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Gastroesophageal reflux disease (GERD) is a prevalent chronic ailment, and present therapeutic approaches are not always effective. This study aimed to find new drug targets for GERD and Barrett's esophagus (BE). We obtained genetic instruments for GERD, BE, and 2004 plasma proteins from recently published genome-wide association studies (GWAS), and Mendelian randomization (MR) was employed to explore potential drug targets. We further winnowed down MR-prioritized proteins through replication, reverse causality testing, colocalization analysis, phenotype scanning, and Phenome-wide MR. Furthermore, we constructed a protein-protein interaction network, unveiling potential associations among candidate proteins. Simultaneously, we acquired mRNA expression quantitative trait loci (eQTL) data from another GWAS encompassing four different tissues to identify additional drug targets. Meanwhile, we searched drug databases to evaluate these targets. Under Bonferroni correction (P < 4.8 × 10-5), we identified 11 plasma proteins significantly associated with GERD. Among these, 7 are protective proteins (MSP, GPX1, ERBB3, BT3A3, ANTR2, CCM2, and DECR2), while 4 are detrimental proteins (TMEM106B, DUSP13, C1-INH, and LINGO1). Ultimately, C1-INH and DECR2 successfully passed the screening process and exhibited similar directional causal effects on BE. Further analysis of eQTLs highlighted 4 potential drug targets, including EDEM3, PBX3, MEIS1-AS3, and NME7. The search of drug databases further supported our conclusions. Our study indicated that the plasma proteins C1-INH and DECR2, along with 4 genes (EDEM3, PBX3, MEIS1-AS3, and NME7), may represent potential drug targets for GERD and BE, warranting further investigation.

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INTRODUCTION: In the United States, clinical guidelines recommend daily use of proton pump inhibitors (PPIs) amongst individuals diagnosed with Barrett's esophagus to decrease the risk of progression to dysplasia and neoplasia. Prior studies documenting adherence to PPIs in this population have not characterized heterogeneity in adherence patterns. Factors that may relate to adherence are incompletely described. METHODS: We used administrative claims data from the Merative MarketScan Commercial Claims and Encounters database to conduct a retrospective study of adherence to prescription PPIs. A cohort of individuals diagnosed with incident Barrett's esophagus between 2010 and 2019 was identified. Group-based trajectory models were generated to detect longitudinal adherence subgroups. RESULTS: 79 701 individuals with a new diagnosis of Barrett's esophagus were identified. The best fitting model detected five distinct adherence trajectory groups: consistently high (44% of the population), moderate decline (18%), slow decline (12%), rapid decline (10%), and decline-then-increase (16%). Compared to individuals starting PPIs, those already using PPIs were less likely to have a declining adherence pattern. Other factors associated with membership in a declining adherence group included (but were not limited to): female sex, having a past diagnosis of anxiety or depression, and having one or more emergency department visits in the past year. DISCUSSION: Using an exploratory method, we detected heterogeneity in adherence to prescription PPIs. Less than half of individuals were classified into the consistently high adherence group, suggesting that many individuals with Barrett's esophagus receive inadequate pharmacologic therapy.

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BACKGROUND & AIMS: Antireflux treatment is recommended to reduce esophageal adenocarcinoma in patients with Barrett's esophagus. Antireflux surgery (fundoplication) counteracts gastroesophageal reflux of all types of carcinogenic gastric content and reduces esophageal acid exposure to a greater extent than antireflux medication (eg, proton pump inhibitors). We examined the hypothesis that antireflux surgery prevents esophageal adenocarcinoma to a larger degree than antireflux medication in patients with Barrett's esophagus. METHODS: This multinational and population-based cohort study included all patients with a diagnosis of Barrett's esophagus in any of the national patient registries in Denmark (2012-2020), Finland (1987-1996 and 2010-2020), Norway (2008-2020), or Sweden (2006-2020). Patients who underwent antireflux surgery were compared with nonoperated patients using antireflux medication. The risk of esophageal adenocarcinoma was calculated using multivariable Cox regression, providing hazard ratios (HRs) and 95% CIs adjusted for age, sex, country, calendar year, and comorbidity. RESULTS: The cohort consisted of 33,939 patients with Barrett's esophagus. Of these, 542 (1.6%) had undergone antireflux surgery. During up to 32 years of follow-up, the overall HR was not decreased in patients having undergone antireflux surgery compared with nonoperated patients using antireflux medication, but rather increased (adjusted HR, 1.9; 95% CI, 1.1-3.5). In addition, HRs did not decrease with longer follow-up, but instead increased for each follow-up category, from 1.8 (95% CI, 0.6-5.0) within 1-4 years of follow-up to 4.4 (95% CI, 1.4-13.5) after 10-32 years of follow-up. CONCLUSIONS: Patients with Barrett's esophagus who undergo antireflux surgery do not seem to have a lower risk of esophageal adenocarcinoma than those using antireflux medication.

