Neoplastic Progression Of Barrett's Esophagus Research Articles

Comparison of interventions for Barrett's esophagus: A network meta-analysis.

Barrett's esophagus (BE) is a precancerous condition that has the potential to develop into esophageal cancer (EC). Currently, there is a wide range of management options available for individuals at different pathological stages in Barrett's esophagus (BE). However, there is currently a lack of knowledge regarding their comparative efficacy. To address this gap, we conducted a network meta-analysis of published randomized controlled trials to examine the comparative effectiveness of all regimens. Data extracted from eligible randomized controlled trials were utilized in a Bayesian network meta-analysis to examine the relative effectiveness of BE's treatment regimens and determine their ranking in terms of efficacy. The ranking probability for each regimen was assessed using the surfaces under cumulative ranking values. The outcomes under investigation were complete ablation of BE, neoplastic progression of BE, and complete eradication of dysplasia. We identified twenty-three RCT studies with a total of 1675 participants, and ten different interventions. Regarding complete ablation of non-dysplastic BE, the comparative effectiveness ranking indicated that argon plasma coagulation (APC) was the most effective regimen, with the highest SUCRA value, while surveillance and PPI/H2RA were found to be the least efficacious regimens. For complete ablation of BE with low-grade dysplasia, high-grade dysplasia, or esophageal cancer, photodynamic therapy (PDT) had the highest SUCRA value of 94.1%, indicating it as the best regimen. Additionally, for complete eradication of dysplasia, SUCRA plots showed a trend in ranking PDT as the highest with a SUCRA value of 91.2%. Finally, for neoplastic progression, radiofrequency ablation (RFA) and surgery were found to perform significantly better than surveillance. The risk of bias assessment revealed that 6 studies had an overall high risk of bias. However, meta-regression with risk of bias as a covariate did not indicate any influence on the model. In terms of the Confidence in Network Meta-Analysis evaluation, a high level of confidence was found for all treatment comparisons. Endoscopic surveillance alone or PPI/H2RA alone may not be sufficient for managing BE, even in cases of non-dysplastic BE. However, APC has shown excellent efficacy in treating non-dysplastic BE. For cases of BE with low-grade dysplasia, high-grade dysplasia, or esophageal cancer, PDT may be the optimal intervention as it can induce regression of BE metaplasia and prevent future progression of BE to dysplasia and EC.

Revisiting Proton Pump Inhibitors as Chemoprophylaxis Against the Progression of Barrett's Esophagus.

Barrett's esophagus (BE) is associated with chronic gastroesophageal reflux disease and is a known precursor to esophageal adenocarcinoma. While endoscopic surveillance strategies and the role for endoscopic eradication therapy have been well established, there has been much interest in identifying chemopreventive agents to disrupt or halt the metaplasia-dysplasia-carcinoma sequence in patients with BE. No pharmacological agent has held more hope in reducing the risk of neoplastic progression in BE than proton pump inhibitors (PPIs). However, data supporting PPIs for chemoprevention have largely been from observational cohort and case-control studies with mixed results. In this review, we revisit the literature and highlight the role of PPIs in patients with BE as it pertains to chemoprophylaxis against the progression of BE to dysplasia and esophageal adenocarcinoma.

Molecular Evolution of Metaplasia to Adenocarcinoma in the Esophagus.

Esophageal adenocarcinoma (EAC) develops from Barrett's esophagus (BE), a condition where the normal squamous epithelia is replaced by specialized intestinal metaplasia in response to chronic gastroesophageal acid reflux. In a minority of individuals, BE can progress to low- and high-grade dysplasia and eventually to intra-mucosal and then invasive carcinoma. BE provides researchers with a unique model to characterize the process by which a carcinoma arises from its precursor lesion. Molecular studies of BE have demonstrated that it is not simply a metaplastic tissue, but rather it harbors frequent alterations that are also present in dysplastic BE and in EAC. Both BE and EAC are characterized by loss of heterozygosity, aneuploidy, specific genetic mutations, and clonal diversity. Epigenetic abnormalities, primary alterations in DNA methylation, are also frequently seen in BE and EAC. Candidate gene and array-based approaches have demonstrated that numerous tumor suppressor genes exhibit aberrant promoter methylation, and some of these altered genes are associated with the neoplastic progression of BE. It has also been shown that the BE and EAC epigenomes are characterized by hypomethylation of intragenic and non-coding regions Recent studies have also provided new insight into the evolutionary forces underlying the molecular alterations seen in BE and EAC and into the molecular pathogenesis of EAC.

