Faculty Profiles - HIRAOKA Sakiko

Papers - HIRAOKA Sakiko

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

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

Journal of gastroenterology 56 ( 6 ) 489 - 526 2021.6

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1007/s00535-021-01784-1

Leucine-rich alpha-2 glycoprotein as a marker of mucosal healing in inflammatory bowel disease. International journal

Eriko Yasutomi, Toshihiro Inokuchi, Sakiko Hiraoka, Kensuke Takei, Shoko Igawa, Shumpei Yamamoto, Masayasu Ohmori, Shohei Oka, Yasushi Yamasaki, Hideaki Kinugasa, Masahiro Takahara, Keita Harada, Masaki Furukawa, Kouichi Itoshima, Ken Okada, Fumio Otsuka, Takehiro Tanaka, Toshiharu Mitsuhashi, Jun Kato, Hiroyuki Okada

Scientific reports 11 ( 1 ) 11086 - 11086 2021.5

Language：English Publishing type：Research paper (scientific journal)

Leucine-rich alpha-2 glycoprotein (LRG) may be a novel serum biomarker for patients with inflammatory bowel disease. The association of LRG with the endoscopic activity and predictability of mucosal healing (MH) was determined and compared with those of C-reactive protein (CRP) and fecal markers (fecal immunochemical test [FIT] and fecal calprotectin [Fcal]) in 166 ulcerative colitis (UC) and 56 Crohn's disease (CD) patients. In UC, LRG was correlated with the endoscopic activity and could predict MH, but the performance was not superior to that of fecal markers (areas under the curve [AUCs] for predicting MH: LRG: 0.61, CRP: 0.59, FIT: 0.75, and Fcal: 0.72). In CD, the performance of LRG was equivalent to that of CRP and Fcal (AUCs for predicting MH: LRG: 0.82, CRP: 0.82, FIT: 0.70, and Fcal: 0.88). LRG was able to discriminate patients with MH from those with endoscopic activity among UC and CD patients with normal CRP levels. LRG was associated with endoscopic activity and could predict MH in both UC and CD patients. It may be particularly useful in CD.

DOI： 10.1038/s41598-021-90441-x

Multicenter survey on mesalamine intolerance in patients with ulcerative colitis. International journal

Sakiko Hiraoka, Akiko Fujiwara, Tatsuya Toyokawa, Reiji Higashi, Yuki Moritou, Shinjiro Takagi, Kazuhiro Matsueda, Seiyuu Suzuki, Jiro Miyaike, Toshihiro Inokuchi, Masahiro Takahara, Jun Kato, Hiroyuki Okada

Journal of gastroenterology and hepatology 36 ( 1 ) 137 - 143 2021.1

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND AND AIM: Although oral mesalamine is the first-choice drug for treating mild-to-moderate ulcerative colitis (UC), some patients show symptoms of intolerance, including exacerbation of diarrhea and abdominal pain. The present study clarified the current state and clinical courses of patients with mesalamine intolerance. METHODS: Patients who were diagnosed with UC and administered oral mesalamine at eight hospitals in Japan with a follow-up period exceeding 1 year were analyzed. RESULTS: Sixty-seven (11%) of 633 patients showed intolerance to at least one formulation of oral mesalamine. The frequency of mesalamine intolerance has increased in recent years, rising from 5.3% in 2007-2010 to 9.1% in 2011-2013 and 16.2% in 2014-2016. The most common complications were the exacerbation of diarrhea (n = 29), a fever (n = 25), and abdominal pain (n = 22). Readministration of mesalamine/sulfasalazine was attempted in 43 patients, mostly with other types of formulation of mesalamine, and more than half of these patients proved to be tolerant. The risk factors for mesalamine intolerance were female gender (odds ratio [OR] = 1.83; 95% confidence interval [CI], 1.08-3.12), age < 60 years old (OR = 2.82; CI, 1.19-8.33), and pancolitis (OR = 2.09; 95% CI, 1.23-3.60). There were no significant differences in the use of anti-tumor necrosis factor-α agents, colectomy, or steroid-free remission at the last visit between patients with and without mesalamine intolerance. CONCLUSIONS: Mesalamine intolerance is not rare, and its frequency has been increasing recently. The prognosis of patients with mesalamine intolerance did not differ significantly from that of those without intolerance.

DOI： 10.1111/jgh.15138

Liquid biopsy for patients with IBD-associated neoplasia. International journal

Hideaki Kinugasa, Sakiko Hiraoka, Kazuhiro Nouso, Shumpei Yamamoto, Mami Hirai, Hiroyuki Terasawa, Eriko Yasutomi, Shohei Oka, Masayasu Ohmori, Yasushi Yamasaki, Toshihiro Inokuchi, Masahiro Takahara, Keita Harada, Takehiro Tanaka, Hiroyuki Okada

BMC cancer 20 ( 1 ) 1188 - 1188 2020.12

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: It is often difficult to diagnose inflammatory bowel disease (IBD)-associated neoplasia endoscopically due to background inflammation. In addition, due to the absence of sensitive tumor biomarkers, countermeasures against IBD-associated neoplasia are crucial. The purpose of this study is to develop a new diagnostic method through the application of liquid biopsy. METHODS: Ten patients with IBD-associated cancers and high-grade dysplasia (HGD) with preserved tumor tissue and blood were included. Tumor and non-tumor tissues were analyzed for 48 cancer-related genes using next-generation sequencing. Simultaneously, circulating tumor DNA (ctDNA) was analyzed for mutations in the target genes using digital PCR. RESULTS: Out of 10 patients, seven had IBD-related cancer and three had IBD-related HGD. Two patients had carcinoma in situ; moreover, three had stageII and two had stage III. To avoid false positives, the mutation rate cutoff was set at 5% based on the control results; seven of 10 (70%) tumor tissue samples were mutation-positive. Mutation frequencies for each gene were as follows: TP53 (20.9%; R136H), TP53 (25.0%; C110W), TP53 (8.5%; H140Q), TP53 (31.1%; R150W), TP53 (12.8%; R141H), KRAS (40.0%; G12V), and PIK3CA (34.1%; R 88Q). The same mutations were detected in the blood of these seven patients. However, no mutations were detected in the blood of the remaining three patients with no tumor tissue mutations. The concordance rate between tumor tissue DNA and blood ctDNA was 100%. CONCLUSION: Blood liquid biopsy has the potential to be a new method for non-invasive diagnosis of IBD-associated neoplasia.

DOI： 10.1186/s12885-020-07699-z

Ulcerative Colitis Associated with a Mixed Neuroendocrine-non-neuroendocrine Neoplasm.

Hideaki Kinugasa, Sakiko Hiraoka, Shohei Oka, Hiroyuki Okada

Internal medicine (Tokyo, Japan) 59 ( 16 ) 2085 - 2086 2020.8

Blue laser imaging and linked color imaging improve the color difference value and visibility of colorectal polyps in underwater conditions. Reviewed International journal

Yasushi Yamasaki, Keita Harada, Shumpei Yamamoto, Eriko Yasutomi, Shotaro Okanoue, Mami Hirai, Shohei Oka, Yuka Obayashi, Hiroyuki Sakae, Kenta Hamada, Toshihiro Inokuchi, Hideaki Kinugasa, Yuusaku Sugihara, Masahiro Takahara, Takehiro Tanaka, Sakiko Hiraoka, Yoshiro Kawahara, Hiroyuki Okada

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 32 ( 5 ) 791 - 800 2020.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND AND AIM: Underwater endoscopic mucosal resection (UEMR) has become widespread for treating colorectal polyps. However, which observational mode is best suited for determining polyp margins underwater remains unclear. To determine the best mode, we analyzed three imaging modes: white light imaging (WLI), blue laser imaging (BLI) and linked color imaging (LCI). METHODS: Images of consecutive colorectal polyps previously examined by these three modes before UEMR were analyzed according to the degree of underwater turbidity (transparent or cloudy). Color differences between the polyps and their surroundings were calculated using the Commission Internationale d'Eclairage Lab color space in which 3-D color parameters were expressed. Eight evaluators, who were blinded to the histology, scored the visibility from one (undetectable) to four (easily detectable) in both underwater conditions. The color differences and visibility scores were compared. RESULTS: Seventy-three polyps were evaluated. Sixty-one polyps (44 adenomatous, 17 serrated) were observed under transparent conditions, and 12 polyps (seven adenomatous, five serrated) were observed under cloudy conditions. Under transparent conditions, color differences for the BLI (8.5) and LCI (7.9) were significantly higher than that of WLI (5.7; P < 0.001). Visibility scores for BLI (3.6) and LCI (3.4) were also higher than that of WLI (3.1; P < 0.0001). Under cloudy conditions, visibility scores for LCI (2.9) and WLI (2.7) were significantly higher than that of BLI (2.2; P < 0.0001 and P = 0.04, respectively). CONCLUSIONS: BLI and LCI were better observational modes in transparent water; however, BLI was unsuitable for cloudy conditions.

DOI： 10.1111/den.13581

Switching between Three Types of Mesalazine Formulation and Sulfasalazine in Patients with Active Ulcerative Colitis Who Have Already Received High-Dose Treatment with These Agents. Reviewed International journal

Eriko Yasutomi, Sakiko Hiraoka, Shumpei Yamamoto, Shohei Oka, Mami Hirai, Yasushi Yamasaki, Toshihiro Inokuchi, Hideaki Kinugasa, Masahiro Takahara, Keita Harada, Jun Kato, Hiroyuki Okada

Journal of clinical medicine 8 ( 12 ) 2019.12

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND AND AIM: Oral mesalazine and sulfasalazine (SASP) are key drugs for treating ulcerative colitis (UC). The efficacy of switching from one of the several mesalazine formulations to another is largely unknown. This study assessed the efficacy of switching among three types of mesalazine formulation and SASP for UC therapy. METHODS: UC patients receiving high-dose mesalazine/SASP who switched to other formulations due to disease activity were considered eligible. Efficacy was evaluated 2, 6, and 12 months after switching. RESULTS: A total of 106 switches in 88 UC patients were analyzed. The efficacy at 2 months after switching was observed in 23/39 (59%) cases from any mesalazine formulation to SASP, in 18/55 (33%) cases from one mesalazine to another, and in 2/12 (17%) cases from SASP to any mesalazine formulation. Nine of 43 effective cases showed inefficacy or became intolerant post-switching. Delayed efficacy more than two months after switching was observed in four cases. Steroid-free remission was achieved in 42/106 (39%) cases-within 100 days in 35 of these cases (83%). CONCLUSIONS: Switching from mesalazine to SASP was effective in more than half of cases. The efficacy of switching between mesalazine formulations was lower but may be worth attempting in clinical practice from a safety perspective.

DOI： 10.3390/jcm8122109

Berberine improved experimental chronic colitis by regulating interferon-γ- and IL-17A-producing lamina propria CD4+ T cells through AMPK activation. Reviewed International journal

Masahiro Takahara, Akinobu Takaki, Sakiko Hiraoka, Takuya Adachi, Yasuyuki Shimomura, Hiroshi Matsushita, Tien Thi Thuy Nguyen, Kazuko Koike, Airi Ikeda, Shiho Takashima, Yasushi Yamasaki, Toshihiro Inokuchi, Hideaki Kinugasa, Yusaku Sugihara, Keita Harada, Shingo Eikawa, Hidetoshi Morita, Heiichiro Udono, Hiroyuki Okada

Scientific reports 9 ( 1 ) 11934 - 11934 2019.8

Language：English Publishing type：Research paper (scientific journal)

The herbal medicine berberine (BBR) has been recently shown to be an AMP-activated protein kinase (AMPK) productive activator with various properties that induce anti-inflammatory responses. We investigated the effects of BBR on the mechanisms of mucosal CD4+T cell activation in vitro and on the inflammatory responses in T cell transfer mouse models of inflammatory bowel disease (IBD). We examined the favorable effects of BBR in vitro, using lamina propria (LP) CD4+ T cells in T cell transfer IBD models in which SCID mice had been injected with CD4+CD45RBhigh T cells. BBR suppressed the frequency of IFN-γ- and Il-17A-producing LP CD4+ T cells. This effect was found to be regulated by AMPK activation possibly induced by oxidative phosphorylation inhibition. We then examined the effects of BBR on the same IBD models in vivo. BBR-fed mice showed AMPK activation in the LPCD4+ T cells and an improvement of colitis. Our study newly showed that the BBR-induced AMPK activation of mucosal CD4+ T cells resulted in an improvement of IBD and underscored the importance of AMPK activity in colonic inflammation.

DOI： 10.1038/s41598-019-48331-w

Long-term outcomes of patients with Crohn's disease who received infliximab or adalimumab as the first-line biologics. Reviewed International journal

Toshihiro Inokuchi, Sakuma Takahashi, Sakiko Hiraoka, Tatsuya Toyokawa, Shinjiro Takagi, Koji Takemoto, Jiro Miyaike, Tsuyoshi Fujimoto, Reiji Higashi, Yuki Morito, Toru Nawa, Seiyuu Suzuki, Mamoru Nishimura, Masafumi Inoue, Jun Kato, Hiroyuki Okada

Journal of gastroenterology and hepatology 34 ( 8 ) 1329 - 1336 2019.8

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND AND AIM: Although previous studies compared the efficacy of infliximab (IFX) versus adalimumab (ADA) as the first-line biologics for Crohn's disease (CD), the difference in long-term prognosis based on which biologic was used first has scarcely been reported. In particular, the clinical courses after loss of response (LOR) of the first-line biologics are largely unknown. METHODS: A multicenter, retrospective study was performed. Disease courses of biologic-naïve CD patients who were started on IFX or ADA treatment were evaluated, even after LOR of the initial biologics. RESULTS: In total, 263 CD patients were eligible for analysis, 183 were treated with IFX first, and 80 were treated with ADA first. The median observation period was 64.2 months. The cumulative steroid-free remission rates and surgery-free rates did not differ significantly between the patients treated with IFX first and those treated with ADA first (log-rank test P = 0.42 and P = 0.74, respectively). In addition, no significant difference was observed in the rate of occurrence of events associated with ineffectiveness (modification of anti-tumor necrosis factor treatment including intensification, switch, discontinuation, or surgery) between the patient groups (log-rank test P = 0.62). The patients treated with IFX first were likely to discontinue the agent due to adverse events, whereas those treated with ADA first were likely to discontinue due to treatment failure or LOR. CONCLUSIONS: No significant difference was observed in the long-term prognosis between biologic-naïve patients with CD who were started treatment with IFX first and ADA first.

DOI： 10.1111/jgh.14624

Prediction of treatment outcome and relapse in inflammatory bowel disease. Reviewed International journal

Jun Kato, Takeichi Yoshida, Sakiko Hiraoka

Expert review of clinical immunology 15 ( 6 ) 667 - 677 2019.6

Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: Prediction of treatment outcome and clinical relapse in patients with inflammatory bowel disease (IBD), either ulcerative colitis (UC) or Crohn's disease (CD), is particularly important because therapeutics for IBD are not always effective and patients in remission could frequently relapse. Because undergoing endoscopy for the purpose is sometimes invasive and burdensome to patients, the performance of surrogate biomarkers has been investigated. Areas covered: We particularly featured the performance of patient symptoms, blood markers including C-reactive protein (CRP), fecal markers including fecal calprotectin (Fcal) and fecal immunochemical test (FIT) for prediction of endoscopic mucosal healing (MH) and prediction of relapse. Studies of other modalities and therapeutic drug monitoring (TDM) have also been explored. Expert opinion: Meticulous evaluation of patient symptoms could be predictive for MH in UC. CRP and Fcal may be accurate in prediction of MH of CD when MH is evaluated throughout the entire intestine including the small bowel. Repeated measurements of fecal markers including Fcal and FIT in patients with clinical remission would raise predictability of relapse. Prediction of treatment outcome by monitoring with blood markers including CRP, fecal markers including Fcal, and TDM has frequently been performed in recent clinical trials and shown to be effective.

DOI： 10.1080/1744666X.2019.1593140

The novel latex agglutination turbidimetric immunoassay system for simultaneous measurements of calprotectin and hemoglobin in feces. Reviewed International journal

Sakiko Hiraoka, Shiho Takashima, Toshihiro Inokuchi, Asuka Nakarai, Masahiro Takahara, Keita Harada, Yasuhiro Seki, Katsunori Watanabe, Jun Kato, Hiroyuki Okada

Intestinal research 17 ( 2 ) 202 - 209 2019.4

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND/AIMS: Fecal calprotectin (Fcal) as well as the fecal immunochemical test (FIT) are useful biomarkers for detecting activity and mucosal healing in inflammatory bowel diseases. Here, we report the performance of simultaneous measurements of Fcal and FIT for ulcerative colitis (UC) patients using the newly-developed latex agglutination turbidimetric immunoassay (LATIA) system. METHODS: Fcal and hemoglobin were measured by the LATIA system in 152 UC patients who underwent colonoscopy. Fcal was also quantified with a conventional enzyme-linked immunosorbent assay (ELISA). Fecal markers were evaluated in conjunction with the mucosal status of UC, which was assessed via the Mayo endoscopic subscore (MES) classification. RESULTS: The LATIA system could quantify calprotectin and hemoglobin simultaneously with the same fecal samples within 10 minutes. The values of the Fcal-LATIA closely correlated with those of the Fcal-ELISA (Spearman rank correlation coefficient, r=0.84; P<0.0001). The values of Fcal for each assay and the FIT all significantly correlated with the MESs (Spearman rank correlation coefficient, Fcal-LATIA: r=0.58, Fcal-ELISA: r=0.55, and FIT: r=0.72). The mucosal healing predictability (determined by an MES of 0 alone) of the Fcal-LATIA, Fcal-ELISA, and FIT-LATIA with the cutoffs determined by receiver operating characteristic curve analysis was 0.79, 0.78, and 0.92 for sensitivity, respectively, and 0.78, 0.69, and 0.73 for specificity, respectively. CONCLUSIONS: The performance of the novel Fcal-LATIA was equivalent to that of the conventional Fcal assay. Simultaneous measurements with FITs would promote the clinical relevance of fecal biomarkers in UC.

DOI： 10.5217/ir.2018.00086

Feasibility of Underwater Clip Closure for Large Mucosal Defects after Colorectal Endoscopic Submucosal Dissection. Reviewed International journal

Yasushi Yamasaki, Keita Harada, Shohei Oka, Shiho Takashima, Toshihiro Inokuchi, Yuusaku Sugihara, Masahiro Takahara, Sakiko Hiraoka, Hiroyuki Okada

Digestion 99 ( 4 ) 327 - 332 2019

Language：English

BACKGROUND/AIMS: Clip closure of mucosal defects after colorectal endoscopic submucosal dissection (C-ESD) may decrease the incidence of delayed adverse events. The size of the defect to be closed by conventional clip is limited, however, and we sometimes encounter incomplete closure when the defect is located at the flexure. As, theoretically, underwater clip closure (UCC) could achieve complete closure despite these difficult cases, we investigated its feasibility. METHODS: We retrospectively analyzed 21 patients who underwent UCC after C-ESD. The main outcome was the UCC success rate, defined as complete closure of the defect. Other outcomes were procedure time, number of clips, and the delayed adverse event rate. RESULTS: The median resected specimen size was 31 mm (range 18-47 mm). The UCC success rate was 100%. The median procedure time was only 11 min (range 6-21 min). The median number of clips was 9 (range 5-16). No delayed adverse event occurred. CONCLUSION: It is feasible to use UCC to close large mucosal defects, although further studies are warranted to assess its efficacy.

DOI： 10.1159/000492815

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

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

Journal of gastroenterology 53 ( 9 ) 1065 - 1078 2018.9

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1007/s00535-018-1486-7

Fecal immunochemical test and fecal calprotectin results show different profiles in disease monitoring for ulcerative colitis Reviewed

Sakiko Hiraoka, Toshihiro Inokuchi, Asuka Nakarai, Shiho Takashima, Daisuke Takei, Yuusaku Sugihara, Masahiro Takahara, Keita Harada, Hiroyuki Okada, Jun Kato

Gut and Liver 12 ( 2 ) 142 - 148 2018.3

Language：English Publishing type：Research paper (scientific journal) Publisher：Editorial Office of Gut and Liver

Background/Aims: Both fecal immunochemical test (FIT) and fecal calprotectin (Fcal) results are useful biomarkers for ulcerative colitis (UC). However, the situations in which each marker should be used are largely unknown. Methods: A total of 110 colonoscopy intervals of UC patients were assessed, and correlations between changes in colonoscopic findings and changes in the two aforementioned fecal markers were examined. Results: Among patients with mucosal healing (MH) and negative FIT or Fcal results at the initial colonoscopy, FIT and Fcal findings exhibited accuracies of 93% (38/41) and 79% (26/33), respectively, for predicting the results of the subsequent examination. Among the 24 patients who showed endoscopic activity at the precedent colonoscopy and MH at the subsequent examination, positive-to-negative conversion of FIT and Fcal findings at the subsequent examination was observed in 92% (12/13) and 62% (8/13) of patients, respectively. Among the 43 patients who showed endoscopic activity at both the precedent and subsequent examinations, Fcal findings reflected the change in endoscopic activity better than FIT results (r=0.59, p&lt
0.0001 vs r=0.30, p=0.054). Conclusions: The FIT is useful for confirming MH and the occurrence of relapse. In contrast, Fcal is useful for monitoring the mucosal status of patients with active inflammation. (Gut Liver 2018
12:142-148).

DOI： 10.5009/gnl17013

Simultaneous measurements of faecal calprotectin and the faecal immunochemical test in quiescent ulcerative colitis patients can stratify risk of relapse Reviewed

Asuka Nakarai, Sakiko Hiraoka, Sakuma Takahashi, Tomoki Inaba, Reiji Higashi, Motowo Mizuno, Shiho Takashima, Toshihiro Inokuchi, Yuusaku Sugihara, Masahiro Takahara, Keita Harada, Jun Kato, Hiroyuki Okada

Journal of Crohn's and Colitis 12 ( 1 ) 71 - 76 2018.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Oxford University Press

Background: Both faecal calprotectin [Fcal] and the faecal immunochemical test [FIT] are useful to predict clinical relapse of ulcerative colitis [UC]. However, the difference between Fcal and FIT in ability to predict relapse has scarcely been reported. Whether the combined use of these two faecal markers increases the predictability is also unknown. Methods: UC patients in clinical remission who underwent colonoscopy were enrolled prospectively, and the Fcal and FIT values were examined at enrolment. Their clinical course was observed for 2 years or until relapse. The correlation between the incidence of relapse and the values of the two markers was examined. Results: A total of 113 patients were enrolled, and 48 [42%] relapsed. Fcal = 75 μg/g and FIT = 110 ng/mL were defined as Fcal-positive and FIT-positive, respectively, according to the receiver operating characteristic curves. Both Fcal-positive and FIT-positive statuses were independent predictive factors of clinical relapse (hazard ratio [HR] 2.29
95% confidence interval [CI], 1.23-4.49
p = 0.0086, and HR 2.91
95% CI, 1.49-5.50
p = 0.0022, respectively). Categorisation of patients into three groups according to the faecal marker status [FIT-positive, FIT-negative and Fcal-positive, and both negative] can efficiently stratify the risk of relapse with graded increases in risk [FIT-negative and Fcal-positive: HR 2.05
95% CI, 1.02-4.43
p = 0.0045, and FIT-positive: HR 5.43
95% CI, 2.57- 11.76
p &lt
0.0001, compared with both negative]. Conclusions: Fcal vs FIT showed distinct properties regarding the prediction of relapse in UC. A risk assessment using both faecal markers could increase the predictability for relapse.

DOI： 10.1093/ecco-jcc/jjx118

Efficacy of restarting anti-tumor necrosis factor α agents after surgery in patients with Crohn's disease Reviewed

Sakiko Hiraoka, Shiho Takashima, Yoshitaka Kondo, Toshihiro Inokuchi, Yuusaku Sugihara, Masahiro Takahara, Seiji Kawano, Keita Harada, Jun Kato, Hiroyuki Okada

Intestinal Research 16 ( 1 ) 75 - 82 2018

Language：English Publishing type：Research paper (scientific journal) Publisher：Korean Association for the Study of Intestinal Diseases

Background/Aims: The efficacy of anti-tumor necrosis factor a (anti-TNFα) antibodies for postoperative Crohn's disease (CD) in patients who were treated with these agents prior to surgery is largely unknown. Methods: CD patients who underwent intestinal resection and received anti-TNFα agents after surgery were divided into 2 groups according to the presence or absence of preoperative anti-TNFα treatment: anti-TNFα restart group or anti-TNFα naïve group. Endoscopic recurrence after surgery was examined according to the preoperative conditions, including administration of anti-TNFα agents before surgery. Results: Thirty-six patients received anti-TNFα antibody after surgery: 22 in the anti-TNFα restart group and 14 in the anti- TNFα naïve group. Endoscopic recurrence after surgery was more frequently observed in the anti-TNFα restart group than in the anti-TNFα naïve group (68% vs. 14%, P &lt
0.001). Multivariate analysis revealed the following significant risk factors of endoscopic recurrence after surgery: anti-TNF restart group (odds ratio [OR], 28.10
95% CI, 3.08-722.00), age at diagnosis &lt
23 years (OR, 24.30
95% CI, 1.67-1,312.00), serum albumin concentration at surgery &lt
3.3 g/dL (OR, 34.10
95% CI, 1.72-2,804.00), and presence of inflammation outside of the surgical site (OR, 21.40
95% CI, 1.02-2,150.00). Treatment intensification for patients with endoscopic recurrence in the anti-TNFα restart group showed limited responses, with only 1 of 12 patients achieving endoscopic remission. Conclusions: The efficacy of restarting anti-TNFα antibody treatment after surgery was limited, and treatment intensification or a change to different classes of biologics should be considered for those patients.

DOI： 10.5217/ir.2018.16.1.75

Findings of Retrograde Contrast Study Through Double-balloon Enteroscopy Predict the Risk of Bowel Resections in Patients with Crohn's Disease with Small Bowel Stenosis Reviewed

Noriko Okazaki, Toshihiro Inokuchi, Sakiko Hiraoka, Masayasu Ohmori, Shiho Takashima, Daisuke Takei, Yuusaku Sugihara, Masahiro Takahara, Keita Harada, Seiji Kawano, Hiroyuki Okada, Jun Kato

INFLAMMATORY BOWEL DISEASES 23 ( 12 ) 2097 - 2103 2017.12

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Background: Patients with Crohn's disease (CD) with small bowel strictures are at risk of surgery. Double-balloon enteroscopy (DBE) can evaluate the status of the small intestine, and retrograde contrast through the scope enables the surgeon to obtain information beyond the reach of the scope. This study aimed to examine whether a retrograde contrast study through DBE could be used as a predictor of subsequent surgery in patients with CD with small intestinal strictures.
Methods: The findings of DBE with retrograde contrast in 48 patients CD with small bowel strictures were examined.
Results: Of the 48 patients, 14 (29%) underwent surgery for small intestinal strictures during a median observation period of 2.4 years (interquartile range: 1.4-3.7 yr). According to the results of the multivariate analysis, a maximum length of strictures >= 20 mm and the ratio of the maximum diameter of prestenotic dilations to the diameter of the normal small intestine >= 1.4 were independent risk factors of surgery for small intestinal strictures (risk ratio = 7.6 [95% confidence interval, 1.8-42.0], P = 0.006; and risk ratio = 52.0 [95% confidence interval, 3.5-2485.1], P = 0.002, respectively). The latter predicted subsequent surgery with 92% sensitivity and 88% specificity. Cumulative surgery-free rates were discriminated significantly according to the presence or absence of these 2 risk factors (log-rank test: P < 0.001).
Conclusions: Findings of retrograde contrast through DBE are helpful to predict risk of surgery in patients with CD with small intestinal strictures.

DOI： 10.1097/MIB.0000000000001175

Consecutive Measurements by Faecal Immunochemical Test in Quiescent Ulcerative Colitis Patients Can Detect Clinical Relapse Reviewed

Sakiko Hiraoka, Jun Kato, Asuka Nakarai, Shiho Takashima, Toshihiro Inokuchi, Daisuke Takei, Yuusaku Sugihara, Masahiro Takahara, Keita Harada, Hiroyuki Okada

JOURNAL OF CROHNS & COLITIS 10 ( 6 ) 687 - 694 2016.6

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

We have reported that results of the quantitative faecal immunochemical test (FIT; haemoglobin concentrations in faeces measured using an antibody for human haemoglobin) effectively reflect the mucosal status of ulcerative colitis (UC). The aim of this study was to evaluate the predictability of flare-up in quiescent UC patients by consecutive FIT evaluation.
Patients with UC who fulfilled the following criteria by index colonoscopy were enrolled: clinical remission; mucosal healing (Mayo endoscopic subscore 0); and negative FIT (less than 100ng/mL). These patients were followed up prospectively every 1-3 months by monitoring patient symptoms and FIT results between index and subsequent colonoscopies.
The intervals between 2 colonoscopies (median 2.51 years) of 83 patients (49 males, median age at onset 34 years, median disease duration 9.74 years) were analysed. None of the 43 (52%) patients who maintained negative FIT throughout the observation period exhibited clinical relapse. On the other hand, 25/40 (63%) patients who showed positive conversion of FIT during the period experienced relapse. The cutoff FIT value of 450ng/mL could predict relapse with 73% positive predictive value and 96% negative predictive value. Moreover, positive conversion of FIT preceded occurrence of symptoms by 1 month or more in nearly one-third of patients with relapse.
Consecutive measurements of FIT in quiescent UC patients who achieved mucosal healing with negative FIT would help identify patients with clinical relapse whose symptoms had not yet presented. Further investigations are required for more precise prediction of relapse with this modality.

DOI： 10.1093/ecco-jcc/jjw025

Fecal Immunochemical Test Versus Fecal Calprotectin for Prediction of Mucosal Healing in Crohn's Disease Reviewed

Toshihiro Inokuchi, Jun Kato, Sakiko Hiraoka, Shiho Takashima, Asuka Nakarai, Daisuke Takei, Yuusaku Sugihara, Masahiro Takahara, Seiji Kawano, Keita Harada, Hiroyuki Okada

INFLAMMATORY BOWEL DISEASES 22 ( 5 ) 1078 - 1085 2016.5

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Background: Mucosal healing (MH) has been proposed as a treatment goal of inflammatory bowel disease patients. We reported recently that not only fecal calprotectin (Fcal) but also the fecal immunochemical test (FIT) can predict MH in ulcerative colitis. However, the predictive power of the fecal markers for MH in Crohn's disease (CD), particularly with small bowel lesions, has not been reported in detail. The aim of this study was to evaluate the predictability of FIT versus Fcal for MH in CD.
Methods: Consecutive CD patients underwent colonoscopy or balloon-assisted enteroscopy according to the disease location. FIT and Fcal were examined using stool samples collected the day before endoscopy.
Results: Seventy-one CD patients were analyzed, of whom 42 (59%) underwent balloon-assisted enteroscopy because of the presence of affected lesions in the small intestine. Both the Fcal and the FIT results were significantly correlated with endoscopic activity (r = 0.67 and 0.54, respectively). However, the FIT results did not correlate with the activity in patients with small bowel lesions alone, whereas Fcal did (r = 0.42 versus 0.78). Fcal predicted MH in CD with 87% sensitivity and 71% specificity, whereas the values for FIT were 96% and 48%, respectively. The specificity for MH among patients with small bowel lesions alone was low for FIT (40%) compared with Fcal (80%).
Conclusions: Both FIT and Fcal were correlated with the mucosal status of CD. However, the specificity of FIT was not satisfactory, particularly for small bowel lesions.

