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1.  Comparison of Endoscopic and Clinical Characteristics of Patients with Familial and Sporadic Barrett’s Esophagus 
Digestive diseases and sciences  2011;56(6):1702-1706.
Background
A proportion of Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) displays familial aggregation, known as familial Barrett’s esophagus (FBE). Pedigrees and characteristics of EAC in these families have been previously described.
Aims
We aimed to evaluate endoscopic and clinical characteristics of Barrett’s esophagus in FBE.
Methods
A cohort of 979 BE patients were retrospectively evaluated for FBE, defined as having a first-degree relative with BE or esophageal cancer, confirmed when possible by interview. FBE and sporadic BE were compared regarding demographic, clinical, and endoscopic characteristics. Potential FBE probands were contacted and interviewed to obtain full family pedigrees.
Results
Of 603 BE probands (61.6% of total cohort) with a documented family history, 35 (5.8%) had FBE. There was no difference between FBE and non-FBE probands with regard to BE length (median: 3 cm, IQR 2-5 vs. 3 cm, IQR 1-6 cm, respectively; p = 0.78) or hiatal hernia size (p = 0.90). FBE probands were younger (mean, 58.4 vs. 63.8; p = 0.02) and had a significant association with less-advanced neoplasia (adjusted OR 0.41, 95% CI 0.19–0.90). There was no obvious association between FBE and other malignancies.
Conclusions
There were no differences in endoscopic characteristics between FBE and non-FBE probands. While FBE patients were younger and had less-advanced neoplasia, we speculate that these findings may have been the result of more aggressive screening due to the family history. Further studies are warranted to determine whether familial clustering is due to genetic predisposition to development of BE or to risk of neoplastic progression.
doi:10.1007/s10620-011-1620-3
PMCID: PMC3144147  PMID: 21347561
Barrett’s esophagus; Epidemiology; Genetic predisposition to disease
2.  Variation In Age At Cancer Diagnosis In Familial Versus Non-Familial 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 Barrett’s Esophagus (FBE) kindreds, defined by 3 or more members affected by Barrett’s 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 non-familial (no affected relatives), duplex (two affected relatives), and multiplex (three or more affected relatives) FBE kindreds.
RESULTS
The study included 830 non-familial, 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 to duplex and non-familial kindreds (57 vs. 62 vs. 63 yrs, respectively, p = 0.0448). Mean body mass index (BMI) 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 to non-familial 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.
doi:10.1158/1055-9965.EPI-11-0927
PMCID: PMC3275661  PMID: 22178570
Esophageal adenocarcinoma; Barrett’s esophagus; genetics; family history
3.  New Strategies in Barrett’s Esophagus Integrating clonal evolutionary theory with clinical management 
Barrett’s esophagus is a condition in which the normal stratified squamous epithelium of the distal esophagus is replaced by intestinal metaplasia. For more than three decades the prevailing clinical paradigm has been that Barrett’s esophagus is a complication of symptomatic reflux disease that predisposes to esophageal adenocarcinoma, yet no clinical strategy for cancer prevention or early detection based on this paradigm has been proven to reduce esophageal adenocarcinoma mortality in a randomized clinical trial in part because only about 5-10% of individuals with Barrett’s esophagus develop esophageal adenocarcinoma. Recent research indicates that Barrett’s metaplasia is an adaptation for mucosal defense in response to chronic reflux in most individuals. The risk of progressing to esophageal adenocarcinoma is determined by development of genomic instability and dynamic clonal evolution in the distal esophagus modulated by host and environmental risk and protective factors, including inherited genotype. The challenge in Barrett’s esophagus lies in integrating knowledge about genomic instability and clonal evolution into clinical management to increase the lifespans and quality of life of individuals with this condition.
doi:10.1158/1078-0432.CCR-09-2358
PMCID: PMC3119197  PMID: 21498395
4.  Evaluation of a Minimally Invasive Cell Sampling Device Coupled with Assessment of Trefoil Factor 3 Expression for Diagnosing Barrett's Esophagus: A Multi-Center Case–Control Study 
PLoS Medicine  2015;12(1):e1001780.
Background
Barrett's esophagus (BE) is a commonly undiagnosed condition that predisposes to esophageal adenocarcinoma. Routine endoscopic screening for BE is not recommended because of the burden this would impose on the health care system. The objective of this study was to determine whether a novel approach using a minimally invasive cell sampling device, the Cytosponge, coupled with immunohistochemical staining for the biomarker Trefoil Factor 3 (TFF3), could be used to identify patients who warrant endoscopy to diagnose BE.
Methods and Findings
A case–control study was performed across 11 UK hospitals between July 2011 and December 2013. In total, 1,110 individuals comprising 463 controls with dyspepsia and reflux symptoms and 647 BE cases swallowed a Cytosponge prior to endoscopy. The primary outcome measures were to evaluate the safety, acceptability, and accuracy of the Cytosponge-TFF3 test compared with endoscopy and biopsy.
In all, 1,042 (93.9%) patients successfully swallowed the Cytosponge, and no serious adverse events were attributed to the device. The Cytosponge was rated favorably, using a visual analogue scale, compared with endoscopy (p < 0.001), and patients who were not sedated for endoscopy were more likely to rate the Cytosponge higher than endoscopy (Mann-Whitney test, p < 0.001). The overall sensitivity of the test was 79.9% (95% CI 76.4%–83.0%), increasing to 87.2% (95% CI 83.0%–90.6%) for patients with ≥3 cm of circumferential BE, known to confer a higher cancer risk. The sensitivity increased to 89.7% (95% CI 82.3%–94.8%) in 107 patients who swallowed the device twice during the study course. There was no loss of sensitivity in patients with dysplasia. The specificity for diagnosing BE was 92.4% (95% CI 89.5%–94.7%). The case–control design of the study means that the results are not generalizable to a primary care population. Another limitation is that the acceptability data were limited to a single measure.
Conclusions
The Cytosponge-TFF3 test is safe and acceptable, and has accuracy comparable to other screening tests. This test may be a simple and inexpensive approach to identify patients with reflux symptoms who warrant endoscopy to diagnose BE.
