Clinical Outcomes of Follow-Up Observation After Endoscopic Submucosal Dissection for Esophageal Squamous Cell Carcinoma Invading the Muscularis Mucosa Without Lymphovascular Involvement.

BACKGROUND: The therapeutic approach after endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma (ESCC) diagnosed as pathological T1a-muscularis mucosa (pT1a-MM) without lymphovascular involvement (LVI) remains uncertain. We aimed to determine whether observation after ESD is acceptable for patients without LVI showing pT1a-MM cancer. METHODS: We retrospectively registered 566 ESCC patients who were treated with ESD at ten institutions between January 2007 and December 2015. Of those, 447 cases showing pT1a-epithelium/lamina propria mucosa (EP/LPM) without LVI and vertical margin (VM) (EP/LPM group), and 41 cases showing pT1a-MM without LVI and VM (MM group) were analyzed in this investigation. The clinical outcomes were assessed between the groups. RESULTS: The 5 year cumulative incidence of metastatic recurrence was 0.5% and 3.3% in the EP/LPM and MM groups, respectively (P = 0.121). Two cases showing pT1a-EP/LPM and one showing pT1a-MM experienced lymph node recurrence. The 5 year cumulative incidence of local recurrence was 1.5% and 3.8% in the EP/LPM and MM groups, respectively (P = 0.455). The 5 year disease-specific survival (DSS) rate was 99.3% and 96.6% in the EP/LPM and MM groups, respectively (P = 0.118), whereas the 5 year overall survival rate was significantly higher in the EP/LPM group than in the MM group (92.6% versus 81.1%, respectively; P = 0.021). CONCLUSIONS: As regards metastatic recurrence and DSS, ESCC patients with pT1a-MM without LVI showed favorable outcomes that were equivalent to those with pT1a-EP/LPM, even when they were not treated with additional therapy after ESD.

Risk and prognostic factors of invasive gastric cancer detection during surveillance endoscopy: Multi-institutional cross-sectional study.

OBJECTIVES: Esophagogastroduodenoscopy (EGD) is important for the detection of curable gastric cancer (GC). However, there are no appropriate surveillance data during routine endoscopic inspections. This study aimed to clarify the risk factors of pT1b or deeper GC detection during surveillance endoscopy. METHODS: This was a retrospective, multicenter, cross-sectional study conducted in 15 Japanese hospitals. We retrospectively analyzed patients with GC who had previously undergone surveillance endoscopy at each institution from January 2014 to March 2020. Patients who had undergone gastrectomy, non-infection of Helicobacter pylori (Hp), and those with intervals <3 months or >10 years from a previous endoscopy were excluded. RESULTS: In total, 1085 patients with GCs detected during surveillance endoscopy were enrolled. The multivariate logistic analysis revealed that current Hp infection (odds ratio [OR] 2.18; 95% confidence interval [CI] 1.50-3.16) and a surveillance interval of >1.5 years (OR 1.96; 95% CI 1.35-2.84) were independent risk factors for pT1b or deeper GC. The 5-year disease-specific survival (5y-DSS) rate of GC was significantly lower in patients with surveillance interval of >1.5 years than in those with surveillance interval of ≤1.5 years (93.7% vs. 98.3%, P < 0.001). Similarly, the 5y-DSS rate of GC was significantly lower in patients with active Hp infection than in those without (93.7% vs. 99.4%, P < 0.001). CONCLUSION: In this study, a surveillance interval of >1.5 years and current Hp infection were independent risk factors for detecting pT1b or deeper GC. Additionally, these factors were poor prognostic factors of the detected GC during surveillance endoscopy.

Endoscopic Submucosal Dissection for Early Gastric Cancer in Patients Aged 85 Years Old or Older Is Associated with a Good Prognosis Compared to Conservative Treatment without Any Invasive Procedure.