DOI： 10.1097/MIB.0000000000000728

Evaluation of Mucosal Healing in Ulcerative Colitis by Fecal Calprotectin Vs. Fecal Immunochemical Test Reviewed

Shiho Takashima, Jun Kato, Sakiko Hiraoka, Asuka Nakarai, Daisuke Takei, Toshihiro Inokuchi, Yuusaku Sugihara, Masahiro Takahara, Keita Harada, Hiroyuki Okada, Takehiro Tanaka, Kazuhide Yamamoto

AMERICAN JOURNAL OF GASTROENTEROLOGY 110 ( 6 ) 873 - 880 2015.6

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

OBJECTIVES: We previously showed that a quantitative fecal immunochemical test (FIT) can predict mucosal healing (MH) in ulcerative colitis (UC). Fecal calprotectin (Fcal) has also been reported as an important biomarker of UC activity. The aim of this study was to compare the predictive ability of these two fecal markers for MH in UC.
METHODS: FIT and Fcal were examined in stool samples from consecutive UC patients who underwent colonoscopy. Mucosal status was assessed via the Mayo endoscopic subscore (MES).
RESULTS: In total, 105 colonoscopies in 92 UC patients were evaluated in conjunction with the FIT and Fcal results. Both FIT and Fcal results were significantly correlated with MES (Spearman's rank correlation coefficient: 0.61 and 0.58, respectively). The sensitivity and specificity of the FIT values (<100 ng/ml) for predicting MH (MES 0 alone) were 0.95 and 0.62, respectively, whereas those of Fcal (<250 mu g/g) were 0.82 and 0.62, respectively. The sensitivities became similar when MH was defined as MES 0 or 1 (0.86 vs. 0.86). Although the predictability of MH evaluated by the area under the receiver operating characteristics curve was similar for the two fecal markers (FIT 0.83 vs. Fcal 0.82 for MES 0 alone), the FIT results were relatively robust regardless of the cutoff value selected.
CONCLUSIONS: Both FIT and Fcal can efficiently predict MH in UC, but FIT appears to be more sensitive than Fcal for predicting MES 0 alone.

DOI： 10.1038/ajg.2015.66

The earliest trough concentration predicts the dose of tacrolimus required for remission induction therapy in ulcerative colitis patients Reviewed

Sakiko Hiraoka, Jun Kato, Yuki Moritou, Daisuke Takei, Toshihiro Inokuchi, Asuka Nakarai, Sakuma Takahashi, Keita Harada, Hiroyuki Okada, Kazuhide Yamamoto

BMC GASTROENTEROLOGY 15 53 2015.4

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Background: Oral tacrolimus therapy is effective for refractory ulcerative colitis (UC), but dose adjustment according to the trough concentrations which varies largely among individuals, is required. This study aimed to identify factors to predict the tacrolimus dose required for achieving the target trough level for remission induction of UC.
Methods: Forty-seven consecutive UC patients who were treated with tacrolimus were retrospectively analyzed. Tacrolimus doses were adjusted every 2 or 3 days to achieve trough concentrations of 10-15 ng/mL. The dose required for reaching the target trough level was analyzed based on disease characteristics, course of trough concentrations, and gene polymorphism related to tacrolimus metabolism.
Results: Median daily dose of tacrolimus required for achieving the target trough level was 0.19 (0.07-0.42) mg/kg, and patients were divided into high or low dose group (< 0.2 mg/kg or > 0.2 mg/kg). The value of initial trough concentration/starting dose was higher in the low dose group than in the high dose group (1.35 ng/mL/mg vs. 0.78 ng/mL/mg, p < 0.0001). Although presence of CYP3A5 *1 was more frequently observed in the high dose group, initial trough concentration was the only significant factor for determining requirement of high dose of tacrolimus (OR = 28.0, 95% confidence interval 3.20 - 631).
Conclusions: The most practical predictor of the dose required for achieving the target trough concentration was the trough concentration measured 2 or 3 days after starting tacrolimus therapy. Our findings would make tarcolimus administration for UC safer, easier and more effective.

DOI： 10.1186/s12876-015-0285-3

Evaluation of Mucosal Healing of Ulcerative Colitis by a Quantitative Fecal Immunochemical Test Reviewed

Asuka Nakarai, Jun Kato, Sakiko Hiraoka, Motoaki Kuriyama, Mitsuhiro Akita, Tomoko Hirakawa, Hiroyuki Okada, Kazuhide Yamamoto

AMERICAN JOURNAL OF GASTROENTEROLOGY 108 ( 1 ) 83 - 89 2013.1

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

OBJECTIVES: Accumulating evidence has underlined the importance of mucosal healing as a treatment goal for ulcerative colitis (UC). Quantitative fecal immunochemical tests (FITs), which can rapidly quantify fecal blood with automated equipment, have been used recently to screen for colorectal neoplasia. The aim of this study is to determine whether an FIT can evaluate mucosal healing in UC.
METHODS: Feces collected from UC patients who underwent colonoscopy were examined by FITs, and results were compared with colonoscopic findings. Mucosal status was assessed using the Mayo endoscopic subscore classification. Maximum score for the colorectum in each patient was recorded.
RESULTS: Evaluated were FIT results in conjunction with 310 colonoscopies that were performed in 152 UC patients. A large majority of patients with a Mayo 0 endoscopic score had negative FIT (<100 ng/ml) results (92 %), and the proportion of negative FIT results decreased with increases in the Mayo score (Mayo 1: 47 %, Mayo 2: 13 %, Mayo 3: 12 %, P < 0.0001, Cochran-Armitage trend test). When the negative FIT was defined as < 100 ng/ml, the sensitivity and specificity of a negative FIT for mucosal healing (Mayo 0) were 0.92 and 0.71, respectively. When mucosal healing was defined as Mayo 0 or 1, those were 0.60 and 0.87, respectively. In addition, a positive FIT (>= 100 ng/ml) predicted mucosal inflammation (Mayo 2 or 3) with sensitivity 0.87 and specificity 0.60, respectively.
CONCLUSIONS: The FIT can effectively and noninvasively evaluate mucosal healing in UC. This easy, rapid method can help evaluate and control disease activity of UC.

DOI： 10.1038/ajg.2012.315

Readministration of Calcineurin Inhibitors for Ulcerative Colitis Reviewed

Sakiko Hiraoka, Jun Kato, Hideyuki Suzuki, Kazuhide Yamamoto

ANNALS OF PHARMACOTHERAPY 46 ( 10 ) 1315 - 1321 2012.10

Language：English Publishing type：Research paper (scientific journal) Publisher：HARVEY WHITNEY BOOKS CO

BACKGROUND: Calcineurin inhibitors (CNIs) such as cyclosporine and tacrolimus have been shown to be effective for treatment of patients with steroid-dependent or steroid-refractory ulcerative colitis (UC) with moderate to severe activity. However, it has not been determined whether readministration of CNIs is effective in patients who experience relapse after remission induced by CNIs.
OBJECTIVE: To determine the effect of readministration of CNIs in patients who had initially responded to CNIs.
METHODS: A review of the medical records of 46 patients with moderate to severe UC who were treated with a CNI at a single tertiary teaching hospital with 840 beds was conducted. Remission was defined as a clinical activity index (CAI) score of 3 or less within 2 months of starting CNI therapy. Response was defined as a CAI score of 4 or higher but had decreased by half from the start of CNI therapy. Relapse was defined as flare-up of symptoms that required an additional treatment or colectomy.
RESULTS: Of the 46 patients, 37 (80%) achieved clinical remission or response with the initial CNI treatment. Among those 37 patients, 19 experienced relapse (median duration to relapse, 6.4 months), 12 of whom were readministered a CNI. Of the 12 patients, 2 achieved clinical remission, 2 had a response, and the remaining 8 had no response to the CNI. In addition, all patients who responded to CNI readministration experienced relapse within 6 months. CNI readministration was significantly less effective than the initial administration for treatment of UC (80% vs 33%; p = 0.0014).
CONCLUSIONS: Readministration of CNIs for relapse after remission with CNI treatment does not seem to be successful. Alternative therapies such as anti-tumor necrosis factor antibody should be used or colectomy should be considered.

DOI： 10.1345/aph.1R210

The Presence of Large Serrated Polyps Increases Risk for Colorectal Cancer Reviewed

Sakiko Hiraoka, Jun Kato, Shigeatsu Fujiki, Eisuke Kaji, Tamiya Morikawa, Takatoshi Murakami, Toru Nawa, Motoaki Kuriyama, Toshio Uraoka, Nobuya Ohara, Kazuhide Yamamoto

GASTROENTEROLOGY 139 ( 5 ) 1503 - + 2010.11

Language：English Publishing type：Research paper (scientific journal) Publisher：W B SAUNDERS CO-ELSEVIER INC

BACKGROUND & AIMS: There is evidence that serrated polyps (serrated adenomas and hyperplastic polyps) have different malignant potential than traditional adenomas. We used a colonoscopy database to determine the association between the presence of serrated colorectal polyps and colorectal neoplasia. METHODS: We performed a multicenter observational study of 10,199 subjects who underwent first-time colonoscopies. Data collected on study subjects included age and sex and the location, size, and histology of polyps or tumors found at colonoscopy. Serrated polyps were defined as those diagnosed by the pathologists in the participating hospitals as a serrated lesion (a lesion given the term of "classical hyperplastic polyp," "traditional serrated adenoma," " sessile serrated adenoma," or "mixed serrated polyp"). Large serrated polyps (LSPs) were defined as those >= 10 mm. RESULTS: There were 1573 patients (15.4%) with advanced neoplasia, 708 patients (6.9%) with colorectal cancer (CRC), and 140 patients (1.4%) with LSPs in our cohort. Multivariate analysis associated the presence of LSPs with advanced neoplasia (odds ratio [OR], 4.01; 95% confidence interval [CI], 2.83-5.69) and CRC (OR, 3.34; 95% CI, 2.16-5.03). The presence of LSPs was the greatest risk factor for CRC, particularly for proximal CRC (OR, 4.79; 95% CI, 2.54-8.42). Proximal and protruded LSPs were the highest risk factors for proximal CRC (OR, 5.36; 95% CI, 2.40-10.8 and OR, 9.00; 95% CI, 2.75-19.2, respectively). CONCLUSIONS: The presence of LSPs is a risk factor for CRC, particularly CRC of the proximal colon.

DOI： 10.1053/j.gastro.2010.07.011

Laterally spreading type of colorectal adenoma exhibits a unique methylation phenotype and K-ras mutations Reviewed

Sakiko Hiraoka, Jun Kato, Masashi Tatsukawa, Keita Harada, Hideyuki Fujita, Tamiya Morikawa, Hidenori Shiraha, Yasushi Shiratori

GASTROENTEROLOGY 131 ( 2 ) 379 - 389 2006.8

Language：English Publishing type：Research paper (scientific journal) Publisher：W B SAUNDERS CO-ELSEVIER INC

Background & Aims: Laterally spreading tumors (LST), characterized by superficial extension along the colonic lumen, have recently been detected by colonoscopy. However, genetic and epigenetic characteristics of these tumors were scarcely reported. Methods: A total of 205 sporadic colorectal adenoma tissues (157 protruded-type, 23 granular-type LST (G-LST), 12 flat-type LST (FLST), and 13 flat-type smaller than 1 cm) were collected. CpG island methylator phenotype (CIMP) was determined by examination of methylation status at p16, methylated in tumor (MINT) 1, 2, 12, and 31 loci. K-ras codon 12 and 13 point mutations were also examined. The relationship between macroscopic appearance and CIMP status or K-ras mutations was analyzed. Results: Among adenomas larger than 1 cm, CpG island methylation involving 2 or more loci (CIMP-high) was more likely to be observed in G-LST (14/23, 61%) than in protruded-type adenomas (18/73, 25%) (P=.002). The prevalence of K-ras mutations in G-LST (18/23, 78%) was significantly higher than that in protruded-type adenomas (18/73, 25%) (P <.0001). Moreover, the prevalence of CIMP-high and K-ras mutations in G-LST located in the proximal colon was much higher (11/13, 85%; and 12/13, 92%, respectively). In contrast, F-LST exhibited low prevalence of CIMP-high (1/12, 8%) and K-ras mutations (2/12, 16%). Conclusions: High prevalence of CIMP-high and K-ras mutations in G-LST, especially in the proximal colon, could strongly suggest that G-LST appearance is associated with a unique carcinogenic pathway.

DOI： 10.1053/j.gastro.2006.04.027

Enhanced expression of decay-accelerating factor, a complement-regulatory protein, in the specialized intestinal metaplasia of Barrett's esophagus Reviewed

S Hiraoka, M Mizuno, J Nasu, H Okazaki, C Makidono, H Okada, R Terada, K Yamamoto, T Fujita, Y Shiratori

JOURNAL OF LABORATORY AND CLINICAL MEDICINE 143 ( 4 ) 201 - 206 2004.4

Language：English Publishing type：Research paper (scientific journal) Publisher：MOSBY, INC

Intestinal-type epithelium in Barrett's esophagus, so-called specialized intestinal metaplasia (SIM), is a risk factor for the development of esophageal adenocarcinoma. Surface expression of decay-accelerating factor (DAF), a complement-regulatory protein, is markedly enhanced in intestinal metaplasia of the gastric mucosa. We therefore examined DAF expression in areas of SIM in Barrett's esophagus in an attempt to determine whether DAF is a biomarker of SIM. We obtained 53 endoscopic biopsy specimens from the esophageal columnar mucosae of 45 patients. We immunohistochemically examined the distribution of DAF and 2 other complement-regulatory proteins: homologous restriction factor-20 and membrane cofactor protein. We also examined the expression of DAF messenger RNA in SIM with the use of laser-capture microdissection and reverse transcription-polymerase chain reaction. Of the 53 specimens, 10 were found histologically to involve areas of SIM, 41 were SIM-negative epithelium, and 2 comprised areas of SIM and SIM-negative epithelium. DAF staining was negligible in 35 of 43 specimens of the SIM-negative columnar epithelium, but DAF was strongly stained on the apical surface in all 12 SIM-positive specimens (P <.0001). In the 2 biopsy specimens in which both SIM and SIM-negative columnar epithelium were present, DAF staining was confined to the area of SIM. The expression of DAF messenger RNA was detected significantly more often in SIM than in SIM-negative columnar epithelium (P =.022). We conclude that DAF may be a surface marker for SIM and therefore useful in the identification of areas of the mucosa at risk for the development of adenocarcinoma in Barrett's esophagus.

DOI： 10.1016/j.lab.2003.12.013

Guidelines for endoscopic diagnosis and treatment of inflammatory bowel diseases. International journal

Takayuki Matsumoto, Tadakazu Hisamatsu, Motohiro Esaki, Teppei Omori, Hirotake Sakuraba, Shinichiro Shinzaki, Ken Sugimoto, Kento Takenaka, Makoto Naganuma, Shigeki Bamba, Takashi Hisabe, Sakiko Hiraoka, Mikihiro Fujiya, Minoru Matsuura, Shunichi Yanai, Kenji Watanabe, Haruhiko Ogata, Akira Andoh, Hiroshi Nakase, Kazuo Ohtsuka, Fumihito Hirai, Mitsuhiro Fujishiro, Yoshinori Igarashi, Shinji Tanaka

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 37 ( 4 ) 319 - 351 2025.4

Language：English Publishing type：Research paper (scientific journal)

In recent years, we have seen a considerable increase in the number of patients with inflammatory bowel diseases of unknown etiology, including both Crohn's disease and ulcerative colitis. Inflammatory bowel diseases can cause intestinal lesions throughout the gastrointestinal tract, necessitating gastrointestinal endoscopy for examining all relevant aspects, especially lesion characteristics, for differential diagnosis and histological diagnosis, to select the appropriate treatment options, determine treatment effectiveness, etc. Specific guidelines are necessary to ensure that endoscopy can be performed in a safe and more tailored and efficient manner, especially since gastrointestinal endoscopy, including enteroscopy, is a common procedure worldwide, including in Japan. Within this context, the Japan Gastroenterological Endoscopy Society has formulated the "Guidelines for the Endoscopic Diagnosis and Treatment of Inflammatory Bowel Diseases" to provide detailed guidelines regarding esophagogastroduodenoscopy, enteroscopy, and colonoscopy procedures for definitive diagnosis, as well as determination of treatment effectiveness in clinical cases of inflammatory bowel diseases.

DOI： 10.1111/den.15002

Acetic Acid-Indigo Carmine Chromocolonoscopy for Proximal Serrated Lesions: A Randomized, Three-Arm Colonoscopy Study. International journal

Hideaki Kinugasa, Sakiko Hiraoka, Sayo Kobayashi, Minoru Matsubara, Teruya Nagahara, Reiji Higashi, Kensuke Takei, Masayasu Ohmori, Takashi Nakamura, Takao Tsuzuki, Shouichi Tanaka, Ryosuke Hirai, Junki Toyosawa, Yuki Aoyama, Yasushi Yamasaki, Toshihiro Inokuchi, Masahiro Takahara, Takehiro Tanaka, Toshiharu Mitsuhashi, Motoyuki Otsuka

The American journal of gastroenterology 2025.3

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: Aggressive colorectal cancer (CRC) frequently originates from serrated lesions (SLs), particularly in the proximal colon, which are challenging to detect using standard screening colonoscopy. Although duplicate examinations or chromocolonoscopies are recommended for detecting proximal SLs, evidence from randomized trials is limited. We evaluated the effectiveness of tandem colonoscopy with an acetic acid-indigo carmine mixture (AIM) for detecting SLs in the proximal colon compared to white-light imaging (WLI) and indigo carmine (IC). METHODS: This three-arm, multicenter, randomized controlled trial involving nine institutions enrolled patients undergoing colonoscopy and assigned them randomly to the WLI, IC, or AIM group. The primary outcomes were the SL-detection rate (SDR) of proximal lesions during the second examination (SDR2nd) and SL additional rate (SAR). Secondary outcomes included the detection and additional rates of other polyps, factors contributing to SAR, and complications. RESULTS: Between 2021 and 2024, 1,319 participants with 1,267 polyps were included in the analysis. With AIM, the SDR2nd and SAR were significantly higher compared to WLI or IC (WLI vs. AIM: 2.7% vs. 14.0%, p<.001; IC vs. AIM: 7.9% vs. 14.0%, p=.002, and WLI vs. AIM: 22.4% vs. 69.3%, p<.001; IC vs. AIM: 45.8% vs. 69.3%, p=.001). AIM conferred a higher adenoma-detection rate (ADR)2nd than with WLI (10.5% vs. 24.7%; p<.001) and was an independent factor for SAR (odds ratio [95% confidence interval]: 7.79 [3.76-17.08]). No major adverse events were observed. CONCLUSIONS: AIM significantly improved proximal colon SDRs and outperformed WLI and IC. The relationship between SDR and CRC incidence warrants further investigation.

DOI： 10.14309/ajg.0000000000003411

Diagnostic accuracy and cut-off values of serum leucine-rich alpha-2 glycoprotein for Crohn's disease activity in the small bowel.

Muneyori Okita, Kento Takenaka, Fumihito Hirai, Shinya Ashizuka, Hideki Iijima, Shigeki Bamba, Toshimitsu Fujii, Kenji Watanabe, Yosuke Shimodaira, Hisashi Shiga, Sakiko Hiraoka, Toshihiro Inokuchi, Takeshi Yamamura, Ryo Emoto, Shigeyuki Matsui

Journal of gastroenterology 2025.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Small bowel (SB) lesions in Crohn's disease (CD) are often asymptomatic despite being highly active. Fecal calprotectin (FC) is the most widely used biomarker of CD activity, but its drawbacks include a large intra-individual sample variability and the burden of collecting stool samples. Meanwhile, serum leucine-rich alpha-2 glycoprotein (LRG) has recently attracted attention as a biomarker that can address the limitations of FC. This study determined the diagnostic accuracy of LRG and its cut-off values for diagnosing CD activity in SB. METHODS: This was a retrospective, multi-center study of CD patients undergoing retrograde balloon-assisted endoscopy. For ileal- and ileocolonic-type patients with a colon SES-CD score of 0, we estimated the receiver operating characteristic curve of LRG and determined the cut-off value to achieve a target sensitivity level of 80%. RESULTS: Among 285 patients with SB lesions, LRG had an area under the curve (AUC) of 0.72 (95% CI 0.67-0.78) with a sensitivity of 80.2% and specificity of 47.2% for a cut-off value of 10.5 when diagnosing endoscopic remission (modified SES-CD ≤ 3), while it had an AUC of 0.72 (95% CI 0.65-0.78) with a sensitivity of 81.2% and specificity of 46.2% for a cut-off value of 10.1 when diagnosing complete ulcer healing (modified SES-CD ≤ 1). CONCLUSION: LRG was effective for diagnosing CD activity in SB, specifically with cut-off values of 10.5 and 10.1 for endoscopic remission and complete ulcer healing, respectively. A future prospective validation study will assess its clinical utility.

DOI： 10.1007/s00535-025-02223-1

Changes of leucine-rich alpha 2 glycoprotein could be a marker of changes of endoscopic and histologic activity of ulcerative colitis. International journal

Yuki Aoyama, Sakiko Hiraoka, Eriko Yasutomi, Toshihiro Inokuchi, Takehiro Tanaka, Kensuke Takei, Shoko Igawa, Keiko Takeuchi, Masahiro Takahara, Junki Toyosawa, Yasushi Yamasaki, Hideaki Kinugasa, Jun Kato, Hiroyuki Okada, Motoyuki Otsuka

Scientific reports 15 ( 1 ) 5248 - 5248 2025.2

Language：English Publishing type：Research paper (scientific journal)

Leucine-rich alpha 2 glycoprotein (LRG) is one of the serum biomarkers for disease activity of ulcerative colitis (UC). We focused on the correlation between the changes of LRG and the changes of endoscopic and histologic activity of UC, in comparison to the changes of fecal calprotectin (Fcal), fecal immunochemical test (FIT), and C-reactive protein (CRP). Seventy-nine patients with two or more colonoscopies were enrolled, and 123 paired colonoscopies and 121 paired biopsies were examined. With regard to the change of endoscopic/histologic activity between the preceding and subsequent colonoscopy, there was improvement (n = 29/45), unchanging (n = 63/36), and worsening (n = 31/40). The correlations between the changes of marker levels and endoscopic/histologic activity were Fcal; r = 0.50/0.39 and FIT; r = 0.41/0.40, LRG; r = 0.42/0.40 and CRP; r = 0.22/0.17. Furthermore, when the correlation between the changes of LRG levels and the changes of endoscopic/histological activity was compared with those of other markers, the correlation of LRG tended to be superior to those of CRP (CRP vs. LRG; p = 0.08/0.01). LRG is equivalent to fecal markers and superior to CRP, when inferring changes in disease activity of UC based on changes in its level.

DOI： 10.1038/s41598-025-89615-8

Case-control study of IL23R rs76418789 polymorphism, smoking, and ulcerative colitis in Japan. International journal

Yoshihiro Miyake, Keiko Tanaka, Chisato Nagata, Shinya Furukawa, Akira Andoh, Tetsuji Yokoyama, Naoki Yoshimura, Kenichiro Mori, Tomoyuki Ninomiya, Yasunori Yamamoto, Eiji Takeshita, Yoshio Ikeda, Mitsuru Saito, Katsuhisa Ohashi, Hirotsugu Imaeda, Kazuki Kakimoto, Kazuhide Higuchi, Hiroaki Nunoi, Yuji Mizukami, Seiyuu Suzuki, Sakiko Hiraoka, Hiroyuki Okada, Keitarou Kawasaki, Masaaki Higashiyama, Ryota Hokari, Hiromasa Miura, Teruki Miyake, Teru Kumagi, Hiromasa Kato, Naohito Hato, Koji Sayama, Yoichi Hiasa

Cytokine 183 156743 - 156743 2024.11

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Interleukin (IL)-23 is involved in the pathogenesis of ulcerative colitis (UC). A genome-wide significant association between IL23R p.G149R (rs76418789) and UC was previously identified in Japan and Korea. This case-control study aims to examine this association within the Japanese population. METHODS: The study included 384 cases diagnosed with UC within the past 4 years and 661 control subjects. Adjustment was made for sex, age, and smoking. RESULTS: The frequency of the AA genotype of rs76418789 was 0.0 % in cases and 0.5 % in control subjects. In comparison to study subjects with the GG genotype of rs76418789, those with the GA or AA genotype had a significantly reduced risk of UC, with an adjusted odds ratio of 0.67 (95 % confidence interval: 0.44-0.999). A significant multiplicative interaction was observed between rs76418789 and having ever smoked influencing UC (p for interaction = 0.03). A significant positive association was found between having ever smoked and UC in individuals with at least one A allele, while no such positive relationship was observed in those with the GG genotype. CONCLUSION: IL23R SNP rs76418789 showed a significant association with UC. This study provides new evidence regarding the interaction between rs76418789 and smoking in relation to UC.

DOI： 10.1016/j.cyto.2024.156743

Short- and longer-term learning effects from virtual scale endoscopy videos: a useful tool for colorectal lesion size estimation (with video). International journal

Ryosuke Hirai, Hideaki Kinugasa, Mikako Ishiguro, Junki Toyosawa, Yuki Aoyama, Shoko Igawa, Yasushi Yamasaki, Toshihiro Inokuchi, Masahiro Takahara, Seiji Kawano, Sakiko Hiraoka, Motoyuki Otsuka

Gastrointestinal endoscopy 2024.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND AND AIMS: Accurate assessment of colorectal polyp size is crucial for determining treatment and surveillance policies. However, visual estimation of lesion diameter is often inaccurate, making simple and effective educational tools essential. We aimed to evaluate the learning effects of virtual scale endoscopy (VSE). METHODS: Thirty-three endoscopists first watched pre-learning videos for SET1. They then estimated the diameters of 20 lesions and referred to instructional videos with VSE for self-study. Subsequently, they watched the post-learning videos for SET2 and estimated the lesion diameters. The error between the estimated and correct lesion sizes of both sets was compared. To evaluate longer-term learning effects, participants answered SET3 and SET4, which consisted of the same questions as SET2 and SET1, respectively, 2-3 months later without watching the instructional video for SET2. RESULTS: The error in the participants' estimation of the correct lesion diameter improved from SET1 to SET2 (34.7 mm ± 6.6 vs. 30.7 mm ± 7.7; p = 0.048), with a significant learning effect and error improvement specifically among non-experts (35.2 mm ± 5.3 vs. 30 mm ± 6.8; p = 0.028). In the SET3 and SET4, participants' errors indicated that the learning effect was well maintained (SET2 vs. SET3; 30.7 mm ± 7.7 vs. 28.6 mm ± 7.2; p = 0.1, and SET1 and SET4: 34.7 mm ± 6.6 vs. 31.7 mm ± 7.1; p = 0.025). CONCLUSIONS: VSE videos are a valuable learning tool for estimating lesion diameter, particularly for novice endoscopists, both in the short- and longer-term.

DOI： 10.1016/j.gie.2024.10.038

増大号炎症性腸疾患2024 主題炎症性腸疾患の内科治療基本治療薬(5-ASA製剤,副腎皮質ステロイド,チオプリン製剤)

平岡佐規子, 石黒美佳子, 豊澤惇希, 青山祐樹, 井川翔子, 竹内桂子, 山崎泰史, 井口俊博, 衣笠秀明, 髙原政宏, 大塚基之, 金谷信彦, 近藤喜太, 田中健大

胃と腸 59 ( 10 ) 1453 - 1461 2024.10

Adverse events after different endoscopic resection procedures for small and intermediate-sized colorectal polyps. International journal

Junki Toyosawa, Yasushi Yamasaki, Yuki Aoyama, Kensuke Takei, Shoko Igawa, Toshihiro Inokuchi, Hideaki Kinugasa, Masahiro Takahara, Sakiko Hiraoka, Hiroyuki Okada, Motoyuki Otsuka

Digestive diseases (Basel, Switzerland) 1 - 9 2024.8

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND AND STUDY AIMS: Cold snare polypectomy (CSP) and underwater endoscopic mucosal resection (UEMR) have been developed recently, in addition to conventional methods, but adverse events of each method have not been fully clarified. We compared outcomes of each method for the appropriate choice. PATIENTS AND METHODS: Patients who underwent CSP, endoscopic mucosal resection (EMR)/hot snare polypectomy (HSP) or UEMR for small and intermediate-sized colorectal polyps between April 2017 and June 2020 were retrospectively examined. The rate of adverse events and recurrences due to each method were determined as main outcomes. Clinical factors related with adverse events were examined. RESULTS: A total of 1,025 patients with 3,163 polyps underwent polypectomy using any of the methods. CSP, EMR/HSP and UEMR were performed for 704 (22.2%), 2,145 (67.8%) and 314 polyps (9.9%), and median size for each method was 4, 6 and 7 mm, respectively. Delayed bleeding for CSP, EMR/HSP and UEMR was 0%, 0.2% and 0.6% (P = 0.15), and perforation was 0%, 0.1% and 0%, respectively (P = 0.62). Recurrence after CSP, EMR/HSP and UEMR was 0.1%, 0.04% and 1.0%, respectively (P < 0.01). Recurrence for UEMR was significantly higher in the early stage of procedure introduction (P = 0.001). Oral anticoagulants were the risk factor for delayed bleeding (P < 0.01, respectively). CONCLUSIONS: There was no significant difference regarding adverse events among each method for small and intermediate-sized polyps, although recurrence rate after UEMR was higher than other methods.

DOI： 10.1159/000540365

Two Cases of Cytomegalovirus Colitis During the Treatment of Immune Checkpoint Inhibitor-Associated Colitis. International journal

Masaya Iwamuro, Takehiro Tanaka, Go Makimoto, Eiki Ichihara, Sakiko Hiraoka

Cureus 16 ( 6 ) e63308 2024.6

Language：English Publishing type：Research paper (scientific journal)

Herein, we outlined two case reports of patients who developed cytomegalovirus colitis following the initiation of corticosteroid therapy for colitis as a result of immune-related adverse events (irAEs). For both patients, endoscopic findings were similar to those observed for patients with irAE colitis but were devoid of the characteristic features associated with cytomegalovirus colitis, including punched-out ulcers. Given the therapeutic disparities between these two conditions, it is imperative to distinguish between these conditions in clinical practice. When addressing exacerbations or refractory manifestations of irAE-associated colitis, clinicians should remain vigilant with regard to the potential for cytomegalovirus infection, even in the absence of punched-out ulcers in the colorectum.

