研究者詳細 - 高林　馨

論文 - 高林　馨

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Novel quantitative assessment indicators for efficiency and precision of endoscopic submucosal dissection in animal training models by analyzing an electrical surgical unit

Masunaga T., Kato M., Sasaki M., Iwata K., Miyazaki K., Kubosawa Y., Mizutani M., Takatori Y., Matsuura N., Nakayama A., Takabayashi K., Yahagi N.

Digestive Endoscopy （Digestive Endoscopy） 36 （ 1 ） 19 - 27 2024年01月

ISSN 09155635

Objectives: Although endoscopic submucosal dissection (ESD) training is important, quantitative assessments have not been established. This study aimed to explore a novel quantitative assessment system by analyzing an electrical surgical unit (ESU). Methods: This was an ex vivo study. Step one: to identify the novel efficiency indicators, 20 endoscopists performed one ESD each, and we analyzed correlations between their resection speed and electrical status. Step two: to identify the novel precision indicators, three experts and three novices performed one ESD each, and we compared the stability of the electrical status. Step three: three novices in step two performed 19 additional ESDs, and we analyzed the learning curve using novel indicators. Results: Step one: the percentage of total activation time (AT) of ESU in the procedure time (β coefficient, 0.80; P < 0.01) and AT required for submucosal dissection (β coefficient, −0.57; P < 0.01) were significantly correlated with the resection speed. Step two: coefficient of variation of the AT per one pulse (0.16 [range, 0.13–0.17] vs. 0.26 [range, 0.20–0.41], P = 0.049) and coefficient of variation of the peak electric power per pulse during mucosal incision (0.14 [range, 0.080–0.15] vs. 0.25 [range, 0.24–0.28], P = 0.049) were significantly lower in the experts than in the novices. Regarding the learning curve, the percentage of total AT of ESU in the procedure time and AT required for submucosal dissection had a trend of improvement. Conclusion: Novel indicators identified by analyzing ESU enable quantitative assessment for endoscopist's skill.

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Downregulation of chemokine receptor 9 facilitates CD4+CD8αα+ intraepithelial lymphocyte development

Ono K., Sujino T., Miyamoto K., Harada Y., Kojo S., Yoshimatsu Y., Tanemoto S., Koda Y., Zheng J., Sayama K., Koide T., Teratani T., Mikami Y., Takabayashi K., Nakamoto N., Hosoe N., London M., Ogata H., Mucida D., Taniuchi I., Kanai T.

Nature Communications （Nature Communications） 14 （ 1 ） 2023年12月

Intestinal intraepithelial lymphocytes (IELs) reside in the gut epithelial layer, where they help in maintaining intestinal homeostasis. Peripheral CD4+ T cells can develop into CD4+CD8αα+ IELs upon arrival at the gut epithelium via the lamina propria (LP). Although this specific differentiation of T cells is well established, the mechanisms preventing it from occurring in the LP remain unclear. Here, we show that chemokine receptor 9 (CCR9) expression is low in epithelial CD4+CD8αα+ IELs, but CCR9 deficiency results in CD4+CD8αα+ over-differentiation in both the epithelium and the LP. Single-cell RNA sequencing shows an enriched precursor cell cluster for CD4+CD8αα+ IELs in Ccr9 −/− mice. CD4+ T cells isolated from the epithelium of Ccr9 −/− mice also display increased expression of Cbfβ2, and the genomic occupancy modification of Cbfβ2 expression reveals its important function in CD4+CD8αα+ differentiation. These results implicate a link between CCR9 downregulation and Cbfb2 splicing upregulation to enhance CD4+CD8αα+ IEL differentiation.

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Effectiveness of endoscopic resection for colorectal neoplasms in ulcerative colitis: a multicenter registration study

Hirai M., Yanai S., Kunisaki R., Nishio M., Watanabe K., Sato T., Ishihara S., Anzai H., Hisabe T., Yasukawa S., Maeda Y., Takishima K., Ohno A., Shiga H., Uraoka T., Itoi Y., Ogata H., Takabayashi K., Yoshida N., Saito Y., Takamaru H., Kawasaki K., Esaki M., Tsuruoka N., Hisamatsu T., Matsumoto T.

