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Background: The cancer risk for each length of Barrett's esophagus (BE) in Japanese is unknown. This nationwide, multi-institutional study aims to clarify the cancer risk by length of BE in the general Japanese population., Methods: Consecutive subjects who underwent upper endoscopic screening at 17 centers between 2013 and 2017 and had at least one follow-up endoscopy by December 2022 were included. The presence/absence of BE and, if present, its length were retrospectively assessed using the retrieved endoscopic images recorded at baseline. Information on the subsequent occurrence of esophageal adenocarcinoma and other upper gastrointestinal cancers was also collected. Cancer incidence was calculated and expressed as %/year., Results: A total of 33,478 subjects were enrolled, and 17,884 (53.4%), 10,641 (31.8%), 4889 (14.6%), and 64 (0.2%) were diagnosed as absent BE, BE < 1 cm, 1-3 cm, and ≥ 3 cm, respectively. During a median follow-up of 80 months, 11 cases of esophageal adenocarcinoma developed. The annual incidence of esophageal adenocarcinoma is 0%/year for absent BE, 0.0032 (0.00066-0.013)%/year for BE < 1 cm, 0.026 (0.011-0.054)%/year for 1-3 cm, and 0.58 (0.042-2.11)%/year for ≥ 3 cm, respectively. Meanwhile, the incidence of esophageal squamous cell carcinoma and gastric cancer were 0.039 (0.031-0.049)%/year and 0.16 (0.14-0.18)%/year, respectively., Conclusions: By enrolling a large number of subjects with long-term follow-up, this study demonstrated that the risk of cancer increased steadily with increasing length of BE in the Japanese population. Therefore, it is important to consider the length of BE when determining the management strategy for BE., (© 2024. Japanese Society of Gastroenterology.)

EP 4 prostanoid receptor (EP 4 R) contributes to the intestinal epithelial Cl - secretion, and inhibition of prostaglandin E (PGE) production by non-steroidal anti-inflammatory drugs (NSAIDs) plays a central role in NSAID-induced enteropathy. Although M 3 muscarinic acetylcholine receptor (M 3 R) also contributes to the intestinal epithelial Cl - secretion, it remains unclear whether M 3 R is involved in NSAID-induced enteropathy due to a lack of selective agents. The present study explored how M 3 R is involved in the regulation of the intestinal epithelial Cl - secretion and its pathophysiological role in NSAID-induced enteropathy. Using the novel highly-selective M 3 positive allosteric modulator PAM-369 that we recently developed, we evaluated the role of M 3 R in the intestinal epithelial secretion ex vivo by measuring the short circuit current (Isc) of intestinal epithelium with a Ussing chamber system and examined whether or not M 3 R protects against small intestinal injury in indomethacin-treated mice. Both the PGE 1 derivative misoprostol and carbachol similarly increased the Isc in a concentration-dependent manner. The Isc increases were abolished either by receptor antagonists (an EP 4 R antagonist and a M 3 R antagonist, respectively) or by removal of extracellular Cl - . PAM-369 enhanced the carbachol-induced Isc by potentiating M 3 R, which could contribute to enhanced intestinal epithelial secretion. Treatment with PAM-369 ameliorated small intestinal injury in indomethacin-treated mice. Importantly, the M 3 R expression was significantly up-regulated, and PAM-369 potentiation of M 3 R was augmented in indomethacin-treated mice compared to untreated mice. These findings show that M 3 R plays a role in maintaining the intestinal epithelial secretion, which could contribute to protection against indomethacin-induced small intestinal injury. M 3 R is a promising target for treating or preventing NSAID-induced enteropathy. KEY MESSAGES: PAM-369, the M 3 positive allosteric modulator, was used to potentiate M 3 R. PAM-369 enhanced carbachol-induced Isc in mouse ileum. PAM-369 ameliorated small intestinal injury in indomethacin-treated mice. M 3 R is a promising target for treating or preventing NSAID-induced enteropathy., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: Mitsuru Esaki is a consultant for AI Medical Service Inc. Haruei Ogino is part of an endowed course supported by Miyarisan Pharmaceutical Co., Ltd.; Fujifilm Medical Co., Ltd.; Terumo Corporation; and Fancl Corporation. Eikichi Ihara received lecture fees from Takeda Pharmaceutical Co., Ltd. and EA Pharma Co., Ltd. The other authors declare no conflicts of interest.

Competing Interests: Mitsuru Esaki is a consultant for AI Medical Service Inc. Ogino Haruei is part of an endowed course supported by Miyarisan Pharmaceutical Co., Ltd.; Fujifilm Medical Co., Ltd.; Terumo Corporation; and Fancl Corporation. Ihara Eikichi received lecture fees from Takeda Pharmaceutical Co., Ltd. and EA Pharma Co., Ltd. The other authors declare no conflicts of interest.

Competing Interests: O. Haruei is part of an endowed course supported by Miyarisan Pharmaceutical Co., Ltd.; Fujifilm Medical Co., Ltd.; Terumo Corporation; and Fancl Corporation. I. Eikichi received lecture fees from Takeda Pharmaceutical Co., Ltd. and EA Pharma Co., Ltd. R. Maruoka, M. Esaki, Y. Minoda, Y. Otsuka, and K. Haraguchi declare that they have no conflicts of interest.