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PURPOSE OF REVIEW: Barrett's esophagus (BE) is associated with chronic gastroesophageal reflux disease and is a known precursor to esophageal adenocarcinoma. While endoscopic surveillance strategies and the role for endoscopic eradication therapy have been well established, there has been much interest in identifying chemopreventive agents to disrupt or halt the metaplasia-dysplasia-carcinoma sequence in patients with BE. RECENT FINDINGS: No pharmacological agent has held more hope in reducing the risk of neoplastic progression in BE than proton pump inhibitors (PPIs). However, data supporting PPIs for chemoprevention have largely been from observational cohort and case-control studies with mixed results. In this review, we revisit the literature and highlight the role of PPIs in patients with BE as it pertains to chemoprophylaxis against the progression of BE to dysplasia and esophageal adenocarcinoma.

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This Guideline is an official statement of the European Society of Gastrointestinal Endoscopy (ESGE). It is an update of the previous (2017) Position Statement on the endoscopic management of Barrett esophagus.

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INTRODUCTION: Esophageal adenocarcinoma incidence has increased significantly despite surveillance endoscopy for Barrett's esophagus (BE) and gastric acid supression medications. This prospective, cohort study's aims were to determine the long-term efficacy of proton-pump inhibitors twice daily (PPI-BID) with cryotherapy (CRYO) for complete ablation of BE. MATERIALS AND METHODS: Consecutive BE patients were managed with a PPI-BID, CRYO ablation, follow-up protocol. Primary outcomes were to determine complete ablation rate of intestinal metaplasia (IM) or dysplasia/carcinoma, and factors affecting recurrence. RESULTS: Sixty-two patients were enrolled: advanced disease (11%), low-grade or indefinite dysplasia (26%), non-dysplastic BE (63%). In 58 completing CRYO, eradication was confirmed in 100% on surveillance endoscopy. Adverse events (5%) were minor (mild pain 4%). IM recurred in 9% after a mean of 52 months, all successfully re-ablated. No second recurrence occurred. The primary predictor of recurrence was noncompliance with PPI-BID. BE or cardia IM recurred in 35% of those taking proton pump inhibitors once daily or less compared with 0% in those on PPI-BID or dexlansoprazole daily (p<.001). CONCLUSIONS: Minimizing acid reflux with at least PPI-BID combined with CRYO ablation appears to be the optimal cost-effective and safe BE treatment for any stage to minimize progression to adenocarcinoma by addressing both the stimulus that causes BE and the presence of goblet cells.

Endoscopic surveillance of Barrett's esophagus (BE) has not made any clear impact on incidence of or mortality from esophageal adenocarcinoma.After cost-effective, safe cryoablation of BE, continued effective acid-reflux control with high-dose proton pump inhibitors is critical to minimize recurrence or progression.Risk factors and costs will define methods and frequency of limited surveillance after ablation of BE.

