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Objective: Epidemiological studies indicate that alcohol increases gastric cancer (GC) risk, yet most studies have focused on heavy alcohol intake, leaving other factors understudied. A comprehensive investigation of the effects of the frequency and amount of alcohol intake may help elucidate the GC risk associated with drinking behavior., Methods: The Health Examinees-Gem (HEXA-G) study, a community-based large-scale prospective cohort study, enrolled Korean adults 40-69 years of age between the years 2004 and 2013. Incident GC cases were identified through linkage to Korea Central Cancer Registry data until December 31, 2017. Self-reported questionnaires were used to survey alcohol consumption-related factors (duration, frequency, amount, and type of alcoholic beverages). The frequency and amount of alcohol consumption were combined to explore GC risk according to 4 drinking patterns: "infrequent-light", "frequent-light", "infrequent-heavy", and "frequent-heavy". We used Cox proportional hazard models to estimate the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs), and investigate the relationship between alcohol intake and GC incidence., Results: A total of 128,218 participants were included in the analysis. During an average follow-up period of 8.6 years, 462 men and 385 women were diagnosed with GC. In men, current drinkers showed a 31% greater risk of GC than non-drinkers (HR 1.31, 95% CI 1.03-1.66), whereas no significant association was observed in women. In men, GC risk was associated with a higher frequency ( P trend 0.02) and dose of ethanol intake in grams ( P trend 0.03). In men, the "frequent-light" (≥5 times/week and <40 g ethanol/day) drinking pattern was associated with a 46% greater risk of GC (HR 1.46, 95% CI 1.02-2.07) than the "infrequent-light" pattern (<5 times/week and <40 g ethanol/day)., Conclusions: This study suggests that frequent intake of alcohol, even in low quantities per session, increases GC risk. Further research is warranted to evaluate the relationship between alcohol and GC in detail., Competing Interests: No potential conflicts of interest are disclosed., (Copyright © 2022 Cancer Biology & Medicine.)

Background: Proton pump inhibitors (PPIs) are one of the most prescribed drugs in the world. Frequent use and long-term maintenance of these drugs drew the attention of researchers for sporadic adverse effects reports., Objective: The purpose of this narrative review is to discuss appropriate data and causality related to these adverse events and PPIs., Methods: A narrative review was conducted by systematizing information about safety and adverse events on PPIs from 2015 to 2020. A structured search on Pubmed was performed to identify systematic reviews and meta-analysis investigating the following situations: a) gastric cancer; b) micronutrients deficiency; c) acid rebound; d) infections; e) fractures; f) dementia; g) kidney disease; and h) sudden death and cardiovascular changes., Results: Recent studies have potentially associated PPIs with some adverse events as osteoporosis-related fractures. There are also reports of intestinal infections, including Clostridium difficile, besides poor vitamins absorption and minerals such as vitamin B12, magnesium, and iron. Furthermore, there are some dementia, pneumonia, kidney disease, myocardial infarction, and stroke reports. For kidney diseases, studies consistently suggest that the use of PPI may be associated with an increased risk of adverse kidney events, especially in the elderly, with long-term PPI use and pre-existing kidney disease. Another additional question is whether chronic PPI use would also lead to the onset of gastric cancer. The abrupt discontinuation of PPIs is also related to increased gastric acid production above pre-PPI treatment levels; this phenomenon is called acid rebound., Conclusion: The key to mitigate adverse effects is the rational use of PPIs at the lowest effective dose and in the shortest possible duration. Although these adverse effects have a potential clinical impact, their causal association is still subject to validation.

Context.—: Hypergastrinemia states such as achlorhydria from gastric mucosal atrophy or a gastrin-producing tumor in humans have been associated with the development of enterochromaffin-like (ECL) cell hyperplasia and gastric neuroendocrine tumors (GNETs). Whether drugs that can elevate serum gastrin levels, such as proton pump inhibitors (PPIs), can produce the same tissue effect is not known, and there is no concrete evidence linking the use of PPIs to GNETs outside animal models and case reports., Objective.—: To explore the clinicopathologic association for GNETs of presumed ECL cell origin that cannot be reliably placed into any of the 3 established categories currently recognized by the World Health Organization., Design.—: This is a retrospective clinicopathologic study of GNETs in the body/fundus during a period of 15 years (2005-2019)., Results.—: Of a total of 87 cases, 57 (65.5%) were associated with atrophic gastritis, 2 (2.3%) were associated with Zollinger-Ellison syndrome, and 28 (32.2%) were unclassified. Of the latter, 11 were consistent with true sporadic/type 3 GNETs, while 17 had background mucosal changes of parietal cell and ECL cell hyperplasia but without underlying detectable gastrinoma, and 88.2% (15 of 17) of patients from this group had documented long-term PPI use. This subtype of GNETs was more commonly multifocal and of higher grade (P = .03) than "true" sporadic GNETs., Conclusions.—: A subset of GNETs arises in the background of gastric mucosal changes suggestive of hypergastrinemia, but without underlying gastrinoma, and could be linked to long-term PPI use., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article.

Background: Postoperative pain increases patients' risk and opioids remain the main analgesics to relieve it. However, improper use of opioids causes many side effects and identification of suitable preoperative biomarkers that predict postoperative opioid consumption may aid clinicians in improving analgesic strategies for patients. The activity of metabolites modulates multiple phenotypes and can function as biomarkers for disease prediction and diagnosis., Objectives: In this study, we explore whether preoperative serum metabolites are associated with postoperative opioid consumption in gastric cancer patients by extreme phenotype sampling., Study Design: This was a case-control, observational study., Setting: This study was conducted at Beijing Cancer Hospital., Methods: One hundred and sixty-nine gastric cancer patients participated in this study. After exclusion of 51 patients, postoperative pain intensity and opioid consumption data of 118 patients were collected. Patients were sorted by gender and classified into 2 groups based on opioid consumption during the 24h postoperative period. Patients in the sufentanil high consumption (SHC) group and patients in the sufentanil low consumption (SLC) group were ranked in the top or bottom 30% of sufentanil consumption, respectively. Untargeted metabolomic analysis of preoperative serum samples from both groups was performed by ultra-performance liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) and orthogonal partial least square discriminant analysis. Allele frequencies of DAO rs10156191 and MAOB rs1799836 SNPs in both groups were detected by Sanger sequencing., Results: Thirty-five metabolites in preoperative serum were significantly different between the SLC and SHC groups. Hydrogen phosphate had the highest area under the curve in a ROC analysis (0.98), suggesting that it may serve as a predictive biomarker for postoperative opioid consumption. Differential metabolites unique to the male and female subgroups were also identified. Histidine metabolism was the most altered pathway between the SLC and SHC groups. There were no significant differences in the allele frequencies of 2 SNPs associated with histamine degradation; however, 2 metabolites of histamine degradation, imidazole-4-acetaldehyde, and methylimidazole acetaldehyde, showed different trends in the 2 groups., Limitations: Our study was restricted to gastric cancer patients with strict exclusion criteria, which may limit the generalizability to other groups., Conclusion: Preoperative serum metabolites were associated with postoperative opioid consumption. Different efficiencies of histamine degradation may be one cause of the variable sensitivity of patients to acute pain and warrants further study.

Objective: To determine whether new users of proton pump inhibitors (PPIs) are at an increased risk of gastric cancer compared with new users of histamine-2 receptor antagonists (H2RAs)., Design: Using the UK Clinical Practice Research Datalink, we conducted a population-based cohort study using a new-user active comparator design. From 1 January 1990 to 30 April 2018, we identified 973 281 new users of PPIs and 193 306 new users of H2RAs. Cox proportional hazards models were fit to estimate HRs and 95% CIs of gastric cancer, and the number needed to harm was estimated using the Kaplan-Meier method. The models were weighted using standardised mortality ratio weights using calendar time-specific propensity scores. Secondary analyses assessed duration and dose-response associations., Results: After a median follow-up of 5.0 years, the use of PPIs was associated with a 45% increased risk of gastric cancer compared with the use of H2RAs (HR 1.45, 95% CI 1.06 to 1.98). The number needed to harm was 2121 and 1191 for five and 10 years after treatment initiation, respectively. The HRs increased with cumulative duration, cumulative omeprazole equivalents and time since treatment initiation. The results were consistent across several sensitivity analyses., Conclusion: The findings of this large population-based cohort study indicate that the use of PPIs is associated with an increased risk of gastric cancer compared with the use of H2RAs, although the absolute risk remains low., Competing Interests: Competing interests: SS participated in advisory meetings or as a guest speaker for Atara Biotherapeutics, Boehringer-Ingelheim, Bristol-Myers-Squibb, Merck and Pfizer, all unrelated to this study. LA served as a consultant for Janssen and Pfizer for work unrelated to this study. The other authors have no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

This study evaluated the chemoprotective effect of scutellarin (SC) in vitro and in vivo against gastric carcinogenesis in rats and celllines and examined the underlying mechanism. Gastric cancer celllines (AGS) was used for the in vitro study and lactate dehydrogenase (LDH) profile, histone deacetylase (HDAC) assay, cell cycle & apoptosis ratio and antioxidant parameters were measured. N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was used to induce gastric carcinogenesis in rats and the rats received the different doses of SC (10, 20 and 30 mg/kg). The body weight and tumor incidence were measured at regular time intervals. The antioxidant and pro-inflammatory cytokines were estimated. The finding of data showed that the drug was effective against AGS cell line. Supplementation of scutellarin revealed an upregulation in body weight compared with the MNNG group rats. Moreover, it also reduced the incidence of tumor. It also altered the significant DNA density, LDH content, mucus content and acidity. Scutellarin treated rats showed improved activity in enzymatic and non-enzymatic antioxidant profile and reversed the content of cytokines compared with MNNG induced gastric cancer group rats. This research reveals the chemoprotective property of the scutellarin and highlights the promising role of drug by alteration of inflammatory pathway by minimizing its adverse effect.

