratio = 1.26). On multivariate analysis, the dose per kg body weight of pethidine (odds ratio = 21.67, p = 0.004) and female sex (odds ratio = 13.12, p = 0.047) were the factors independently associated with post-endoscopic nausea. The prevalence of nausea after esophagogastroduodenoscopy was 0.49% (18/3, 654). In conclusion, post-endoscopic nausea was associated with the dose of pethidine and female sex.

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5-Aminosalicylic acid aggravates colitis mimicking exacerbation of ulcerative colitis

Miyoshi J., Matsuoka K., Yoshida A., Naganuma M., Hisamatsu T., Yajima T., Inoue N., Okamoto S., Iwao Y., Ogata H., Ueno F., Hibi T., Kanai T.

Intestinal Research （Intestinal Research） 16 （ 4 ） 635 - 640 2018年10月

ISSN 15989100

© 2018. Korean Association for the Study of Intestinal Diseases. Ulcerative colitis (UC) is one of the major clinical phenotypes of inflammatory bowel diseases. Although 5-aminosalicylic acid (5-ASA) is widely used for UC and its efficacy and safety have been demonstrated, a few patients paradoxically develop a severe exacerbation of colitis by 5-ASA administration. It is crucial to know clinical features including endoscopic findings in this condition for making a correct diagnosis and a prompt decision to withdraw the medication. Here, we report case series with UC exacerbated by 5-ASA. Medical records of 8 UC patients experiencing an exacerbation of colitis after induction of 5-ASA that was improved by the withdrawal of 5-ASA but also re-aggravated by dose increase or re-administration of 5-ASA were reviewed. The patients were newly diagnosed with UC, started 5-ASA and developed an exacerbation in approximately 2 to 3 weeks. They did not appear to have systemic allergic reactions. Seven of the 8 patients had a high fever. Three of 5 patients who undertook total colonoscopy showed right-side-dominant colitis. These findings suggest clinical characteristics in this condition. Further assessment of clinical and endoscopic features in more cases is necessary for establishing diagnostic criteria and understanding underlying mechanisms in those cases where 5-ASA aggravates the colitis.

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Clarithromycin expands CD11b<sup>+</sup>Gr-1<sup>+</sup>cells via the STAT3/Bv8 axis to ameliorate lethal endotoxic shock and post-influenza bacterial pneumonia

Namkoong H., Ishii M., Fujii H., Yagi K., Asami T., Asakura T., Suzuki S., Hegab A., Kamata H., Tasaka S., Atarashi K., Nakamoto N., Iwata S., Honda K., Kanai T., Hasegawa N., Koyasu S., Betsuyaku T.

PLoS Pathogens （PLoS Pathogens） 14 （ 4 ） 2018年04月

ISSN 15537366

© 2018 Namkoong et al. Macrolides are used to treat various inflammatory diseases owing to their immunomodulatory properties; however, little is known about their precise mechanism of action. In this study, we investigated the functional significance of the expansion of myeloid-derived suppressor cell (MDSC)-like CD11b+Gr-1+cells in response to the macrolide antibiotic clarithromycin (CAM) in mouse models of shock and post-influenza pneumococcal pneumonia as well as in humans. Intraperitoneal administration of CAM markedly expanded splenic and lung CD11b+Gr-1+cell populations in naïve mice. Notably, CAM pretreatment enhanced survival in a mouse model of lipopolysaccharide (LPS)-induced shock. In addition, adoptive transfer of CAM-treated CD11b+Gr-1+cells protected mice against LPS-induced lethality via increased IL-10 expression. CAM also improved survival in post-influenza, CAM-resistant pneumococcal pneumonia, with improved lung pathology as well as decreased interferon (IFN)-γ and increased IL-10 levels. Adoptive transfer of CAM-treated CD11b+Gr-1+cells protected mice from post-influenza pneumococcal pneumonia. Further analysis revealed that the CAM-induced CD11b+Gr-1+cell expansion was dependent on STAT3-mediated Bv8 production and may be facilitated by the presence of gut commensal microbiota. Lastly, an analysis of peripheral blood obtained from healthy volunteers following oral CAM administration showed a trend toward the expansion of human MDSC-like cells (Lineage−HLA-DR−CD11b+CD33+) with increased arginase 1 mRNA expression. Thus, CAM promoted the expansion of a unique population of immunosuppressive CD11b+Gr-1+cells essential for the immunomodulatory properties of macrolides.

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Evidence-based clinical practice guidelines for inflammatory bowel disease

Matsuoka K., Kobayashi T., Ueno F., Matsui T., Hirai F., Inoue N., Kato J., Kobayashi K., Kobayashi K., Koganei K., Kunisaki R., Motoya S., Nagahori M., Nakase H., Omata F., Saruta M., Watanabe T., Tanaka T., Kanai T., Noguchi Y., Takahashi K., Watanabe K., Hibi T., Suzuki Y., Watanabe M., Sugano K., Shimosegawa T.

