Details of a Researcher - Kanai, Takanori

Papers - Kanai, Takanori

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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

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

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

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

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

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

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

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

Hisamatsu T., Kato S., Kunisaki R., Matsuura M., Nagahori M., Motoya S., Esaki M., Fukata N., Inoue S., Sugaya T., Sakuraba H., Hirai F., Watanabe K., Kanai T., Naganuma M., Nakase H., Suzuki Y., Watanabe M., Hibi T., Nojima M., Matsumoto T., Endo K., Hanai H., Kobayashi T., Hiraoka S., Hisamatsu T., Honda Y., Inoue T., Inoue S., Ishida T., Ito H., Iwakiri R., Izumi M., Kagaya T., Kamata N., Naganawa Y., Kaneto H., Kani K., Kinjyo F., Yasaka H., Kurahara K., Kyouwon L., Yano Y., Matsui T., Tanaka H., Munemoto Y., Naito Y., Nakagawa T., Yokoyama Y., Nakamura S., Okazaki K., Ouchi S., Saruta M., Sasaki M., Takeshima F., Tamaki H., Tanaka S., Tanida S., Mizoshita T., Tominaga K., Yamashita M., Yoshida A., Yoshimura N.

Journal of Gastroenterology (Journal of Gastroenterology) 54 ( 10 ) 860 - 870 2019

ISSN 09441174

© 2019, Japanese Society of Gastroenterology. Background: The risk:benefit ratio of concomitant use of thiopurines with scheduled adalimumab (ADA) maintenance therapy for Crohn’s disease is controversial. The aim of this study is to identify the influence of withdrawal of thiopurines in patients in remission with combination therapy in an open-label, randomised, controlled trial (DIAMOND2; UMIN000009596). Methods: Patients in corticosteroid-free clinical remission (CFCR) for ≥ 6 months with ADA (40 mg, s.c., every other week) scheduled maintenance combined with thiopurines were randomised into two groups, “continue” (Con) or “discontinue” (Dis) group of thiopurines, whereas all other patients kept receiving scheduled ADA maintenance therapy for 52 weeks. The primary endpoint was the proportion of patients in CFCR at week 52. Secondary endpoints were endoscopic remission (ER), trough levels of ADA in serum, and safety. Results: Fifty patients were randomised to Con or Dis groups. Characteristics of patients were not significantly different between the groups. CFCR and ER prevalence at week 52 were not significantly different between groups (log rank, P = 0.704, P = 1.000, respectively). Trough levels of ADA were not significantly different between groups (P = 0.515). The proportion of patients with AAA positivity at week 52 was not significantly different (P = 0.437). ER at week 0 was involved in ER and triple remission at week 52. No serious adverse effects were observed in either group. Conclusion: Continuation of thiopurines > 6 months offers no clear benefit over scheduled ADA monotherapy. CFCR, ER, and ADA trough level at week 52 were not significantly different between groups. ER at week 0 may be involved in better long-term clinical outcomes.

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Toll-Like Receptor 7 Agonist–Induced Dermatitis Causes Severe Dextran Sulfate Sodium Colitis by Altering the Gut Microbiome and Immune Cells

Kiyohara H., Sujino T., Teratani T., Miyamoto K., Arai M., Nomura E., Harada Y., Aoki R., Koda Y., Mikami Y., Mizuno S., Naganuma M., Hisamatsu T., Kanai T.

Cellular and Molecular Gastroenterology and Hepatology (Cellular and Molecular Gastroenterology and Hepatology) 7 ( 1 ) 135 - 156 2019