An 82-year-old Japanese man underwent esophagogastroduodenoscopy for postprandial epigastric discomfort. The patient was diagnosed with hypozincemia with a serum zinc level of 63μg/dL (normal range:80-130μg/dL), and he had commenced oral intake of zinc acetate 1 month before the esophagogastroduodenoscopy. Endoscopy showed erosions with white-coated mucosa surface adhesions and erythema on the lesser curvature of the gastric body. Moderately differentiated tubular adenocarcinoma was suspected based on the biopsy examination findings;therefore, he was referred to our hospital for further examination and treatment. A repeat endoscopy showed two erosions with white-coated mucosa surface adhesion and erythema on the lesser curvature of the gastric body. However, the lesion location was different from that detected in the initial endoscopy. The biopsy showed no neoplastic changes. Therefore, based on the endoscopic findings and history of oral zinc acetate administration, we diagnosed the gastric mucosal injury as zinc acetate-associated gastric lesions. The cessation of zinc acetate intake resulted in the resolution of gastric lesions. Reassessment of the biopsy specimen from the initial endoscopy revealed erosions, epithelial cells showing infarct-like necrosis, degenerative atypical cells, and necrotic substances, which were misdiagnosed as neoplastic changes. This case highlights the importance of recognizing the typical endoscopic features of a zinc acetate-associated gastric lesion to enable its prompt diagnosis during esophagogastroduodenoscopy.

The association between alcohol intake and stomach cancer risk remains controversial. We undertook a pooled analysis of data from six large-scale Japanese cohort studies with 256 478 participants on this topic. Alcohol intake as ethanol was estimated using a validated questionnaire. The participants were followed for incidence of stomach cancer. We calculated study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for stomach cancer according to alcohol intake using a Cox regression model. Summary HRs were estimated by pooling the study-specific HRs using a random-effects model. During 4 265 551 person-years of follow-up, 8586 stomach cancer cases were identified. In men, the multivariate-adjusted HRs (95% CIs) of stomach cancer were 1.00 (0.87-1.15) for occasional drinkers, and 1.00 (0.91-1.11) for <23 g/d, 1.09 (1.01-1.18) for 23 to <46 g/d, 1.18 (1.09-1.29) for 46 to <69 g/d, 1.21 (1.05-1.39) for 69 to <92 g/d, and 1.29 (1.11-1.51) for ≥92 g/d ethanol in regular drinkers compared with nondrinkers. In women, the multivariate-adjusted HRs were 0.93 (0.80-1.08) for occasional drinkers, and 0.85 (0.74-0.99) for <23 g/d, and 1.22 (0.98-1.53) for ≥23 g/d in regular drinkers compared with nondrinkers. The HRs for proximal and distal cancer in drinkers vs nondrinkers were 1.69 (1.15-2.47) and 1.24 (0.99-1.55) for ≥92 g/d in men, and 1.60 (0.76-3.37) and 1.18 (0.88-1.57) for ≥23 g/d in women, respectively. Alcohol intake increased stomach cancer risk in men, and heavy drinkers showed a greater point estimate of risk for proximal cancer than for distal cancer., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Aristolochic acid I (AAI) is a well-known nephrotoxic carcinogen, which is currently reported to be also associated with hepatocellular carcinoma (HCC). Whether AAI is a direct hepatocarcinogen remains controversial. In this study we investigated the association between AAI exposure and HCC in adult rats using a sensitive rat liver bioassay with several cofactors. Formation of glutathione S-transferase placental form-positive (GST-P + ) foci was used as the marker for preneoplastic lesions/clonal expansion. We first conducted a medium-term (8 weeks) study to investigate whether AAI had any tumor-initiating or -promoting activity. Then a long-term (52 weeks) study was conducted to determine whether AAI can directly induce HCC. We showed that oral administration of single dose of AAI (20, 50, or 100 mg/kg) in combination with partial hepatectomy (PH) to stimulate liver proliferation did not induce typical GST-P + foci in liver. In the 8-week study, only high dose of AAI (10 mg · kg -1  · d -1 , 5 days a week for 6 weeks) in combination with PH significantly increased the number and area of GST-P + foci initiated by diethylnitrosamine (DEN) in liver. Similarly, only high dose of AAI (10 mg· kg -1 · d -1 , 5 days a week for 52 weeks) in combination with PH significantly increased the number and area of hepatic GST-P + foci in the 52-week study. No any nodules or HCC were observed in liver of any AAI-treated groups. In contrast, long-term administration of AAI (0.1, 1, 10 mg· kg -1 · d -1 ) time- and dose-dependently caused death due to the occurrence of cancers in the forestomach, intestine, and/or kidney. Besides, AAI-DNA adducts accumulated in the forestomach, kidney, and liver in a time- and dose-dependent manner. Taken together, AAI promotes clonal expansion only in the high-dose group but did not induce any nodules or HCC in liver of adult rats till their deaths caused by cancers developed in the forestomach, intestine, and/or kidney. Findings from our animal studies will pave the way for further large-scale epidemiological investigation of the associations between AA and HCC., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Benzo(a)pyrene (BaP) is a polycyclic aromatic hydrocarbon widespread in the environment and closely associated to tobacco use, which is an important risk factor for highly incident stomach cancer. Menthol, a monoterpene extracted from Mentha genus species, has multiple biological properties, including anti-inflammatory and gastroprotective properties, but its effects on carcinogenesis are still to be fully understood. Thus, we evaluated the modifying effects of Ment against BaP-induced forestomach carcinogenesis. Female Swiss mice received BaP by intragastrical (i.g.) administration (50 mg/kg of body weight [b wt], 2×/week), from weeks 1-5 weeks. Concomitantly, mice received Menthol at 25 (Ment25) or 50 (Ment50) mg/kg b wt (i.g, 3×/week). Animals were euthanized at weeks 5 (n = 5 mice/group) or 30 (n = 10 mice/group). At week 5, both Ment doses reduced peripheral leukocyte blood genotoxicity 4 h after the last BaP administration, but only Ment50 attenuated this biomarker 8 h after the last BaP administration. In accordance to these findings, both Ment interventions attenuated BaP-induced increase in the percentage of H2A.X-positive forestomach epithelial cells. Moreover, Ment50 reduced cell proliferation and apoptosis (i.e., Ki-67 and caspase-3, respectively) in forestomach epithelium but exerted no significant effects on NFκB, and Nrf2 protein levels. At week 30, Ment50 reduced by ~55% the incidence of BaP-induced forestomach diffuse hyperplasia and multiplicity of forestomach tumors (squamous cell papillomas and carcinomas). Our findings indicate that Ment50, administered during initiation phase, attenuates forestomach carcinogenesis by reducing early genotoxicity, cell proliferation, and apoptosis induced by BaP., (© 2021 Wiley Periodicals LLC.)

The present study was aimed to evaluate the chemopreventive potential of galangin against benzo(a)pyrene (BaP)-induced stomach carcinogenesis in Swiss albino mice. Stomach cancer was induced in experimental mice using BaP oral administration. The mice were treated with galangin (10 mg/kg b.wt.) before and during BaP administration. Oral administration of galangin at a dose of 10 mg/kg b.wt. significantly (p < 0.05) prevented the tumor incidence, tumor volume in the experimental animals. Further, galangin pretreatment prevents BaP-induced lipid peroxidation and restores BaP-mediated loss of cellular antioxidants status. It has also been found that galangin prevents BaP-induced activation of phase I detoxification enzymes. Furthermore, galangin pretreatment prevented the BaP-induced overexpression of cytochrome P450s isoform genes (CYP1A1, CYP1B1), aryl hydrocarbon receptor system (AhR, ARNT), transcriptional activators (CBP/p300, NF-kB), tumor growth factors, proto-oncogenes, invasion markers (TGFB, SRC-1, MYC, iNOS, MMP2, MMP9) and Phase II metabolic isoenzyme genes (GST) in the stomach tissue homogenate when compared to the control groups. The western blot results confirm that galangin (10 mg/kg. b.wt.) treatment significantly prevented the BaP-mediated expression of ArR, ARNT, and CYP1A1 proteins in the mouse stomach tissue. Therefore, the present results confirm that galangin prevents BaP-induced stomach carcinogenesis probably through modulating ArR and ARNT expression in the experimental mice.