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BACKGROUND & AIMS: Barrett's esophagus is considered to be a metaplastic lesion that predisposes for esophageal adenocarcinoma. Development of Barrett's esophagus is considered to be driven by sonic hedgehog mediated bone morphogenetic protein (BMP) signaling. We aimed to investigate in preclinical in vivo models whether targeting canonical BMP signaling could be an effective treatment for Barrett's esophagus. METHODS AND RESULTS: Selective inhibition of BMP2 and BMP4 within an in vivo organoid model of Barrett's esophagus inhibited development of columnar Barrett's cells, while favoring expansion of squamous cells. Silencing of noggin, a natural antagonist of BMP2, BMP4, and BMP7, in a conditional knockout mouse model induced expansion of a Barrett's-like neo-columnar epithelium from multi-lineage glands. Conversely, in this model specific inhibition of BMP2 and BMP4 led to the development of a neo-squamous lineage. In an ablation model, inhibition of BMP2 and BMP4 resulted in the regeneration of neo-squamous epithelium after the cryoablation of columnar epithelium at the squamocolumnar junction. Through lineage tracing the generation of the neo-squamous mucosa was found to originate from K5+ progenitor squamous cells. CONCLUSIONS: Here we demonstrate that specific inhibitors of BMP2 and BMP4 attenuate the development of Barrett's columnar epithelium, providing a novel potential strategy for the treatment of Barrett's esophagus and the prevention of esophageal adenocarcinoma.

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Barrett esophagus is a premalignant change of the esophagus; however, malignant transformation to esophageal adenocarcinoma is rare in patients without dysplasia. Barrett esophagus is estimated to affect up to 5.6% of the U.S. population. Risk factors for Barrett esophagus include gastroesophageal reflux disease, obesity, age older than 50 years, male sex, tobacco use, and a family history of Barrett esophagus or esophageal adenocarcinoma. Patients who experience chronic gastroesophageal reflux symptoms plus additional risk factors should be considered for screening. Mucosal change consistent with Barrett esophagus is visualized during upper endoscopy; biopsy confirms the diagnosis and determines if dysplasia is present. Management of Barrett esophagus depends on the presence and severity of dysplasia; endoscopic treatment of dysplasia decreases the risk of malignant transformation. Surveillance after diagnosis is recommended to monitor for dysplasia and diagnose and treat esophageal adenocarcinoma at an earlier stage. Patients with Barrett esophagus should be offered proton pump inhibitor therapy to control reflux symptoms and possibly decrease the risk of developing esophageal adenocarcinoma. Statins, nonsteroidal anti-inflammatory drugs, and aspirin are associated with a decreased risk of esophageal adenocarcinoma in patients with Barrett esophagus; however, they should not generally be prescribed in the absence of another indication. Mortality benefits of screening and surveillance are uncertain.

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The present study aims to compare the effectiveness of surgical and medical therapy in reducing the risk of cancer in Barrett's esophagus in a long-term evaluation. A prospective cohort was designed that compared Barrett's esophagus patients submitted to medical treatment with omeprazole or laparoscopic Nissen fundoplication. The groups were compared using propensity score matching paired by Barrett's esophagus length. A total of 398 patients met inclusion criteria. There were 207 patients in the omeprazole group (Group A) and 191 in the total fundoplication group (Group B). After applying the propensity score matching paired by Barrett's esophagus length, the groups were 180 (Group A) and 190 (Group B). Median follow-up was 80 months. Group B was significantly superior for controlling GERD symptoms. Group B was more efficient than Group A in promoting Barrett's esophagus regression or blocking its progression. Group B was more efficient than Group A in preventing the development of dysplasia and cancer. Logistic regression was performed for the outcomes of adenocarcinoma and dysplasia. Age and body mass index were used as covariates in the logistic regression models. Even after regression analysis, Group B was still superior to Group A to prevent esophageal adenocarcinoma or dysplasia transformation (odds ratio [OR]: 0.51; 95% confidence interval [CI]: 0.27-0.97, for adenocarcinoma or any dysplasia; and OR: 0.26; 95% CI: 0.08-0.81, for adenocarcinoma or high-grade dysplasia). Surgical treatment is superior to medical management, allowing for better symptom control, less need for reflux medication use, higher regression rate of the columnar epithelium and intestinal metaplasia, and lower risk for progression to dysplasia and cancer.