DOI： 10.7759/cureus.63308

Efficacy and safety of filgotinib for ulcerative colitis: A real-world multicenter retrospective study in Japan. International journal

Shintaro Akiyama, Kaoru Yokoyama, Soichi Yagi, Shinichiro Shinzaki, Kozo Tsuruta, Shinichiro Yoshioka, Minako Sako, Hiromichi Shimizu, Mariko Kobayashi, Toshiyuki Sakurai, Kei Nomura, Tomoyoshi Shibuya, Masahiro Takahara, Sakiko Hiraoka, Kyohei Sugai, Shunichi Yanai, Atsushi Yoshida, Miki Koroku, Teppei Omori, Masayuki Saruta, Takayuki Matsumoto, Ryuichi Okamoto, Kiichiro Tsuchiya, Toshimitsu Fujii

Alimentary pharmacology & therapeutics 59 ( 11 ) 1413 - 1424 2024.6

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND AND AIMS: While filgotinib, an oral Janus kinase (JAK) 1 preferential inhibitor, is approved for moderately to severely active ulcerative colitis (UC), real-world studies assessing its short- and long-term efficacy and safety are limited. METHODS: This is a multicenter, retrospective study of UC patients who started filgotinib between March 2022 and September 2023. The primary outcome was clinical remission, defined as a partial Mayo score ≤1 with a rectal bleeding score of 0, or Simple Clinical Colitis Activity Index (SCCAI) ≤2 with a blood-in-stool score of 0. Secondary outcomes included clinical response, corticosteroid-free remission, and endoscopic improvement. Outcomes were assessed at 10, 26, and 58 weeks based on patients with available follow-up. Adverse events were evaluated. RESULTS: We identified 238 UC patients and 54% had prior exposure to biologics/JAK inhibitors. The median baseline partial Mayo score and SCCAI were 5 (IQR 3-6) and 4 (IQR 2-7). Clinical remission rates based on per-protocol analysis at 10, 26, and 58 weeks were 47% (70/149), 55.8% (48/86), and 64.6% (31/48), respectively. At a median follow-up of 28 weeks (IQR 10-54) with a discontinuation rate of 39%, the rates of clinical remission, clinical response, corticosteroid-free remission, and endoscopic improvement were 39.9% (81/203), 54.7% (111/203), and 36.5% (74/203), and 43.5% (10/23), respectively. These rates were comparable between biologic/JAK inhibitor-naïve and -experienced patients. While three patients (1.3%) developed herpes zoster infection, no cases of thrombosis or death were reported. CONCLUSIONS: Real-world data demonstrate favourable clinical and safety outcomes of filgotinib for UC.

DOI： 10.1111/apt.17961

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

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

Journal of gastroenterology 59 ( 6 ) 468 - 482 2024.6

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1007/s00535-024-02099-7

炎症性腸疾患内視鏡診療ガイドライン

松本主之, 久松理一, 江崎幹宏, 大森鉄平, 櫻庭裕丈, 新崎信一郎, 杉本健, 竹中健人, 長沼誠, 馬場重樹, 久部高司, 平岡佐規子, 藤谷幹浩, 松浦稔, 梁井俊一, 渡辺憲治, 緒方晴彦, 安藤朗, 仲瀬裕志, 大塚和朗, 平井郁仁, 藤城光弘, 五十嵐良典, 田中信治, 日本消化器内視鏡学会, 厚生労働科学研究費補助金難治性疾患政策研究事業難治性炎症性腸管障害に関する調査研究(久松班)

Gastroenterological Endoscopy 66 ( 6 ) 1387 - 1426 2024.6

Endoscopic manifestation of intestinal transplant-associated microangiopathy after stem cell transplantation. International journal

Masaya Iwamuro, Daisuke Ennishi, Nobuharu Fujii, Ken-Ichi Matsuoka, Takehiro Tanaka, Toshihiro Inokuchi, Sakiko Hiraoka, Motoyuki Otsuka

BMC gastroenterology 24 ( 1 ) 140 - 140 2024.4

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Endoscopic features of intestinal transplant-associated microangiopathy (iTAM) have not been comprehensively investigated. This study aimed to examine the endoscopic characteristics of patients diagnosed with iTAM. METHODS: This retrospective analysis included 14 patients pathologically diagnosed with iTAM after stem cell transplantation for hematolymphoid neoplasms (n = 13) or thalassemia (n = 1). The sex, age at diagnosis, endoscopic features, and prognosis of each patient were assessed. Serological markers for diagnosing transplant-associated thrombotic microangiopathy were also evaluated. RESULTS: The mean age at the time of iTAM diagnosis was 40.2 years. Patients diagnosed based on the pathognomonic pathological changes of iTAM presented with diverse symptoms at the times of endoscopic examinations, including diarrhea (n = 10), abdominal pain (n = 5), nausea (n = 4), appetite loss (n = 2), bloody stools (n = 2), abdominal discomfort (n = 1), and vomiting (n = 1). At the final follow-up, six patients survived, while eight patients succumbed, with a median time of 100.5 days (range: 52-247) post-diagnosis. Endoscopic manifestations included erythematous mucosa (n = 14), erosions (n = 13), ulcers (n = 9), mucosal edema (n = 9), granular mucosa (n = 9), and villous atrophy (n = 4). Erosions and/or ulcers were primarily observed in the colon (10/14, 71%), followed by the ileum (9/13, 69%), stomach (4/10, 40%), cecum (5/14, 36%), duodenum (3/10, 30%), rectum (4/14, 29%), and esophagus (1/10, 10%). Cytomegalovirus infection (n = 4) and graft-versus-host disease (n = 2) coexisted within the gastrointestinal tract. Patients had de novo prolonged or progressive thrombocytopenia (6/14, 43%), decreased hemoglobin concentration (4/14, 29%), reduced serum haptoglobin level (3/14, 21%), and a sudden and persistent increase in lactate dehydrogenase level (2/14, 14%). Peripheral blood samples from 12 patients were evaluated for schistocytes, with none exceeding 4%. CONCLUSIONS: This study provides a comprehensive exploration of the endoscopic characteristics of iTAM. Notably, all patients exhibited erythematous mucosa throughout the gastrointestinal tract, accompanied by prevalent manifestations, such as erosions (93%), ulcers (64%), mucosal edema (64%), granular mucosa (64%), and villous atrophy (29%). Because of the low positivity for serological markers of transplant-associated thrombotic microangiopathy in patients with iTAM, endoscopic evaluation and biopsy of these lesions are crucial, even in the absence of these serological features.

DOI： 10.1186/s12876-024-03221-y

UnderwaterとUnder-gelでの大腸腫瘍性病変に対する境界診断能の検討

豊澤惇希, 山崎泰史, 青山祐樹, 井川翔子, 井口俊博, 衣笠秀明, 高原政宏, 平岡佐規子, 大塚基之

Gastroenterological Endoscopy 66 ( Suppl.1 ) 969 - 969 2024.4

大腸鋸歯状病変の病態解明と診療戦略 Serrated polyposis syndromeの臨床病理学的特徴とその発癌ポテンシャルの検討

平井亮佑, 衣笠秀明, 平岡佐規子, 田中健大, 大塚基之

日本消化器病学会雑誌 121 ( 臨増総会 ) A215 - A215 2024.3

神経線維腫症の消化管合併症に関する検討

本田真奈美, 岩室雅也, 山崎泰史, 田中健大, 川野誠司, 平岡佐規子, 河原祥朗, 大塚基之

日本消化器病学会雑誌 121 ( 臨増総会 ) A349 - A349 2024.3

Utility of Combined Use of Transabdominal Ultrasonography and Fecal Immunochemical Test Examinations in Ulcerative Colitis.

Masahiro Takahara, Sakiko Hiraoka, Masayasu Ohmori, Keiko Takeuchi, Kensuke Takei, Yuki Aoyama, Eriko Yasutomi, Shoko Igawa, Toshihiro Inokuchi, Junki Toyosawa, Yasushi Yamasaki, Hideaki Kinugasa, Keita Harada, Hideki Onishi, Hiroyuki Okada

Acta medica Okayama 78 ( 1 ) 79 - 83 2024.2

Language：English Publishing type：Research paper (scientific journal)

This study examined the utility of the combined use of transabdominal ultrasonography (TUS) and fecal immunochemical testing (FIT) to detect mucosal inflammation, vis-a-vis the Mayo endoscopic subscore (MES), in ulcerative colitis (UC). Sixty-three UC patients who underwent TUS and FIT were retrospectively enrolled. For TUS, the colon was divided into five segments, and the bowel wall thickness was measured and evaluated. The accuracy of FIT (> 100 ng/ml) in detecting mucosal inflammation (MES>0) was 0.93, whereas that of TUS (BWT>2 mm) in each segment was 0.84-0.97. The combined use of TUS and FIT may be helpful in noninvasive treatment strategies.

DOI： 10.18926/AMO/66674

Coffee and caffeine intake reduces risk of ulcerative colitis: a case-control study in Japan. International journal

Keiko Tanaka, Hitomi Okubo, Yoshihiro Miyake, Chisato Nagata, Shinya Furukawa, Akira Andoh, Tetsuji Yokoyama, Naoki Yoshimura, Kenichiro Mori, Tomoyuki Ninomiya, Yasunori Yamamoto, Eiji Takeshita, Yoshio Ikeda, Mitsuru Saito, Katsuhisa Ohashi, Hirotsugu Imaeda, Kazuki Kakimoto, Kazuhide Higuchi, Hiroaki Nunoi, Yuji Mizukami, Seiyuu Suzuki, Sakiko Hiraoka, Hiroyuki Okada, Keitarou Kawasaki, Masaaki Higashiyama, Ryota Hokari, Hiromasa Miura, Teruki Miyake, Teru Kumagi, Hiromasa Kato, Naohito Hato, Koji Sayama, Yoichi Hiasa

Journal of gastroenterology and hepatology 39 ( 3 ) 512 - 518 2023.12

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND AND AIM: Although diet is one of the potential environmental factors affecting ulcerative colitis (UC), evidence is not sufficient to draw definitive conclusions. This Japanese case-control study examined the association between the consumption of coffee, other caffeine-containing beverages and food, and total caffeine and the risk of UC. METHODS: The study involved 384 UC cases and 665 control subjects. Intake of coffee, decaffeinated coffee, black tea, green tea, oolong tea, carbonated soft drinks, and chocolate snacks was measured with a semiquantitative food-frequency questionnaire. Adjustments were made for sex, age, pack-years of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, body mass index, and intake of vitamin C, retinol, and total energy. RESULTS: Higher consumption of coffee and carbonated soft drinks was associated with a reduced risk of UC with a significant dose-response relationship (P for trend for coffee and carbonated soft drinks were <0.0001 and 0.01, respectively), whereas higher consumption of chocolate snacks was significantly associated with an increased risk of UC. No association was observed between consumption of decaffeinated coffee, black tea, green tea, or oolong tea and the risk of UC. Total caffeine intake was inversely associated with the risk of UC; the adjusted odds ratio between extreme quartiles was 0.44 (95% confidence interval: 0.29-0.67; P for trend <0.0001). CONCLUSIONS: We confirmed that intake of coffee and caffeine is also associated with a reduced risk of UC in Japan where people consume relatively low quantities of coffee compared with Western countries.

DOI： 10.1111/jgh.16439

Low Patient Weight and Long Intubation Time Are Key Factors for Pain during Colonoscopy.

Shohei Oka, Keita Harada, Shumpei Yamamoto, Eriko Yasutomi, Shoko Igawa, Masayasu Ohmori, Mami Hirai, Yasushi Yamasaki, Toshihiro Inokuchi, Hideaki Kinugasa, Masahiro Takahara, Sakiko Hiraoka, Hiroyuki Okada

Acta medica Okayama 77 ( 5 ) 471 - 478 2023.10

Language：English Publishing type：Research paper (scientific journal)

Although the clinical usefulness of colonoscopy has been established, the procedure remains painful for many patients. This study was designed to clarify the factors predicting colonoscopy-related pain. We evaluated 283 consecutive patients who completed a first-ever, total colonoscopy without sedatives or analgesics. The severity of pain symptoms was evaluated by a numeric rating scale (NRS) in a questionnaire immediately after the colonoscopy. Patient backgrounds and endoscopic findings were analyzed to evaluate their association with pain. Out of 283 patients, 53 scored their pain 0-1 on the NRS while 48 scored it 6-10. We defined the colonoscopies of the former and latter patients as painless and painful, respectively, and compared the two. Multivariate analyses revealed that low body weight (OR 4.95, 95%CI 1.89-12.99) and longer intubation time (OR 3.63, 95%CI 1.46-9.03) were significant risk factors for painful colonoscopy. To identify factors contributing to the increased intubation time, we divided subjects into short- and long-intubation-time groups based on a median insertion time of 7 min. Older age (OR 2.28, 95%CI 1.31-3.98), previous abdominal surgery (OR 1.93, 95%CI 1.13-3.32) and findings of invasive cancer (OR 10.90, 95%CI 1.34-88.90) were significant factors for longer intubation time.

DOI： 10.18926/AMO/65969

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

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

Journal of gastroenterology 58 ( 10 ) 1015 - 1029 2023.10

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1007/s00535-023-02029-z

Vulvar Crohn's disease presenting with multiple exophytic nodules and labial swelling: A case report. International journal

Ai Kajita, Yoshio Kawakami, Sakiko Hiraoka, Junko Haraga, Shin Morizane

The Journal of dermatology 50 ( 12 ) e411-e412 2023.8

Predictive Factors for Efficacy of Oral Tacrolimus Induction Therapy in Moderate to Severe Ulcerative Colitis Patients: Large Multicenter Retrospective Cohort Study. International journal

Naoki Oshima, Sakiko Hiraoka, Ryohei Hayashi, Sakuma Takahashi, Manabu Ishii, Shinichi Hashimoto, Kazuo Yashima, Shoko Igawa, Toshihiro Inokuchi, Yoshitaka Ueno, Tomoki Inaba, Hiroshi Matsumoto, Kousaku Kawashima, Taro Takami, Hajime Isomoto, Akiko Shiotani, Shinji Tanaka, Shunji Ishihara

Inflammatory bowel diseases 30 ( 7 ) 1087 - 1093 2023.8

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Tacrolimus (TAC), a calcineurin inhibitor, is used for remission induction therapy in patients with moderate to severe ulcerative colitis (UC), with short-term efficacy and related predictive factors shown in previous cohort studies. However, most studies reported data for only a limited number of patients enrolled from a single center. We performed a large multicenter retrospective cohort study to identify factors related to prediction of clinical remission in UC patients treated with oral TAC. METHODS: The medical records of patients with moderate to severe UC treated with oral TAC as induction therapy at 7 institutions between April 2009 and March 2017 were retrospectively reviewed. RESULTS: A total of 216 patients who received TAC for induction were analyzed, of whom 123 (56.9%) showed clinical remission at week 12. Logistic regression analysis indicated that previous or current use of antitumor necrosis factor (TNF)-α antibodies (odds ratio [OR], 0.259; P = .006), and concomitant treatment with 5-aminosalicylate (5-ASA) at the baseline (OR, 0.268; P = .005) were independent predictive factors correlated with failure of clinical remission, whereas higher levels of C-reactive protein (OR, 1.124; P = .014) predicted achievement of clinical remission. CONCLUSIONS: Results of this multicenter study clearly indicate the efficacy of TAC induction therapy for patients with moderate to severe UC. Notably, previous or current use of anti-TNF-α antibodies was associated with poor achievement of clinical remission by week 12.

DOI： 10.1093/ibd/izad150

血流豊富な粘膜下腫瘍の形態を呈した上行結腸血管周囲類上皮細胞腫の1例

青山祐樹, 井口俊博, 平岡佐規子, 豊澤惇希, 竹井健介, 井川翔子, 山崎泰史, 衣笠秀明, 高原政宏, 庄司良平, 近藤喜太, 柳井広之, 大塚基之

日本消化器内視鏡学会中国支部例会 130回 81 - 81 2023.6

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

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

Journal of gastroenterology 58 ( 3 ) 205 - 216 2023.3

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1007/s00535-022-01949-6

RNA editing is a valuable biomarker for predicting carcinogenesis in ulcerative colitis. International journal

Kazutaka Takahashi, Kunitoshi Shigeyasu, Yoshitaka Kondo, Kazuyoshi Gotoh, Shuya Yano, Yuzo Umeda, Toshihiro Inokuchi, Caiming Xu, Kazuhiro Yoshida, Hibiki Umeda, Toshiaki Takahashi, Sho Takeda, Ryuichi Yoshida, Fuminori Teraishi, Hiroyuki Kishimoto, Yoshiko Mori, Kazuhiro Noma, Yoshinaga Okugawa, Sakiko Hiraoka, Hiroyuki Michiue, Hiroshi Tazawa, Osamu Matsushita, Ajay Goel, Toshiyoshi Fujiwara

Journal of Crohn's & colitis 17 ( 5 ) 754 - 766 2022.12

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND AND AIMS: Ulcerative colitis (UC) can develop colitis-associated colorectal neoplasm (CAN). Adenine-to-inosine RNA editing, which is regulated by adenosine deaminase acting on RNA (ADAR), induces the posttranscriptional modification of critical oncogenes, including antizyme inhibitor 1 (AZIN1), leading to colorectal carcinogenesis. Therefore, we hypothesized that ADAR1 might be involved in the development of CAN in UC. METHODS: We systematically analyzed a cohort of 139 UC cases (40 acute phase, 73 remission phase, 26 CAN). The degree of inflammation was evaluated using the Mayo endoscopic score (MES). RESULTS: The type 1 IFN-related inflammation pathway was upregulated in the rectum of active UC, rectum of UC-CAN, and tumor site of UC-CAN patients. ADAR1 expression was upregulated in the entire colon of CAN cases, while it was down-regulated in non-CAN MES0 cases. ADAR1 expression in the rectum predicted the development of CAN better than p53 or β-catenin, with an area under the curve of 0.93. The high expression of ADAR1 and high AZIN1 RNA editing in UC was triggered by type 1 IFN stimulation from UC-specific microbiomes, such as Fusobacterium in vitro analyses. The induction of AZIN1 RNA editing by ADAR1, whose expression is promoted by Fusobacterium, may induce carcinogenesis in UC. CONCLUSIONS: The risk of CAN can be evaluated by assessing ADAR1 expression in the rectum of MES0 UC patients, freeing UC patients from unnecessary colonoscopy and reducing their physical burden. RNA editing may be involved in UC carcinogenesis, and may be used to facilitate the prevention and treatment of CAN in UC.

DOI： 10.1093/ecco-jcc/jjac186

【高齢者潰瘍性大腸炎の現状】高齢者潰瘍性大腸炎の内科的治療とその見極め

井口俊博, 高原政宏, 平岡佐規子

日本消化器病学会雑誌 119 ( 11 ) 992 - 1003 2022.11

Language：Japanese Publisher：(一財)日本消化器病学会

近年,高齢潰瘍性大腸炎(UC)患者数が増加しており,特に若年発症して長期経過を追っている高齢UC症例と異なり,高齢になって新規に発症したUCは治療に難渋する症例が少なくない.また年齢だけで高齢者の全身状態を判断することはできず,症例によって脆弱性やリスクが異なるため,注意が必要である.現在使用できる治療薬はいずれも高齢者を対象とした試験を経ず保険収載されており,リアルワールドデータを基に有効性,安全性の判断をせざるを得ない.高齢者特有の併存疾患の管理,ポリファーマシーと相互作用,認知症,身体機能低下,易感染状態などのリスクを考慮し,重篤な状態になる前に常に早期介入を心掛ける必要がある.(著者抄録)

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2022&ichushi_jid=J01118&link_issn=&doc_id=20221116250003&doc_link_id=10.11405%2Fnisshoshi.119.992&url=https%3A%2F%2Fdoi.org%2F10.11405%2Fnisshoshi.119.992&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

【潰瘍性大腸炎内科診療の新時代】日常診療に有用な潰瘍性大腸炎のバイオマーカー

青山祐樹, 平岡佐規子, 井口俊博, 竹井健介, 井川翔子, 竹内桂子, 高原政宏

医学と薬学 79 ( 11 ) 1461 - 1468 2022.10

手技の解説クローン病におけるダブルバルーン内視鏡下逆行性造影の実際

井口俊博, 川野誠司, 平岡佐規子

Gastroenterological Endoscopy 64 ( 10 ) 2308 - 2316 2022.10

Language：Japanese Publisher：(一社)日本消化器内視鏡学会

クローン病患者の7割以上が小腸病変を有するとされ,小腸病変のモニタリングとその制御は患者のQOLに直結する.従ってクローン病診療では,全小腸を高精度でかつ手軽に,そして低侵襲にモニタリングすることが求められるが,残念ながらすべてを兼ね備えた検査やマーカーは未だ存在しない.ダブルバルーン内視鏡検査は,クローン病小腸病変に対するモニタリング検査の1つとして,また時に内視鏡的拡張術目的に広く使用されている.当科ではダブルバルーン内視鏡検査の際に通常の観察に加えて先端バルーンを拡張させて逆行性造影を行い,それまでは難しかった深部小腸の評価をルーチンで行っている.本稿では,クローン病小腸病変に対するダブルバルーン内視鏡下逆行性造影の手順やコツを解説する.(著者抄録)

クローン病患者の内視鏡活動性と活動性の変化を予測するバイオマーカーは?

井口俊博, 平岡佐規子, 豊澤惇希, 竹井健介, 青山祐樹, 井川翔子, 竹内桂子, 山崎泰史, 衣笠秀明, 高原政宏, 原田馨太, 岡田裕之

日本消化器病学会雑誌 119 ( 臨増大会 ) A750 - A750 2022.10

The Colon Wall Thickness Measured Using Transabdominal Ultrasonography Is Useful for Detecting Mucosal Inflammation in Ulcerative Colitis.

Masahiro Takahara, Sakiko Hiraoka, Masayasu Ohmori, Keiko Takeuchi, Kensuke Takei, Eriko Yasutomi, Shoko Igawa, Shumpei Yamamoto, Yasushi Yamasaki, Toshihiro Inokuchi, Hideaki Kinugasa, Keita Harada, Hideki Ohnishi, Hiroyuki Okada

Internal medicine (Tokyo, Japan) 61 ( 18 ) 2703 - 2709 2022.9

Language：English Publishing type：Research paper (scientific journal)

Objective Transabdominal ultrasonography (TUS) is a non-invasive procedure that is reportedly useful for managing ulcerative colitis (UC) and assessing bowel wall thickness (BWT), the most common measure of mucosal inflammation. However, the exact range of BWT that reflects disease activity remains undetermined. The present study clarified the BWT due to disease activity by comparing the use of TUS in each segment of the colon versus using colonoscopy (CS) and determined the usefulness of TUS in patients with UC. Methods We divided the colon into five segments and measured the BWT using TUS. The results were then compared to the Mayo endoscopic subscore (MES) classification to determine the accuracy of BWT measurement. Patients Eighty patients with UC who underwent TUS within 14 days of CS were retrospectively registered. Results We evaluated a total of 268 images depicting each segment among 80 patients with UC. The BWT was positively correlated with endoscopic activity (0.69, p<0.0001). In each segment, the relationship between a BWT>2 mm and an MES>0 had the highest sensitivity, specificity, and accuracy (0.85-1.00, 0.67-0.92, and 0.81-0.97, respectively). Conclusion This study concluded that TUS was a useful method of detecting an MES>0, which indicates the presence of inflammation and its location among UC patients. MES>0 was found to be highly accurate when a BWT>2 mm was considered positive. This non-invasive method may help control disease activity in patients with UC.

DOI： 10.2169/internalmedicine.8827-21

IL12B rs6887695 polymorphism and interaction with alcohol intake in the risk of ulcerative colitis in Japan. International journal

Yoshihiro Miyake, Keiko Tanaka, Chisato Nagata, Shinya Furukawa, Akira Andoh, Tetsuji Yokoyama, Naoki Yoshimura, Kenichiro Mori, Tomoyuki Ninomiya, Yasunori Yamamoto, Eiji Takeshita, Yoshio Ikeda, Mitsuru Saito, Katsuhisa Ohashi, Hirotsugu Imaeda, Kazuki Kakimoto, Kazuhide Higuchi, Hiroaki Nunoi, Yuji Mizukami, Seiyuu Suzuki, Sakiko Hiraoka, Hiroyuki Okada, Keitarou Kawasaki, Masaaki Higashiyama, Ryota Hokari, Hiromasa Miura, Teruki Miyake, Teru Kumagi, Hiromasa Kato, Naohito Hato, Koji Sayama, Yoichi Hiasa

Cytokine 155 155901 - 155901 2022.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The interleukin (IL)-23/Th17 pathway plays a critical role in ulcerative colitis (UC). The IL-12p40 subunit, which is shared by IL-23 and IL-12, is encoded by the IL12B gene. The current case-control study investigated the association between IL12B SNP rs6887695 and the UC risk. METHODS: There were 384 cases within 4 years of UC diagnosis and 661 controls who were enrolled. Adjustments were made for sex, age, pack-years of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, and body mass index. RESULTS: Subjects with the GG IL12B SNP rs6887695 genotype had a significantly increased risk of UC compared with those with the CC genotype (adjusted odds ratio [AOR], 1.60; 95% confidence interval [CI], 1.08-2.36). This positive association was also significant using the additive and recessive models (AOR, 1.25; 95% CI, 1.03-1.52; AOR, 1.50; 95% CI, 1.08-2.09, respectively). An independent inverse relationship was observed between ever alcohol consumption and the UC risk in those with the CC genotype while no significant association was found in those with at least one G allele (P for interaction = 0.0008). CONCLUSIONS: IL12B SNP rs6887695 was significantly associated with UC. The influence of alcohol consumption might rely on rs6887695.

DOI： 10.1016/j.cyto.2022.155901

消化管疾患と性差女性IBD患者における月経周期と腹部症状との関わりを探る

井口俊博, 平岡佐規子, 青山祐樹, 竹井健介, 井川翔子, 竹内桂子, 高原政宏, 近藤喜太

日本高齢消化器病学会誌 25 ( 1 ) 144 - 144 2022.7

Usefulness of Intestinal Ultrasound to Detect Small Intestinal Stenosis in Patients with Crohn's Disease. International journal

Keiko Takeuchi, Toshihiro Inokuchi, Masahiro Takahara, Masayasu Ohmori, Eriko Yasutomi, Shohei Oka, Shoko Igawa, Kensuke Takei, Yuki Baba, Seiji Kawano, Yasushi Yamasaki, Hideaki Kinugasa, Keita Harada, Sakiko Hiraoka, Hiroyuki Okada

Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine 42 ( 2 ) 373 - 383 2022.6

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: Double balloon enteroscopy (DBE) with retrograde contrast is useful as a monitoring tool for small intestinal lesions in Crohn's disease (CD), but these are burdensome for patients. Intestinal ultrasound (IUS) can be used with ease in daily clinical practice, but there is less evidence regarding the accuracy of detection of small intestinal stenosis in CD. This study aimed to examine the diagnostic power of IUS for small intestinal stenosis in patients with CD. METHODS: The findings of DBE and IUS in 86 patients with CD with small intestinal lesions were evaluated. Using DBE as the reference standard, we examined the detection rate of IUS for small intestinal stenosis. We evaluated three parameters: luminal narrowing, prestenotic dilation, and to-and-fro movement for determining stenosis using IUS. In addition, we compared the characteristics between the stenosis-detectable and stenosis-undetectable groups by IUS. RESULTS: Of the 86 patients, 30 had small intestinal stenosis. In IUS findings, when lesions that met two or more of the three parameters were judged as stenosis, the detection rate was 70.0% for sensitivity, 98.2% for specificity, and 88.4% for accuracy. Moreover, there were patients with a younger age at diagnosis (P < 0.05) and more ileocolonic disease location (P < 0.05) in the stenosis-detectable group by IUS. The stenoses detected by IUS were significantly longer than those undetected by IUS (14.1 mm versus 5.2 mm, P < 0.05). CONCLUSIONS: IUS delivered reliable results for clinically important small intestinal stenosis of CD with high diagnostic accuracy.

DOI： 10.1002/jum.16038

【Common diseaseとなった潰瘍性大腸炎の現状と診療のコツ】5-ASA製剤の種類,適応症例と使い方および副作用不耐も含めて

安富絵里子, 井口俊博, 平岡佐規子

臨床消化器内科 37 ( 7 ) 759 - 764 2022.6

Language：Japanese Publisher：(株)日本メディカルセンター

＜文献概要＞5-アミノサリチル酸(5-ASA)製剤は潰瘍性大腸炎(UC)の寛解導入と寛解維持に有効であり,軽症〜中等症のUCに用いる基本薬である.本邦ではサラゾスルファピリジンと3種類のメサラジン製剤を用いることが可能で,それぞれ5-ASAの放出機構,薬物動態に特徴がある.寛解導入効果は標準用量から高用量の5-ASAで有効性が認められており,十分量の投与が必要である.また,寛解維持にはアドヒアランスの遵守が重要である.5-ASAは全身の免疫抑制作用はなく安全性は高いとされるが,副作用もある.とくに,腹部症状の悪化をきたす「5-ASAアレルギー」と呼ばれるものがあり,5-ASA製剤内服開始1〜2週間程度で出現することが多い.近年その増加も指摘されており,注意を要する.

【潰瘍性大腸炎内科診療の即戦力を身につける!-急増する患者の日常診療に求められる必須アップデート-】基準治療 5-ASA製剤と局所製剤の最適化熟知し使いこなす!