The Japan Gastroenterological Association (JGA) published the first version of clinical guidelines for chronic diarrhea 2023. These guidelines describe the definition, classification, diagnostic criteria, diagnostic testing methods, epidemiology, pathophysiology, and treatment of chronic diarrhea, and provide flowcharts for the diagnosis and treatment of chronic diarrhea based on the latest evidence. Treatment for chronic diarrhea begins by distinguishing secondary chronic constipation with a clear etiology, such as drug-induced diarrhea, food-induced diarrhea, systemic disease-associated diarrhea, infection-associated diarrhea, organic disease-associated diarrhea, and bile acid diarrhea. The first line of treatment for chronic diarrhea in the narrow sense, defined in these guidelines as functional diarrhea in routine medical care, is lifestyle modification and dietary therapy. The first medicines to be considered for oral treatment are probiotics for regulating the gut microbiome and anti-diarrheals. Other medications, such as 5HT3 receptor antagonists, anticholinergics, Kampo medicine, psychotherapy, antibiotics, bulking agents, adrenergic agonists, and somatostatin analogs, lack sufficient evidence for their use, highlighting a challenge for future research. This Clinical Guidelines for Chronic Diarrhea 2023, which provides the best clinical strategies for treating chronic diarrhea in Japan, will also be useful for medical treatment worldwide., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

The Japan Gastroenterological Association published the first version of its clinical guidelines for chronic constipation 2023. Based on the latest evidence, these guidelines describe the definition, classification, diagnostic criteria, diagnostic testing methods, epidemiology, pathophysiology, and treatment of chronic constipation. They include flowcharts for both diagnosis and treatment of chronic constipation. In the treatment of chronic constipation, the first step involves differentiating between secondary forms, such as organic disease-associated constipation, systemic disease-associated constipation, and drug-induced constipation. The next step is to determine whether the chronic constipation stems from a motility disorder, a form of primary chronic constipation. For functional constipation and constipation-predominant irritable bowel syndrome, treatment should be initiated after evaluating symptoms like reduced bowel movement frequency type or defecation difficulty type. The first line of treatment includes the improvement of lifestyle habits and diet therapy. The first drugs to consider for oral treatment are osmotic laxatives. If these are ineffective, secretagogues and ileal bile acid transporter inhibitors are candidates. However, stimulant laxatives are exclusively designated for as-needed use. Probiotics, bulk-forming laxatives, prokinetics, and Kampo medicines, for which there is insufficient evidence, are considered alternative or complementary therapy. Providing the best clinical strategies for chronic constipation therapy in Japan, these clinical guidelines for chronic constipation 2023 should prove useful for its treatment worldwide., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Objectives: Reflux hypersensitivity (RH) is a form of refractory gastroesophageal reflux disease in which duodenogastroesophageal reflux (DGER) plays a role. This study aimed to determine the usefulness of an endoscopy system equipped with image-enhanced technology for evaluating DGER and RH., Methods: The image enhancement mode for detecting bilirubin and calculated values were defined as the Bil mode and Bil value, respectively. First, the visibility of the Bil mode was validated for a bilirubin solution and bile concentrations ranging from 0.01% to 100% (0.002-20 mg/dL). Second, visibility scores of the Bil mode, when applied to the porcine esophagus sprayed with a bilirubin solution, were compared to those of the blue laser imaging (BLI) and white light imaging (WLI) modes. Third, a clinical study was conducted to determine the correlations between esophageal Bil values and the number of nonacid reflux events (NNRE) during multichannel intraluminal impedance-pH monitoring as well as the utility of esophageal Bil values for the differential diagnosis of RH., Results: Bilirubin solution and bile concentrations higher than 1% were visualized in red using the Bil mode. The visibility score was significantly higher with the Bil mode than with the BLI and WLI modes for 1% to 6% bilirubin solutions (P < 0.05). The esophageal Bil value and NNRE were significantly positively correlated (P = 0.031). The area under the receiver operating characteristic curve for the differential diagnosis of RH was 0.817., Conclusion: The Bil mode can detect bilirubin with high accuracy and could be used to evaluate DGER in clinical practice., (© 2023 Japan Gastroenterological Endoscopy Society.)

The density of the side chain introduced to a polymer main chain greatly influences the properties and functions of the polymer. This work first reports on the packing structure and properties at an interface of a poly(substituted methylene) where an azobenzene side chain is introduced at every carbon atom in the main chain (C1PAz). The structure and properties are compared with those of a conventional vinyl polymer [poly(methacrylate)] possessing an identical side-chain structure (C2PAz). The packing structure in the bulk state analyzed by X-ray measurements revealed that C1PAz adopts a highly ordered rectangular unit cell structure, whereas C2PAz shows a less ordered lamellar one. Langmuir film balance experiments indicated that both polymers with the trans -azobenzene give essentially the identical 2D side-chain occupying area on water, which agrees well with the smectic B (hexatic packing) model based on the X-ray data. Upon transfer onto a solid substrate, only C1PAz shows a conformational transformation to a spread bilayer-type layer, most probably due to conformational frustration stemming from the crowding of the side chains. This study proposes new insights into the effects of side-chain density on the self-assembly and photoreaction of azobenzene-containing polymers, which are expected to expand the possibilities of polymer design for various applications.

Background: In gastric solid-type poorly differentiated adenocarcinoma (PDA), the role of microsatellite instability and immune escape mechanism remains unclear. The current study aimed to elucidate the clinical significance of mismatch repair (MMR) status, genome profile, C-X-C motif chemokine receptor 2 (CXCR2) expression, and myeloid-derived suppressor cell (MDSC) infiltration in solid-type PDA., Methods: In total, 102 primary solid-type PDA cases were retrieved, and classified into 46 deficient-MMR (dMMR) and 56 proficient-MMR (pMMR) cases based on immunohistochemistry (IHC) and polymerase chain reaction-based molecular testing results. The mRNA expression profiles (NanoString nCounter Assay) of stage-matched dMMR (n = 6) and pMMR (n = 6) cases were examined. The CXCR2 expression and MDSC infiltration (CD11b- and CD33-positive cells) were investigated via IHC in all solid-type PDA cases., Results: mRNA analysis revealed several differentially expressed genes and differences in biological behavior between the dMMR (n = 46) and pMMR (n = 56) groups. In the multivariate analysis, the dMMR status was significantly associated with a longer disease-free survival (hazard ratio = 5.152, p = 0.002) and overall survival (OS) (hazard ratio = 5.050, p = 0.005). CXCR2-high expression was significantly correlated with a shorter OS in the dMMR group (p = 0.018). A high infiltration of CD11b- and CD33-positive cells was significantly correlated with a shorter OS in the pMMR group (p = 0.022, 0.016, respectively)., Conclusions: dMMR status can be a useful prognostic predictor, and CXCR2 and MDSCs can be novel therapeutic targets in patients with solid-type PDA., (© 2024. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Background: Achalasia is an esophageal motility disorder with an unknown etiology. We aimed to determine the pathogenesis of achalasia by studying alterations in esophageal smooth muscle contraction and the associated inflammatory response, and evaluate the role of esophageal microbiota in achalasia development., Methods: We analyzed esophageal mucosa and lower esophageal sphincter (LES) samples, obtained from patients with type II achalasia who underwent peroral endoscopic myotomy. Esophageal conditioned media obtained from patients were transferred into the mouse esophagus to determine whether the esophageal intraluminal environment is associated with achalasia., Results: Approximately 30% of 20-kDa myosin light chains (LC 20 ) was phosphorylated in LES from the control group under resting and stimulated conditions, whereas less than 10% of LC 20 phosphorylation was detected in achalasia under all conditions. The hypophosphorylation of LC 20 in achalasia was associated with the downregulation of the myosin phosphatase-inhibitor protein CPI-17. Th17-related cytokines, including IL-17A, IL-17F, IL-22, and IL-23A, were significantly upregulated in achalasia. α-Diversity index of esophageal microbiota and the proportion of several microbes, including Actinomyces and Dialister, increased in achalasia. Actinomyces levels positively correlated with IL-23A levels, whereas Dialister levels were positively associated with IL-17A, IL-17F, and IL-22 levels. Esophageal IL-17F levels increased in mice after oral administration of the conditioned media., Conclusions: In LES of patients with achalasia, hypophosphorylation of LC 20 , a possible cause of impaired contractility, was associated with CPI-17 downregulation and an increased Th17-related immune response. The esophageal intraluminal environment, represented by the esophageal microbiota, could be associated with the development and exacerbation of achalasia., (© 2024. Japanese Society of Gastroenterology.)