Detection of genetic alterations in cfDNA as a possible strategy to monitor the neoplastic progression of Barrett's esophagus

Barrett's esophagus (BE) is associated with an increased risk of developing esophageal adenocarcinoma. Despite the low absolute risk of neoplastic progression of BE, probability increases with the diagnosis of dysplasia. For this reason, BE patientsundergo an endoscopy-based surveillance that is, however, burdensome for patients, subject to inter-observer subjectivity, and expensive for nationalhealth systems. Thus, less invasive and low-cost diagnostic tools are needed. This study is aimed at finding a simple and reliable method to detect in the circulating cell-free DNA (cfDNA) of BE patients evidence of the molecular instability that accompaniesBE carcinogenesis. We chose the loss of heterozygosity analysis because chromosomal region gains or losses have been described in BE and esophageal adenocarcinoma. Furthermore, this analysis does not require an a priori knowledge of tumor specific mutations and/or rearrangements. Previous data showed a good consistency between tissue and cfDNA alterations. Here, we report that, in the cfDNA of dysplastic BE patients, the frequency of genetic alterationsis statistically higher than that of metaplastic BE patients (P=0.005). Interestingly, after endoscopic treatment, the alteration frequency dropped, suggesting that cfDNA can also be used to monitor curativeeffects. Among the used markers, those that map nearby TP53 gene were the most discriminant between metaplastic and dysplastic BE. Furthermore, longitudinal follow-up cases showed that genetic alterations can be found incfDNA before the appearance of a detectable lesion. Altogether, our data suggest that the use of liquid biopsy could become a minimally invasive diagnostictool to implement BE patient monitoring.

Value of cyclin A immunohistochemistry for cancer risk stratification in Barrett esophagus surveillance: A multicenter case-control study.

The value of endoscopic Barrett esophagus (BE) surveillance based on histological diagnosis of low-grade dysplasia (LGD) remains debated given the lack of adequate risk stratification. The aim of this study was to evaluate the predictive value of cyclin A expression and to combine these results with our previously reported immunohistochemical p53, AMACR, and SOX2 data, to identify a panel of biomarkers predicting neoplastic progression in BE.We conducted a case-control study within a prospective cohort of 720 BE patients. BE patients who progressed to high-grade dysplasia (HGD, n = 37) or esophageal adenocarcinoma (EAC, n = 13), defined as neoplastic progression, were classified as cases and patients without neoplastic progression were classified as controls (n = 575). Cyclin A expression was determined by immunohistochemistry in all 625 patients; these results were combined with the histological diagnosis and our previous p53, AMACR, and SOX2 data in loglinear regression models. Differences in discriminatory ability were quantified as changes in area under the ROC curve (AUC) for predicting neoplastic progression.Cyclin A surface positivity significantly increased throughout the metaplasia-dysplasia-carcinoma sequences and was seen in 10% (107/1050) of biopsy series without dysplasia, 33% (109/335) in LGD, and 69% (34/50) in HGD/EAC. Positive cyclin A expression was associated with an increased risk of neoplastic progression (adjusted relative risk (RR) 2.4; 95% CI: 1.7-3.4). Increases in AUC were substantial for P53 (+0.05), smaller for SOX2 (+0.014), minor for cyclin A (+0.003), and none for AMARC (0.00).Cyclin A immunopositivity was associated with an increased progression risk in BE patients. However, compared to p53 and SOX2, the incremental value of cyclin A was limited. The use of biomarkers has the potential to significantly improve risk stratification in BE.

1328P - Immunohistochemical biomarkers for risk stratification of neoplastic progression in Barrett esophagus

1328P - Immunohistochemical biomarkers for risk stratification of neoplastic progression in Barrett esophagus

SOX2 as a novel marker to predict neoplastic progression in Barrett's esophagus.

