Randomised controlled, patient-blinded, multicentre, superiority trial to evaluate the efficacy of the line-attached sheath-type traction device for endoscopic submucosal dissection in patients with superficial gastric neoplasms.

INTRODUCTION: EndoTrac is a line-attached sheath-type traction device that enables us to control the direction and the force of traction during endoscopic submucosal dissection (ESD). The efficacy of EndoTrac for gastric ESD has not been fully verified. METHODS AND ANALYSIS: The G-Trac study is a multicentre (nine general hospitals and two university hospitals in Japan) collaborative trial assessing the efficacy of EndoTrac for gastric ESDs. Patients with superficial gastric neoplasms will be enrolled and randomly assigned to undergo either conventional ESD or EndoTrac ESD. Allocation will be stratified according to tumour location, operator experience and tumour diameter at an allocation rate of 1:1. The type of endoknife used will be confirmed before randomisation. The primary outcome, procedure time, will be compared between the groups in both intention-to-treat and per-protocol analyses using the Wilcoxon rank sum test. The efficacy-related, safety-related and device-related outcomes will be assessed in the secondary analysis. The planned sample size of the 142 patients in the two groups will enable us to detect a difference with a power of 80% by using the Wilcoxon rank sum test, assuming an effect size of 0.54, asymptotic relative efficiency of 0.864 and a two-sided type 1 error rate of 5%. ETHICS AND DISSEMINATION: This trial was approved by the certified review board of Kobe University (22 December 2022). The results from this trial will be disseminated through peer-review journals, presentations at national and international conferences, and data sharing with other researchers. TRIAL REGISTRATION NUMBER: jRCT1052220166.

Outcomes of endoscopic submucosal dissection for esophageal cancer with segmental absence of intestinal musculature.

BACKGROUND AND AIMS: Perforation during esophageal endoscopic submucosal dissection (ESD) typically results from electrical damage. However, there are cases in which perforation occurs because of segmental absence of intestinal musculature (SAIM) without iatrogenic muscular injury. We investigated the occurrence rate and clinical course of SAIM during esophageal ESD. METHODS: We conducted a retrospective review of esophageal ESDs performed between 2013 and 2019 at 10 centers in Japan. RESULTS: Five of 1708 (0.29%) patients received ESD for esophageal cancer and had SAIM. The median muscular defect size was 20 mm. All lesions were resected without discontinuation. After resection, 3 patients were closed with Endoloop. Four patients had mediastinal emphysema. All patients were managed conservatively. CONCLUSIONS: SAIM is a very rare condition that is usually only diagnosed during ESD. Physicians performing esophageal ESD should be aware of SAIM. When SAIM is detected, the ESD technique should be modified to prevent full-thickness perforation.

Assessment of predictive factors associated with the technical difficulty of endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma: Japanese multicenter retrospective study.

OBJECTIVES: Endoscopic submucosal dissection (ESD) for superficial esophageal squamous cell carcinoma (ESCC) is performed for the treatment of lesions with varied backgrounds and factors. However, the predictive factors associated with the technical difficulty of ESD remain unknown in patients with varied lesions. Therefore, this study aimed to identify the predictive factors associated with the technical difficulty of ESD for ESCC using a retrospective cohort. METHODS: This multicenter, retrospective study was conducted in 10 hospitals in Japan. Consecutive patients who underwent esophageal ESD between January 2013 and December 2019 were enrolled. Lesions of subepithelial tumors, adenocarcinoma, and adenoma were excluded. Difficult lesions were defined as ESD requiring a long procedure time (≥120 min), perforation development, piecemeal resection, or discontinued ESD. In the present study, the clinical factors were assessed to identify the technical difficulty of ESD using univariate and multivariate analyses. RESULTS: Among 1708 lesions treated with esophageal ESD, eight subepithelial tumors, 44 adenocarcinomas, and two adenomas were excluded. Finally, 1505 patients with 1654 lesions were analyzed, and 217 patients with 217 lesions (13.1%) were classified as patients with difficult lesions. In multivariate analysis, the predictive factors associated with the technical difficulty of ESD were as follows: tumors with varices, tumors with diverticulum, antiplatelet use (discontinued), circumference of tumor (≥1/2), preoperative tumor size ≥30 mm, trainee, and nonhigh-volume center. CONCLUSION: This multicenter retrospective study identified the predictive factors associated with the technical difficulty of ESD for ESCC with varied backgrounds and factors.

