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Supplementary Table 3 from A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

Supplementary Table 1 from A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

Supplementary Table 4 from A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

Supplementary Figure 2 from A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

Supplementary Figure 1 from A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

Supplementary Table 2 from A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible., Studies of the genetic association between vitamin D and cancer risk have typically been underpowered. Here the authors analyse this using Mendelian Randomisation with more than 70 vitamin D variants obtained from the UK Biobank and large-scale data from various consortia, confirming null associations between vitamin D and most cancers.

Background & Aims Eosinophilic esophagitis (EoE) is assessed endoscopically (endoscopic activity), based on grades of edema, rings, exudates, furrows, and strictures (EREFS). We examined variations in endoscopic assessments of severity, developed and validated 3 EREFS-based scoring systems, and assessed responsiveness of these systems using data from a randomized placebo-controlled trial of patients with EoE. Methods For the development set, 5 gastroenterologists reviewed EREFS findings from 266 adults with EoE and provided endoscopist global assessment scores (EndoGA, scale of 0 to 10); variation (ΔEndoGA) was assessed using linear regression. We evaluated simple scores (features given arbitrary values from 0 to 3) and developed 2 scoring systems (adjusted score range, 0–100). We then fitted our linear regression model with mean EndoGA to data from 146 adults recruited in centers in Switzerland and the United States between April 2011 and December 2012. For the validation set, we collected data from 120 separate adults (recruited in centers in Switzerland and the United States between May 2013 and July 2014), assessing regression coefficient-based scores using Bland-Altman method. We assessed the responsiveness of our scoring systems using data from a randomized trial of patients with EoE given fluticasone (n=16) or placebo (n=8). Results The distribution of EndoGA values differed among endoscopists (mean ΔEndoGA, 2.6±1.8; range 0–6.6). We developed 2 regression-based scoring systems to assess overall and proximal and distal esophageal findings; variation in endoscopic features accounted for more than 90% of the mean EndoGA variation. In the validation group, differences between mean EndoGA and regression-based scores were small (ranging from –4.70 to 2.03), indicating good agreement. In analyses of data from the randomized trial, the baseline to end of study change in patients given fluticasone was a reduction of 24.3 in simple score (reduction of 4.6 in patients given placebo, P=.052); a reduction of 23.5 in regression-based overall score (reduction of 6.56 in patients given placebo, P=.12), and a reduction of 23.8 (reduction of 8.44 in patients given placebo, P=.11). Conclusion Assessments of endoscopic activity in patients with EoE vary among endoscopists. In an analysis of data from a randomized controlled trial, we found that newly developed scoring systems are no better than simple scoring system in detecting changes in endoscopic activity. These results support the use of a simple scoring system in evaluation of endoscopic activity in patients with EoE. clinicaltrials.gov no: NCT00939263 and NCT 01386112

The strong male predominance in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) remains inadequately explained, but sex hormones might be involved. We hypothesized that single nucleotide polymorphisms (SNPs) in the androgen pathway influence risk of developing BE and EAC. This genetic-epidemiological analysis included 14 studies from Australia, Europe and North America. Polymorphisms in 16 genes coding for the androgen pathway were analyzed using a gene-based approach: versatile gene-based test association study. This method evaluates associations between a trait and all SNPs within a specific gene rather than each SNP marker individually as in a conventional GWAS. The data were stratified for sex, body-mass index, waist-to-hip ratio, tobacco smoking and gastroesophageal reflux status. Included were data from 1,508 EAC patients, 2,383 BE patients and 2,170 control participants. SNPs within the gene CYP17A1 were associated with risk of BE in the sexes combined (p = 0.002) and in males (p = 0.003), but not in females separately (p = 0.3). This association was found in tobacco smokers (p = 0.003) and in BE patients without reflux (p = 0.004), but not in nonsmokers (p = 0.2) or those with reflux (p = 0.036). SNPs within JMJD1C were associated with risk of EAC in females (p = 0.001). However, none of these associations replicated in a subsequent sample. Fourteen other genes studied did not reach statistically significant levels of association with BE, EAC or the combination of BE and EAC, after correcting for the number of genes included in the analysis. In conclusion, genetic variants in the androgen-related genes CYP17A1 and JMJD1C might be associated with risk of BE and EAC, respectively, but replication data with larger sample sizes are needed.

OBJECTIVES: There is no "gold standard" for assessing disease activity in patients with eosinophilic esophagitis (EoE). We aimed to compare physicians' judgment of EoE activity with patients' judgment of symptom severity. We also aimed to examine the relative contribution of symptoms as well as endoscopic and histologic findings in shaping physicians' judgment of EoE activity. METHODS: Six gastroenterologists (all EoE experts) assessed EoE associated symptoms in adult patients. Patients completed a symptom instrument and provided global assessment of EoE symptom severity (PatGA) (Likert scale: 0 (inactive) to 10 (most active)). Following esophagogastroduodenoscopy with biopsy sampling gastroenterologists provided a global assessment of EoE activity (PhysGA) (Likert scale from 0 to 10) based on patient history and endoscopic and histologic findings. Linear regression and analysis of variance was used to quantify the extent to which variations in severity of EoE symptoms and endoscopic and histologic findings explain variations in PhysGA. RESULTS: A total of 149 EoE patients were prospectively included (71.8 male median age at inclusion 38 years 71.8 with concomitant allergies). A moderate positive correlation between PhysGA and PatGA (rho=0.442 P

Background High-resolution manometry using the Chicago classification, which utilizes parameters including integrated relaxation pressure (IRP), distal contractile integral (DCI), and contractile front velocity (CFV), shows better diagnostic ability than previous conventional criteria. However, the current normal cut-off values for the Chicago classification are based on individuals aged 19–48 years and do not include older people. Here, we aimed to assess the normal values for the Chicago classification in individuals aged 20–67 years and compare the parameters across age groups. Methods Fifty-four asymptomatic healthy individuals (27 male and 27 female; age range. 20–67 years) were prospectively enrolled. To evaluate the effect of age and sex on manometric profiles, we attempted to enroll equal numbers of male and female subjects for each decade. Manometry was performed in both the supine and sitting positions. Key Results The distal latency (DL) was significantly shorter with increasing age in both measurement positions. Furthermore, IRP was significantly higher with increasing age in both positions. Spearman's ranked correlation coefficient analysis indicated that DCI and IRP in both positions were positively correlated with age. Conclusions & Inferences Age affects the key parameters currently used in the Chicago classification, including IRP, DCI, and DL. Larger prospective studies with older subjects are needed to determine the age-related normal values for the Chicago classification system.

