Margaret Kinnard

Familial aggregation of Barrett’s oesophagus, oesophageal adenocarcinoma, and oesophagogastric junctional adenocarcinoma in Caucasian adults

Background: Although familial clusters of Barrett’s oesophagus and oesophageal adenocarcinoma have been reported, a familial predisposition to these diseases has not been systematically investigated. Aims: To determine whether Barrett’s oesophagus and oesophageal (or oesophagogastric junctional) adenocarcinoma aggregate in families. Patients and methods: A structured questionnaire eliciting details on reflux symptoms, exposure history, and family history was given to Caucasian case (n=58) subjects with Barrett’s oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma, and to Caucasian control (n=106) subjects with symptomatic gastro-oesophageal reflux disease without Barrett’s oesophagus. Reported diagnoses of family members were confirmed by review of medical records. Results: The presence of a positive family history (that is, first or second degree relative with Barrett’s oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma) was significantly higher among case subjects compared with controls (24% v 5%; p<0.005). Case subjects were more likely to be older (p<0.001) and male (74% v 43% male; p<0.0005) compared with control subjects. In a multivariate logistic regression analysis, family history was independently associated with the presence of Barrett’s oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma (odds ratio 12.23, 95% confidence interval 3.34–44.76) after adjusting for age, sex, and the presence of obesity 10 or more years prior to study enrolment. Conclusions: Individuals with Barrett’s oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma are more likely to have a positive family history of Barrett’s oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma than individuals without Barrett’s oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma. A positive family history should be considered when making decisions about screening endoscopy in patients with symptoms of gastro-oesophageal reflux.

Familiality in Barrett's esophagus, adenocarcinoma of the esophagus, and adenocarcinoma of the gastroesophageal junction

Background and Aim: The familial aggregation of Barretts esophagus, adenocarcinoma of the esophagus, and adenocarcinoma of the gastroesophageal junction, jointly termed familial Barretts esophagus, may represent a complex genetic trait. The aim of this study was to determine the proportion of patients with these diseases who have familial Barretts esophagus. Methods: Information on gastroesophageal reflux symptoms, known risk factors for Barretts esophagus, and family history of Barretts esophagus and cancers, was collected at six hospitals using a structured questionnaire from probands with either long-segment Barretts esophagus, adenocarcinoma of the esophagus, or adenocarcinoma of the gastroesophageal junction. Family history of Barretts esophagus or esophageal cancer in a first- or second-degree relative was determined by reviewing medical records of all relatives reported to be affected. Results: Seventy one of 411 (17.3%) probands reported an affected first- and/or second-degree relative. Upon review of medical records of the reportedly affected relatives, familial Barretts esophagus was definitively determined in the case of 30 (7.3%) probands comprising 17 of 276 (6.2%) with Barretts esophagus, 11 of 116 (9.5%) with adenocarcinoma of the esophagus, and 2 of 21 (9.5%) with adenocarcinoma of the gastroesophageal junction. The diagnosis in the relative reported by the proband to be affected was found not to be Barretts esophagus or adenocarcinoma in 15 (3.6%) cases. The diagnosis could not be determined in 26 (6.3%) cases in which the proband reported an affected relative. There were no significant differences in age of disease onset, gender, race, or gastroesophageal reflux symptoms between definitive familial Barretts esophagus probands and nonfamilial probands. Conclusion: Familial Barretts esophagus can be confirmed in 7.3% of persons presenting with Barretts esophagus, adenocarcinoma of the esophagus, or adenocarcinoma of the gastroesophageal junction. (Cancer Epidemiol Biomarkers Prev 2006;15(9):1668–73)

Gastroesophageal reflux symptoms in patients with adenocarcinoma of the esophagus or cardia.

The efficacy of endoscopic screening for chronic gastroesophageal reflux symptoms of heartburn and regurgitation in adult subjects depends on the sensitivity of this strategy for detecting Barrett esophagus in subjects before the development of adenocarcinoma of the esophagus or cardia. The aim of the current study was to determine what proportion of patients with cancer of the esophagus or cardia would have been candidates for a screening endoscopy before their cancer diagnosis based on the presence and duration of preceding reflux symptoms.

Endoscopic retrograde cholangiopancreatography in children and adolescents.

Objectives Endoscopic retrograde cholangiopancreatography (ERCP) is becoming a more frequently used diagnostic and therapeutic tool in children. We sought to determine the indications, feasibility, safety, and effect on patient management of ERCP in pediatric patients of varying age. Methods All ERCPs performed during a 4-year period in patients aged 18 years or less at an academic hospital were retrospectively reviewed. The indications, type of anesthesia administered, type of duodenoscope used, diagnostic findings, therapeutic interventions, complication rate, and effect on management were compared between children (age 0–12 years) and adolescents (age 13–18 years). Results A total of 53 procedures were performed in 43 patients whose median age was 13.5 years. ERCP was successful in 50 of 53 cases (94%) with a complication rate of 6%. Endoscopic therapy was provided in 24 of 53 cases (45%). Compared with adolescents (n = 28), children (n = 25) were more likely to receive general anesthesia (96% vs. 29%;P < 0.001) and undergo ERCP with a pediatric duodenoscope (0% vs. 40%). ERCP affected management in 73% of cases, equally in both groups. Conclusion ERCP is a successful and safe diagnostic and therapeutic modality in a variety of pancreatobiliary disorders that directly affects management in children of all ages.