Long-Term Outcomes of Endoscopic Submucosal Dissection for Early Remnant Gastric Cancer: A Retrospective Multicenter Study.

INTRODUCTION: Favorable long-term outcomes of endoscopic submucosal dissection (ESD) for early remnant gastric cancer (ERGC) have been reported in single-center studies from advanced institutions. However, no studies have examined the long-term outcomes using a multicenter database. This study aimed to investigate the long-term outcomes of the aforementioned approach using a large multicenter database. METHODS: This retrospective multicenter cohort study included 242 cases with 256 lesions that underwent ESD for ERGC between April 2009 and March 2019 across 12 centers. We investigated the long-term outcomes of these patients with the Kaplan-Meier method, and the relationship between curability, additional treatment, or hospital category, and the survival time was evaluated using the log-rank test. RESULTS: During the median follow-up period of 48.4 months, the 5-year overall survival rate was 81.3%, and the 5-year gastric cancer-specific survival rate was 98.1%. The survival time of patients of endoscopic curability (eCura) C-2 without additional surgery was significantly shorter than the corresponding of patients of eCura A/B/C-1 and eCura C-2 with additional surgery. There was no significant difference in either overall survival or gastric cancer-specific survival rate between the high-volume and non-high-volume hospitals. CONCLUSION: The gastric cancer-specific survival of ESD for ERGC using a multicenter database was favorable. ESD for ERGC is widely applicable regardless of the hospital case volume. Management in accordance with the latest guidelines will lead to long-term survival.

Safety and efficacy of endoscopic submucosal dissection for superficial esophageal cancer with esophageal varices.

BACKGROUND: Heavy drinking is associated with esophageal cancer and esophageal varices. However, there are limited reports of endoscopic resection for esophageal cancer with esophageal varices. In this multicenter study, we clarified the safety and efficacy of endoscopic submucosal dissection for superficial esophageal cancer with esophageal varices. METHODS: In this multicenter, retrospective, observational study, patients underwent esophageal endoscopic submucosal dissection at 10 referral centers in Japan from January 2013 to December 2019. We analyzed characteristics including backgrounds and varices, treatment outcomes, and adverse events in cases with esophageal varices. RESULTS: A total of 1708 patients were evaluated, 27 (1.6%) of whom had esophageal varices. In patients with esophageal varices, the en bloc resection rate and R0 resection rate were 100% and 77.8%, respectively. Patients with esophageal varices had longer procedure times than patients without esophageal varices (p = 0.015). There was no significant difference in adverse events. There was no significant difference in procedure time and number of adverse events between patients who underwent pretreatment and those who did not. There was no significant difference in these outcomes for patients with lesions on varices compared to those without. Child-Pugh classification and location of the lesions also did not affect these outcomes. CONCLUSIONS: Esophageal cancer with esophageal varices could be treated endoscopically safely and effectively.

Pembrolizumab-related cholangitis with multiple fatal liver abscesses after endoscopic biliary drainage: a case report and review of the literature.

A 60-year-old male with cStage IVB lung cancer was treated with pembrolizumab. However, after five courses of pembrolizumab, he developed pembrolizumab-related cholangitis. Imaging studies showed enlargement and diffuse wall thickening of the gallbladder and mild dilation of the bile ducts without any obvious obstruction. As the patient experienced severe abdominal pain, we suspected bile stasis and performed biliary drainage. However, his condition did not improve, and he developed multiple liver abscesses and died during immunosuppressive therapy. Our case suggests that in ir-cholangitis, the indication and method of endoscopic retrograde cholangiopancreatography should be carefully judged.

The risk scoring system for assessing the technical difficulty of endoscopic submucosal dissection in cases of remnant gastric cancer after distal gastrectomy.