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DESCRIPTION: Proton pump inhibitors (PPIs) are among the most commonly used medications in the world. Developed for the treatment and prevention of acid-mediated upper gastrointestinal conditions, these agents are being used increasingly for indications where their benefits are less certain. PPI overprescription imposes an economic cost and contributes to polypharmacy. In addition, PPI use has been increasingly linked to a number of adverse events (PPI-associated adverse events [PAAEs]). Therefore, de-prescribing of PPIs is an important strategy to lower pill burden while reducing real costs and theoretical risks. The purpose of this clinical update was to provide Best Practice Advice (BPA) statements about how to approach PPI de-prescribing in ambulatory patients. METHODS: Our guiding principle was that, although PPIs are generally safe, patients should not use any medication when there is not a reasonable expectation of benefit based on scientific evidence or prior treatment response. Prescribers are responsible for determining whether PPI use is absolutely or conditionally indicated and, when uncertainty exists, to incorporate patient perspectives into PPI decision making. We collaboratively outlined a high-level "process map" of the conceptual approach to de-prescribing PPIs in a clinical setting. We identified the following 3 key domains that required BPA guidance: documentation of PPI indication; identifying suitable candidates for consideration of de-prescribing; and optimizing successful de-prescribing. Co-authors drafted 1 or more potential BPAs, supported by literature review, for each domain. All co-authors reviewed, edited, and selected or rejected draft BPAs for inclusion in the final list submitted to the American Gastroenterological Association Governing Board. Because this was not a systematic review, we did not carry out a formal rating of the quality of evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: All patients taking a PPI should have a regular review of the ongoing indications for use and documentation of that indication. This review should be the responsibility of the patient's primary care provider. BEST PRACTICE ADVICE 2: All patients without a definitive indication for chronic PPI should be considered for trial of de-prescribing. BEST PRACTICE ADVICE 3: Most patients with an indication for chronic PPI use who take twice-daily dosing should be considered for step down to once-daily PPI. BEST PRACTICE ADVICE 4: Patients with complicated gastroesophageal reflux disease, such as those with a history of severe erosive esophagitis, esophageal ulcer, or peptic stricture, should generally not be considered for PPI discontinuation. BEST PRACTICE ADVICE 5: Patients with known Barrett's esophagus, eosinophilic esophagitis, or idiopathic pulmonary fibrosis should generally not be considered for a trial of de-prescribing. BEST PRACTICE ADVICE 6: PPI users should be assessed for upper gastrointestinal bleeding risk using an evidence-based strategy before de-prescribing. BEST PRACTICE ADVICE 7: Patients at high risk for upper gastrointestinal bleeding should not be considered for PPI de-prescribing. BEST PRACTICE ADVICE 8: Patients who discontinue long-term PPI therapy should be advised that they may develop transient upper gastrointestinal symptoms due to rebound acid hypersecretion. BEST PRACTICE ADVICE 9: When de-prescribing PPIs, either dose tapering or abrupt discontinuation can be considered. BEST PRACTICE ADVICE 10: The decision to discontinue PPIs should be based solely on the lack of an indication for PPI use, and not because of concern for PAAEs. The presence of a PAAE or a history of a PAAE in a current PPI user is not an independent indication for PPI withdrawal. Similarly, the presence of underlying risk factors for the development of an adverse event associated with PPI use should also not be an independent indication for PPI withdrawal.