The value of Barrett's esophagus (BE) surveillance based on the histological diagnosis of low-grade dysplasia (LGD) remains debated given the lack of adequate risk stratification. The aim of this study was to evaluate the predictive value (PV) of SOX2 expression for neoplastic progression in BE patients. We conducted a case-control study within a prospective cohort of 720 BE patients. Patients with neoplastic progression, defined as the development of high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC), were classified as cases and patients without neoplastic progression were classified as controls. SOX2 expression was determined by immunohistochemistry in more than 12,000 biopsies from 635 patients; these results were combined with our previous p53 immunohistochemical data. Nondysplastic BE showed homogeneous nuclear staining for SOX2, whereas SOX2 was progressively lost in dysplastic BE. Loss of SOX2 was seen in only 2% of biopsy series without dysplasia, in contrast to 28% in LGD and 67% in HGD/EAC. Loss of SOX2 expression was associated with an increased risk of neoplastic progression in BE patients after adjusting for gender, age, BE length, and esophagitis (adjusted relative risk 4.8; 95% CI 3.2-7.0). The positive PV for neoplastic progression increased from 16% with LGD alone to 56% with concurrent loss of SOX2 and aberrant p53 expression. SOX2 expression is lost during transition from nondysplastic BE to HGD/EAC, and it is associated with an increased risk of neoplastic progression. The highest PV is achieved by concurrent loss of SOX2 and aberrant p53 expression in BE patients with LGD. The use of these markers has the potential to significantly improve risk stratification of Barrett surveillance.

Molecular Occurrences in the Neoplastic Progression of Barrett Esophagus

AbstractBarrett esophagus is the known precursor lesion of esophageal adenocarcinoma; however, the natural history of Barrett esophagus and its associated dysplasia is a matter of considerable debate and difficult to establish on a patient-by-patient basis. Clinical management and surveillance are c

Tissue and Serum Mesothelin Are Potential Markers of Neoplastic Progression in Barrett's Associated Esophageal Adenocarcinoma

Mesothelin is overexpressed in several malignancies and is purportedly a specific marker of malignant transformation. In this pilot study, we investigated whether tissue and serum mesothelin are potential markers of neoplastic progression in Barrett's esophagus (BE) and in esophageal adenocarcinoma (EAC). Mesothelin expression was retrospectively evaluated in normal, BE, and EAC tissue from surgically resected esophageal specimens (n = 125). In addition, soluble mesothelin-related peptide (SMRP) levels were measured in serum. Normal esophageal mucosa did not express mesothelin. BE tissue with high-grade dysplasia specifically expressed mesothelin, whereas BE tissue with low-grade or without dysplasia did not. Fifty-seven (46%) EAC tumors were positive for mesothelin. EAC tumors with BE expressed mesothelin more often than those without BE (58% vs. 35%, P = 0.01). SMRP levels were elevated in 70% of EAC patients (mean = 0.89 nmol/L; range: 0.03-3.77 nmol/L), but not in patients with acid reflux and/or BE. Mesothelin is commonly expressed in BE-associated EAC. On the basis of this pilot study, a prospective study is under way to evaluate tissue and serum mesothelin which are potential markers of neoplastic progression in BE and in EAC (NCT01393483). Current surveillance methods in Barrett's esophagus are invasive and neither cost-effective nor sensitive. This pilot study suggests that serum mesothelin is a marker of neoplastic transformation in BE and may provide a noninvasive method to improve identification of malignant transformation.

Risk factors for neoplastic progression in Barrett’s esophagus

Barrett's esophagus (BE) confers a significant increased risk for development of esophageal adenocarcinoma (EAC), with the pathogenesis appearing to progress through a "metaplasia-dysplasia-carcinoma" (MDC) sequence. Many of the genetic insults driving this MDC sequence have recently been characterized, providing targets for candidate biomarkers with potential clinical utility to stratify risk in individual patients. Many clinical risk factors have been investigated, and associations with a variety of genetic, specific gastrointestinal and other modifiable factors have been proposed in the literature. This review summarizes the current understanding of the mechanisms involved in neoplastic progression of BE to EAC and critically appraises the relative roles and contributions of these putative risk factors from the published evidence currently available.