Gastrointestinal Endoscopy （Gastrointestinal Endoscopy） 98 （ 5 ） 806 - 812 2023年11月

ISSN 00165107

Background and Aims: Patients with ulcerative colitis (UC) are at risk of developing colorectal cancer. The feasibility of endoscopic resection (ER) for UC-associated neoplasia has been suggested, but its efficacy and safety remain unclear. We aimed to assess the efficacy and safety of ER for colorectal neoplasms in patients with UC. Methods: This was a retrospective, multicenter cohort study of patients with UC who initially underwent ER or surgery for colorectal neoplasms between April 2015 and March 2021. Patients who had prior colorectal neoplastic lesions were excluded. Results: Among 213 men and 123 women analyzed, the mean age at UC onset was 41.6 years, and the mean age at neoplasia diagnosis was 56.1 years for 240 cases of total colitis, 59 cases of left-sided colitis, 31 cases of proctitis, and 6 cases of segmental colitis. EMR was performed for 142 lesions, and endoscopic submucosal dissection (ESD) was performed for 96 lesions. The perforation rate was 2.5% for all 238 lesions removed by ER and 6.3% for the 96 lesions removed by ESD. Among 146 ER lesions followed up with endoscopy, the local recurrence rate was 2.7%. The incidence of metachronous neoplasia after ER was 6.1%. All patients were followed a median of 34.7 months after initial treatment, and 5 died (all surgical cases). Overall survival was significantly higher in the ER group than in the surgery group (P =.0085). Conclusions: ER for colorectal neoplasms in UC may be acceptable in selected cases, although follow-up for metachronous lesions is necessary.

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Intensive endoscopic resection strategy for multiple duodenal polyposis associated with familial adenomatous polyposis

Iwata K., Kato M., Sasaki M., Miyazaki K., Kubosawa Y., Masunaga T., Mizutani M., Hayashi Y., Takatori Y., Matsuura N., Nakayama A., Takabayashi K., Kanai T., Yahagi N.

Journal of Gastroenterology and Hepatology (Australia) （Journal of Gastroenterology and Hepatology (Australia)） 38 （ 9 ） 1592 - 1597 2023年09月

ISSN 08159319

Background and Aim: Multiple duodenal polyposis associated with familial adenomatous polyposis (FAP) is a high risk of duodenal cancer development. We evaluated the feasibility of intensive endoscopic resection that is a comprehensive treatment strategy combining multiple kinds of endoscopic treatments. Methods: This is a retrospective observational study. From January 2012 to July 2022, a total of 28 consecutive patients in FAP who underwent endoscopic resection for multiple duodenal polyposis more than twice were included. Various endoscopic treatments, such as cold polypectomy (CP), endoscopic mucosal resection (EMR), underwater EMR (UEMR), endoscopic submucosal dissection (ESD), and endoscopic papillectomy (EP), were applied depending on lesions size and location. We evaluated individual information from patients' medical records, including patient characteristics, lesion characteristics, details of endoscopic treatment, pathologic findings, and Spigelman index (SI). We compared the differences in the number of treatments and observation periods with and without SI decrease. Results: A total of 1040 lesions were removed by 138 sessions of endoscopic resections. The median follow-up period was 3.2 years. At the beginning of the endoscopic intervention, median SI was 9 (6–11) and the proportion of Spigelman stage (SS) IV was 61%. Repeated endoscopic treatments finally reduced SI in 26 patients (93%), and the proportion of SS IV significantly decreased to 13% with every endoscopic treatment. The mean SI change was −4.2 points per year (95% confidence interval: −0.6 to −5.9). There were no patients required surgical duodenectomy during the follow-up period. Conclusion: Intensive resection has a potential of downstaging duodenal lesions associated with FAP.

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Modified double-layered suturing for a mucosal defect after colorectal endoscopic submucosal dissection (Origami method) (with video)

Masunaga T., Kato M., Sasaki M., Iwata K., Miyazaki K., Kubosawa Y., Mizutani M., Takatori Y., Matsuura N., Nakayama A., Takabayashi K., Yahagi N.

Gastrointestinal Endoscopy （Gastrointestinal Endoscopy） 97 （ 5 ） 962 - 969 2023年05月

ISSN 00165107

Background and Aims: Through-the-scope clips (TTSCs) are among the most common devices used to close colorectal post–endoscopic submucosal dissection (ESD) defects. Although TTSCs are easy to deliver, even to the proximal colon, simple clipping of large defects results in mucosa–mucosa closure, which could be unreliable. We developed a novel endoscopic closure technique using a modified double-layered suturing called the origami method (OGM). This method closes not only the mucosal layer but also the muscle layer with only TTSCs, which can obtain robust closure even for large defects. This study aimed to evaluate the feasibility of this new closure method for colorectal post-ESD defects. Methods: This retrospective observational study was conducted at a tertiary care hospital. We reviewed the cases of the OGM attempted after colorectal ESD at our institute between October 2021 and October 2022 and measured the clinical characteristics and outcomes of enrolled cases. Results: The OGM was attempted in 47 cases after colorectal ESD. Thirty-one cases (66%) were in the proximal colon, 5 (11%) in the distal colon, 6 (13%) in the upper rectum, and 5 (10%) in the lower rectum. The median defect size was 38 mm, with the largest being 85 mm. Complete closure was achieved in 44 cases (94%), including all lower rectum cases. No perforations were caused by clips during closure, and delayed perforation and bleeding were not observed. Conclusions: This new closure method is feasible and recommended. The OGM could achieve reliable closure of large defects in any location, including the proximal colon and thick-walled lower rectum, using only TTSCs.