BACKGROUND: Endoscopic submucosal dissection (ESD) for remnant gastric cancer (RGC) after distal gastrectomy (DG) is considered technically challenging due to the narrow working space, and severe fibrosis and staples from the previous surgery. Technical difficulties of ESD for RGC after DG have not been thoroughly investigated. This study aimed to develop and validate a risk-scoring system for assessing the technical difficulty of ESD for RGC after DG in a large multicenter cohort. METHODS: We investigated patients who underwent ESD for RGC after DG in 10 institutions between April 2008 and March 2018. A difficult case was defined as ESD lasting ≥ 120 min, involving piecemeal resection, or the occurrence of perforation during the procedure. A risk-scoring system for the technical difficulty of the procedure was developed based on multiple logistic regression analyses, and its performance was internally validated using bootstrapping. RESULTS: A total of 197 consecutive patients with 201 lesions were analyzed. There were 90 and 111 difficult and non-difficult cases, respectively. The scoring model consisted of four independent risk factors and points of risk scores were assigned for each as follows: tumor size > 20 mm: 2 points; anastomosis site: 2 points; suture line: 1 point; and non-expert endoscopist: 2 points. The C-statistics of the scoring system for technical difficulty was 0.72. CONCLUSIONS: We developed a validated risk-scoring model for predicting the technical difficulty of ESD for RGC after DG that can contribute to its safer and more reliable performance.

Efficacy of forced coagulation with low high-frequency power setting during endoscopic submucosal dissection.

AIM: To investigated the hemostatic ability of the S and F1-10 methods in clinical and ex vivo studies. METHODS: The hemostatic abilities of the two methods were analyzed retrospectively in all six gastric endoscopic submucosal dissection cases. The treated vessel diameter, compressed vessel frequency, and bleeding frequency after cutting the vessels were noted by the recorded videos. The coagulation mechanism of the two power settings was evaluated using the data recording program and histological examination on macro- and microscopic levels in the ex vivo experiments using porcine tissues. RESULTS: F1-10 method showed a significantly better hemostatic ability for vessels ≥ 2 mm in diameter and a trend of overall better coagulation effect, evaluated by the bleeding rate after cutting the vessels. F1-10 method could sustain electrical current longer and effectively coagulate the tissue wider and deeper than the S method in the porcine model. CONCLUSION: F1-10 method is suggested to achieve a stronger hemostatic effect than the S method in clinical procedures and ex vivo models.

Role of Src Family Kinases in Regulation of Intestinal Epithelial Homeostasis.

Proper regulation of epithelial cell turnover is important for the structural integrity and homeostasis of various tissues, including the intestine. Here we show that ablation of Csk, a negative regulator of Src family kinases (SFKs), specifically in intestinal epithelial cells (IECs) resulted in the development of hyperplasia throughout the intestinal epithelium of mice. Such conditional ablation of Csk also increased the proliferative activity and turnover of IECs, disturbed the differentiation of Paneth and goblet cells, reduced the number of intestinal stem cells, and attenuated the expression of Wnt target genes in the intestine. Moreover, the tyrosine phosphorylation of focal adhesion kinase (FAK) and the activities of both Rac and Yes-associated protein (YAP) were increased in intestinal crypts or organoids of the mutant mice, whereas inhibition of Rac or YAP activity rescued the mutant phenotypes. Our results thus suggest that SFKs promote the proliferation of IECs in intestinal crypts through activation of Rac or YAP and that they thereby contribute to the proper regulation of IEC turnover and intestinal homeostasis.

Promotion of Intestinal Epithelial Cell Turnover by Commensal Bacteria: Role of Short-Chain Fatty Acids.

The life span of intestinal epithelial cells (IECs) is short (3-5 days), and its regulation is thought to be important for homeostasis of the intestinal epithelium. We have now investigated the role of commensal bacteria in regulation of IEC turnover in the small intestine. The proliferative activity of IECs in intestinal crypts as well as the migration of these cells along the crypt-villus axis were markedly attenuated both in germ-free mice and in specific pathogen-free (SPF) mice treated with a mixture of antibiotics, with antibiotics selective for Gram-positive bacteria being most effective in this regard. Oral administration of chloroform-treated feces of SPF mice to germ-free mice resulted in a marked increase in IEC turnover, suggesting that spore-forming Gram-positive bacteria contribute to this effect. Oral administration of short-chain fatty acids (SCFAs) as bacterial fermentation products also restored the turnover of IECs in antibiotic-treated SPF mice as well as promoted the development of intestinal organoids in vitro. Antibiotic treatment reduced the phosphorylation levels of ERK, ribosomal protein S6, and STAT3 in IECs of SPF mice. Our results thus suggest that Gram-positive commensal bacteria are a major determinant of IEC turnover, and that their stimulatory effect is mediated by SCFAs.

