Gary W. Falk

A Combination of Esomeprazole and Aspirin Reduces Tissue Concentrations of Prostaglandin E2 in Patients With Barrett's Esophagus

UNLABELLEDnBACKGROUND& AIMS: Proton pump inhibitors and nonsteroidal anti-inflammatory drugs might prevent esophageal adenocarcinoma in patients with Barretts esophagus (BE), but there are limited data from clinical trials to support this concept. We conducted a randomized, double-blind, placebo-controlled, phase 2 trial to assess the effects of the combination of aspirin (3 different doses) and esomeprazole on tissue concentrations of prostaglandin (PG) E(2) in patients with BE with no dysplasia or low-grade dysplasia.nnnMETHODSnParticipants were recruited through the multicenter Cancer Prevention Network and randomly assigned to groups that were given 40 mg esomeprazole twice daily in combination with an aspirin placebo once daily (arm A; n = 30), with 81 mg aspirin once daily (arm B; n = 47), or with 325 mg aspirin once daily (arm C; n = 45) for 28 days. We collected esophageal biopsy specimens before and after the intervention period to determine the absolute change in mean concentration of PGE(2) (the primary end point).nnnRESULTSnBased on data from 114 patients, baseline characteristics were similar among groups. The absolute mean tissue concentration of PGE(2) was reduced by 67.6 ± 229.68 pg/mL in arm A, 123.9 ± 284.0 pg/mL in arm B (P = .10 vs arm A), and 174.9 ± 263.62 pg/mL in arm C (P = .02 vs arm A).nnnCONCLUSIONSnIn combination with esomeprazole, short-term administration of higher doses of aspirin, but not lower doses or no aspirin, significantly reduced tissue concentrations of PGE(2) in patients with BE with either no dysplasia or low-grade dysplasia. These data support further evaluation of higher doses of aspirin and esomeprazole to prevent esophageal adenocarcinoma in these patients. Clinical trial registration number NCT00474903.

Alginate therapy is effective treatment for GERD symptoms: a systematic review and meta-analysis

In patients with gastroesophageal reflux disease (GERD) and erosive esophagitis, treatment with proton pump inhibitors (PPIs) is highly effective. However, in some patients, especially those with nonerosive reflux disease or atypical GERD symptoms, acid-suppressive therapy with PPIs is not as successful. Alginates are medications that work through an alternative mechanism by displacing the postprandial gastric acid pocket. This study performed a systematic review and meta-analysis to examine the benefit of alginate-containing compounds in the treatment of patients with symptoms of GERD. PubMed/MEDLINE, Embase, and the Cochrane library electronic databases were searched through October 2015 for randomized controlled trials comparing alginate-containing compounds to placebo, antacids, histamine-2 receptor antagonists (H2RAs), or PPIs for the treatment of GERD symptoms. Additional studies were identified through a bibliography review. Non-English studies and those with pediatric patients were excluded. Meta-analyses were performed using random-effect models to calculate odds ratios (OR). Heterogeneity between studies was estimated using the I2 statistic. Analyses were stratified by type of comparator. The search strategy yielded 665 studies and 15 (2.3%) met inclusion criteria. Fourteen were included in the meta-analysis (N = 2095 subjects). Alginate-based therapies increased the odds of resolution of GERD symptoms when compared to placebo or antacids (OR: 4.42; 95% CI 2.45-7.97) with a moderate degree of heterogeneity between studies (I2 = 71%, P = .001). Compared to PPIs or H2RAs, alginates appear less effective but the pooled estimate was not statistically significant (OR: 0.58; 95% CI 0.27-1.22). Alginates are more effective than placebo or antacids for treating GERD symptoms.