Background Long-lasting food impactions requiring endoscopic bolus removal occur frequently in patients with eosinophilic esophagitis (EoE) and harbor a risk for severe esophageal injuries. We evaluated whether treatment with swallowed topical corticosteroids is able to reduce the risk of occurrence of this complication. Methods We analyzed data from the Swiss EoE Cohort Study. Patients with yearly clinic visits, during which standardized assessment of symptoms, endoscopic, histologic, and laboratory findings was carried out, were included. Results A total of 206 patients (157 males) were analyzed. The median follow-up time was 5 years with a total of 703 visits (mean 3.41 visits/patient). During the follow-up period, 33 patients (16 % of the cohort) experienced 42 impactions requiring endoscopic bolus removal. We evaluated the following factors regarding the outcome ‘bolus impaction’ by univariate logistic regression modeling: swallowed topical corticosteroid therapy (OR 0.503, 95%-CI 0.255–0.993, P = 0.048), presence of EoE symptoms (OR 1.150, 95%-CI 0.4668–2.835, P = 0.761), esophageal stricture (OR 2.832, 95%-CI 1.508–5.321, P = 0.001), peak eosinophil count >10 eosinophils/HPF (OR 0.724, 95%-CI 0.324–1.621, P = 0.433), blood eosinophilia (OR 1.532, 95%-CI 0.569–4.118, P = 0.398), and esophageal dilation (OR 1.852, 95%-CI 1.034–3.755, P = 0.017). In the multivariate model, the following factors were significantly associated with bolus impaction: swallowed topical corticosteroid therapy (OR 0.411, 95%-CI 0.203–0.835, P = 0.014) and esophageal stricture (OR 2.666, 95%-CI 1.259–5.645, P = 0.01). Increasing frequency of use of swallowed topical steroids was associated with a lower risk for bolus impactions. Conclusions Treatment of EoE with swallowed topical corticosteroids significantly reduces the risk for long-lasting bolus impactions.

Morning dose or twice-daily proton pump inhibitor (PPI) use is often prescribed to heal severe reflux esophagitis.Compare the effect of single dose morning (control arm) versus nighttime (experimental arm) omeprazole/sodium bicarbonate (Zegerid(®)) (IR-OME) on esophagitis and gastroesophageal reflux symptoms.Adult outpatients with Los Angeles grade C or D esophagitis were allocated to open-label 40 mg IR-OME once a day for 8 weeks in a prospective, randomized, parallel design, single center study. Esophagogastroduodenoscopy (EGD) and validated self-report symptom questionnaires were completed at baseline and follow-up. Intention-to-treat and per-protocol analyses were performed.Ninety-two of 128 (72 %) eligible subjects participated [64 (70 %) male, mean age 58 (range 19-86), median BMI 29 (range 21-51), 58 C:34 D]. Overall, 81 (88 %) subjects healed [n = 70 (76 %)] or improved [n = 11 (12 %)] erosions. There was no significant difference (morning vs. night) in mucosal healing [81 vs. 71 %, (p = 0.44)] or symptom resolution [heartburn (77 vs. 65 %, p = 0.12), acid regurgitation (82 vs. 73 %, p = 0.28)]. Prevalence of newly identified Barrett's esophagus was 14 % with half diagnosed only after treatment.Once-daily IR-OME (taken morning or night) effectively heals severe reflux esophagitis and improves GERD symptoms. Results support the clinical practice recommendation to repeat EGD after 8 weeks PPI therapy in severe esophagitis patients to assure healing and exclude Barrett's esophagus.

Esophageal adenocarcinoma (EA) is an increasingly common cancer with poor survival. Barrett's esophagus (BE) is the main precursor to EA, and every year 0.12% to 0.5% of BE patients progress to EA. BE typically arises on a background of chronic gastroesophageal reflux (GERD), one of the risk factors for EA.We used genome-wide association data to investigate the genetic architecture underlying GERD, BE, and EA. We applied a method to estimate the variance explained (array heritability, h(2)g) and the genetic correlation (rg) between GERD, BE, and EA by considering all single nucleotide polymorphisms (SNPs) simultaneously. We also estimated the polygenic overlap between GERD, BE, and EA using a prediction approach. All tests were two-sided, except in the case of variance-explained estimation where one-sided tests were used.We estimated a statistically significant genetic variance explained for BE (h(2)g = 35%; standard error [SE] = 6%; one-sided P = 1 × 10(-9)) and for EA (h(2)g = 25 %; SE = 5%; one-sided P = 2 × 10(-7)). The genetic correlation between BE and EA was found to be high (rg = 1.0; SE = 0.37). We also estimated a statistically significant polygenic overlap between BE and EA (one-sided P = 1 × 10(-6)), which suggests, together with the high genetic correlation, that shared genes underlie the development of BE and EA. Conversely, no statistically significant results were obtained for GERD.We have demonstrated that risk to BE and EA is influenced by many germline genetic variants of small effect and that shared polygenic effects contribute to risk of these two diseases.