Editors' Summary
Background
Barrett's esophagus is a condition in which the cells lining the esophagus (the tube that transports food from the mouth to the stomach) change and begin to resemble the cells lining the intestines. Although some people with Barrett's esophagus complain of burning indigestion or acid reflux from the stomach into the esophagus, many people have no symptoms or do not seek medical advice, so the condition often remains undiagnosed. Long-term acid reflux (gastroesophageal reflux disease), obesity, and being male are all risk factors for Barrett's esophagus, but the condition's exact cause is unclear. Importantly, people with Barrett's esophagus are more likely to develop esophageal cancer than people with a normal esophagus, especially if a long length (segment) of the esophagus is affected or if the esophagus contains abnormally growing “dysplastic” cells. Although esophageal cancer is rare in the general population, 1%–5% of people with Barrett's esophagus develop this type of cancer; about half of people diagnosed with esophageal cancer die within a year of diagnosis.
Why Was This Study Done?
Early detection and treatment of esophageal cancer increases an affected individual's chances of survival. Thus, experts recommend that people with multiple risk factors for Barrett's esophagus undergo endoscopic screening—a procedure that uses a small camera attached to a long flexible tube to look for esophageal abnormalities. Once diagnosed, patients with Barrett's esophagus generally enter an endoscopic surveillance program so that dysplastic cells can be identified as soon as they appear and removed using endoscopic surgery or “radiofrequency ablation” to prevent cancer development. However, although endoscopic screening of everyone with reflux symptoms for Barrett's esophagus could potentially reduce deaths from esophageal cancer, such screening is not affordable for most health care systems. In this case–control study, the researchers investigate whether a cell sampling device called the Cytosponge coupled with immunohistochemical staining for Trefoil Factor 3 (TFF3, a biomarker of Barrett's esophagus) can be used to identify individuals who warrant endoscopic investigation. A case–control study compares the characteristics of patients with and without a specific disease. The Cytosponge is a small capsule-encased sponge that is attached to a string. The capsule rapidly dissolves in the stomach after being swallowed, and the sponge collects esophageal cells for TFF3 staining when it is retrieved by pulling on the string.
What Did the Researchers Do and Find?
The researchers enrolled 463 individuals attending 11 UK hospitals for investigational endoscopy for dyspepsia and reflux symptoms as controls, and 647 patients with Barrett's esophagus who were attending hospital for monitoring endoscopy. Before undergoing endoscopy, the study participants swallowed a Cytosponge so that the researchers could evaluate the safety, acceptability, and accuracy of the Cytosponge-TFF3 test for the diagnosis of Barrett's esophagus compared with endoscopy. Nearly 94% of the participants swallowed the Cytosponge successfully, there were no adverse effects attributed to the device, and those participants that swallowed the device generally rated the experience as acceptable. The overall sensitivity of the Cytosponge-TFF3 test (its ability to detect true positives) was 79.9%. That is, 79.9% of the individuals with endoscopically diagnosed Barrett's esophagus were identified as having the condition using the new test. The sensitivity of the test was greater among patients who had a longer length of affected esophagus and importantly was not reduced in patients with dysplasia. Compared to endoscopy, the specificity of the Cytosponge-TFF3 test (its ability to detect true negatives) was 92.4%. That is, 92.4% of people unaffected by Barrett's esophagus were correctly identified as being unaffected.
What Do These Findings Mean?
The case–control design of this study means that its results are not generalizable to a primary care population. Also, the study used only a single measure of the acceptability of the Cytosponge-TFF3 test, Nevertheless, these findings indicate that this minimally invasive test for Barrett's esophagus is safe and acceptable, and that its accuracy is similar to that of colorectal cancer and cervical cancer screening tests. The Cytosponge-TFF3 test might, therefore, provide a simple, inexpensive way to identify those patients with reflux symptoms who warrant endoscopy to diagnose Barrett's esophagus, although randomized controlled trials of the test are needed before its routine clinical implementation. Moreover, because most people with Barrett's esophagus never develop esophageal cancer, additional biomarkers ideally need to be added to the test before its routine implementation to identify those individuals who have the greatest risk of esophageal cancer, and thereby avoid overtreatment of Barrett's esophagus.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001780.
The US National Institute of Diabetes and Digestive and Kidney Diseases provides detailed information about Barrett's esophagus and gastroesophageal reflux disease
The US National Cancer Institute provides information for patients and health professionals about esophageal cancer (in English and Spanish)
Cancer Research UK (a non-profit organization) provides detailed information about Barrett's esophagus (including a video about having the Cytosponge test and further information about this study, the BEST2 Study) and about esophageal cancer
The UK National Health Service Choices website has pages on the complications of gastroesophageal reflux and on esophageal cancer (including a real story)
Heartburn Cancer Awareness Support is a non-profit organization that aims to improve public awareness and provides support for people affected by Barrett's esophagus; the organization's website explains the range of initiatives to promote education and awareness as well as highlighting personal stories of those affected by Barrett's esophagus and esophageal cancer
The British Society of Gastroenterology has published guidelines on the diagnosis and management of Barrett's esophagus
The UK National Institute for Health and Care Excellence has published guidelines for gastroesophageal reflux
The Barrett's Esophagus Campaign is a UK-based non-profit organization that supports research into the condition and provides support for people affected by Barrett's esophagus; its website includes personal stories about the condition
In a multi-center case-control study, Rebecca Fitzgerald and colleagues examine whether a minimally invasive cell sampling device could be used to identify patients who warrant endoscopy to diagnose Barrett's esophagus.
doi:10.1371/journal.pmed.1001780
PMCID: PMC4310596  PMID: 25634542
5.  Role of epigenetic alterations in the pathogenesis of Barrett’s esophagus and esophageal adenocarcinoma 
Barrett’s esophagus, a pre-malignant condition that can lead to esophageal adenocarcinoma, is characterized by histological changes in the normal squamous epithelium of the esophagus. Numerous molecular changes occur during the multistage conversion of Barrett’s metaplasia to dysplasia and frank adenocarcinoma. Epigenetic changes, especially changes in DNA methylation are widespread during this process. Aberrant DNA methylation has been shown to occur at promoters of tumor suppressor genes, adhesion molecules and DNA repair genes during Barrett’s esophagus. These epigenetic alterations can be used as molecular biomarkers for risk stratification and early detection of esophageal adenocarcinoma. We also show that genome wide analysis of methylation surprisingly reveals that global hypomethylation and not hypermethylation is the dominant change during Barrett’s metaplasia. The transformation of Barrett’s esophagus to frank adenocarcinoma is in turn characterized by much smaller wave of selective promoter hypermethylation. These studies reveal many novel, potential targets for new therapies and illustrate the utility of incorporating these epigenetic changes as biomarkers during endoscopic surveillance interval for patients with Barrett’s esophagus.