Identification of Barrett's Esophagus in Relatives by Endoscopic Screening

AIM:Familial aggregation of Barretts esophagus and its associated cancers has been termed familial Barretts esophagus (FBE). The aim of the study was to determine whether endoscopic screening would identify Barretts esophagus (BE) in relatives of probands with BE or esophageal adenocarcinoma (EAC).METHODS:All living first-degree relatives of patients with long segment BE or EAC presenting to the endoscopy suite of two academic hospitals were sent validated questionnaires inquiring about gastroesophageal reflux symptoms and prior endoscopic evaluation. First-degree relatives of affected probands or affected relatives who reported no prior upper endoscopy were offered screening unsedated esophagoscopy. Relatives with chronic gastroesophageal reflux symptoms were also offered an alternative of conventional sedated upper endoscopy. The yield of screening endoscopy was measured. Screening endoscopy findings were then compared between family members of known FBE patients and those with “isolated” disease.RESULTS:One hundred and ninety-eight relatives from 69 families, 23 known FBE probands and 46 probands with apparently “isolated” disease, were enrolled. Forty relatives (29 FBE relatives and 11 relatives of probands with “isolated” disease) reported prior upper endoscopy. Screening upper endoscopies performed on 62 (25 FBE and 37 “isolated” disease relatives) of the remaining 158 relatives identified Barretts epithelium in 13 (21%). Compared to probands with apparently “isolated” disease, Barretts epithelium (EAC, BE, or SSBE) was identified significantly more often in siblings and offspring of FBE probands, p≤ 0.05. Endoscopic screening of relatives of FBE probands identified a multigeneration multiplex FBE pedigree consistent with an autosomally dominant inherited trait. Endoscopic screening of relatives of probands with reported “isolated” diseased did not identify any new FBE pedigrees.CONCLUSIONS:Endoscopy identified EAC, long-segment BE, and short-segment BE in a substantial proportion of first-degree relatives of affected members of FBE families. A familial susceptibility to develop Barretts epithelium appears to be present in a subset of patients with BE and EAC.

Assessment of Familiality, Obesity, and Other Risk Factors for Early Age of Cancer Diagnosis in Adenocarcinomas of the Esophagus and Gastroesophageal Junction

OBJECTIVES:Adenocarcinomas of the esophagus and adenocarcinomas of the gastroesophageal junction are postulated to be complex genetic diseases. Combined influences of environmental factors and genetic susceptibility likely influence the age at which these cancers develop. The aim of this study was to determine whether familiality and other recognized risk factors are associated with the development of these cancers at an earlier age.METHODS:A structured validated questionnaire was utilized to collect self-reported data on gastro-esophageal reflux symptoms, risk factors for Barretts esophagus (BE) and family history, including age of cancer diagnosis in affected relatives from probands with BE, adenocarcinoma of the esophagus, or adenocarcinoma of the gastroesophageal junction, at five tertiary care academic hospitals. Medical records of all relatives reported to be affected were requested from hospitals providing this cancer care to confirm family histories. Familiality of BE/cancer, obesity (defined as body mass index >30), gastroesophageal reflux symptoms, and other risk factors were assessed for association with a young age of cancer diagnosis.RESULTS:A total of 356, 216 non-familial and 140 familial, cancers were studied. The study population consisted of 292 (82%) men and 64 (18%) women. Mean age of cancer diagnosis was no different in a comparison of familial and non-familial cancers, 62.6 vs. 61.9 years, P=0.70. There were also no significant differences in symptoms of gastroesophageal reflux, body mass index, race, gender, and smoking history between familial and non-familial cancers. Mean age of cancer diagnosis was significantly younger in those who were obese 1 year before diagnosis as compared to those who were non-obese, mean age 58.99 vs. 63.6 years, P=0.008. Multivariable modeling of age at cancer diagnosis showed that obesity 1 year before diagnosis was associated with a younger age of cancer diagnosis (P=0.005) after adjustment for heartburn and regurgitation duration.CONCLUSIONS:Obesity is associated with the development of esophageal and gastroesophageal junctional adenocarcinomas at an earlier age. Familial cancers arise at the same age as non-familial cancers and have a similar risk factor profile.