Aliment Pharmacol Ther 2012; 35: #–# Summary Background The consensus statements for eosinophilic oesophagitis recommend that ambulatory pH monitoring is one means of determining if gastro-oesophageal reflux is the cause of oesophageal eosinophilia and should guide pharmacological therapy. Aim To evaluate prospectively the accuracy of pH monitoring as a predictor of endoscopic, histological and symptomatic response in patients with oesophageal eosinophilia. Methods We conducted a prospective trial in which patients with oesophageal eosinophilic infiltration with ≥15 eos/hpf underwent a 24-h pH study and were placed in one of two treatment arms for 6 weeks based on positive or negative results. Patients with abnormal acid exposure were treated with esomeprazole 40 mg twice daily and others were treated with oral viscous budesonide 1 g twice daily. Response to treatment was assessed by oesophageal histology (

Background Minimally invasive esophagectomy (MIE) has been performed using a variety of techniques evolving during the past decade. We present our initial experience and outcomes of patients undergoing transthoracic MIE using a circular end-to-side anastomosis created with the transorally directed EEA circular stapler OrVil (Covidien, New Haven, CT). Complications, including anastomotic leak and stricture occurrence, are reviewed. Methods A retrospective review evaluated consecutive patients undergoing MIE for esophageal cancer or related disease with intrathoracic end-to-side anastomoses using the transorally directed EEA circular stapler from December 2007 to May 2010. Medical records were reviewed for demographics, staging, neoadjuvant chemoradiotherapy, comorbidities, adjuvant therapy, complications, and survival. Results During this period, 51 consecutive patients (84% male; mean age, 65 years) underwent MIE. Neoadjuvant chemoradiotherapy was performed in 32 patients, and 4 had intraoperative radiotherapy. Mean operative time was 338 minutes (range, 211 to 565 minutes), including the 4 patients with intraoperative radiotherapy. Operative time improved with experience (excluding intraoperative radiotherapy) from a mean of 378 minutes (patients 1 to 14) to 300 minutes (patients 37 to 51). Median hospital stay was 11 days (range, 6 to 48 days). Anastomotic leaks occurred in 5 patients (9.8%). Postoperative deaths included 1 in-hospital (2.0%) and 2 (3.9%) after discharge. Stricture was diagnosed and treated in 7 patients (13.7%). Follow-up was a median of 12 months (range, 1 to 31 months). Conclusions Transthoracic MIE using an end-to-side anastomosis with the transorally directed EEA circular stapler resulted in acceptable stricture and leak rates with good outcomes comparable to published outcomes for open surgical resections.

Upper abdominal pain (UAP) in patients with gallstones is often treated by cholecystectomy but it frequently persists. We aimed to identify symptoms associated with relief.We followed 1008 patients who received cholecystectomy for gallstones and UAP at the Mayo Clinic (Rochester, Minnesota) or Kaiser Permanente (San Diego, California) for 12 months. A validated, self-completed biliary symptoms questionnaire identified features of UAP, gastroesophageal reflux disease (GERD), and irritable bowel syndrome (IBS); the questionnaire was given initially and 3 and 12 months after cholecystectomy, to identify features that predicted sustained relief of UAP.Five hundred ninety-four patients (59%) reported relief from UAP. Factors associated univariately (P.05) with relief included frequency of UAP ≤1 per month, onset ≤1 year preoperatively, usual duration (30 minutes to 24 hours, most often in the evening or night), and severity5/10. Compared to no features, multiple predictive features of UAP (frequency, onset, duration, or timing) were associated with increasing odds ratios (95% confidence interval) for relief: 1, 2, or 3 features (4.2 [1.1-16]; P = .03) and 4 features (6.3 [1.6-25]; P = .008). Negative univariate associations included lower abdominal pain (LAP), usual bowel pattern, nausea ≥1 per week, often feeling bloated or burpy, GERD, and/or IBS. There was an inverse association between relief and somatization; relief was not associated with postprandial UAP. Multivariable logistic regression analysis revealed independent associations (P.05) with UAP frequency, onset, and nocturnal awakening, but inverse associations with lower abdominal pain, abnormal bowel pattern, and frequent bloated or burpy feelings.UAP features and concomitant GERD, IBS, and somatization determine the odds for relief from UAP after cholecystectomy.

The following on Barrett's esophagus registries contains commentaries on the data sets to be included, organizational issues, and the demographic, lifestyle, and diagnostic differences between the United States and Europe. The importance of collaborative studies is also discussed.

The following on prevalence and incidence of adenocarcinomas in Barrett's esphophagus (BE) includes commentaries on the mechanisms of a potential protective effect of proton pump inhibitors (PPIs) on progression of BE to high-grade dysplasia; evaluation of the role of PPIs in decreasing the risk of degeneration; the geographical variations of incidence of BE; the role of the nonmorphologic biomarkers; the relationship between length of BE and development of cancer; the confounding factors in incidence rates of BE; the role of the increase of cell differentiation and apoptosis induced by PPIs in the diminution of cancer risk; the frequency of occult neoplastic foci and unsuspected invasive cancer in surgical specimens; the influence on the indications of endoscopic therapy; the overestimation of regression in surgical series; attempts to evaluate the reasons for variations of cancer incidence in the literature; and progress in screening and surveillance for BE.

