Risk stratification of synchronous gastric cancers including alcohol-related genetic polymorphisms.

BACKGROUND AND AIM: We previously identified that ever-smoking and severe gastric atrophy in pepsinogen are risk factors for synchronous gastric cancers (SGCs). This study aimed to determine the association of alcohol drinking status or alcohol-related genetic polymorphism with SGCs and also stratify their risk. METHODS: This multi-center prospective cohort study included patients who underwent endoscopic submucosal dissection for the initial early gastric cancers at 22 institutions in Japan. We evaluated the association of alcohol drinking status or alcohol dehydrogenase 1B (ADH1B) and acetaldehyde dehydrogenase 2 (ALDH2) genotypes with SGCs. We then stratified the risk of SGCs by combining prespecified two factors and risk factors identified in this study. RESULTS: Among 802 patients, 130 had SGCs. Both the ADH1B Arg and ALDH2 Lys alleles demonstrated a significant association with SGCs on multivariate analysis (odds ratio, 1.77), although alcohol drinking status showed no association. The rates of SGCs in 0-3 risk factors in the combined evaluation of three risk factors (ever-smoking, severe gastric atrophy in pepsinogen, and both the ADH1B Arg and ALDH2 Lys alleles) were 7.6%, 15.0%, 22.0%, and 32.1%, respectively. The risk significantly increased from 0 to 3 risk factors on multivariate analysis (P for trend <0.001). CONCLUSIONS: Both the ADH1B Arg and ALDH2 Lys alleles were at high risk for SGCs. The risk stratification by these three factors may be a less invasive and promising tool for predicting their risk.

Smoking history and severe atrophic gastritis assessed by pepsinogen are risk factors for the prevalence of synchronous gastric cancers in patients with gastric endoscopic submucosal dissection: a multicenter prospective cohort study.

BACKGROUND: No studies have evaluated the relationship between lifestyle and synchronous gastric cancers (SGCs) in patients with endoscopic submucosal dissection (ESD) for early gastric cancers (EGCs). Using data from the Tohoku gastrointestinal (GI) study, we aimed to identify factors associated with SGCs. METHODS: Tohoku GI study is a multicenter prospective cohort study investigating the relationship between lifestyle and metachronous gastric cancers. Patients who had a schedule to undergo ESD for primary EGCs were enrolled. We used logistic regression analysis to examine the relationship of 15 candidate factors, including lifestyle, with the prevalence of SGCs in this study. RESULTS: Of 850 patients between 2016 and 2019, 16.0% (136 patients) had SGCs. In multivariate analysis, smoking history (odds ratio [OR], 1.93; p = 0.048) and severe atrophic gastritis assessed by pepsinogen (OR, 1.92; p = 0.004) were risk factors for the prevalence of SGCs. Regarding smoking, current smoking (OR, 2.33; p = 0.021), but not former smoking (OR, 1.76; p = 0.098), was a significant risk factor for its prevalence. In the stratified analysis, severe atrophic gastritis assessed by pepsinogen was a risk factor in patients without Helicobacter pylori (H. pylori) eradication (OR, 2.10; p = 0.002), but not a risk factor in those with H. pylori eradication (OR, 0.75; p = 0.737). CONCLUSION: Smoking history was a risk factor for the prevalence of SGCs in patients with ESD for EGCs, and severe atrophic gastritis assessed by pepsinogen was also a risk factor when H. pylori was not eradicated.

The Impact of Duodenal Mucosal Vulnerability in the Development of Epigastric Pain Syndrome in Functional Dyspepsia.

An unidentified cause of functional dyspepsia (FD) is closely associated with medication resistance. Acid suppression is a traditional and preferential method for the treatment of FD, but the efficacy of this treatment varies between epigastric pain syndrome (EPS) and postprandial syndrome (PDS): it is efficient in the former but not much in the latter. Transepithelial electrical resistance (TEER), a surrogate of mucosal barrier function, was measured under pH 3 and pH 5 acidic conditions using duodenal biopsy specimens obtained from the patients with EPS and PDS and asymptomatic healthy controls. The infiltration of inflammatory cells to the duodenal mucosa was accessed by immunohistochemical analysis. The duodenal mucosal TEER in EPS patients was decreased by exposure to the acidic solution compared to that of the controls and the PDS patients. The decrease in TEER of the EPS patients was observed even under pH 5 weak acidic condition and was correlated to degree of the epigastric pain. Moreover, the duodenal mucosa of EPS patients presented an increase in mast cells and plasma cells that expressed Ig-E. Duodenal mucosal vulnerability to acid is likely to develop EPS.

