Barrett's Patients Research Articles

Frequency of endoscopic surveillance for Barrett's esophagus is influenced by health insurance status: results from a population-based analysis.

Factors that influence the frequency of surveillance endoscopy for nondysplastic Barrett's esophagus are not well understood. The objective of this study is to assess factors which influence the frequency of endoscopic surveillance for Barrett's esophagus, including health insurance/third-party payer status. Cases of nondysplastic Barrett's esophagus undergoing esophagogastroduodenoscopy with biopsy were identified using longitudinal data from the Healthcare Utilization Project database in 2005-2006 and followed through 2011. The threshold for appropriate surveillance utilization was defined as two to four surveillance esophagogastroduodenoscopies over a standardized 5-year period. Patients' insurance status was designated as either Medicare, Medicaid, private, or noninsured. 36,676 cases of nondysplastic Barrett's esophagus were identified. Among these, 4,632 patients (12.6%) underwent between two and four surveillance esophagogastroduodenoscopies in 5 years of follow-up versus 31,975 patients (87.3%) who underwent fewer than two esophagogastroduodenoscopies during follow-up. Multivariate analysis found that Barrett's patients insured through Medicaid (OR 1.273; 95% CI =1.065-1.522) or without insurance (OR =2.453; 95% CI =1.67-3.603) were at increased likelihood of being under-surveilled. This study identified a difference in frequency of surveillance esophagogastroduodenoscopy for Barrett's esophagus by payer status. Patients without health insurance and those whose primary insurance was Medicaid were at increased odds for under-surveillance. These data suggest that a more robust system for tracking and ensuring longitudinal follow-up of patients with Barrett's esophagus, with attention to the uninsured and underinsured population, may be needed to ensure optimal surveillance.

Metabolomic Evidence for a Field Effect in Histologically Normal and Metaplastic Tissues in Patients with Esophageal Adenocarcinoma

Patients with Barrett's esophagus (BO) are at increased risk of developing esophageal adenocarcinoma (EAC). Most Barrett's patients, however, do not develop EAC, and there is a need for markers that can identify those most at risk. This study aimed to see if a metabolic signature associated with the development of EAC existed. For this, tissue extracts from patients with EAC, BO, and normal esophagus were analyzed using 1H nuclear magnetic resonance. Where possible, adjacent histologically normal tissues were sampled in those with EAC and BO. The study included 46 patients with EAC, 7 patients with BO, and 68 controls who underwent endoscopy for dyspeptic symptoms with normal appearances. Within the cancer cohort, 9 patients had nonneoplastic Barrett's adjacent to the cancer suitable for biopsy. It was possible to distinguish between histologically normal, BO, and EAC tissue in EAC patients [area under the receiver operator curve (AUROC) 1.00, 0.86, and 0.91] and between histologically benign BO in the presence and absence of EAC (AUROC 0.79). In both these cases, sample numbers limited the power of the models. Comparison of histologically normal tissue proximal to EAC versus that from controls (AUROC 1.00) suggests a strong field effect which may develop prior to overt EAC and hence be useful for identifying patients at high risk of developing EAC. Excellent sensitivity and specificity were found for this model to distinguish histologically normal squamous esophageal mucosa in EAC patients and healthy controls, with 8 metabolites being very significantly altered. This may have potential diagnostic value if a molecular signature can detect tissue from which neoplasms subsequently arise.

Systematic review with meta-analysis: prevalent vs. incident oesophageal adenocarcinoma and high-grade dysplasia in Barrett's oesophagus.