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Usefulness of texture and color enhancement imaging in assessing mucosal healing in patients with ulcerative colitis

Hayashi Y., Takabayashi K., Kato M., Tojo A., Aoki Y., Hagihara Y., Yoshida K., Yoshimatsu Y., Kiyohara H., Sugimoto S., Nanki K., Mikami Y., Sujino T., Mutaguchi M., Kawaguchi T., Hosoe N., Yahagi N., Ogata H., Kanai T.

Gastrointestinal Endoscopy （Gastrointestinal Endoscopy） 97 （ 4 ） 759 - 766.e1 2023年04月

ISSN 00165107

Background and aims: Endoscopic remission is known to be defined as a Mayo endoscopic subscore (MES) of ≤1 in patients with ulcerative colitis (UC). However, some individuals experience relapse even after showing endoscopic remission under white-light imaging (WLI), and no tool exists that can detect these individuals. The aim of this study was to clarify the usefulness of texture and color enhancement imaging (TXI) in the assessment of inflammation in patients with UC. Methods: This was a prospective, single-arm, observational study conducted at a university hospital. From January 2021 to December 2021, 146 UC patients with endoscopic remission were enrolled. Images were evaluated by WLI, TXI, and pathologic evaluation, followed by prognostic studies. The primary endpoint of the study was the cumulative relapse of UC in each TXI score. The secondary endpoints were the association between TXI and pathologic scores, predictors of relapse, and interobserver agreement between the MES and TXI scores. Results: Patients with TXI score 2 had significantly lower UC relapse-free rates than did those with TXI scores 0-1 (log-rank test, P < .01). When pathologic remission was defined as Matts grade ≤2, the rate of pathologic remission decreased significantly with higher TXI scores (P = .01). In multivariate analysis, TXI score 2 was the only risk factor for UC relapse (P < .01; hazard ratio, 4.16; 95% confidence interval, 1.72-10.04). Interobserver agreement on the TXI score was good (κ = 0.597-0.823). Conclusion: TXI can be used to identify populations with poor prognosis in MES 1, for whom treatment intensification has been controversial.

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Closure of large mucosal defects for prevention of strictures after duodenal endoscopic submucosal dissection (with video)

Kubosawa Y., Kato M., Sasaki M., Iwata K., Miyazaki K., Masunaga T., Hayashi Y., Mizutani M., Kiguchi Y., Takatori Y., Matsuura N., Nakayama A., Takabayashi K., Kanai T., Yahagi N.

Gastrointestinal Endoscopy （Gastrointestinal Endoscopy） 97 （ 3 ） 484 - 492 2023年03月

ISSN 00165107

Background and Aims: Although lesions occupying a large circumference are associated with the risk of post–endoscopic submucosal dissection (ESD) strictures, the corresponding data for duodenal lesions are unknown. We aimed to analyze the incidence of post-ESD strictures after wide-field duodenal ESD. Methods: In this retrospective study of duodenal lesions treated with ESD between July 2010 and August 2021, we included lesions that resulted in mucosal defects occupying more than half of the circumference and excluded lesions located in bulbs and involving Vater's papilla. We analyzed the incidence rates of stricture and luminal narrowing, in addition to bleeding and perforation as the outcomes in this study. Stricture was defined as the inability of the endoscope to pass through the lumen. A single endoscopist reviewed all endoscopic images and judged the degree of luminal narrowing. Results: Eighty lesions were included, of which 2 involved mucosal defects occupying more than 90% of the circumference. The wound was closed, at least partially, in 90% in all lesions and in 86% of lesions with a mucosal defect occupying more than 75% of the circumference. None of the lesions caused delayed perforation and stricture, whereas 2 lesions caused delayed bleeding. Only 6 lesions caused luminal narrowing. When examined by the degree of closure, the rate of luminal narrowing increased with complete closure, incomplete closure, and nonclosure (4.9%, 9.1%, and 25.0%, respectively). Conclusions: Suturing may prevent post-ESD bleeding and perforation as well as stricture formation in cases of duodenal tumors, with mucosal defects occupying a large circumference.