Abstract 4565: Tissue protein biomarkers of neoplastic progression in Barrett's esophagus

Abstract The incidence rate of esophageal adenocarcinoma (EAC) has risen by 350% since 1970, outpacing all other cancers (www.nci.gov). There are approximately 15,000 new cases of esophageal cancer per year in the United States, half of which are EAC. The incidence of EAC is 4 cases per 100,000 person years. This cancer is associated with a dismal prognosis, with an overall five-year survival of less than 15%. Although the survival rate depends on the stage of disease, more than 50% of patients present with dysphagia (difficulty swallowing) secondary to obstruction from the tumor and with incurable disease. Upon review of the Surveillance Epidemiology and End Results database for the last 27 years, it is ominous that the incidence rate for esophageal cancer is mirrored precisely by the age-adjusted mortality for a given year. Currently, risk for esophageal cancer is determined solely by the histologic appearance of Barrett's esophagus (BE), however there is a large degree of intra- and inter-observer variability among pathologists. The ability to identify and validate protein biomarkers of disease progression from Barrett's metaplasia to esophageal adenocarcinoma, when treatment outcome is still favorable, would result in a reduction in mortality by aiding in the identification of new diagnostic and treatment options for this disease. We hypothesized that signature protein biomarkers predictive of BE progression could be identified in tissue biopsies that correlate with the metaplasia-dysplasia-carcinoma pathway, which may provide a more reliable set of diagnostic tools, prognostic markers, and therapeutic targets for EAC. Cells from formalin-fixed paraffin embedded (FFPE) tissue sections from defined histological regions of metaplasia (n=9), dysplasia (n=10) and adenocarcinoma (n=12) of the esophagus were procured by laser capture microdissection. A mass spectrometry (MS)-friendly heat-induced/enzyme-mediated antigen retrieval method developed in our laboratory was utilized to produce global tryptic digests from the LCM-procured cells. The digests were randomized and analyzed by high-resolution liquid chromatography-tandem mass spectrometry with an Orbitrap MS, resulting in the identification of an average of 2015 peptides and 652 proteins per sample, with an average relative standard deviation of 15%. Spectral counting and hierarchical cluster analysis enabled the identification of over 80 proteins whose abundances significantly change as a function of neoplastic progression of BE. Several of these putative BE progression biomarkers were validated by quantitative multiple reaction monitoring MS and/or immunohistochemistry, including mucin 5 A/C and 2, cytokeratin 20 and galectin 3. This study is the largest and most comprehensive discovery-driven proteomic analysis of Barrett's esophagus tissue where multiple candidates of progression have been validated by orthogonal techniques. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4565.

Chromosomal abnormalities and novel disease‐related regions in progression from Barrett's esophagus to esophageal adenocarcinoma

Barrett's esophagus (BE) is a metaplastic condition caused by chronic gastroesophageal reflux which represents an early step in the development of esophageal adenocarcinoma (EAC). Single-nucleotide polymorphism microarray (SNP-chip) analysis is a novel, precise, high-throughput approach to examine genomic alterations in neoplasia. Using 250K SNP-chips, we examined the neoplastic progression of BE to EAC, studying 11 matched sample sets: 6 sets of normal esophagus (NE), BE and EAC, 4 of NE and BE and 1 of NE and EAC. Six (60%) of 10 total BE samples and 4 (57%) of 7 total EAC samples exhibited 1 or more genomic abnormalities comprising deletions, duplications, amplifications and copy-number-neutral loss of heterozygosity (CNN-LOH). Several shared abnormalities were identified, including chromosome 9p CNN-LOH [2 BE samples (20%)], deletion of CDKN2A [4 BE samples (40%)] and amplification of 17q12-21.2 involving the ERBB2, RARA and TOP2A genes [3.1 Mb, 2 EAC (29%)]. Interestingly, 1 BE sample contained a homozygous deletion spanning 9p22.3-p22.2 (1.2 Mb): this region harbors only 1 known gene, basonuclin 2 (BNC2). Real-time PCR analysis confirmed the deletion of this gene and decreased the expression of BNC2 mRNA in the BE sample. Furthermore, transfection and stable expression of BNC2 caused growth arrest of OE33 EAC cells, suggesting that BNC2 functions as a tumor suppressor gene in the esophagus and that deletion of this gene occurs during the development of EAC. Thus, this SNP-chip analysis has identified several early cytogenetic events and novel candidate cancer-related genes that are potentially involved in the evolution of BE to EAC.