PMCID: PMC3396065  PMID: 22808291
Barrett’s esophagus; DNA methylation; esophageal adenocarcinoma; global hypomethylation
6.  Diagnosis and management of Barrett’s esophagus for the endoscopist 
In Barrett’s esophagus, the stratified squamous epithelium lining the esophagus is replaced by specialized intestinal-type columnar epithelium. The prevalence of Barrett’s esophagus has ranged from 0.9% to 4.5%. The rate of progression from Barrett’s esophagus to esophageal adenocarcinoma is 0.5% per patient-year. Proton-pump inhibitors are the mainstay of symptom control in Barrett’s patients. Nondysplastic Barrett’s and Barrett’s with low-grade dysplasia (LGD) are typically managed by periodic surveillance. Radiofrequency ablation is being evaluated as a modality for managing nondysplastic Barrett’s and Barrett’s with LGD. The options for the management of Barrett’s patients with high-grade dysplasia (HGD) include endoscopic therapy, surgery, and intensive surveillance until biopsy reveals adenocarcinoma. Endoscopic therapy involves endoscopic mucosal resection (EMR) and ablation. More aggressive techniques such as endoscopic submucosal dissection and larger segment endoscopic mucosal resection are under study. In this review, we discuss the diagnosis and management of Barrett’s esophagus. The recommendations from the major gastroenterologic societies and the current and investigational endoscopic modalities for the management of Barrett’s esophagus with and without dysplasia are reviewed.
doi:10.1177/1756283X10365439
PMCID: PMC3002583  PMID: 21180605
Barrett esophagus; endoscopic surgical procedures; esophageal neoplasms
7.  Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett’s esophagus 
Nature genetics  2012;44(10):1131-1136.
Barrett’s Esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia. Barrett’s Esophagus strongly predisposes to esophageal adenocarcinoma (EAC), a tumour with a very poor prognosis. We have undertaken the first genome-wide association study on Barrett’s Esophagus, comprising 1,852 UK cases and 5,172 UK controls in discovery and 5,986 cases and 12,825 controls in the replication. Two regions were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined=4.09×10−9, OR(95%CI) =1.21(1.13-1.28)) and chromosome 16q24, rs9936833 (Pcombined=2.74×10−10, OR(95%CI) =1.14(1.10-1.19)). The top SNP on chromosome 6p21 is within the major histocompatibility complex, and the closest protein-coding gene to rs9936833 on chromosome 16q24 is FOXF1, which is implicated in esophageal development and structure. We found evidence that the genetic component of Barrett’s Esophagus is mediated by many common variants of small effect and that SNP alleles predisposing to obesity also increase risk for Barrett’s Esophagus.
doi:10.1038/ng.2408
PMCID: PMC3459818  PMID: 22961001
Barrett’s Esophagus; Esophageal adenocarcinoma (EAC); Gastro-esophageal reflux disease (GERD); Genome-wide association (GWA) study; Single nucleotide polymorphisms (SNPs)
8.  Natural history of Barrett's esophagus 
The natural history of Barrett’s esophagus (BE) is difficult to quantify because, by definition, it should describe the course of the condition if left untreated. Pragmatically, we assume that patients with BE will receive symptomatic treatment with acid suppression, usually a proton pump inhibitor, to treat their heartburn. This paper describes the development of complications of stricture, ulcer, dysplasia and adenocarcinoma from this standpoint. Controversies over the definition of BE and its implications in clinical practice are presented. The presence of intestinal metaplasia and its relevance to cancer risk is discussed, and the need to measure the extent of the Barrett’s epithelium (long and short segments) using the Prague guidelines is emphasized. Guidelines and international consensus over the diagnosis and management of BE are being regularly updated. The need for expert consensus is important due to the lack of randomized trials in this area. After searching the literature, we have tried to collate the important studies regarding progression of Barrett’s to dysplasia and adenocarcinoma. No therapeutic studies yet reported show a clear reduction in the development of cancer in BE. The effect of pharmacological and surgical intervention on the natural history of Barrett’s is a subject of ongoing research, including the Barrett’s Oesophagus Surveillance Study and the aspirin and esomeprazole cancer chemoprevention trial with interesting results. The geographical variation and the wide range of outcomes highlight the difficulty of providing an individualized risk profile to patients with BE. Future studies on the interaction of genome wide abnormalities in Barrett’s and their interaction with environmental factors may allow individualization of the risk of cancer developing in BE.
doi:10.3748/wjg.v18.i27.3483
PMCID: PMC3400849  PMID: 22826612
Barrett’s esophagus; Columnar lined esophagus; Dysplasia; Adenocarcinoma; Gastroesophageal reflux; Surgery
9.  Alcohol types and sociodemographic characteristics as risk factors for Barrett’s esophagus 
Gastroenterology  2008;136(3):806-815.
Background & Aims
Little is known about the effects of alcohol use and sociodemographics on the risk of Barrett’s esophagus, a precursor to esophageal adenocarcinoma. We evaluated the association between alcohol use, alcohol type, sociodemographic profiles, other lifestyle factors and the risk of Barrett’s esophagus.
Methods
Using a case-control study within the Kaiser Permanente Northern California membership, patients with a new diagnosis of Barrett’s esophagus (n=320) diagnosed between 2002–2005 were matched to persons with gastroesophageal reflux disease (GERD) (n=316) and to population controls (n=317). We collected information using validated questionnaires during direct in-person interviews. Analyses used multivariate unconditional logistic regression.
Results
Total alcohol use was not significantly associated with the risk of Barrett’s esophagus, although stratification by beverage type showed an inverse association for wine drinkers compared to nondrinkers (7+ drinks wine/week vs. none: OR=0.44, 95%CI (0.20–0.99); multivariate analysis). Among population controls, those who preferred wine were more likely to have college degrees and regularly take vitamin supplements than those who preferred beer or liquor, although adjustment for these factors or GERD symptoms did not eliminate the inverse association between wine consumption and Barrett’s esophagus. Education status was significantly inversely associated with the risk of Barrett’s esophagus.
Conclusions
There are associations between alcohol types, socioeconomic status and the risk of Barrett’s esophagus. Although choice of alcoholic beverages was associated with several factors, multiple adjustments (including for GERD) did not eliminate the association between alcohol and Barrett’s esophagus. Further research to evaluate the associations among socioeconomic status, GERD, and Barrett’s esophagus is warranted.
doi:10.1053/j.gastro.2008.11.042
PMCID: PMC2675884  PMID: 19111726
10.  Math1/Atoh1 contributes to intestinalization of esophageal keratinocytes by inducing the expression of Muc2 and Keratin-20 
Digestive diseases and sciences  2011;57(4):845-857.