The proportion of oesophageal adenocarcinoma that is detected concurrently with initial Barrett's oesophagus diagnosis is not well studied. To compare the proportion of prevalent adenocarcinoma vs. incident adenocarcinoma found during surveillance of Barrett's. We performed a systematic search of MEDLINE, EMBASE and Web of Science (from their inception to 31 May 2015) for cohort studies in adults with Barrett's (nondysplastic Barrett's ± Barrett's with low-grade dysplasia) with minimum average follow-up of 3 years, and providing numbers of prevalent adenocarcinoma detected (concurrently with Barrett's diagnosis and up to 1 year afterwards) vs. incident adenocarcinoma detected (greater than 1 year after Barrett's diagnosis). Pooled weighted proportions of prevalent and incident adenocarcinoma were calculated, using a random effects model. On meta-analysis of 13 studies reporting on 603 adenocarcinomas in 9657 Barrett's patients, 85.1% of adenocarcinomas were classified as prevalent [95% confidence interval (CI), 78.1-90.2%) and 14.9% as incident (95% CI, 9.8-21.9%), with substantial heterogeneity (I(2) = 66%). Among nine studies reporting on 787 high-grade dysplasia and oesophageal adenocarcinomas in 8098 Barrett's patients, the proportion of prevalent high-grade dysplasia-oesophageal adenocarcinoma was similar at 80.5% (95% CI, 68.1-88.8%, I(2) = 87%). These results remained stable across multiple subgroup analyses including study quality, setting, duration of follow-up and presence of baseline dysplasia. In our meta-analysis, four of five patients diagnosed with adenocarcinoma or high-grade dysplasia at index endoscopy or within 1 year of Barrett's follow-up were considered to be prevalent cases. Continued efforts are needed to identify patients with Barrett's before the development of adenocarcinoma.

Dynamic clonal equilibrium and predetermined cancer risk in Barrett's oesophagus.

Surveillance of Barrett's oesophagus allows us to study the evolutionary dynamics of a human neoplasm over time. Here we use multicolour fluorescence in situ hybridization on brush cytology specimens, from two time points with a median interval of 37 months in 195 non-dysplastic Barrett's patients, and a third time point in a subset of 90 patients at a median interval of 36 months, to study clonal evolution at single-cell resolution. Baseline genetic diversity predicts progression and remains in a stable dynamic equilibrium over time. Clonal expansions are rare, being detected once every 36.8 patient years, and growing at an average rate of 1.58 cm2 (95% CI: 0.09–4.06) per year, often involving the p16 locus. This suggests a lack of strong clonal selection in Barrett's and that the malignant potential of ‘benign' Barrett's lesions is predetermined, with important implications for surveillance programs.

Black raspberries in cancer clinical trials: Past, present and future.

BACKGROUNDBlack raspberries (BRB) inhibit a broad range of cancers in preclinical models, including in vivo models of oral, esophageal, colon, breast and skin cancer. Promising preclinical results have led to clinical evaluations in cancer patients or patients at increased risk for cancer development.OBJECTIVETo summarize clinical investigations targeting cancer or precancerous lesions with BRB and discuss future directions.METHODSA thorough literature search was conducted through December 1, 2015 to identify all published studies evaluating BRB in cancer focused clinical trials.RESULTSResearch investigating BRB in clinical settings report positive effects on preneoplastic lesions or cancers of the oral cavity, esophagus and colon. BRB treatment resulted in: histologic regression of oral intraepithelial neoplasia associated with improved histologic grade and significantly reduced loss of heterozygosity at tumor suppressor gene loci, modulated genes linked to RNA processing and growth factor recycling; in the colon, BRB inhibited FAP-associated polyp progression, demethylated tumor suppressor genes and improved plasma cytokine profiles; in Barrett’s patients, BRB consumption increased tissue levels of GST-pi and decreased 8-isoprostane, a marker of lipid peroxidation/oxidative stress.CONCLUSIONSThe precise dose, duration and optimum mode of BRB delivery for cancer inhibition remains to be fully elucidated. Common themes across studies support that BRB are anti-proliferative, anti- inflammatory, reduce oxidative stress and restore tumor suppressive activity. Future directions are included in the conclusions section.