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Novel closure method for a large mucosal defect after endoscopic resection: String clip suturing method with an anchor

Mizutani M., Kato M., Sasaki M., Iwata K., Miyazaki K., Masunaga T., Kubosawa Y., Hayashi Y., Takatori Y., Matsuura N., Nakayama A., Takabayashi K., Kanai T., Yahagi N.

Digestive Endoscopy （Digestive Endoscopy） 35 （ 3 ） 394 - 399 2023年03月

ISSN 09155635

Duodenal endoscopic submucosal dissection (ESD) is a high-risk technique; however, prophylactic closure of mucosal defects reduces the risk. Unfortunately, we have encountered cases where closure is difficult, especially in large lesions. Therefore, we developed a novel closure technique, a string clip suturing method with an anchor (SCSM-A). This study aimed to elucidate the feasibility of this method. Five patients underwent this method for the closure of mucosal defects after duodenal ESD. The initial string clip was deployed at the anal end of the mucosal defects and the second clip was deployed at the other end of the mucosal defect. A third clip was deployed on the muscular layer in the middle of the mucosal defect. The free end of the string was pulled, and additional clips were deployed around the first to the third clips for complete closure. Because of grasping the muscle layer, SCSM-A can be employed for secure closure without creating a pocket. We reviewed the background and clinical course of hospitalization of patients who underwent this method. The resected specimens ranged from 52 to 103 mm in diameter. Complete closure of the mucosal defects was possible in all the cases. There were no adverse events, and no cases required additional treatment. All the patients were discharged within 7 days. The new method achieved secure closure even for large mucosal defects after duodenal ESD. This is a technique that can be applied to other organs, e.g., the colon.

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D-amino Acids Ameliorate Experimental Colitis and Cholangitis by Inhibiting Growth of Proteobacteria: Potential Therapeutic Role in Inflammatory Bowel Disease

Umeda S., Sujino T., Miyamoto K., Yoshimatsu Y., Harada Y., Nishiyama K., Aoto Y., Adachi K., Hayashi N., Amafuji K., Moritoki N., Shibata S., Sasaki N., Mita M., Tanemoto S., Ono K., Mikami Y., Sasabe J., Takabayashi K., Hosoe N., Suzuki T., Sato T., Atarashi K., Teratani T., Ogata H., Nakamoto N., Shiomi D., Ashida H., Kanai T.

Cellular and Molecular Gastroenterology and Hepatology （Cellular and Molecular Gastroenterology and Hepatology） 16 （ 6 ） 1011 - 1031 2023年01月

Background & Aims: D-amino acids, the chiral counterparts of protein L-amino acids, were primarily produced and utilized by microbes, including those in the human gut. However, little was known about how orally administered or microbe-derived D-amino acids affected the gut microbial community or gut disease progression. Methods: The ratio of D- to L-amino acids was analyzed in feces and blood from patients with ulcerative colitis (UC) and healthy controls. Also, composition of microbe was analyzed from patients with UC. Mice were treated with D-amino acid in dextran sulfate sodium colitis model and liver cholangitis model. Results: The ratio of D- to L-amino acids was lower in the feces of patients with UC than that of healthy controls. Supplementation of D-amino acids ameliorated UC-related experimental colitis and liver cholangitis by inhibiting growth of Proteobacteria. Addition of D-alanine, a major building block for bacterial cell wall formation, to culture medium inhibited expression of the ftsZ gene required for cell fission in the Proteobacteria Escherichia coli and Klebsiella pneumoniae, thereby inhibiting growth. Overexpression of ftsZ restored growth of E. coli even when D-alanine was present. We found that D-alanine not only inhibited invasion of pathological K. pneumoniae into the host via pore formation in intestinal epithelial cells but also inhibited growth of E. coli and generation of antibiotic-resistant strains. Conclusions: D-amino acids might have potential for use in novel therapeutic approaches targeting Proteobacteria-associated dysbiosis and antibiotic-resistant bacterial diseases by means of their effects on the intestinal microbiota community.

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Feasibility and Safety of Endoscopic Ischemic Polypectomy and Clinical Outcomes in Patients with Peutz–Jeghers Syndrome (with Video)

Limpias Kamiya K.J.L., Hosoe N., Takabayashi K., Okuzawa A., Sakurai H., Hayashi Y., Miyanaga R., Sujino T., Ogata H., Kanai T.