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BACKGROUND: Observational studies demonstrate a protective effect of statins on the development and progression of esophageal adenocarcinoma. The role of statins in the prevention of reflux-induced esophageal changes remains unknown. AIMS: Using a mixed gastroduodenal reflux mouse model, we hypothesized that oral administration of simvastatin would attenuate reflux-induced mucosal changes of the distal esophagus. METHODS: Human Barrett's (CPB) and esophageal adenocarcinoma (FLO1 and OE19) cells were treated with simvastatin. Cell proliferation and apoptosis were evaluated using the MTS proliferation and annexin V apoptosis assays, respectively. A reflux mouse model was generated by performing a side-to-side anastomosis between the gastroesophageal junction and first portion of the duodenum (duodeno-gastroesophageal anastomosis, DGEA). DGEA mice were fed a standard or simvastatin-containing diet following surgery. Mice were euthanized 6 weeks post-operatively. RESULTS: Simvastatin significantly decreased proliferation and increased apoptosis in all cell lines. Compared to control animals, mice undergoing DGEA who were fed a standard diet demonstrated a fourfold increase in mucosal thickness and significant increase in proliferating cells (p < 0.0001). DGEA mice fed a simvastatin-containing diet had an attenuated response to reflux, with a significant reduction in mucosal hyperplasia and proliferation (p < 0.0001). DGEA mice fed a simvastatin-containing diet demonstrated significant upregulation of procaspase-3 (p = 0.009) and cleaved caspase-3 (p = 0.034) in the distal esophagus. CONCLUSIONS: We demonstrate for the first time a reduction in reflux-induced histologic changes of the distal esophagus following oral administration of simvastatin in vivo. These findings identify simvastatin as a potential preventative agent to inhibit the development and progression of reflux-induced esophageal injury.

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BACKGROUND: Barrett's esophagus (BE) is an important risk factor for high-grade dysplasia (HGD) and/or esophageal adenocarcinoma (EAC). The effect of proton pump inhibitors (PPIs) on the chemoprevention of HGD and/or EAC arising from BE remains controversial. RESEARCH DESIGN AND METHODS: PubMed, EMBASE, and Cochrane Library databases were systematically searched. Risk ratios (RRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were pooled by a random-effect model. Heterogeneity and its potential source were assessed. RESULTS: Fifteen studies with 26,291 BE patients were included. Meta-analysis of eight cohort studies showed that PPIs can significantly reduce the risk of HGD and/or EAC in BE patients (RR = 0.46; P < 0.001), but meta-analysis of six case-control studies showed no significant benefit of PPIs (OR = 0.64; P = 0.334). Heterogeneity was significant among both cohort and case-control studies, which might be attributed to the information sources of PPIs. There was no significant protective effect of high-dose PPIs on HGD and/or EAC in one RCT (RR = 0.84; P = 0.21), meta-analysis of two cohort studies (RR = 0.61; P = 0.28), or meta-analysis of two case-control studies (OR = 0.32; P = 0.08). CONCLUSIONS: Chemoprevention of HGD and/or EAC by PPIs may be considered in BE patients. However, there might not be further preventive effect of high-dose PPIs.

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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.

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Esophageal cancer is a malignancy that has a poor prognosis, which is mainly due to patients presenting once the cancer is in the advances stages. Chemotherapy has been the mainstay for treating esophageal cancer. However, these agents are not consistently effective and fail to differentiate between the different subtypes of esophageal cancers. Targeted therapies have slowly been introduced into the clinical setting, and initial results seem to be promising. Nevertheless, these medications are not universally cheap and also have non-negligible side effects. Therefore, identifying other classes of drugs which could possess anti-esophageal cancer properties is appealing. In addition to expediting the research and development phases of drug discovery, these agents will have known side effect profiles. Statins are a class of cholesterol-lowering medications that have been prescribed for decades. There is a growing body of literature that has shown the anticancer properties of statins in the setting of various malignancies. Herein, we summarize and assimilate the current evidence pertaining to the potential anti-esophageal cancer benefits of statins. We also discuss the limitations of the published studies and consider the future role statins can play in treating patients with esophageal cancers.