Ethyl acrylate (EA) was classified by IARC as a Group-2B Carcinogen based, in part, on data suggesting increased incidence of thyroid neoplasia in rats and mice exposed chronically to EA vapors. We examined chronic exposure of rats and mice to EA vapors, evaluated the data on the incidence of thyroid follicular neoplasia, and determined the relevance of thyroid tumors to human health risk. The data revealed a small statistically significant increase in thyroid tumors in EA-exposed male rats and mice. The tumor incidences were within the range of historical controls and were not consistently dose-dependent. Most thyroid tumors in exposed animals were benign. Chronic exposure of EA to rats and mice (drinking water or gavage) and dogs (capsules) had no evidence of thyroid neoplasia. Results from chronic studies, in vivo and in vitro data, and ToxCastTM/Tox 21 HTPS did not support genotoxic/mutagenic potential for EA. This suggests that the associations between EA exposure and thyroid neoplasia represent chance or random observations rather than a compound-mediated effect. Due to species-specific physiological differences, the hypothalamic-pituitary-thyroid axis of rodents is more sensitive to endocrine disruptive chemicals than that of humans which further suggests that findings in rodents have questionable relevance to human health., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Gastric cancer(GC), one of the most common malignancies worldwide, seriously threatens human health due to its high morbidity and mortality. Precancerous lesion of gastric cancer(PLGC) is a critical stage for preventing the occurrence of gastric cancer, and PLGC therapy has frequently been investigated in clinical research. Exploring the proper animal modeling methods is necessary since animal experiment acts as the main avenue of the research on GC treatment. At present, N-methyl-N'-nitro-N-nitroso-guanidine(MNNG) serves as a common chemical inducer for the rat model of GC and PLGC. In this study, MNNG-based methods for modeling PLGC rats in related papers were summarized, and the applications and effects of these methods were demonstrated by examples. Additionally, the advantages, disadvantages, and precautions of various modeling methods were briefly reviewed, and the experience of this research group in exploring modeling methods was shared. This study is expected to provide a reference for the establishment of MNNG-induced PLGC animal model, and a model support for the following studies on PLGC.

Pseudo-signet ring parietal cell vacuolation has been described as a mimic of invasive signet ring cell carcinoma. Moreover, signet ring cell carcinoma has been described in a fundic gland polyp. This case demonstrates parietal cell vacuolation in a fundic gland polyp in a patient on a long-term proton pump inhibitor.

Asbestos has been recognized as a human carcinogen associated with malignant mesothelioma, cancers of lung, larynx, and ovary. However, a putative association between gastric cancer and asbestos exposure remains controversial. In this study, we aimed to explore gastric cancer risk of workers potentially exposed to asbestos in Taiwan. The asbestos occupational cohort was established from 1950 to 2015 based on the Taiwan Labor Insurance Database, and Taiwan Environmental Protection Agency regulatory datasets, followed by the Taiwan Cancer Registry for the period 1980-2015. Standardized incidence ratios (SIRs) for cancer were computed for the whole cohort using reference rates of the general population, and also reference labor population. Compared with the general population, SIR of the asbestos occupational cohort for the gastric cancer increased both in males (1.05, 95% confidence interval (CI): 1.02-1.09) and females (1.10, 95% CI: 1.01-1.18). A total of 123 worksites were identified to have cases of malignant mesothelioma, where increased risk for gastric cancer was found with a relative risk of 1.76 (95% CI: 1.63-1.90). This 35-year retrospective cohort study of asbestos-exposed workers in Taiwan may provide support for an association between occupational exposure to asbestos and gastric cancer.

The aim of this study was to explore the male predominance in esophageal and gastric adenocarcinoma by evaluating the preventive potential of androgen deprivation therapy (ADT). This matched cohort study was based on a national Swedish database of prostate cancer patients in 2006-2013. Prostate cancer patients receiving ADT were the exposed group. Prostate cancer-free men from the general population were randomly selected and matched to the index case by birth year and county of residence, forming the unexposed control group. The participants were followed until a diagnosis of esophageal or gastric cancer, death, emigration, or end of the study period. The risk of esophageal adenocarcinoma, cardia gastric adenocarcinoma, non-cardia gastric adenocarcinoma, and esophageal squamous-cell carcinoma among ADT-exposed compared to unexposed was calculated by multivariable Cox proportional hazard regression. The hazard ratios (HRs) and 95% confidence intervals (CIs) were adjusted for confounders. There was a risk reduction of non-cardia gastric adenocarcinoma among ADT-users compared to non-users (HR 0.49 [95% CI 0.24-0.98]). No such decreased risk was found for esophageal adenocarcinoma (HR 1.17 [95% CI 0.60-2.32]), cardia gastric adenocarcinoma (HR 0.99 [95% CI 0.40-2.46]), or esophageal squamous cell carcinoma (HR 0.99 [95% CI 0.31-3.13]). This study indicates that androgen deprivation therapy decreases the risk of non-cardia gastric adenocarcinoma, while no decreased risk was found for esophageal adenocarcinoma, cardia gastric adenocarcinoma, or esophageal squamous-cell carcinoma.

Nitrate and nitrite are precursors in the endogenous formation of N-nitroso compounds (NOC) which are potent animal carcinogens for the organs of the digestive system. We evaluated dietary intakes of nitrate and nitrite, as well as nitrate ingestion from drinking water (public drinking water supplies (PWS)), in relation to the incidence (1986-2014) of cancers of the esophagus (n = 36), stomach (n = 84), small intestine (n = 32), liver (n = 31), gallbladder (n = 66), and bile duct (n = 58) in the Iowa Women's Health Study (42,000 women aged from 50 to 75 in 1986). Dietary nitrate and nitrite were estimated using a food frequency questionnaire and a database of nitrate and nitrite levels in foods. Historical nitrate measurements from PWS were linked to the enrollment address by duration. We used Cox regression to compute hazard ratios (HR) and 95% confidence intervals (CI) for exposure quartiles (Q), tertiles (T), or medians, depending on the number of cancer cases. In adjusted models, nitrite intake from processed meats was associated with an increased risk of stomach cancer (HR Q4vsQ1 = 2.2, CI: 1.2-4.3). A high intake of total dietary nitrite was inversely associated with gallbladder cancer (HR Q4vsQ1 = 0.3, CI: 0.1-0.96), driven by an inverse association with plant sources of nitrite (HR Q4vsQ1 = 0.3, CI: 0.1-0.9). Additionally, small intestine cancer was inversely associated with a high intake of animal nitrite (HR T3vsT1 = 0.2, CI: 0.1-0.7). There were no other dietary associations. Nitrate concentrations in PWS (average, years ≥ 1/2 the maximum contaminant level) were not associated with cancer incidence. Our findings for stomach cancer are consistent with prior dietary studies, and we are the first to evaluate nitrate and nitrite ingestion for certain gastrointestinal cancers.

Gastric cancer is one of the most common and deadly cancers among men and women and is the third leading cause of cancer mortality worldwide. Thus, discovering and developing novel therapeutics for gastric cancer has become a global priority. In this study, we synthesized two novel anthraquinone-based aspirin derivatives, Asp-X 3 and Asp-X 3 -CH 3 , with therapeutic potential for gastric cancer. The structures of the two compounds were determined by 1D, 2D-NMR, and High-Resolution Mass (HRSM). Asp-X 3 and Asp-X 3 -CH 3 could inhibit the growth of gastric cancer cells (SGC7901), yielding IC 50 values 10-fold lower than that of Aspirin. Asp-X 3 and Asp-X 3 -CH 3 were less toxic to gastric mucosal cells, yielding IC 50 values that were about 2-fold higher than the corresponding IC 50 values determined with SGC7901 cells. Asp-X 3 -CH 3 and Asp-X 3 also induced SGC7901 cells to undergo apoptosis, yielding apoptotic rates that were about twice the rate induced by Aspirin. Asp-X 3 -CH 3 did not cause significant loss of COX-1 expression in gastric mucosal cells, whereas Asp-X 3 and Aspirin both caused significant loss of COX-1 expression as demonstrated by Western blot, consistent with their effects on the content of PGE 2 in these cells as determined by ELISA assay. However, both Asp-X 3 -CH 3 and Asp-X 3 exerted a similar effect on the level of COX-2 in gastric cancer cells, causing as much as 90% and 95% reduction in COX-2 expression, respectively. Taken together, the results suggested that Asp-X 3 -CH 3 and Asp-X 3 were potentially better agents than Aspirin for the inhibition of gastric cancer cell growth, but Asp-X 3 -CH 3 was more effective., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Proton pump inhibitors (PPIs) are commonly prescribed medications. Long-term use of PPIs has been suspected to have a provocative effect on gastric cancer. This study was to determine the association between PPI vs histamine 2 receptor antagonist (H2RA) use and the risk of gastric cancer in a region where the risk of this malignancy is high., Methods: A population-based cohort study using the Korean National Health Insurance Services Database. The participants with first prescription of PPIs and H2RA with normal esophagogastroduodenoscopy finding from 2004 through 2015 were collected. Among them, 50% of participants were systematic stratified randomly sampled. There were 122,118 users of PPIs or H2RAs who use medication more than cumulative defined daily dose of 180 days. The users were followed up from long-term use threshold until gastric cancer, death from non-gastric cancer cause, gastric surgery, or study end (December 2017)., Results: After calculating propensity score weights, we included 39,799 PPI and 38,967 H2RA users. Among the new PPI and H2RA users, we identified 411 cases of incident gastric cancer from 182,643 person-years of follow-up observation and 397 cases from 178,846 person-years of follow-up observation, respectively. Compared with H2RA users, PPI users did not experience significantly different gastric cancer incidence (adjusted hazard ratio, 1.01; 95% confidence interval, 0.88-1.16; P = 0.89). Sensitivity analyses confirmed that gastric cancer incidence did not differ between PPI and H2RA users., Discussion: In this large study, long-term treatment with PPIs vs H2RAs did not show higher risk of gastric cancer even in a high-risk region., (Copyright © 2021 by The American College of Gastroenterology.)