INTRODUCTION: Studies have reported the feasibility of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) in elderly people with respect to both short- and long-term outcomes. As the elderly population in society increases, the requirement for managing super-elderly patients aged ≥85 years with EGC will also increase. This study aims to identify the long-term clinical outcomes of ESD for clinical T1N0 EGC in patients aged ≥85 years. METHODS: A total of 370 consecutive patients aged ≥85 years with clinical T1N0 EGC who were managed in 11 institutions were reviewed retrospectively. On the basis of treatment strategy, we compared the overall survival (OS) and disease-specific survival (DSS) after performing propensity score-matched analysis between patients undergoing ESD (ESD group) and those not undergoing treatment (conservative treatment group). The potential prognostic factors were also investigated in the propensity score-matched patients. RESULTS: After propensity score matching, we found that the 3-year OS and DSS rates were significantly higher in the ESD group than in the conservative treatment group (OS, 82.2% vs. 50.5%; p < 0.001; DSS, 100% vs. 80.1%; p = 0.008). Furthermore, ESD was identified as a significant factor for prolonged OS, whereas Charlson comorbidity index (CCI) ≥3 and prognostic nutritional index (PNI) <36.2 were associated with reduced OS. CONCLUSION: ESD was associated with improved OS in patients with clinical T1N0 EGC aged ≥85 years compared with the absence of treatment. Furthermore, CCI and PNI were helpful for patient selection.

Subepithelial Serotonin Reduces Small Intestinal Epithelial Cell Tightness via Reduction of Occluding Expression.

BACKGROUND: The precise pathogenesis of irritable bowel syndrome (IBS) remains unresolved; however, recent studies have reported that patients with diarrhea-predominant IBS exhibit an increased small intestinal permeability and increased number of enterochromaffin cells containing high 5-hydroxytryptamine (5HT; serotonin) levels. In this study, we investigated whether 5HT has the potential to modulate small intestinal epithelial cell permeability, focusing on tight junction-associated proteins. METHODS: The differentiated Caco-2 cell monolayer on porous filters (Millicell) was used. Then, 5HT was added to the lower Millicell compartment for 7 days. Intestinal epithelial cell permeability was assessed by measuring the flux of paracellular permeability markers. We further assessed the expression of occludin in the 5HT-stimulated Caco-2 monolayer. RESULTS: We found that 5HT did not affect the viability of Caco-2 cells at concentrations up to 100 µM during the experimental period. Administration of 5HT to the basal side of Caco-2 cells increased the flux of 3H-labeled mannitol (182 Da) but did not increase that of FITC-dextran (4000 Da). Among the tight junction proteins, the expression of occludin was specifically decreased by stimulation with 5HT at a concentration of 100 µM. CONCLUSION: In conclusion, excessive 5HT in the basal side increased the permeability of intestinal epithelial cells via reduction of occludin expression.

Prognostic risk factors associated with esophageal squamous cell carcinoma patients undergoing endoscopic submucosal dissection: a multi-center cohort study.

BACKGROUND: Long-term outcomes of endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma (ESCC) have not been assessed in a large, multicenter cohort. We aimed to evaluate long-term outcomes of ESD for ESCC in a real-world setting. METHODS: We retrospectively recruited 659 patients who underwent ESD for ESCC at ten institutions from January 2007 to December 2015. Of these, 566 patients were analyzed and classified into three groups according to the pathologic invasion depth after ESD: epithelium/lamina propria mucosa (EP/LPM group: 454 patients), muscularis mucosa/submucosa invasion ≤ 200 µm below the inferior margin of the muscularis mucosa (MM/SM1 group: 81 patients), and submucosa invasion > 200 µm below the MM inferior margin (SM2 group: 31 patients). RESULTS: The 5-year overall survival rates in the EP/LPM, MM/SM1, and SM2 groups were 92.6%, 80.0%, and 62.7%, respectively, while the 5-year disease-specific survival rates were 99.7%, 96.9%, and 88.3%, respectively. Multivariate analyses revealed that the invasion depth, Charlson Comorbidity Index (CCI), and prognostic nutritional index (PNI) were independent prognostic factors. Hazard ratios in the MM/SM1 and SM2 groups were 2.25 (95% confidence interval [CI] 1.04-4.83; P = 0.038) and 3.18 (95% CI 1.08-9.34; P = 0.036), respectively, compared to those in the EP/LPM group, while those for patients with a CCI ≥ 3 and PNI ≤ 47.75 were 3.25 (95% CI 1.79-5.89; P < 0.001) and 2.42 (95% CI 1.26-4.65; P = 0.008), respectively. CONCLUSIONS: This study identified that invasion depth, presence of comorbid diseases and preoperative nutritional status are independent prognostic risk factors associated with ESCC patients undergoing ESD.