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Hypergastrinemia has been associated with high-grade dysplasia and adenocarcinoma in patients with Barrett's esophagus, and experimental studies suggest proinflammatory and proneoplastic effects of gastrin on Barrett's esophagus. This is of potential concern, as patients with Barrett's esophagus are treated with medications that suppress gastric acid production, resulting in increased physiologic levels of gastrin. We aimed to determine whether treatment with the novel gastrin/CCK2 receptor antagonist netazepide reduces expression of markers associated with inflammation and neoplasia in Barrett's esophagus. This was a randomized, double-blind, placebo-controlled trial of netazepide in patients with Barrett's esophagus without dysplasia. Subjects were treated for 12 weeks, with endoscopic assessment at baseline and at end of treatment. The primary outcome was within-individual change in cellular proliferation as assessed by Ki67. Secondary analyses included changes in gene expression, assessed by RNA-sequencing, and safety and tolerability. A total of 20 subjects completed the study and were included in the analyses. There was no difference between arms in mean change in cellular proliferation (netazepide: +35.6 Ki67+ cells/mm2, SD 620.7; placebo: +307.8 Ki67+ cells/mm2, SD 640.3; P = 0.35). Netazepide treatment resulted in increased expression of genes related to gastric phenotype (TFF2, MUC5B) and certain cancer-associated markers (REG3A, PAX9, MUC1), and decreased expression of intestinal markers MUC2, FABP1, FABP2, and CDX1 No serious adverse events related to study drug occurred. The gastrin/CCK2 receptor antagonist netazepide did not reduce cellular proliferation in patients with nondysplastic Barrett's esophagus. Further research should focus on the biological effects of gastrin in Barrett's esophagus.Prevention Relevance: Treatment of patients with Barrett's esophagus with a gastrin/CCK2 receptor antagonist did not have obvious chemopreventive effects.

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PURPOSE: Previous research on the association between proton pump inhibitor (PPI) use and the risk of progression to high-grade dysplasia (HGD)/esophageal adenocarcinoma (EAC) in Barrett's Esophagus (BE) patients has generated inconsistent findings. This meta-analysis was performed to clarify the association. METHODS: We performed a comprehensive search strategy to select relevant studies up to September 2020. Heterogeneity was assessed using the I-squared statistic. Odds ratios (OR) and 95% confidence intervals (CI) were calculated through either fixed-effects or random-effects model. Duration-response was also performed to assess the gain effects of different PPI intake duration. Sensitivity analysis, subgroup analyses, and tests for publication bias or other small-study effects were conducted. RESULTS: Twelve studies with 155,769 subjects were included. The PPI use was associated with the reduced risk of BE progression to HGD/EAC (OR = 0.47, 95% CI = 0.32-0.71). In the duration-response analysis, the estimated OR for decreased risk of HGD/EAC with PPI intake duration of 12 months was 0.81 (95% CI = 0.71-0.91). Sensitivity analysis suggested the results of this meta-analysis were stable. No publication bias was detected. CONCLUSIONS: PPI use is associated with a decreased risk of HGD/EAC in patients with BE. For further investigation, that more well-designed studies are still needed to elucidate the protective effect of PPI usage on BE patients to prevent HGD/EAC.

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AIM: To determine predictors of insufficient effectiveness of proton pump inhibitors based on the parameters of 24-hours pH-impedance and features of motor function of the esophagus in patients with Barrett's esophagus. MATERIALS AND METHODS: 17 patients with histologically verified Barrett's esophagus undergoing acid-suppressive therapy were examined. All patients underwent 24-hours pH-impedance and high-resolution esophageal manometry. RESULTS: According to daily pH-impedance, group 1 consisted of 11 patients with an adequate response to antisecretory therapy, group 2 6 patients with insufficient effectiveness of antisecretory therapy, 5 of whom had no clinical manifestations. The total number of reflux averaged 52 and 91, respectively, in groups 1 and 2. The average number of acid reflux in group 1 was 4.36, in group 2 40.5. The average number of non-acid reflux prevailed in patients of group 2, averaging 58, compared with group 1, where the average was 47. According to the results of high-resolution esophageal manometry, when assessing the structure and function of the esophageal-gastric junction, violations were detected in 6 out of 17 patients. Disorders of the motor function of the thoracic esophagus were detected in 10 out of 17 patients. The tone of the lower esophageal sphincter in group 1 patients was significantly higher in comparison with patients in group 2. CONCLUSION: A number of patients with Barrett's esophagus have insufficient effectiveness of antisecretory therapy, which may not manifest itself clinically and thereby increase the risk of progression. There was a tendency to more frequent motor disorders in the group with insufficient effectiveness of antisecretory therapy, as well as significantly lower tone of the lower esophageal sphincter, which may be a potential predictor of suboptimal effectiveness of antisecretory therapy.