安富絵里子, 井口俊博, 平岡佐規子

消化器内科 4 ( 6 ) 40 - 47 2022.6

Language：Japanese Publisher：(株)医学出版

5-aminosalicylic acid(5-ASA)製剤は軽症から中等症までの潰瘍性大腸炎(UC)の寛解導入・寛解維持の両方に用いることのできる基本薬である。日本ではサラゾスルファピリジンと3種類のメサラジン製剤およびそれらのジェネリック製剤、局所製剤(坐剤・注腸製剤)を使用することができる。5-ASA製剤の最大用量の投与により7割前後の症例で有効性が見込まれる。5-ASA製剤による治療中に再燃をきたした場合はアドヒアランスや用量の確認、局所製剤の追加や5-ASA製剤のローテーションも考慮される。また、5-ASA製剤は安全性の高い薬であるが、気を付けるべき副作用もある。特に、治療開始1〜2週間後に発熱、下痢、腹痛の悪化を呈した場合は5-ASA製剤によるアレルギーを疑う。UCの増悪と鑑別が難しい場合もあるが、疑わしい症例に遭遇した場合は5-ASAアレルギーの可能性を念頭におき、製剤を中止することが必要である。(著者抄録)

The diagnostic ability to classify neoplasias occurring in inflammatory bowel disease by artificial intelligence and endoscopists: A pilot study. International journal

Shumpei Yamamoto, Hideaki Kinugasa, Kenta Hamada, Masahiro Tomiya, Takayoshi Tanimoto, Akimitsu Ohto, Akira Toda, Daisuke Takei, Minoru Matsubara, Seiyu Suzuki, Kosuke Inoue, Takehiro Tanaka, Sakiko Hiraoka, Hiroyuki Okada, Yoshiro Kawahara

Journal of gastroenterology and hepatology 37 ( 8 ) 1610 - 1616 2022.5

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND AND AIM: Although endoscopic resection with careful surveillance instead of total proctocolectomy become to be permitted for visible low-grade dysplasia, it is unclear how accurately endoscopists can differentiate these lesions, as classifying neoplasias occurring in inflammatory bowel disease (IBDN) is exceedingly challenging due to background chronic inflammation. We evaluated a pilot model of an artificial intelligence (AI) system for classifying IBDN and compared it with the endoscopist's ability. METHODS: This study used a deep convolutional neural network, the EfficientNet-B3. Among patients who underwent treatment for IBDN at two hospitals between 2003 and 2021, we selected 862 non-magnified endoscopic images from 99 IBDN lesions and utilized 6 375 352 images that were increased by data augmentation for the development of AI. We evaluated the diagnostic ability of AI using two classifications: the "adenocarcinoma/high-grade dysplasia" and "low-grade dysplasia/sporadic adenoma/normal mucosa" groups. We compared the diagnostic accuracy between AI and endoscopists (three non-experts and four experts) using 186 test set images. RESULTS: The diagnostic ability of the experts/non-experts/AI for the two classifications in the test set images had a sensitivity of 60.5% (95% confidence interval [CI]: 54.5-66.3)/70.5% (95% CI: 63.8-76.6)/72.5% (95% CI: 60.4-82.5), specificity of 88.0% (95% CI: 84.7-90.8)/78.8% (95% CI: 74.3-83.1)/82.9% (95% CI: 74.8-89.2), and accuracy of 77.8% (95% CI: 74.7-80.8)/75.8% (95% CI: 72-79.3)/79.0% (95% CI: 72.5-84.6), respectively. CONCLUSIONS: The diagnostic accuracy of the two classifications of IBDN was higher than that of the experts. Our AI system is valuable enough to contribute to the next generation of clinical practice.

DOI： 10.1111/jgh.15904

Fever and electrocoagulation syndrome after colorectal endoscopic submucosal dissection for patients with immunosuppressants and steroids. International journal

Shumpei Yamamoto, Hideaki Kinugasa, Yasushi Yamasaki, Mami Hirai, Soichiro Ako, Kensuke Takei, Shoko Igawa, Eriko Yasutomi, Shohei Oka, Masayasu Ohmori, Toshihiro Inokuchi, Keita Harada, Sakiko Hiraoka, Kazuhiro Nouso, Takehiro Tanaka, Hiroyuki Okada

DEN open 2 ( 1 ) e83 2022.4

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: Transient fever and electrocoagulation syndrome after colorectal endoscopic submucosal dissection (ESD) remain a challenge. The aim of this study was to assess the risk factors of post-ESD fever and post-ESD coagulation syndrome (PECS), focusing on the involvement of immunosuppressive drugs and steroids (IM). METHODS: This retrospective analysis included 510 patients who underwent colorectal ESD at Okayama University Hospital from 2015 to 2020. The incidence rate, clinical outcome, and factors associated with post-ESD fever and PECS were investigated. RESULTS: Post-ESD fever and PECS occurred in 63 patients (12.4%) and 43 patients (8.4%), respectively. In multivariate analysis, the American Society of Anesthesiologists Physical Status ≥3, the use of immunosuppressants or prednisolone ≥5mg (IM group), and injury to muscle layer/perforation were significantly associated with post-ESD fever. In PECS, IM group, tumors located on the right side, treatment time ≥60 min, injury to the muscle layer, and multiple lesions were independent risk factors. Both post-ESD fever and PECS improved conservatively in the IM group, and no serious complication was observed. CONCLUSIONS: The use of IM was a risk factor for both post-ESD fever and PECS. However, there were no serious complications in colorectal ESD for patients taking IM.

DOI： 10.1002/deo2.83

UnderwaterとUnder-gelでの大腸腫瘍性病変に対する境界診断能の検討

豊澤惇希, 山崎泰史, 岡田裕之, 竹井健介, 青山祐樹, 井川翔子, 安富絵里子, 山本峻平, 竹内桂子, 高原政宏, 衣笠秀明, 原田馨太, 平岡佐規子

Gastroenterological Endoscopy 64 ( Suppl.1 ) 761 - 761 2022.4

消化管の炎症性疾患における超音波の役割クローン病の活動性評価における経腹超音波検査の有用性

高原政宏, 平岡佐規子, 大森正泰, 竹内佳子, 井口俊博, 大西秀樹, 岡田裕之

超音波医学 49 ( Suppl. ) S243 - S243 2022.4

Metformin ameliorates chronic colitis in a mouse model by regulating interferon-γ-producing lamina propria CD4+ T cells through AMPK activation. International journal

Masahiro Takahara, Akinobu Takaki, Sakiko Hiraoka, Kensuke Takei, Eriko Yasutomi, Shoko Igawa, Shumpei Yamamoto, Shohei Oka, Masayasu Ohmori, Yasushi Yamasaki, Toshihiro Inokuchi, Hideaki Kinugasa, Keita Harada, Heiichiro Udono, Hiroyuki Okada

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 36 ( 2 ) e22139 2022.2

Language：English Publishing type：Research paper (scientific journal)

Metformin, a commonly prescribed drug for type 2 diabetes mellitus, has been shown to activate AMP-activated protein kinase (AMPK). Notably, AMPK activation has recently been observed to be associated with anti-inflammatory responses. Metformin is also reported to elicit anti-inflammatory responses in CD4+ T cells, resulting in improvement in experimental chronic inflammatory diseases, such as systemic lupus erythematosus. To investigate the effect of metformin on inflammatory bowel disease (IBD), we developed a T cell-transfer model of chronic colitis in which SCID mice were injected with CD4+ CD45RBhigh T cells to induce colitis. We examined the effects of metformin via in vitro and in vivo experiments on lamina propria (LP) CD4+ T cells. We observed that metformin suppresses the frequency of interferon (IFN) -γ-producing LP CD4+ T cells in vitro, which were regulated by AMPK activation, a process possibly induced by the inhibition of oxidative phosphorylation. Furthermore, we examined the effects of metformin on an in vivo IBD model. Metformin-treated mice showed AMPK activation in LP CD4+ T cells and ameliorated colitis. Our study demonstrates that metformin-induced AMPK activation in mucosal CD4+ T cells contributes to the improvement of IBD by suppressing IFN-γ production. Moreover, our results indicate that AMPK may be a target molecule for the regulation of mucosal immunity and inflammation. Thus, AMPK-activating drugs such as metformin may be potential therapeutic agents for the treatment of IBD.

DOI： 10.1096/fj.202100831RR

A consensus statement on health-care transition for childhood-onset inflammatory bowel disease patients. International journal

Hideki Kumagai, Toshiaki Shimizu, Itaru Iwama, Shin-Ichiro Hagiwara, Takahiro Kudo, Michiko Takahashi, Takeshi Saito, Reiko Kunisaki, Motoi Uchino, Sakiko Hiraoka, Makoto Naganuma, Ken Sugimoto, Jun Miyoshi, Tomoyoshi Shibuya, Tadakazu Hisamatsu

Pediatrics international : official journal of the Japan Pediatric Society 64 ( 1 ) e15241 2022.1

Language：English Publishing type：Research paper (scientific journal)

Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder of the intestine. The incidence of IBD is increasing worldwide, including Japan, and in approximately 25% of all affected patients it is diagnosed before 18 years of age. For the health maintenance of such patients, planned transition to adult care systems is essential. Previous Japanese surveys have revealed gaps between adult and pediatric gastroenterologists with regard to their knowledge and perception of health-care transition for patients with childhood-onset IBD. In 2021-2022, several Web workshops to discuss issues related to the transitional care of IBD patients were held by the Ministry of Health, Labour and Welfare of Japan as part of their program for research on intractable diseases. Clinicians experienced in IBD treatment for pediatric and adult patients participated. As a result, this panel of adult and pediatric gastroenterologists developed five consensus statements on the issue of "transfer from pediatric to adult care" and nine statements on the issue of "addressing transitional care (transition program)." To address current gaps in health-care transition for childhood-onset IBD patients, a programmed approach to transition, and better partnerships between pediatric and adult gastroenterologists are indicated. It is hoped that this consensus statement will provide a basis for the development of appropriate guidelines for clinical practice.

DOI： 10.1111/ped.15241

潰瘍性大腸炎患者における直腸粘膜内のリンパ球分画構成の検討

岩室雅也, 高橋孝英, 田中健大, 平岡佐規子, 岡田裕之

日本消化管学会雑誌 6 ( Suppl. ) 208 - 208 2022.1

[The medical treatment of elderly patients with ulcerative colitis and its limitation].

Toshihiro Inokuchi, Masahiro Takahara, Sakiko Hiraoka

Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology 119 ( 11 ) 992 - 1003 2022

Enriched CD45RA-CD62L+ central memory T and decreased CD3+CD56+ natural killer T lymphocyte subsets in the rectum of ulcerative colitis patients. International journal

Masaya Iwamuro, Takahide Takahashi, Natsuki Watanabe, Takehiro Tanaka, Toshihiro Inokuchi, Sakiko Hiraoka, Fumio Otsuka, Hiroyuki Okada

International journal of immunopathology and pharmacology 36 20587384211051982 - 20587384211051982 2022

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: To investigate the distinctive features of lymphocytes promoting inflammation in ulcerative colitis. METHODS: We performed flow cytometric analysis of peripheral blood mononuclear cells (PBMCs) and colorectal mucosa lymphocytes in ulcerative colitis patients (n = 13) and control patients (n = 5). RESULTS: CD62L+/CD3+CD4+ (35.7 ± 14.0% vs. 19.9 ± 6.4%) and CD62L+/CD3+CD4- cells (17.1 ± 17.4% vs. 2.4 ± 3.9%) were higher in the rectum of ulcerative colitis patients than in control patients. Subpopulation analysis revealed that CD45RA-CD62L+/CD3+CD4+, that is, central memory T cell fraction in CD4+ T cells, was significantly increased in the rectum of ulcerative colitis, compared to that in control patients (23.3 ± 10.5% vs. 8.2 ± 4.0%). Comparison of rectum and colon samples in ulcerative colitis patients indicated that CD56+/CD3+ was decreased in the rectum compared to that in the colon (11.3 ± 12.5% vs. 21.3 ± 16.5%). The ratio of CD56+/CD3+ was also decreased in the rectum of active ulcerative colitis patients compared to that in ulcerative colitis patients at the endoscopic remission stages (2.8 ± 1.7% vs. 18.5 ± 13.3%). CONCLUSION: We demonstrated that CD62L+ T lymphocytes, particularly the CD45RA-CD62L+ T cell subset that represents central memory T cells, were increased in the rectum of patients with ulcerative colitis. In addition, the CD56+/CD3+ subset (natural killer T cells) was decreased in the rectum compared to that of less inflamed colonic mucosa. These results suggest that the enrichment of central memory T lymphocytes and the reduction of natural killer T cells in the gut mucosa are involved in the pathogenesis of ulcerative colitis.

DOI： 10.1177/20587384211051982

Clinical utility of a serum glycome analysis in patients with colorectal cancer Reviewed International journal

Takei D, Harada K, Nouso K, MiyaharaK, Dohi C, Matsushita H, Kinugasa H, Hiraoka S, Nishimura S-I, Okada H

J. Gastroen. Hepatol. 37 ( 4 ) 727 - 733 2022

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND AND AIM: Serum glycans are known to be good markers for the early diagnosis and prognostic prediction in many cancers. The aims of this study were to reveal the serum glycan changes comprehensively during the process of carcinogenesis from colorectal adenoma (CRA) to colorectal cancer (CRC) and to evaluate the usefulness of the glycan profiles as clinical markers for CRC. METHODS: Serum samples were obtained from 80 histologically proven CRC and 36 CRA cases. The levels of glycans in the serum were examined with a comprehensive, quantitative, high-throughput unique glycome analysis, and their diagnostic and prognostic abilities were evaluated. RESULTS: Among 34 stably detected glycans, nine were differentially expressed between CRC and CRA. Serum levels of hybrid type glycans were increased in patients with CRC compared with those with CRA (P < 0.001), and both hybrid-type and multi-antennary glycans were significantly increased in advanced cancer cases. The glycan, m/z 1914, showed the highest diagnostic value among the decreased glycans, whereas m/z 1708 showed the highest among the increased glycans. The glycan ratio m/z 1708/1914 showed a higher area under the receiver operating characteristic curve (0.889) than any other single glycan or conventional tumor marker, such as carcinoembryonic antigen (0.766, P = 0.040) and carbohydrate antigen 19-9 (0.615, P < 0.001). High m/z 1708/1914 was also correlated with an advanced cancer stage and short overall survival. CONCLUSION: Serum glycans, especially the m/z 1708/1914 ratio, were useful for the diagnosis, staging, and prognosis prediction of CRC.

DOI： 10.1111/jgh.15781

A nationwide survey concerning the mortality and risk of progressing severity due to arterial and venous thromboembolism in inflammatory bowel disease in Japan.

Katsuyoshi Ando, Mikihiro Fujiya, Kenji Watanabe, Sakiko Hiraoka, Hisashi Shiga, Shinji Tanaka, Hideki Iijima, Tsunekazu Mizushima, Taku Kobayashi, Masakazu Nagahori, Hiroki Ikeuchi, Shingo Kato, Takehiro Torisu, Kiyonori Kobayashi, Masaaki Higashiyama, Toshiro Fukui, Takashi Kagaya, Motohiro Esaki, Shunichi Yanai, Daiki Abukawa, Makoto Naganuma, Satoshi Motoya, Masayuki Saruta, Shigeki Bamba, Makoto Sasaki, Kazuhiko Uchiyama, Katsuyuki Fukuda, Hideo Suzuki, Hiroshi Nakase, Toshiaki Shimizu, Masahiro Iizuka, Mamoru Watanabe, Yasuo Suzuki, Tadakazu Hisamatsu

Journal of gastroenterology 56 ( 12 ) 1062 - 1079 2021.12

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The mortality and risk factors of severe disease and death due to arterial and venous thromboembolism (ATE and VTE, respectively) in patients with inflammatory bowel disease (IBD) remain unclear, especially in Asia. AIMS: This study aimed to reveal the mortality and risk factors of TE in IBD patients in Japan. METHODS: In the primary surveillance, responses to questionnaires regarding the number of cases of severe TE and TE-associated death in IBD patients in a span of over the past 10 years were obtained from 32 institutions in Japan. In the secondary surveillance, detailed data about IBD patients with TE were collected. The characteristics, laboratory data, therapy status, and situation at the time of TE development were retrospectively collected, and the data were compared between the patients with and without severe TE and TE-associated death. RESULTS: The incidence of TE was 1.89% among 31,940 IBD patients. The frequencies of severe TE and TE-associated mortality were 10.7% and 1.0% among the total IBD and TE with IBD patients, respectively. The only risk factor for severe ATE and ATE-associated death was ischemic heart disease. The independent risk factors for severe VTE and VTE-associated death were age (≤ 45 years old), the site of VTE, and disease severity, with anti-TNF therapy as a potential negative risk factor. Patients with severe VTE had a high risk of developing persistent VTE and sequelae. CONCLUSION: Unlike ATE, the incidence of VTE was comparable in Asian and Western countries. Therapeutic and prophylactic strategies for managing IBD-associated TE in Asia are urgently needed.

DOI： 10.1007/s00535-021-01829-5

Active and passive smoking and risk of ulcerative colitis: A case-control study in Japan. International journal

Atsushi Nishikawa, Keiko Tanaka, Yoshihiro Miyake, Chisato Nagata, Shinya Furukawa, Akira Andoh, Tetsuji Yokoyama, Naoki Yoshimura, Kenichiro Mori, Tomoyuki Ninomiya, Yasunori Yamamoto, Eiji Takeshita, Yoshio Ikeda, Mitsuru Saito, Katsuhisa Ohashi, Hirotsugu Imaeda, Kazuki Kakimoto, Kazuhide Higuchi, Hiroaki Nunoi, Yuji Mizukami, Seiyuu Suzuki, Sakiko Hiraoka, Hiroyuki Okada, Keitarou Kawasaki, Masaaki Higashiyama, Ryota Hokari, Hiromasa Miura, Teruki Miyake, Teru Kumagi, Hiromasa Kato, Naohito Hato, Koji Sayama, Yoichi Hiasa

Journal of gastroenterology and hepatology 37 ( 4 ) 653 - 659 2021.11

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND AND AIM: Although an inverse relationship between current smoking and the development of ulcerative colitis (UC) has been shown in North America and Europe, evidence is limited in Asian countries, where the incidence of UC is rapidly increasing. This Japanese case-control study examined the association between active and passive smoking and risk of UC. METHODS: A self-administered questionnaire was used to obtain information on smoking and potential confounding factors in 384 cases with a diagnosis of UC within the past 4 years and 665 controls. RESULTS: Compared with having never smoked, having ever smoked was associated with an increased risk of UC (adjusted odds ratio [OR] = 1.70, 95% confidence interval [CI]: 1.23-2.37). No association was observed between current smoking and risk of UC, but former smokers had a significant elevation in risk (adjusted OR = 2.40, 95% CI: 1.67-3.45). There was a positive dose-response relationship with pack-years smoked (P for trend = 0.006). Among never smokers, passive smoking exposure at home was significantly associated with an increased risk of UC (adjusted OR = 1.90, 95% CI: 1.30-2.79). A significant dose-response gradient was also observed between pack-years of passive smoking at home and risk of UC (P for trend = 0.0003). CONCLUSIONS: We confirmed that former smoking elevated the risk of UC, whereas an inverse association between current smoking and the risk of UC did not reach a statistically significant level. Passive smoking may be associated with an increased risk of UC.

DOI： 10.1111/jgh.15745

Evaluation of complete cold forceps polypectomy resection rate for 3- to 5-mm colorectal polyps. International journal

Yasushi Yamasaki, Keita Harada, Shumpei Yamamoto, Eriko Yasutomi, Mami Hirai, Masayasu Ohmori, Shohei Oka, Toshihiro Inokuchi, Hideaki Kinugasa, Yuusaku Sugihara, Masahiro Takahara, Sakiko Hiraoka, Takehiro Tanaka, Toshiharu Mitsuhashi, Hiroyuki Okada

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 33 ( 6 ) 948 - 954 2021.9

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND AND STUDY AIMS: The propriety of cold forceps polypectomy (CFP) using jumbo biopsy forceps for diminutive polyps remains controversial. We conducted a prospective study to evaluate the complete CFP resection rate of 3-5-mm polyps using additional endoscopic mucosal resection (EMR) specimens following CFP. PATIENTS AND METHODS: Patients with 3-5-mm protruded or flat elevated colorectal polyps diagnosed endoscopically as adenomas or serrated lesions were prospectively enrolled. CFP using jumbo biopsy forceps was used to remove the eligible polyps and repeated until the absence of residuals were confirmed via image-enhanced endoscopy or chromoendoscopy. After CFP, saline was injected at the defect, and the marginal specimen of the defect was resected using EMR to histologically evaluate the residue. The primary outcome was the complete CFP resection rate, which was defined as no residue at the EMR site. Other outcomes were the number of CFP bites and the complete resection rate by lesion size. RESULTS: Eighty patients with 120 polyps were enrolled. The mean polyp size was 4.1 ± 0.7 mm. The overall complete resection rate was 96.7% (95% confidence interval [CI], 91.7-98.7), and the rates for 3-, 4- and 5-mm polyps were 100% (95% CI, 86.7-100), 96.0% (95% CI, 86.5-98.9) and 95.5% (95% CI, 85.1-98.8), respectively. The one-bite CFP rates were 92%, 60% and 31% for the 3-, 4- and 5-mm polyps, respectively. CONCLUSIONS: The complete CFP resection rate for 3-5-mm polyps was acceptable, although the one-bite clearance rate decreased as the polyp size increased (UMIN000028841).

DOI： 10.1111/den.13895

A novel clip closure method using precutting and a reopenable clip after colorectal endoscopic submucosal dissection. International journal

Masayasu Ohmori, Yasushi Yamasaki, Shumpei Yamamoto, Hideaki Kinugasa, Keita Harada, Sakiko Hiraoka, Hiroyuki Okada

Endoscopy 54 ( 8 ) E401-E402 2021.8

Anti-proteinase 3 antineutrophil cytoplasmic antibody reflects disease activity and predicts the response to steroid therapy in ulcerative colitis. International journal

Yuki Aoyama, Tomoki Inaba, Sakuma Takahashi, Hisae Yasuhara, Sakiko Hiraoka, Takeshi Morimoto, Hugh Shunsuke Colvin, Masaki Wato, Midori Ando, Satoko Nakamura, Koichi Mizobuchi, Hiroyuki Okada

BMC gastroenterology 21 ( 1 ) 325 - 325 2021.8

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Serum anti-proteinase 3 antineutrophil cytoplasmic antibody (PR3-ANCA) is a disease-specific antibody against granulomatosis with polyangiitis. PR3-ANCA is a useful serological marker for disease severity in ulcerative colitis (UC). The purpose of this study was to investigate whether PR3-ANCA levels could also predict the success of induction therapy and to compare its performance against other markers, including serum CRP and fecal hemoglobin. METHODS: This was a multicenter retrospective study. In total, 159 patients with active-phase UC underwent colonoscopy. Disease activity was measured using the Mayo endoscopic subscore (MES). PR3-ANCA positivity and the response to induction therapy, either 5-aminosalicylic acid or steroid, were assessed. PR3-ANCA, CRP, and fecal hemoglobin were measured during the active phase, and during clinical remission. RESULTS: Eighty-five (53.5%) of 159 patients with active UC were positive for PR3-ANCA. PR3-ANCA titers were significantly higher in the group of patients with MES 3 compared to patients with MES 1 (P = 0.002) or MES 2 (P = 0.035). Steroid therapy was administered to 56 patients with a median partial Mayo score of 7 (5-9), which is equivalent to moderate-to-severe disease activity. PR3-ANCA positivity of non-responders to steroid therapy was significantly higher than that of responders (71.9% vs, 41.7%, P = 0.030), whereas CRP and fecal hemoglobin were not predictive of steroid response. Multivariate analysis demonstrated that PR3-ANCA positivity was associated with non-response to steroid therapy (odds ratio 5.19; 95% confidence interval, 1.54-17.5; P = 0.008). Of the 37 patients treated to clinical remission who were also positive for PR3-ANCA during the active phase, 27 had an MES of ≥ 1, and 10 patients had an MES of 0. In clinical remission, the proportion of patients with MES 0 in 17 patients whose PR3-ANCA became negative was significantly higher than that in 20 patients whose PR3-ANCA remained positive (47.1% vs. 10.0%, P = 0.023). CONCLUSIONS: PR3-ANCA not only serves as a marker of disease activity, but also predicts the failure of steroid therapy in moderate-to-severe UC. TRIAL REGISTRATION: This study was retrospectively registered in the UMIN Clinical Trials Registry System (000039174) on January 16, 2020.

DOI： 10.1186/s12876-021-01903-5

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

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

Journal of gastroenterology and hepatology 36 ( 7 ) 1744 - 1753 2021.7

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1111/jgh.15401

Heterogeneous distribution of Fusobacterium nucleatum in the progression of colorectal cancer. International journal

Shumpei Yamamoto, Hideaki Kinugasa, Mami Hirai, Hiroyuki Terasawa, Eriko Yasutomi, Shohei Oka, Masayasu Ohmori, Yasushi Yamasaki, Toshihiro Inokuchi, Keita Harada, Sakiko Hiraoka, Kazuhiro Nouso, Takehiro Tanaka, Fuminori Teraishi, Toshiyoshi Fujiwara, Hiroyuki Okada

Journal of gastroenterology and hepatology 36 ( 7 ) 1869 - 1876 2021.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND AND AIM: Fusobacterium nucleatum (Fn) is involved in colorectal cancer (CRC) growth and is a biomarker for patient prognosis and management. However, the ecology of Fn in CRC and the distribution of intratumoral Fn are unknown. METHODS: We evaluated Fn and the status of KRAS and BRAF in 200 colorectal neoplasms (118 adenomas and 82 cancers) and 149 matched adjacent normal mucosas. The differentiation status between "surface" and "deep" areas of cancer tissue and matched normal mucosa were analyzed in 46 surgical samples; the Ki-67 index was also evaluated in these samples. RESULTS: Fusobacterium nucleatum presence in the tumor increased according to pathological stage (5.9% [adenoma] to 81.8% [stage III/IV]), while Fn presence in normal mucosa also increased (7.6% [adenoma] to 40.9% [stage III/IV]). The detection rates of Fn on the tumor surface and in deep areas were 45.7% and 32.6%, while that of normal mucosa were 26.1% and 23.9%, respectively. Stage III/IV tumors showed high Fn surface area expression (66.7%). Fn intratumoral heterogeneity (34.8%) was higher than that of KRAS (4.3%; P < 0.001) and BRAF (2.2%; P < 0.001). The Ki-67 index in Fn-positive cases was higher than that in negative cases (93.9% vs 89.0%; P = 0.01). CONCLUSIONS: Fusobacterium nucleatum was strongly present in CRC superficial areas at stage III/IV. The presence of Fn in the deep areas of adjacent normal mucosa also increased. The intratumoral heterogeneity of Fn is important in the use of Fn as a biomarker, as Fn is associated with CRC proliferative capacity.

DOI： 10.1111/jgh.15361

Two Cases of Endometriosis in the Cecum Detected by Contrast-enhanced Computed Tomography with Air/Carbon Dioxide Insufflation.

Masaya Iwamuro, Takehiro Tanaka, Yuusaku Sugihara, Keita Harada, Sakiko Hiraoka, Yoshitaka Kondo, Hiroyuki Okada

Internal medicine (Tokyo, Japan) 60 ( 11 ) 1697 - 1701 2021.6

Language：English Publishing type：Research paper (scientific journal)

We herein report two patients with endometriosis in the cecum. Both patients presented with a protruding, subepithelial tumor on colonoscopy and were diagnosed with cecal endometriosis after surgical resection. It is notable that the cecal lesions were not initially identified on computed tomography (CT), while CT colonography with air/carbon dioxide insufflation resulted in the detection of the cecal tumor. These cases highlight the possibility of false-negative results on conventional CT in patients with cecal endometriosis. We consider CT colonography with air/carbon dioxide insufflation useful for detecting cecal tumors in such cases.

DOI： 10.2169/internalmedicine.6418-20

Leucine-rich alpha-2 glycoprotein is a potential biomarker to monitor disease activity in inflammatory bowel disease receiving adalimumab: PLANET study.

Shinichiro Shinzaki, Katsuyoshi Matsuoka, Hiroki Tanaka, Fuminao Takeshima, Shingo Kato, Takehiro Torisu, Yuki Ohta, Kenji Watanabe, Shiro Nakamura, Naoki Yoshimura, Taku Kobayashi, Akiko Shiotani, Fumihito Hirai, Sakiko Hiraoka, Mamoru Watanabe, Minoru Matsuura, Shohei Nishimoto, Shinta Mizuno, Hideki Iijima, Tetsuo Takehara, Tetsuji Naka, Takanori Kanai, Takayuki Matsumoto

Journal of gastroenterology 56 ( 6 ) 560 - 569 2021.6

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: This multicenter prospective study (UMIN000019958) aimed to evaluate the usefulness of serum leucin-rich alpha-2 glycoprotein (LRG) levels in monitoring disease activity in inflammatory bowel disease (IBD). METHODS: Patients with moderate-to-severe IBD initiated on adalimumab therapy were enrolled herein. Serum LRG, C-reactive protein (CRP), and fecal calprotectin (fCal) levels were measured at week 0, 12, 24, and 52. Colonoscopy was performed at week 0, 12, and 52 for ulcerative colitis (UC), and at week 0, 24, and 52 for Crohn's disease (CD). Endoscopic activity was assessed using the Simple Endoscopic Score for Crohn's Disease (SES-CD) for CD and the Mayo endoscopic subscore (MES) for UC. RESULTS: A total of 81 patients was enrolled. Serum LRG levels decreased along with improvements in clinical and endoscopic outcomes upon adalimumab treatment (27.4 ± 12.6 μg/ml at week 0, 15.5 ± 7.7 μg/ml at week 12, 15.7 ± 9.6 μg/ml at week 24, and 14.5 ± 6.8 μg/ml at week 52), being correlated with endoscopic activity at each time point (SES-CD: r = 0.391 at week 0, r = 0.563 at week 24, r = 0.697 at week 52; MES: r = 0.534 at week 0, r = 0.429 at week 12, r = 0.335 at week 52). Endoscopic activity better correlated with LRG compared to CRP and fCal on pooled analysis at all time points (SES-CD: LRG: r = 0.636, CRP: r = 0.402, fCal: r = 0.435; MES: LRG: r = 0.568, CRP: 0.389, fCal: r = 0.426). CONCLUSIONS: Serum LRG is a useful biomarker of endoscopic activity both in CD and UC during the adalimumab treatment.

DOI： 10.1007/s00535-021-01793-0

診断講座症例から学ぶIBD鑑別診断のコツ(第50回) 5-ASAアレルギー

安富絵里子, 平岡佐規子, 竹井健介, 井川翔子, 岡昌平, 井口俊博, 高原政宏, 岡田裕之

IBD Research 15 ( 2 ) 109 - 114 2021.6

Language：Japanese Publisher：(株)先端医学社

5-アミノサリチル酸(5-ASA)製剤は軽症から中等症の潰瘍性大腸炎(UC)に対する第一選択薬で基本的には安全な薬剤である。しかしながら、5-ASA製剤の投与に伴いUCの増悪と鑑別がむずかしい下痢・血便の増悪を伴う『5-ASAアレルギー』が起こり得、さらに最近、その頻度も増加傾向にあるとされ注目されている。まず5-ASAアレルギーという病態があることを認識し、経過から5-ASAアレルギーの可能性を疑う場合、5-ASA製剤を中止する『勇気』をもつことが大事である。また、その後の経過が難治になる症例もありうるため、早めに専門医への紹介を考慮すべきである。(著者抄録)

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

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

Journal of gastroenterology and hepatology 36 ( 4 ) 864 - 872 2021.4

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1111/jgh.15288

IBD診療における超音波の有用性クローン病小腸狭窄病変に対する経腹壁超音波検査の病変検出率の検討

竹内桂子, 井口俊博, 高原政宏, 大森正泰, 竹井健介, 安富絵里子, 岡昌平, 大西秀樹, 平岡佐規子, 岡田裕之

超音波医学 48 ( Suppl. ) S309 - S309 2021.4

Intestinal cancer in patients with Crohn's disease: A systematic review and meta-analysis. International journal

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

Journal of gastroenterology and hepatology 36 ( 2 ) 329 - 336 2021.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Wiley

BACKGROUND AND AIM: Although surveillance colonoscopy is recommended by several guidelines for Crohn's disease (CD), the evidence is insufficient to support the validity of this recommendation. Moreover, the efficacy of surveillance colonoscopy for anorectal cancer remains unclear. Therefore, we performed a systematic review of cancer in patients with CD before considering the proper surveillance methods. METHODS: We conducted a systematic review and meta-analysis examining the incidence of intestinal cancer and a literature review to clarify the characteristic features of cancer in CD. We performed the systematic literature review of studies published up to May 2019. RESULTS: Overall, 7344 patients were included in eight studies. The standardized incidence ratios (95% confidence intervals) of colorectal cancer (CRC) and small bowel cancer (SBC) were 2.08 (1.43-3.02) and 22.01 (9.10-53.25), respectively. The prevalence of CRC and SBC was 57/7344 (0.77%) and 17/7344 (0.23%), respectively, during a median follow-up of 12.55 years. Additionally, 54 studies reporting 208 anorectal cancer cases were identified. In patients with anorectal cancer, the prognosis for survival was 2.1 ± 2.3 years, and advanced cancer greater than stage T3 occurred in 46/74 patients (62.1%). Many more reports of anorectal cancer were published in Asia than in Western countries. CONCLUSION: Although we were unable to state a recommendation for surveillance for SBC, we should perform cancer surveillance for CRC in patients with CD. However, the characteristics of cancer may differ according to geography or race. We must establish proper and effective surveillance methods that are independently suitable to detect these differences.