Gastric carcinoma is one of the most aggressive types of cancer that ranks fifth among all cancer incidences and third in cancer mortality. As it exhibits a prolonged asymptomatic condition and high recurrence rate, it is a great challenge to treat gastric cancer. Traditional medicine that utilizes herbal phytochemicals to treat various diseases is a potent alternative for current allopathic treatment. Hence, we evaluated the potency of a phytochemical bilobalide for treating gastric cancer in in vitro and in vivo models. Bilobalide, a sesquiterpenoid, is present in the Ginkgo biloba plant that belongs to the family of Ginkgoaceae. The cytotoxicity effect of bilobalide was evaluated in both gastric cancer (AGS) cells and normal gastric epithelial cells. Apoptosis-inducing property of bilobalide against the AGS cell line was analyzed with different fluorescent staining techniques and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and cell cycle analysis was carried out by flow cytometry. The in vivo studies were assessed with N-methyl-N-nitrosourea (MNU)-induced gastric cancer in rats. Serum-specific gastric markers were quantified and histopathological analysis of stomach tissue was performed. The expression of target-signaling molecules was analyzed by a reverse-transcription polymerase chain reaction. The in vitro results proved that bilobalide effectively suppressed the AGS cell growth and induced cell death by nuclear damage and apoptosis induction. The bilobalide treatment effectively arrested the cell cycle of AGS cells via inhibiting the PI3K-signaling pathway. Our in vivo results also confirmed that the bilobalide persuasively inhibited the MNU-induced gastric carcinoma via inhibiting the thioredoxin-fold family proteins and inflammatory markers' expression. Overall, our results authentically prove that bilobalide possesses therapeutic potency to cure gastric carcinoma., (© 2021 Wiley Periodicals LLC.)

Gastric cancer has the fifth-highest incidence rate and is the third leading cause of cancer-related deaths worldwide. The incidence of gastric cancer is higher in men than in women, but for the diffuse types of gastric cancer, the trend is opposite. Estrogen is considered the prime culprit behind these differences. Nevertheless, the action of estrogen in gastric cancers remains unclear. In this study, we investigated the effect of estrogen on diffuse-type gastric cancer. Human female diffuse gastric cancer SNU-16 cells were transplanted into male and female mice to analyze the effect of endogenous estrogen on tumor growth. Furthermore, the effect of exogenous estrogen was evaluated in ovariectomized mice. Expressed genes were compared between female and male xenograft models using RNA sequencing analysis. Furthermore, human gene expression omnibus databases were utilized to examine the effect of our target genes on overall survival. SNU-16-derived tumor growth was faster in female mice than in male mice. In total RNA sequencing, interferon gamma receptor 2 ( IFNGR2 ), IQ motif containing E ( IQCE ), transient receptor potential cation channel subfamily M member 4 ( TRPM4 ), and structure-specific endonuclease subunit SLX4 ( SLX4 ) were found. These genes could be associated with the tumor growth in female diffuse-type gastric cancer which was affected by endogenous estrogen. In an ovariectomized gastric cancer xenograft model, exogenous estrogen promoted tumor growth. Especially, our results indicated that estrogen induced G protein-coupled estrogen receptor expression in these mice. These results suggest that estrogen aggravates tumor progression in female diffuse gastric cancer., 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 © 2021 Lee, Kim, Lee and Jung.)

Gastric cancer (GC) represents the fifth most human malignant disease and the third-most common cause of cancer-related death. Gambogic acid (GA) is a natural compound with a polyprenylated xanthone structure and possesses remarkable antitumor activity in a variety of cancer cells. However, the mechanism underlying the inhibitory effect of GA in GC is far from being completely understood. The goal of the present study is to investigate whether potential microRNAs are involved in antitumor effect of GA toward GC and to elucidate the possible mechanisms. We identified that miR-26a-5p was significantly increased by GA in GC cell lines and xenograft tumor. Downregulation of miR-26a-5p not only prevented GA-induced inhibition on GC cell growth, but also suppressed GA-induced apoptosis of GC cells. Informatics assay predicted that Wnt5a was regulated by miR-26a-5p and GA-induced downregulation of Wnt5a was prevented by anti-miR-26a-5p. Reporter gene assay showed that miR-26a-5p could negatively regulate Wnt5a through direct binding with 3'-UTR messenger RNA of Wnt5a. Thus, upregulation of Wnt5a exhibited the same action tendency for GA-induced GC cell growth and apoptosis as observed by downregulation of miR-26a-5p. In conclusion, these results indicated that the inhibitory effect of GA on GC was mediated by the upregulation of miR-26a-5p and downregulation of Wnt5a. Our study provided new clues for the potential therapeutic effect of GA against GC and highlighted the importance of miR-26a-5p/Wnt5a pathway in the regulation of GC development., (© 2021 Wiley Periodicals LLC.)

Stomach cancer is one of the most common cancers in the world. The relationship between alcohol consumption and the risk of stomach cancer remains unclear. Epidemiology studies investigating this relationship have shown inconsistent findings. A meta-analysis was performed to explore the association between alcohol consumption and increased stomach cancer risk. Eighty-one epidemiology studies, including 68 case-control studies and 13 cohort studies, were included in this study. A significant association was found between alcohol consumption and increased risk of stomach cancer (OR = 1.20, 95% CI 1.12-1.27). To explore the source of the significant heterogeneity (p < 0.05, I 2  = 86%), analysis was stratified by study type (case-control study and cohort study), control type (hospital-based control and population-based control), gender (male, female, and mix), race (White and Asian), region (United States, Sweden, China, Japan), subsite of stomach cancer, and type of alcohol. The stratified analyses found that region and cancer subsite are major sources of the high heterogeneity. The inconsistent results in different regions and different subsites might be related to smoking rates, Helicobacter pylori infection, obesity, and potential genetic susceptibility. The positive association between drinking and increased risk of stomach cancer is consistent in stratified analyses. The dose-response analysis showed a clear trend that a higher daily intake of alcohol is associated with a higher risk of stomach cancer., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background & Aims: Immune checkpoint inhibitors have limited efficacy in many tumors. We investigated mechanisms of tumor resistance to inhibitors of programmed cell death-1 (PDCD1, also called PD-1) in mice with gastric cancer, and the role of its ligand, PD-L1., Methods: Gastrin-deficient mice were given N-methyl-N-nitrosourea (MNU) in drinking water along with Helicobacter felis to induce gastric tumor formation; we also performed studies with H/K-ATPase-hIL1B mice, which develop spontaneous gastric tumors at the antral-corpus junction and have parietal cells that constitutively secrete interleukin 1B. Mice were given injections of an antibody against PD-1 or an isotype control before tumors developed, or anti-PD-1 and 5-fluorouracil and oxaliplatin, or an antibody against lymphocyte antigen 6 complex locus G (also called Gr-1), which depletes myeloid-derived suppressor cells [MDSCs]), after tumors developed. We generated knock-in mice that express PD-L1 specifically in the gastric epithelium or myeloid lineage., Results: When given to gastrin-deficient mice before tumors grew, anti-PD-1 significantly reduced tumor size and increased tumor infiltration by T cells. However, anti-PD-1 alone did not have significant effects on established tumors in these mice. Neither early nor late anti-PD-1 administration reduced tumor growth in the presence of MDSCs in H/K-ATPase-hIL-1β mice. The combination of 5-fluorouracil and oxaliplatin reduced MDSCs, increased numbers of intra-tumor CD8 + T cells, and increased the response of tumors to anti-PD-1; however, this resulted in increased tumor expression of PD-L1. Expression of PD-L1 by tumor or immune cells increased gastric tumorigenesis in mice given MNU. Mice with gastric epithelial cells that expressed PD-L1 did not develop spontaneous tumors, but they developed more and larger tumors after administration of MNU and H felis, with accumulation of MDSCs., Conclusions: In mouse models of gastric cancer, 5-fluorouracil and oxaliplatin reduce numbers of MDSCs to increase the effects of anti-PD-1, which promotes tumor infiltration by CD8 + T cells. However, these chemotherapeutic agents also induce expression of PD-L1 by tumor cells. Expression of PD-L1 by gastric epithelial cells increases tumorigenesis in response to MNU and H felis, and accumulation of MDSCs, which promote tumor progression. The timing and site of PD-L1 expression is therefore important in gastric tumorigenesis and should be considered in design of therapeutic regimens., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The chemical quality of groundwater supplies in two high-risk area (HRA) and low-risk area (LRA) for gastric cancer in Iran was assessed through hydrogeochemical analysis and water quality indices. For this aim, Piper and Schoeller diagrams and water quality index (WQI) were applied. In addition, exposure to nitrate via drinking water and its corresponding risk were also assessed using Monte Carlo simulation technique. Data on physicochemical properties of groundwater resources were obtained from Iran Water Resources Management Company. Sampling and analysis of tap water for nitrate concentration were conducted in two cities of Shiraz (as a representative of LRA) and Ardabil (as a representative of HRA). According to Piper diagrams, the dominant hydrogeochemical facies of groundwater supplies in HRA and LRA were Na-HCO 3 (43.75%) and Ca-HCO 3 (41.77%), respectively. The predominant cations in groundwater resources of HRA were found to be Na + (68.06%) and Ca 2+ (31.94%). For LRA, the typical cations were in decreasing trend: Ca 2+ (39.64%) > Mg 2+ (18.35%) > Na + (17.26%). For two areas, HCO 3 - , SO 4 2- and Cl - were, respectively, the most frequent anions. Two-sample Wilcoxon test showed that there were statistically significant difference between two areas in terms of anions and cations concentrations (p value < 0.05). The mean of total hardness (Ca 2+  + Mg 2+ ) concentration of water supplies in LRA (528.1 mg/L) was higher than HRA (263.1 mg/L), whereas the mean of Na + concentration was found to be lower in LRA (90.6 mg/L) compared with HRA (108.1 mg/L). The sum of nitrate intake and its risk in LRA was higher than HRA. WQI results showed that drinking water quality in HRA and LRA ranged from excellent to poor and most water resources were of a good quality class. Further studies are suggested to investigate the role of drinking water in the etiology of gastric cancer in Iran.