Associations of Serum Adiponectin and Leptin With Barrett’s Esophagus

BACKGROUND & AIMSnCentral adiposity is a risk factor for Barretts esophagus (BE). Serum levels of adiponectin and leptin are deregulated in obese states and are implicated as putative mediators in the pathophysiology of esophageal columnar metaplasia. We describe associations between serum adiponectin and leptin levels with BE.nnnMETHODSnPatients were recruited prospectively for a case-control study. Fasting serum levels of adiponectin and leptin were measured in 135 patients with BE and compared with 2 separate control groups: 133 subjects with gastroesophageal reflux disease (GERD) and 1157 colon screening controls.nnnRESULTSnMultivariate analyses adjusted for age, race, and waist-to-hip ratio showed that patients within the highest tertile of serum adiponectin level had decreased odds of BE compared with screening colonoscopy controls (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.22-0.80). This effect was more pronounced in men (OR, 0.35; 95% CI, 0.17-0.74) compared with women (OR, 0.71; 95% CI, 0.17-3.03). In comparisons of BE cases with GERD controls, subjects within the highest tertile of serum adiponectin level showed decreased odds of BE (OR, 0.65; 95% CI, 0.31-1.36), however, this was not statistically significant. Patients in the highest tertile of serum leptin level did not have a significantly increased risk of BE in comparison with GERD (OR, 1.32; 95% CI, 0.61-2.88) or screening colonoscopy controls (OR, 1.57; 95% CI, 0.82-3.04) in analyses including both sexes. Based on sex-specific analyses, sex did not significantly alter the association of leptin with odds of BE.nnnCONCLUSIONSnSerum adiponectin was associated inversely with BE and this effect was more pronounced in men, whereas serum leptin showed no evidence of association with BE in comparisons with multiple control groups. The exact mechanism, if any, by which these adipokines promote metaplasia in the esophagus needs to be explored further.

Clinical Presentation of Eosinophilic Esophagitis in Adults

Eosinophilic esophagitis (EoE) is an increasingly recognized immune antigen-mediated esophageal disease found in both children and adults. It is defined as a clinicopathologic disease characterized by symptoms of esophageal dysfunction accompanied by an eosinophil-predominant esophageal inflammation that occurs in the absence of other causes of esophageal eosinophilia. Classic symptoms in adults include dysphagia to solids and food bolus impaction but a variety of other symptoms are also encountered. Despite the increasing awareness of EoE among practicing physicians, a long delay from onset of symptoms to diagnosis remains a problem in this disease.

Health-Related Quality of Life and Costs Associated With Eosinophilic Esophagitis: A Systematic Review

Background & Aims Eosinophilic esophagitis (EoE) is a chronic immune‐mediated disease characterized by esophageal inflammation and dysfunction. Little is known about the humanistic and economic burden of the disease on patients, their caregivers, and the health care system. A systematic review was conducted to evaluate the existing literature on the disease burden of EoE for patients and their caregivers. Methods The MEDLINE, Embase, and Evidence‐Based Medicine Reviews databases and recent congresses were searched on March 23, 2017, for English‐language publications describing the impact of EoE on health‐related quality of life (HRQoL) in children and adults, and the economic burden associated with the disease. Results Of 676 articles identified, 22 met the inclusion criteria and were included in this analysis (HRQoL, 13; economic burden, 7; cost effectiveness, 2). The included studies showed that EoE is associated with a significant impact on HRQoL, resulting in disruption to and restrictions on daily life for patients, their caregivers, and, in some instances, their families. Treatment with topical corticosteroids, the 6‐food elimination diet, or the cow’s milk elimination diet significantly improved the HRQoL of patients with EoE. Symptom severity was associated strongly with the impact of EoE on HRQoL. Medical resource utilization costs for patients with EoE were significantly higher than those for healthy controls. Conclusions EoE negatively impacts the HRQoL of patients and their families, and is a burden to the health care system. Although data are sparse, currently available treatments appear to improve HRQoL.

Barrett's esophagus surveillance: When, how often, does it work?

Barretts esophagus is a well-known risk factor for the development of esophageal adenocarcinoma. Current practice guidelines recommend endoscopic surveillance of patients with Barretts esophagus in an attempt to detect cancer at an early and potentially curable stage. This review addresses the rationale behind surveillance and criteria for inclusion of patients in surveillance programs as well as the appropriate technique and intervals that should be used. This work addresses other key topics in Barretts esophagus surveillance, including the efficacy of surveillance programs, physician compliance with surveillance guidelines, cost-effectiveness of surveillance programs, and areas for future research.

Barrett's oesophagus: Frequency and prediction of dysplasia and cancer

The incidence of oesophageal adenocarcinoma is continuing to increase at an alarming rate in the Western world today. Barretts oesophagus is a clearly recognized risk factor for the development of oesophageal adenocarcinoma, but the overwhelming majority of patients with Barretts oesophagus will never develop oesophageal cancer. A number of endoscopic, histologic and epidemiologic riskxa0factors identify Barretts oesophagus patients at increased risk for progression to high-grade dysplasia and oesophageal adenocarcinoma. Endoscopic factors include segment length, mucosal abnormalities as seemingly trivial as oesophagitis and the 12 to 6xa0oclock hemisphere of the oesophagus. Both intestinal metaplasia and low grade dysplasia, the latter only if confirmed by a pathologist with expertise in Barretts oesophagus pathologic interpretation are the histologic risk factors for progression. Epidemiologic risk factors include ageing, male gender, obesity, and smoking. Factors that may protect against the development of adenocarcinoma include a diet rich in fruits and vegetables, and the use of proton pump inhibitors, aspirin/NSAIDs and statins.