DOI： 10.1111/jgh.15229

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/jgh.15229

Genetic Background of Mesalamine-induced Fever and Diarrhea in Japanese Patients with Inflammatory Bowel Disease. International journal

Kaoru Suzuki, Yoichi Kakuta, Takeo Naito, Tetsuya Takagawa, Hiroyuki Hanai, Hiroshi Araki, Yu Sasaki, Hirotake Sakuraba, Makoto Sasaki, Tadakazu Hisamatsu, Satoshi Motoya, Takayuki Matsumoto, Motoyuki Onodera, Yoh Ishiguro, Hiroshi Nakase, Akira Andoh, Sakiko Hiraoka, Masaru Shinozaki, Toshimitsu Fujii, Takehiko Katsurada, Taku Kobayashi, Mikihiro Fujiya, Takafumi Otsuka, Naoki Oshima, Yasuo Suzuki, Yuichirou Sato, Ryota Hokari, Mitsunori Noguchi, Yuki Ohta, Minoru Matsuura, Yosuke Kawai, Katsushi Tokunaga, Masao Nagasaki, Hisaaki Kudo, Naoko Minegishi, Daisuke Okamoto, Yusuke Shimoyama, Rintaro Moroi, Masatake Kuroha, Hisashi Shiga, Dalin Li, Dermot P B McGovern, Yoshitaka Kinouchi, Atsushi Masamune

Inflammatory bowel diseases 28 ( 1 ) 21 - 31 2021.1

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Some patients with inflammatory bowel disease (IBD) who were under mesalamine treatment develop adverse reactions called "mesalamine allergy," which includes high fever and worsening diarrhea. Currently, there is no method to predict mesalamine allergy. Pharmacogenomic approaches may help identify these patients. Here we analyzed the genetic background of mesalamine intolerance in the first genome-wide association study of Japanese patients with IBD. METHODS: Two independent pharmacogenetic IBD cohorts were analyzed: the MENDEL (n = 1523; as a discovery set) and the Tohoku (n = 788; as a replication set) cohorts. Genome-wide association studies were performed in each population, followed by a meta-analysis. In addition, we constructed a polygenic risk score model and combined genetic and clinical factors to model mesalamine intolerance. RESULTS: In the combined cohort, mesalamine-induced fever and/or diarrhea was significantly more frequent in ulcerative colitis vs Crohn's disease. The genome-wide association studies and meta-analysis identified one significant association between rs144384547 (upstream of RGS17) and mesalamine-induced fever and diarrhea (P = 7.21e-09; odds ratio = 11.2). The estimated heritability of mesalamine allergy was 25.4%, suggesting a significant correlation with the genetic background. Furthermore, a polygenic risk score model was built to predict mesalamine allergy (P = 2.95e-2). The combined genetic/clinical prediction model yielded a higher area under the curve than did the polygenic risk score or clinical model alone (area under the curve, 0.89; sensitivity, 71.4%; specificity, 90.8%). CONCLUSIONS: Mesalamine allergy was more common in ulcerative colitis than in Crohn's disease. We identified a novel genetic association with and developed a combined clinical/genetic model for this adverse event.

DOI： 10.1093/ibd/izab004

Histologic Transformation from Follicular Lymphoma to Diffuse Large B-cell Lymphoma Detected during Colonoscopy.

Masaya Iwamuro, Yasushi Yamasaki, Takehiro Tanaka, Noboru Asada, Ken-Ichi Matsuoka, Sakiko Hiraoka, Yoshiro Kawahara, Hiroyuki Okada

Acta medica Okayama 75 ( 5 ) 625 - 629 2021

Language：English Publishing type：Research paper (scientific journal)

A 77-year-old Japanese woman who had been treated for follicular lymphoma for 8 years developed abdominal pain and intra-abdominal lymphadenopathies. Colonoscopy revealed an elevated lesion in the rectum, which presented as two humps with erosions. A diagnosis of histologic transformation of follicular lymphoma to diffuse large B-cell lymphoma was made by endoscopic biopsy. This case underscores the importance of endoscopy examinations and biopsy of newly emerged gastrointestinal lesions for the prompt diagnosis of histologic transformation, since salvage chemotherapy must be initiated quickly in such cases.

DOI： 10.18926/AMO/62775

Dietary intake of vegetables, fruit, and antioxidants and risk of ulcerative colitis: A case-control study in Japan. International journal

Yoshihiro Miyake, Keiko Tanaka, Chisato Nagata, Shinya Furukawa, Akira Andoh, Tetsuji Yokoyama, Naoki Yoshimura, Kenichiro Mori, Tomoyuki Ninomiya, Yasunori Yamamoto, Eiji Takeshita, Yoshio Ikeda, Mitsuru Saito, Katsuhisa Ohashi, Hirotsugu Imaeda, Kazuki Kakimoto, Kazuhide Higuchi, Hiroaki Nunoi, Yuji Mizukami, Seiyuu Suzuki, Sakiko Hiraoka, Hiroyuki Okada, Keitarou Kawasaki, Masaaki Higashiyama, Ryota Hokari, Hiromasa Miura, Teruki Miyake, Teru Kumagi, Hiromasa Kato, Naohito Hato, Koji Sayama, Yoichi Hiasa

Nutrition (Burbank, Los Angeles County, Calif.) 91-92 111378 - 111378 2021

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: Oxidative stress is considered one of the etiologic factors involved in ulcerative colitis (UC), yet there is limited epidemiologic information regarding the relationship between antioxidant intake and the risk of UC. The aim of the present case-control study in Japan was to examine the association between intake of green and yellow vegetables, other vegetables, fruit, vitamin C, vitamin E, retinol, alpha-carotene, beta-carotene, and cryptoxanthin and UC risk. METHODS: A total of 384 cases within 4 y of diagnosis with UC and 665 controls were included in the study. Data on dietary intake and confounders were obtained using a self-reported questionnaire. Information on dietary factors was collected using a 169-item semiquantitative food-frequency questionnaire. Adjustment was made for sex, age, pack-y of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, and body mass index. RESULTS: Higher intake levels of other vegetables, vitamin C, and retinol were independently associated with a reduced risk of UC. The adjusted odds ratio between extreme quartiles was 0.51 (95% confidence interval [CI], 0.34-0.76; P for trend ≤ 0.001) for other vegetables, 0.45 (95% CI, 0.30-0.69, P for trend ≤ 0.001) for vitamin C, and 0.64 (95% CI, 0.43-0.95, P for trend = 0.04) for retinol. There were no associations between intake of green and yellow vegetables, fruit, vitamin E, alpha-carotene, beta-carotene, or cryptoxanthin and UC risk (P for trend = 0.29, 0.56, 0.89, 0.20, 0.69, and 0.22, respectively). CONCLUSIONS: Intake of other vegetables, vitamin C, and retinol was inversely associated with UC risk.

DOI： 10.1016/j.nut.2021.111378

Three cases of diverticula-related granulation polyp in the colon

Masaya Iwamuro, Takehiro Tanaka, Tomohiro Toji, Shumpei Yamamoto, Mami Hirai, Shohei Oka, Sakiko Hiraoka, Yoshiro Kawahara, Hiroyuki Okada

Gastroenterological Endoscopy 62 ( 12 ) 3057 - 3063 2020.12

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japan Gastroenterological Endoscopy Society

Granulation polyps are found in the colorectum often in association with postoperative anastomotic sites or scars after endoscopic resection. Meanwhile, few cases of granulation polyps that occur in relation to colonic diverticula have been reported. Herein, we report three cases of diverticula-related granulation polyps in the colon. In all three cases, a reddish polyp that protruded from a diverticulum was found in the sigmoid colon. White exudate and tortuous capillaries were observed on the surface of the polyps. On magnifying endoscopic observation, the surface structure was unclear or had disappeared. We speculate that these endoscopic features are specific to granulation polyps in the colon. It is noteworthy that in one patient with laryngeal cancer, the polyp was false-positive for a tumor on positron emission tomography, showing significant tracer accumulation. Differentiation of granulation polyp from cancer metastasis to the colon is important in such patients. It is essential to be able to make a precise diagnosis of diverticula-related granulation polyp in the colon based on endoscopic features.

DOI： 10.11280/gee.62.3057

憩室内に形成された大腸肉芽性ポリープの3例

岩室雅也, 田中健大, 都地友紘, 山本峻平, 平井麻美, 岡昌平, 平岡佐規子, 河原祥朗, 岡田裕之

Gastroenterological Endoscopy 62 ( 12 ) 3057 - 3063 2020.12

Language：Japanese Publisher：(一社)日本消化器内視鏡学会

大腸肉芽性ポリープは術後の吻合部や内視鏡治療後の創にみられることが多く,憩室に関連して発生した肉芽性ポリープの報告は少ない.今回筆者らは憩室関連肉芽性ポリープの3例を経験したので報告した.3例ともにS状結腸に憩室内から突出する発赤調ポリープを呈し,表面に白色付着物と蛇行する毛細血管を伴っていた.また拡大観察で表面構造は不明瞭または消失といった特徴を有しており,生検により肉芽性ポリープと診断した.また,1例ではポジトロン断層法検査でポリープに集積を認めた.上記の内視鏡所見を認める場合は,憩室関連肉芽性ポリープを鑑別に挙げるべきと考えられた.(著者抄録)

Factors Predicting a Favorable Disease Course Without Anti-TNF Therapy in Crohn's Disease Patients.

Toshihiro Inokuchi, Sakiko Hiraoka, Eriko Yasutomi, Shohei Oka, Yasushi Yamasaki, Hideaki Kinugasa, Masahiro Takahara, Seiji Kawano, Keita Harada, Hiroyuki Okada, Jun Kato

Acta medica Okayama 74 ( 4 ) 265 - 274 2020.8

Language：English Publishing type：Research paper (scientific journal)

Determining factors that predict a favorable disease course without anti-tumor necrosis factor (TNF) agents would help establish a more cost-effective strategy for Crohn's disease (CD). A retrospective chart review was performed for CD patients with disease durations > 10 years who had not received anti-TNF agents as first-line therapy. Patients were divided into 2 groups: those who received neither anti-TNF agents nor bowel resection (G1), and those who had received an anti-TNF agent and/or bowel resection (G2). The patient backgrounds, therapies and clinical courses were compared between the groups. A total of 62 CD patients met the inclusion criteria (males: 71%; median duration of follow-up: 19 years). Six patients were included in G1; they were significantly less likely to have upper gastrointestinal lesions than G2 (p=0.007). A multivariate analysis revealed that the significant factors for avoidance of bowel resection without anti-TNF treatment were non-stricturing and non-penetrating behaviors, and absence of upper gastrointestinal lesions at the diagnosis (hazard ratios 0.41 and 0.52; p=0.004 and 0.04, respectively). In consideration of the long treatment course of CD, patients with non-stricturing and non-penetrating behaviors and no upper gastrointestinal lesions should not be treated with anti-TNF agents as first-line therapy.

DOI： 10.18926/AMO/60363

【分子標的時代のIBD診療-IBDの寛解導入,寛解維持の実践】IBD治療における寛解導入と寛解維持に関するトピック IBD寛解維持期における便中マーカーによるモニタリング

平岡佐規子, 安富絵里子, 岡昌平, 井口俊博, 高原政宏, 岡田裕之

臨床消化器内科 35 ( 10 ) 1256 - 1262 2020.8

Language：Japanese Publisher：(株)日本メディカルセンター

＜文献概要＞炎症性腸疾患(IBD)診療における治療の選択肢は年々増えており,多くの患者に速やかな寛解導入,長期の寛解維持が望めるようになってきた.しかし,いったん寛解となっても再燃する場合はあり,その場合にはいかに早期に治療介入できるかが,重要となってくる.再燃を早期に発見するためには,臨床症状の確認とともに,粘膜治癒と相関し,かつ,非侵襲性で繰り返し測定可能なバイオマーカーをうまく利用することが重要である.バイオマーカーの有力な候補として,便中マーカーである便中カルプロテクチン,免疫学的便潜血法がある.臨床的寛解であっても継続的にそれら測定値の上昇を認めた場合は,再燃の可能性を考える必要がある.

Clinical Characteristics and Risk Factors for Rebleeding in Patients with Obscure Gastrointestinal Bleeding.

Yuki Baba, Seiji Kawano, Yoshiyasu Kono, Toshihiro Inokuchi, Hiromitsu Kanzaki, Masaya Iwamuro, Keita Harada, Sakiko Hiraoka, Yoshiro Kawahara, Hiroyuki Okada

Internal medicine (Tokyo, Japan) 59 ( 11 ) 1345 - 1350 2020.6

Language：English Publishing type：Research paper (scientific journal)

Objective With the advent of capsule endoscopy (CE) and double-balloon endoscopy (DBE), the diagnosis and treatment of obscure gastrointestinal bleeding (OGIB) have markedly progressed. However, rebleeding sometimes occurs and is difficult to diagnose and treat. The aim of the present study was to investigate the clinical features of OGIB and risk factors for rebleeding in our hospital. Methods A total of 195 patients who underwent CE and/or DBE for OGIB in our hospital from January 2009 to July 2016 were included in the present study. We analyzed 168 cases of small intestinal OGIB, after excluding 27 cases of extra small intestinal bleeding. The clinical characteristics and risk factors related to rebleeding were retrospectively studied. Results Among the 168 patients who were included in the analysis, 95 patients (56.5%) were male. The mean age was 64.5 years (range, 8 to 87 years). Hypertension (31.0%) was the most frequent comorbidity, followed by chronic kidney disease (19.0%). The final diagnoses were ulcerative lesions (n=50, 29.8%), vascular lesions (n=30, 17.9%), tumors (n=7, 4.2%), and diverticula (n=2, 1.2%). The bleeding source was undetermined in the remaining 79 cases (47.0%). Rebleeding was confirmed in 29 cases (17.3%). In a univariate analysis, chronic kidney disease, vascular lesions, and overt previous bleeding were significantly associated with the risk of rebleeding. A multivariate analysis showed that chronic kidney disease, vascular lesion, and overt previous bleeding were significantly associated with the risk of rebleeding. Conclusion Patients with OGIB with overt previous bleeding, vascular lesions, and/or chronic kidney disease had a higher risk of rebleeding.

DOI： 10.2169/internalmedicine.3628-19

経皮肝腫瘍生検にて診断しえた末梢型T細胞リンパ腫の1例

大山淳史, 大西秀樹, 足立卓哉, 和田望, 高原政宏, 坂田雅浩, 安中哲也, 平岡佐規子, 丹羽知子, 戸田由香, 岡田裕之

日本消化器病学会中国支部例会プログラム・抄録集 113回 105 - 105 2020.5

Observer agreement for the diagnosis of intestinal acute graft-vs.-host disease based on the presence of villous atrophy in the terminal ileum. International journal

Yuusaku Sugihara, Sakiko Hiraoka, Eriko Yasutomi, Shohei Oka, Yasushi Yamasaki, Toshihiro Inokuchi, Hideaki Kinugasa, Masahiro Takahara, Yuki Morito, Sakuma Takahashi, Keita Harada, Takehiro Tanaka, Fumio Otsuka, Hiroyuki Okada

Experimental and therapeutic medicine 19 ( 4 ) 3076 - 3080 2020.4

Language：English Publishing type：Research paper (scientific journal)

Intestinal graft-vs.-host disease (GVHD) is a serious complication of allo-hematopoietic stem cell transplantation (allo-HSCT). Villous atrophy in the terminal ileum is considered a useful diagnostic indicator for GVHD. However, the inter- and intra-observer agreement regarding the ileocolonoscopic findings indicative of acute intestinal GVHD, i.e., villous atrophy in the terminal ileum, are currently insufficient in multiple institutions. Thus, the present study aimed to investigate the incidence of villous atrophy in the terminal ileum to diagnose acute intestinal GVHD and determine the inter- and intra-observer agreement regarding this result for experienced endoscopists from multiple institutions. Consecutive patients who underwent allo-HSCT were referred to our institution between May 2008 and September 2015. A total of 54 patients underwent total ileocolonoscopy after allo-HSCT due to suspected intestinal acute GVHD. Subsequently, three observers from different institutions evaluated the cases for the presence of villous atrophy in the terminal ileum. In this study, the pathology results were a gold standard to evaluate the predictive value of ileocolonoscopy detection. Definitive pathological and non-pathological GVHD was diagnosed in 22 and 32 cases, respectively. The results of examining whether villous atrophy could predict GVHD were as follows. For three observers (A, B and C), the sensitivity of villous atrophy in the terminal ileum was 86.4, 77.3 and 79.2%, respectively, whereas the specificity was 62.5, 62.5 and 86.7%, respectively. The positive predictive value (PPV) and negative predictive value (NPV) of villous atrophy for GVHD were as follows: The PPV of appearance was 61.3, 58.6 and 82.6%, respectively, whereas the NPV was 87.0, 80.0 and 83.9%, respectively. Kappa coefficients for the inter-observer reliability were 0.85, 0.63 and 0.63 for observers A and B, A and C, and B and C, respectively. The intra-observer kappa coefficient was 0.88 for observer A, 0.73 for observer B and 0.75 for observer C. A substantial observer agreement was achieved for the analysis of villous atrophy in the terminal ileum and the agreement for the predictive histological diagnosis was also excellent. Based on the results of the present study, identification of villous atrophy in the terminal ileum was a clinically effective diagnostic parameter, even if different endoscopists were involved in the diagnosis at multiple institutions. The present study was registered as a trial with the University Hospital Medical Information Network (UMIN; registration no. UMIN000025390).

DOI： 10.3892/etm.2020.8538

Cytomegalovirus Colitis Followed by Colonic Pseudolipomatosis and Gastric Emphysema in a Post-resuscitation Patient. Reviewed

Masaya Iwamuro, Takehiro Tanaka, Nao Yamauchi, Yuri Nakashima, Takahira Wada, Sakiko Hiraoka, Yoshiro Kawahara, Hiroyuki Okada

Internal medicine (Tokyo, Japan) 59 ( 4 ) 519 - 525 2020.2

Language：English Publishing type：Research paper (scientific journal)

A 64-year-old Japanese man suffered cardiopulmonary arrest, which may have resulted from sepsis and/or hyperosmolar hyperglycemic non-ketonic coma, and was admitted after successful resuscitation. He had watery diarrhea on day 18 and was diagnosed with cytomegalovirus enterocolitis. In addition, computed tomography performed on day 27 and colonoscopy revealed gastric emphysema and intestinal pseudolipomatosis, respectively. This report is the first to describe a patient with cytomegalovirus enterocolitis and subsequent gastric emphysema and pseudolipomatosis. Gastrointestinal cytomegalovirus infection may underlie gastric emphysema and intestinal pseudolipomatosis, particularly in patients with relative or obvious immune dysfunction.

DOI： 10.2169/internalmedicine.3633-19

潰瘍性大腸炎における経腹超音波検査の有用性

高原政宏, 平岡佐規子, 安富絵里子, 岡昌平, 平井麻美, 井口俊博, 竹中龍太, 藤木茂篤, 岡田裕之

日本内科学会雑誌 109 ( Suppl. ) 188 - 188 2020.2

Appendiceal Orifice Inflammation in Ulcerative Colitis Mimicking Mucosa-Associated Lymphoid Tissue Lymphoma in the Cecum. International journal

Masaya Iwamuro, Takahide Takahashi, Takehiro Tanaka, Tomohiro Toji, Sakiko Hiraoka, Seiji Kawano, Yoshiro Kawahara, Hiroyuki Okada

Case reports in gastrointestinal medicine 2020 8893604 - 8893604 2020

Language：English

A 55-year-old Japanese woman, who had been diagnosed with ulcerative colitis at 18 years of age, underwent screening endoscopy examinations. Esophagogastroduodenoscopy revealed an extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) of the stomach. Colonoscopy showed a slightly elevated reddish lesion with dilated microvessels but no erosions or ulcers. Although MALT lymphoma in the cecum was endoscopically suspected, flow cytometry and pathological analyses led to the diagnosis of appendiceal orifice inflammation in ulcerative colitis. This case highlights the diversity of the endoscopic appearance of appendiceal orifice inflammation in ulcerative colitis.

DOI： 10.1155/2020/8893604

A Granulation Polyp in the Colon Masquerading as Metastatic Cancer. Reviewed

Masaya Iwamuro, Masahiro Takahara, Tatsuhiro Yamazaki, Takehiro Tanaka, Yoshitaka Kondo, Sakiko Hiraoka, Hiroyuki Okada

Acta medica Okayama 73 ( 5 ) 457 - 461 2019.10

Language：English

A 60-year-old Caucasian male was diagnosed with lung adenocarcinoma and multiple metastases to the bone, spleen, and brain. He underwent radiotherapy for the brain and lumbar spine metastases, plus chemotherapy (cisplatin and pemetrexed). The chemotherapy was discontinued due to vomiting and hyponatremia, and nivolumab was then administered. Eight months later, 18F-fluorodeoxyglucose positron emission tomography showed tracer uptake in the colon. Colonoscopy revealed a reddish multinodular polyp in the sigmoid colon. The polyp showed irregular microvessels. No colonic mucosal surface structures were observed. Colonic metastasis of the lung carcinoma was highly suspected; the polyp was therefore surgically removed. The histological analysis revealed granulation tissue and suppurative inflammation without neoplastic changes. We diagnosed the lesion as a granulation polyp. Despite the difficulty in diagnosing these lesions due to their rarity and similarity to metastatic colon tumors, we suggest that recognizing the endoscopic features of the polyp surface may allow a preoperative diagnosis.

DOI： 10.18926/AMO/57377

Paradoxical Roles of Oxidative Stress Response in the Digestive System before and after Carcinogenesis. Reviewed International journal

Akinobu Takaki, Seiji Kawano, Daisuke Uchida, Masahiro Takahara, Sakiko Hiraoka, Hiroyuki Okada

Cancers 11 ( 2 ) 2019.2

Language：English Publishing type：Research paper (scientific journal)

Oxidative stress is recognized as a cancer-initiating stress response in the digestive system. It is produced through mitochondrial respiration and induces DNA damage, resulting in cancer cell transformation. However, recent findings indicate that oxidative stress is also a necessary anticancer response for destroying cancer cells. The oxidative stress response has also been reported to be an important step in increasing the anticancer response of newly developed molecular targeted agents. Oxidative stress might therefore be a cancer-initiating response that should be downregulated in the precancerous stage in patients at risk of cancer but an anticancer cell response that should not be downregulated in the postcancerous stage when cancer cells are still present. Many commercial antioxidant agents are marketed as "cancer-eliminating agents" or as products to improve one's health, so cancer patients often take these antioxidant agents. However, care should be taken to avoid harming the anticancerous oxidative stress response. In this review, we will highlight the paradoxical effects of oxidative stress and antioxidant agents in the digestive system before and after carcinogenesis.

DOI： 10.3390/cancers11020213

Comparison of Two Electrosurgical Modes for Endoscopic Submucosal Dissection of Superficial Colorectal Neoplasms: A Prospective Randomized Study. Reviewed

Yuusaku Sugihara, Keita Harada, Shohei Oka, Eriko Yasutomi, Yasushi Yamasaki, Toshihiro Inokuchi, Hideaki Kinugasa, Masahiro Takahara, Sakiko Hiraoka, Fumio Otsuka, Hiroyuki Okada

Acta medica Okayama 73 ( 1 ) 81 - 84 2019.2

Language：English Publishing type：Research paper (scientific journal)

Endoscopic submucosal dissection (ESD) is reportedly one of the standard treatment strategies for large superficial colorectal neoplasms in Japan because of its high en bloc resection rate. A few technical issues regarding ESD should be considered, one of which is the selection of the Endo-cut I mode versus the Swift-coagulation mode as the electrosurgical unit mode setting during submucosal dissection. We seek to determine which of these two modes is more suitable for submucosal dissections of colorectal tumors with regard to procedure time and safety.

DOI： 10.18926/AMO/56463

Lymphoproliferative disease in a patient with Takayasu arteritis and ulcerative colitis Reviewed

Yosuke Asano, Ken-Ei Sada, Keigo Hayashi, Yuriko Yamamura, Sumie Hiramatsu, Keiji Ohashi, Yoshia Miyawaki, Michiko Morishita, Haruki Watanabe, Yoshinori Matsumoto, Tomoko Kawabata, Noriyuki Tanaka, Sakiko Hiraoka, Jun Wada

Modern Rheumatology Case Reports 3 ( 1 ) 34 2019.1

A Case of Diffuse Esophageal Spasm Treated with Peroral Endoscopic Myotomy. Reviewed

Sugihara Y, Harada K, Kato R, Yamauchi K, Sakae H, Kawano S, Hiraoka S, Kawahara Y, Otsuka F, Okada H

Acta medica Okayama 72 ( 6 ) 595 - 600 2018.12

Language：English Publishing type：Research paper (scientific journal)

The indications for peroral endoscopic myotomy (POEM) have been expanded to include diffuse esophageal spasm (DES). A 67-year-old Japanese man presented with a 4-year history of dysphagia. Endoscopy and upper gastrography revealed abnormal peristaltic movements involving interruption of normal peristalsis, and a diverticulum located at the 2 o'clock esophageal position. High-resolution manometry indicated DES. POEM with a long (15 cm) myotomy was performed for the abnormal contractions, which subsequently disappeared along with dysphagia improvement. Our results suggest that esophageal motility disorders accompanying a diverticulum may be eliminated by POEM without treating the diverticulum itself. We speculate that POEM ameliorates esophageal diverticulum by reducing internal esophageal pressure.

DOI： 10.18926/AMO/56378

Pseudolipomatosis of the Colon and Cecum Followed by Pneumatosis Intestinalis. Reviewed

Iwamuro M, Tanaka T, Kawabata T, Sugihara Y, Harada K, Hiraoka S, Okada H

Internal medicine (Tokyo, Japan) 57 ( 17 ) 2501 - 2504 2018.9

Language：English Publishing type：Research paper (scientific journal)

A 74-year-old Japanese woman was diagnosed with pseudolipomatosis of the cecum and ascending colon. Colonoscopy was performed, which revealed the presence of slightly elevated white lesions, while a magnifying observation showed microbubbles within the mucosa. A month after colonoscopy, the patient was diagnosed with pneumatosis intestinalis. Although the exact pathogenesis is unclear, pneumatosis intestinalis may arise secondary to pseudolipomatosis. This case also indicates that a magnifying observation during colonoscopy may aid in the diagnosis of pseudolipomatosis of the large intestine, since it shows microbubbles within the mucosa, which may be a distinctive feature reflecting the pathology of this disease.

DOI： 10.2169/internalmedicine.0730-17

食道アカラシアバルーン拡張術およびHeller-Dor手術施行後の下部食道運動異常に対しPOEM(peroral endoscopic myotomy)が著効した1例

杉原雄策, 原田馨太, 加藤諒, 山内健司, 高嶋志保, 山崎泰史, 井口俊博, 高原政宏, 川野誠司, 平岡佐規子, 眞部紀明, 大塚文男, 岡田裕之

岡山医学会雑誌 130 ( 2 ) 67 - 71 2018.8

Language：Japanese Publisher：岡山医学会

症例は80歳代男性で、約60年前に嚥下障害を発症し、食道アカラシアと診断されていた。約15年前に症状が悪化し、食道アカラシアバルーン拡張術を2回施行された。一旦は症状が改善したが、5年前に再度悪化をきたし、Heller-Dor手術を施行された。症状は改善していたが、1年前より嚥下障害と嘔吐が出現した。アカラシアバルーン拡張術およびHeller-Dor手術を施行後、新たに発生した下部食道の運動異常と、それに伴う逆流が、症状再発の原因と診断し、経口内視鏡下筋層切開術(POEM)を施行した。下部食道の運動異常は消失し、バリウムの逆流も認めなかった。経過は良好で、術後4病日に退院となった。現在まで、症状の悪化や再発はきたしていない。

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J00175&link_issn=&doc_id=20180806220002&doc_link_id=10.4044%2Fjoma.130.67&url=https%3A%2F%2Fdoi.org%2F10.4044%2Fjoma.130.67&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

An Elevated Platelet Count Increases the Risk of Relapse in Ulcerative Colitis Patients with Mucosal Healing. Reviewed International journal

Nakarai A, Kato J, Hiraoka S, Takashima S, Inokuchi T, Takahara M, Sugihara Y, Harada K, Okada H

Gut and liver 12 ( 4 ) 420 - 425 2018.7

Language：English Publishing type：Research paper (scientific journal)

Background/Aims: Although mucosal healing (MH) has been considered a treatment goal for patients with ulcerative colitis (UC), the risk factors predictive of relapse in patients who achieve MH are unknown. Because the platelet count has been shown to be a marker of inflammation in inflammatory bowel diseases, this study aimed to assess whether the platelet count could predict relapse in UC patients with MH. Methods: A prospective observational study was performed. UC patients with MH were consecutively enrolled in the study and monitored for at least 2 years or until relapse. The correlation between the incidence of relapse and the platelet count at the time of study enrollment was examined. Results: In total, 43 patients were enrolled, and 14 patients (33%) relapsed. The median platelet count at the time of enrollment in the patients who relapsed significantly differed from that in the patients who did not relapse (27.2×10⁴/μL vs 23.8×10⁴/μL, respectively; p=0.016). A platelet count ＞25.0×10⁴/μL was a significant risk factor for relapse based on a multivariate analysis (hazard ratio, 4.85; 95% confidence interval, 1.07 to 25.28), and according to the Kaplan-Meier analysis, this cutoff could identify patients susceptible to relapse (p=0.041, log-rank test). Conclusions: The platelet count could be used as a predictor of relapse in UC patients with MH.