57 Significant Reduction in the Disease Progression in Barrett's Esophagus Low-Grade Dysplasia Patients Treated With Endoscopic Eradiation Therapy Compared With Surveillance Endoscopy: A Systematic Review and Meta-Analysis

57 Significant Reduction in the Disease Progression in Barrett's Esophagus Low-Grade Dysplasia Patients Treated With Endoscopic Eradiation Therapy Compared With Surveillance Endoscopy: A Systematic Review and Meta-Analysis

The socioeconomic profile of a Barrett’s oesophagus cohort assessed by the 2010 Index of Multiple Deprivation

Several reports have described the relationship between socioeconomic status and oesophageal adenocarcinoma but only one with its precursor condition, Barrett's oesophagus. We therefore investigated such an association. The majority (88%) of patients diagnosed with Barrett's at Rotherham District General Hospital between 28 April 1978 and 31 August 2012 consented to inclusion in the UK Barrett's Oesophagus Registry. Those residing within Rotherham form the basis of this study. We assessed socioeconomic status using the Index of Multiple Deprivation 2010 scores which can be assigned to every English postcode. The scores for the whole of England were divided into five equal groups; those of the 6257 postcodes within Rotherham (including those of Barrett's patients) were compared against the national quintile relevant to their score. We examined the ratio of observed against expected numbers of Barrett's in each quintile before and since 2001, the median year of diagnosis. The study group comprised 1076 patients with Barrett's oesophagus. Before 2001 their distribution across the deprivation quintiles was similar to that expected. Since then it has changed significantly, with 37% more Barrett's patients than expected among the two least deprived quintiles, but 11% fewer than expected in the larger population comprising the two most deprived quintiles (P=0.0001). There was no significant difference in the distribution of sex (P=0.27), nor the mean age at diagnosis between the two time periods (P=0.92). Since 2001, there has been a major change in the distribution of Barrett's in relation to socioeconomic status, measured by the Index of Multiple Deprivation.

The importance of a second opinion in the diagnosis of Barrett's esophagus: a "real life" study.

Barrett's esophagus is a precancerous lesion, and its identification with the early detection of dysplasia is of paramount importance to prevent adenocarcinoma onset. However, there is still debate on the correct pathological identification of Barrett's esophagus (and of associated dysplasia), and most studies have been conducted in an experimental setting. To assess previous uncertain diagnoses of Barrett's (with and without dysplasia) via a second opinion of an expert pathologist in a real life setting. Histological sections of 32 suspected Barrett's patients from ten general Pathology units were centralized into one single unit in which an expert pathologist reviewed the slides blindly. Overall, in 78% of cases there was diagnostic discordance; in particular, in 64% of cases the presence of low grade dysplasia was not confirmed. Of interest, 28% of cases with the original diagnosis were reclassified as non-Barrett's. The pathological diagnosis of Barrett's esophagus, especially with regard to the presence of dysplasia, is still misinterpreted, particularly in the setting of general Pathology units. Thus, a second opinion from an experienced pathologist may help in the interpretation of the results and in starting appropriate follow-up programs.

Fluorescence characteristics of human Barrett tissue specimens grafted on chick chorioallantoic membrane.

To improve (pre)malignant lesion identification in Barrett’s esophagus (BE), recent research focuses on new developments in fluorescence imaging and spectroscopy to enhance tissue contrast. Our aim was to validate the chorioallantoic membrane (CAM) model as a preclinical tool to study the fluorescence characteristics such as autofluorescence and exogenously induced fluorescence of human Barrett’s tissue. Therefore, esophageal biopsy specimens from Barrett’s patients were freshly grafted onto the CAM of fertilized hen’s eggs to simulate the in vivo situation. The BE biopsy specimens stayed between 1 and 9 days on the CAM to study the persistence of vitality. Fluorescence spectroscopy was performed using six excitation wavelengths (369, 395, 400, 405, 410, 416 nm). Obtained autofluorescence spectra were compared with in vivo spectra of an earlier study. Exogenous administration of 5-aminolevulinic-acid to the biopsy specimens was followed by fluorescence spectroscopy at several time points. Afterwards, the biopsy specimens were harvested and histologically evaluated. In total, 128 biopsy specimens obtained from 34 patients were grafted on the CAM. Biopsy specimens which stayed on average 1.7 days on the CAM were still vital. Autofluorescence spectra of the specimens correlated well with in vivo spectra. Administered 5-aminolevulinic-acid to the biopsy specimens showed conversion into protoporphyrin-IX. In conclusion, we showed that grafting freshly collected human BE biopsy specimens on the CAM is feasible. Our results suggest that the CAM model might be used to study the fluorescence behavior of human tissue specimens. Therefore, the CAM model might be a preclinical research tool for new photosensitizers.