© 2018 The Authors Background & Aims: Psoriasis and inflammatory bowel disease (IBD) are both chronic inflammatory diseases occurring in the skin and gut, respectively. It is well established that psoriasis and IBD have high concordance rates, and similar changes in immune cells and microbiome composition have been reported in both conditions. To study this connection, we used a combination murine model of psoriatic dermatitis and colitis in which mice were treated topically with the Toll-like receptor 7 agonist imiquimod (IMQ) and fed dextran sulfate sodium (DSS). Methods: We applied IMQ topically to B6 mice (IMQ mice) and subsequently fed them 2% DSS in their drinking water. Disease activity and immune cell phenotypes were analyzed, and the microbial composition of fecal samples was investigated using 16S ribosomal RNA sequencing. We transplanted feces from IMQ mice to germ-free IQI/Jic (IQI) mice and fed them DSS to assess the effect of the gut microbiome on disease. Results: We first confirmed that IMQ mice showed accelerated DSS colitis. IMQ mice had decreased numbers of IgD + and IgM + B cells and increased numbers of non–cytokine-producing macrophages in the gut. Moreover, the gut microbiomes of IMQ mice were perturbed, with significant reductions of Lactobacillus johnsonii and Lactobacillus reuteri populations. Germ-free mice transplanted with feces from IMQ mice, but not with feces from untreated mice, also developed exacerbated DSS colitis. Conclusions: These results suggest that skin inflammation may contribute to pathogenic conditions in the gut via immunologic and microbiological changes. Our finding of a novel potential skin–gut interaction provides new insights into the coincidence of psoriasis and IBD.

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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 2018.11

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 2018.11

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 2018.10

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 ) 2018.04

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 2018.03

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

KANAI Takanori

PLoS One (PLoS ONE) 13 ( 10 ) 2018

© 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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Future perspectives on fecal microbiota transplantation

KANAI Takanori

Nihon Shokakibyo Gakkai Zasshi (Journal of Japanese Society of Gastroenterology) 115 ( 5 ) 449 - 459 2018

ISSN 04466586

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Acquisition of double mutation in gyrA caused high resistance to sitafloxacin in Helicobacter pylori after unsuccessful eradication with sitafloxacin-containing regimens

KANAI Takanori

United European Gastroenterol J (United European Gastroenterology Journal) 6 ( 3 ) 391 - 397 2018

ISSN 20506406

© 2017, © Author(s) 2017. Background and aim: Although sitafloxacin (STFX)-containing regimens are effective rescue treatments for Helicobacter pylori infection, prevalence of fluoroquinolone resistance in H. pylori has increased rapidly worldwide. The change in resistance levels and gyrA mutations, a major cause of fluoroquinolone resistance, after unsuccessful STFX-containing treatment has not been investigated. Methods: We conducted a retrospective, non-randomized study to compare the minimum inhibitory concentrations (MICs) of STFX and the location of gyrA mutations in H. pylori before and after unsuccessful eradication with STFX-containing regimens at Keio University Hospital between December 2011 and March 2015. Results: A total of 266 patients treated with STFX-containing regimens for third-line H. pylori eradication were evaluated. Double mutations in gyrA were acquired by 20.8% of strains that exhibited seven-fold increased STFX MICs, compared to pre-treatment MICs. The STFX MICs did not increase, however, when the location of the gyrA mutations did not change after treatment. Double mutations in gyrA developed in 60.0% of the strains in which eradication failed, which exhibited a baseline mutation at position D91, and in 11.1% of strains with baseline mutations at position N87. Conclusion: Acquisition of double mutations in gyrA evoked high-level resistance to STFX in H. pylori after unsuccessful eradication with STFX-containing regimens.

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Burden of impaired sleep quality on work productivity in functional dyspepsia

KANAI Takanori

United European Gastroenterol J (United European Gastroenterology Journal) 6 ( 3 ) 398 - 406 2018

ISSN 20506406

© 2017, © Author(s) 2017. Background: Impaired sleep quality is common, and can reduce work productivity in patients with functional dyspepsia (FD). Objective: The objective of this article is to evaluate whether there is a direct association between the presence of FD and the severity of impaired sleep quality, and to calculate the economic loss due to the decreased work productivity associated with sleep quality. Methods: In Study 1, using a web-based survey completed by workers with and without FD, we evaluated impaired sleep quality, work and daily productivity, and the severity of reflux and bowel symptoms. In Study 2, the association between the presence of FD and the severity of impaired sleep quality was validated in a hospital-based cohort. Results: In both Study 1 and 2, although impaired sleep quality was more frequent in participants with FD than in those without FD, the independent association between the presence of FD and the severity of impaired sleep quality was not observed after adjustment for the severity of reflux and bowel symptoms. FD participants with impaired sleep quality reported additional economic loss of 53,500 Japanese yen/month. Conclusion: Although the association between impaired sleep quality and FD was indirect, concomitant impaired sleep quality could worsen economic loss.