Nitric oxide could promote development of Barrett's esophagus by S-nitrosylation-induced inhibition of Rho-ROCK signaling in esophageal fibroblasts.

Barrett's esophagus arises in the process of wound healing in distal esophageal epithelium damaged by gastroesophageal reflux disease. Differentiation of fibroblast into myofibroblasts, a smooth muscle cell-like phenotype and tissue contraction are crucial processes in wound healing. No study has evaluated mechanism by which luminal esophageal nitric oxide (NO) affect Rho-associated coiled coil-forming protein kinase (Rho-ROCK) signaling pathway, a key factor of tissue contraction, in stromal fibroblasts to develop Barrett's esophagus. Using esophageal fibroblasts, we performed collagen-based cell contraction assays and evaluated influence of Rho-ROCK signaling in the exposure to acidic bile salts and NOC-9, which is an NO donor. We found that enhanced cell contraction induced by acidic bile salts was inhibited by NO, accompanied by decrease in phosphorylated myosin light chain expression and stress fiber formation. NO directly S-nitrosylated GTP-RhoA and consequently blocked Rho-ROCK signaling. Moreover, exposure to NO and Y27632, a Rho-ROCK signaling inhibitor, decreased α-SMA expression and increased bone morphogenetic protein-4 (BMP4) expression and secretion. These findings could account for the increased expression of BMP4 in the columnar epithelial cells and stromal fibroblasts in human Barrett's esophagus. NO could impair wound contraction by blocking the Rho-ROCK signaling pathway and promote the development of Barrett's esophagus.NEW & NOTEWORTHY Barrett's esophagus is the condition where esophageal epithelium damaged by gastroesophageal reflux disease (GERD) is abnormally healed via replacing of metaplastic columnar epithelium, but very few studies have conducted focusing wound healing in the development of Barrett's esophagus. Esophageal luminal nitric oxide inhibits Rho-ROCK signaling pathway in esophageal fibroblasts, which leads to delay tissue contraction, a pivotal step in proper wound healing. Moreover, this inhibition increases tissue BMP4 expression. Impaired wound healing could be related to Barrett's esophagus.

The Ameliorating Effect of Switching to Vonoprazan: A Novel Potassium-Competitive Acid Blocker in Patients with Proton Pump Inhibitor Refractory Non-Erosive Reflux Disease.

INTRODUCTION: Weakly acidic reflux has been reported to be the major cause of symptoms in patients with proton pump inhibitor (PPI)-refractory nonerosive reflux disease (NERD) undergoing PPI treatment. We previously reported that reflux at pH 4-5 was the main factor that induced symptoms in such patients. The present study aimed to elucidate the symptom-ameliorating effect of vonoprazan (VPZ) by evaluating the change in the pH value of the refluxate using multichannel intraluminal impedance and pH (MII-pH) monitoring. METHODS: We retrospectively evaluated the records of MII-pH monitoring in 29 symptom index (SI) and/or symptom association probability (SAP)-positive patients with PPI-refractory NERD. After switching to VPZ 20 mg/day, we performed MII-pH monitoring again. We assessed the change in the score of the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG), the pH value of the refluxate, and the percent times of intragastric pH <4 or <5 before and after switching. We divided the patients into the following 2 groups according to the FSSG score after switching: effective and noneffective groups. RESULTS: Among of the 29 SI/SAP-positive patients, 16 underwent switching to VPZ. Furthermore, of these 16 patients, 10 underwent MII-pH monitoring again after switching. The FSSG score decreased, the pH value of the refluxate increased, and the percent times of intragastric pH <4 or <5 reduced after switching when compared with the findings before switching. In the effective group, both the proportion of reflux at pH <4 and that of reflux at pH 4-5 decreased while taking VPZ when compared with the findings while taking double-dose PPI. In the noneffective group, the proportion of reflux at pH <4 decreased but that of reflux at pH 4-5 increased and that of reflux at pH <5 did not change overall while taking VPZ. In addition, the percent times of intragastric pH <5 values were low in the effective group. CONCLUSION: Symptom suppression appears to be inadequate in patients with persistent reflux at pH 4-5 even with VPZ 20 mg/day. Strong acid suppressive therapy with VPZ to increase the pH value of the refluxate to ≥5 is useful for symptom improvement.