DOI： 10.5009/gnl17236

Villous atrophy in the terminal ileum is a specific endoscopic finding correlated with histological evidence and poor prognosis in acute graft-versus-host disease after allo-hematopoietic stem cell transplantation. Reviewed International journal

Sugihara Y, Hiraoka S, Fujii N, Takashima S, Yamasaki Y, Inokuchi T, Takahara M, Kuwaki K, Harada K, Tanaka T, Okada H

BMC gastroenterology 18 ( 1 ) 111 - 111 2018.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Graft-versus-host disease (GVHD) is a common complication of allo-hematopoietic stem cell transplantation (allo-HSCT). Endoscopic biopsy can provide a definitive diagnosis, but the optimal endoscopic approach for diagnosis remains uncertain. This study evaluated whether ileocolonoscopic imaging can predict acute GVHD severity after allo-HSCT. METHODS: Consecutive patients who underwent allo-HSCT were referred to our institution, and those diagnosed with acute GVHD by pathology were included in this retrospective study. RESULTS: Fifty-one of 261 patients who underwent ileocolonoscopy were suspected to have acute intestinal GVHD. We performed univariate and multivariate conditional logistic regression with stepwise variable selection; villous atrophy in the terminal ileum remained a statistically significant predictor of GVHD severity (odds ratio, 4.69; 95% confidence interval, 1.07-20.60, P = 0.04). Patients were classified into three groups based on ileal endoscopic findings in the terminal ileum: group S, GVHD with severe villous atrophy; group M, mild atrophy; and group N, no atrophy. Compared with patients in groups M and N, those in group S had significant clinical GVHD at diagnosis (P = 0.03). In group S, three of four, compared with five of 13 patients in groups M and N, required the addition of second-line agents (P = 0.02). CONCLUSIONS: This study showed that severe atrophy of the terminal ileum predicts severe clinical GVHD that is likely to be refractory to steroid treatment. Thus, the severity of terminal ileum atrophy may serve as a tool in predicting clinically severe GVHD. TRIAL REGISTRATION: Trial Registration Number UMIN 000022805 , Registration date July 1, 2016.

DOI： 10.1186/s12876-018-0829-4

Evaluation of the Upper Gastrointestinal Tract in Ulcerative Colitis Patients. Reviewed

Kato R, Iwamuro M, Hiraoka S, Takashima S, Inokuchi T, Takahara M, Kondo Y, Tanaka T, Okada H

Acta medica Okayama 72 ( 2 ) 105 - 113 2018.4

Language：English Publishing type：Research paper (scientific journal)

To analyze the clinical characteristics of patients with ulcerative colitis who have upper gastrointestinal lesions, we retrospectively reviewed the data of 216 patients with ulcerative colitis who underwent esophagogastroduodenoscopy at our institute in April 2008-March 2016. We investigated the endoscopic features and compared the clinical characteristics between the patients with and without upper gastrointestinal lesions. Forty-two patients (19.4%) had upper gastrointestinal lesions, including multiple erosions (n=18), bamboo joint-like appearance (n=17), mucosa with white spots (n=4), friable mucosa (n=2), ulcer (n=1), and purulent deposits within the mucosa (n=1) in the stomach and/or duodenum. Compared to the patients without upper gastrointestinal lesions, those with upper gastrointestinal lesions showed significantly more frequent extraintestinal manifestations (19.0% vs. 8.0%, p<0.05) and a significant history of colectomy (33.3% vs. 12.1%, p<0.01). There were no significant differences with regard to the sex ratio, age at esophagogastroduodenoscopy, gastrointestinal symptoms, time since the diagnosis of ulcerative colitis, type of colitis at the initial diagnosis of ulcerative colitis, or gastric atrophy between the groups. In conclusion, gastroduodenal lesions were identified in 19.4% of the patients with ulcerative colitis. Esophagogastroduodenoscopy is particularly recommended for ulcerative colitis patients who show extraintestinal manifestations and for those who have undergone a colectomy.

DOI： 10.18926/AMO/55850

Ten Initial Cases of Peroral Endoscopic Myotomy for Treatment of Esophageal Motility Disorders at Okayama University Hospital. Reviewed

Sugihara Y, Harada K, Kato R, Yamauchi K, Takashima S, Takei D, Yamasaki Y, Inokuchi T, Takahara M, Hiraoka S, Okada H

Acta medica Okayama 72 ( 2 ) 99 - 104 2018.4

Language：English Publishing type：Research paper (scientific journal)

Peroral endoscopic myotomy (POEM) for treatment of esophageal motility disorders has recently been reported to be highly effective and less invasive than other treatment. POEM was recently introduced in Okayama University Hospital under the supervision of a physician from a high-volume center. To verify the safety and efficacy of POEM during its introduction in our institution. We examined 10 cases in whom POEM was performed between January 2016 and April 2017. The patients included 7 men and 3 women, with a median age (range) of 49 years (17-74) and median symptom duration of 6 years (1-21). Seven patients had a straight esophagus, and the remaining 3 had a sigmoid esophagus. According to the Chicago classification, 6 patients were diagnosed with type I achalasia, 2 with type II achalasia, and 2 with distal esophagus spasm. Treatment outcomes and adverse events were evaluated. Treatment success was defined as a > 3 decrease in Eckardt score or a score of <3 at the time of discharge. The treatment success rate was 90%, with the average Eckardt score decreasing significantly, from 4.7 to 0.9 (p<0.05). No mucosal perforation, severe infection, mediastinitis, severe bleeding, or gastroesophageal reflux occurred intraoperatively or postoperatively. POEM was introduced to Okayama University Hospital, and the first 10 cases were accomplished safely and effectively under the supervision of an expert physician from a high-volume center.

DOI： 10.18926/AMO/55849

パテンシーカプセルが回腸に長期滞留したクローン病の1例

岩室雅也, 高嶋志保, 井口俊博, 高原政宏, 川野誠司, 平岡佐規子, 近藤喜太, 田中健大, 岡田裕之

日本消化器病学会雑誌 115 ( 2 ) 203 - 210 2018.2

Language：Japanese Publisher：(一財)日本消化器病学会

40歳男性。21歳時にクローン病と診断され加療中。イレウス症状を繰り返すため当院紹介。CT検査では回腸狭窄および同部位に高吸収の人工物を認めた。ダブルバルーン内視鏡検査では回腸に多発狭窄を認め、小腸部分切除を施行したところ、狭窄部の近位側に異物を認めた。抽出した異物の解析により、30ヵ月前に嚥下したパテンシーカプセルの非溶解性コーティング膜の滞留と診断した。(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J01118&link_issn=&doc_id=20180223480008&doc_link_id=130006379165&url=https%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F130006379165&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

Two Cases of Leiomyoma in the Colon Masquerading as Other Types of Colonic Pedunculated Polyps. Reviewed International journal

Ikeda A, Iwamuro M, Tanaka T, Inokuchi T, Nakarai A, Sugihara Y, Harada K, Hiraoka S, Kawahara Y, Okada H

Case reports in gastrointestinal medicine 2018 8272313 - 8272313 2018

Language：English

We describe two cases of leiomyoma in the colon that were diagnosed histologically after endoscopic resection. The first case was a 79-year-old Japanese woman who presented with a pedunculated polyp of 14 mm length at the splenic flexure. Preoperative diagnosis suggested a colonic mucosubmucosal elongated polyp. The second case was a 29-year-old Japanese woman who presented with a pedunculated polyp of 40 mm length at the hepatic flexure and had an ulcer on top of the polyp. Preoperative diagnosis suggested an inflammatory fibroid polyp. A pathological diagnosis of colonic leiomyoma was made after endoscopic resection in both cases. Both tumors were confirmed to originate, not from the proper muscle layer, but from the muscularis mucosae. These cases underscore that although colonic involvement is infrequent, leiomyomas can display pedunculated morphology in the colon rather than the typical gross appearance of gastrointestinal submucosal tumors seen with sessile morphology.

DOI： 10.1155/2018/8272313

Author's Reply Reviewed

Sakiko Hiraoka, Jun Kato, Hiroyuki Okada

Intestinal Research 16 ( 2 ) 321 - 322 2018

Usefulness of biomarkers for disease activity and mucosal healing in patients with inflammatory bowel disease Reviewed

Sakiko Hiraoka, Jun Kato, Hiroyuki Okada

Journal of Japanese Society of Gastroenterology 115 ( 3 ) 262 - 271 2018

Retention of patency capsule in a patient with Crohn's disease Reviewed

Masaya Iwamura, Shiho Takashima, Toshihiro Iguchi, Masahiro Takahara, Seiji Kawano, Sakiko Hiraoka, Yuta Kondo, Takehi Tanaka, Hiroyuki Okada

Journal of Japanese Society of Gastroenterology 115 ( 2 ) 203 - 210 2018

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japanese Society of Gastroenterology

A 40-year-old Japanese man with abdominal pain was referred to our hospital. The patient had been diagnosed with Crohn's disease at the age of 21 years and had since then received treatment with mesalazine and had been advocated an elemental diet. About 30 months before his visit to the hospital, he had swallowed a patency capsule, the retention of which in the ileum was subsequently detected on abdominal ultrasonography. The patient was advised to undergo the evaluation of stenosis, but he refused further investigation at that time. Computed tomography scanning performed at our institution revealed stenosis of the ileum and the presence of a high-density material in the proximal side of the stenosis. Double-balloon enteroscopy and enterography with contrast media revealed multiple stenoses of the ileum. The stenotic ileum was surgically resected, and a foreign body was removed. Electron microscopy analysis revealed that the foreign body was the cellophane wall of the PillCamTM patency capsule. Thus, the retention of the cellophane wall of a patency capsule after consumption was diagnosed for the current case on the basis of the study findings.

DOI： 10.11405/nisshoshi.115.203

Colonoscopy examination requires a longer time in patients with acromegaly than in other individuals Reviewed

Masaya Iwamuro, Miho Yasuda, Kou Hasegawa, Satoshi Fujisawa, Kanako Ogura-Ochi, Yuusaku Sugihara, Keita Harada, Sakiko Hiraoka, Hiroyuki Okada, Fumio Otsuka

Endocrine Journal 65 ( 2 ) 151 - 157 2018

Language：English Publishing type：Research paper (scientific journal) Publisher：Japan Endocrine Society

This study aimed to determine the prevalence of colorectal neoplasms and to investigate the rate of and time required for cecal intubation in patients with acromegaly. A database search performed at our institution identified 29 patients with acromegaly who underwent colonoscopy. Data regarding the endoscopic, biological, and pathological examinations performed were retrospectively reviewed from the clinical records. Subsequently, the rate of and time required for cecal intubation were investigated in 23 patients with acromegaly and compared with the corresponding data of the control group. Control subjects were selected from a 2:1 matched historical control cohort, according to baseline characteristics. The mean age of the acromegaly group (17 female and 12 male) was 60.4 ± 12.6 years. Twelve patients had adenoma (41.4%), eight patients had hyperplastic polyps (27.6%), three patients had sessile serrated adenoma/polyps (10.3%), and three patients had colon cancer (10.3%). Successful cecal intubation was achieved in all patients in both groups. The difference in the time required for successful intubation between the acromegaly group (15.7 ± 9.8 minutes) and the control group (8.7 ± 6.0 minutes) was statistically significant. Linear regression analysis revealed that increased patient age was significantly related to longer colonoscope insertion times. In conclusion, although cecal intubation during colonoscopy was successful in all participants, it required a longer time in patients with acromegaly. Our results underscore the importance of and certain technical difficulties involved in colonoscopy procedures in patients with acromegaly, especially in older patients.

DOI： 10.1507/endocrj.EJ17-0322

Metachronous Neoplasia and Local Recurrence after Colorectal Endoscopic Submucosal Dissection Reviewed

Daisuke Takei, Keita Harada, Shiho Takashima, Toshihiro Inokuchi, Asuka Nakarai, Yusaku Sugihara, Masanobu Takahara, Sakiko Hiraoka, Hiroyuki Okada

ACTA MEDICA OKAYAMA 71 ( 6 ) 475 - 483 2017.12

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

Several reports discussed colonoscopic surveillance after polypectomy and endoscopic mucosal resection (EMR) for colorectal polyps, but only a few reports focused on prognostic analyses, and none involved meta-chronous neoplasia after colorectal endoscopic submucosal dissection (ESD). We conducted the present study to assess the risk of adenoma recurrence requiring endoscopic treatment, and to establish appropriate post-ESD colonoscopic surveillance. We enrolled 116 patients who had undergone colorectal ESD at Okayama University Hospital between February 2008 and July 2014 and had been followed-up > 12 months. We retrospectively analyzed clinicopathological features of 101 lesions from 101 patients. Metachronous adenomas were detected in 21 cases (20.8%). We divided the patients into 2 groups according to the occurrence of metachronous adenomas. Our comparison of clinicopathological characteristics between these groups showed that in the metachronous adenomas group the number of synchronous adenomas at index colonoscopy was high and the rate of laterally spreading tumor-nongranular (LST-NG) was higher. A multivariate analysis indicated that the number of synchronous adenomas was significantly associated with metachronous adenomas (HR: 2.54, 95% CI: 1.04-6.52, p < 0.05). The colonoscopic surveillance planning after colorectal ESD should be more meticulous for patients with more synchronous adenomas.

DOI： 10.18926/AMO/55584

The Usefulness of Colonoscopy for the Detection of Ileal Involvement in Intestinal Follicular Lymphoma Patients Reviewed

Masaya Iwamuro, Katsuyoshi Takata, Eiko Hayashi, Seiji Kawano, Sakiko Hiraoka, Yoshiro Kawahara, Tadashi Yoshino, Hiroyuki Okada

ACTA MEDICA OKAYAMA 71 ( 5 ) 391 - 398 2017.10

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

To evaluate the usefulness of colonoscopy for the detection of ileal involvement in patients with intestinal follicular lymphoma, seventeen patients with intestinal follicular lymphoma who underwent colonoscopy and biopsy sampling from the terminal ileum were enrolled. The patients were divided into 2 groups: cases with ileal involvement (n=6) and cases without ileal involvement (n=11). Patients' clinical backgrounds were compared between the two groups. Subsequently, 10 board-certified endoscopists independently evaluated the endoscopic pictures and determined whether the ileum was involved with follicular lymphoma. Infiltration of follicular lymphoma cells were identified in 6 patients (35.3%). Cases with positive ileal involvement were diagnosed with follicular lymphoma at a younger age than were cases without ileal involvement (55.4 +/- 7.4 vs. 68.1 +/- 10.3 years, p=0.011). Macroscopically, in patients with ileal involvement, there were multiple polypoid elevations smaller than 5 mm in 4 cases, single polypoid elevation smaller than 5 mm in 1 case, and single polypoid elevation larger than 5 mm in 1 case. In patients without ileal involvement, there were no lesions in the terminal ileum in 7 cases, and multiple polypoid elevations smaller than 5 mm were seen in 4 cases. The accuracy of the macroscopic evaluation by 10 board-certified endoscopists was 68.8%. Colonoscopy is particularly recommended during the initial workup of patients with follicular lymphoma diagnosed at age <= 60 years. The diagnosis of ileal involvement based on morphology alone is difficult; thus, biopsy and pathologic diagnosis are required for accurate diagnosis.

DOI： 10.18926/AMO/55436

当院での潰瘍性大腸炎患者における上部消化管病変の検討

加藤諒, 岩室雅也, 平岡佐規子, 高嶋志保, 半井明日香, 井口俊博, 岡田裕之

Gastroenterological Endoscopy 59 ( Suppl.2 ) 2237 - 2237 2017.9

Two electrosurgical endo-knives for endoscopic submucosal dissection of colorectal superficial neoplasms: a prospective randomized study. Reviewed International journal

Sugihara Y, Harada K, Kawahara Y, Takei D, Takashima S, Inokuchi T, Nakarai A, Takahara M, Kuwaki K, Hiraoka S, Okada H

Endoscopy international open 5 ( 8 ) E729 - E735 2017.8

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND AND STUDY AIMS : Few studies have directly compared endo-knives for endoscopic submucosal dissection (ESD) in humans. We compared the performances of the Mucosectom2 and SB knife Jr. PATIENTS AND METHODS: Two trainee endoscopists performed ESD of 36 lesions in this prospective, randomized controlled trial. Mucosal incision with a 1.5-mm Dual knife and submucosal dissection using the Mucosectom2 were performed in 1 group. Mucosal incision with a 1.5-mm Dual knife and submucosal dissection with a SB knife Jr. were performed in the other group. The primary outcome was the ESD procedure time. Secondary outcomes were total procedure time, self-completion rates, and adverse events. RESULTS : ESD time in Mucosectom2 patients was not significantly shorter than in SB knife Jr. patients (57 ± 32 min vs. 61 ± 44 min, respectively; P = 0.94). Total procedure time in Mucosectom2 patients was not significantly shorter than in SB knife Jr. patients (81 ± 42 min vs. 82 ± 51 min, respectively; P = 0.85). The trainee self-completion rate was slightly higher in SB knife Jr. patients than in Mucosectom2 patients, although the difference was not significant (94 % vs. 100 %, respectively; P = 0.959). Fewer hemostatic procedures using the Coagrasper were performed in Mucosectom2 patients than in SB knife Jr. patients, although the difference was not significant (0.62 vs. 0.7, respectively; P = 0.432). CONCLUSIONS: Mucosectom2 and SB knife Jr. did not significantly differ in performance for colorectal ESD to safely and reliably enhance ESD. Knife selection is not as important for learning colorectal ESD as patient- and lesion-related factors.

DOI： 10.1055/s-0043-111792

Comparing reduced-dose sodium phosphate tablets to 2 L of polyethylene glycol: A randomized study Reviewed

Soichiro Ako, Koji Takemoto, Eriko Yasutomi, Chihiro Sakaguchi, Mayu Murakami, Tomoko Sunami, Shohei Oka, Hamada Kenta, Noriko Okazaki, Yuki Baba, Yasushi Yamasaki, Toshiyuki Asato, Daisuke Kawai, Ryuta Takenaka, Hirohumi Tsugeno, Sakiko Hiraoka, Jun Kato, Shigeatsu Fujiki

WORLD JOURNAL OF GASTROENTEROLOGY 23 ( 24 ) 4454 - 4461 2017.6

Language：English Publishing type：Research paper (scientific journal) Publisher：BAISHIDENG PUBLISHING GROUP INC

AIM
To compare the tolerability and quality of bowel cleansing between 2 L polyethylene glycol (PEG) and reduced-dose sodium phosphate (NaP) tablets as a preparation for colonoscopy.
METHODS
Two hundred patients were randomly assigned to the PEG or NaP groups at the same ratio. The NaP group patients took 30 tablets with 2 L of clear liquid, while the PEG group patients took 2L of PEG. Tolerability was assessed by a questionnaire about taste, volume, and the overall impression. The bowel cleansing quality was evaluated by colonoscopists.
RESULTS
Although NaP showed better tolerability in terms of taste, volume and overall impression (P < 0.01, P < 0.01 and P = 0.02, respectively), the overall cleansing quality was better in the PEG group (P < 0.01). A subgroup analysis, stratified by sex and age, indicated that NaP was associated with better tolerability and equivalent bowel cleansing quality in females of < 50 years of age.
CONCLUSION
Despite the better tolerability, the use of 30 NaP tablets with 2 L of clear liquid should be limited due to its lower cleansing quality; however, in certain cases the regimen may deserve consideration, particularly in cases involving young women.

DOI： 10.3748/wjg.v23.i24.4454

Acute Appendicitis Caused by Previous Endoscopic Submucosal Dissection for an Adenoma Adjacent to the Appendiceal Orifice. Reviewed International journal

Kato R, Harada K, Harada K, Takei D, Sugihara Y, Takashima S, Inokuchi T, Takahara M, Hiraoka S, Omura Y, Oda W, Okada H

Case reports in gastroenterology 11 ( 2 ) 271 - 276 2017.5

Language：English

Endoscopic submucosal dissection (ESD) is a groundbreaking treatment for tumors adjacent to the appendiceal orifice that are difficult to remove by conventional endoscopic mucosal resection, and successful cases are increasingly reported. However, little is known about the subsequent complications, especially long-term complications. A female in her early 70s with a 15-mm cecal tumor adjacent to the appendiceal orifice - discovered incidentally during a screening colonoscopy - underwent hybrid ESD of the lesion. We completely resected the tumor, and she was discharged 5 days later with a pathological diagnosis of high-grade tubular adenoma. Ten months postoperatively, she experienced sudden-onset right lower quadrant pain and was diagnosed with acute appendicitis at another hospital. Due to suspicion that her condition was the result of residual tumor, her surgeon performed an emergency laparoscopic cecectomy. The pathological examination of the resected specimen showed thick scarring adjacent to the appendiceal orifice and no residual tumor. The previous ESD was identified as the cause of the scar, and the scar was the only finding to account for the patient's appendicitis. This case is significant because the patient required additional surgery due to a complication of ESD. Further, it indicates that acute appendicitis may be a late complication of submucosal dissection near the appendiceal orifice. As ESD becomes more widely used, it is likely that more cecal tumors will be treated endoscopically. It is important to be aware of the late complications of ESD for these tumors.

DOI： 10.1159/000475753

A Calcium Enterolith in a Patient with Crohn's Disease and Its In Vitro Dissolubility in Citric Acid. Reviewed

Iwamuro M, Urata H, Hiraoka S, Ohmori M, Kondo Y, Kawahara Y, Okada H

Case reports in gastrointestinal medicine 2017 2951547 2017

Two Cases of Rectal Xanthoma Presenting as Yellowish to Whitish Lesions during Colonoscopy. Reviewed International journal

Iwamuro M, Tanaka T, Takei D, Sugihara Y, Harada K, Hiraoka S, Kawahara Y, Okada H

Case reports in gastrointestinal medicine 2017 5975107 - 5975107 2017

Language：English

Two cases of rectal xanthomas are described. One case is that of a 56-year-old Japanese man in whom multiple yellowish spots measuring approximately 3 to 5 mm were observed in the rectum during colonoscopy. The other case is that of a 78-year-old Japanese man in whom colonoscopy showed a whitish plaque of 4 mm in diameter in the rectum. Biopsy examinations performed on both patients revealed the deposition of xanthoma cells within the rectal mucosa. Within the gastrointestinal tract, xanthomas most frequently arise in the stomach, whereas the colorectum is rarely affected. Despite this infrequency, the two cases indicate that xanthomas should be recalled when yellowish to whitish lesions are observed in the colorectum.

DOI： 10.1155/2017/5975107

P2-10 慢性腸炎マウスモデルにおけるベルベリンの改善効果と作用機序の検討

高原政宏, 高木章乃夫, 平岡佐規子, 池田愛璃, 足立卓哉, 松下浩志, 小池和子, 岡田裕之

日本臨床免疫学会会誌 40 ( 4 ) 311b - 311b 2017

Language：Japanese Publisher：日本臨床免疫学会

<p>【背景】生薬であるベルベリン（BBR）は下痢止めとして臨床応用されているが，抗炎症など多彩な作用も有することが明らかになっている．BBRは細胞のエネルギーの調節因子であるAMPKを活性化させることが知られており，近年，このAMPKがT細胞を含む免疫細胞の応答に関わっていることが報告されている．【目的，方法】慢性腸炎マウスモデルを用いて，大腸炎粘膜のCD4⁺T細胞（LP CD4⁺T細胞）におけるBBRの抗炎症作用とその機序についての検証をin vitroおよびIn vivoで行う．1）CD4⁺CD45RB^highT細胞移入腸炎マウスのLPCD4⁺T細胞をPMA/Ionomysinで刺激し，IFN-γ産生細胞を誘導，BBRの効果について，AMPKの関与も含めて検討．2）上記腸炎マウスにBBRを含んだ餌を投与し，腸炎の抑制効果について検討．【結果】1）LP CD4⁺T細胞はBBRと共培養すると，IFN-γ産生細胞が優位に低下し，ウェスタンブロッティングでは，AMPKの活性化を認めた．次に，AMPKのagonistとantagonistを用いた培養系でIFN-γの産生を調べたところ，agonistで抑制，antagonistで増加を認めた．以上から，BBRにより活性化されたAMPKがIFN-γを制御していることが示唆された．2）上記腸炎マウスにBBRを経口投与した結果，腸炎は優位に抑制された．【結論】BBRは，慢性腸炎マウスモデルの腸炎を抑制し，その作用機序の一つとしてAMPKを介した機序が示唆された．</p>

DOI： 10.2177/jsci.40.311b

A Novel Role of Spred2 in the Colonic Epithelial Cell Homeostasis and Inflammation Reviewed

Sakuma Takahashi, Teizo Yoshimura, Takahiro Ohkura, Masayoshi Fujisawa, Soichiro Fushimi, Toshihiro Ito, Junya Itakura, Sakiko Hiraoka, Hiroyuki Okada, Kazuhide Yamamoto, Akihiro Matsukawa

SCIENTIFIC REPORTS 6 37531 2016.11

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Rapid and adequate mucosal healing is important for a remission of ulcerative colitis (UC) patients. Here, we examined whether Spred2, a member of the Sprouty-related EVH1-domain-containing proteins that inhibit the Ras/Raf/ERK pathway, plays a role in colonic mucosal homeostasis and inflammation by using Spred2 knockout (KO) mice. We first detected increased epithelial cell proliferation and cadherin 1 expression in the colon of naive Spred2 KO mice compared to wild-type mice. Interestingly, Spred2 KO mice were resistant to dextran sulfate sodium (DSS)-induced acute colitis as indicated by lower levels of body weight loss and disease activity index. Histologically, epithelial cell injury and inflammation were milder in the colonic mucosa of Spred2 KO mice on day 3 and almost undetectable by day 8. Experiments with bone chimeric mice indicated that Spred2 deficiency in non-hematopoietic cells was responsible for the reduced sensitivity to DSS. Finally, Spred2 KO mice developed significantly fewer tumors in response to azoxymethane plus DSS. Taken together, our results demonstrate, for the first time, that Spred2 plays an important role in the regulation of colonic epithelial cell proliferation and inflammation by potentially down-regulating the activation of ERK. Thus, Spred2 may be a new therapeutic target for the treatment of UC.

DOI： 10.1038/srep37531

Ulcerative colitis patients in clinical remission demonstrate correlations between fecal immunochemical test results, mucosal healing, and risk of relapse Reviewed

Asuka Nakarai, Jun Kato, Sakiko Hiraoka, Shiho Takashima, Daisuke Takei, Toshihiro Inokuchi, Yuusaku Sugihara, Masahiro Takahara, Keita Harada, Hiroyuki Okada

WORLD JOURNAL OF GASTROENTEROLOGY 22 ( 21 ) 5079 - 5087 2016.6

Language：English Publishing type：Research paper (scientific journal) Publisher：BAISHIDENG PUBLISHING GROUP INC

AIM: To assess the risk of relapse in ulcerative colitis (UC) patients in clinical remission using mucosal status and fecal immunochemical test (FIT) results.
METHODS: The clinical outcomes of 194 UC patients in clinical remission who underwent colonoscopy were based on evaluations of Mayo endoscopic subscores (MESs) and FIT results.
RESULTS: Patients with an MES of 0 (n = 94, 48%) showed a ten-fold lower risk of relapse than those with an MES of 1-3 (n = 100, 52%) (HR = 0.10, 95%CI: 0.05-0.19). A negative FIT result (fecal hemoglobin concentrations <= 100 ng/mL) was predictive of patients with an MES of 0, with a sensitivity of 0.94 and a specific of 0.76. Moreover, patients with a negative FIT score had a six-fold lower risk of clinical relapse than those with a positive score (HR = 0.17, 95%CI: 0.10-0.28). Inclusion of the distinguishing parameter, sustaining clinical remission > 12 mo, resulted in an even stronger correlation between negative FIT results and an MES of 0 with respect to the risk of clinical relapse (HR = 0.11, 95%CI: 0.04-0.23).
CONCLUSION: Negative FIT results one year or more after remission induction correlate with complete mucosal healing (MES 0) and better prognosis. Performing FIT one year after remission induction may be useful for evaluating relapse risk.

DOI： 10.3748/wjg.v22.i21.5079

【IBD治療のcritical point-私ならこうする】潰瘍性大腸炎ステロイド依存性の見極めと治療方針チオプリン製剤による寛解維持療法

井口俊博, 平岡佐規子, 高嶋志保, 半井明日香, 高原政宏, 岡田裕之

臨床消化器内科 31 ( 6 ) 655 - 659 2016.5

Language：Japanese Publisher：(株)日本メディカルセンター

チオプリン製剤は潰瘍性大腸炎においてステロイド依存例に対するステロイド減量効果,および寛解維持効果を有する貴重な薬剤である.活性体である6-TGN(6-thioguanine nucleotide)に変換され安定して薬効を発揮するまでに時間が必要であり,しばしば副作用を伴うことから使用に当たり習熟が不可欠である.しかし投与開始後から慎重にモニタリングを行うことで対応可能であり,その有効性,利便性,医療経済の観点から抗TNFα抗体製剤に優先してチオプリン製剤を活用すべきである.(著者抄録)

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J01937&link_issn=&doc_id=20160530220007&doc_link_id=10.19020%2FJ01937.2016299263&url=https%3A%2F%2Fdoi.org%2F10.19020%2FJ01937.2016299263&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Lymphoid hyperplasia of the colon and its association with underlying allergic airway diseases Reviewed

Masaya Iwamuro, Sakiko Hiraoka, Hiroyuki Okada, Yoshinari Kawai, Yoshio Miyabe, Katsuyoshi Takata, Seiji Kawano, Kazuhide Yamamoto

INTERNATIONAL JOURNAL OF COLORECTAL DISEASE 31 ( 2 ) 313 - 317 2016.2

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

The purpose of this study was to determine the prevalence of lymphoid hyperplasia in the lower gastrointestinal tract and its role in patients undergoing colonoscopic examinations, particularly focusing on any allergic predisposition.
A database search performed at the Department of Gastroenterology at Onomichi Municipal Hospital identified seven patients with lymphoid hyperplasia in the large intestine (i.e., cecum, colon, and/or rectum). Data regarding the endoscopic, biological, and pathological examinations performed and the allergic histories for each patient were retrospectively reviewed from the clinical records.
Median age of the patients (four males, three females) was 50 years. Lymphoid hyperplasia was seen in the cecum (n = 5), ascending colon (n = 2), and transverse colon (n = 1). Six patients (85.7 %) had one of the allergic airway diseases: allergic rhinoconjunctivitis for pollen (n = 3), bronchial asthma (n = 1), infantile asthma (n = 1), or allergic bronchitis (n = 1). Drug allergy (n = 3) and urticaria (n = 2) were also found. All seven patients had one or more allergic diseases; however, none had a history of food allergy. Blood tests for allergens revealed that six patients (85.7 %) had positive reactions to inherent allergens, whereas only one patient had a positive reaction to food allergens.
Our results indicate that lymphoid hyperplasia in the large intestine may be associated with allergic airway diseases rather than with food allergies; thus, its presence may be useful to detect patients with underlying airway hyperreactivity.