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Establishment of a Novel Scoring System for Colon Capsule Endoscopy to Assess the Severity of Ulcerative Colitis-Capsule Scoring of Ulcerative Colitis

KANAI Takanori

Inflamm Bowel Dis (Inflammatory Bowel Diseases) 24 ( 12 ) 2641 - 2647 2018

ISSN 10780998

© 2018 Crohn's & Colitis Foundation. Published by Oxford University Press. All rights reserved. Background: The usefulness of second-generation colon capsule endoscopy (CCE-2) for ulcerative colitis (UC) has not been fully demonstrated. This study aimed to develop an endoscopic severity score of UC for CCE-2. Methods: Patients diagnosed with UC were enrolled prospectively and underwent colonoscopy and CCE-2 on the same day. The collected CCE-2 videos were adopted for the development of the score. These videos were scored by 4 blinded inflammatory bowel disease experts. The items validated with the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) were used as the candidate items, some of which were automatically assessed using the workstation. Each item was divided into proximal and distal parts at the splenic flexure and then individually assessed. The image readers simultaneously evaluated the inflammation severity using the visual analog scale (VAS). The descriptors that contribute to this scale were evaluated, and a model to predict the VAS was constructed. The UCEIS was scored by other endoscopists using colonoscopy videos. The correlation coefficients with fecal calprotectin, blood tests, and Lichtiger index were calculated. Results: The final scoring system was fixed as "vascular pattern sum (proximal + distal) + bleeding sum + erosions and ulcers sum (minimum- maximum, 0-14)" and was named Capsule Scoring of Ulcerative Colitis (CSUC). The correlation coefficient of CSUC with biomarkers and clinical score was similar to that of the UCEIS. Conclusions: We developed a new simple score using the 3 descriptors of CCE-2.

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Safety and efficacy of ultra-tapered mechanical dilator for EUS-guided hepaticogastrostomy and pancreatic duct drainage compared with electrocautery dilator (with video)

KANAI Takanori

Endosc Ultrasound (Endoscopic Ultrasound) 7 ( 6 ) 376 - 382 2018

ISSN 23039027

© 2018 SPRING MEDIA PUBLISHING CO. LTD Background and Objectives: Successful tract dilation is one of the most important steps to accomplish EUS-guided drainage. Although mechanical dilation is safer than electrocautery dilation, no dedicated mechanical dilator (MD) is currently available. Thus, we developed a new ultra-tapered MD for EUS-guided drainage. This study aimed to evaluate the safety and usefulness of this novel MD. Patients and Methods: Consecutive patients who underwent EUS-guided hepaticogastrostomy (EUS-HGS) or EUS-guided pancreatic duct drainage (EUS-PD) at two centers were included in the study. Dilation of the needle tract was initially performed with a diathermic sheath or the ultra-tapered MD. Technical success and adverse events were assessed. Results: Sixty-four patients (mean age = 68.9 ± 13.8 years, 35 men) underwent EUS-HGS (49 patients) and EUS-PD (15 patients). Thirty-three patients were included in the cautery dilator (CD) group and 31 in the ultra-tapered MD group. Initial dilation of the puncture site was achieved in 95.3% (61/64): 97% (32/33) of the patients in the CD group and 93.3% (29/31) of the patients in the MD group (P > 0.05). Adverse events were observed in 14 patients: abdominal pain in 8 patients and bleeding in 6 patients at the puncture site. All bleedings occurred in the CD group and there was no patient in whom bleeding occurred after EUS intervention in the MD group (P = 0.04). Conclusion: The novel ultra-tapered MD designed for interventional EUS appears to be safe and useful as it reduced postprocedure bleeding with a high technical success rate compared with the conventional electrocautery dilator.

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