Protein tyrosine phosphatase SAP-1 protects against colitis through regulation of CEACAM20 in the intestinal epithelium.

Intestinal epithelial cells contribute to regulation of intestinal immunity in mammals, but the detailed molecular mechanisms of such regulation have remained largely unknown. Stomach-cancer-associated protein tyrosine phosphatase 1 (SAP-1, also known as PTPRH) is a receptor-type protein tyrosine phosphatase that is localized specifically at microvilli of the brush border in gastrointestinal epithelial cells. Here we show that SAP-1 ablation in interleukin (IL)-10-deficient mice, a model of inflammatory bowel disease, resulted in a marked increase in the severity of colitis in association with up-regulation of mRNAs for various cytokines and chemokines in the colon. Tyrosine phosphorylation of carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 20, an intestinal microvillus-specific transmembrane protein of the Ig superfamily, was greatly increased in the intestinal epithelium of the SAP-1-deficient animals, suggesting that this protein is a substrate for SAP-1. Tyrosine phosphorylation of CEACAM20 by the protein tyrosine kinase c-Src and the consequent association of CEACAM20 with spleen tyrosine kinase (Syk) promoted the production of IL-8 in cultured cells through the activation of nuclear factor-κB (NF-κB). In addition, SAP-1 and CEACAM20 were found to form a complex through interaction of their ectodomains. SAP-1 and CEACAM20 thus constitute a regulatory system through which the intestinal epithelium contributes to intestinal immunity.

Regulation by gut commensal bacteria of carcinoembryonic antigen-related cell adhesion molecule expression in the intestinal epithelium.

Carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 1 and CEACAM20, immunoglobulin superfamily members, are predominantly expressed in intestinal epithelial cells (IECs) and co-localized at the apical surface of these cells. We here showed that the expression of mouse CEACAM1 and CEACAM20 at both mRNA and protein levels was markedly reduced in IECs of the small intestine by the treatment of mice with antibiotics against Gram-positive bacteria. The expression of both proteins was also decreased in IECs of the small intestine from germ-free mice, compared with that from control specific-pathogen-free mice. Exposure of intestinal organoids to IFN-γ markedly increased the expression of either CEACAM1 or CEACAM20, whereas the exposure to TNF-α increased the expression of the former protein, but not that of the latter. In contrast, the expression of CEACAM20, but not of CEACAM1, in intestinal organoids was markedly increased by exposure to butyrate, a short-chain fatty acid produced by bacterial fermentation in the intestine. Collectively, our results suggest that Gram-positive bacteria promote the mRNA expression of CEACAM1 or CEACAM20 in the small intestine. Inflammatory cytokines or butyrate likely participates in such effects of commensal bacteria.

Tyrosine Phosphorylation of Carcinoembryonic Antigen-related Cell Adhesion Molecule 20 and Its Functional Role.

Carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 20 is an immunoglobulin-superfamily transmembrane protein that contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic region. However, the mechanism for tyrosine phosphorylation of, or the physiological function of, this protein remains largely unknown. Here we have shown that CEACAM20 is indeed tyrosine-phosphorylated by either treatment with pervanadate or forced expression of c-Src. In addition, Tyr522, Tyr559 or Tyr570, the latter two of which are within the ITAM, is likely important for such tyrosine phosphorylation. Forced expression of Myc-tagged wild-type CEACAM20 promoted the phagocytic activity of cultured cells for microbeads coupled with anti-Myc antibodies. By contrast, such phagocytic activity was markedly reduced when a mutant form of CEACAM20, in which Tyr559 and Tyr570 were substituted with phenylalanine, was expressed. Furthermore, the CEACAM20-mediated phagocytic activity was markedly prevented by the treatment with an inhibitor for either Src family kinases (SFKs), Syk, phosphoinositide 3-kinase (PI3K) or phospholipase C-γ (PLCγ). Inhibition of actin polymerization by Cytochalasin D significantly inhibited the CEACAM20-mediated phagocytosis. These results thus suggest that tyrosine phosphorylation of CEACAM20 likely promotes phagocytic activity of the cells. The CEACAM20-mediated phagocytic activity requires the activation of SFKs, Syk, PI3K or PLCγ.