Context: Aristolochia manshuriensis Kom (Aristolochiaceae) (AMK) is known for toxicity and mutagenicity. Objective: The tumorigenic role of AMK has yet to be understood. Materials and methods: AMK extracts were extracted from root crude drug. SD (Sprague Dawley) rats underwent gavage with AMK (0.92 g/kg) every other day for 10 (AMK-10) or 20 (AMK-20) weeks. Stomach samples were gathered for histopathological evaluation, microarray and mRNA analysis. Results: The gastric weight to body weight ratio (GW/BW) is 1.7 in the AMK-10 cohort, and 1.8 in AMK-20 cohort compared to control (CTL) cohort. Liver function was damaged in AMK-10 and AMK-20 rats compared to CTL rats. There were no significant changes of CRE (creatinine) in AMK-10 and AMK-20 rats. Histopathological analysis revealed that rats developed dysplasia in the forestomach in AMK-10 rats, and became gastric carcinoma in AMK-20 rats. Genes including Mapk13 , Nme1 , Gsta4 , Gstm1 , Jun , Mgst2 , Ggt6 , Gpx2 , Gpx8 , Calml3 , Rasgrp2 , Cd44 , Gsr , Dgkb , Rras , and Amt were found to be critical in AMK-10 and AMK-20 rats. Pik3cb , Plcb3 , Tp53 , Hras , Myc , Src , Akt1 , Gnai3 , and Fgfr3 worked in AMK-10 rats, and PDE2a and PDE3a played a pivotal role in AMK-20 rats. Discussion and conclusions: AMK induced benign or malignant gastric tumours depends on the period of AMK administration. Genes including Mapk13 , Nme1 , Gsta4 , Gstm1 , Jun , Mgst2 , Ggt6 , Gpx2 , Gpx8 , Calml3 , Rasgrp2 , Cd44 , Gsr , Dgkb , Rras , Amt , Pik3cb , Plcb3 , Tp53 , Hras , Myc , Src , Akt1 , Gnai3 , Fgfr3 , PDE2a , and PDE3a were found to be critical in aristolochic acid-induced gastric tumour process.

Background: Acid-suppressive agents (ASAs) may be associated with cancer; previous studies reported that the risk of cancer with acid suppressants has differed depending on the site of cancer. Here, we conducted a systematic review and meta-analysis of the association between ASA use and the type of cancer risk., Methods: MEDLINE, EMBASE, and Cochrane library databases were searched for publications up to the end of September 2019 for MeSH terms and text words related to cancer and ASAs. Studies on the association between ASAs and cancer risk, which included a control group and reported the relative risk of cancer, were included. The inverse-variance random effect model was used to estimate the pooled relative risk (RR) and 95% confidence interval (CI), and subgroup analysis for type of acid suppressants, drug uptake duration, and cumulative doses was performed. Heterogeneity was assessed using the I 2 test and Q statistic., Results: Thirty-nine cohort and case-control studies were included. ASA use was found to be significantly associated with a 46% higher risk of gastric cancer (RR, 1.46; 95% CI, 1.18-1.80) and a 53% higher risk of liver cancer (RR, 1.53; 95% CI, 1.31-1.78) compared with nonuse; however, there was no significant association for esophageal, colorectal, pancreatic, lung, breast, prostate, and kidney cancer; melanoma; and lymphoma., Conclusions: ASAs were significantly associated with an increased risk of gastric and liver cancer; therefore, special attention of ASA use considering the potential risk of gastric and liver cancer is needed.

In 1955, an outbreak of arsenic poisoning caused by the ingestion of arsenic-contaminated Morinaga Dry Milk occurred in western Japan. This study aimed to assess the mortality and cancer incidence risk among Japanese individuals who were poisoned during this time as infants. In total, 6223 survivors (mean age at enrollment, 27.5 y) who had ingested contaminated milk when they were aged ≤ 2 y participated in this study. Follow-up was conducted from 1982 to 2018 (mean follow-up duration, 30.3 y). Standardized mortality ratio (SMR) and standardized incidence ratio (SIR) were used to compare mortality and cancer incidence rates of subjects with the respective Japanese population rates, and 95% confidence intervals (95% CIs) of the SMR and SIR were also calculated. In total, 561 deaths and 524 new cancer cases were observed. A statistically significant increase in mortality rate was observed for all causes (SMR, 1.15; 1.01-1.19), nervous system disease (2.83, 1.62-4.19), respiratory disease (2.02, 1.37-2.62), genitourinary system disease (2.25, 1.10-3.73), and traffic accident (2.03, 1.14-3.04). In contrast, a significant decrease in cancer incidence rate was observed for all cancers (SIR, 0.96; 0.84-0.99), stomach cancer (0.77, 0.57-0.92), colon cancer (0.63, 0.41-0.85), rectum cancer (0.69, 0.43-0.95), and breast cancer (0.72, 0.52-0.89). Liver cancer showed a high mortality rate (SMR, 1.68; 1.06-2.31). In this study, after the long-term follow-up we revealed overall and cause-specific mortality and cancer incidence risk among survivors who ingested arsenic-contaminated dry milk as infants., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Stomach cancer is among the most common forms of cancers, and diet and environmental factors play important roles in its malignancy. This study was conducted to evaluate the trace metal contents in the scalp hair of stomach cancer patients and healthy donors to investigate probable relationship between metal imbalances and cancer. The samples were digested in HNO 3 -HClO 4 mixture and the metals were quantified by flame atomic absorption spectrophotometry. Median level of Cr was found to be significantly higher in the patients than in the controls, while median levels of Fe, Mn and Cd were considerably reduced. The correlation pattern of metals in the patients manifested significantly divergent mutual relationships compared with the controls. Multivariate analyses showed appreciably diverse apportionment of the metals in the patients and healthy donors. Variations in the metal levels were also observed for various types (adenocarcinoma and gastrointestinal stromal tumour) as well as stages (I, II, III and IV) of stomach cancer patients. Most of the metals revealed noticeable disparities in their levels based on gender, habitat, dietary habit and smoking habit of patients and controls. Accordingly, the essential/toxic metals exhibited significant imbalance due to pathogenesis of stomach among the patients.