Population-based data on the epidemiology and outcomes of subjects with intestinal metaplasia of the gastroesophageal junction (IMGEJ) and Barrett's esophagus (BE) are limited. The objectives of this study were to (i) estimate the incidence of IMGEJ and BE diagnosed from clinically indicated endoscopy in Olmsted County, MN, over three decades (1976-2006) and prevalence as of 1 January 2007, (ii) compare baseline characteristics of subjects with IMGEJ and BE, and (iii) study the natural history and survival of both cohorts.This was a population-based cohort study. The study setting was Olmsted County, MN. Patients with BE (columnar segment1 cm with intestinal metaplasia) and IMGEJ (intestinal metaplasia in biopsies from the gastroesophageal junction) from 1976 to 2006 in Olmsted County, MN, were identified using Rochester Epidemiology Project resources. Demographic and clinical data were abstracted from medical records and pathology confirmed by gastrointestinal pathologists. The association of baseline characteristics with overall and progression-free survival was assessed using proportional hazards regression models. Outcome measures were baseline characteristics and overall survival of subjects with IMGEJ compared to those with BE.In all, 487 patients (401 with BE and 86 with IMGEJ) were identified and followed for a median interval of 7 (BE subjects) to 8 (IMGEJ subjects) years. Subjects with BE were older, heavier, reported reflux symptoms more often, and had higher prevalence of advanced neoplasia than those with IMGEJ. No patient with IMGEJ progressed to esophageal adenocarcinoma (EAC) in contrast to BE subjects who had a cumulative risk of progression of 7% at 10 years and increased risk of death from EAC (standardized mortality ratio 9.62). The overall survival of subjects with BE and IMGEJ did not differ from that expected in similar age- and sex-distributed white Minnesota populations.Subjects with IMGEJ appear to have distinct clinical characteristics and substantially lower cancer progression risk compared to those with BE.

Eosinophilic esophagitis (EoE) is defined by a minimum of 15 eosinophils (eos) per high-powered field (HPF) on esophageal biopsy, along with esophageal symptoms and the exclusion of gastroesophageal reflux (GERD). The clinical significance of fewer eosinophils is unknown.Fifty-nine adult patients without a previous diagnosis of EoE with esophageal biopsies containing 1-14 eos per HPF (low grade eosinophilia) and 418 adult patients with ≥15 eos per HPF were identified by retrospective review. Patients were divided into group A (1-9 eos per HPF), group B (10-14 eos per HPF), and group C (≥15 eos per HPF) with a chart review of clinical and demographic data.While dysphagia and atopy (asthma and allergic rhinitis) were more common in patients with ≥15 eos per HPF (group C) than those with low grade esophageal eosinophilia (groups A and B) (93 vs. 88%, P = 0.02), food impaction and heartburn occurred at an equal frequency across all patient groups. Endoscopic findings were likewise similar between groups. Of the 14 patients with low grade esophageal eosinophilia who underwent repeat endoscopy a mean interval of 42 weeks (range 8-118 weeks) later, five (36%) met conventional diagnostic criteria for EoE of 15 or greater eos per HPF. Follow-up in ten patients treated with topical corticosteroids noted improvement in nine, with mean follow-up of 8 weeks (range 4-12 weeks).Some adult patients with dysphagia and less than 15 eos per HPF have similar endoscopic findings and clinical course to patients meeting the consensus definition of EoE. Further evaluation of patients with low grade esophageal eosinophilia is needed.

Several small series have suggested an increased risk of complications associated with esophageal dilation in patients with eosinophilic esophagitis (EoE).To quantitate the risk and identify risk factors for esophageal complications in dilation in EoE patients.Retrospective, uncontrolled, single-center study.Tertiary referral hospital.A total of 161 EoE patients (mean ± standard deviation age 44.3 ± 15.3 years, 112 men, 49 women, 150 white patients, 10 unknown, 1 Asian).Through-the-scope balloon or Savary dilation of EoE.The rate of complications defined as deep mucosal tear, major bleeding, or perforation, and determination of risk factors for complications.A total of 293 dilations were performed in 161 patients. Complications reported were deep mucosal tear in 9.2% (n = 27), major bleeding in 0.3% (n = 1), and immediate perforation in 1.0% (n = 3). All patients with perforations were successfully treated medically without surgery (mean ± standard deviation hospital stay 5.3 ± 3.2 days). Factors associated with an increased risk of complications were luminal narrowing in the upper (odds ratio [OR], 5.62; 95% CI, 2.07-15.26; P.001) and middle third of the esophagus (OR, 4.93; 95% CI, 1.64-14.83; P.005) compared with lower third, luminal stricture unable to be traversed with a standard upper endoscope (OR, 2.48; 95% CI, 1.06-5.83; P = .037), and use of Savary dilator (OR, 2.63; 95% CI, 1.18-5.83; P = .018).Retrospective design, uncontrolled study.Deep mucosal tears are common after dilation (9%), but the risk of immediate transluminal perforation with EoE is approximately 1%. The risk of severe complications is increased in patients with more proximal stricture and strictures that initially prevent endoscope passage.