Impaired Mucosal Integrity in Proximal Esophagus Is Involved in Development of Proton Pump Inhibitor-Refractory Nonerosive Reflux Disease.

BACKGROUND AND OBJECTIVE: Weakly acidic reflux reaching to the proximal esophagus is closely related to the perception of gastroesophageal reflux in patients with nonerosive reflux disease despite treatment with a proton pump inhibitor (PPI). However, little is known about the involvement of the patients' mucosal integrity of the proximal esophagus. METHODS: We recruited 15 symptomatic nonerosive gastroesophageal reflux disease (GERD) patients with a positive symptom index despite PPI treatment and 11 healthy asymptomatic volunteers as controls. The biopsy specimens obtained from the proximal and distal esophagus were applied to a mini-Ussing chamber system to measure transepithelial electrical resistance (TEER) against a pH 4 weak acid. The esophageal biopsy samples were subjected to quantitative real-time PCR and immunohistochemical analysis. RESULTS: In the proximal esophagus, the weak acid exposure reduced the TEER in the PPI-refractory patients compared to that in the controls. The frequency of the reflux extending to the proximal esophagus had a significant correlation with the reduction in the proximal esophageal TEER in the patients. The reduced TEER in the proximal esophagus was accompanied by an increase in IL-8 and IL-1ß mRNA and a decrease in occludin mRNA levels. The proximal esophageal mucosa in the patients presented infiltration of CD3-positive lymphocytes and an increased expression of solute carrier organic anion transporter family member 2A1 (SLCO2A1), a passage gate of reflux symptom-evoking molecules. CONCLUSIONS: The reflux perception is related to an impairment of the proximal esophageal mucosal integrity in patients with nonerosive reflux disease despite PPI.

Influence of the pH Value of Refluxate and Proximal Extent on Heartburn Perception in Patients with Proton Pump Inhibitor-Refractory Non-Erosive Reflux Disease.

BACKGROUND AND OBJECTIVES: Weakly acidic reflux has been reported as the major cause of symptom occurrence in patients with proton pump inhibitor (PPI)-refractory non-erosive reflux disease (NERD). This study is aimed at clarifying whether the pH value of weakly acidic reflux affects the induction of symptoms. METHODS: We retrospectively evaluated the records of combined multichannel intraluminal impedance and pH monitoring in 57 patients with PPI-refractory NERD. Weakly acidic refluxes were divided into 3 categories based on the pH value of the refluxate: pH 4-5, 5-6, and 6-7. RESULTS: A total of 29 patients were positive in the symptom index. The symptom provocation rate in reflux of pH 4-5 (19%) was much higher than in that of pH 5-6 (11%) and pH 6-7 (12%). In the reflux at pH 4-5, the symptom provocation rate in the proximal reflux was higher than that in the distal reflux (p < 0.05), whereas the reflux at pH 5-6 and pH 6-7 was not significantly different in the symptom provocation rate between the proximal and distal refluxes. CONCLUSION: Reflux at pH <5 reaching the proximal esophagus was the main factor in the induced symptoms of patients with PPI-refractory NERD.

Difficult Preoperative Diagnosis of Lymphoepithelioma-Like Carcinoma of the Esophagus.

A 60-year-old man with a medical history of diabetes, liver cirrhosis, and distal gastrectomy was referred for further examination of a 10-mm pale-colored submucosal tumor around 40 cm from the incisors. Narrow band imaging-magnifying endoscopy revealed the lesion covered by smooth epithelium with irregular microvascular architecture in a sparse distribution. Endosonography showed an irregular-shaped hypoechoic lesion in the submucosa. With no evidence of metastases, we performed en bloc endoscopic submucosal dissection, whose specimen revealed esophageal lymphoepithelioma-like carcinoma invading up to 500 µm in the submucosa, a rare disease entity. Despite no additional treatment, he was alive without recurrence for longer than 88 months.