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Barrett's esophagus (BE), a recognized risk factor for esophageal adenocarcinoma (EAC), is routinely managed with proton pump inhibitors (PPIs) when symptomatic. Several lines of evidence suggest that PPIs may prevent malignant transformation. Chronic use of other common drugs, namely, statins nonsteroidal anti-inflammatory drugs (NSAIDs) and metformin, may also interfere with BE carcinogenesis, but confirmatory evidence is lacking. We identified 1,943 EAC cases and 19,430 controls (matched 10:1) between 2007 and 2013 that met our specified inclusion criteria in the SEER-Medicare database. Conditional logistic regression was used to generate odds ratios (OR) and 95% confidence intervals (95% CI). Wald χ2 tests were used to assess significance of covariates. Compared with controls, EAC cases had a higher prevalence of BE (26.2%). Use of PPIs, NSAIDs, statins, or metformin reduced the odds of EAC (PPIs: 0.10; 95% CI, 0.09-0.12; NSAIDs: 0.62; 95% CI, 0.51-0.74; statins: 0.15; 95% CI, 0.13-0.17; metformin: 0.76; 95% CI, 0.62-0.93). When stratified by BE, these associations persisted, though no association was found between NSAID use and EAC risk for participants with BE. Dual use of PPIs with NSAIDs or statins, and NSAID, statin, or metformin use alone also showed significant EAC risk reduction among all participants and those without BE. Use of PPIs alone and with NSAIDs, statins, or metformin was associated with reduced risk of EAC; however, a history of BE may diminish drug efficacy. These results indicate that common pharmacologic agents alone or in combination may decrease EAC development.Prevention Relevance: The use of common drugs, such as proton pump inhibitors, statins, non-steroidal anti-inflammatory drugs, or metformin, may reduce one's risk of developing esophageal adenocarcinoma. These results suggest that repurposing agents often used for common chronic conditions may be a new strategy for cancer prevention efforts.

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BACKGROUND: Receptor tyrosine kinases of the epidermal growth factor receptor (EGFR) family such as human epidermal receptor-2 (HER2) are involved in the development and progression of esophageal adenocarcinoma (EAC). Prior studies have demonstrated that group IIa secretory phospholipase A2 (sPLA2 IIa) can function as a ligand for the EGFR family of receptors and lead to an increase in receptor signaling. AIMS: We hypothesized that sPLA2 IIa inhibition downregulates the expression of EGFR and HER-2 in EAC and through this mechanism decreases proliferation in EAC. METHODS: Normal human esophageal epithelium, Barrett's esophagus (BE), and EAC tissue samples were assayed for baseline expression of EGFR, HER-2, and sPLA2 IIa. sPLA2 IIa was attenuated via inhibitor or lentiviral knockdown in esophageal cell lines, and cells were assayed for EGFR and HER2 expression as well as proliferation. FLO1 EAC cells were injected into the flank of nude mice. After randomization, mice received daily group IIA sPLA2 inhibitor or a control solution, and tumor volume was measured with calipers. RESULTS: sPLA2 IIa, EGFR, and HER2 expression increased across the spectrum of normal esophageal epithelium to EAC. sPLA2 IIa inhibition and knockdown decreased the expression of HER-2 and EGFR and proliferation. Mice treated with sPLA2 IIa inhibitor had smaller tumors than controls. CONCLUSIONS: sPLA2 IIa inhibition decreases EGFR and HER2 expression and lowers proliferation of human EAC. The discovery of sPLA2 IIa inhibition's ability to attenuate growth factor receptor signaling underscores the exciting potential of sPLA2 IIa inhibitors as therapeutics in the treatment of EAC.

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