The management of esophageal cancer with involvement of celiac lymph nodes is controversial. The purpose of this retrospective study was to evaluate the clinical importance of metastases to celiac lymph nodes in patients with carcinoma of the distal esophagus or gastroesophageal junction (GEJ) who undergo surgical treatment with curative intent. We reviewed the medical records of 310 patients who underwent definitive esophagectomy at the Mayo Clinic, Rochester, Minnesota, between 1976 and 1999 for carcinoma of the distal esophagus or GEJ. The disease location was distal esophagus in 163 and GEJ in 147. Fifty-two patients (17%) were found to have celiac node involvement. The survival of these patients was compared with that of 97 N0 patients and 161 N1 patients without celiac node involvement. Squamous cell carcinoma and adenocarcinomas were found in 24% and 76%, respectively. Ivor Lewis esophagectomy was the most common surgical procedure (76%), followed by transhiatal resection (14%) and modified Ivor Lewis procedure (5%). The median number of nodes resected was 15 (range, 2-45). The median survival of the entire group was 18.8 months. The median survival was 48 months (range, 1.6 months-22 years) for N0 patients and 15.9 months (range, 0.03 months-14.4 years) for N1 patients without celiac node disease (P < 0.001). The median survival was 11.7 months (range, 2.2 months-15.7 years) for celiac node-positive patients, and this difference was statistically significant when compared with survival in N0 patients (P= 0.001) but not when compared with that in N1 patients without celiac node disease (P= 0.57). Survival at 3 and 5 years was 61% and 45% for N0 patients, 21% and 9% for N1 patients without celiac node disease, and 18% and 11% for patients with celiac node disease, respectively. At 10 years, 7% of patients with celiac node involvement in their resected specimen were alive. By multivariate analysis, patients with 4 or more positive lymph nodes had the worst prognosis (risk ratio [RR], 2.63; 95% confidence interval [CI], 1.98-3.48), regardless of their location. We concluded that celiac node metastases were not an adverse prognostic indicator in patients with celiac node involvement compared with N1 patients without celiac node disease. Overall, the number of positive nodes, not their location, correlated best with survival. Although median survival was poor, a small number of patients with resected celiac node disease had long-term survival. Patients with undetected celiac node disease at the time of surgical resection who were subsequently found to have celiac node involvement appeared to have a prognosis similar to that of patients with stage III disease. Therefore, treatment with curative intent should be considered for fit patients with celiac node disease.

Patients with esophageal carcinoma (EC) report deficits in quality of life (QOL), depending on the extent of malignant disease and the goals of treatment at the time of QOL measurement. To quantify the association of marital status and changes in QOL over time in patients with EC and patients with Barrett's esophagus (BE). Eligible patients in the Mayo Clinic Esophageal Adenocarcinoma and Barrett’s Esophagus Registry completed QOL assessments at baseline and approximately 1 year later. QOL was determined with a ten-point linear analog self-assessment scale evaluating overall QOL and 12 subscales. Overall, 489 BE patients and 212 EC patients were evaluated. Married EC patients reported higher baseline QOL in legal concerns (8.1 vs. 7.1; p = .04) and friend and family support (9.3 vs. 8.4; p = .02) than single EC patients. Over time, married EC patients had a decrease in pain frequency QOL compared to single EC patients (−0.9 vs. +0.6; p = .02), with other QOL measures being stable. Married BE patients showed higher social activity QOL at baseline than single BE patients (7.5 vs. 6.9; p = .02); QOL was stable over time between the marital status groups. Minor, but statistically significant, changes were reported regarding QOL in two categories at baseline and over time among married and single patients with EC. Minor differences may be present between married and single EC patients regarding spiritual QOL at baseline and in overall physical well-being QOL at baseline and over time, although these differences did not reach statistical significance.

The aim of this study was to develop the Mayo Dysphagia Questionnaire-30 Day (MDQ-30), a tool to measure esophageal dysphagia, by adapting items from validated instruments for use in clinical trials, and assess its feasibility, reproducibility, and concurrent validity. Outpatients referred to endoscopy for dysphagia or seen in a specialty clinic were recruited. Feasibility testing was done to identify problematic items. Reproducibility was measured by test-retest format. Concurrent validity reflects agreement between information gathered in a structured interview versus the patients' written responses. The MDQ-30, a 28-item instrument, took 10 min (range = 5-30 min) to complete. Four hundred thirty-one outpatients [210 (49%) men; mean age = 61 years] participated. Overall, most concurrent validity kappa values for dysphagia were very good to excellent with a median of 0.78 (min 0.28, max 0.95). The majority of reproducibility kappa values for dysphagia were moderate to excellent with a median kappa value of 0.66 (min 0.07, max 1.0). Overall, concurrent validity and reproducibility kappa values for gastroesophageal reflux disease (GERD) symptoms were 0.81 (95% CI = 0.72, 0.91) and 0.66 (95% CI = 0.55, 0.77), respectively. Individual item percent agreement was generally very good to excellent. Internal consistency was excellent. We conclude that the MDQ-30 is an easy-to-complete tool to evaluate reliably dysphagia symptoms over the last 30 days.

The effort to improve outcomes in esophageal cancer has included attempts at improving staging and patient selection. 2-Deoxy-2-[(18)F]fluoro-Dglucose positron emission tomography (FDG-PET) has been extensively studied in this context and has been widely accepted as a staging tool. Its role in restaging or assessing therapeutic response is investigational and promising. Laparoscopy has also been studied as a means for improving staging, but its role may be limited in the era of PET. This article discusses the literature assessing these modalities, particularly with regard to the practical management of the patient in the clinic.

Gastroesophageal reflux disease (GERD) is a common chronic disorder that is associated with a huge economic burden in the western countries and significantly decreased quality of life. This review focuses on the various multicultural issues in the epidemiology, pathophysiology, diagnosis, and treatment of GERD. The prevalence of GERD appears to be highest in North America and Europe, whereas epidemiologic data from the Indian subcontinent, Africa, South America, and the Middle East are sparse. A limited number of studies have elucidated ethnic differences in GERD in multiracial populations. African Americans and Asians appear to be at a lower risk for the development of complicated GERD including Barrett's esophagus (BE). Whether the pathophysiology of GERD differs among different populations remains to be answered satisfactorily. It appears that most of the factors involved in the pathogenesis of GERD, as described in western populations, are present in Asians but at a lower scale. The current recommendations for the management of GERD by the American College of Gastroenterology may not meet the need for different ethnic groups or for different geographic regions. Recognition of language barriers in understanding the common terms used to describe reflux symptoms should be borne in mind while treating GERD patients with different ethnic backgrounds. In addition, a universally accepted definition for treatment success in GERD patients is lacking. Given the negative impact on health-related quality of life, significant cost ramifications, and increased risk for BE and esophageal adenocarcinoma, the study of multicultural issues in GERD should be considered.

