Haifa, Israel
Haifa, Israel

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Ek W.E.,QIMR Berghofer Medical Research Institute | Ek W.E.,University of Washington | Levine D.M.,Karolinska Institutet | D'Amato M.,Karolinska Institutet | And 27 more authors.
Journal of the National Cancer Institute | Year: 2013

Background 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. Methods 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, h2 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 twosided, except in the case of variance-explained estimation where one-sided tests were used. Results We estimated a statistically significant genetic variance explained for BE (h2 g = 35%; standard error [SE] = 6%; one-sided P = 1 × 10-9) and for EA (h2 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. Conclusions 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. © The Author 2013.


Kephart G.M.,Mayo Medical School | Alexander J.A.,Mayo Medical School | Arora A.S.,Mayo Medical School | Romero Y.,Mayo Medical School | And 3 more authors.
American Journal of Gastroenterology | Year: 2010

Objectives: Eosinophilic esophagitis (EoE) is characterized by infiltration of eosinophils into esophageal epithelium. Blood levels of an eosinophil granule protein, eosinophil-derived neurotoxin (EDN), have been proposed as a biomarker for EoE. However, information regarding localization of EDN in the diseased tissues has not been available. The goal of this study was to evaluate the magnitude and distribution of EDN deposition in tissue specimens from the esophagus of EoE patients. Methods: We studied specimens from 10 adult EoE patients and eight histologically normal controls (three under age 17). Sections from mid-esophageal biopsy specimens were stained for EDN by immunofluorescence, using a polyclonal rabbit antibody to EDN. Cellular staining (i.e., infiltration of intact eosinophils) and extracellular staining (i.e., deposition of released EDN) were scored in a blinded manner on an established 7-point scale. Results: Esophageal biopsy specimens from histologically normal controls showed no or few intact eosinophils and no or minimal extracellular EDN deposition. In contrast, EDN staining was clearly observed in specimens from all EoE patients. In some EoE patients, marked extracellular EDN deposition was observed despite relatively small numbers of intact eosinophils. Overall, there was no correlation between the eosinophil infiltration and the extracellular EDN staining scores. Conclusions: Marked tissue deposition of extracellular EDN is present in the esophagus of EoE patients. Tissue eosinophil counts may underestimate how extensively eosinophils are involved, particularly in individuals with marked eosinophil degranulation. Evaluation of EDN staining in esophageal biopsy specimens may be useful to diagnose and manage patients with EoE. © 2010 by the American College of Gastroenterology.


Shields H.M.,Beth Israel Deaconess Medical Center | Nardone G.,University of Naples Federico II | Zhao J.,Chongqing Medical University | Wang W.,536 Hospital of PLA | And 12 more authors.
Annals of the New York Academy of Sciences | Year: 2011

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. © 2011 New York Academy of Sciences.


Gralnek I.M.,Technion - Israel Institute of Technology | Gralnek I.M.,GI Outcomes Unit | Ron-Tal Fisher O.,Technion - Israel Institute of Technology | Holub J.L.,Oregon Health And Science University | Eisen G.M.,Oregon Health And Science University
Gastrointestinal Endoscopy | Year: 2013

Background: Data on the role of colonoscopy in hematochezia are almost exclusively derived from clinical experience in tertiary care practice. Objective: To characterize the patient population who received colonoscopy for hematochezia in a consortium of diverse gastroenterology practices. Design: Retrospective analysis. Setting: Clinical Outcomes Research Initiative Database, 2002 to 2008. Patients: Adults undergoing colonoscopy for the indication of hematochezia. Main Outcome Measurements: Demographics, comorbidity, practice setting, adverse events, and colonoscopy procedure characteristics and findings. Age-stratified analyses and analyses of inpatient- versus outpatient-performed colonoscopies were also performed. Results: A total of 966,536 colonoscopies were performed during the study period, 76,186 (7.9%) were performed for evaluation of hematochezia. The majority of patients were white non-Hispanic men younger than 60 years old who underwent colonoscopy at a community practice site (79.1%) and had a low-risk American Society of Anesthesiologists (ASA) score (81.5%), in whom colonoscopy reached the cecum (94.8%), and serious adverse events were rare. Colonoscopy findings were hemorrhoids (64.4%), diverticulosis (38.6%), and polyp or multiple polyps (38.8%). From the overall cohort, 38.3% were 60 years of age and older. The older age cohort had significantly more white non-Hispanic females, high-risk ASA scores, incomplete colonoscopies, and unplanned events. Colonoscopy findings demonstrated significantly higher rates of diverticulosis, polyp or multiple polyps, mucosal abnormality/colitis, tumor, and solitary ulcer (P <.0001). There were 3941 (5.2%) who underwent inpatient-performed colonoscopy. One third of this cohort (32.6%) was defined as having a high ASA score. Limitations: Retrospective database review. Conclusions: These results describe patient populations and characterize colonoscopy findings in individuals presenting with hematochezia primarily in a community practice setting. © 2013 American Society for Gastrointestinal Endoscopy.


Schoepfer A.M.,University of Lausanne | Straumann A.,University of Basel | Straumann A.,Swiss EoE Research Group | Panczak R.,University of Bern | And 75 more authors.
Gastroenterology | Year: 2014

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. © 2014 AGA Institute.