A newly identified susceptibility locus near FOXP1 modifies the association of gastroesophageal reflux with Barrett's esophagus.

Important risk factors for esophageal adenocarcinoma and its precursor, Barrett's esophagus, include gastroesophageal reflux disease, obesity, and cigarette smoking. Recently, genome-wide association studies have identified seven germline single-nucleotide polymorphisms (SNP) that are associated with risk of Barrett's esophagus and esophageal adenocarcinoma. Whether these genetic susceptibility loci modify previously identified exposure-disease associations is unclear. We analyzed exposure and genotype data from the BEACON Consortium discovery phase GWAS, which included 1,516 esophageal adenocarcinoma case patients, 2,416 Barrett's esophagus case patients, and 2,187 control participants. We examined the seven newly identified susceptibility SNPs for interactions with body mass index, smoking status, and report of weekly heartburn or reflux. Logistic regression models were used to estimate ORs for these risk factors stratified by SNP genotype, separately for Barrett's esophagus and esophageal adenocarcinoma. The odds ratio for Barrett's esophagus associated with at least weekly heartburn or reflux varied significantly with the presence of at least one minor allele of rs2687201 (nominal P = 0.0005, FDR = 0.042). ORs (95% CIs) for weekly heartburn or reflux among participants with 0, 1, or 2 minor alleles of rs2687201 were 6.17 (4.91-7.56), 3.56 (2.85-4.44), and 3.97 (2.47-6.37), respectively. No statistically significant interactions were observed for smoking status and body mass index. Reflux symptoms are more strongly associated with Barrett's esophagus risk among persons homozygous for the major allele of rs2687201, which lies approximately 75 kb downstream of the transcription factor gene FOXP1. The novel gene-exposure interaction discovered in this study provides new insights into the etiology of esophageal adenocarcinoma.

Assessment of Esophageal Adenocarcinoma Risk Using Somatic Chromosome Alterations in Longitudinal Samples in Barrett's Esophagus.

Cancers detected at a late stage are often refractory to treatments and ultimately lethal. Early detection can significantly increase survival probability, but attempts to reduce mortality by early detection have frequently increased overdiagnosis of indolent conditions that do not progress over a lifetime. Study designs that incorporate biomarker trajectories in time and space are needed to distinguish patients who progress to an early cancer from those who follow an indolent course. Esophageal adenocarcinoma is characterized by evolution of punctuated and catastrophic somatic chromosomal alterations and high levels of overall mutations but few recurrently mutated genes aside from TP53. Endoscopic surveillance of Barrett's esophagus for early cancer detection provides an opportunity for assessment of alterations for cancer risk in patients who progress to esophageal adenocarcinoma compared with nonprogressors. We investigated 1,272 longitudinally collected esophageal biopsies in a 248 Barrett's patient case-cohort study with 20,425 person-months of follow-up, including 79 who progressed to early-stage esophageal adenocarcinoma. Cancer progression risk was assessed for total chromosomal alterations, diversity, and chromosomal region-specific alterations measured with single-nucleotide polymorphism arrays in biopsies obtained over esophageal space and time. A model using 29 chromosomal features was developed for cancer risk prediction (area under receiver operator curve, 0.94). The model prediction performance was robust in two independent esophageal adenocarcinoma sets and outperformed TP53 mutation, flow cytometric DNA content, and histopathologic diagnosis of dysplasia. This study offers a strategy to reduce overdiagnosis in Barrett's esophagus and improve early detection of esophageal adenocarcinoma and potentially other cancers characterized by punctuated and catastrophic chromosomal evolution.

Fluorescence in situ hybridization identifies high risk Barrett's patients likely to develop esophageal adenocarcinoma.