Background
Esophageal intestinal metaplasia, also known as Barrett’s esophagus, is the replacement of the normal epithelium with one that resembles the intestine morphologically. Generally, this includes intestinal mucin-secreting goblet cells. Barrett’s esophagus is an important risk factor for adenocarcinoma development. In vitro models for Barrett’s esophagus have not, to date, focused on the induction of goblet cells in Barrett’s epithelium.
Aims
To explore the contribution of Math1/Atoh1 in the induction of Barrett’s esophagus and intestinal mucin-secreting goblet cells from normal human esophageal epithelium.
Methods
We explored the level and pattern of Math1/Atoh1 mRNA and protein expression in human Barrett’s esophagus. Then, using retroviral-mediated gene expression, we induced Math1 mRNA and protein expression in a human esophageal keratinocyte cell line. We evaluated the effects of this ectopic Math1 expression upon cell proliferation and gene expression patterns in cells cultured under 2-dimensional and 3-dimensional tissue engineering conditions.
Results
Math1/Atoh1 mRNA and protein are detected in human Barrett’s esophagus specimens, but the mRNA levels vary considerable. In the keratinocyte expression studies, we observed that Math1/Atoh1 ectopic expression significantly reduced cell proliferation and altered cell morphology. Moreover, Math1/Atoh1 expression is associated with a more intestinalized gene expression pattern that is distinct from prior published studies using other intestinal transcription factors. Most significantly we observe the induction of the Barrett’s esophagus markers Mucin-2 and Keratin-20 with Math1/Atoh1 expression.
Conclusions
We conclude that ectopic Math1/Atoh1 expression makes unique contributions to the intestinalization of esophageal epithelium in Barrett’s esophagus.
doi:10.1007/s10620-011-1998-y
PMCID: PMC3407817  PMID: 22147253
Barrett’s esophagus; Math1/Atoh1; Keratin-20; metaplasia; Mucin-2; organotypic culture
11.  Gene Expression Profiling Reveals Stromal Genes Expressed in Common Between Barrett’s Esophagus and Adenocarcinoma 
Gastroenterology  2006;131(3):925-933.
Background & Aims
Barrett’s esophagus is a precursor of esophageal adenocarcinoma. DNA microarrays that enable a genome-wide assessment of gene expression enhance the identification of specific genes as well as gene expression patterns that are expressed by Barrett’s esophagus and adenocarcinoma compared to normal tissues. Barrett's esophagus length has also been identified as a risk factor for progression to adenocarcinoma, but whether there are intrinsic biological differences between short and long-segment Barrett's esophagus can be explored with microarrays.
Methods
Gene expression profiles for endoscopically obtained biopsies of Barrett’s esophagus or esophageal adenocarcinoma, and associated normal esophagus and duodenum were identified for 17 patients using DNA microarrays. Unsupervised and supervised approaches for data analysis defined similarities and differences between the tissues as well as correlations with clinical phenotypes.
Results
Each tissue displays a unique expression profile that distinguishes it from each other. Barrett’s esophagus and esophageal adenocarcinoma express a unique set of stromal genes that is distinct from normal tissues, but similar to other cancers. Adenocarcinoma also showed lower and higher expression for many genes compared to Barrett's esophagus. No difference in gene expression was found between short and long-segment Barrett's esophagus.
Conclusions
The genome-wide assessment provided by current DNA microarrays reveals many candidate genes and patterns not previously identified. Stromal gene expression in Barrett’s esophagus and adenocarcinoma are similar, indicating that these changes precede neoplasia.
doi:10.1053/j.gastro.2006.04.026
PMCID: PMC2575112  PMID: 16952561
12.  Dietary Factors and the Risks of Esophageal Adenocarcinoma and Barrett’s Esophagus 
Nutrition research reviews  2010;23(2):230-246.
Incidence rates for esophageal adenocarcinoma have increased by over 500% during the past few decades without clear reasons. Gastroesophageal reflux disease (GERD), obesity, and smoking have been identified as risk factors, although the demographic distribution of these risk factors is not consistent with the demographic distribution of esophageal adenocarcinoma, which is substantially more common among whites and males than any other demographic groups. Numerous epidemiological studies have suggested associations between dietary factors and the risks of esophageal adenocarcinoma and its precursor, Barrett’s esophagus, though a comprehensive review is lacking. The main aim of the present review is to consider the evidence linking dietary factors with the risks of esophageal adenocarcinoma, Barrett’s esophagus, and the progression from Barrett’s esophagus to esophageal adenocarcinoma. The existing epidemiological evidence is strongest for an inverse relationship between intake of vitamin C, β-carotene, fruits and vegetables, particularly raw fruits and vegetables and dark-green, leafy and cruciferous vegetables, carbohydrates, fiber and iron and the risk of esophageal adenocarcinoma and Barrett’s esophagus. Patients at higher risk for Barrett’s esophagus and esophageal adenocarcinoma may benefit from increasing their consumption of fruits and vegetables and reducing their intake of red meat and other processed food items. Further research is needed to evaluate the relationship between diet and the progression of Barrett’s esophagus to esophageal adenocarcinoma. Evidence from cohort studies will help determine whether randomized chemoprevention trials are warranted for the primary prevention of Barrett’s esophagus or its progression to cancer.
doi:10.1017/S0954422410000132
PMCID: PMC3062915  PMID: 20624335
13.  Familial aggregation of Barrett’s oesophagus, oesophageal adenocarcinoma, and oesophagogastric junctional adenocarcinoma in Caucasian adults 
Gut  2002;51(3):323-328.
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.
PMCID: PMC1773365  PMID: 12171951
Barrett’s oesophagus; oesophageal adenocarcinoma; oesophagogastric junctional adenocarcinoma; gastro-oesophageal reflux disease
14.  Biomarkers in the molecular pathogenesis of esophageal (Barrett) adenocarcinoma 
Current Oncology  2006;13(1):33-43.
Since the early 1970s, a dramatic change has occurred in the epidemiology of esophageal malignancy in both North America and Europe: the incidence of adenocarcinomas of the lower esophagus and esophagogastric junction is increasing. Several lifestyle factors are implicated in this change, including gastroesophageal reflux disease (gerd). Primary esophageal adenocarcinomas are thought to arise from Barrett esophagus, an acquired condition in which the normal esophageal squamous epithelium is replaced by a specialized metaplastic columnar-cell-lined epithelium.