Complete one-to-one correspondence between magnifying endoscopic and histopathologic images: the KOTO method II.

Recent advances in magnifying endoscopy with narrow-band imaging/blue laser imaging have aided in the diagnosis of gastrointestinal lesions. However, it requires knowledge of the relationship between magnifying endoscopic and histopathological images. We propose a novel method which makes possible a complete correspondence between magnifying endoscopic and histopathological images at the single glandular duct level. The KOTO method II enables three-dimensional visualization of the correlation between the endoscopic surface pattern of the mucosa and histopathological images. This method may be helpful in the development of diagnosis using magnifying endoscopy.

Clinical Outcomes of Vonoprazan-Treated Patients after Endoscopic Submucosal Dissection for Gastric Neoplasms: A Prospective Multicenter Observation Study.

BACKGROUND: Vonoprazan (VPZ) has the potential to prevent delayed bleeding and promote ulcer healing after endoscopic submucosal dissection (ESD) similar to proton pump inhibitors (PPIs). OBJECTIVE: We aimed to evaluate the outcomes of VPZ-treated patients after ESD and compared the efficacy and feasibility in preventing a delayed bleeding and in healing an artificial ulcer after ESD between the VPZ and PPI therapies. METHODS: This was a prospective, observation study in 11 Japanese medical institutions. We enrolled and evaluated 223 patients who underwent gastric ESD followed by VPZ treatment (VPZ group). We selected 385 patients who underwent gastric ESD followed by PPI treatment as historical controls (PPI group) to compare the outcomes between the VPZ and PPI groups using a propensity score matching analysis. RESULTS: Among the 223 patients treated with VPZ, 173 were men and 50 were women with a median age of 72 years and with a median tumor size of 12.0 mm. Rates of en bloc resection and complete resection were 99.1 and 94.2%, respectively. Lymphovascular invasion was found in 6 (6.3%) cases. Intraoperative perforation and delayed bleeding occurred in 3 (1.3%) and 10 patients (4.5%), respectively. Scarring of artificial post-ESD ulcer was found in 153 patients (68.6%) at 6 weeks after ESD. The 205 pairs of propensity score-matched patients were comparable between the VPZ and PPI groups. The rate of delayed bleeding in the VPZ and PPI groups was 3.9 and 4.4%, respectively (difference, 0.5 percentage points; 95% confidence interval, -3.7 to 2.8%; non-inferiority, p = 0.01). Therefore, VPZ therapy demonstrated non-inferiority against PPI therapy in reducing the rate of delayed bleeding. The scar-stage ulcer at 6 weeks in the VPZ group and 8 weeks in the PPI group was 68.3 and 74.6%, respectively (p = 0.19). CONCLUSIONS: VPZ therapy showed an efficacy and feasibility in preventing a delayed bleeding after ESD similar to the PPI therapy. VPZ for 6 weeks and PPI for 8 weeks were similarly effective for an artificial ulcer healing after ESD.

Efficacy and Feasibility of Magnifying Blue Laser Imaging without Biopsy Confirmation for the Diagnosis of the Demarcation of Gastric Tumors: A Randomized Controlled Study.

BACKGROUND: Accurate diagnosis of the demarcation line (DL) of gastric tumors is essential for curative complete resection by endoscopic submucosal dissection (ESD). It is controversial to perform only magnifying endoscopy for diagnosing the DL of gastric tumors prior to ESD. This study aimed to evaluate the diagnostic accuracy for the DL of gastric adenomas and well-differentiated adenocarcinomas using only magnifying blue laser imaging (M-BLI) compared with that using both M-BLI and biopsy confirmation. METHODS: In this prospective, single-center study, 96 well-differentiated adenocarcinomas and 32 gastric adenomas were enrolled between July 2015 and December 2016. A total of 122 lesions with a clear DL on M-BLI were randomly allocated to undergo M-BLI only (the M-BLI group) or M-BLI with biopsy confirmation (the M-BLI-BC group), performed as biopsies in 4 directions from noncancerous tissues ≈ 5 mm outside the lesion before ESD. The primary end point was to clarify the noninferiority of M-BLI without biopsy confirmation compared with that with biopsy confirmation, in terms of the diagnostic accuracy and complete resection. RESULTS: There were no significant differences in sex, median age, color, circumference, macroscopic type, biopsy-based diagnosis, and Helicobacter pylori infection between the 2 groups. The diagnostic accuracy for the DL was 100 and 95.0% and the complete resection was 100 and 100% in the M-BLI and M-BLI-BC groups, respectively. CONCLUSION: The diagnostic ability of M-BLI is excellent in diagnosing the demarcation of gastric adenoma and well-differentiated adenocarcinoma. Biopsy confirmation is not needed for these lesions with a clear DL by M-BLI.