Barrett's esophagus (BE) with high-grade dysplasia (HGD) defines a group of individuals at high risk of progression to esophageal adenocarcinoma (EA). Fluorescence in situ hybridization (FISH) has been shown to be useful for the detection of dysplasia and EA in endoscopic brushing specimens from BE patients. The aim of this study was to determine whether FISH in combination with histological findings would further identify more rapid progressors to EA. This is a retrospective cohort study of high-risk patients, having a history of biopsy-confirmed HGD without EA, with an endoscopic brushing specimen analyzed by FISH while undergoing endoscopic surveillance and treatment between April 2003 and October 2010. Brushing specimens were assessed by FISH probes targeting 8q24 (MYC), 9p21 (CDKN2A), 17q12 (ERBB2), and 20q13 (ZNF217) and evaluated for the presence of polysomy, defined as multiple chromosomal gains (displaying ≥ 3 signals for ≥ 2 probes). Specimens containing ≥ 4 cells exhibiting polysomy were considered polysomic. HGD was confirmed by at least two experienced gastrointestinal pathologists. Of 245 patients in this study, 93 (38.0%) had a polysomic FISH result and 152 (62.0%) had a non-polysomic FISH result. Median follow-up was 3.6 years (interquartile range [IQR] 2-5 years). Patients with a polysomic FISH result had a significantly higher risk of developing EA within 2 years (14.2%) compared with patients with a non-polysomic FISH result (1.4%, P < 0.001). These findings suggest that a polysomic FISH result in BE patients with simultaneous HGD identifies patients at a higher risk for developing EA compared with those with non-polysomy.

Sa1892 Barrett's Esophagus Screening and Surveillance Criteria May Not Target Many Patients at Risk for Gastroesophageal Junction Tumors

Sa1892 Barrett's Esophagus Screening and Surveillance Criteria May Not Target Many Patients at Risk for Gastroesophageal Junction Tumors

In healthy volunteers, immunohistochemistry supports squamous to columnar metaplasia as mechanism of expansion of cardia, aggravated by central obesity

IntroductionRecently, we showed that the length of cardiac mucosa in healthy volunteers correlated with age and obesity. We have now examined the immunohistological characteristics of this expanded cardia to determine...

Sa1854 Evaluation of Clinical and Endoscopic Parameters As Predictors for Neoplastic Progression in Barrett's Patients With a Diagnosis of Indefinite for Dysplasia

Sa1854 Evaluation of Clinical and Endoscopic Parameters As Predictors for Neoplastic Progression in Barrett's Patients With a Diagnosis of Indefinite for Dysplasia

Sa1842 In Esophageal Epithelial Cells From Barrett's Patients, Protein Kinase a Phosphorylates SOX9, Enhancing Its Binding to Target Gene Promoters: A Potential Role for SOX9 in Barrett's Pathogenesis

in response to DCA treatment. 14% of the K14-Cdx2 mice treated with DCA developed two nodules each at the SCJ, whereas none of the K14-Cdx2 mice receiving water alone developed nodules. In contrast, 70% of the IL-1β mice, and an equal number of Cdx2/IL1β mice developed nodular disease at the SCJ after DCA treatment. All DCA treatmentassociated nodules were histologically consistent with metaplasia. However overall the double-transgenic mice had half as many nodules as IL-1β mice. Cdx2 did not affect IL-1β mRNA levels in the double transgenic mice, nor was the inflammation associated with IL1β expression reduced in the Cdx2/IL-1β mice compared to IL-1β mice, as determined by CD45R+ cell infiltration in the esophagi and forestomach. Moreover, cell proliferation rates were not altered by Cdx2 expression, as EdU incorporation was not significantly different. Lastly, the morphologic appearance of the nodules in all three lines, K14-Cdx2, L2-IL-1β, and K14-Cdx2/L2-IL-1β mice was similar, with abundant alcian blue expressing goblet cells detected, along with expression of other markers of intestinalization. Further molecular characterization of the metaplastic nodules by cDNA microarray profiling is underway. Conclusion: Ectopic expression of Cdx2 in the IL-1Beta mouse model for BE reduces the nodular intestinal metaplasia disease burden. These studies raise new questions as to the specific role of inflammation and intestinal transcription factors in the development of Barrett's esophagus in humans.