DOI： 10.1007/s00384-015-2392-6

Fecal immunochemical test as a biomarker for inflammatory bowel diseases: Can it rival fecal calprotectin? Reviewed

Jun Kato, Sakiko Hiraoka, Asuka Nakarai, Shiho Takashima, Toshihiro Inokuchi, Masao Ichinose

Intestinal Research 14 ( 1 ) 5 - 14 2016

Language：English Publisher：Korean Association for the Study of Intestinal Diseases

Accurate evaluation of disease activity is essential for choosing an appropriate treatment and follow-up plan for patients with inflammatory bowel disease (IBD). Endoscopy is required for accurately evaluating disease activity, but the procedures are sometimes invasive and burdensome to patients. Therefore, alternative non-invasive methods for evaluating or predicting disease activity including mucosal status are desirable. Fecal calprotectin (Fcal) is the most widely used fecal marker for IBD, and many articles have described the performance of the marker in predicting disease activity, mucosal healing (MH), treatment efficacy, and risk of relapse. Fecal immunochemical test (FIT) can quantify the concentration of hemoglobin in stool and was originally used for the screening of colorectal cancer. We recently reported that FIT is also a useful biomarker for IBD. A direct comparison between the use of Fcal and FIT showed that both methods predicted MH in ulcerative colitis equally well. However, in the case of Crohn's disease, FIT was less sensitive to lesions in the small intestine, compared to Fcal. FIT holds several advantages over Fcal in regards to user-friendliness, including a lower cost, easy and clean handling, and the ability to make rapid measurements by using an automated measurement system. However, there is insufficient data to support the application of FIT in IBD. Further studies into the use of FIT for evaluating the inflammatory status of IBD are warranted.

DOI： 10.5217/ir.2016.14.1.5

Clinical Features of Intestinal Behcet's Disease Associated with Myelodysplastic Syndrome and Trisomy 8 Reviewed

Seiji Kawano, Sakiko Hiraoka, Hiroyuki Okada, Mitsuhiro Akita, Masaya Iwamuro, Kazuhide Yamamoto

ACTA MEDICA OKAYAMA 69 ( 6 ) 365 - 369 2015.12

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

Several studies have identified a relationship between myelodysplastic syndrome and Beket's disease (BD), especially intestinal BD, and trisomy 8 appears to play an important role in these disorders. Despite this, only few case reports or series have been reported in gastroenterology, meaning that endoscopic findings and characteristics of intestinal 131) have not been clarified yet. In this report, we describe three cases of intestinal BD associated with myelodysplastic syndrome and trisomy 8, and discuss the clinical features and problems of these disorders from a gastroenterology perspective.

DOI： 10.18926/AMO/53912

An open-label prospective randomized multicenter study of intensive versus weekly granulocyte and monocyte apheresis in active crohn's disease Reviewed

Naoki Yoshimura, Yoko Yokoyama, Katsuyoshi Matsuoka, Hiroki Takahashi, Ryuichi Iwakiri, Takayuki Yamamoto, Tomoo Nakagawa, Takumi Fukuchi, Satoshi Motoya, Reiko Kunisaki, Shingo Kato, Fumihito Hirai, Yoh Ishiguro, Satoshi Tanida, Sakiko Hiraoka, Keiichi Mitsuyama, Shunji Ishihara, Shinji Tanaka, Michiro Otaka, Taro Osada, Takashi Kagaya, Yasuo Suzuki, Hiroshi Nakase, Hiroyuki Hanai, Kenji Watanabe, Nobuhito Kashiwagi, Toshifumi Hibi

BMC GASTROENTEROLOGY 15 163 2015.11

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Background: Granulocyte and monocyte adsorptive apheresis (GMA) has shown efficacy in patients with active Crohn's disease (CD). However, with routine weekly therapy, it may take several weeks to achieve remission. This study was performed to assess clinical efficacy and safety of intensive GMA in patients with active CD.
Methods: In an open-label, prospective, randomized multicentre setting, 104 patients with CD activity index (CDAI) of 200 to 450 received intensive GMA, at two sessions per week (n = 55) or one session per week (n = 49). Clinical remission was defined as a CDAI score <150. Patients in each arm could receive up to 10 GMA sessions. However, GMA treatment could be discontinued when CDAI decreased to <150 (clinical remission level).
Results: Of the 104 patients, 99 were available for efficacy evaluation as per protocol, 45 in the weekly GMA group, and 54 in the intensive GMA group. Remission was achieved in 16 of 45 patients (35.6 %) in the weekly GMA and in 19 of 54 (35.2 %) in the intensive GMA (NS). Further, the mean time to remission was 35.4 +/- 5.3 days in the weekly GMA and 21.7 +/- 2.7 days in the intensive GMA (P = 0.0373). Elevated leucocytes and erythrocyte sedimentation rate were significantly improved by intensive GMA, from 8005/mu L to 6950/mu L (P = 0.0461) and from 54.5 mm/hr to 30.0 mm/hr (P = 0.0059), respectively. In both arms, GMA was well tolerated and was without safety concern.
Conclusions: In this study, with respect to remission rate, intensive GMA was not superior to weekly GMA, but the time to remission was significantly shorter in the former without increasing the incidence of side effects. UMIN registration # 000003666.

DOI： 10.1186/s12876-015-0390-3

[A case of asymptomatic Sjögren's syndrome who developed interstitial pneumonia during monoclonal antibody therapy of Crohn's disease]. Reviewed

Kohno H, Okada H, Hiraoka S, Tanaka T

Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology 112 ( 7 ) 1326 - 1333 2015.7

Language：Japanese Publisher：The Japanese Society of Gastroenterology

A 67-year-old woman was diagnosed with ileocolic Crohns disease at 61 years of age. Remission had been induced by the monoclonal antibody adalimumab, and maintenance therapy had continued since her diagnosis. However, she developed respiratory symptoms, including a dry cough. A chest CT scan revealed interstitial shadows in the lower pulmonary lobes. Although no sicca symptoms were noted, she was serologically positive for both anti-Sjögrens syndrome-related antigen A and B antibodies, and salivary gland biopsy showed lymphocytic infiltration. Consequently, she was diagnosed as having asymptomatic Sjögrens syndrome. Infection or drug-induced pulmonary disease was considered unlikely, and the interstitial pneumonia was considered an extra-glandular presentation of Sjögrens syndrome. Thus, interstitial shadows, which appear during immunotherapy for Crohns disease, could indicate asymptomatic Sjögrens syndrome; clinicians should consider this rare clinical picture when assessing such a patient.

DOI： 10.11405/nisshoshi.112.1326

Other Link： http://search.jamas.or.jp/link/ui/2015305791

Endoscopic radial incision and cutting method for refractory stricture of a rectal anastomosis after surgery Reviewed

Keita Harada, Seiji Kawano, Sakiko Hiraoka, Yoshiro Kawahara, Yoshitaka Kondo, Hiroyuki Okada

ENDOSCOPY 47 E552 - E553 2015

An Effective and Safe Sedation Technique Combining Target-Controlled Infusion Pump with Propofol, Intravenous Pentazocine, and Bispectral Index Monitoring for Peroral Double-Balloon Endoscopy Reviewed

Seiji Kawano, Hiroyuki Okada, Masaya Iwamuro, Yoshiyasu Kouno, Kou Miura, Toshihiro Inokuchi, Hiromitsu Kanzaki, Keisuke Hori, Keita Harada, Sakiko Hiraoka, Yoshiro Kawahara, Kazuhide Yamamoto

DIGESTION 91 ( 2 ) 112 - 116 2015

Language：English Publishing type：Research paper (scientific journal) Publisher：KARGER

Background/Aims: Because peroral double-balloon endoscopy (DBE) is a time-consuming, painful procedure, sedation with analgesics, and/or anesthetics is generally required. The aim of this prospective study was to investigate the safety and efficacy of our sedation protocol for peroral DBE, which consisted of target-controlled infusion (TCI) anesthesia with propofol, an intravenous bolus of pentazocine, and bispectral index (BIS) monitoring. Methods: A total of 34 consecutive patients who underwent DBE by the oral approach were enrolled. Patients were primarily sedated with a continuous infusion of propofol and adjusted in accordance with the BIS levels. The bolus infusion of pentazocine was performed when the propofol infusion was insufficient. The primary outcome measure of this study was to ensure the safety and efficacy of this sedation technique. The secondary purpose was to identify the characteristics of the patient who required the bolus infusion of pentazocine. Results: Five patients (14.7%) required a reduction in the dose of propofol. However, no patient experienced any serious adverse events. All patients (100%) and 80.6% (25/31) of endoscopists answered that the sedation protocol was 'excellent' or 'enough' for peroral DBE. Eleven patients (32.3%) required a bolus injection of pentazocine. Age < 60 years and a total procedure time of > 70 min were significant risk-factors for pentazocine use. Conclusions: A combination of propofol via TCI pump, bolus injection of pentazocine as needed, and BIS monitoring was a safe and effective procedure for peroral DBE. Reasonable satisfaction indices were obtained from both patients and endoscopists. Pentazocine was required for young patients and in cases with longer procedure times. (c) 2015 S. Karger AG, Basel

DOI： 10.1159/000369614

Prognosis of ulcerative colitis differs between patients with complete and partial mucosal healing, which can be predicted from the platelet count Reviewed

Asuka Nakarai, Jun Kato, Sakiko Hiraoka, Toshihiro Inokuchi, Daisuke Takei, Yuki Moritou, Mitsuhiro Akita, Sakuma Takahashi, Keisuke Hori, Keita Harada, Hiroyuki Okada, Kazuhide Yamamoto

WORLD JOURNAL OF GASTROENTEROLOGY 20 ( 48 ) 18367 - 18374 2014.12

Language：English Publishing type：Research paper (scientific journal) Publisher：BAISHIDENG PUBLISHING GROUP INC

AIM: To determine the difference in clinical outcome between ulcerative colitis (UC) patients with Mayo endoscopic subscore (MES) 0 and those with MES 1.
METHODS: UC patients with sustained clinical remission of 6 mo or more at the time of colonoscopy were examined for clinical outcomes and the hazard ratios of clinical relapse according to MES. Parameters, including blood tests, to identify predictive factors for MES 0 and slight endoscopic recurrence in clinically stable patients were assessed. Moreover, a receiver operating characteristic curve was generated, and the area under the curve was calculated to indicate the utility of the parameters for the division between complete and partial mucosal healing. All P values were two-sided and considered significant when less than 0.05.
RESULTS: A total of 183 patients with clinical remission were examined. Patients with MES 0 (complete mucosal healing: n = 80, 44%) were much less likely to relapse than those with MES 1 (partial mucosal healing: n = 89, 48%) (P < 0.0001, log-rank test), and the hazard ratio of risk of relapse in patients with MES 1 vs MES 0 was 8.17 (95% CI: 4.19-17.96, P < 0.0001). The platelet count (PLT) < 26 x 10(4)/mu L was an independent predictive factor for complete mucosal healing (OR = 4.1, 95% CI: 2.15-7.99). Among patients with MES 0 at the initial colonoscopy, patients of whom colonoscopy findings shifted to MES 1 showed significant increases in PLT compared to those who maintained MES 0 (3.8 x 10(4)/mu L vs -0.6 x 10(4)/mu L, P < 0.0001).
CONCLUSION: The relapse rate differed greatly between patients with complete and partial mucosal healing. A shift from complete to partial healing in clinically stable UC patients can be predicted by monitoring PLT. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.

DOI： 10.3748/wjg.v20.i48.18367

Long-term follow-up of ulcerative colitis patients treated on the basis of their cytomegalovirus antigen status Reviewed

Toshihiro Inokuchi, Jun Kato, Sakiko Hiraoka, Hideyuki Suzuki, Asuka Nakarai, Tomoko Hirakawa, Mitsuhiro Akita, Sakuma Takahashi, Keita Harada, Hiroyuki Okada, Kazuhide Yamamoto

WORLD JOURNAL OF GASTROENTEROLOGY 20 ( 2 ) 509 - 517 2014.1

Language：English Publishing type：Research paper (scientific journal) Publisher：BAISHIDENG PUBL GRP CO LTD

AIM: To clarify the impact of cytomegalovirus (CMV) activation and antiviral therapy based on CMV antigen status on the long-term clinical course of ulcerative colitis (UC) patients.
METHODS: UC patients with flare-up were divided into CMV-positive and -negative groups according to the CMV antigenemia assay. The main treatment strategy provided for the patients in the CMV-positive group comprised a dose reduction of corticosteroids and administration of ganciclovir.
RESULTS: The median number of days to initial remission was significantly greater for the patients in the CMV-positive group (21 d vs 16 d, P = 0.009). However, the relapse rate after remission and colectomy rate during more than 30 mo of observation did not differ between the two groups. Multivariate analysis revealed that administration of ganciclovir was the only independent factor for avoiding colectomy in patients of the CMV-positive group.
CONCLUSION: CMV antigen status did not significantly affect the long-term prognosis in UC patients under treatment with appropriate antiviral therapy. (C) 2014 Baishideng Publishing Group Co., Limited. All rights reserved.

DOI： 10.3748/wjg.v20.i2.509

【大腸側方発育型腫瘍(LST)-新たな時代へ】LSTの遺伝子学的特徴大腸癌の発癌機序からみたLSTの位置づけ

平岡佐規子, 原田馨太, 加藤順

Intestine 18 ( 1 ) 53 - 60 2014.1

Language：Japanese Publisher：(株)日本メディカルセンター

側方に発育する大腸腫瘍であるLST-G,LST-NG,sessile serrated adenoma/polyp(SSA/P)は,分子生物学的にも違いがあり,それぞれ異なった発癌過程を反映する形態変化と考えられる.形態により違いのみられるおもな遺伝子変化は,RAS/RAF/MAPK系シグナルの遺伝子変異(K-ras,BRAF変異)とDNAメチル化の頻度(CIMP)であり,LST-GはK-ras変異,CIMP-low,LST-NGはCIMP-negative,SSA/PはBRAF変異,CIMP-highがそれぞれ特徴的である.(著者抄録)

Slight Increases in the Disease Activity Index and Platelet Count Imply the Presence of Active Intestinal Lesions in C-reactive Protein-negative Crohn's Disease Patients Reviewed

Asuka Nakarai, Jun Kato, Sakiko Hiraoka, Toshihiro Inokuchi, Daisuke Takei, Yuki Morito, Mitsuhiro Akita, Sakuma Takahashi, Keisuke Hori, Keita Harada, Hiroyuki Okada, Kazuhide Yamamoto

INTERNAL MEDICINE 53 ( 17 ) 1905 - 1911 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC INTERNAL MEDICINE

Objective Although the serum C-reactive protein (CRP) level may, to some extent, predict the disease activity in patients with Crohn's disease (CD), it is not always elevated during periods of disease activity. This study aimed to identify factors predicting the presence of active intestinal lesions in CD patients without an elevated CRP level.
Methods CD patients in whom the presence or absence of active intestinal lesions was evaluated using endoscopic and/or radiologic modalities were divided into two groups based on a negative (< 3 mg/L) or positive (>= 3 mg/L) CRP level. The correlations between the presence of active intestinal lesions and various clinical variables, including the Crohn's Disease Activity Index (CDAI), leukocyte and platelet counts and hemoglobin, serum albumin and CRP levels, were determined in the CRP-negative patients.
Results Of the 128 patients examined, 70 had a negative CRP status, approximately half of whom had active intestinal lesions. The multivariate analysis revealed a CDAI of > 100 and platelet count of > 33x10(4)/mu L to be significant predictive factors for the presence of active lesions in the CRP-negative patients [CDAI > 100, odds ratio (OR) = 5.55; 95% confidence interval (CI), 1.80-18.74, platelet count > 33x10(4)/mu L, OR = 5.94; 95% CI, 1.34-28.87]. The sensitivity of fulfillment of either criterion for the presence of active intestinal lesions was 83%, while the specificity of fulfillment of both criteria was 94%.
Conclusion A relatively low CDAI and platelet count were identified as predictive markers of the presence of active intestinal lesions in CRP-negative CD patients. These results suggest that symptoms and laboratory data should be evaluated very carefully in such patients.

DOI： 10.2169/internalmedicine.53.2627

Serum Glycan Markers for Evaluation of Disease Activity and Prediction of Clinical Course in Patients with Ulcerative Colitis Reviewed

Koji Miyahara, Kazuhiro Nouso, Shunsuke Saito, Sakiko Hiraoka, Keita Harada, Sakuma Takahashi, Yuki Morimoto, Sayo Kobayashi, Fusao Ikeda, Yasuhiro Miyake, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada, Maho Amano, Kazuko Hirose, Shin-Ichiro Nishimura, Kazuhide Yamamoto

PLoS ONE 8 ( 10 ) e74861 2013.10

Language：English Publishing type：Research paper (scientific journal)

Background:The aims of this study were to determine the change of whole-serum N-glycan profile in ulcerative colitis (UC) patients and to investigate its clinical utility.Methods:We collected serum from 75 UC patients at the time of admission and the same number of age/sex-matched healthy volunteers. Serum glycan profile was measured by comprehensive quantitative high-throughput glycome analysis and was compared with disease activity and prognosis.Results:Out of 61 glycans detected, 24 were differentially expressed in UC patients. Pathway analysis demonstrated that highly sialylated multi-branched glycans and agalactosyl bi-antennary glycans were elevated in UC patients
in addition, the glycan ratio m/z 2378/1914, which also increased in UC, showed the highest Area under Receiver Operating Characteristic curve (0.923) for the diagnosis of UC. Highly sialylated multi-branched glycans and the glycan ratio m/z 2378/1914 were higher in the patients with total colitis, Clinical Activity Index &gt
10, Mayo endoscopic score 3, or a steroid-refractory status. In particular, the glycan ratio m/z 2378/1914 (above median) was an independent prognostic factor for the need for an operation (hazard ratio, 2.67
95% confidence interval, 1.04-7.84).Conclusions:Whole-serum glycan profiles revealed that the glycan ratio m/z 2378/1914 and highly sialylated multi-branched glycans increase in UC patients, and are correlated with disease activity. The glycan ratio m/z 2378/1914 was an independent predictive factor of the prognosis of UC. © 2013 Miyahara et al.

DOI： 10.1371/journal.pone.0074861

潰瘍性大腸炎の活動性・予後予測における血清糖鎖マーカーの有用性

宮原孝治, 能祖一裕, 平岡佐規子, 森元裕貴, 高橋索真, 小林沙代, 斎藤俊介, 原田馨太, 山本和秀, 天野麻穂, 西村紳一郎

日本臨床分子医学会学術総会プログラム・抄録集 50回 76 - 76 2013.4

Noninvasive evaluation of mucosal healing in inflammatory bowel diseases Reviewed

Jun Kato, Sakiko Hiraoka, Asuka Nakarai, Masao Ichinose

Clinical Journal of Gastroenterology 6 ( 1 ) 1 - 7 2013.2

Language：English

Current opinions increasingly cite the need to achieve not only clinical response but also endoscopic mucosal healing in the treatment of both types of inflammatory bowel disease: ulcerative colitis (UC) and Crohn's disease (CD). Although endoscopic procedures are necessary for confirmation of mucosal healing, undergoing colonoscopy is invasive and burdensome to patients. Therefore, alternative noninvasive methods of evaluating or predicting mucosal status have been eagerly desired. For this purpose, blood, fecal, and radiologic modalities have been suggested and examined. C-reactive protein and fecal markers such as fecal calprotectin can evaluate active inflammation to some extent in both UC and CD. However, their predictive values for mucosal healing have not yet been fully evaluated and current knowledge indicates that the values were rather insufficient. Radiologic modalities such as computed tomography, magnetic resonance, and ultrasound can also evaluate mucosal inflammation but are currently not suitable for detection of healing. Capsule endoscopy may be optimal for evaluating mucosal status of the small bowel in CD patients, but sufficient data are not yet available, particularly for mucosal healing. Thus, these candidates for the surrogate modality are currently imperfect for evaluation of mucosal healing, but the changes in values/findings of these modalities after initiation of therapy appear to be rather promising as a marker of efficacy of the therapy. Finally, our recent data showed that a fecal immunochemical test for evaluation of mucosal healing in UC was very promising and this method should be further evaluated in CD also. © 2012 Springer Japan.

DOI： 10.1007/s12328-012-0346-x

Is presence or history of extracolonic primary malignancy a risk for colorectal Neoplasia? An analysis of patients who underwent colonoscopy Reviewed

Mitsuhiro Akita, Sakiko Hiraoka, Eisuke Kajia, Koji Takemoto, Yasuhiro Nagahara, Hiroshi Yamamot, Kazuhide Yamamoto, Jun Kato

Acta Medica Okayama 67 ( 5 ) 285 - 292 2013

Language：English Publishing type：Research paper (scientific journal)

Whether presence or history of extracolonic primary malignancy is a risk for colorectal neoplasia is not fully known. In this study, 26,452 first-time colonoscopy cases were examined using a colonoscopy database. Among the analyzed subjects, 3,026 (11%) subjects had history or concomitance of extracolonic primary malignancy, while the remaining 23,426 subjects did not. Colorectal neoplasia was observed in 39% of all the subjects. A crude comparison showed that the prevalence of any type of colorectal neoplasia was higher in subjects with extracolonic malignancy than in those without (42% vs. 39%, p = 0.0012). However, after adjusting for confounding factors, the odds ratios (ORs) of subjects with extracolonic malignancy for having colorectal neoplasia, advanced neoplasia, and cancer were all less than 1.0, and all significantly different from those of subjects without extracolonic malignancy. Analysis according to the type of extracolonic malignancy revealed that gastric cancer cases had a significantly lower risk for colorectal advanced neoplasia (OR: 0.81
95% CI: 0.67-0.99). Among major malignancies, only esophageal squamous cell cancer cases had increased risk for colorectal neoplasia (OR: 1.66
95% CI: 1.20-2.29). Patients with presence or history of extracolonic malignancy did not carry a higher risk of occurrence of colorectal neoplasia. © 2013 by Okayama University Medical School.

DOI： 10.18926/AMO/51864

Development of Invasive Colon Cancer with Microsatellite Instability in a Patient with Hyperplastic Polyposis Syndrome Reviewed

Joichiro Horii, Jun Kato, Takeshi Nagasaka, Sakiko Hiraoka, Dong-Sheng Sun, Kazuo Watanabe, Isao Fujita, Tatsuya Toyokawa, Jun Tomoda, Kazuhide Yamamoto

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 42 ( 5 ) 451 - 454 2012.5

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

The serrated pathway has recently been proposed as a route for the development of colorectal cancer with microsatellite instability. Hyperplastic polyposis syndrome is a rare syndrome defined by the presence of numerous serrated polyps, with a high risk of developing into colorectal cancer. We present here a case of hyperplastic polyposis syndrome developing into colorectal cancer with microsatellite instability from a serrated polyp. BRAF mutation and the loss of MLH1 protein were observed in the colorectal cancer, but not in the other serrated polyps around the colorectal cancer, suggesting that colorectal cancer with microsatellite instability develops rapidly from a specific serrated polyp with distinct molecular properties.

DOI： 10.1093/jjco/hys031

Externalization of Saw-Tooth Architecture in Small Serrated Polyps Implies the Presence of Methylation of IGFBP7 Reviewed

Eisuke Kaji, Toshio Uraoka, Jun Kato, Sakiko Hiraoka, Hideyuki Suzuki, Mitsuhiro Akita, Shunsuke Saito, Takehiro Tanaka, Nobuya Ohara, Kazuhide Yamamoto

DIGESTIVE DISEASES AND SCIENCES 57 ( 5 ) 1261 - 1270 2012.5

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Serrated polyps have been considered to be precursors of colorectal cancer with microsatellite instability. However, the biological and/or morphological changes which occur during the course of serrated polyp to cancer remain to be elucidated.
Twenty-eight colorectal serrated polyps including five mixed polyps (MP) from 20 patients were observed by chromoendoscopy with magnification, and subsequently resected endoscopically. The presence of mutations in two genes (K-ras and BRAF) and the methylation status of six genes (MLH1-A, MLH1-C, ESR1, P16, SOCS1, and IGFBP7) were examined.
The 28 polyps included 32 histological serrated lesions (22 sessile serrated adenomas [SSA], six hyperplastic polyps [HP], and four traditional serrated adenoma [TSA]-like lesions). BRAF mutation was frequently observed in SSAs (19/22), while K-ras mutation was dominant in HPs (5/6). The externalization of saw-tooth architecture in serrated polyps was endoscopically observed more frequently in those with high levels of IGFBP7 methylation (P = 0.03). Moreover, the endoscopic finding was observed in five of six small serrated lesions (< 10 mm) which contained both BRAF mutation and high levels of IGFBP7 methylation. TSA-like lesions in small MPs demonstrated the endoscopic finding with no or little MLH1 methylation, while the counterparts in the mixed polyps had high levels of MLH1 methylation with relatively low levels of IGFBP7 methylation.
Our data suggests two distinct pathways may be involved in the early stages of the serrated pathway: one where MLH1 is primarily methylated, and a second where methylated IGFBP7 is associated with an externalization of saw-tooth architecture.

DOI： 10.1007/s10620-011-2008-0

Detectability of colorectal neoplasia with fluorine-18-2-fluoro-2-deoxy-d-glucose positron emission tomography and computed tomography (FDG-PET/CT) Reviewed

Tomoko Hirakawa, Jun Kato, Yoshihiro Okumura, Keisuke Hori, Sakuma Takahashi, Hideyuki Suzuki, Mitsuhiro Akita, Reiji Higashi, Shunsuke Saito, Eisuke Kaji, Toshio Uraoka, Sakiko Hiraoka, Kazuhide Yamamoto

JOURNAL OF GASTROENTEROLOGY 47 ( 2 ) 127 - 135 2012.2

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

The purpose of this study was to analyze the detectability of colorectal neoplasia with fluorine-18-2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (FDG-PET/CT).
Data for a total of 492 patients who had undergone both PET/CT and colonoscopy were analyzed. After the findings of PET/CT and colonoscopy were determined independently, the results were compared in each of the six colonic sites examined in all patients. The efficacy of PET/CT was determined using colonoscopic examination as the gold standard.
In all, 270 colorectal lesions 5 mm or more in size, including 70 pathologically confirmed malignant lesions, were found in 172 patients by colonoscopy. The sensitivity and specificity of PET/CT for detecting any of the colorectal lesions were 36 and 98%, respectively. For detecting lesions 11 mm or larger, the sensitivity was increased to 85%, with the specificity remaining consistent (97%). Moreover, the sensitivity for tumors 21 mm or larger was 96% (48/50). Tumors with malignant or high-grade pathology were likely to be positive with PET/CT. A size of 10 mm or smaller [odds ratio (OR) 44.14, 95% confidence interval (95% CI) 11.44-221.67] and flat morphology (OR 7.78, 95% CI 1.79-36.25) were significant factors that were associated with false-negative cases on PET/CT.
The sensitivity of PET/CT for detecting colorectal lesions is acceptable, showing size- and pathology-dependence, suggesting, for the most part, that clinically relevant lesions are detectable with PET/CT. However, when considering PET/CT for screening purposes caution must be exercised because there are cases of false-negative results.

DOI： 10.1007/s00535-011-0473-z

DNA Methylation of Colon Mucosa in Ulcerative Colitis Patients: Correlation with Inflammatory Status Reviewed

Shunsuke Saito, Jun Kato, Sakiko Hiraoka, Joichiro Horii, Hideyuki Suzuki, Reiji Higashi, Eisuke Kaji, Yoshitaka Kondo, Kazuhide Yamamoto

INFLAMMATORY BOWEL DISEASES 17 ( 9 ) 1955 - 1965 2011.9

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Background: Although DNA methylation of colonic mucosa in ulcerative colitis (UC) has been suggested, the majority of published reports indicate the correlation between methylation of colon mucosa and occurrence of UC-related dysplasia or cancer without considering the mucosal inflammatory status. The aim of this study was to verify whether mucosal inflammation-specific DNA methylation occurs in the colon of UC.
Methods: Of 15 gene loci initially screened, six loci (ABCB1, CDH1. ESR1, GDNF, HPP1, and MYOD1) methylated in colon mucosa of UC were analyzed according to inflammatory status using samples from 28 surgically resected UC patients.
Results: Four of six regions (CDH1, GDNF, HPP1, and MYOD1) were more highly methylated in the active inflamed mucosa than in the quiescent mucosa in each UC patient (P = 0.003, 0.0002, 0.02, and 0.048, respectively). In addition, when the methylation status of all samples taken from examined patients was stratified according to inflammatory status, methylation of CDHI and GDNF loci was significantly higher in active inflamed mucosa than in quiescent mucosa (P = 0.045 and 0.002, respectively). Multiple linear regression analysis revealed that active inflammation was an independent factor of methylation for CDHI and GDNF. DNA methyltransferase 1 and 3b were highly expressed in colon epithelial cells with active mucosa] inflammation, suggesting their involvement in inflammation-dependent methylation.
Conclusions: Methylation in colonic mucosa of UC was correlated with mucosal inflammatory status, suggesting the involvement of methylation due to chronic active inflammation in UC carcinogenesis.

DOI： 10.1002/ibd.21573

Is sigmoidoscopy sufficient for evaluating inflammatory status of ulcerative colitis patients? Reviewed

Jun Kato, Motoaki Kuriyama, Sakiko Hiraoka, Kazuhide Yamamoto

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 26 ( 4 ) 683 - 687 2011.4

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Background and Aims:
An adequate range of colonic observations for precise evaluation of inflammation in ulcerative colitis (UC) patients has not been reported.
Methods:
Retrospective analysis of 545 colonoscopic examinations of UC patients was carried out. Severity of mucosal inflammation was evaluated using the Mayo score of endoscopic index at each location (rectum, sigmoid colon, descending colon, and the oral side of the splenic flexure) in each patient. The colonic site with maximum inflammation was determined for each patient.
Results:
Of 545 patients, 319 (59%) had maximum inflammation in the rectum, 79 (14%) in the sigmoid colon, 70 (13%) in the descending colon, and 77 (14%) on the oral side of the splenic flexure. Severe inflammatory activity (Mayo 3) was observed more frequently in patients who had maximum activity in the descending colon or the more proximal portion than those who had this in the rectum or sigmoid colon (42% vs 25%, P < 0.0001). The first-attack patients were significantly more frequently found in patients with maximum severity in the descending colon or the oral side of splenic flexure than those with maximum severity in the rectum or sigmoid colon (P = 0.016). Moreover, among 134 patients with no inflammation in the rectum and sigmoid colon, 54 (40%) had inflamed mucosa in the descending colon or the more proximal portion.
Conclusions:
Sigmoidoscopy is not sufficient for evaluating inflammation in UC patients. In particular, colonoscopy is necessary for first-attack patients and patients who have a discrepancy between rectosigmoid observation and symptoms.