Effectiveness of including probiotics to Helicobacter pylori eradication therapies.

The eradication rate of Helicobacter pylori (H. pylori) with proton pump inhibitors, amoxicillin, and clarithromycin has reportedly decreased. Some studies have found probiotics to be useful in eradicating H. pylori, but these effects have not been sufficiently investigated. We aimed to elucidate the role of probiotics in eradicating H. pylori infection. Patients in our hospital with H. pylori infection that received standard treatment from January 2015 to December 2016 were retrospectively evaluated (n = 468). They were divided into three groups based on their treatment regime, being either proton pump inhibitors, amoxicillin, or clarithromycin (PPI group), vonoprazan, amoxicillin, or clarithromycin (VPZ group), and proton pump inhibitors, amoxicillin, or clarithromycin/probiotics (Miya-BM®) (PPI + MBM group). We retrospectively evaluated the H. pylori eradication rate and reported side effects. According to intention-to-treat analyses, the eradication rate of H. pylori was significantly higher in the PPI + MBM group (87.1%) than in the PPI group (70.1%). There was no difference in side effects between any of the three groups. In conclusion, Miya-BM® may have an additive effect when included with eradication therapies for H. pylori.

Can image-enhanced endoscopy improve the diagnosis of Kyoto classification of gastritis in the clinical setting?

Endoscopic diagnosis of Helicobacter pylori (H. pylori) infection, the most common cause of gastric cancer, is very important to clarify high-risk patients of gastric cancer for reducing morbidity and mortality of gastric cancer. Recently, the Kyoto classification of gastritis was developed based on the endoscopic characteristics of H. pylori infection-associated gastritis for clarifying H. pylori infection status and evaluating risk factors of gastric cancer. Recently, magnifying endoscopy with narrow-band imaging (NBI) has reported benefits of the accuracy and reproducibility of endoscopic diagnosis for H. pylori-related premalignant lesions. In addition to NBI, various types of image-enhanced endoscopies (IEEs) are available including autofluorescence imaging, blue laser imaging, and linked color imaging. This review focuses on understanding the clinical applications and the corresponding evidences shown to improve the diagnosis of gastritis based on Kyoto classification using currently available advanced technologies of IEEs.

Efficacy and safety of endoscopic submucosal dissection using a scissors-type knife with prophylactic over-the-scope clip closure for superficial non-ampullary duodenal epithelial tumors.

BACKGROUND AND STUDY AIM: This study aimed to assess the safety and feasibility of endoscopic submucosal dissection (ESD) using a scissors-type knife with prophylactic closure using over-the-scope clip (OTSC) for superficial non-ampullary duodenal epithelial tumors (SNADETs). PATIENTS AND METHODS: Consecutive patients who underwent ESD for SNADETs >10 mm between January 2009 and July 2019 were retrospectively enrolled. We performed ESD using either a needle-type knife (Flush Knife-ESD) or a scissors-type knife (Clutch Cutter-ESD). Mucosal defects were prophylactically closed using three methods: conventional clip, laparoscopic closure, or OTSC. RESULTS: A total of 84 lesions were resected using the Flush Knife-ESD and the Clutch Cutter-ESD (37 and 47 patients, respectively), and conventional clip, laparoscopic closure, and OTSC for mucosal defect closure after ESD were applied in 13, 13, and 56 lesions, respectively. The R0 resection rate was significantly higher in the Clutch Cutter-ESD than that in the Flush Knife-ESD (97.9% vs 83.8%, respectively, P = 0.040). The intraoperative perforation rate was significantly lower in the Clutch Cutter-ESD than in the Flush Knife-ESD (0% vs 13.5%, respectively, P = 0.014). Complete closure rates of conventional clip, laparoscopic closure, and OTSC were 76.9%, 92.3%, and 98.2%, respectively (P = 0.021); and delayed perforation rates were 15.4%, 7.7%, and 1.8%, respectively (P = 0.092). CONCLUSIONS: Endoscopic submucosal dissection using a scissors-type knife with prophylactic OTSC closure is safe and feasible for the low-invasive treatment of SNADETs.