Eosinophilic oesophagitis endotype classification by molecular, clinical, and histopathological analyses: a cross-sectional study

BACKGROUNDnEosinophilic oesophagitis is understood in terms of quantifiable histological, endoscopic, and molecular features. Data are scant for inter-relations of these features and their potential to identify distinct disease endotypes. We aimed to identify clinical-pathological correlations between endoscopic and histological disease variables by transcription profiling of the oesophagus of patients with eosinophilic oesophagitis of varying severity and disease activity states.nnnMETHODSnWe did a cross-sectional study across ten hospital sites in the USA associated with the Consortium of Eosinophilic Gastrointestinal Disease Researchers. We analysed oesophageal biopsy specimens taken from paediatric and adult patients with eosinophilic oesophagitis (discovery cohort), using the eosinophilic oesophagitis diagnostic panel (EDP), a set of 96 informative transcripts. Histological and endoscopic features were assessed by quantification of oesophageal eosinophils and use of the eosinophilic oesophagitis histology scoring system (HSS) and the eosinophilic oesophagitis endoscopic reference score (EREFS). Associations among the various histological, endoscopic, and molecular features were analysed by Spearman correlation. Results were replicated in a biologically independent, single-centre, validation cohort of patients with active eosinophilic oesophagitis.nnnFINDINGSnThe discovery cohort contained 185 samples and the validation cohort comprised 100 specimens. In the discovery cohort, EDP showed intersite consistency, significant correlation with oesophageal eosinophils (p<0·0001), and similar findings between paediatric and adult patients. Of eight HSS domains, basal zone hyperplasia correlated with the EDP (median Spearman ρ 0·47 [IQR 0·36-0·60]). Of five EREFS features, distal furrows correlated with the EDP (median Spearman ρ 0·42 [0·32-0·50]). By analysing active eosinophilic oesophagitis in the discovery cohort, the EDP identified three clusters associated with distinct endotypes (termed EoEe1-3) despite similar eosinophil levels. EoEe1 was associated with a normal-appearing oesophagus (risk ratio [RR] 3·27, 95% CI 1·04-10·27; p=0·0443), an inverse association with a history of oesophageal dilation (0·27, 0·09-0·82; p=0·0105) and showed relatively mild histological, endoscopic, and molecular changes. EoEe2 showed an inflammatory and steroid-refractory phenotype (RR 2·77, 95% CI 1·11-6·95; p=0·0376) and had the highest expression of inflammatory cytokines and steroid-responding genes. EoEe3 was associated with a narrow-calibre oesophagus (RR 7·98, 95% CI 1·84-34·64; p=0·0013) and adult onset (2·22, 1·19-4·12; p=0·0155), and showed the highest degree of endoscopic and histological severity and the lowest expression of epithelial differentiation genes. These endotypes were replicated in the validation cohort by clustering and with an eosinophilic oesophagitis endotype-prediction algorithm.nnnINTERPRETATIONnOur new disease classification stratifies patients with eosinophilic oesophagitis into subgroups with potential clinical and therapeutic significance and provides a framework for a precision medicine approach to eosinophilic oesophagitis.nnnFUNDINGnNational Institutes of Health.

Endoscopic submucosal dissection for Barrett-associated neoplasia: is it ready for the endoscopist’s toolbox?

