Published papers

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.

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.

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.

Background and Aim: In patients with Crohn’s disease (CD) and small bowel stenosis, endoscopic balloon dilation (EBD) is considered to be useful in improving stenotic symptoms and avoiding surgery. However, it carries risks such as bleeding and perforation. The aim of this study was to identify the indications for endoscopic intervention in patients with CD and small bowel stenosis. Methods: From November 2007 to March 2020, 143 CD patients with small bowel stenosis were enrolled in this study. We identified the factors associated with not requiring endoscopic intervention during long-term follow-up of these patients. Results: Forty of the 143 patients had abdominal symptoms of stenosis and had undergone EBD, whereas the remaining 103 were asymptomatic and had not undergone endoscopic intervention. During long-term follow-up, 95 of those 103 patients never required endoscopic or surgical intervention. Multivariate logistic regression analysis revealed that not consuming an elemental diet (OR 3.18, 95% CI 1.48–6.82; p <.01) and ileocecal valve (ICV) stenosis (OR 0.30, 95% CI 0.11–0.83; p =.02) were independently associated with not requiring EBD. The cumulative emergency hospitalisation-free rate also tended to be higher in patients not consuming an elemental diet or with ICV stenosis. Conclusions: Two factors, namely not consuming an elemental diet and ICV stenosis, predict a long-term intervention-free prognosis in CD patients with small bowel stenosis.Key messages When an endoscopically impassable small bowel stenosis is found in a CD patient, long-term follow-up without endoscopic intervention may be possible if the patient is asymptomatic, is not using an elemental diet, and the stenosis is ICV.

Background and Aims: It has been reported that the prophylactic closure of mucosal defects after duodenal endoscopic resection (ER) can reduce delayed adverse events; however, under certain circumstances, this can be technically challenging. Therefore, the aim of this study was to determine the predictors of difficulty during the complete closure of mucosal defects after duodenal ER. Methods: This was a retrospective study of duodenal lesions that underwent ER between July 2010 and May 2020. We reviewed the endoscopic images and analyzed the relationships between the degree of closure or closure time and clinical features of the lesions using univariate and multivariate analyses. Results: We analyzed 698 lesions. The multivariate analysis revealed that lesion location in the medial or anterior wall (odds ratio, 2.8; 95% confidence interval, 1.36-5.85; P < .01) and a large lesion size (odds ratio, 1.4; 95% confidence interval, 1.07-1.89; P = .03) were independent predictors of an increased risk of incomplete closure. Moreover, a large lesion size (β coefficient, .304; P < .01), an occupied circumference over 50% (β coefficient, .178; P < .01), intraoperative perforation (β coefficient, .175; P < .01), treatment period (β coefficient, .143; P < .01), and treatment with endoscopic submucosal dissection (β coefficient, .125; P < .01) were independently and positively correlated with a prolonged closure time in the multiple regression analysis. Conclusions: This study revealed that lesion location in the medial or anterior wall and lesion size affected the incomplete closure of mucosal defects after duodenal ER, and lesion size, occupied circumference, intraoperative perforation, treatment period, and treatment method affected closure time.

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.

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.

Background: Small bowel lesions of Crohn’s disease (CD) are known to be associated with a poor prognosis; however, endoscopic healing leads to favorable patients’ outcome. The aim of this study was to clarify the clinical impact of assessing deep small bowel lesions (DSB) using balloon-assisted enteroscopy (BAE) on CD patients in clinical remission. Methods: From January 2012 to July 2018, a total of 100 CD patients in clinical remission were enrolled to undergo trans-anal enteroscopy using single-balloon enteroscope. Endoscopic evaluations at the terminal ileum (TI) were performed using a partial Simple Endoscopic Score for CD (pSES-CD). Endoscopic evaluations at the DSB used a modified partial SES-CD (mpSES-CD). We evaluated the factors associated with relapse, and the correlation of endoscopic score between the TI and DSB. For this study, relapse was defined as hospitalization within a year from enteroscopy. Results: 30 patients (30.0%) relapsed within a year from enteroscopy. Multivariate logistic regression analysis revealed that the Harvey–Bradshaw Index (OR 1.77, 95% CI 1.18–2.65; p = 0.003) and an mpSES-CD at DSB (OR 3.10, 95% CI 1.86–5.15; p = 0.001) were independent predictors for relapse, whereas a SES-CD at the TI did not exhibit independence. There was a significant correlation trend between the relapse rate and greater than 5 points of an mpSES-CD at DSB; however, there was no correlation between the relapse rate and pSES-CD at the TI. Conclusion: Even when Crohn's disease is in remission, it is important to evaluate DSB using BAE to assess endoscopic mucosal healing.

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.