Objectives: Stomach cancer (SC) is one of the most common and deadly types of cancer. It is the third leading cause of cancer deaths worldwide. The effect of environmental and ecological factors in SC have been assessed in some studies. Thus, we aimed to synthesize the environmental and ecological factors of SC incidence and mortality., Content: In this systematic review study, the scientific databases, including Web of Science, Scopus and PubMed, were searched from inception to November 2019 for all primary articles written in English by using relevant Medical Subject Heading (Mesh) terms. Two independent authors conducted the screening process to decide on the eligibility and inclusion of the articles in the study. The third author acted as an arbiter to resolve any disagreements., Summary and Outlook: A total of 157 potentially relevant articles were identified from the initial search 38 of which met the eligibility criteria; finally, 34 articles were included in the systematic review. The results revealed that soil arsenic exposure, coal and other opencast mining installations, living near incinerators and installations for the recovery or disposal of hazardous waste, installations for the production of cement, lime, plaster, and magnesium oxide, proximity to a metal industry sources, dietary iron, ingested asbestos, farming, arsenic in soil, altitude, organochlorines and environmental exposure to cadmium and lead have positive associations with SC incidence or death. Most of the ecological and environmental factors such as living near the mineral industries, the disposal of hazardous waste, metal industry sources and environmental exposure to cadmium and lead are positively related to SC mortality and incidence. However, solar UV-B, heat index and dietary zinc can be taken into account as protective factors against SC mortality and incidence., (© 2020 Walter de Gruyter GmbH, Berlin/Boston.)

Background/purpose: Talc powder is widely used in various industries, but the carcinogenic effects associated with talc are not well understood. The objective of this study was to estimate the risk of stomach cancer after occupational talc exposure., Methods: We conducted a meta-analysis was performed to calculate the meta-relative risk (mRR) of stomach cancer. We searched the MEDLINE, EMBASE, CNKI and Wanfang Data databases for publications prior to January 1, 2017 using talc, cancer, and mortality as the search terms. Only cohort studies with occupational talc exposure and stomach cancer statistics were included., Results: All pooled analyses were based on random-effects models. We selected 13 observational studies (12 publications) for the meta-analysis, and heterogeneity was observed among studies. Workers exposed to all forms of talc had a significantly increased mRR of 1.21 (95% CI: 1.03-1.42, p = 0.02) for stomach cancer. Workers exposed to talc not containing asbestiform fibers also had an increased mRR of 1.26 (95% CI: 0.97-1.63, p = 0.09)., Conclusion: The available data showed a positive association between occupational talc exposure and risk of stomach cancer. The association between talc not containing asbestiform fibers and risk of stomach cancer was not significant. Further epidemiological studies are required to evaluate the safety of talc., (Copyright © 2018. Published by Elsevier B.V.)

Objective: To formulate a decision analysis model based on recently published data that addresses the dilemma, whether improvement in quality of life rationalises continued proton pump inhibitors (PPI) use despite the risk of gastric cancer (GC) in patients with functional dyspepsia (FD)., Design: A Markov model consisting of an initial decision regarding treatment with PPI (denoting it by PPI strategy) or any other treatment without PPI (denoting it by placebo strategy) was designed., Data Sources: Data from prospective cross-sectional studies indicating risk stratification for GC after the use of PPI, combined with a Markov model that comprised the following states: Live, GC stages 1-4, Death., Outcome Measures: The primary outputs included quality-adjusted life years (QALYs) and life expectancy (LE). The improvement in utility in FD without PPI as compared with PPI use was tested (PPI vs placebo strategies). Sensitivity analyses were performed to evaluate the robustness of the model and address uncertainty in the estimation of model parameters., Setting: We considered only patients whose symptoms were relieved with PPIs and thus, had a better quality of life compared with patients who did not receive PPIs., Results: The base case model showed that PPIs compared with placebo decreased LE by 58.4 days with a gain of 2.1 QALY. If utility (quality of life of patients with FD using PPI compared with patients with FD without PPI) improved by more than 0.8%, PPI use is considered better than placebo. Older patients benefited less from PPI treatment than did younger patients., Conclusion: To bridge the gap between evidence and decision making, we found that even a small improvement in the QALY justified continuing PPI treatment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Neuroendocrine tumors (NETs) throughout the body are the focus of much current interest. Most occur in the gastrointestinal tract and have shown a major increase in incidence over the past 30 years, roughly paralleling the world-wide increase in the use of proton pump inhibitor (PPI) drugs. The greatest rise has occurred in gastric carcinoids (g-NETs) arising from enterochromaffin-like (ECL) cells. These tumors are long known to occur in auto-immune chronic atrophic gastritis (CAG) and Zollinger-Ellison syndrome (ZES), with or without multiple endocrine neoplasia type-1 (MEN-1), but the incidences of these conditions do not appear to have increased over the same time period. Common to these disease states is persistent hypergastrinemia, generally accepted as causing g-NETs in CAG and ZES, and postulated as having similar tumorigenic effects in PPI users. In efforts to study the increase in their occurrence, g-NETs have been classified in a number of discussed ways into different grades that differ in their incidence and apparent pathogenesis. Based on a large amount of experimental data, tumorigenesis is mediated by gastrin's effects on the CCK2R-receptor on ECL-cells that in turn leads to hyperplasia, dysplasia, and finally neoplasia. However, in all three conditions, the extent of response of ECL-cells to gastrin is modified by a number of genetic influences and other underlying risk factors, and by the duration of exposure to the hormonal influence. Data relating to trophic effects of hypergastrinemia due to PPI use in humans are reviewed and, in an attached Appendix A, all 11 reports of g-NETs that occurred in long-term PPI users in the absence of CAG or ZES are summarized. Mention of additional suspected cases reported elsewhere are also listed. Furthermore, the risk in humans may be affected by the presence of underlying conditions or genetic factors, including their PPI-metabolizer phenotype, with slow metabolizers likely at increased risk. Other problems in estimating the true incidence of g-NETs are discussed, relating to non-reporting of small tumors and failure of the Surveillance, Epidemiology, and End Results Program (SEER) and other databases, to capture small tumors or those not accorded a T1 rating. Overall, it appears likely that the true incidence of g-NETs may be seriously underestimated: the possibility that hypergastrinemia also affects tumorigenesis in additional gastrointestinal sites or in tumors in other organ systems is briefly examined. Overall, the risk of developing a g-NET appears greatest in patients who are more than 10 years on drug and on higher doses: those affected by chronic H. pylori gastritis and/or consequent gastric atrophy may also be at increased risk. While the overall risk of g-NETs induced by PPI therapy is undoubtedly low, it is real: this necessitates caution in using PPI therapy for long periods of time, particularly when initiated in young subjects.

Background: Gastric cancer (GC) may arise in any region of the stomach. Poorly diagnosed GC results in almost one million mortalities annually worldwide. Kirenol is a bioactive compound present in the Sieges beckia sps., Objective: In this current, we investigate the anticancer capacity of kirenol against the MNG-stimulated GC in rats via modulating the antioxidants status and inhibition of NF-κB cascade., Methodology: GC was provoked in the rats via supplementing 100 mg/kg of MNU through the intragastric route for 16 weeks concomitantly with 30 mg/kg of kirenol treatment. The body weight, tumor volume, and incidence of all animals were tabulated every week. The status of gastrin, ALP, LDH, and γ-GT was studied through the ELISA tests. The lipid peroxidation, enzymatic, and nonenzymatic antioxidants were determined via standard procedures. Expression of thioredoxin, glutaredoxin, NF-κB, TNF-α, IL-6, PGE2 was studied through RT-PCR. The gastric mucosa was analyzed microscopically., Results: Kirenol treatment appreciably improved the body weight and diminished the tumor volume and incidences in the MNG-challenged rats. The lipid peroxidation was diminished and the enzymatic and non-enzymatic antioxidants were improved by the kirenol treatment. Kirenol suppressed the status of serum markers of GC and gastrin, ALP, LDH, and γ-GT. The mRNA expression of thioredoxin, glutaredoxin, NF-κB, TNF-α, IL-6, PGE2 was downregulated via the kirenol in the MNG-challenged rats. Histopathological analysis result also confirmed the therapeutic role of kirenol., Conclusion: These findings proved that the kirenol appreciably prevented the MNG-triggered GC in rats and it may become a potential drug for the GC treatment in the future.

Introduction and Aim: Adequately preserved slides and tissue blocks in pathology archives, when re-reviewed and associated with patient charts, are important tools to further assess prevalence changes and associations of certain pathologies. Our aim was to identify whether proton-pump inhibitor (PPI) use, dose, and duration of use were associated with gastric polyps and their phenotypes in a case-control study., Methods: The slides from patients with a morphologic diagnosis of either hyperplastic polyps or fundic gland polyps were retrieved from the 1980, 1990, 2000, 2010, and 2016 surgical pathology files at a tertiary care hospital in Mexico City and re-evaluated. Cases were paired by age and sex with patients that underwent endoscopy and gastric mucosa biopsy in the same year, with no evidence of polyps., Results: A total of 133 (3.8%) patients with gastric polyps were identified from 3,499 gastric biopsies taken in the abovementioned years and compared with 133 paired controls. Dyspepsia was more prevalent in the controls (p=0.002) and abdominal pain was more prevalent in the patients with gastric polyps (p=0.001). PPI use (OR 7.7, 95% confidence interval, 4.4-13.3) and taking more than one PPI medication (OR 4.9, 95% confidence interval, 1.09-22.3) were significantly associated with the presence of gastric polyps. The fundic gland phenotype in the oxyntic mucosa was more frequently associated with PPI use (p<0.042), with a continuous increase in its prevalence starting in the year 2000 (p=0.017 for trend)., Conclusion: PPI administration for at least one year was associated with gastric fundic gland polyps., (Copyright © 2019 Asociación Mexicana de Gastroenterología. Publicado por Masson Doyma México S.A. All rights reserved.)