High-Fat Diet Causes Constipation in Mice via Decreasing Colonic Mucus.

BACKGROUND: Constipation is one of the most common gastrointestinal complaints. Although the causes of constipation are varied, dietary habits have a significant influence. Excessive fat intake is suggested as one of the main causes of constipation; however, the exact mechanism is unknown. AIMS: To investigate whether a high-fat diet (HFD) causes constipation in mice and to clarify the underlying mechanism, focusing on the amount of colonic mucus. METHODS: Six-week-old male C57BL/6 mice were randomly divided into two groups: mice fed with HFD and those with normal chow diet (NCD). Fecal weight, water content, total gastrointestinal transit time, and colon transit time were measured to determine whether the mice were constipated. The colonic mucus was evaluated by immunostaining and quantified by spectrometry. Malondialdehyde (MDA) was measured using the thiobarbituric acid (TBA) test as a marker for oxidative stress. RESULTS: Compared to the NCD group, the weight of feces was less in the HFD group. In the functional experiment, the total gastrointestinal transit time and colon transit time were longer in the HFD group. Furthermore, HFD significantly reduced the amount of colonic mucus. In addition, the reduction in colonic mucus caused by surfactant resulted in constipation in the NCD group. CONCLUSIONS: HFD causes constipation with delayed colon transit time possibly via the reduction in colonic mucus in mice.

Linked color imaging identifies important risk factors associated with gastric cancer after successful eradication of Helicobacter pylori.

BACKGROUND AND AIMS: Limited studies have evaluated the risk factors of gastric cancer (GC) after eradication of Helicobacter pylori (H pylori) using endoscopic findings. We aimed to investigate GC detection-related endoscopic findings after eradication of H pylori using linked color imaging (LCI), a novel image-enhanced endoscopy. METHODS: This single-center, cross-sectional study evaluated background mucosa-associated endoscopic findings described in the Kyoto classification of gastritis in patients with newly detected GC after eradication of H pylori (CA group, n = 109) and those without GC (NC group, n = 85) using white-light imaging (WLI) and LCI. RESULTS: Severe atrophy and map-like redness were significantly more frequent in the CA group than in the NC group using WLI (79.8% vs 63.5%, P = .01; 61.5% vs 37.7%, P = .001, respectively) and LCI (79.8% vs 63.5%, P = .01; 78.0% vs 45.9%, P < .0001, respectively). Regular arrangement of collecting venules (RAC) was significantly less frequent in the CA group than in the NC group using WLI (40.3% vs 64.7%, P = .0009) and LCI (37.6% vs 62.4%, P = .0006). Map-like redness was an independent positive risk factor (WLI: odds ratio [OR], 2.05; 95% confidence interval [CI], 1.09-3.87; P = .03; LCI: OR, 3.62; 95% CI, 1.88-6.97; P < .001), whereas RAC was an independent negative risk factor (WLI: OR, 0.42; 95% CI, 0.21-0.82; P = .01; LCI: OR, 0.46; 95% CI, 0.23-0.93, P = .03) for detection of GC after eradication of H pylori. CONCLUSIONS: Map-like redness, which was identified more frequently using LCI than WLI, and the absence of RAC were associated with detection of GC after eradication of H pylori.

Clinical and Pathological Challenges in the Diagnosis of Gastric-Type Differentiated Adenocarcinoma in the Stomach: A Study of Endoscopic Submucosal Dissection Cases.