Immune checkpoint inhibitors (ICPI) have been reported to be effective in various carcinomas. They excessively activate the immune system, resulting in frequent immune-related adverse events (irAEs). Colitis induced by ICPI is one of the most common and is known as immune-mediated colitis (IMC). Although IMC and inflammatory bowel disease (IBD) are similar in many respects, there are very few reports of IMC in patients with preexisting IBD such as ulcerative colitis (UC) and Crohn's disease (CD). Whether preexisting IBD is concerned with the development of the colitis is not well known. Here, we reported the case who developed severe ulcerative colitis which started from IMC. It is an important case to follow the time course of the colitis developed. Our conclusion indicated that frequent colonoscopy was important for the management of IMC in a patient who has suffered chronic inflammatory disease, such as UC.

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.

A 77-year-old female who had an acute severe abdominal pain was taken to the emergency room in the previous hospital. CT scans showed jejunum and ileum wall thickening and fatty deposits around the small intestinal tract, and gastrointestinal perforation could not be ruled out. By using single anal and oral balloon endoscopy, we observed mild edema with petechial erythema, shallow erosions with edematous mucosa and ulcers with surrounded disrupted villous structures at the jejunum and ileum. Histological analysis revealed atypical lymphocytes infiltrating the small intestinal mucosa demonstrating intraepithelial lymphocytosis. Immunohistochemical staining revealed that CD3, CD7, and CD56 staining was positive, and CD4, CD5, and CD8 staining was negative in infiltrated lymphocytes. We made the diagnosis of monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) with the combination of HE staining and IHC. PET-CT showed abnormal uptake in irregular wall thickening of the small intestine, lymph nodes, ribs, spine and pelvic bone. She was treated with chemotherapy (etoposide, prednisolone, oncovin, cyclophosphamide, hydroxydaunorubicin) and is still alive 1 year after the diagnosis. We reported the various endoscopic findings in the same MEITL patient by using single balloon endoscopy. We also summarized endoscopic characteristics of MEITL patients.

Background and Aims: Duodenal endoscopic submucosal dissection (ESD) is considered technically challenging and has a high risk of adverse events. However, we recently made some progress with the ESD technique and device by introducing 2 features: a water pressure (WP) method and a second-generation ESD knife (DualKnife) with a water jet function (DualKnife J). The present study aimed to assess whether these changes improved the clinical outcomes of duodenal ESD. Methods: This was a retrospective observational study. Among all patients who underwent ESD for superficial duodenal epithelial tumors from June 2010 to December 2018, patients in whom a single expert performed the procedure were included in this study. Various factors, including the use of the WP method and ESD devices (DualKnife or DualKnife J) and the treatment phase (early, mid, and late), were analyzed to determine whether they were associated with intraprocedural perforation and procedure time. Treatment phase was assigned by dividing the study population equally into 3 subgroups according to the treatment phase. Results: The procedure time was significantly shorter, and the proportion of patients with intraprocedural perforations was the lowest in the late phase. Multivariate analysis of the use of the WP method revealed that it significantly decreased the intraprocedural perforation rate (odds ratio, 0.39; 95% confidence interval, 0.16-0.96), and analysis of the use of both the WP method (β coefficient, −0.40; P <.01) and the DualKnife J (β coefficient, −0.10; P =.032) revealed they were independently and negatively correlated with procedure time. Conclusion: The present study reveals that the WP method significantly reduced the intraprocedural perforation rate and that both the WP method and the DualKnife J significantly shortened procedure times for duodenal ESD.

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.

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.

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.

Background: Ulcerative colitis (UC) is characterized by chronic intestinal epithelial damage, and previous studies have evaluated the epithelial structure of patients with active UC using electron microscopy. Aims: This study aimed to assess the intestinal epithelial structure using scanning electron microscopy (SEM) and the features of patients with UC who are in remission. Methods: In total, eight healthy controls and 20 patients with UC were enrolled, and colonic tissue samples from the cecum and rectum were collected. Then, we compared the epithelial surface structure on SEM between patients with UC who are in clinical remission and healthy controls. Results: In healthy controls, the colonic surface comprises small lobes (termed units), with one crypt located in the middle of each unit. In patients with UC, we found irregular unit and crypt mouth size, double crypt sign (> 1 crypt per unit), and lower number of small vesicles in the intestinal epithelial cells. Compared with healthy controls, patients with UC often presented with irregular unit size, double crypt sign, and irregular crypt mouth size in the rectum. The small vesicles were observed less frequently in patients with UC than in healthy controls. Conclusions: SEM revealed a unique epithelial structure in patients with UC who are in remission.

Chronic enteropathy associated with solute carrier organic anion transporter family, member 2A1 (SLCO2 A1) (CEAS) is a rare autosomal recessive hereditary disease characterized by chronic persistent anemia and hypoproteinemia. Its diagnosis typically requires a genetic analysis. The efficacy of immunohistochemical staining with SLCO2A1 polyclonal antibody as a pre-diagnostic tool for CEAS has been previously reported. We herein report a patient with CEAS in whom immunohistochemical staining confirmed SLCO2A1 protein expression. The immunopositive results may have been due to nonsense-mediated RNA decay. As immunohistochemical staining of SLCO2A1 protein may show immunopositive results, a genetic analysis should also be performed when CEAS is strongly clinically suspected.