SUMMARY. Lymph node involvement may impact postoperative therapeutic decision-making and prognosis in patients undergoing esophagectomy. This study evaluates which surgical approach yields the most lymph nodes. We undertook a retrospective chart review of esophagectomies performed by six surgeons from April 1994 to February 2004 using a prospective general thoracic surgery database at Mayo Clinic, Rochester, Minnesota, US. Lymph nodes were categorized into one of 17 regions per the American Joint Committee on Cancer, with the total number of lymph nodes, summed over each region, used as the primary outcome. A total of 517 esophagectomies were performed: 68 transhiatal, 392 Ivor Lewis, and 57 extended Ivor Lewis. A mean of 18.7 (SD 8.5) lymph nodes were retrieved with the Ivor Lewis approach as compared to 17.4 (SD 9.2) with the extended Ivor Lewis approach (P = 0.30). Since there was no statistical difference between the number of nodes collected in either Ivor Lewis approach, they were collapsed into one group for comparison with the transhiatal cases. Significantly more lymph nodes were collected with an Ivor Lewis approach (mean 18.5, SD 8.6) than with a transhiatal approach (mean 9.0, SD 5.0, P

Background The incidence rates of adenocarcinoma involving specific gastric and esophageal subsites are changing significantly, but the risk factors associated with those subsite changes remain controversial. We aimed to describe the site-specific risk factors associated with adenocarcinoma of the stomach and esophagus. Methods Using the Rochester Epidemiology Project, all cases of gastric and esophageal adenocarcinoma among Olmsted County, Minnesota, residents first diagnosed between 1971 and 2000 were identified. Complete inpatient and outpatient records were reviewed and specific subsites defined. Risk factors were assessed in cases, and age- and sex-matched controls. Results A total of 186 incident cases of gastric or esophageal adenocarcinoma were identified between 1971 and 2000, in Olmsted County. Gastroesophageal reflux disease (GERD) was a significant risk factor for both esophageal (OR 5.5, 95% CI 1.2-25) and esophagogastric junction adenocarcinoma (OR 13.0, 95% CI 1.7-99), but not for either proximal or distal gastric cancer. Smoking (OR 2.8, 95% CI 1.0-7.8) was associated with distal gastric cancer. Proton pump inhibitor (PPI) exposure was limited and was not a significant risk factor at any subsite. Conclusions This identification of distinct risk factors by subsite supports the concept that esophageal and gastric adenocarcinomas are two different diseases. Adenocarcinoma of the junction is probably a form of esophageal cancer and should not be coded with gastric neoplasms.

While multiple instruments characterize upper gastrointestinal symptoms, a validated instrument devoted to the measurement of a spectrum of esophageal dysphagia attributes is not available. Therefore, we constructed and validated the Mayo Dysphagia Questionnaire (MDQ). The 27 items of the MDQ underwent content validity, feasibility, concurrent validity, reproducibility, internal consistency, and construct validity testing. To assess content validity, five esophageal subspecialty gastroenterologists reviewed the items to ensure inclusion of pertinent domains. Feasibility testing was done with eight outpatients who refined problematic items. To assess concurrent validity, 70 patient responses on the MDQ were compared to responses gathered in a structured patient-physician interview. A separate group of 70 outpatients completed the MDQ twice to assess the reproducibility of each item. A total of 148 patients participated in the validation process (78 [53%] men; mean age 62). On average, the MDQ took 6 minutes to complete. A single item (odynophagia) tested poorly with a kappa value of

Background & aimsIt is not clear whether symptoms alone can be used to estimate the biologic activity of eosinophilic esophagitis (EoE). We aimed to evaluate whether symptoms can be used to identify patients with endoscopic and histologic features of remission.MethodsBetween April 2011 and June 2014, we performed a prospective, observational study and recruited 269 consecutive adults with EoE (67% male; median age, 39 years old) in Switzerland and the United States. Patients first completed the validated symptom-based EoE activity index patient-reported outcome instrument and then underwent esophagogastroduodenoscopy with esophageal biopsy collection. Endoscopic and histologic findings were evaluated with a validated grading system and standardized instrument, respectively. Clinical remission was defined as symptom score

Veterans Affairs Center for Clinical Management Research; Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan; Division of Gastroenterology, St Paul’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada; Departments of Family Medicine and Urology, University of Michigan Medical School, Ann Arbor, Michigan; and Division of Gastroenterology, McGill University, McGill University Health Centre, Montreal, Quebec, Canada

Incidence of esophageal adenocarcinoma (EA) has increased substantially in recent decades. Multiple risk factors have been identified for EA and its precursor, Barrett's esophagus (BE), such as reflux, European ancestry, male sex, obesity, and tobacco smoking, and several germline genetic variants were recently associated with disease risk. Using data from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) genome-wide association study (GWAS) of 2,515 EA cases, 3,295 BE cases, and 3,207 controls, we examined single nucleotide polymorphisms (SNPs) that potentially affect the biogenesis or biological activity of microRNAs (miRNAs), small non-coding RNAs implicated in post-transcriptional gene regulation, and deregulated in many cancers, including EA. Polymorphisms in three classes of genes were examined for association with risk of EA or BE: miRNA biogenesis genes (157 SNPs, 21 genes); miRNA gene loci (234 SNPs, 210 genes); and miRNA-targeted mRNAs (177 SNPs, 158 genes). Nominal associations (P0.50), and we did not find evidence for interactions between variants analyzed and two risk factors for EA/BE (smoking and obesity). This analysis provides the most extensive assessment to date of miRNA-related SNPs in relation to risk of EA and BE. While common genetic variants within components of the miRNA biogenesis core pathway appear unlikely to modulate susceptibility to EA or BE, further studies may be warranted to examine potential associations between unassessed variants in miRNA genes and targets with disease risk.