Today, gerd is recognized as an important risk factor in Barrett esophagus. Progression of Barrett esophagus to invasive adenocarcinoma is reflected histologically by the metaplasia–dysplasia–carcinoma sequence. Although several molecular alterations associated with progression of Barrett esophagus to invasive adenocarcinoma have been identified, relatively few will ultimately have clinical application. Currently, the histologic finding of high-grade dysplasia remains the most reliable predictor of progression to invasive esophageal adenocarcinoma. However other promising molecular biomarkers include aneuploidy; 17p loss of heterozygosity, which implicates the TP53 tumour suppressor gene; cyclin D1 protein overexpression; and p16 alterations. It is anticipated that models incorporating combinations of objective scores of sociodemographic and lifestyle risk factors (that is, age, sex, body mass index), severity of gerd, endoscopic and histologic findings, and a panel of biomarkers will be developed to better identify patients with Barrett esophagus at increased risk for malignant progression, leading to more rational endoscopic surveillance and screening programs.
PMCID: PMC1891165  PMID: 17576439
Barrett esophagus; esophageal adenocarcinoma; molecular pathogenesis; biomarkers
15.  Alterations of glutathione S-transferase and matrix metalloproteinase-9 expressions are early events in esophageal carcinogenesis 
AIM: To investigate the role of glutathione S-transferase (GST) and matrix metalloproteinase-9 (MMP-9) expressions in the development and progression of reflux esophagitis-Barrett’s metaplasia-dysplasia-adenocarcinoma sequence in the esophagus.
METHODS: GST and MMP-9 expressions were analyzed in 51 paraffin-embedded tissue samples by immunohistochemistry including patients with reflux esophagitis (n = 7), Barrett’s metaplasia (n = 14), Barrett and esophagitis (n = 8), Barrett and dysplasia (n = 7), esophageal adenocarcinoma (n = 8) and a control group without any histological changes (n = 7). Immunostaining was determined semiquantitatively. Statistical analysis with one-way ANOVA, LSD test and correlation analysis were performed. P value of < 0.05 was considered significant.
RESULTS: GST expression was significantly higher while MMP-9 expression was significantly lower in control group compared to Barrett’s metaplasia and the other groups. No major changes were observed between Barrett, esophagitis, and Barrett and concomitant esophagitis. Barrett and concomitant dysplasia, and adenocarcinoma revealed a significant lower expression of GST and higher levels of MMP-9 compared to all other groups. Adenocarcinoma showed almost no expression of GST and significantly higher levels of MMP-9 than Barrett and concomitant dysplasia. Alterations of GST and MMP-9 were inversely correlated (r = - 0.82).
CONCLUSION: Decreased GST and increased expression of MMP-9 in Barrett’s metaplasia-dysplasia-adenocarcinoma sequence as compared to normal tissue suggest their association with esophageal tumorigenesis. Loss of GST and gain of MMP-9 in Barrett with dysplasia compared to non-dysplastic metaplasia indicate that these alterations may be early events in carcinogenesis. Quantification of these parameters in Barrett’s esophagus might be useful to identify patients at higher risk for progression to cancer.
doi:10.3748/wjg.v13.i5.676
PMCID: PMC4065999  PMID: 17278189
Glutathione S-transferase; Matrix metallo-proteinase-9; Barrett’s metaplasia; Esophagus; Adenocarcinoma; Dysplasia
16.  Beyond Field Effect: Analysis of Shrunken Centroids in Normal Esophageal Epithelia Detects Concomitant Esophageal Adenocarcinoma 
Background and Aims
Because of the extremely low neoplastic progression rate in Barrett’s esophagus, it is difficult to diagnose patients with concomitant adenocarcinoma early in their disease course. If biomarkers existed in normal squamous esophageal epithelium to identify patients with concomitant esophageal adenocarcinoma, potential applications would be far-reaching. The aim of the current study was to identify global gene expression patterns in normal esophageal epithelium capable of revealing simultaneous esophageal adenocarcinoma, even located remotely in the esophagus.
Methods
Tissues comprised normal esophageal epithelia from 9 patients with esophageal adenocarcinoma, 8 patients lacking esophageal adenocarcinoma or Barrett’s, and 6 patients with Barrett’s esophagus alone. cDNA microarrays were performed, and pattern recognition in each of these subgroups was achieved using shrunken nearest centroid predictors.
Results
Our method accurately discriminated normal esophageal epithelia of 8/8 patients without esophageal adenocarcinoma or Barrett’s esophagus and of 6/6 patients with Barrett’s esophagus alone from normal esophageal epithelia of 9/9 patients with Barrett’s esophagus and concomitant esophageal adenocarcinoma. Moreover, we identified genes differentially expressed between the above subgroups. Thus, based on their corresponding normal esophageal epithelia alone, our method accurately diagnosed patients who had concomitant esophageal adenocarcinoma.
Conclusions
These global gene expression patterns, along with individual genes culled from them, represent potential biomarkers for the early diagnosis of esophageal adenocarcinoma from normal esophageal epithelia. Genes discovered in normal esophagus that are differentially expressed in patients with vs. without esophageal adenocarcinoma merit further pursuit in molecular genetic, functional, and therapeutic interventional studies.
PMCID: PMC2323355  PMID: 18425214
17.  Beyond Field Effect: Analysis of Shrunken Centroids in Normal Esophageal Epithelia Detects Concomitant Esophageal Adenocarcinoma 
Background and Aims:
Because of the extremely low neoplastic progression rate in Barrett’s esophagus, it is difficult to diagnose patients with concomitant adenocarcinoma early in their disease course. If biomarkers existed in normal squamous esophageal epithelium to identify patients with concomitant esophageal adenocarcinoma, potential applications would be far-reaching. The aim of the current study was to identify global gene expression patterns in normal esophageal epithelium capable of revealing simultaneous esophageal adenocarcinoma, even located remotely in the esophagus.
Methods:
Tissues comprised normal esophageal epithelia from 9 patients with esophageal adenocarcinoma, 8 patients lacking esophageal adenocarcinoma or Barrett’s, and 6 patients with Barrett’s esophagus alone. cDNA microarrays were performed, and pattern recognition in each of these subgroups was achieved using shrunken nearest centroid predictors.
Results:
Our method accurately discriminated normal esophageal epithelia of 8/8 patients without esophageal adenocarcinoma or Barrett’s esophagus and of 6/6 patients with Barrett’s esophagus alone from normal esophageal epithelia of 9/9 patients with Barrett’s esophagus and concomitant esophageal adenocarcinoma. Moreover, we identified genes differentially expressed between the above subgroups. Thus, based on their corresponding normal esophageal epithelia alone, our method accurately diagnosed patients who had concomitant esophageal adenocarcinoma.