Esophageal adenocarcinoma continues to be a vexing problem for the Western world, where its incidence has increased at an alarming rate and is projected to continue to increase in the coming decades as well [1]. Compounding this problem is the fact that most patients who have esophageal adenocarcinoma present with late-stage symptomatic disease and accompanying poor survival; in only a small minority has the precursor lesion of Barrett’s esophagus been diagnosed. That said, the treatment of early neoplasia in Barrett’s esophagus has advanced dramatically in recent years. Whereas surgical esophagectomy, with its well-documented limitations, was once viewed as the treatment of choice, endoscopic therapy consisting of endoscopic mucosal resection (EMR) of visible lesions followed by ablation of the residual Barrett’s segment, typically with radiofrequency ablation, has become the standard of care and is endorsed by both professional society guidelines and an international consensus panel [2,3]. The Wiesbaden group first demonstrated the remarkable efficacy of EMR for early neoplasia in Barrett’s esophagus in a landmark study published in 2007, with a 5-year survival rate of 98% but a recurrence rate of 11% [4]. Importantly, lesions eligible for EMR were characterized by the following criteria: lesion diameter smaller than 20mm and macroscopically Paris type I, IIa, IIb, or IIc lesions smaller than 10mm; well-differentiated or moderately differentiated grade of adenocarcinoma; lesion limited to the mucosa; and absence of invasion into lymph vessels or veins. The Wiesbaden group subsequently found that recurrence of neoplasia after endoscopic resection was related to factors such as failure to ablate the residual Barrett’s segment completely, multifocal neoplasia, piecemeal resection, and long-segment Barrett’s esophagus [5]. Finally, the group’s longterm results for EMR in patients who had Barrett’s esophagus with mucosal adenocarcinoma were published in the summer of 2014 [6]. In this remarkable study of 1000 patients, the majority were treated with the multiband ligator device, and 49% underwent piecemeal resection followed by ablation of the residual, nondysplastic Barrett’s segment; complete remission of all high grade dysplasia and intraepithelial neoplasia was noted in 96.3% of patients, tumor-related death occurred in 0.2%, and the rate of disease-free survival was 87.1% at 5 years. Other studies have confirmed the remarkable long-term efficacy and safety of EMR with or without radiofrequency ablation for early neoplasia in Barrett’s esophagus [7–10]. Therefore, it would appear that most patients who have early neoplasia in Barrett’s esophagus can be treated effectively and safely with endoscopic eradication therapy, as previously described. Endoscopic submucosal dissection (ESD) is the “new kid on the block,” so to speak, to enter the fray in the endoscopic treatment of Barrett-associated neoplasia. Pioneered in Japan, where it is widely used for the treatment of superficial gastric cancer, ESD has also been employed in the colon and esophagus, most notably for esophageal squamous cell carcinoma. Proponents of ESD point to the ability of this technique to achieve the en bloc resection of larger lesions; in addition, a more precise histologic assessment of lesion margins is possible than can be achieved in piecemeal EMR specimens [11]. However, these advantages come at a price, including increases in procedure time, technical complexity, and complications (e.g., perforation, stenosis, bleeding) in comparison with standard EMR. To date, little is known about the role, if any, of ESD in the treatment of Barrett’s-associated neoplasia because only small numbers of patients have been described, primarily in Asia. In the one Western study, of 30 patients with high grade dysplasia or intramucosal adenocarcinoma, Neuhaus et al. achieved complete endoscopic resec-

Natural history of eosinophilic esophagitis: a systematic review of epidemiology and disease course

SUMMARY Eosinophilic esophagitis is a chronic immune-mediated esophageal disorder. For its timely diagnosis, clinicians must recognize common symptoms, and understand differences in symptoms across patient groups. The aim of this study is to systematically review the epidemiology and natural history of eosinophilic esophagitis. The MEDLINE, Embase, and Cochrane databases were searched from 1974 to February 2017 for studies describing the epidemiology and natural history of eosinophilic esophagitis. Congress abstracts from 2014 to 2016 were also searched. Search results were screened against predetermined inclusion/exclusion criteria by two independent reviewers, and data extraction was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Of 1376 articles identified, 47 met the inclusion criteria: 20 on epidemiology and 27 on natural history. Incidence and prevalence of eosinophilic esophagitis varied widely across North America and Europe, and increased over time. Incidence increased 131-fold in the Netherlands (1996–2010), 20-fold in Denmark (1997–2006), and 5.1-fold in Calgary, Canada (2004–2008). The most commonly reported symptoms were emesis and abdominal pain in children, and dysphagia and food impaction in adults. Age at diagnosis was 5.9–12.0 years in children, and approximately 30 years in adults. Time between symptom onset and diagnosis was 1.2–3.5 years in children and 3.0–8.0 years in adults. Diagnostic delay was associated with an increased risk of endoscopic features of fibrostenosis. Symptoms of eosinophilic esophagitis differed significantly by age and race. In conclusion, there is an increasing incidence and prevalence of eosinophilic esophagitis. The considerable delay between symptom onset and diagnosis suggests that clinicians do not readily recognize the disease, which may have important clinical ramifications.