Aneuploidy and Overexpression of Ki67 and p53 as Markers for Neoplastic Progression in Barrett's Esophagus: A Case–Control Study

Surveillance of patients with Barrett's esophagus (BE) aims at early detection and treatment of neoplastic changes, particularly esophageal adenocarcinoma (EAC). The histological evaluation of biopsy samples has its limitations, and biomarkers may improve early identification of BE patients at risk for progression to EAC. The aim of this study was to determine the predictive value of p53, Ki67, and aneuploidy as markers of neoplastic progression in BE. A total of 27 BE patients with histologically proven progression to high-grade dysplasia (HGD) or EAC (cases) and 27 BE patients without progression (controls) were selected and matched for age, gender, and duration of follow-up. Dysplasia grade was determined in 212 biopsy samples obtained during surveillance endoscopies from cases and in 231 biopsy samples collected from controls. DNA ploidy status was determined by flow cytometry, whereas Ki67 and p53 expression was determined by immunohistochemistry. Hazard ratios (HRs) were calculated by Cox regression adjusted for potentially confounding variables. A univariate analysis showed that low-grade dysplasia (LGD) increased the risk of developing HGD/EAC compared with no dysplasia (HR 3.6; 95% confidence interval (CI): 1.6 - 8.1). Aneuploidy (HR 3.5; 95% CI: 1.3-9.4), strong Ki67 overexpression (HR 5.2; 95% CI: 1.5-17.6), and moderate p53 overexpression (HR 6.5; 95% CI: 2.5-17.1) were also associated with an increased risk of developing HGD/EAC, independent of the histological result. A multivariable analysis showed that in the presence of LGD, p53 overexpression, and to a lesser extent, Ki67 overexpression remained important risk factors for neoplastic progression, whereas aneuploidy was no longer predictive. p53 overexpression and, to a lesser extent, Ki67 overexpression could predict neoplastic progression in BE irrespective of the histological result. These markers may be useful for identifying patients at an increased risk of developing EAC, either alone or used as a panel.

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

Esophageal adenocarcinoma risk in Barrett's esophagus (BE) is increased 30- to 125-fold versus the general population. Among all BE patients, however, neoplastic progression occurs only once per 200 patient-years. Molecular biomarkers are therefore needed to risk-stratify patients for more efficient surveillance endoscopy and to improve the early detection of progression. We therefore performed a retrospective, multicenter, double-blinded validation study of eight BE progression prediction methylation biomarkers. Progression or nonprogression were determined at 2 years (tier 1) and 4 years (tier 2). Methylation was assayed in 145 nonprogressors and 50 progressors using real-time quantitative methylation-specific PCR. Progressors were significantly older than nonprogressors (70.6 versus 62.5 years; P < 0.001). We evaluated a linear combination of the eight markers, using coefficients from a multivariate logistic regression analysis. Areas under the ROC curve (AUC) were high in the 2-year, 4-year, and combined data models (0.843, 0.829, and 0.840; P < 0.001, <0.001, and <0.001, respectively). In addition, even after rigorous overfitting correction, the incremental AUCs contributed by panels based on the 8 markers plus age versus age alone were substantial (Delta-AUC = 0.152, 0.114, and 0.118, respectively) in all 3 models. A methylation biomarker-based panel to predict neoplastic progression in BE has potential clinical value in improving both the efficiency of surveillance endoscopy and the early detection of neoplasia.

W1888 Overexpression of p53 and Ki67 and Aneuploidy As Markers for Neoplastic Progression in Barrett Esophagus: A Nested Case-Control Study

W1888 Overexpression of p53 and Ki67 and Aneuploidy As Markers for Neoplastic Progression in Barrett Esophagus: A Nested Case-Control Study

M1596 Evaluation of p53, Ki67 and Flow Cytometry for Prediction of Neoplastic Progression in Barrett Esophagus

M1596 Evaluation of p53, Ki67 and Flow Cytometry for Prediction of Neoplastic Progression in Barrett Esophagus

Aneuploidy and high expression of p53 and Ki67 is associated with neoplastic progression in Barrett esophagus