Digestive Diseases and Sciences （Digestive Diseases and Sciences） 68 （ 1 ） 252 - 258 2023年01月

ISSN 01632116

Objectives: Peutz–Jeghers syndrome (PJS) is a rare autosomal dominant hereditary disease with a clinical features related to gastrointestinal (GI) hamartomatous polyposis, frequently observed in the small bowel. Balloon-assisted enteroscopy (BAE) has made non-surgical treatment of GI polyps possible. Endoscopic mucosal resection (EMR) has been performed but was associated with complications and difficulties. Recently, endoscopic ischemic polypectomy (EIP) has been developed and its usefulness reported. The study evaluated the feasibility and safety of EIP and the clinical outcomes of patients with PJS. Methods: We retrospectively collected data of consecutive patients with PJS between September 2009 and March 2021. Data regarding clinical characteristics, follow-up methods, endoscopic management, and complications were collected. EIP feasibility and safety were assessed. Results: Twenty-two patients were included. The observation period was 70 months (range, 5–153). Of the 124 therapeutic endoscopy procedures performed, 68 used BAE. Of the 607 polyps treated, 329 polyps were located in the small bowel. EIP was able to treat a greater number of polyps per patient than EMR (P < 0.003), without any complications, carcinoma, or intussusception in the small bowel (P < 0.001). During the follow-up period, 3 patients developed GI cancer. Conclusion: Long-term follow-up in patients with PJS showed that EIP was a feasible and safe technique.

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Artificial intelligence quantifying endoscopic severity of ulcerative colitis in gradation scale

Takabayashi K., Kobayashi T., Matsuoka K., Levesque B.G., Kawamura T., Tanaka K., Kadota T., Bise R., Uchida S., Kanai T., Ogata H.

Digestive Endoscopy （Digestive Endoscopy） 2023年

ISSN 09155635

Objectives: Existing endoscopic scores for ulcerative colitis (UC) objectively categorize disease severity based on the presence or absence of endoscopic findings; therefore, it may not reflect the range of clinical severity within each category. However, inflammatory bowel disease (IBD) expert endoscopists categorize the severity and diagnose the overall impression of the degree of inflammation. This study aimed to develop an artificial intelligence (AI) system that can accurately represent the assessment of the endoscopic severity of UC by IBD expert endoscopists. Methods: A ranking-convolutional neural network (ranking-CNN) was trained using comparative information on the UC severity of 13,826 pairs of endoscopic images created by IBD expert endoscopists. Using the trained ranking-CNN, the UC Endoscopic Gradation Scale (UCEGS) was used to express severity. Correlation coefficients were calculated to ensure that there were no inconsistencies in assessments of severity made using UCEGS diagnosed by the AI and the Mayo Endoscopic Subscore, and the correlation coefficients of the mean for test images assessed using UCEGS by four IBD expert endoscopists and the AI. Results: Spearman's correlation coefficient between the UCEGS diagnosed by AI and Mayo Endoscopic Subscore was approximately 0.89. The correlation coefficients between IBD expert endoscopists and the AI of the evaluation results were all higher than 0.95 (P < 0.01). Conclusions: The AI developed here can diagnose UC severity endoscopically similar to IBD expert endoscopists.

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Risk of venous thromboembolism with a central venous catheter in hospitalized Japanese patients with inflammatory bowel disease: a propensity score-matched cohort study

Aoki Y., Kiyohara H., Mikami Y., Nanki K., Kawaguchi T., Yoshimatsu Y., Sugimoto S., Sujino T., Takabayashi K., Hosoe N., Ogata H., Iwao Y., Kanai T.

Intestinal Research （Intestinal Research） 21 （ 3 ） 318 - 327 2023年

ISSN 15989100

Background/Aims: Thromboprophylaxis is recommended for hospitalized patients with inflammatory bowel disease (IBD) in Western countries, although it is selectively administered to high-risk patients in East Asia. A central venous catheter (CVC) is commonly placed in patients with IBD. Although CVC placement is considered a risk factor for venous thromboembolism (VTE), the degree of increased risk in patients with IBD is uncertain. This study aimed to identify the risk of VTE with CVC placement in hospitalized Japanese patients with IBD without thromboprophylaxis. Methods: This retrospective cohort study included patients with ulcerative colitis or Crohn’s disease who were admitted for disease flares at Keio University Hospital between January 2016 and December 2020. Patients who already had thrombosis or were administered any antithrombotic treatment on admission were excluded. VTE development during the hospitalization was surveyed, and VTE risk associated with CVC indwelling was estimated using propensity score matching and inverse probability of treatment weighting analyses. Results: Altogether, 497 hospitalized patients with IBD (ulcerative colitis, 327; Crohn’s disease, 170) were enrolled. VTE developed in 9.30% (12/129) of catheterized patients and in 0.82% (3/368) of non-catheterized patients. The propensity score matching yielded 127 matched pairs of patients. The catheterized group demonstrated higher odds for VTE than the non-catheterized group (odds ratio, 13.15; 95% confidence interval, 1.68–102.70). A similar result was obtained in the inverse probability of treatment weighting analysis (odds ratio, 11.02; 95% confidence interval, 2.64–46.10). Conclusions: CVC placement is a major risk factor for VTE among hospitalized Japanese patients with IBD without thromboprophylaxis.