Journal of Gastroenterology （Journal of Gastroenterology） 53 （ 3 ） 305 - 353 2018年03月

ISSN 09441174

© 2018, The Author(s). Inflammatory bowel disease (IBD) is a chronic disorder involving mainly the intestinal tract, but possibly other gastrointestinal and extraintestinal organs. Although etiology is still uncertain, recent knowledge in pathogenesis has accumulated, and novel diagnostic and therapeutic modalities have become available for clinical use. Therefore, the previous guidelines were urged to be updated. In 2016, the Japanese Society of Gastroenterology revised the previous versions of evidence-based clinical practice guidelines for ulcerative colitis (UC) and Crohn’s disease (CD) in Japanese. A total of 59 clinical questions for 9 categories (1. clinical features of IBD; 2. diagnosis; 3. general consideration in treatment; 4. therapeutic interventions for IBD; 5. treatment of UC; 6. treatment of CD; 7. extraintestinal complications; 8. cancer surveillance; 9. IBD in special situation) were selected, and a literature search was performed for the clinical questions with use of the MEDLINE, Cochrane, and Igaku Chuo Zasshi databases. The guidelines were developed with the basic concept of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Recommendations were made using Delphi rounds. This English version was produced and edited based on the existing updated guidelines in Japanese.

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Factors predicting the therapeutic response to infliximab during maintenance therapy in Japanese patients with Crohn's disease

金井隆典

PLoS ONE （PLoS ONE） 13 （ 10 ） 2018年

© 2018 Hsieh et al. Since anti-tumor necrosis factor (TNF)-α agents (TNF-α inhibitors) induce both clinical response and remission in patients with moderate to severe inflammatory bowel disease (IBD), the use of anti-TNF therapies has fundamentally changed the approach to treatment for patients with IBD. Infliximab (IFX) is a TNF-α inhibitor approved for the induction and remission of Crohn's disease (CD). However, even among patients who initially demonstrate a clinical response to IFX therapy, secondary loss of response occurs, although the reason remains unknown. We therefore investigated predictive factors associated with the response to IFX in long-term maintenance treatment in Japanese CD patients. Eight types of single-nucleotide polymorphisms (SNPs) were investigated using the real-time PCR method, and patient characteristics were collected from the electronic medical records. The Crohn's Disease Activity Index criteria were used as the response to IFX therapy. The observation period was 1 year after IFX had been administered for more than 1 year. Associations between the IFX response and patient characteristics were evaluated using the multivariate logistic regression model. We studied 121 unrelated adult Japanese with CD treated for more than 1 year with IFX as outpatients at Keio University Hospital from November 1, 2014 to November 30, 2015. Among them, 71 were classified as in remisson. In multivariate analysis, patients with the TNF-α 857C>T C/C genotype, shorter disease duration, without double dosing, and combination treatment with an immunomodulator had higher remisson rates than those with the C/T or T/T genotype, longer disease duration, with double dosing, and no combination treatment with an immunomodulator. The response to IFX in Japanese CD patients may therefore be predicted by these 4 characteristics in actual clinical practice.

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Reconstruction of the Human Colon Epithelium In Vivo

金井隆典

Cell Stem Cell （Cell Stem Cell） 22 （ 2 ） 171 - 176.e5 2018年

ISSN 19345909

© 2017 Elsevier Inc. Genetic lineage tracing has revealed that Lgr5 + murine colon stem cells (CoSCs) rapidly proliferate at the crypt bottom. However, the spatiotemporal dynamics of human CoSCs in vivo have remained experimentally intractable. Here we established an orthotopic xenograft system for normal human colon organoids, enabling stable reconstruction of the human colon epithelium in vivo. Xenografted organoids were prone to displacement by the remaining murine crypts, and this could be overcome by complete removal of the mouse epithelium. Xenografted organoids formed crypt structures distinctively different from surrounding mouse crypts, reflecting their human origin. Lineage tracing using CRISPR-Cas9 to engineer an LGR5-CreER knockin allele demonstrated self-renewal and multipotency of LGR5 + CoSCs. In contrast to the rapidly cycling properties of mouse Lgr5 + CoSCs, human LGR5 + CoSCs were slow-cycling in vivo. This organoid-based orthotopic xenograft model enables investigation of the functional behaviors of human CoSCs in vivo, with potential therapeutic applications in regenerative medicine. Sugimoto et al. established an orthotopic xenotransplantation system for human normal colon organoids. Using LGR5-CreER knockin organoids for genetic lineage tracing, they demonstrated the self-renewal and multipotency of LGR5 + colon stem cells in mouse colon. Interestingly, human LGR5 + colon stem cells showed slower cycling than those of mice in vivo.