Conclusions:
These global gene expression patterns, along with individual genes culled from them, represent potential biomarkers for the early diagnosis of esophageal adenocarcinoma from normal esophageal epithelia. Genes discovered in normal esophagus that are differentially expressed in patients with vs. without esophageal adenocarcinoma merit further pursuit in molecular genetic, functional, and therapeutic interventional studies.
PMCID: PMC2323355  PMID: 18425214
18.  NSAIDs Modulate CDKN2A, TP53, and DNA Content Risk for Progression to Esophageal Adenocarcinoma 
PLoS Medicine  2007;4(2):e67.
Background
Somatic genetic CDKN2A, TP53, and DNA content abnormalities are common in many human cancers and their precursors, including esophageal adenocarcinoma (EA) and Barrett's esophagus (BE), conditions for which aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been proposed as possible chemopreventive agents; however, little is known about the ability of a biomarker panel to predict progression to cancer nor how NSAID use may modulate progression. We aimed to evaluate somatic genetic abnormalities with NSAIDs as predictors of EA in a prospective cohort study of patients with BE.
Methods and Findings
Esophageal biopsies from 243 patients with BE were evaluated at baseline for TP53 and CDKN2A (p16) alterations, tetraploidy, and aneuploidy using sequencing; loss of heterozygosity (LOH); methylation-specific PCR; and flow cytometry. At 10 y, all abnormalities, except CDKN2A mutation and methylation, contributed to EA risk significantly by univariate analysis, ranging from 17p LOH (relative risk [RR] = 10.6; 95% confidence interval [CI] 5.2–21.3, p < 0.001) to 9p LOH (RR = 2.6; 95% CI 1.1–6.0, p = 0.03). A panel of abnormalities including 17p LOH, DNA content tetraploidy and aneuploidy, and 9p LOH was the best predictor of EA (RR = 38.7; 95% CI 10.8–138.5, p < 0.001). Patients with no baseline abnormality had a 12% 10-y cumulative EA incidence, whereas patients with 17p LOH, DNA content abnormalities, and 9p LOH had at least a 79.1% 10-y EA incidence. In patients with zero, one, two, or three baseline panel abnormalities, there was a significant trend toward EA risk reduction among NSAID users compared to nonusers (p = 0.01). The strongest protective effect was seen in participants with multiple genetic abnormalities, with NSAID nonusers having an observed 10-y EA risk of 79%, compared to 30% for NSAID users (p < 0.001).
Conclusions
A combination of 17p LOH, 9p LOH, and DNA content abnormalities provided better EA risk prediction than any single TP53, CDKN2A, or DNA content lesion alone. NSAIDs are associated with reduced EA risk, especially in patients with multiple high-risk molecular abnormalities.
In a ten-year study of people with Barrett's esophagus, nonsteroidal anti-inflamatory drugs were associated with reduced risk of esophageal adenocarcinoma, especially in patients with multiple high-risk molecular abnormalities.
Editors' Summary
Background.
Normally, the cells in the human body divide only when extra cells are needed, after an injury, for example. Sometimes, however, cells accumulate genetic changes (mutations) that allow them to divide uncontrollably to form a disorganized mass or tumor. If these altered cells also acquire mutations that allow them to spread around the body, a malignant tumor or cancer results. Scientists have identified numerous genetic changes that occur in tumors and are now investigating whether these molecular abnormalities can be used as “biomarkers” to choose the best treatments for patients, to identify who will benefit from cancer-prevention strategies, to detect cancer early, and to predict which cancers are most likely to become life-threatening. This last application is particularly important for cancers with a well-defined premalignant stage. Because the cells in premalignant tissues have acquired some of the genetic changes required for cancer development, they are more likely to become malignant than normal cells. Barrett's esophagus, for example, is a premalignant disorder of the muscular tube that takes food from the mouth to the stomach. People with Barrett's esophagus are much more likely to develop esophageal cancer than the general population.
Why Was This Study Done?
Esophageal cancer is often incurable by the time it is detected, so it would be helpful to know which people with Barrett's esophagus are most likely to develop esophageal cancer—only 1 in 200 of them develop cancer each year. In this study, the researchers evaluated whether a panel of genetic alterations could identify this subset of patients. They also investigated whether the regular use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) affects the risk of developing esophageal cancer in people with Barrett's esophagus—other evidence suggests that NSAIDs may help to prevent several types of cancer, including esophageal cancer.
What Did the Researchers Do and Find?
The researchers took esophageal tissue samples from patients with Barrett's esophagus and looked for alterations in the genes encoding the tumor-suppressor proteins TP53 and CDKN2A. These proteins normally stop cells dividing but are often inactivated in cancer cells by mutation of one of the two gene copies that encode each of them and also loss of the other copy (so-called “loss of heterozygosity” or LOH). The researchers also looked for changes in the cellular DNA content of the samples (tumor cells often contain unusual amounts of DNA) and asked the study participants about their NSAID use before waiting to see which participants developed esophageal cancer. After 10 y, the participants whose tissue samples had LOH of the short arms (p) of Chromosome 17 or 9 (the sites of the genes encoding TP53 and CDKN2A, respectively), or an altered DNA content, were more likely to have developed esophageal cancer than those without these abnormalities; those whose samples contained all three abnormalities had the highest risk of developing esophageal cancer. Overall, just 12% of patients with no abnormalities but nearly 80% of patients with three abnormalities developed esophageal cancer. NSAID use reduced the risk of cancer development in all the participants, but its effect was greatest in those with three genetic abnormalities.
What Do These Findings Mean?
These findings suggest that the combined measurement of 17pLOH, 9pLOH, and cellular DNA content might be a powerful way to identify those patients with Barrett's esophagus who are most likely to develop esophageal cancer. They also suggest that NSAID use is associated with a reduced risk of esophageal cancer, particularly in patients with multiple genetic abnormalities. Because very few participants developed cancer during the study, these results need confirming in more patients. Also, the ability of NSAIDs to prevent the progression of Barrett's esophagus to esophageal cancer needs testing in multicenter randomized trials; the use of the panel of abnormalities described here to identify the people with Barrett's esophagus most at risk of developing esophageal cancer should facilitate such studies.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040067.
CancerQuest information from Emory University (Atlanta, Georgia, United States) on cancer biology, including the role of tumor suppressor proteins
US National Cancer Institute patient and physician information on esophageal cancer and its prevention
MedlinePlus encyclopedia pages on Barrett's esophagus and esophageal cancer
Cancerbackup (UK charity) patient information on esophageal cancer and Barrett's esophagus
doi:10.1371/journal.pmed.0040067
PMCID: PMC1808095  PMID: 17326708
19.  Expression of the bile acid receptor FXR in Barrett's esophagus and enhancement of apoptosis by guggulsterone in vitro 
Molecular Cancer  2006;5:48.