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Characteristics of flat-type ulcerative colitis-associated neoplasia on chromoendoscopic imaging with indigo carmine dye spraying

Takabayashi K., Sugimoto S., Nanki K., Yoshimatsu Y., Kiyohara H., Mikami Y., Sujino T., Kato M., Hosoe N., Shimoda M., Yahagi N., Ogata H., Iwao Y., Kanai T.

Digestive Endoscopy （Digestive Endoscopy） 2023年

ISSN 09155635

Objectives: Despite recent advances in endoscopic equipment and diagnostic techniques, early detection of ulcerative colitis-associated neoplasia (UCAN) remains difficult because of the complex background of the inflamed mucosa of ulcerative colitis and the morphologic diversity of the lesions. We aimed to describe the main diagnostic patterns for UCAN in our cohort, including lateral extension surrounding flat lesions. Methods: Sixty-three lesions in 61 patients with flat-type dysplasia that were imaged with dye chromoendoscopy (DCE) were included in this analysis. These DCE images were analyzed to clarify the dye-chromoendoscopic imaging characteristics of flat dysplasia, and the lesions were broadly classified into dysplastic and nondysplastic mucosal patterns. Results: Dysplastic mucosal patterns were classified into two types: small round patterns with round to roundish structures, and mesh patterns with intricate mesh-like structures. Lesions with a nondysplastic mucosal pattern were divided into two major types: a ripple-like type and a gyrus-like type. Of note, 35 lesions (55.6%) had a small round pattern, and 51 lesions (80.9%) had some type of mesh pattern. About 70% of lesions with small round patterns and 49% of lesions with mesh patterns were diagnosed as high-grade dysplasia or carcinoma, while about 30% of lesions with small round patterns and 51% of lesions with mesh patterns were diagnosed as low-grade dysplasia. Conclusion: When a characteristic mucosal pattern, such as a small round or mesh pattern, is found by DCE, the possibility of UCAN should be considered.

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Red dichromatic imaging reduces bleeding and hematoma during submucosal injection in esophageal endoscopic submucosal dissection

Miyazaki K., Kato M., Sasaki M., Iwata K., Masunaga T., Kubosawa Y., Hayashi Y., Mizutani M., Kiguchi Y., Takatori Y., Mutaguchi M., Matsuura N., Nakayama A., Takabayashi K., Kanai T., Yahagi N.

Surgical Endoscopy （Surgical Endoscopy） 36 （ 11 ） 8076 - 8085 2022年11月

ISSN 09302794

Background: Bleeding and hematoma formation during submucosal injection in esophageal endoscopic submucosal dissection (ESD) reduce the visibility of the submucosa. Red dichromatic imaging (RDI) is an endoscopic technique that provides better visualization of the deep submucosal blood vessels. We speculated that blood vessel injury could be avoided with RDI. This pilot study evaluated the role of RDI in preventing bleeding and hematoma formation during esophageal ESD. Methods: This was a single-center retrospective observational study. We examined 60 patients who underwent ESD with white light imaging (WLI) and RDI. A single endoscopist reviewed all of the surgical videos to document the incidence and severity of bleeding episodes. Eighteen videos provided adequate quality and detail, and the number of blood vessels traversing the mucosal incision lines of the lesions in these videos was evaluated under WLI and RDI. Results: The WLI group had a significantly higher incidence of hematomas per unit area compared to the RDI group (0.18/cm2 [range 0–0.38] vs. 0 [0–0.18]/cm2, p = 0.024). The WLI group also had a significantly higher incidence of total bleeding episodes compared to the RDI group (42.9% [range 21.7–60.4] vs 16.7% [range 13.8–22.9], p < 0.001). Significantly more blood vessels were visible under RDI compared to WLI (5 [range 4–8] vs. 2 [range 1–5], p = 0.0020). Conclusion: RDI reduced the incidence of bleeding and hematoma formation during submucosal injection in esophageal ESD. It was assumed that the improvement of blood vessel visibility by RDI might have contributed to the result.