BACKGROUND/AIMS: Gastric-type differentiated adenocarcinoma (GDA) of the stomach is a rare variant of gastric cancer that is highly infiltrating and exhibits early metastasis. However, the endoscopic and pathological features of "early-stage" GDA remain unknown. The aim of this study is to characterize early-stage GDA. METHODS: We retrospectively enrolled 479 differentiated-type early gastric cancer cases who underwent endoscopic submucosal dissection (ESD). GDA cases were selected based on morphology and immunohistochemistry. Clinicopathological data were compared between gastric- and intestinal-type differentiated adenocarcinomas (IDAs). RESULTS: Thirteen lesions were classified as GDAs. GDAs as well as IDAs showed irregular microvascular and microsurface patterns with clear demarcation line on magnifying endoscopy with narrow band imaging (M-NBI). The rate of pathological misdiagnosis of GDAs in biopsy specimens was higher than that of IDAs (p = 0.016). GDA was significantly associated with positive lymphovascular invasion (p = 0.016). There was one intramucosal lesion with lymphatic invasion in GDA. CONCLUSIONS: Although M-NBI is useful to detect GDA, the pathological diagnosis of GDAs in biopsy specimens often remains challenging. When suspicious lesions are not diagnosed as GDA, they should be followed up intensively, or diagnostic ESD has to be performed. ESD specimens should be carefully evaluated because of a higher incidence of lymphovascular invasion.

Efficacy of Magnifying Narrow Band Imaging for Delineating Horizontal Margins of Early Gastric Cancer.

BACKGROUND/AIMS: The aim of this study was to evaluate the diagnostic accuracy of magnifying narrow-band imaging (M-NBI) with histopathological confirmation in identifying the demarcation line (DL) of early gastric cancer (EGC). METHODS: EGCs resected by endoscopic submucosal dissection after identifying the DL using M-NBI following histopathological confirmation were included. After determining the DL for the entire EGC lesion using M-NBI, at least 4 biopsies were taken from non-cancerous tissues outside the EGC lesion for histopathological confirmation. RESULTS: A total of 330 EGCs were analyzed in this study. The rate of biopsy-negative and negative horizontal margin were 96.7% (319/330) and 97.9% (323/330) in EGC respectively. Tumors larger than 20 mm showed a higher risk for showing remnant cancer cells on biopsies taken outside the DL. Risk factors for a positive horizontal resection margin were tumor size > 20 mm and moderately or poorly differentiated adenocarcinomas. CONCLUSION: The assessment of demarcation of EGC using M-NBI was excellent in well-differentiated (WD) adenocarcinoma and lesions below 20 mm in size. However, histopathological confirmation is needed to assess the demarcation of non-WD adenocarcinomas and EGC over 20 mm in size.

Transforming growth factor ß1-induced collagen production in myofibroblasts is mediated by reactive oxygen species derived from NADPH oxidase 4.

Intestinal fibrosis with stricture formation is a severe complication of Crohn's disease (CD). Though new therapeutic targets to enable the prevention or treatment of intestinal fibrosis are needed, markers of this condition and the basic mechanisms responsible have not been established. NADPH oxidase (NOX) 4 has already been reported to play a key role in models of fibrogenesis, including that of the lung. However, its importance in intestinal fibrogenesis remains unclear. In this study, we examined the role of NOX4 in collagen production by intestinal myofibroblasts stimulated with transforming growth factor (TGF)-ß1. Using LmcMF cells, an intestinal subepithelial myofibroblast (ISEMF) line, we first examined the induction of collagen production by TGF-ß1. Subsequently, we investigated the role of NOX4 in TGF-ß1-induced collagen I production in these cells using SB525334 (an SMAD2/3 inhibitor), diphenyleneiodonium (an NOX inhibitor), and Nox4 small interfering RNA (siRNA). Production of collagen was assessed with Sirius red staining, and Nox4 expression was measured by quantitative real-time PCR. Reactive oxygen species (ROS) production was determined using DCFDA and fluorescent microscopy. We observed that TGF-ß1 induced collagen production via NOX4 activation and ROS generation in LmcMF cells. Nox4 siRNA and inhibitors of TGF-ß1 receptor and NOX significantly reduced TGF-ß1-induced ROS and collagen production. Thus, in the present study, we revealed that collagen production in ISEMFs is induced via an NOX4-dependent pathway. This work supports a function for NOX4 in intestinal fibrogenesis and identifies it as a potential therapeutic target in recalcitrant fibrotic disorders of CD patients.