Ron-Tal Fisher O.,Technion - Israel Institute of Technology | Gralnek I.M.,Technion - Israel Institute of Technology | Gralnek I.M.,GI Outcomes Unit | Eisen G.M.,Oregon Health And Science University | And 2 more authors.
Gastrointestinal Endoscopy | Year: 2014

Background Data on the use of endoscopic hemostasis performed during colonoscopy for hematochezia are primarily derived from expert opinion and case series from tertiary care settings. Objectives To characterize patients with hematochezia who underwent in-patient colonoscopy and compare those who did and did not receive endoscopic hemostasis. Design Retrospective analysis. Setting Clinical Outcomes Research Initiative National Endoscopic Database, 2002 to 2008. Patients Adults with hematochezia. Interventions None. Main Outcome Measurements Demographics, comorbidities, practice setting, adverse events, and colonoscopy procedural characteristics and findings. Results We identified 3151 persons who underwent in-patient colonoscopy for hematochezia. Endoscopic hemostasis was performed in 144 patients (4.6%). Of those who received endoscopic hemostasis, the majority were male (60.3%), white (83.3%), and older (mean age 70.9 ± 12.3 years); had a low-risk American Society of Anesthesiologists classification (53.9%); and underwent colonoscopy in a community setting (67.4%). The hemostasis-receiving cohort was significantly more likely to be white (83.3% vs 71.0%, P =.02), have more comorbidities (classes 3 and 4, 46.2% vs 36.0%, P =.04), and have the cecum reached (95.8% vs 87.7%, P =.003). Those receiving hemostasis were significantly more likely to have an endoscopic diagnosis of arteriovenous malformations (32.6% vs 2.6%, P =.0001) or a solitary ulcer (8.3% vs 2.1%, P <.0001). Limitations Retrospective database analysis. Conclusions Less than 5% of persons presenting with hematochezia and undergoing inpatient colonoscopy received endoscopic hemostasis. These findings differ from published tertiary care setting data. These data provide new insights into in-patient colonoscopy performed primarily in a community practice setting for patients with hematochezia. © 2014 by the American Society for Gastrointestinal Endoscopy.


PubMed | GI Outcomes Unit, Northwestern University, U.S. National Institutes of Health, University of Lausanne and 12 more.
Type: Journal Article | Journal: Gastroenterology | Year: 2014

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.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).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.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.


Safroneeva E.,University of Bern | Straumann A.,Swiss EoE Research Group | Straumann A.,University of Basel | Coslovsky M.,University of Bern | And 26 more authors.
Gastroenterology | Year: 2016

Background & Aims It 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. Methods Between 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 <20 (range, 0-100); histologic remission was defined as a peak count of <20 eosinophils/mm2 in a high-power field (corresponds to approximately <5 eosinophils/median high-power field); and endoscopic remission as absence of white exudates, moderate or severe rings, strictures, or combination of furrows and edema. We used receiver operating characteristic analysis to determine the best symptom score cutoff values for detection of remission. Results Of the study subjects, 111 were in clinical remission (41.3%), 79 were in endoscopic remission (29.7%), and 75 were in histologic remission (27.9%). When the symptom score was used as a continuous variable, patients in endoscopic, histologic, and combined (endoscopic and histologic remission) remission were detected with area under the curve values of 0.67, 0.60, and 0.67, respectively. A symptom score of 20 identified patients in endoscopic remission with 65.1% accuracy and histologic remission with 62.1% accuracy; a symptom score of 15 identified patients with both types of remission with 67.7% accuracy. Conclusions In patients with EoE, endoscopic or histologic remission can be identified with only modest accuracy based on symptoms alone. At any given time, physicians cannot rely on lack of symptoms to make assumptions about lack of biologic disease activity in adults with EoE. ClinicalTrials.gov, Number: NCT00939263. © 2016 AGA Institute.


Jung K.W.,Barretts Esophagus Unit | Talley N.J.,Barretts Esophagus Unit | Talley N.J.,University of Newcastle | Talley N.J.,Callaghan Innovation | And 14 more authors.
American Journal of Gastroenterology | Year: 2011

Objectives: 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. Methods: This was a population-based cohort study. The study setting was Olmsted County, MN. Patients with BE (columnar segment 1 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. Results: 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. Conclusions: Subjects with IMGEJ appear to have distinct clinical characteristics and substantially lower cancer progression risk compared to those with BE. © 2011 by the American College of Gastroenterology.


PubMed | GI Outcomes Unit, Northwestern University, University of Lausanne, Food Allergy Center at Tufts Medical Center and Floating Hospital for Children and 12 more.
Type: Journal Article | Journal: Gastroenterology | Year: 2016

It 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.Between 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 <20 (range, 0-100); histologic remission was defined as a peak count of <20 eosinophils/mm(2) in a high-power field (corresponds to approximately <5 eosinophils/median high-power field); and endoscopic remission as absence of white exudates, moderate or severe rings, strictures, or combination of furrows and edema. We used receiver operating characteristic analysis to determine the best symptom score cutoff values for detection of remission.Of the study subjects, 111 were in clinical remission (41.3%), 79 were in endoscopic remission (29.7%), and 75 were in histologic remission (27.9%). When the symptom score was used as a continuous variable, patients in endoscopic, histologic, and combined (endoscopic and histologic remission) remission were detected with area under the curve values of 0.67, 0.60, and 0.67, respectively. A symptom score of 20 identified patients in endoscopic remission with 65.1% accuracy and histologic remission with 62.1% accuracy; a symptom score of 15 identified patients with both types of remission with 67.7% accuracy.In patients with EoE, endoscopic or histologic remission can be identified with only modest accuracy based on symptoms alone. At any given time, physicians cannot rely on lack of symptoms to make assumptions about lack of biologic disease activity in adults with EoE. ClinicalTrials.gov, Number: NCT00939263.

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