This article has an accompanying continuing medical education activity on page e12. Learning Objective: At the conclusion of this exercise, the learner will understand the approach to counseling patients regarding the optimal method and frequency of radiologic imaging, indications for invasive tests like endoscopic ultrasonography (EUS) and surgery, select patients for follow-up after surgery, decide the duration of such follow-up, and decide when to stop surveillance for those with and without surgery.

Background: The strong male predominance in oesophageal adenocarcinoma (OAC) and Barrett’s oesophagus (BO) continues to puzzle. Hormonal influence, e.g. oestrogen or oxytocin, might contribute. Methods: This genetic-epidemiological study pooled 14 studies from three continents, Australia, Europe, and North America. Polymorphisms in 3 key genes coding for the oestrogen pathway (receptor alpha (ESR1), receptor beta (ESR2), and aromatase (CYP19A1)), and 3 key genes of the oxytocin pathway (the oxytocin receptor (OXTR), oxytocin protein (OXT), and cyclic ADP ribose hydrolase glycoprotein (CD38)), were analysed using a gene-based approach, versatile gene-based test association study (VEGAS). Results: Among 1508 OAC patients, 2383 BO patients, and 2170 controls, genetic variants within ESR1 were associated with BO in males (p = 0.0058) and an increased risk of OAC and BO combined in males (p = 0.0023). Genetic variants within OXTR were associated with an increased risk of BO in both sexes combined (p = 0.0035) and in males (p = 0.0012). We followed up these suggestive findings in a further smaller data set, but found no replication. There were no significant associations between the other 4 genes studied and risk of OAC, BO, separately on in combination, in males and females combined or in males only. Conclusion: Genetic variants in the oestrogen receptor alpha and the oxytocin receptor may be associated with an increased risk of BO or OAC, but replication in other large samples are needed.

Summary Background The incidence rates of gastric and oesophageal adenocarcinoma are changing significantly, but little is known about specific sub-sites. Aim To use a population-based approach to describe the trends in the site-specific incidence of oesophageal and gastric adenocarcinoma. Methods Using the Rochester Epidemiology Project, all cases of gastric and oesophageal adenocarcinoma among Olmsted County, Minnesota, residents first diagnosed between 1971 and 2000 were identified (n = 186). Complete in-patient and out-patient records were reviewed and site determined from pathological, surgical, endoscopic and radiological reports. Results Between the decades of 1971–1980 and 1991–2000, the incidence of oesophageal adenocarcinoma increased significantly from 0.4 to 2.5 per 100 000 person-years. The incidence of adenocarcinoma of the oesophagogastric junction also increased from a rate of 0.6 to 2.2 per 100 000 person-years. The incidence rate of cancer involving the gastric cardia was stable but the incidence of adenocarcinoma involving distal gastric sites declined. Combined oesophageal and oesophagogastric junction adenocarcinoma (4.7 per 1 000 000 person-years) was as common as gastric adenocarcinoma (3.4 per 100 000 person-years) in 1991–2000. Conclusions The incidence rates of adenocarcinoma involving proximal gastric sub-sites do not appear to be increasing in a manner similar to those involving oesophageal sub-sites.

BACKGROUND & AIMS: Standardized instruments are needed to assess the activity of eosinophilic esophagitis (EoE) and to provide end points for clinical trials and observational studies. We aimed to develop and validate a patient-reported outcome (PRO) instrument and score, based on items that could account for variations in patient assessments of disease severity. We also evaluated relationships between patient assessment of disease severity and EoE-associated endoscopic, histologic, and laboratory findings. METHODS: We collected information from 186 patients with EoE in Switzerland and the United States (69.4% male; median age, 43 y) via surveys (n = 135), focus groups (n = 27), and semistructured interviews (n = 24). Items were generated for the instruments to assess biologic activity based on physician input. Linear regression was used to quantify the extent to which variations in patient-reported disease characteristics could account for variations in patient assessment of EoE severity. The PRO instrument was used prospectively in 153 adult patients with EoE (72.5% male; median age, 38 y), and validated in an independent group of 120 patients with EoE (60.8% male; median age, 40.5 y). RESULTS: Seven PRO factors that are used to assess characteristics of dysphagia, behavioral adaptations to living with dysphagia, and pain while swallowing accounted for 67% of the variation in patient assessment of disease severity. Based on statistical consideration and patient input, a 7-day recall period was selected. Highly active EoE, based on endoscopic and histologic findings, was associated with an increase in patient-assessed disease severity. In the validation study, the mean difference between patient assessment of EoE severity (range, 0-10) and PRO score (range, 0-8.52) was 0.15. CONCLUSIONS: We developed and validated an EoE scoring system based on 7 PRO items that assess symptoms over a 7-day recall period. Clinicaltrials.gov number: NCT00939263.

Colorectal cancer in African Americans has an increased incidence and mortality relative to Whites. The mean age of CRC development in African Americans is younger than that of Whites. There is also evidence for a more proximal colonic distribution of cancers and adenomas in African Americans. African Americans are less likely to have undergone diagnostic testing and screening for colorectal cancer. Special efforts are needed to improve colorectal cancer screening participation rates in African Americans. Clinical gastroenterologists should play an active role in educating the public and primary care physicians about special issues surrounding colorectal cancer in African Americans. Community healthcare groups and gastrointestinal specialists should develop culturally sensitive health education programs for African Americans regarding colorectal cancer. The high incidence and younger age at presentation of colorectal cancer in African Americans warrant initiation of colorectal cancer screening at the age 45 yr rather than 50 yr.