DOI： 10.1111/j.1440-1746.2010.06562.x

Analysis of K-ras, BRAF, and PIK3CA mutations in laterally-spreading tumors of the colorectum Reviewed

Eisuke Kaji, Jun Kato, Hideyuki Suzuki, Mitsuhiro Akita, Joichiro Horii, Shunsuke Saito, Reiji Higashi, Shin Ishikawa, Motoaki Kuriyama, Sakiko Hiraoka, Toshio Uraoka, Kazuhide Yamamoto

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 26 ( 3 ) 599 - 607 2011.3

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Background and Aims: Laterally-spreading tumors (LST) are a newly-recognized category of colorectal neoplasia, and are defined as lesions larger than 10 mm in diameter and extending circumferentially rather than vertically. However, genetic features of this new category of tumors are not fully elucidated. The aim of this study was to evaluate genetic alterations in LST.
Methods: We examined K-ras, BRAF, and phosphoinositide-3-kinase catalytic-alpha polypeptide (PIK3CA) mutations in 101 LST, including 68 LST-granular type (LST-G) and 33 LST-non-granular type by direct sequencing. As controls, we examined these gene mutations in 66 protruded colon adenomas (10 mm or larger) and 44 advanced colon cancers.
Results: K-ras, BRAF, and PIK3CA mutations were observed in 59 (58%), zero (0%), and three (3%) LST, respectively. LST-G morphology in the right-sided colon was significantly correlated with the existence of K-ras mutations, whereas a size of 20 mm or larger was the only predictor of mutations in the left-sided colorectum. The frequency of K-ras mutations in LST was particularly marked in the left-sided colorectum compared to protruded adenomas or advanced cancers (LST vs protruded adenomas, P < 0.001; LST vs advanced cancers, P = 0.002), whereas in the right-sided colon, K-ras mutations were equally frequent. PIK3CA mutations were not familiar in either LST (3%) or advanced cancers (9%).
Conclusions: K-ras mutations were involved in colorectal LST in different manners according to tumor location.

DOI： 10.1111/j.1440-1746.2010.06485.x

Serum Folate and Homocysteine Levels Are Associated With Colon Tumorigenesis in End-Stage Renal Disease Patients Reviewed

Eisuke Kaji, Jun Kato, Shunsuke Saito, Keita Harada, Kenji Kuwaki, Masashi Tatsukawa, Tamiya Morikawa, Sakiko Hiraoka, Hiroshi Matsushima, Kazuhide Yamamoto

NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL 63 ( 2 ) 202 - 211 2011

Language：English Publishing type：Research paper (scientific journal) Publisher：LAWRENCE ERLBAUM ASSOC INC-TAYLOR & FRANCIS

The aim of this study was to evaluate the effect of folate and homocysteine on colon tumorigenesis by performing colonoscopy and examining serum folate and homocysteine levels in end-stage renal disease (ESRD) patients. We performed colonoscopy in 72 ESRD patients who were undergoing hemodialysis and also measured their serum folate and homocysteine levels. Serum folate and homocysteine concentrations of the 72 ESRD patients were 6.0 +/- 3.9 g/l and 37.3 +/- 25.5 mol/l, respectively. Colorectal neoplasia was detected in 47 (65%) of the patients. Compared to a control group, ESRD patients had significantly more and larger neoplasia (P = 0.002 and 0.001, respectively). Multivariate analysis revealed that ESRD patients with lower levels of serum homocysteine had significantly more and larger neoplasia than those with higher levels (P = 0.02 and 0.03, respectively). In addition, patients with a shorter duration of hemodialysis were likely to have larger neoplasia. ESRD patients had higher than normal serum homocysteine levels. Interestingly, patients with lower homocysteine levels were likely to carry more and larger colorectal neoplasia. These results suggest that suppression of folate metabolism and an elevated serum homocysteine concentration are inversely associated with colon tumorigenesis in ESRD patients.

DOI： 10.1080/01635581.2011.523501

TOLERABILITY AND USEFULNESS OF MERCAPTOPURINE IN AZATHIOPRINE-INTOLERANT JAPANESE PATIENTS WITH ULCERATIVE COLITIS Reviewed

Motoaki Kuriyama, Jun Kato, Hideyuki Suzuki, Mitsuhiro Akita, Sakiko Hiraoka, Hiroyuki Okada, Kazuhide Yamamoto

DIGESTIVE ENDOSCOPY 22 ( 4 ) 289 - 296 2010.10

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Background and Aim:
Azathioprine (AZA) and mercaptopurine (6-MP) are established as effective therapeutic drugs for the induction and maintenance of remission in patients with ulcerative colitis (UC). However, AZA is often intolerable due to adverse effects. Evidence regarding the approach of switching from AZA to 6-MP in patients of Asian ethnicity is lacking. We assessed the tolerability and usefulness of 6-MP in Japanese UC patients who had shown intolerance to AZA.
Methods:
One-hundred and ten UC patients who had been treated with AZA and/or 6-MP from January 1985 to October 2008 were examined retrospectively.
Results:
Among 110 patients, 107 were treated first with AZA; only three were treated first with 6-MP. Thirty-five (33%) of the 107 patients were intolerant of AZA, with adverse effects including myelosuppression (8/35, 23%), hepatotoxicity (8/35, 23%), and abdominal symptoms (6/35, 17%). Among 35 AZA-intolerant patients, 23 were switched to 6-MP treatment. The cumulative probability of colectomy was significantly higher in patients not treated with 6-MP than in patients treated with 6-MP (log-rank test, P = 0.0002). Among the 26 patients (23 AZA-intolerant and three AZA-untreated) treated with 6-MP, 22 (85%) could tolerate the therapy. Adverse effects due to 6-MP were abdominal symptoms (2/4), myelosuppression (1/4), and rash (1/4). The median initial dose of 6-MP was 20 mg/day, and the median final dose was 30 mg/day.
Conclusions:
6-MP was tolerated in 83% of AZA-intolerant patients, and it was effective for maintenance therapy of UC patients. 6-MP treatment should be considered in AZA-intolerant patients.

DOI： 10.1111/j.1443-1661.2010.01009.x

Prediction of flare-ups of ulcerative colitis using quantitative immunochemical fecal occult blood test Reviewed

Motoaki Kuriyama, Jun Kato, Koji Takemoto, Sakiko Hiraoka, Hiroyuki Okada, Kazuhide Yamamoto

WORLD JOURNAL OF GASTROENTEROLOGY 16 ( 9 ) 1110 - 1114 2010.3

Language：English Publishing type：Research paper (scientific journal) Publisher：W J G PRESS

AIM: To examine the feasibility of predicting the flare-up of ulcerative colitis (UC) before symptoms emerge using the immunochemical fecal occult blood test (I-FOBT).
METHODS: We prospectively measured fecal hemoglobin concentrations in 78 UC patients using the I-FOBT every 1 or 2 mo.
RESULTS: During a 20 mo-period, 823 fecal samples from 78 patients were submitted. The median concentration of fecal hemoglobin was 41 ng/mL (range: 0-392500 ng/mL). There were three types of patients with regard to the correlation between I-FOBT and patient symptoms; the synchronous transition type with symptoms (44 patients), the unrelated type with symptoms (19 patients), and the flare-up predictive type (15 patients). In patients with the flare-up predictive type, the values of I-FOBT were generally low during the study period with stable symptoms. Two to four weeks before the flare-up of symptoms, the I-FOBT values were high. Thus, in these patients, I-FOBT could predict the flare-up before symptoms emerged.
CONCLUSION: Flare-up could be predicted by I-FOBT in approximately 20% of UC patients. These results warrant periodical I-FOBT in UC patients. (C) 2010 Baishideng. All rights reserved.

DOI： 10.3748/wjg.v16.i9.1110

Specific endoscopic features of ulcerative colitis complicated by cytomegalovirus infection Reviewed

Hideyuki Suzuki, Jun Kato, Motoaki Kuriyama, Sakiko Hiraoka, Kenji Kuwaki, Kazuhide Yamamoto

WORLD JOURNAL OF GASTROENTEROLOGY 16 ( 10 ) 1245 - 1251 2010.3

Language：English Publishing type：Research paper (scientific journal) Publisher：W J G PRESS

AIM: To identify specific colonoscopic findings in patients with ulcerative colitis (UC) complicated by cytomegalovirus (CMV) infection.
METHODS: Among UC patients who were hospitalized due to exacerbation of symptoms, colonoscopic findings were compared between 15 CMV-positive patients and 58 CMV-negative patients. CMV infection was determined by blood test for CMV antigenemia. Five aspects of mucosal changes were analyzed (loss of vascular pattern, erythema, mucosal edema, easy bleeding, and mucinous exudates) as well as five aspects of ulcerative change (wide mucosal defect, punched-out ulceration, longitudinal ulceration, irregular ulceration, and cobblestone-like appearance). Sensitivity, specificity, positive predictive value, and negative predictive value of each finding for CMV positivity were determined.
RESULTS: The sensitivity of irregular ulceration for positive CMV was 100%. The specificity of wide mucosal defect was 95%. Punched-out ulceration and longitudinal ulceration exhibited relatively high sensitivity and specificity (more than 70% for each).
CONCLUSION: Specific colonoscopic findings in patients with UC complicated by CMV infection were identified. These findings may facilitate the early diagnosis of CMV infection in UC patients. (C) 2010 Baishideng. All rights reserved.

DOI： 10.3748/wjg.v16.i10.1245

Methylation status of normal background mucosa is correlated with occurrence and development of neoplasia in the distal colon Reviewed

Sakiko Hiraoka, Jun Kato, Joichiro Horii, Shunsuke Saito, Keita Harada, Hideyuki Fujita, Motoaki Kuriyama, Koji Takemoto, Toshio Uraoka, Kazuhide Yamamoto

HUMAN PATHOLOGY 41 ( 1 ) 38 - 47 2010.1

Language：English Publishing type：Research paper (scientific journal) Publisher：W B SAUNDERS CO-ELSEVIER INC

The aim of this study is to evaluate the methylation status of normal colonic mucosa in relation to the stage of neoplasia arising from the mucosa. The methylation status of 2 age-related loci (ESR1 and MYOD1) and global methylation (the mean of Alu and Sat2) in the normal colonic mucosa of 156 patients with and without colorectal neoplasia were examined. The distal colon and proximal colon were analyzed separately because neoplasia is biologically and clinically different between these sites. The methylation status was determined by MethyLight using percentage of methylated reference (PMR). In the distal colon, methylation of the age-related loci decreased as the stage of neoplasia increased (patients with no neoplasia or with adenoma <= 9 mm versus patients with advanced adenoma or with invasive cancer: ESR1-PMR median, 21.0 versus 15.7; P = .015; MYOD1-PMR median, 5.35 versus 3.80; P = .0037, respectively). Interestingly, global methylation was inversely correlated with the stage of neoplasia (59.7 versus 61.5; P = .054). In contrast, the proximal colon showed no significant correlations. The methylation of MYOD1 in the normal mucosa was significantly correlated with K-ras mutation in neoplastic tissue arising from the mucosa. Specific epigenetic changes in normal colonic mucosa may be correlated with the occurrence and development of neoplasia in the distal colon. (c) 2010 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2009.06.002

Methylation of estrogen receptor 1 in colorectal adenomas is not age-dependent, but is correlated with K-ras mutation Reviewed

Joichiro Horii, Sakiko Hiraoka, Jun Kato, Shunsuke Saito, Keita Harada, Hideyuki Fujita, Eisuke Kaji, Kazuhide Yamamoto

CANCER SCIENCE 100 ( 6 ) 1005 - 1011 2009.6

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL PUBLISHING, INC

The promoter region of estrogen receptor 1 (ESR1) has been shown to be methylated in normal colorectal mucosa in an age-dependent manner. However, the methylation of this region in colorectal tumors has not sufficiently been investigated. The methylation status of ESR1 in 105 colorectal adenoma tissues was examined by MethyLight and presented as the percentage of methylated references (PMR). Factors that affect the PMR of ESR1 in adenomas were determined using parameters including patient age, sex, past history of malignancy, family history of colorectal cancer, smoking and drinking habits, clinical characteristics of adenomas (location, size, macroscopic appearance, and histology), and K-ras mutation. Multiple linear regression revealed that the PMR was not correlated with patient age. K-ras mutation was significantly correlated with the higher methylation status of ESR1 in adenoma (t-value = 3.21, P = 0.0018), whereas alcohol exposure was significantly correlated with lower methylation status (t-value = -2.37, P = 0.02). Because methylation of O(6)-methylguanine DNA methyltransferase (MGMT) has been reported to be correlated with K-ras G-to-A transition, methylation of ESR1 was compared with that of MGMT with regard to K-ras mutation. Contrary to expectations, methylation of MGMT was not significantly correlated with K-ras G-to-A transition, but that of ESR1 was strongly correlated with K-ras G-to-A transition. Thus, the methylation status of ESR1 in adenomas was not correlated with patient age, but was associated with K-ras mutation, suggesting that methylation of ESR1 in tumors functions differently from that in normal colon mucosa. (Cancer Sci 2009; 100: 1005-1011).

DOI： 10.1111/j.1349-7006.2009.01140.x

Ratio of Platelet Reduction is an Early Predictive Factor for the Effectiveness of Leukocytapheresis for Ulcerative Colitis Patients Reviewed

Koji Takemoto, Motoaki Kuriyama, Jun Kato, Hideyuki Suzuki, Shin Ishikawa, Sakiko Hiraoka, Kazuhide Yamamoto

THERAPEUTIC APHERESIS AND DIALYSIS 13 ( 1 ) 6 - 13 2009.2

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL PUBLISHING, INC

Leukocytapheresis is effective for ulcerative colitis (UC), and both peripheral leukocyte and platelet counts decrease during apheresis. While leukocyte counts increase and overshoot after finishing the apheresis procedure, platelet reduction continues even after apheresis. The aim of this study is to elucidate the impact of the overshoot of leukocyte and continuous platelet reduction on the efficacy of leukocytapheresis for UC. Leukocyte and platelet counts before and one hour after each leukocytapheresis session of 43 UC cases were examined (31 entered remission, but 12 did not). The correlation between the efficacy of leukocytapheresis and leukocyte overshoot or platelet reduction was examined. The average increase ratio of leukocytes in the initial five sessions of the responders was not significantly different from that of the non-responders (95% vs. 92%, P = 0.28). In contrast, the average decrease ratio of platelets in the initial five sessions of the responders was significantly higher than that of the non-responders (34% vs. 27%, P = 0.0041). Moreover, the platelet reduction at the third and fourth apheresis sessions in the responders was remarkably greater than that in the non-responders (33% vs. 20%, P = 0.0018). The efficiency of platelet reduction could be a predictive factor for the efficacy of leukocytapheresis.

DOI： 10.1111/j.1744-9987.2009.00649.x

A case of small early cancer of sigmoid colon, which recurred with liver metastasis 18 months after surgical resection Reviewed

Keita Harada, Jun Kato, Koji Takemoto, Toshio Uraoka, Sakiko Hiraoka, Hiroyuki Yanai, Kazuhide Yamamoto

Journal of Japanese Society of Gastroenterology 106 ( 5 ) 660 - 667 2009

Language：Japanese Publishing type：Research paper (scientific journal)

A 74-year-old man was referred to our hospital with positive fecal occult blood test. Colonoscopic examination revealed a 7-mm 0-Is type polyp in the sigmoid colon. Endoscopic mucosal resection for this lesion completely removed the lesion and the histologic diagnosis was well differentiated adenocarcinoma. Cancer cells invaded the submucosa to a depth of 900μm, and vascular invasion was found. Therefore, the patient underwent additional surgical resection with lymph node dissection. During follow-up, however, serum CEA increased beyond the normal limit 18 months after surgical operation, and a 15-mm single liver metastasis was found through enhanced CT scan abdominal imaging, the FDG-PET scan, and ultrasonography. We have to pay attention to metachronous liver metastasis especially when the vascular invasion is suspected in the resected sample, even if the lesion is completely removed.

Age-related methylation in normal colon mucosa differs between the proximal and distal colon in patients who underwent colonoscopy Reviewed

Joichiro Horii, Sakiko Hiraoka, Jun Kato, Keita Harada, Kenji Kuwaki, Hideyuki Fujita, Shinichi Toyooka, Kazuhide Yamamoto

CLINICAL BIOCHEMISTRY 41 ( 18 ) 1440 - 1448 2008.12

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Objectives: To examine the difference in the methylation status ill normal colon mucosa between the proximal and distal colon. in relation to the correlation between the methylation status of normal mucosa and characteristics of neoplasia.
Design and methods: Paired biopsy specimens of normal mucosa from the proximal and distal colon of 82 patients who underwent colonoscopy were obtained. The methylation status of the promoter region of estrogen receptor 1 (ESR1) and myogenic differentiation 1 (MYOD1) was examined.
Results: Normal mucosa was more highly methylated ill the distal than in the proximal colon in both ESR1 and MYOD1 loci (p<0.0001 and p = 0.0009, respectively). Advanced characteristics of polyps in the distal colon were frequently observed in patients with lower methylation of ESR1 in the distal colon normal mucosa.
Conclusions: Methylation levels in normal mucosa differ between the proximal and distal colon, and lower methylation of ESR1 in the distal colon normal mucosa may correlate with advanced features of neoplasia in the distal colon. (c) 2008 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

DOI： 10.1016/j.clinbiochem.2008.08.089

Genetic and epigenetic alterations of Ras signalling pathway in colorectal neoplasia: analysis based on tumour clinicopathological features. International journal

K Harada, S Hiraoka, J Kato, J Horii, H Fujita, K Sakaguchi, Y Shiratori

British journal of cancer 97 ( 10 ) 1425 - 31 2007.11

Language：English Publishing type：Research paper (scientific journal)

Activation of RAS signalling induced by K-ras/BRAF mutations is a hallmark of colorectal tumours. In addition, Ras association domain families 1 and 2 (RASSF1 and RASSF2), the negative regulators of K-ras, are often inactivated by methylation of the promoter region in those tumours. However, reports showing differences in the occurrence of these alterations on the basis of tumour characteristics have been scarce. We analysed K-ras/BRAF mutations and the methylation status of RASSF1 and RASSF2 promoter regions in 120 colorectal adenomas with respect to their clinicopathological features. K-ras/BRAF mutations and RASSF2 methylation were observed in 49 (41%) and 30 (25%) of the samples, respectively, while RASSF1 methylation was observed in only 3 (2.5%). Adenomas with RASSF2 methylation often carried K-ras/BRAF mutations simultaneously (22 out of 30, P<0.01). Multivariate analysis revealed that the concomitance of these alterations was frequently observed in serrated adenomas (odds ratio (OR) 11.11; 95% confidence interval (CI) 1.96-63.00), but rarely in adenomas located in the sigmoid or descending colon (OR 0.13; 95% CI 0.03-0.58). A comparison between adenomas and cancers showed a significantly higher prevalence of these alterations in cancers than in adenomas in the proximal colon (58 vs 27%, P=0.02). Frequency and the time point of the occurrence of Ras signalling disorders differ according to colorectal neoplasia's characteristics, particularly the location.

Decreased expression of hMLH1 correlates with reduced 5-fluorouracil-mediated apoptosis in colon cancer cells Reviewed

Hideyuki Fujita, Jun Kato, Joichiro Horii, Keita Harada, Sakiko Hiraoka, Hidenori Shiraha, Kohsaku Sakaguchi, Yasushi Shiratori

ONCOLOGY REPORTS 18 ( 5 ) 1129 - 1137 2007.11

Language：English Publishing type：Research paper (scientific journal) Publisher：PROFESSOR D A SPANDIDOS

Patients with sporadic microsatellite instable colorectal cancers, in most of which the function of the hMLH1 mismatch repair gene is impaired, do not gain a survival benefit from 5-fluorouracil (5-FU)-based chemotherapy. However, the effect of hMLH1 on the cytotoxicity induced by 5-FU has not yet been sufficiently confirmed. In this study, we assessed the effect of hMLH1 on cytotoxicity and apoptosis induced by 5-FU using newly developed cell lines. We constructed two cell lines: SW480 (originally hMLH1-proficient), in which the expression of hMLH1 was reduced using a small interfering RNA (siRNA) technique, and HCT116 (originally hMLH1-deficient), in which the expression of hMLH1 can be regulated by doxycycline. Using these, cell lines, a clonogenic survival assay, 4',6-diamidino-2-phenylindole (DAPI) staining and an Annexin-V assay were performed. Moreover, the incorporation of 5-FU into DNA was determined using tritium-labeled 5-FU. In both of our two cell lines, hMLH1-deficient cells exhibited approximately 2.4-fold clonal surviving fraction compared to hMLH1-proficient cells for 10 days after the administration of 5-FU. Additionally, hMLH1-deficient cells treated with 5-FU exhibited 34-45% less apoptosis than hMLH1-proficient cells according to the results of DAPI staining and Annexin-V assay. Furthermore, hMLH1-deficient cells treated with 5-FU exhibited an approximately 2-fold greater incorporation of 5-FU into DNA than control cells, suggesting that the recognition of 5-FU-incorporated DNA is impaired in hMLH1-deficient cells, resulting in reduced apoptosis. Our conclusions were that decreased expression of hMLH1 in colon cancer cells reduced the apoptosis induced by 5-M, suggesting that hMLH1 is a key determinant of 5-FU chemosensitivity.

Centrifugal leukocytapheresis therapy for ulcerative colitis without concurrent corticosteroid administration Reviewed

H Okada, R Takenaka, S Hiraoka, C Makidono, S Hori, J Kato, H Okazaki, H Kawamoto, M Mizuno, Y Shiratori

THERAPEUTIC APHERESIS AND DIALYSIS 10 ( 3 ) 242 - 246 2006.6

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING

Corticosteroid administration is an important therapy for active ulcerative colitis. However, long-term corticosteroid use is associated with serious complications such as osteoporosis, diabetes, and growth retardation. The effect of combination therapy corticosteroid plus leukocytapheresis has been previously reported, but that of leukocytapheresis with no corticosteroid is unknown. We carried out a preliminary study of six patients (two men and four women) with active ulcerative colitis (severe in two, moderately severe in four) who did not respond to 5-aminosalicylate derivatives, but refused corticosteroid use. Centrifugal leukocytapheresis was carried out once per week totaling four sessions per course. Treatment was considered effective when patients experienced clinical remission, which was defined as a frequency of diarrhea of four times or less and absence of visible blood in the stool, after one course. Leukocytapheresis was effective in five of six patients(83%). With cases stratified by severity, both severe cases and three of four moderately severe cases showed effectiveness. Clinical activity scores according to Lichtiger et al. in cases where leukocytapheresis was effective decreased from 9.8 to 6.6 at 1 week (P < 0.0001), declining further 2.4 at the end of the course. No obvious complications of leukocytapheresis were noted except for a decrease in hemoglobin by 1 g/dL. Centrifugal leukocytapheresis without corticosteroid treatment can induce remission in patients with active ulcerative colitis, and might be particularly beneficial for patients in whom adverse effects preclude the use of corticosteroids.

DOI： 10.1111/j.1744-9987.2006.00379.x

Therapeutic efficacy of leukocytapheresis in a pregnant woman with severe active ulcerative colitis Reviewed

H. Okada, C. Makidono, R. Takenaka, S. Hiraoka, A. Fujiwara, J. Kato, Y. Kawahara, H. Kawamoto, M. Mizuno, Y. Shiratori

DIGESTION 74 ( 1 ) 15 - 18 2006

Language：English Publishing type：Research paper (scientific journal) Publisher：KARGER

Leukocytapheresis has recently been used to induce remission in patients with ulcerative colitis (UC) who fail to respond to corticosteroids. We could not find a report in the literature on leukocytapheresis for UC with gestational exacerbation. We have recently encountered this unique condition and report the details here. A 30-year-old Japanese woman with left-sided severe UC was corticosteroid-dependent and had recurrence of the active disease during tapering of corticosteroid. She declined any dose increase and the use of any immunosuppressive agent because she was in the 13th week of pregnancy. Then, concomitant leukocytapheresis was performed without increasing the corticosteroid dose. Recovery was rapid and dramatic. Mucous and bloody stool decreased after the first session, and she had remission 2 weeks later. She underwent a total of four sessions without complications. After 6 weeks, she was discharged from our hospital and underwent maintenance treatment as an outpatient with mesalazine and corticosteroid tapering. Subsequently, she gave birth to a healthy baby girl by an uncomplicated vaginal delivery while keeping the remitted stage of UC. Copyright (c) 2006 S. Karger AG, Basel.

DOI： 10.1159/000095478

Stool decay-accelerating factor as a marker for monitoring the disease activity during leukocyte apheresis therapy in patients with refractory ulcerative colitis Reviewed

H Kohno, M Mizuno, J Nasu, C Makidono, S Hiraoka, T Inaba, K Yamamoto, H Okada, T Fujita, Y Shiratori

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 20 ( 1 ) 73 - 78 2005.1

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING ASIA

Background and Aims: We have shown previously that concentrations of stool decay-accelerating factor (DAF; CD55), a complement regulatory protein, in patients with ulcerative colitis (UC) are increased in relation to the severity of the colonic mucosal inflammation. In the present study, we evaluated the usefulness of stool DAF as a marker for monitoring disease activity in patients with steroid-resistant active UC being treated with leukocyte apheresis performed with a centrifugal cell separator.
Methods: Twenty-one patients with active and steroid-resistant UC were treated with leukzocyte apheresis once a week for 4 weeks, and stool DAF concentrations were determined weekly by immunoassay.
Results: After treatment, 11 (52%) of the 21 UC patients went into remission. Stool DAF concentrations decreased promptly and steadily in the responsive group. The difference reached statistical significance as soon as after the second apheresis session (P < 0.003), compared with values before the therapy and corresponding values in the non-responsive group (P = 0.024). The reduction in stool DAF concentrations after the second apheresis session was significantly greater in the responsive group (median 90%, range 22-90%) than in the non-responsive group (median -13%. range -307-94%) (P = 0.008). Hematological tests, that is, white blood cell (WBC) count and C-reactive protein, declined significantly during the apheresis therapy, but not in relation to therapeutic response.
Conclusion: Stool DAF concentration is a useful marker in the clinical response of UC patients to treatment with leukocyte apheresis. (C) 2005 Blackwell Publishing Asia Pty Ltd.

DOI： 10.1111/j.1400-1746.2004.03545.x

Complement regulatory proteins in normal human esophagus and esophageal squamous cell carcinoma Reviewed

K Shimo, M Mizuno, J Nasu, S Hiraoka, C Makidono, H Okazaki, K Yamamoto, H Okada, T Fujita, Y Shiratori

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 19 ( 6 ) 643 - 647 2004.6

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING ASIA

Background: Altered expression of three complement regulatory proteins, decay-accelerating factor (CD55), membrane cofactor protein (CD46) and homologous restriction factor 20 (CD59) has been identified in human gastrointestinal malignancies, but their expression in esophageal cancer has not been described. Therefore the purpose of the present paper was to study the distribution of these proteins in human normal and malignant esophageal mucosa.
Methods and results: In the normal esophageal mucosa, CD55 predominantly stained on the cell membrane of squamous epithelium in the superficial and prickle cell layers, whereas CD46 most intensely stained on the cell membrane in the basal and parabasal cell layers. In contrast to this reciprocal expression of CD55 and CD46, CD59 was broadly distributed on the cell membrane in all layers. In the esophageal squamous cell carcinoma, CD55 staining was intense in the stroma but was negligible in the cancer cells. In contrast, CD46 and CD59 stained almost uniformly on the tumor cell membrane. There was a significant difference in the intensity of the staining of CD55 and CD46 among cells in various layers of normal esophageal mucosa and esophageal carcinoma cells, but not in the staining of CD59. Similar expression patterns of the three complement regulatory proteins in carcinoma cells and in normal epithelium in the basal and parabasal cell layers were observed.
Conclusions: These observations on the expression of the three complement regulatory proteins would help understanding of the host immune responses involving the complement system against esophageal squamous cell carcinoma. (C) 2004 Blackwell Publishing Asia Pty Ltd.

DOI： 10.1111/j.1440-1746.2003.03328.x

Increased serum concentrations and surface expression on peripheral white blood cells of decay-accelerating factor (CD55) in patients with active ulcerative colitis Reviewed

C Makidono, M Mizuno, J Nasu, S Hiraoka, H Okada, K Yamamoto, T Fujita, Y Shiratori

JOURNAL OF LABORATORY AND CLINICAL MEDICINE 143 ( 3 ) 152 - 158 2004.3

Language：English Publishing type：Research paper (scientific journal) Publisher：MOSBY, INC

Inflammatory stimuli induce expression and release of decay-accelerating factor (DAF), a complement-regulatory protein present on peripheral-blood cells. Therefore, in ulcerative colitis (UC), an inflammatory colonic disease in which activated leukocytes are involved, DAF may be released from leukocytes into the circulation. In this study we compared serum DAF concentrations and surface DAF expression on peripheral-blood cells in patients with UC with disease activity. Peripheral-blood samples were obtained from 60 patients with UC (30 with active and 30 with inactive disease) and 19 healthy volunteers. Serum DAF concentrations were determined by means of immunoassay, and surface DAF expression on blood cells was examined with the use of flow cytometry. Serum DAF concentrations in patients with active disease (mean 48.6 ng/mL) were significantly higher than those in patients whose disease was in remission (33.3 ng/mL; P = .0003) and those in healthy controls (32.3 ng/mL; P = .0007). Surface DAF expression on neutrophils, CD14+ monocytes, and subsets of lymphocytes in patients with active UC was significantly increased compared with that in patients with UC in remission and in healthy controls. The increased serum DAF concentrations and surface DAF expression on leukocyte fractions in patients with active disease fell to significantly lower levels when the disease had gone into remission after medical therapy. Serum DAF concentrations are increased in UC patients in relation to disease activity. The likely source of increased DAF concentrations is peripheral-blood leukocytes that have been activated as part of the UC disease process.

DOI： 10.1016/j.lab.2003.11.004

Difference in Ulex europaeus agglutinin I-binding activity of decay-accelerating factor detected in the stools of patients with colorectal cancer and ulcerative colitis Reviewed

H Okazaki, M Mizuno, J Nasu, C Makidono, S Hiraoka, K Yamamoto, H Okada, T Fujita, T Tsuji, Y Shiratori

JOURNAL OF LABORATORY AND CLINICAL MEDICINE 143 ( 3 ) 169 - 174 2004.3

Language：English Publishing type：Research paper (scientific journal) Publisher：MOSBY, INC

Expression of decay-accelerating factor (DAF, CD55), a complement-regulatory glycoprotein, is enhanced in colorretal-cancer (CC) cells and colonic epithelium in ulcerative colitis UC, and stools from these patients contain increased amounts of DAF. Carbohydrate chains of glycoproteins are often altered during malignant transformation or inflammation. In this study, we investigated whether DAF molecules in patients with CC and those with UC differ with respect to oligosacchadde side chains. We analyzed DAF in stools and homogenates of colonic-tissue specimens obtained from patients with CC or UC using solid-phase enzyme-linked assay and Western blotting for reactivity with the lectins Ulex europaeus agglutinin l (UEA-l), wheat-germ agglutinin, peanut agglutinin, and concanavalin A. UEA-l bound to DAF in stools from patients with UC but not in that from the stools of CC patients, as demonstrated on the solid-phase enzyme-linked assay (P < .05, Mann-Whitney U test) and Western blotting. Binding of UEA-l was specifically inhibited by the addition of fucose. The difference in LEA-l reactivity with DAF was observed also in colonic-tissue homogenates from patients with UC and those with CC. DAF expressed in the mucosa and excreted into the stools of UC patients is different from that expressed in CC with regard to UEA-l reactivity. Future studies should be directed toward determining whether a qualitatively unique isoform of DAF is present, of which sugar chains are specific to CC in UC patients.

DOI： 10.1016/j.lab.2003.11.005

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