Background: Endoscopic submucosal dissection (ESD) is the standard treatment for early gastric neoplasms (EGN). Controlling intraoperative bleeding is crucial for ensuring safe and reliable procedures. ESD using the spray coagulation mode (SCM-ESD) has been developed to control bleeding more effectively than ESD using the conventional forced coagulation mode (FCM-ESD). This study aims to compare the hemostatic efficacies of SCM-ESD and FCM-ESD., Methods: This multicenter, prospective, parallel, randomized, open-label superiority trial will be conducted in five Japanese institutions. Patients with a preoperative diagnosis of intramucosal EGC will be randomized to undergo either SCM-ESD or FCM-ESD. The primary outcome measure is the completion of ESD with an electrosurgical knife alone, without the use of hemostatic forceps. Secondary outcomes include the number and duration of hemostasis using hemostatic forceps, procedure time, curability, and safety. A total of 130 patients will be enrolled in this study., Discussion: This trial will provide evidence on the hemostatic efficacy of SCM-ESD compared with FCM-ESD in patients with intramucosal EGN, potentially improving the safety and reliability of ESD procedures., Trial Registration: The trial has been registered at the University Hospital Medical Information Network Clinical Trials Registration (UMIN-CTR) as UMIN000040518. The reception number is R000054009., (© 2024. The Author(s).)

Competing Interests: Conflict of Interest E. Ihara participated in the funded research of Takeda Pharmaceutical. E. Ihara has received a lecture fee from Takeda Pharmaceutical. Yoshihiro Ogawa is conducting a joint study with Fancl Corporation and Fujifilm Medical Co., Ltd. The other authors declare they have no conflict of interest.

Competing Interests: H. Ogino is involved in the endowed course supported by Miyarisan Pharmaceutical Co. Ltd., Fujifilm Medical Co., Ltd., Terumo Corporation, Fancl Corporation, and Muta Hospital. E. Ihara participated in the funded research of Takeda Pharmaceutical. E. Ihara has received a lecture fee from Takeda Pharmaceutical. Yoshihiro Ogawa is conducting a joint study with Fancl Corporation and Fujifilm Medical Co., Ltd. The other authors declare that they have no conflict of interest.

Competing Interests: H. Ogino and E. Ihara are involved in the endowed course supported by Miyarisan Pharmaceutical Co. Ltd., Fujifilm Medical Co., Ltd., Terumo Corporation, Fancl Corporation, and Muta Hospital. E. Ihara has also received a lecture fee from Takeda Pharmaceutical Co. K. Nishioka, M. Esaki, T. Iwasa, Y, Minoda, and N. Shiga declare that they have no conflict of interest.

Competing Interests: Although there is no conflict of interest for this paper, Y. Minoda has an research and development consulting agreement with Olympus Corporation.

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: Y. M. has an R&D consulting contract with Olympus Corporation. E. I. received lecture fees from Takeda Pharmaceutical Co., Ltd., and belonged to an endowed course supported by companies including Ono Pharmaceutical Co., Ltd., Miyarisan Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Fujifilm Medical Co., Ltd., Terumo Corporation, FANCL Corporation, Ohga Pharmacy, and Abbott Japan, LLC. E. I. also received a lecture honorarium from Takeda Pharmaceutical Company until March 2023. M. T. has received a donation from Olympus Corporation for the project of international medical tele education. However, there is no COI related to this report. No COI exists for the other authors related to this article.

Competing Interests: E. Ihara has participated in funded research and received a lecture fee from Takeda Pharmaceutical Co., Ltd. and belongs to the endowed course supported by Ono Pharmaceutical Co., Ltd., Miyarisan Pharmaceutical Co. Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Otsuka Pharmaceutical Factory, Inc., Fujifilm Medical Co., Ltd., Termo Corporation, Fancl Corporation, Ohga Pharmacy, and Abbott Japan, LLC. M. Esaki, M. Kubokawa, Y. Minoda, H. Ogino, T. Osoegawa, and Y. Susuki declare that they have no conflict of interest.

Competing Interests: E. Ihara participated in the funded research of Takeda Pharmaceutical, and belongs to the endowed course supported by the following companies, including Ono Pharmaceutical, Miyarisan Pharmaceutical, Sanwa Kagaku Kenkyusho, Otsuka Pharmaceutical Factory, Fujifilm Medical, Termo Corporation, Fancl Corporation, and Ohga Pharmacy. E. Ihara has received a lecture fee from Takeda Pharmaceutical. Yoshihiro Ogawa is conducting a joint study with Fancl Corporation and Fujifilm Medical Co., Ltd.