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Single-cell transcriptomics of human gut T cells identifies cytotoxic CD4+CD8A+ T cells related to mouse CD4 cytotoxic T cells

Tanemoto S., Sujino T., Miyamoto K., Moody J., Yoshimatsu Y., Ando Y., Koya I., Harada Y., Tojo A.O., Ono K., Hayashi Y., Takabayashi K., Okabayashi K., Teratani T., Mikami Y., Nakamoto N., Hosoe N., Ogata H., Hon C.C., Shin J.W., Kanai T.

Frontiers in Immunology （Frontiers in Immunology） 13 2022年10月

Cytotoxic CD4+ T cells (CD4-CTLs) show the presence of cytolytic granules, which include the enzymes granzyme and perforin. The cells have a pathogenic and protective role in various diseases, including cancer, viral infection, and autoimmune disease. In mice, cytotoxic CD4+ T cells express CD8αα+ and reside in the intestine (mouse CD4+CTLs; mCD4-CTLs). The population of cytotoxic CD4+ T cells in the human intestine is currently unknown. Moreover, it is unclear how cytotoxic CD4 T cells change in patients with inflammatory bowel disease (IBD). Here, we aimed to identify cytotoxic CD4+ T cells in the human intestine and analyze the characteristics of the population in patients with IBD using single-cell RNA-seq (scRNA-seq). In CD4+ T cells, granzyme and perforin expression was high in humanMAIT (hMAIT) cells and hCD4+CD8A+ T cell cluster. Both CD4 and CD8A were expressed in hTreg, hMAIT, and hCD4+CD8A+ T cell clusters. Next we performed fast gene set enrichment analysis to identify cell populations that showed homology to mCD4CTLs. The analysis identified the hCD4+CD8A+ T cell cluster (hCTL-like population; hCD4-CTL) similar to mouse CTLs. The percentage of CD4+CD8A+ T cells among the total CD4+ T cells in the inflamed intestine of the patients with Crohn’s disease was significantly reduced compared with that in the noninflamed intestine of the patients. In summary, we identified cytotoxic CD4+CD8+ T cells in the small intestine of humans. The integration of the mouse and human sc-RNA-seq data analysis highlight an approach to identify human cell populations related to mouse cell populations, which may help determine the functional properties of several human cell populations in mice.

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Enrichment of type I interferon signaling in colonic group 2 innate lymphoid cells in experimental colitis

Irie E., Ishihara R., Mizushima I., Hatai S., Hagihara Y., Takada Y., Tsunoda J., Iwata K., Matsubara Y., Yoshimatsu Y., Kiyohara H., Taniki N., Sujino T., Takabayashi K., Hosoe N., Ogata H., Teratani T., Nakamoto N., Mikami Y., Kanai T.

Frontiers in Immunology （Frontiers in Immunology） 13 2022年10月

Group 2 innate lymphoid cells (ILC2s) serve as frontline defenses against parasites. However, excluding helminth infections, it is poorly understood how ILC2s function in intestinal inflammation, including inflammatory bowel disease. Here, we analyzed the global gene expression of ILC2s in healthy and colitic conditions and revealed that type I interferon (T1IFN)-stimulated genes were up-regulated in ILC2s in dextran sodium sulfate (DSS)-induced colitis. The enhancement of T1IFN signaling in ILC2s in DSS-induced colitis was correlated with the downregulation of cytokine production by ILC2s, such as interleukin-5. Blocking T1IFN signaling during colitis resulted in exaggeration of colitis in both wild-type and Rag2-deficient mice. The exacerbation of colitis induced by neutralization of T1IFN signaling was accompanied by reduction of amphiregulin (AREG) in ILC2s and was partially rescued by exogenous AREG treatment. Collectively, these findings show the potential roles of T1IFN in ILC2s that contribute to colitis manifestation.

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Efficacy of capnographic and bispectral index monitoring on trans-oral therapeutic endoscopy: A prospective observational study

Hayashi Y., Hosoe N., Takabayashi K., Limpias Kamiya K.J.L., Tojo A., Sakurai H., Kinoshita S., Sujino T., Nakayama A., Kato M., Yahagi N., Ogata H., Kanai T.