Ginger ( Zingiber officinale ) is a spice and also an herbal medicine used worldwide for managing GI tract disturbances. However, its role in gastric cancer is sparingly known. This study ensures the standardization of gastric cancer by the induction of N -nitroso N -methyl Urea (MNU) and to determine the role of the aqueous extract of ginger (AGE) in MNU-induced gastric cancer in albino Wistar rats. Accordingly, the anticancer potential of AGE and its possible mode of action were assessed on rats exposed to MNU, by various biochemical and molecular assays. As evidenced by the extent of lipid peroxidation, gastrin levels and histopathological sections in MNU-induced cancerous lesions at 8 wk which was stabilized at 16 wk confirming the induction of gastric carcinoma by the chemical carcinogen. Further, results revealed that AGE alleviated the oxidative stress as evidenced by the stomach antioxidant enzymes (SOD, catalase, GPx, and GR), markers of oxidative stress (TRx, GRx) and Gastrin, a specific marker for gastric cancer and a decreased level of pro-inflammatory markers (NF-kB, TNF-α, IL-6, PGE 2 ) which was further confirmed by histopathological analysis. AGE is responsible to mitigate oxidative stress and inflammation related to gastric cancer and could be used as a potential dietary intervention in gastric cancer therapy.

Gastric cancer is recognized as one of the most common cancer. In-depth research of gastric precancerous lesions (GPL) plays an important role in preventing the occurrence of gastric cancer. Meanwhile, traditional treatment provides a novel sight in the prevention of occurrence and development of gastric cancer. The current study was designed to assess the effects of therapy with Weipixiao (WPX) decoction on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced GPL rats and the underlying molecular mechanisms. After 10-weeks treatment, all rats were sacrificed. Histopathological changes of gastric tissue were assessed via hematoxylin-eosin (HE) and High-iron diamine-Alcian blue-Periodic acid-Schiff (HID-AB-PAS) staining. To be fully evidenced, RT-qPCR, Western blot and immunohistochemistry were used to detect the expressions of LDHA, CD147, HIF-1α, MCT4, PI3K, AKT, mTOR and miRNA-34a, which were crucial factors for evaluating GPL in the aspect of glycolysis pathogenesis. According to the results of HE and HID-AB-PAS staining, it could be confirmed that MNNG-induced GPL rats were obviously reversed by WPX decoction. Additionally, the increased gene levels of LDHA, CD147, MCT4, PI3K, AKT, mTOR and HIF-1α in model group were down-regulated by WPX decoction, while miRNA-34a expression was decreased and up-regulated by WPX decoction. The significantly increased protein levels of LDHA, CD147, MCT4, PI3K, AKT, mTOR and HIF-1α induced by MNNG were attenuated in rats treated with WPX decoction. In brief, the findings of this study imply that abnormal glycolysis in MNNG-induced GPL rats was relieved by WPX decoction via regulation of the expressions of LDHA, CD147, HIF-1α, MCT4, PI3K, AKT, mTOR and miRNA-34a., (Copyright © 2019. Published by Elsevier Masson SAS.)

Background: A healthy gastric mucosal epithelium exhibits tumor-suppressive properties. Gastric epithelial cell dysfunction contributes to gastric cancer development. Oxysterols provided from food or cholesterol oxidation in the gastric epithelium may be further sulfated by hydroxysteroid sulfotransferase 2B1 (SULT2B1), which is highly abundant in the gastric epithelium. However, the effects of SULT2B1 on gastric epithelial function and gastric carcinogenesis are unclear., Methods: A mouse gastric tumor model was established using carcinogenic agent 3-methylcholanthrene (3-MCA). A SULT2B1 deletion (SULT2B1 -/- ) human gastric epithelial line GES-1 was constructed by CRISPR/CAS9 genome editing system., Results: The gastric tumor incidence was higher in the SULT2B1 -/- mice than in the wild-type (WT) mice. In gastric epithelial cells, adenovirus-mediated SULT2B1b overexpression reduced the levels of oxysterols, such as 24(R/S),25-epoxycholesterol (24(R/S),25-EC) and 27-hydroxycholesterol (27HC). This condition also increased PI3K/AKT signaling to promote gastric epithelial cell proliferation, epithelization, and epithelial development. However, SULT2B1 deletion or SULT2B1 knockdown suppressed PI3K/AKT signaling, epithelial cell epithelization, and wound healing and induced gastric epithelial cell malignant transition upon 3-MCA induction., Conclusions: The abundant SULT2B1 expression in normal gastric epithelium might maintain epithelial function via the PI3K/AKT signaling pathway and suppress gastric carcinogenesis induced by a carcinogenic agent.

People of north-eastern states of India consume raw areca-nut (RAN) and lime which could lead to oral, esophageal and gastric cancers. However, the incidence of these cancers are significantly lesser in those who consume pieces of Potentilla fulgens root along with RAN. Since evaluation of anticancer role, if any, of P. fulgens on RAN-mediated genetic alterations in human is difficult because of other compounding factors, this study was undertaken in mice to focus on gastric carcinogenesis since ad libitum administration of RAN extract with lime in drinking water induced stomach cancer due to greater exposure of its lining. A total of 160 mice were used at different time points and either methanol extract of P. fulgens roots (PRE) or mixture of four compounds of ethyl-acetate fraction (EA-mixture) was mixed with mice feed. Histological studies revealed that RAN + lime induced cancer in all the mice and interestingly only 20% developed cancer when PRE/EA-mixture was provided along with RAN + lime. Higher frequency of precocious anaphase and over expression of p53 and Securin genes were significantly reduced by PRE/EA-mixture. Thus PRE/EA-mixture mitigates the RAN-induced tumor-initiating process in stomach by maintaining expression of tumor suppressor and check-point genes under control.

Background and Aim: This study aims to systematically analyze the effect of long-term therapy with proton pump inhibitors (PPIs) on the risk of gastric cancer., Methods: PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), and China biomedical literature database (CBM) were searched for studies before February 2019. We evaluated the quality of the included articles through the Newcastle-Ottawa Scale and gathered relevant data to calculate the pooled odds ratio (OR) through Stata14.0., Results: Seven relevant articles conformed to the inclusion criteria; 943 070 patients were included. The pooled OR was 2.50; 95% CI (1.74, 3.85); the subgroup analysis results showed that patients who had used PPIs for more than 36 months were most likely to develop gastric cancer, and an increased risk was observed among patients after Helicobacter pylori eradication. Noncardia gastric cancer was more likely to develop., Conclusions: Long-term use of PPIs can possibly increase the risk of gastric cancer even among patients after H. pylori eradication; in particular, for noncardia gastric cancer, the risk increases with longer durations of PPI use. Due to the limited number of studies, more high-quality studies are required to be designed., (© 2019 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Ochratoxin A (OTA), one of the most abundant food-contaminating mycotoxins, is a possible carcinogen to humans. We previously demonstrated that long-term (40 weeks) OTA exposure induces the malignant transformation of human gastric epithelium cells (GES-1) in vitro. However, the specific mechanism underlying OTA-induced gastric carcinogenesis is complex. In the present study, we used 2-DE and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI/TOF MS) combined with bioinformatics and immunoblotting to investigate the differentially expressed proteins between GES-1 and OTA-malignant transformed GES-1 cells (OTA-GES-1 T cells) in vitro. We found that four differentially expressed proteins were identified after malignant transformation, including actin, cytoplasmic 1 (ACTB), F-actin-capping protein subunit alpha-1 (CAPZA1), Annexin A3 (ANXA3), thioredoxin peroxidase B from red blood cells (TPx-B) and Fibrinogen beta B (Fibrinogen β). Among the differentially expressed proteins, the effect of Annexin A3 was analyzed by MTT assay, western blot, cell cycle analysis, wound healing assay, Transwell assay, and colony formation assay in OTA-GES-1 T cells. The results showed that inhibition of Annexin A3 by siRNA effectively prevented the proliferation, migration, and invasion abilities of OTA-GES-1 T cells. Collectively, the results of this study will guide future research on OTA carcinogenicity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: There is increasing interest in the potential association between proton pump inhibitors (PPIs) and the risk of gastric and oesophageal cancer, yet the effect of duration of treatment needs clarification., Methods: This Swedish population-based cohort study assessed the influence of time since initiation of PPI treatment on the risk of gastric and oesophageal cancer, presented as standardised incidence ratios and 95% confidence intervals., Results: The risk of gastric and oesophageal cancer during the first year was 7-10 times higher than the background population, and remained 24-202% increased without any decrease over time after the first year., Conclusion: PPI use was associated with an increased risk of gastric and oesophageal cancer and the risk remained increased over follow-up. These results support our original hypothesis that use of PPIs may be a risk factor for gastric and oesophageal cancer in the general population of maintenance users, independent of underlying indications., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Acrylamide has been classified as a probable human carcinogen based chiefly on laboratory evidence. However, the influence of dietary acrylamide intake on risk of esophageal, gastric, and colorectal cancer has not been extensively studied. We aimed to evaluate the association between dietary acrylamide intake and esophageal, gastric, and colorectal cancer using data from the Japan Public Health Center-based Prospective Study., Methods: Our study included 87,628 participants who completed a food-frequency questionnaire at enrollment in 1990 and 1993. We used Cox proportional hazards regression models to estimate hazards ratios and 95% confidence intervals (CI) after adjusting for confounding factors., Results: After 15.5, 15.3, and 15.3 mean years of follow-up for esophageal, gastric, and colorectal cancer, we identified and analyzed 391 esophageal, 2,218 gastric, and 2,470 colorectal cancer cases, respectively. Compared with the lowest quintile of acrylamide intake, the multivariate HR for the highest quintile was 0.86 (95% CI, 0.53-1.39; P trend = 0.814), 0.84 (95% CI, 0.69-1.01; P trend = 0.301), and 0.93 (95% CI, 0.79-1.08; P trend = 0.165) for esophageal, gastric, and colorectal cancer, respectively, in the multivariable-adjusted model. Furthermore, no significant associations were observed when the participants were stratified by cancer subsites., Conclusions: In conclusion, this study demonstrated that dietary acrylamide intake was not associated with increased risk of esophageal, gastric, or colorectal cancer among the Japanese population., Impact: It is the first time to assess the effect of dietary acrylamide intake on risk of digestive system cancer in Asian populations., (©2019 American Association for Cancer Research.)