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Human Pancreatic Tumor Organoids Reveal Loss of Stem Cell Niche Factor Dependence during Disease Progression

金井隆典

Cell Stem Cell （Cell Stem Cell） 22 （ 3 ） 454 - 467.e6 2018年

ISSN 19345909

© 2017 Elsevier Inc. Despite recent efforts to dissect the inter-tumor heterogeneity of pancreatic ductal adenocarcinoma (PDAC) by determining prognosis-predictive gene expression signatures for specific subtypes, their functional differences remain elusive. Here, we established a pancreatic tumor organoid library encompassing 39 patient-derived PDACs and identified 3 functional subtypes based on their stem cell niche factor dependencies on Wnt and R-spondin. A Wnt-non-producing subtype required Wnt from cancer-associated fibroblasts, whereas a Wnt-producing subtype autonomously secreted Wnt ligands and an R-spondin-independent subtype grew in the absence of Wnt and R-spondin. Transcriptome analysis of PDAC organoids revealed gene-expression signatures that associated Wnt niche subtypes with GATA6-dependent gene expression subtypes, which were functionally supported by genetic perturbation of GATA6. Furthermore, CRISPR-Cas9-based genome editing of PDAC driver genes (KRAS, CDKN2A, SMAD4, and TP53) demonstrated non-genetic acquisition of Wnt niche independence during pancreas tumorigenesis. Collectively, our results reveal functional heterogeneity of Wnt niche independency in PDAC that is non-genetically formed through tumor progression. Sato and colleagues established a library of patient-derived pancreas cancer organoids and identified heterogeneous patterns of dependency on Wnt ligands among pancreas cancers. Biological and genetic analyses highlighted GATA6 as a mediator of the Wnt niche requirement, which links pancreatic tumor progression to independence from the stem cell niche.

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Fecal microbiota transplantation for recurrent Clostridium difficile infection in a patient with ulcerative colitis

金井隆典

Intestinal Research （Intestinal Research） 16 （ 1 ） 142 - 146 2018年

ISSN 15989100

© 2018. Korean Association for the Study of Intestinal Diseases. Fecal microbiota transplantation (FMT) has been reported as a safe and effective therapy in patients with refractory and recurrent Clostridium difficile infection (CDI). FMT has also been reported as a promising therapy in patients with ulcerative colitis (UC). Both, CDI and UC, are believed to be caused by dysbiosis, such as altered compositions or decreased diversity of the intestinal microbiota. This report describes a patient with UC in remission with a second recurrent episode of CDI, who was treated with FMT. A single FMT performed via colonoscopy completely resolved the patient's diarrhea and eradicated C. difficile bacteriologically without any severe complications. Molecular biological analysis of the patient's fecal microbiota showed that FMT could dramatically change the altered composition of intestinal microbiota and restore its diversity. Despite the restoration of the intestinal microbiota, FMT could not prevent a relapse of UC in this patient. However, it improved the intestinal symptoms of CDI and could prevent further recurrences of CDI.

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Complications and outcomes of routine endoscopy in the very elderly.

金井隆典

Endosc Int Open 2018年

Efficacy of Bifidobacterium breve Fermented Milk in Maintaining Remission of Ulcerative Colitis

金井隆典

Digestive Diseases and Sciences （Digestive Diseases and Sciences） 63 （ 7 ） 1910 - 1919 2018年

ISSN 01632116

© 2018, The Author(s). Background: Fermented milk products containing Bifidobacterium breve strain Yakult (BFM) may improve clinical status in ulcerative colitis (UC) patients. Aims: To assess efficacy of BFM in maintaining remission in Japanese patients with quiescent UC. Methods: This double-blind study (B-FLORA) enrolled 195 patients with quiescent UC, randomized to receive one pack of BFM fermented milk per day [Bifidobacterium breve strain Yakult (10 billion bacteria) and Lactobacillus acidophilus (1 billion bacteria)] (n = 98) or matching placebo (n = 97) for 48 weeks. The primary efficacy endpoint was relapse-free survival (relapse: rectal bleeding score ≥ 2 on Sutherland disease activity index scale for 3 consecutive days and/or initiation of remission induction therapy for worsening of UC). Results: An interim analysis was conducted after inclusion and follow-up of one-third of patients for the first phase of the study (n = 195). Relapse-free survival was not significantly different between the BFM and placebo groups (P = 0.643; hazard ratio 1.16; 95% CI 0.63–2.14, log-rank test), nor was the incidence of relapse. Therefore, the study was discontinued for lack of efficacy. An exploratory analysis of fecal samples from a subgroup of patients revealed no effects of either study beverage on intestinal microbiota, but there was a significant decrease in Bifidobacterium species before relapse, regardless of treatment group. Three mild adverse events occurred for which a causal relationship with the study beverage could not be ruled out (placebo: abdominal bloating and stress in one patient; BFM: body odor in one patient). Conclusions: BFM had no effect on time to relapse in UC patients compared with placebo. Study Registration: UMIN000007593.

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金井　隆典

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