Journal of Gastroenterology and Hepatology (Australia) （Journal of Gastroenterology and Hepatology (Australia)） 37 （ 10 ） 2004 - 2010 2022年10月

ISSN 08159319

Background and Aim: Oral therapeutic and invasive endoscopy requires deep sedation to reduce patient distress due to prolonged examination and procedures. The usefulness of capnography and bispectral index (BIS) monitoring in the early hypoxia detection in oral therapeutic and invasive endoscopy has yet to be evaluated. This study aimed to investigate the clinical impact of capnography and BIS monitoring on hypoxic events during oral therapeutic and invasive endoscopic procedures. Methods: This is a prospective observational study. Trans-oral non-intubated therapeutic and/or invasive endoscopic procedures were performed with conventional monitoring (pulse oximetry, pulse, and blood pressure) as well as additional monitoring (BIS and end-tidal CO2 concentration). Hypoxia is defined as oxygen saturation of <90% that lasts >15 s. The clinical impact of capnography and BIS monitoring on hypoxic events during oral therapeutic and invasive endoscopic procedures were investigated with the risk factors for hypoxia in each patient. Results: Patients with hypoxia had significantly more apneas detected using capnography than other patients. The multivariate analysis revealed the detected apnea by capnography as an independent risk factor for hypoxia (odds ratio: 3.48[95% confidence interval: 1.24–9.78], P = 0.02). The BIS was not significantly different as a risk factor for hypoxia; however, per-event analysis revealed significantly decreased BIS values over time in 3 min before hypoxic events. Conclusions: Apnea detected by capnography was an independent predictor of hypoxia. The BIS value was not associated with hypoxia events; however, it showed a significant downward trend before hypoxia events.

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Development of a Deep-Learning Algorithm for Small Bowel-Lesion Detection and a Study of the Improvement in the False-Positive Rate

Hosoe N., Horie T., Tojo A., Sakurai H., Hayashi Y., Kamiya K.J.L.L., Sujino T., Takabayashi K., Ogata H., Kanai T.

Journal of Clinical Medicine （Journal of Clinical Medicine） 11 （ 13 ） 2022年07月

Deep learning has recently been gaining attention as a promising technology to improve the identification of lesions, and deep-learning algorithms for lesion detection have been actively developed in small-bowel capsule endoscopy (SBCE). We developed a detection algorithm for abnormal findings by deep learning (convolutional neural network) the SBCE imaging data of 30 cases with abnormal findings. To enable the detection of a wide variety of abnormal findings, the training data were balanced to include all major findings identified in SBCE (bleeding, angiodysplasia, ulceration, and neoplastic lesions). To reduce the false-positive rate, “findings that may be responsible for hemorrhage” and “findings that may require therapeutic intervention” were extracted from the images of abnormal findings and added to the training dataset. For the performance evaluation, the sensitivity and the specificity were calculated using 271 detectable findings in 35 cases. The sensitivity was calculated using 68,494 images of non-abnormal findings. The sensitivity and specificity were 93.4% and 97.8%, respectively. The average number of images detected by the algorithm as having abnormal findings was 7514. We developed an image-reading support system using deep learning for SBCE and obtained a good detection performance.

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Texture and color enhancement imaging in combination with indigo carmine dye spraying to highlight the border of flat ulcerative colitis–associated neoplasia

Takabayashi K., Kato M., Sugimoto S., Yahagi N., Kanai T.

Gastrointestinal Endoscopy （Gastrointestinal Endoscopy） 95 （ 6 ） 1273 - 1275 2022年06月

ISSN 00165107

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Aryl hydrocarbon receptor signals in epithelial cells govern the recruitment and location of Helios+ Tregs in the gut

Yoshimatsu Y., Sujino T., Miyamoto K., Harada Y., Tanemoto S., Ono K., Umeda S., Yoshida K., Teratani T., Suzuki T., Mikami Y., Nakamoto N., Sasaki N., Takabayashi K., Hosoe N., Ogata H., Sawada K., Imamura T., Yoshimura A., Kanai T.

Cell Reports （Cell Reports） 39 （ 6 ） 2022年05月

CD4+Foxp3+ regulatory T cells (Tregs) are essential for homeostasis in the colon, but the mechanism by which local environmental cues determine the localization of colonic Tregs is unclear. Here, we administer indigo naturalis (IN), a nontoxic phytochemical aryl hydrocarbon receptor (AhR) agonist used for treating patients with ulcerative colitis (UC) in Asia, and we show that IN increases Helios+ Tregs and MHC class II+ epithelial cells (ECs) in the colon. Interactions between Tregs and MHC class II+ ECs occur mainly near the crypt bottom in the steady state, whereas Tregs dramatically increase and shift toward the crypt top following IN treatment. Moreover, the number of CD25+ T cells is increased near the surface of ECs in IN-treated UC patients compared with that in patients treated with other therapies. We also highlight additional AhR-signaling mechanisms in intestinal ECs that determine the accumulation and localization of Helios+ Tregs in the colon.

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