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

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