Background and Aim: Colonic self-expandable metallic stent (SEMS) placement enables preoperative total colonoscopy (TCS) in patients with obstructive colorectal cancer. Following SEMS placement, it is possible to assess the presence or absence of synchronous proximal colon cancers and perform preoperative endoscopic resection (ER) for neoplastic lesions proximal to the primary lesion. The objective of this study was to determine the usefulness and safety of preoperative TCS and ER after SEMS placement in patients with obstructive colorectal cancer., Methods: From April 2016 to March 2022, we enrolled 100 patients with obstructive colorectal cancer who underwent SEMS placement, including 86 patients who underwent preoperative TCS after SEMS placement. Complications associated with preoperative TCS and ER after SEMS placement and the characteristics of the neoplastic lesions were assessed., Results: The success rate of SEMS placement as bridge-to-surgery was 98.0%; six patients had associated complications. Preoperative TCS was performed 8 (range: 1-30) days after SEMS placement. Four patients had synchronous advanced cancers. Nine non-advanced synchronous cancers, 116 adenomas, and 18 sessile-serrated lesions were treated by preoperative TCS and ER after SEMS placement. No procedure-related complications, namely stent migration, bleeding, and perforation were observed. Forty-five patients underwent follow-up TCS 1 year after surgery. Only one patient with submucosal invasive cancer required a second surgery., Conclusions: Preoperative TCS and ER after SEMS placement was performed with no complications. This approach allows preoperative evaluation of the entire colon and the treatment of precancerous lesions. (240 words)., (© 2023. The Author(s).)

Background: We have determined that the impaired accommodation of the lower esophageal sphincter (LES) underlies the pathogenesis of esophagogastric junction outflow obstruction (EGJOO). We have also found that acotiamide may treat EGJOO by improving impaired LES accommodation. The effects of acotiamide in patients with EGJOO need to be further confirmed in a prospective study., Methods: This trial is a multicenter, randomized, double-blind, placebo-controlled study to compare the efficacy and safety of acotiamide (300 mg/day or 600 mg/day) with those of a placebo in the treatment of patients with EGJOO. The primary endpoint will be the proportion of patients who report an improvement in symptom of food sticking in the chest after 4 weeks of treatment period 1. The secondary endpoints will be the proportion of patients with normalized integrated relaxation pressure (IRP), the value of change from baseline in the distal contractile integral, basal LES pressure, EGJOO-quality of life score, Gastrointestinal Symptom Rating Scale, and the correlation between IRP and each symptom score. During the 2-year trial period, 42 patients from five institutions will be enrolled., Discussion: This trial will provide evidence to clarify the efficacy and safety of acotiamide as a treatment for patients with EGJOO. Acotiamide might help improve the quality of life of patients with EGJOO and is expected to prevent the progression of EGJOO to achalasia., Trial Registration: This study was approved by the Institutional Review Board (IRB) of Kyushu University Hospital as well as the local IRBs of the participating sites for clinical trials and registered in the Japan Registry of Clinical Trials (jRCT: 2071210072). The registration date is on October 11, 2021., (© 2023. The Author(s).)