Objectives Gallstone disease is common and causes high health care costs, but a measure of symptomatic biliary disease for outcome studies is lacking. We aimed to develop a reproducible, valid, discriminative, disease-specific measure of biliary symptoms. Methods We created the self-report Biliary Symptoms Questionnaire (BSQ) by combining possible biliary symptoms with validated items for gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), and other disorders. We developed the final version through an iterative process and assessed reproducibility by the test–retest method, concurrent validity by comparing BSQ responses with symptoms obtained by structured interview, and discriminative validity by comparing BSQ-based diagnoses of biliary symptoms, GERD, and IBS with patients’ final diagnoses. A shortened version (sBSQ) also underwent reproducibility testing. Results A total of 245 outpatients (mean age, 55.2 yr; 61% female) participated. Median completion times for the BSQ and sBSQ were 36 and 10 min, respectively. For the BSQ, median κ values were 0.65 (range −0.03 to 0.95) for reproducibility and 0.61 (range 0.15–0.95) for concurrent validity. Using BSQ responses, investigators distinguished IBS and GERD 79–90% of the time. For the sBSQ, the median κ value for reproducibility was 0.72 (range 0.32–0.86). Conclusions The BSQ is reproducible and has good concurrent and discriminative validity for biliary symptoms. The abridged sBSQ has good reproducibility. These instruments may be useful in future outcome studies.

Relatives of patients with Barrett's esophagus have an increased prevalence of reflux symptoms. Our aim was to find if these relatives were at increased risk of having Barrett's esophagus.First degree relatives of patients with Barrett's esophagus completed the Reflux Symptom Questionnaire. Relatives with reflux symptoms, never previously investigated. were invited for endoscopy. Controls were patients with similar reflux symptoms and no family histories of Barrett's esophagus.We found previously undiagnosed Barrett's esophagus (3 cm) in eight of 100 relatives (8%) from 53 families and in five of 100 controls (5%) (adjusted OR = 1.58, 95% CI = 0.46-5.45). Including another 27 previously investigated cases, 10 of the 53 families had two or more cases of Barrett's esophagus. Barrett's esophagus prevalence increased with age (p = 0.014) and was associated with reflux symptoms of10 yr (p = 0.020), and Barrett's esophagus was twice as common in males (p = 0.28). Reflux esophagitis was found in 74% of relatives and 57% of controls without Barrett's (p = 0.04).The risk of Barrett's esophagus in any one symptomatic relative of a patient with Barrett's esophagus was not statistically higher than in other persons with reflux symptoms. However, more relatives of Barrett's esophagus patients have reflux symptoms, so the overall prevalence of Barrett's esophagus and reflux esophagitis in relatives may also be greater than in the general population. In considering whether to screen patients with reflux symptoms for Barrett's esophagus, age and duration of symptoms are stronger predictors than having a relative with Barrett's esophagus.

Impact of Display Alternatives in the Determination of Bolus Handling: A Study Using High-Resolution Manometry With Impedance

Incidence of esophageal adenocarcinoma (EA) in Western countries has increased markedly in recent decades. Although several risk factors have been identified for EA and its precursor, Barrett’s esophagus (BE), including reflux, Caucasian race, male gender, obesity, and smoking, less is known about the role of inherited genetic variation. Frequent somatic mutations in the tumor suppressor genes CDKN2A and TP53 were recently reported in EA tumors, while somatic alterations at 9p (CDKN2A) and 17p (TP53) have been implicated as predictors of progression from BE to EA. Motivated by these findings, we used data from a genome-wide association study of 2515 EA cases and 3207 controls to analyze 37 germline single nucleotide polymorphisms at the CDKN2A and TP53 loci. Three CDKN2A polymorphisms were nominally associated (P < 0.05) with reduced risk of EA: rs2518720 C>T [intronic, odds ratio 0.90, P = 0.0121, q = 0.3059], rs3088440 G>A (3′UTR, odds ratio 0.84, P = 0.0186, q = 0.3059), and rs4074785 C>T (intronic, odds ratio 0.85, P = 0.0248, q = 0.3059). None of the TP53 single nucleotide polymorphisms reached nominal significance. Two of the CDKN2A variants identified were also associated with reduced risk of progression from BE to EA, when assessed in a prospective cohort of 408 BE patients: rs2518720 (hazard ratio 0.57, P = 0.0095, q = 0.0285) and rs3088440 (hazard ratio 0.34, P = 0.0368, q = 0.0552). In vitro functional studies of rs3088440, a single nucleotide polymorphism located in the seed sequence of a predicted miR-663b binding site, suggested a mechanism whereby the G>A substitution may attenuate miR-663b-mediated repression of the CDKN2A transcript. This study provides the first evidence that germline variation at the CDKN2A locus may influence EA susceptibility.

Background Data from observational studies suggest that body mass index (BMI) is causally related to esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE). However, the relationships may be affected by bias and confounding. Methods We used data from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study: 999 patients with EAC, 2061 patients with BE, and 2169 population controls. We applied the two-stage control function instrumental variable method of the Mendelian randomization approach to estimate the unbiased, unconfounded effect of BMI on risk of EAC and BE. This was performed using a genetic risk score, derived from 29 genetic variants shown to be associated with BMI, as an instrument for lifetime BMI. A higher score indicates propensity to obesity. All tests were two-sided. Results The genetic risk score was not associated with potential confounders, including gastroesophageal reflux symptoms and smoking. In the instrumental variable analyses (IV), EAC risk increased by 16% (IV-odds ratio [OR] = 1.16, 95% confidence interval [CI] = 1.01 to 1.33) and BE risk increased by 12% (IV-OR = 1.12, 95% CI = 1.00 to 1.25) per 1 kg/m2 increase in BMI. BMI was statistically significantly associated with EAC and BE in conventional epidemiologic analyses. Conclusions People with a high genetic propensity to obesity have higher risks of esophageal metaplasia and neoplasia than people with low genetic propensity. These analyses provide the strongest evidence to date that obesity is independently associated with BE and EAC, and is not due to confounding or bias inherent in conventional epidemiologic analyses.