Pseudo-buried Barrett’s post radiofrequency ablation for Barrett’s esophagus, with or without prior endoscopic resection

In our experience, biopsies from small residual islands of nonburied Barrett's mucosa after radiofrequency ablation (RFA) are occasionally reported by pathologists to contain "buried Barrett's" upon histological evaluation, despite the fact that these islands of columnar mucosa were visible endoscopically. The aim of this study was to evaluate the frequency of buried Barrett's in biopsies obtained from small residual Barrett's islands ( < 5 mm) sampled post-RFA, compared with biopsies from normal neosquamous epithelium. Biopsies obtained from normal-appearing neosquamous epithelium and from small Barrett's islands ( < 5 mm) in 69 consecutive Barrett's patients treated with RFA were evaluated for the presence of buried columnar mucosa. A total of 2515 biopsies were obtained from neosquamous epithelium during follow-up post-RFA. Buried glands were found in 0.1 % of biopsies from endoscopically normal neosquamous epithelium. However, when small islands of columnar mucosa were biopsied, buried glands were detected in 21 % of biopsies. To avoid accidental sampling of small islands resulting in a false-positive histological diagnosis of buried Barrett's, thorough inspection should be performed before obtaining biopsies during post-RFA follow-up.

Different Histological Status of Gastritis in Superficial Adenocarcinoma of the Esophagogastric Junction

Although many gastric cancers arise in chronic gastritis, the association between adenocarcinoma of the esophagogastric junction and the status of background gastritis remains unclear. We aim to investigate the histological status of gastritis in the background fundic gland mucosa of adenocarcinoma of the esophagogastric junction. The present study included 121 consecutive patients with superficial adenocarcinoma of the esophagogastric junction obtained by surgical and/or endoscopic resection. We re-evaluated the histogenesis of adenocarcinoma of the esophagogastric junction, including the background fundic gland mucosa using the Updated Sydney System. The prevalence of histologic atrophic gastric mucosa with gastritis (positive gastritis), non-atrophic gastric mucosa without gastritis (negative gastritis) and Barrett's adenocarcinoma was examined. Histologic-positive gastritis was found in 67 (55%) of all patients, in 24 (38%) of 63 Barrett's adenocarcinoma patients and in 43 (74%) of 58 non-Barrett's adenocarcinoma patients (P < 0.01). A higher female ratio in non-Barrett's adenocarcinoma with gastritis patients `and younger age in non-Barrett's adenocarcinoma without gastritis patients were shown. There were no differences in clinicopathological features related to the gastritis status in Barrett's adenocarcinoma patients. Reflux esophagitis was observed in most (81%) of all patients, and 32 (74%) of the non-Barrett's adenocarcinoma with gastritis patients. In the 67 positive gastritis patients, the mean Updated Sydney System scores of glandular atrophy and intestinal metaplasia were 1.45 and 1.10, respectively, and these scores were higher in the non-Barrett's adenocarcinoma patients than in the Barrett's adenocarcinoma patients. This study suggests that about half of the patients with adenocarcinoma of the esophagogastric junction harbor histological gastritis. Adenocarcinoma of the esophagogastric junction is considered to be a heterogeneous entity, including Barrett's esophagus-related, positive gastritis-related, and Barrett's esophagus and gastritis-unrelated adenocarcinoma of the esophagogastric junction.

Barrett's oesophagus: epidemiology, cancer risk and implications for management

Although endoscopic surveillance of patients with Barrett's oesophagus has been widely implemented, its effectiveness is debateable. The recently reported low annual oesophageal adenocarcinoma risk in population studies, the failure to...

DYSREGULATION OF THE PROTEIN SECRETORY PATHWAY IN OESOPHAGEAL CANCER PROGRESSION

IntroductionOesophageal adenocarcinoma commonly arises from a premalignant lesion known as Barrett's oesophagus. Many patients are asymptomatic and present to the clinic with very advanced disease and poor prognosis. Deoxycholic acid...