Background & Aims: Hybrid endoscopic submucosal dissection (H-ESD), which incorporates endoscopic submucosal dissection (ESD) with endoscopic mucosal resection, has been developed to make ESD technically easier. This study aimed to determine if H-ESD is superior to conventional ESD (C-ESD) for small early gastric neoplasms (EGNs)., Methods: We conducted a multi-center, prospective, open-label, randomized controlled trial to compare the treatment outcomes of H-ESD and C-ESD (Hybrid-G Trial). Patients with differentiated type intramucosal EGN ≤20 mm in diameter and without ulceration were randomly assigned (1:1) to groups that underwent H-ESD or C-ESD. A single multi-functional snare, SOUTEN (ST1850-20, Kaneka, Medix, Tokyo, Japan), was used for H-ESD. The primary outcome was procedure time. Secondary outcomes included mucosal incision time, time and speed of submucosal dissection, curability, and endoscopic procedural adverse events., Results: A total of 39 and 40 patients underwent H-ESD and C-ESD, respectively. The procedure time of H-ESD was significantly shorter than that of C-ESD (33.16 min vs 62.46 min; H-ESD/C-ESD ratio: 0.53; 95% confidence interval, 0.41-0.69; P < .0001). There was no significant difference in mucosal incision time between the 2 groups; the time and speed of submucosal dissection of H-ESD were significantly shorter than those of C-ESD. No difference was observed between the 2 groups in other outcomes., Conclusions: H-ESD has significantly shorter procedure time than C-ESD, with high and comparable curability and safety for both H-ESD and C-ESD. H-ESD can be a good option for the endoscopic treatment of small EGNs. (UMIN Clinical Trials Registry, Numbers: UMIN000041244)., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: EUS-guided FNA/biopsy (EUS-FNA/B) is the citerion standard for diagnosing subepithelial lesions (SELs); however, its diagnostic ability for SELs <20 mm is low. We developed a new diagnostic method to differentiate between GI stromal tumor (GIST) and non-GIST by measuring high-frequency impedance (H-impedance) using an EUS-FNB needle., Methods: The H-impedance of gastric epithelial neoplasms from 16 cases were measured with a conventional impedance probe to confirm whether H-impedance is clinically useful for assessing cell density (study 1). The H-impedance values of exposed SELs from 25 cases with use of the conventional probe (study 2) and nonexposed SELs from 20 cases with use of the EUS-FNB needle probe (study 3) were measured to determine the diagnostic ability of H-impedance for differentiating GISTs from non-GISTs., Results: H-impedance significantly positively correlated with cell density (P = .030) (study 1). The H-impedance of GIST (99.5) measured with a conventional probe was significantly higher than with those of the muscular layer (82.4) and leiomyoma (89.2) (P < .01) (study 2). The H-impedance of GIST measured with the EUS-FNB needle was also significantly higher than that of leiomyoma (GIST: 80.2 vs leiomyoma, 71.8; P = .015). The diagnostic yield of the impedance method for differentiating GISTs from non-GISTs had 94.4% accuracy, 88.9% sensitivity, 100% specificity, and 0.95 area under the curve. Diagnostic ability was not affected by lesion size (P = .86) (study 3)., Conclusion: Auxiliary differential diagnosis between gastric GISTs and non-GISTs by the H-impedance measurement during EUS-FNB could be a good option, especially when the lesion is <20 mm., (Copyright © 2023 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Peroral endoscopic myotomy (POEM) is conducted for patients with esophageal motility disorders based on high-resolution manometry (HRM) findings. However, the impact of POEM on HRM findings and the associations between post-POEM HRM and outcomes have not been clarified., Methods: In a multicenter, observational, cohort study, patients with achalasia treated by POEM received follow-up HRM. Associations between patient characteristics, POEM procedures, and post-POEM HRM findings, including integrated relaxation pressure (IRP) and distal contractile integral (DCI), were investigated. Furthermore, POEM procedure outcomes were compared with post-POEM HRM findings., Results: Of 2171 patients, 151 (7.0%) showed residual high post-POEM IRP (≥26 mm Hg; Starlet [Starmedical Ltd, Tokyo, Japan]). In a multivariate analysis, high pre-POEM IRPs (odds ratio [OR], 24.3) and gastric myotomy >2 cm (OR, .22) were found to be positive and negative predictive factors of high post-POEM IRPs, respectively. Peristalsis recovery (DCI ≥500 mm Hg/cm/s, at least 1 swallow; Starlet) was visible in 121 of 618 patients (19.6%) who had type II to III achalasia. High pre-POEM IRP (OR, 2.65) and DCI ≥500 (OR, 2.98) predicted peristalsis recovery, whereas esophageal dilation (OR, .42) predicted a risk of no recovery. Extended myotomy did not reveal a significant impact on peristalsis recovery. High or low post-POEM IRP and DCI did not increase the incidence of clinical failure, reflux esophagitis, or symptomatic GERD., Conclusions: Extended gastric myotomy decreased IRP values, whereas peristalsis recovery depended on the characteristics of achalasia. A residual high post-POEM IRP does not necessarily mean clinical failure. Routine HRM follow-up is not recommended after POEM., (Copyright © 2023 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background: The specific role of the M 3 muscarinic acetylcholine receptor in gastrointestinal motility under physiological conditions is unclear, due to a lack of subtype-selective compounds., Aims: The objective of this study was to determine the region-specific role of the M 3 receptor in gastrointestinal motility., Methods: We developed a novel positive allosteric modulator (PAM) for the M 3 receptor, PAM-369. The effects of PAM-369 on the carbachol-induced contractile response of porcine esophageal smooth muscle and mouse colonic smooth muscle (ex vivo) and on the transit in mouse small intestine and rat colon (in vivo) were examined., Results: PAM-369 selectively potentiated the M 3 receptor under the stimulation of its orthosteric ligands without agonistic or antagonistic activity. Half-maximal effective concentrations of PAM activity for human, mouse, and rat M 3 receptors were 0.253, 0.345, and 0.127 μM, respectively. PAM-369 enhanced carbachol-induced contraction in porcine esophageal smooth muscle and mouse colonic smooth muscle without causing any contractile responses by itself. The oral administration of 30 mg/kg PAM-369 increased the small intestinal transit in both normal motility and loperamide-induced intestinal dysmotility mice but had no effects on the colonic transit, although the M 3 receptor mRNA expression is higher in the colon than in the small intestine., Conclusions: This study provided the first direct evidence that the M 3 receptor has different region-specific roles in the motility function between the small intestine and colon in physiological and pathophysiological contexts. Selective PAMs designed for targeted subtypes of muscarinic receptors are useful for elucidating the subtype-specific function., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Neuroendocrine neoplasms of the ampulla of Vater (ampullary NEN) have features of both gastrointestinal and pancreato-biliary (PB) NEN. However, the limited number of studies examining ampullary NEN makes it difficult to clarify their unique characteristics. This study aimed to elucidate the clinical characteristics of ampullary NEN., Methods: We enrolled 162 patients with PB-NEN diagnosed at Kyushu University Hospital between 2011 and 2020. Clinical features, pathological diagnoses, treatments, and prognoses were retrospectively analyzed. We also compared ampullary NEN with pancreatic NEN (PanNEN)., Results: We analyzed 10 ampullary NEN cases and 149 PanNEN cases. The ampullary NEN cases consisted of 4 cases of neuroendocrine tumor Grade 1 (NET G1), 1 NET G2 (Grade 2), and 5 neuroendocrine carcinomas (NECs). The incidences of NEC and cholangitis were significantly higher in ampullary NEN than in PanNEN. All ampullary NETs had a submucosal tumor-like appearance, as identified by endoscopic ultrasound-guided fine needle aspiration. We treated small NET G1 (<10 mm) with endoscopic papillectomy and large NET G1 with pancreaticoduodenectomy. There were no cases of recurrence after resection. All ampullary NECs presented with the characteristic endoscopic finding of a "crater sign" similar to deep-mining ulcers seen in gastric malignant lymphoma. Four cases underwent surgical resection, and 1 case was unresectable. Two patients who underwent multidisciplinary treatment were maintained without recurrence for over 2 years., Conclusions: Endoscopic findings showed identifiable distinctions between ampullary NETs and NECs., (© 2022 S. Karger AG, Basel.)

Background/aims: The etiology of superficial non-ampullary duodenal epithelial tumors (SNADETs) remains unclear. Recent studies have reported conflicting associations between duodenal tumor development and Helicobacter pylori infection or endoscopic gastric mucosal atrophy. As such, the present study aimed to clarify the relationship between SNADETs and H. pylori infection and/or endoscopic gastric mucosal atrophy., Methods: This retrospective case-control study reviewed data from 177 consecutive patients with SNADETs who underwent endoscopic or surgical resection at seven institutions in Japan over a three-year period. The prevalence of endoscopic gastric mucosal atrophy and the status of H. pylori infection were compared in 531 sex- and age-matched controls selected from screening endoscopies at two of the seven participating institutions., Results: For H. pylori infection, 85 of 177 (48.0%) patients exhibited SNADETs and 112 of 531 (21.1%) control patients were non-infected (p<0.001). Non-atrophic mucosa (C0 to C1) was observed in 96 of 177 (54.2%) patients with SNADETs and 112 of 531 (21.1%) control patients (p<0.001). Conditional logistic regression analysis revealed that non-atrophic gastric mucosa was an independent risk factor for SNADETs (odds ratio, 5.10; 95% confidence interval, 2.44-8.40; p<0.001)., Conclusion: Non-atrophic gastric mucosa, regardless of H. pylori infection status, was a factor independently associated with SNADETs.