Dendrobium officinale is a herb in traditional Chinese medicine where D. officinale polysaccharides (DOP) are the main active ingredient. This study aimed at evaluating DOP efficiency at inhibiting 1-Methyl-2-nitro-1-nitrosoguanidine (MNNG) induced precancerous lesions of gastric cancer (PLGC) in rats through the Wnt/b-catenin pathway and analyzing the variations of serum endogenous metabolites. PLGC was established in male Sprague-Dawley (SD) rats by administering 150 μg/mL MNNG in drinking water for 7 months and giving 0.1 mL of 10% NaCl once weekly during the initial 20 weeks. Treatment with DOP inhibited the progress of PLGC through decreasing the expression of β-catenin by immunohistochemical analysis. The futher study indicated DOP downregulated gene expression of Wnt2β, Gsk3β, PCNA, CyclinD1, and β-catenin, as well as protein expression of Wnt2β, PCNA, and β-catenin. On the other hand, there were nine endogenous metabolites identified after the DOP treatment. Among these, the most significant one is betaine because of its strong antioxidant activity, leading to an anti-tumor effect. DOP can inhibit MNNG-induced PLGC models via regulating Wnt/β-catenin pathway and by changing endogenous metabolites.

A 51-year-old woman had been taking proton pump inhibitor since August 2008. In May, 2016, endoscopic findings showed no atrophy and no intestinal metaplasia in the stomach, and multiple fundic gland polyps were identified in the stomach. A biopsy of a pedunculated polyp measuring 10 millimeters in diameter at the greater curvature of the middle gastric body demonstrated well differentiated tubular adenocarcinoma. In July 2016, we treated this lesion and two other semipedunculated polyps located near the first polyp and also measuring 10 mm in diameter by endoscopic mucosal resection. The final diagnosis of all lesions was a fundic gland polyp with low grade dysplasia and the cutting end was negative.

Objective: To explore the changes of Sonic Hedgehog (Shh) signaling pathway in the stomach mucosa during the formation of gastric precancerous lesions., Methods: A total of 72 suckling rats in half genders were randomly and equally divided into the normal group and model group. The rats in the model group were administered with 0.1 ml 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) at the dosage of 800 mg/L for 10 days, whereas the rats in the normal group were similarly administered with normal saline. A total of 12 rats in each group were killed at the end of 10th, 22nd, and 34th weeks in half gender, respectively. Histopathological changes of the gastric mucosa were observed by hematoxylin and eosin (HE) staining; the levels of Shh, Ptch1, Smo, Gli1, Gli2, Gli3, SuFu, Cyclin D1, Cyclin E1, c-Myc, and β-actin mRNAs in the gastric mucosa were determined by real-time polymerase chain reaction; while the protein expression of Shh, Ptch1, Smo, Gli1, SuFu, Cyclin D1, Cyclin E1, c-Myc, and p-c-Myc was detected by western blot analysis., Results: With the development of atrophy and dysplasia of gastric mucosa, the levels of Shh, Smo, Gli1, Cyclin D1, Cyclin E1, and c-Myc mRNAs increased, while those of Ptch1 and SuFu decreased. The expression of Shh, Smo, Gli1, Cyclin D1, Cyclin E1, and p-c-Myc proteins were elevated, while the expression of Ptch1 and SuFu proteins were decreased, however, without statistical difference., Conclusions: Shh signaling is activated during the formation of gastric precancerous lesions, which indicates that the Shh signaling pathway participates in the development and progression of gastric precancerous lesions., (© 2018 Wiley Periodicals, Inc.)

Background: Phthalates are used as excipients in some drug products, and up to a 50-fold increased urinary excretion of phthalate metabolites compared to non-users has been demonstrated in users of such products. In vitro studies have demonstrated that phthalates stimulate mechanisms involved in gastric cancer development. We therefore examined the association between cumulative phthalate exposure from drug products and the risk of gastric adenocarcinomas. Methods: Using the Danish Cancer Registry, we identified all patients with incident gastric adenocarcinoma from 2008 to 2015 ( n  = 1525). Cancer cases were matched to 10 controls. Linking information retrieved from nationwide Danish registries, we determined individual cumulative phthalate exposure to the ortho -phthalates diethyl phthalate (DEP), dibutyl phthalate (DBP) and enteric phthalate polymers from prescription drugs. The association between cumulative phthalate exposure and gastric adenocarcinoma was estimated using conditional logistic regression, adjusting for socioeconomical status and drugs or comorbidities known or suspected to modify the risk of gastric adenocarcinoma. Results: No association was seen for the risk of gastric adenocarcinomas among individuals with high cumulative exposure to ortho -phthalates (exceeding 500 mg) (OR adj 1.22, 95% CI: 0.84-1.77). Likewise, no associations were observed individually for DEP (OR adj 1.06 95% CI: 0.63-1.76) or DBP (OR adj 1.32 95% CI: 0.78-2.23). Cumulative exposure to enteric phthalate polymers exceeding 10,000 mg, did not reveal an association with gastric adenocarcinoma (OR adj 0.79, 95% CI: 0.54-1.16) and no association was seen for individual compounds. Additionally, no dose-response pattern was observed across exposure strata ( p  = .39, test for trend). Conclusion: We did not find an increased risk of gastric adenocarcinoma among Danish users of phthalate-containing drug products. Our study is limited by a low number of cases exposed to high cumulative doses of phthalates.

Objective: To investigate the protective effect and molecular mechanisms of Weining granule on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric cancer in rats., Methods: A total of sixty healthy male wistar rats were randomly divided into five groups, including control group (CG), gastric cancer model group (MG), low-dose Weining granule treated group (LWT), medium-dose Weining granule treated group (MWT), and high-dose Weining granule treated group (HWT). Except the control group, the other groups were treated with MNNG to establish a rat model of gastric cancer. Low-dose Weining granule treated group, medium-dose Weining granule treated group, and high-dose Weining granule treated group were fed 9.0, 18.0 and 36.0 g/kg Weining granule, respectively. Histopathologic and molecular biologic technology were adopted to determine the protective effect of Weining granule on MNNG-induced gastric cancer in rats. The pathological changes of gastrointestinal tissue were observed. Meanwhile, the differential expression of proliferation, apoptosis and angiogenesis markers were determined, including proliferating cell nuclear antigen (PCNA), pokemon, cyclin D1, B-cell lymphoma-2 (Bcl-2), caspase-3, phosphatase and tensin homolog (PTEN) and vascular endothelial growth factor (VEGF)., Results: After the MNNG treated, the pathological changes of stomach tissue were improved noticeably, including the intestinal metaplasia and atypic hyperplasia. The experiment was completed in 58 rats (96.67%). As compared with gastric cancer model group, the general states of rats were improved significantly after treated with different dose Weining granule. Moreover, treatment with different doses of Weining granule could inhibit the protein and mRNA expression of PCNA, pokemon, cyclin D1, Bcl-2, and VEGF, while increase caspase-3 and PTEN (P < 0.01)., Conclusion: Weining granule could improve gastric cancer by suppressing cell proliferation, promoting tumor cell apoptosis, and inhibiting angiogenesis.