Background
Barrett's esophagus, a risk factor for esophageal adenocarcinoma, is associated with reflux disease. The aim of this study was to assess the expression of bile acid receptors in the esophagus (normal, esophagitis, Barrett's esophagus and adenocarcinoma) and to investigate their possible function.
Results
the expression of the bile acid receptors FXR and VDR in esophageal biopsies from patients with a normal mucosa, esophagitis, Barrett's esophagus or adenocarcinoma (n = 6 per group) and in cell lines derived from Barrett's esophagus and esophageal adenocarcinoma, was assessed by real time Q-PCR and immunohistochemistry. The effect of guggulsterone, an antagonist of bile acid receptors, on apoptosis of Barrett's esophagus-derived cells was assessed morphologically, by flow cytometry and by measuring caspase 3 activity.
The expression of FXR was increased in esophagitis, Barrett's esophagus and adenocarcinoma compared to normal mucosa by a mean of 44, 84 and 16, respectively. Immunohistochemistry showed a weak expression in normal esophagus, a strong focal reactivity in Barrett's esophagus, and was negative in adenocarcinoma. VDR expression did not significantly differ between groups. In cell cultures, the expression of FXR was high in Barrett's esophagus-derived cells and almost undetectable in adenocarcinoma-derived cells, whereas VDR expression in these cell lines was not significantly different. In vitro treatment with guggulsterone was associated with a significant increase in the percentage of apoptotic cells and of the caspase 3 activity.
Conclusion
the bile acid receptor FXR is significantly overexpressed in Barrett's esophagus compared to normal mucosa, esophagitis and esophageal adenocarcinoma. The induction of apoptosis by guggulsterone in a Barrett's esophagus-derived cell line suggests that FXR may contribute to the regulation of apoptosis.
doi:10.1186/1476-4598-5-48
PMCID: PMC1624849  PMID: 17054793
20.  DNA promoter hypermethylation of p16 and APC predicts neoplastic progression in Barrett’s esophagus 
Introduction
Prediction of progression to cancer in patients with Barrett’s esophagus is difficult using current techniques. We determined whether DNA promoter hypermethylation of genes frequently methylated in esophageal adenocarcinoma (p16 and APC) could be used as predictors of progression in Barrett’s esophagus.
Methods
We first performed a cross-sectional study to evaluate the prevalence of gene hypermethylation in biopsies from patients with normal esophagus (n=17), Barrett’s esophagus (n=102), and adenocarcinoma (n=42). We then performed a nested case-control study comparing gene hypermethylation in Barrett’s esophagus patients who progressed from baseline pathology to high-grade dysplasia or cancer (n=7) versus patients who did not progress (n=50).
Results
None of the patients with normal esophagus had p16 or APC hypermethylation. Hypermethylation was prevalent in Barrett’s esophagus without dysplasia or low-grade dysplasia (p16=31% and APC=50%; p<0.01) and high-grade dysplasia or adenocarcinoma (p16=54% and APC=68%; p<0.001) compared to normal esophagus (not detected). Patients who progressed from baseline pathology to high-grade dysplasia or cancer had higher prevalence of hypermethylation in their initial esophagus biopsies compared to those who did not progress for both p16 (100% vs. 33%; p=0.008) and APC (86% vs. 40%; p=0.02). Hypermethylation of both p16 and APC was a strong predictor of subsequent progression to cancer during a mean follow-up time of 4.1 years (adjusted OR [95% CI]=14.97 [1.73,inf], p=0.01). Among patients who were negative for both p16 and APC hypermethylation, none progressed from baseline pathology to high-grade dysplasia or cancer.
Conclusions
Hypermethylation of both p16 and APC strongly predicts progression to high-grade dysplasia or cancer in patients with Barrett’s esophagus. Absence of p16 and APC hypermethylation is associated with a benign course.
doi:10.1038/ajg.2009.300
PMCID: PMC3090447  PMID: 19584833
21.  Age- and Gender-Specific Yield of Barrett’s Esophagus by Endoscopy Indication 
Gastrointestinal endoscopy  2009;71(1):21.
Background
Barrett’s esophagus is a precursor of esophageal adenocarcinoma, both of which are associated with gastroesophageal reflux disease (GERD). Screening GERD patients for Barrett’s esophagus has been suggested, but it is not known which patients should be screened, and at what age.
Objective
To determine the age-specific yield of endoscopy for Barrett’s esophagus stratified by gender and indication for endoscopy.
Design
Retrospective cross-sectional study.
Setting
National Endoscopic Database of the Clinical Outcomes Research Initiative (CORI).
Patients
155,641 patients undergoing their first endoscopy at one of the CORI sites for clinical indication.
Interventions
N/A
Main Outcome Measurements
Age-specific yield of Barrett’s esophagus.
Results
Among white men with GERD, the yield for Barrett’s esophagus rises steeply from early adulthood (2.1% in 3rd decade of life) to middle adulthood (9.3% in 6th decade), and then plateaus (difference for 8th decade minus 6th decade = −1.1%, 95% confidence interval [CI] = −3.9%, +1.7%). There is no difference in yield of Barrett’s esophagus between middle-aged white women with GERD and white men without GERD (difference = −0.46%, 95% CI = −1.23%, +0.31%).
Limitations
Possible bias by selection for endoscopy, and potential for misclassification of GERD status.
Conclusions
The yield of upper endoscopy for diagnosis of Barrett’s esophagus increases rapidly among white men with GERD until approximately age 50, then reaches a plateau. White women with GERD are at no increased risk compared to white men without GERD.
doi:10.1016/j.gie.2009.06.035
PMCID: PMC2813379  PMID: 19748616
Barrett’s esophagus; Epidemiology
22.  Gene expression in Barrett’s esophagus and reflux esophagitis induced by gastroduodenoesophageal reflux in rats 
AIM: To investigate the difference of gene expression profiles between Barrett’s esophagus and reflux eso-phagitis induced by gastroduodenoesophageal reflux in rats.
METHODS: Eight-week-old Sprague-Dawley rats were treated esophagoduodenostomy to produce gastroduode-noesophageal reflux, and another group received sham operation as control. Esophageal epithelial tissues were dissected and frozen in liquid nitrogen immediately for pathology 40 wk after surgery. The expression profiles of 4096 genes in reflux esophagitis and Barrett’s esophagus tissues were compared with normal esophageal epithelium by cDNA microarray.