Endoscopic submucosal dissection (ESD) is globally performed to treat early epithelial tumors of the gastrointestinal tract, but delayed perforation is a problematic procedure-related complication. To address this problem, closure of ESD-induced mucosal defects with a detachable snare has been reported. However, one problem is that this method usually requires some degree of skill and replacing a single-channel scope with a two-channel scope. We developed the clip stopper closure (CSC) method using a detachable snare in combination with the ZEOCLIP, which can be easily performed with a single-channel scope, for ESD-induced mucosal defects. Six consecutive cases were treated with this closure method for colonic ESD-induced mucosal defects. The median closure time was 12.5 (10-24) min, and the success rate of this procedure was 100%. Our CSC method was able to be performed in any part of the colon. In conclusion, the CSC method using a detachable snare in combination with the ZEOCLIP is a simple but promising closure technique for ESD-induced mucosal defects., (© 2022 Japan Gastroenterological Endoscopy Society.)

Background: Mucosal incision-assisted biopsy (MIAB) is a valuable alternative to endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNAB) for sampling gastric subepithelial lesions (SELs). This study aimed to evaluate the potential risk of dissemination and impact on postoperative prognosis associated with MIAB, which has not yet been investigated., Methods: Study 1: A prospective observational study was conducted to examine the presence or absence and growth rate of tumor cells in gastric juice before and after the procedure in patients with SELs who underwent MIAB (n = 25) or EUS-FNAB (n = 22) between September 2018 and August 2021. Study 2: A retrospective study was conducted to examine the impact of MIAB on postoperative prognosis in 107 patients with gastrointestinal stromal tumors diagnosed using MIAB (n = 39) or EUS-FNAB (n = 68) who underwent surgery between January 2001 and July 2020., Results: In study 1, although no tumor cells were observed in gastric juice in MIAB before the procedure, they were observed in 64% of patients after obtaining samples (P < 0.001). In contrast, no tumor cells were observed in the gastric juice in EUS-FNAB before and after the procedure. In study 2, there was no significant difference in 5-year disease-free survival between MIAB (100%) and EUS-FNAB (97.1%) (P = 0.27)., Conclusion: MIAB is safe, with little impact on postoperative prognosis, although the procedure releases some tumor cells after damaging the SEL's pseudocapsule., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: Eikichi Ihara participated in funded research for Takeda Pharmaceutical Co., Ltd. and belongs to the endowed course supported by the companies mentioned, including Ono Pharmaceutical Co., Ltd., Miyarisan Pharmaceutical Co. Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Otsuka Pharmaceutical Factory, Inc., Fujifilm Medical Co., Ltd., Termo Corporation, FANCL Corporation, and Ohga Pharmacy. Eikichi Ihara also received a lecture fee from Takeda Pharmaceutical Co. The remaining authors declare that they have no conflict of interest.

Competing Interests: Eikichi Ihara participated in the funded research of Takeda Pharmaceutical Co., Ltd. and belongs to the endowed course supported by the companies mentioned, including Ono Pharmaceutical Co., Ltd., Miyarisan Pharmaceutical Co. Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Otsuka Pharmaceutical Factory, Inc., Fujifilm Medical Co., Ltd., Termo Corporation, Fancl Corporation, and Ohga Pharmacy. Eikichi Ihara received a lecture fee from Takeda Pharmaceutical Co. The others have no conflicts of interest or financial ties to disclose.

Competing Interests: Prodi GI traction wire was provided by Covidien Japan Inc. free of charge. Eikichi Ihara participated in the funded research of Takeda Pharmaceutical Co., Ltd. and belongs to the endowed course supported by the companies mentioned, including Ono Pharmaceutical Co., Ltd., Miyarisan Pharmaceutical Co. Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Otsuka Pharmaceutical Factory, Inc., Fujifilm Medical Co., Ltd., Termo Corporation, Fancl Corporation, Ohga Pharmacy, and Abbott Japan, LLC. Eikichi Ihara received a lecture fee from Takeda Pharmaceutical Co.

We aimed to establish a novel murine model of autoimmune autonomic ganglionopathy (AAG), which represents autoimmune dysautonomia, associated with MHC class II to understand its pathomechanism and the pathogenicity of nicotinic acetylcholine receptor (nAChR) antibodies. The amino acid sequence of the mouse nAChRα3 protein was analyzed using an epitope prediction tool to predict the possible MHC class II binding mouse nAChRα3 peptides. We focused on two nAChRα3 peptides in the extracellular region, and experimental AAG (EAAG) was induced by immunization of C57BL/6 mice with these two different peptides. EAAG mice were examined both physiologically and histologically. Mice with EAAG generated nAChRα3 antibodies and exhibited autonomic dysfunction, including reduced heart rate, excessive fluctuations in systolic blood pressure, and intestinal transit slowing. Additionally, we observed skin lesions, such as alopecia and skin ulcers, in immunized mice. Neuronal cell density in the sympathetic cervical ganglia in immunized mice was significantly lower than that in control mice at the light microscopic level. We interpreted that active immunization of mice with nAChRα3 peptides causes autonomic dysfunction similar to human AAG induced by an antibody-mediated mechanism. We suggested a mechanism by which different HLA class II molecules might preferentially affect the nAChR-specific immune response, thus controlling diversification of the autoantibody response. Our novel murine model mimics AAG in humans and provides a useful tool to investigate its pathomechanism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yamakawa, Nakane, Ihara, Tawara, Ikeda, Igarashi, Komohara, Takamatsu, Ikeda, Tomita, Murai, Ando, Mukaino, Ogawa and Ueda.)