A Segregation Analysis of Barrett's Esophagus and Associated Adenocarcinomas

Familial aggregation of esophageal adenocarcinomas, esophagogastric junction adenocarcinomas, and their precursor Barretts esophagus (BE) has been termed familial BE (FBE). Numerous studies documenting increased familial risk for these diseases raise the hypothesis that there may be an inherited susceptibility to the development of BE and its associated cancers. In this study, using segregation analysis for a binary trait as implemented in S.A.G.E. 6.0.1, we analyzed data on 881 singly ascertained pedigrees to determine whether FBE is caused by a common environmental or genetic agent and, if genetic, to identify the mode of inheritance of FBE. The inheritance models were compared by likelihood ratio tests and Akaikes A Information Criterion. Results indicated that random environmental and/or multifactorial components were insufficient to fully explain the familial nature of FBE, but rather, there is segregation of a major type transmitted from one generation to the next (P < 10−10). An incompletely dominant inheritance model together with a polygenic component fits the data best. For this dominant model, the estimated penetrance of the dominant allele is 0.1005 [95% confidence interval (95% CI), 0.0587-0.1667] and the sporadic rate is 0.0012 (95% CI, 0.0004-0.0042), corresponding to a relative risk of 82.53 (95% CI, 28.70-237.35) or odds ratio of 91.63 (95% CI, 32.01-262.29). This segregation analysis provides epidemiologic evidence in support of one or more rare autosomally inherited dominant susceptibility allele(s) in FBE families and, hence, motivates linkage analyses. Cancer Epidemiol Biomarkers Prev; 19(3); 666–74

Variation in age at cancer diagnosis in familial versus nonfamilial Barrett's esophagus

Background: Genetic influences may be discerned in families that have multiple affected members and may manifest as an earlier age of cancer diagnosis. In this study, we determine whether cancers develop at an earlier age in multiplex Familial Barretts Esophagus (FBE) kindreds, defined by 3 or more members affected by Barretts esophagus (BE) or esophageal adenocarcinoma (EAC). Methods: Information on BE/EAC risk factors and family history was collected from probands at eight tertiary care academic hospitals. Age of cancer diagnosis and other risk factors were compared between nonfamilial (no affected relatives), duplex (two affected relatives), and multiplex (three or more affected relatives) FBE kindreds. Results: The study included 830 nonfamilial, 274 duplex, and 41 multiplex FBE kindreds with 274, 133, and 43 EAC and 566, 288, and 103 BE cases, respectively. Multivariable mixed models adjusting for familial correlations showed that multiplex kindreds were associated with a younger age of cancer diagnosis (P = 0.0186). Median age of cancer diagnosis was significantly younger in multiplex compared with duplex and nonfamilial kindreds (57 vs. 62 vs. 63 years, respectively, P = 0.0448). Mean body mass index was significantly lower in multiplex kindreds (P = 0.0033), as was smoking (P < 0.0001), and reported regurgitation (P = 0.0014). Conclusions: Members of multiplex FBE kindreds develop EAC at an earlier age compared with nonfamilial EAC cases. Multiplex kindreds do not have a higher proportion of common risk factors for EAC, suggesting that this aggregation might be related to a genetic factor. Impact: These findings indicate that efforts to identify susceptibility genes for BE and EAC will need to focus on multiplex kindreds. Cancer Epidemiol Biomarkers Prev; 21(2); 376–83. ©2011 AACR.

Ultrathin Esophagoscopy in Screening for Barrett's Esophagus at a Veterans Administration Hospital: Easy Access Does Not Lead to Referrals

OBJECTIVE:Unsedated, ultrathin esophagoscopy has been shown to be tolerable, safe, and accurate. Survey data have suggested that accessibility of unsedated esophagoscopy would increase referrals for Barretts esophagus (BE) screening. Our purpose was to evaluate primary-care physician referrals for BE screening when unsedated esophagoscopy is made available.METHODS:We studied primary-care referrals for unsedated esophagoscopy in a VA internal medicine clinic. Patients over age 45 with chronic heartburn for >5 yr or >3 times weekly and who had no previous EGD were eligible for screening with unsedated esophagoscopy. All primary providers received a 15-min education session on screening. Baseline referral rate was determined retrospectively. Longitudinal data were then collected during three phases of the study: (a) primary provider-initiated referrals, (b) primary provider-initiated referrals with weekly reminders from investigators, and (c) investigator recruitment.RESULTS:Baseline referral rate averaged 0.5 patients per month. Availability of unsedated esophagoscopy and an education session increased the rate of referral to 0.66 patients per month. Weekly reminders to primary physicians further increased the rate to 1.33 referrals per month. Investigator recruitment produced a rate of 2.67 referrals per month. Of the 77 patients offered screening, 25 (32%) declined. Of the 52 patients screened, three (5.8%) were diagnosed with BE.CONCLUSIONS:Accessibility of unsedated esophagoscopy itself does not lead to a large increase in the number of primary care referrals for BE screening. Factors that prevent primary care physicians from referring patients for screening need to be identified and effective interventions to change referral patterns need to be implemented for unsedated screening programs to be successful.

Sa1826 Predicting Barrett's Esophagus in Families of Patients With Barrett's Esophagus: A BETRNet Model Fitting Clinical Data to a Genetic Paradigm

Predicting Barretts Esophagus in Families of Patients With Barretts Esophagus: A BETRNet Model Fitting Clinical Data to a Genetic Paradigm Xiangqing Sun, Amitabh Chak, Gary W. Falk, William M. Grady, Margaret F. Kinnard, sumeet K. mittal, Marcia I. Canto, Nicholas J. Shaheen, Jean S. Wang, Prasad G. Iyer, Julian A. Abrams, Joseph Willis, Sanford Markowitz, Jill Barnholtz-Sloan, Wendy Brock, Robert Elston