RESULTS: Four hundred and forty-eight genes in Barrett’s esophagus were more than three times different from those in normal esophageal epithelium, including 312 up-regulated and 136 down-regulated genes. Two hundred and thirty-two genes in RE were more than three times different from those in normal esophageal epithelium, 90 up-regulated and 142 down-regulated genes. Compared to reflux esophagitis, there were 214 up-regulated and 142 down-regulated genes in Barrett’s esophagus.
CONCLUSION: Esophageal epithelium exposed excessively to harmful ingredients of duodenal and gastric reflux can develop esophagitis and Barrett’s esophagus gradually. The gene expression level is different between reflux esophagitis and Barrett’s esophagus and the differentially expressed genes might be related to the occurrence and development of Barrett’s esophagus and the promotion or progression in adenocarcinoma.
doi:10.3748/wjg.v11.i21.3277
PMCID: PMC4316063  PMID: 15929182
Gastroduodenoesophageal reflux; Esophagitis; Barrett’s esophagus; Gene expression
23.  Changes in Screening, Prognostication and Therapy for Esophageal Adenocarcinoma in Barrett’s Esophagus 
Purpose of review
Significant changes in concepts of managing Barrett’s esophagus have led to change in the recommendations concerning screening, surveillance, biomarkers, and therapies in this condition over the past several years. We summarize the important changes in this regard.
Recent findings
Narrow band imaging and esophageal capsule endoscopy are alternative methods to screen for Barrett’s esophagus. Narrow band imaging provides clear visualization of the mucosal pit patterns and vascular patterns, which improve the diagnostic value for specialized intestinal mataplasia. Esophageal capsule endoscopy is a new potential tool which allows a direct noninvasive visualization of esophagus. Research efforts are currently directed towards risk stratification of patients and biomarkers have been developed to predict development of esophageal adenocarcinoma. Recent studies have reported that frequent loss of heterozygosity (LOH) as well as allelic imbalances in chromosomes in esophageal adenocarcinoma. Fluorescent in situ hybridization technique which uses fluorescently labeled DNA probes to detect chromosomal alterations in cells obtained from cytology specimens has been developed. It showed more sensitive and specific for abnormalities than PCR based techniques. Currently, many studies support the concept of endoscopic elimination of dysplastic lesions in the esophagus by a mucosal ablation therapy. Photodynamic therapy and radiofrequency ablation are recently developed, emerging techniques.
Summary
Recent advances in screening, prognostication and therapy for esophageal adenocarcinoma in Barrett’s Esophagus have brought a significant new insight in clinical practices and will eventually ensure better patients outcomes.
doi:10.1097/MOG.0b013e32832c148f
PMCID: PMC3762463  PMID: 19461512
narrow band imaging; esophageal capsule endoscopy; fluorescent in situ hybridization; photodynamic therapy; radiofrequency ablation
24.  Complex Segregation Analysis of Pedigrees from the Gilda Radner Familial Ovarian Cancer Registry Reveals Evidence for Mendelian Dominant Inheritance 
PLoS ONE  2009;4(6):e5939.
Background
Familial component is estimated to account for about 10% of ovarian cancer. However, the mode of inheritance of ovarian cancer remains poorly understood. The goal of this study was to investigate the inheritance model that best fits the observed transmission pattern of ovarian cancer among 7669 members of 1919 pedigrees ascertained through probands from the Gilda Radner Familial Ovarian Cancer Registry at Roswell Park Cancer Institute, Buffalo, New York.
Methodology/Principal Findings
Using the Statistical Analysis for Genetic Epidemiology program, we carried out complex segregation analyses of ovarian cancer affection status by fitting different genetic hypothesis-based regressive multivariate logistic models. We evaluated the likelihood of sporadic, major gene, environmental, general, and six types of Mendelian models. Under each hypothesized model, we also estimated the susceptibility allele frequency, transmission probabilities for the susceptibility allele, baseline susceptibility and estimates of familial association. Comparisons between models were carried out using either maximum likelihood ratio test in the case of hierarchical models, or Akaike information criterion for non-nested models. When assessed against sporadic model without familial association, the model with both parent-offspring and sib-sib residual association could not be rejected. Likewise, the Mendelian dominant model that included familial residual association provided the best-fitting for the inheritance of ovarian cancer. The estimated disease allele frequency in the dominant model was 0.21.
Conclusions/Significance
This report provides support for a genetic role in susceptibility to ovarian cancer with a major autosomal dominant component. This model does not preclude the possibility of polygenic inheritance of combined effects of multiple low penetrance susceptibility alleles segregating dominantly.
doi:10.1371/journal.pone.0005939
PMCID: PMC2694280  PMID: 19536330
25.  Optimal management of Barrett’s esophagus: pharmacologic, endoscopic, and surgical interventions 
Esophageal adenocarcinoma and its precursor, Barrett’s esophagus, are rapidly rising in incidence. This review serves to highlight the role of pharmacologic, endoscopic, and surgical intervention in the management of Barrett’s esophagus, which requires acid suppression and endoscopic assessment. Treatment with a proton pump inhibitor may decrease acid exposure and delay the progression to dysplasia. Patients who require aspirin for cardioprotection or other indications may also benefit in terms of a protective effect against the development of esophageal cancer. However, without other indications, aspirin is not indicated solely to prevent cancer. A careful endoscopic examination should include assessment of any visible lesions in a Barrett’s segment. An expert gastrointestinal pathologist should confirm neoplasia in the setting of Barrett’s esophagus. For those patients with high-grade dysplasia or intramucosal carcinoma, careful consideration of endoscopic therapy or surgical therapy must be given. All visible lesions in the setting of dysplasia should be targeted with focal endoscopic mucosal resection for both accurate histopathologic diagnosis and treatment. The remainder of the Barrett’s epithelium should be eradicated to address all synchronous and metachronous lesions. This may be done by tissue acquiring or nontissue acquiring means. Radiofrequency ablation has a positive benefit-risk profile for flat Barrett’s esophagus. At this time, endoscopic therapy is not indicated for nondysplastic Barrett’s esophagus. Esophagectomy is still reserved for selected cases with evidence of lymph node metastasis, unsuccessful endoscopic therapy, or with high-risk features of high-grade dysplasia or intramucosal carcinoma.
doi:10.2147/TCRM.S23425
PMCID: PMC3233528  PMID: 22162921
Barrett’s esophagus; high-grade dysplasia; esophagectomy; ablation; endoscopic mucosal resection

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