Background: High-resolution manometry (HRM) is the gold standard for diagnosing esophageal motility disorders (EMDs); however, it requires specialized equipment. The development of more accessible screening examinations is expected. We evaluated the utility of barium esophagography (BE) screening using two novel findings to diagnose EMDs., Methods: Between January 2013 and October 2020, 244 patients with suspected EMDs who underwent both HRM and BE were analyzed. The EMD diagnosis was based on HRM findings using Chicago Classification version 3.0. BE was performed using sequential esophagography with barium sulfate. Three conventional BE findings (air-fluid level, rosary-bead/corkscrew appearance, and absent/weak peristalsis) and two novel BE findings (wave appearance and supra-junctional ballooning) were used for diagnosis., Results: The sensitivity and specificity of BE screening using the two novel findings and conventional findings to diagnose EMDs were 79.4% and 88%, respectively [area under the receiver-operating characteristic curve (AUC) = 0.837]. Without these novel findings, they were 63.9% and 96%, respectively (AUC = 0.800), respectively. Achalasia was highly correlated with the air-fluid level (88.7%). Absent contractility was highly correlated with absent/weak peristalsis (85.7%). Relatively high correlations were observed between distal esophageal spasm and rosary-bead/corkscrew appearance (60%), and between achalasia and wave appearance (59.7%). The intra-observer reproducibility and inter-observer agreement for individual BE findings were 84.4% and 75%, respectively. Wave appearance was associated with higher integrated relaxation pressure (IRP) and shorter distal latency. Supra-junctional ballooning was associated with higher IRP., Conclusions: BE screening using two additional novel findings to diagnose EMDs could be useful in general practice., (© 2022. Japanese Society of Gastroenterology.)

Although a large-caliber endoscope (LCE) is indispensable for through-the-scope placement of a self-expandable metallic stent (SEMS) in patients with malignant colonic obstruction (MCO), inaccessibility of the target obstructing lesion (TOL) by the endoscope is a significant cause of unsuccessful procedures. We herein present a novel salvage procedure when the TOL is not directly accessible by an LCE in conditions such as coexisting peritoneal carcinomatosis involving the colon. The salvage procedure, termed over-the-catheter endoscope replacement (OCER), starts with an ultraslim endoscope suitable for deep insertion beyond a tortuous colon for traversing a guidewire through the TOL. The ultraslim endoscope is then withdrawn and replaced by an LCE through the following steps. An endoscopic retrograde cholangiopancreatography catheter is preloaded in the LCE, the catheter alone is passed over the guidewire already traversed through the TOL, and the LCE is navigated over the catheter as far as possible toward the TOL to deliver the SEMS delivery system in a standard through-the-scope manner or further in an over-the-wire manner even if LCE insertion is incomplete. Among the 165 patients with MCO who underwent stenting during our study period, OCER led to successful procedures in all nine patients whose TOLs were initially inaccessible because of colon-involving peritoneal carcinomatosis. By utilizing the functions of distinctive endoscopes in a unique and complementary way, OCER can be a practical salvage option for challenging cases of MCO that are highly prone to unsuccessful palliation by conventional SEMS placement., (© 2022 The Authors. Digestive Endoscopy published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Gastrointestinal stromal tumors (GISTs) are common subepithelial lesions (SELs) and require treatment considering their malignant potential. We recently developed an endoscopic ultrasound-based artificial intelligence (EUS-AI) system to differentiate GISTs from non-GISTs in gastric SELs, which were used to train the system. We assessed whether the EUS-AI system designed for diagnosing gastric GISTs could be applied to non-gastric GISTs. Between January 2015 and January 2021, 52 patients with non-gastric SELs (esophagus, n = 15; duodenum, n = 26; colon, n = 11) were enrolled. The ability of EUS-AI to differentiate GISTs from non-GISTs in non-gastric SELs was examined. The accuracy, sensitivity, and specificity of EUS-AI for discriminating GISTs from non-GISTs in non-gastric SELs were 94.4%, 100%, and 86.1%, respectively, with an area under the curve of 0.98 based on the cutoff value set using the Youden index. In the subanalysis, the accuracy, sensitivity, and specificity of EUS-AI were highest in the esophagus (100%, 100%, 100%; duodenum, 96.2%, 100%, 0%; colon, 90.9%, 100%, 0%); the cutoff values were determined using the Youden index or the value determined using stomach cases. The diagnostic accuracy of EUS-AI increased as lesion size increased, regardless of lesion location. EUS-AI based on gastric SELs had good diagnostic ability for non-gastric GISTs., (© 2022. The Author(s).)

Competing Interests: Eikichi Ihara participated in a funded study of Takeda Pharmaceutical Co., Ltd. and belongs to the endowed course supported by the companies mentioned, including Ono Pharmaceutical Co., Ltd., Miyarisan Pharmaceutical Co. Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Otsuka Pharmaceutical Factory, Inc., Fujifilm Medical Co., Ltd., Termo Corporation, Fancl Corporation, and Ohga Pharmacy. Eikichi Ihara received a lecture fee from Takeda Pharmaceutical Co. The other co-authors have no conflicts of interest or financial ties to disclose.

Solid-type poorly differentiated adenocarcinoma (PDA) of the stomach is frequently associated with microsatellite instability (MSI) and aberrations of the SWI/SNF chromatin remodeling complex. Previous studies showed that aberrant ARID1A and SMARCA4 expression induces mesenchymal transition. We analyzed 51 primary-site cases and 209 metastatic lymph nodes among solid-type PDA for the expression of SWI/SNF complex subunits (ARID1A, SMARCA4, SMARCB1, SMARCC2) and epithelial-mesenchymal transition (EMT) markers (E-cadherin, β-catenin, Snail). We also analyzed 40 cases of non-solid-type PDA as a stage-matched control group. Aberrant expression of ARID1A (39%) and SMARCA4 (49%) was more common in solid-type PDA than in non-solid-type PDA (ARID1A, P = 0.0049; SMARCA4, P < 0.0001). The group of solid-type PDA with aberrant ARID1A showed significantly longer overall and progression-free survival than the corresponding ARID1A-retained group (P = 0.0405 and P = 0.0296, respectively). Aberrant expression of EMT factors inducing mesenchymal transition in the groups with solid-type PDA at the primary site or metastatic lymph nodes with aberrant ARID1A was less common than in the corresponding groups with retained ARID1A (E-cadherin, primary site P = 0.0341, lymph node P < 0.0001; β-catenin, primary site P = 0.0293, lymph node P = 0.0010; Snail, primary site P = 0.0169, lymph node P = 0.0828). Furthermore, N3 of the TNM classification was more frequently observed in the group with solid-type PDA with retained ARID1A than in the corresponding ARID1A-aberrant group (P = 0.0288). Mesenchymal transition was not induced in the ARID1A-aberrant group, in which patients had favorable prognosis, and preserved epithelial characteristics in EMT may play an important role in low tumor aggressiveness of solid-type PDA., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Endoscopic submucosal dissection (ESD) is effective for the treatment of colorectal neoplasms. We have developed a self-completion ESD (S-ESD) using Endosaber without requiring additional instruments or assistance. This prospective cohort study was conducted to investigate the feasibility of S-ESD for colorectal neoplasms. Patients with colorectal neoplasms measuring 20-40 mm in size were enrolled. A single operator, without assistance, performed ESD using only the Endosaber. The primary outcome was the success rate of S-ESD. Secondary outcomes included procedure time, the rates of en bloc, complete, and curative resection, and complication rates, including the incidence of perforation and delayed bleeding. In total, 15 patients with 15 lesions were enrolled. The median size of the resected lesions was 28 mm (interquartile range 25-29 mm). S-ESD success rate of 100% was achieved. The median procedure time was 44 min (29.5-53.5 min). We observed en bloc, complete, and curative resection rates of 100%, 93.3%, and 86.7%, respectively, and a complication rate of 6.7% (perforation: 0%, delayed bleeding: 6.7%). S-ESD for colorectal neoplasms was successfully performed with favorable treatment outcomes and low complication rates. S-ESD reduces the number of devices and extent of assistance, making S-ESD a simple and cost-effective procedure., (© 2022. The Author(s).)

Competing Interests: Eikichi Ihara participated in the funded research of Takeda Pharmaceutical Co., Ltd. and belongs to the endowed course supported by the companies mentioned, including Ono Pharmaceutical Co., Ltd., Miyarisan Pharmaceutical Co. Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Otsuka Pharmaceutical Factory, Inc., Fujifilm Medical Co., Ltd., Termo Corporation, Fancl Corporation, and Ohga Pharmacy. Eikichi Ihara received a lecture fee from Takeda Pharmaceutical Co.

In Japan, with the increasing prevalence of gastroesophageal reflux disease (GERD) and growing public interest, the Japanese Society of Gastroenterology issued Evidence-based Clinical Practice Guidelines for GERD (1st edition) in 2009 and a revised 2nd edition in 2015. A number of studies on GERD were subsequently conducted in Japan and abroad, and vonoprazan, a potassium-competitive acid blocker (P-CAB), became available for the first time in Japan in February 2015. The revised 3rd edition (Japanese edition), which incorporates new findings and information, was published in April 2021. These guidelines are summarized herein, particularly sections related to the treatment of GERD. The important clinical issues addressed in the present revision are (i) the introduction of treatment algorithms that classify GERD into reflux esophagitis and non-erosive reflux disease, (ii) the clarification of treatment algorithms based on to the severity of reflux esophagitis, and (iii) the positioning of vonoprazan in the treatment for GERD. The present guidelines propose vonoprazan as the initial/maintenance treatment for severe reflux esophagitis. They also recommend vonoprazan or PPI as an initial treatment for mild reflux esophagitis and recommended PPI and proposed vonoprazan as maintenance treatment. These updated guidelines offer the best clinical strategies for GERD patients in Japan and hope that they will be of global use for the diagnosis and treatment for GERD., (© 2022. The Author(s).)

Objectives: We have found that an altered lower esophageal sphincter (LES) accommodation response is an underlying cause of esophagogastric junction outflow obstruction (EGJOO). The objective of this study was to examine the treatment effect of acotiamide, a prokinetic agent which improves impaired gastric accommodation in functional dyspepsia, in patients with EGJOO., Methods: A prospective observational longitudinal study was conducted between October 2014 and March 2020. Acotiamide (100 mg, 3 times a day) was administered to 25 patients with EGJOO for 4 weeks. High-resolution manometry (HRM) was performed just before and after 4 weeks of treatment., Results: As the primary outcome, the extent of integrated relaxation pressure (IRP) after treatment (14.6, 12.1-22.0 mmHg) was significantly lower than that before treatment (19.4, 17.1-27.4 mmHg). The extent of LES accommodation index after treatment (32.7, 21.0-40.0 mmHg) was also significantly lower than that before treatment (39.3, 31.2-50.2 mmHg). Acotiamide normalized the IRP (< 15 mmHg) in 13 of 25 patients with EGJOO (52%), and the IRP was decreased in 20 of 25 patients with EGJOO (80%). As the secondary outcome, the total FSSG score in 25 patients with EGJOO before and after acotiamide treatment showed no significant difference. In a sub-analysis of 13 patients in whom EGJOO was normalized by acotiamide, however, dysphagia was reported to be significantly improved by acotiamide., Conclusions: Acotiamide has a treatment effect on patients with EGJOO via a reduction in the IRP level through the lowering of both the basal LES pressure and LES accommodation response. Dysphagia is a key symptom to be evaluated and treated in patients with EGJOO., (© 2021. The Japan Esophageal Society.)

Intestinal mucosal injury that develops as a complication of tocilizumab (TCZ) is usually associated with diverticulosis. We herein report a rare case of TCZ-induced intestinal mucosal injury in the absence of diverticulosis. A 74-year-old woman suffering from rheumatoid arthritis started taking TCZ. Six months later, she complained of hematochezia and abdominal pain. Colonoscopy revealed multiple ulcers spreading from the cecum to the transverse colon but no diverticulosis. These lesions were cured at three months after the discontinuation of TCZ. We should consider TCZ as a risk factor for intestinal mucosal injury, even if patients have no history of intestinal disease associated with diverticulosis.