Unless detected at an early stage, esophageal adenocarcinoma (EAC) has a poor prognosis. Changes in cellular DNA content and expression levels of p53 and Ki67 in Barrett esophagus (BE) are associated with the development EAC and might serve as markers to identify EAC at an early stage. The aim of this study was to examine the presence of these three markers in various steps of neoplastic progression in BE towards EAC. Dysplasia was graded in 212 biopsy sets taken during follow-up upper endoscopy in 27 patients in whom ultimately high-grade dysplasia (HGD) or EAC was detected. Ploidy status was determined by flow cytometry, whereas Ki67 and p53 expression were determined by immunohistochemistry. Smoothing splines were used to analyze trends in time. We found an increasing fraction of Ki67 overexpression and, to a lesser extent, abnormal DNA content in biopsies closer to the time-point of detecting HGD/EAC in BE, suggesting the potential value of these biomarkers in identifying patients at increased risk of progression towards HGD/EAC. Accumulation of p53 was seen several years before development of HGD/EAC, and may therefore be an early marker in BE at a stage when dysplasia is not yet detected. A prospective follow-up study is needed to confirm these findings.

Hypermethylation of the somatostatin promoter is a common, early event in human esophageal carcinogenesis

The promoter of somatostatin (SST), a primary inhibitor of gastrin-stimulated gastric acid secretion, is hypermethylated in 80% of human colon cancers. The aim of the current study was to investigate whether and at what stage promoter hypermethylation of SST is involved in human esophageal carcinogenesis. SST promoter hypermethylation was examined by real-time methylation-specific polymerase chain reaction (PCR) (MSP) in 260 human esophageal tissue specimens. Real-time reverse-transcriptase PCR and MSP were also performed on esophageal cancer cell lines before and after treatment with 5-aza-2'-deoxycytidine (5-Aza-dC). SST hypermethylation showed highly discriminative receiver-operator characteristic curve profiles, clearly distinguishing esophageal squamous cell carcinomas (ESCC) and esophageal adenocarcinomas (EAC) from normal esophagus (NE) (P < .01). Both SST methylation frequency and normalized methylation value (NMV) were significantly higher in Barrett metaplasia without dysplasia or EAC (BE), low-grade and high-grade (HGD) dysplasia occurring in BE, EAC, and ESCC than in NE (P < .01). SST hypermethylation frequency was significantly lower in NE (9%) than in BE (70%), HGD (71.4%), or EAC (71.6%), whereas 14 (53.8%) of 26 ESCCs exhibited SST hypermethylation. There was a significant relation between SST hypermethylation and BE segment length, a known clinical risk factor for neoplastic progression. Demethylation of KYSE220 ESCC and OE33 EAC cells with 5-Aza-dC reduced SST methylation and increased SST mRNA expression. SST mRNA levels in native unmethylated EACs were significantly higher than in native methylated EACs (P < .05). SST promoter hypermethylation is a common event in human esophageal carcinomas and is related to early neoplastic progression in Barrett esophagus.

The Role of Chemoprevention in Barrett Esophagus and Esophageal Adenocarcinoma

Esophageal adenocarcinoma (EAC) is a highly lethal cancer and is the most rapidly increasing cancer in the Western countries. In the United States, the incidence of EAC has increased 6-fold and despite recent advances, the 5-year survival is appalling. The high proportion of patients presenting with advanced disease, the poor response to therapy, and low survival rates warrants identification of potential agents for chemoprevention. Barrett esophagus (BE) is a well-established premalignant condition for the development of EAC. A better understanding of the pathogenesis and development of strategies to halt progression along the metaplasia-dysplasia-carcinoma sequence are desirable. The utility of rigorous acid inhibition with proton pump inhibitors (PPIs) as chemopreventive agents has been contested. Acid exposure increases cell proliferation and decreases apoptosis in BE and EAC. Therefore, preventing exposure of the esophageal mucosa to gastric acid by potent antisecretory agents may decrease cancer risk in BE patients. Studies have shown that PPI therapy does not lead to reliable regression of BE. Although, recent studies suggest decreased risk of dysplasia with PPIs, the effect of PPIs on progression of BE is unclear. There is epidemiologic and experimental evidence to suggest that chemoprevention using nonsteroidal anti-inflammatory drugs, aspirin, and selective cyclo-oxygenase-2 (COX-2) inhibitors may reduce the risk of cancer in BE patients. Their chemopreventive action is mediated by inhibition of COX-2 and resultant decrease in eicosanoid-prostaglandin E2 production. Increased COX-2 expression has been demonstrated in BE including a progressive increase along the metaplasia-dysplasia-carcinoma sequence contributing to increased cell proliferation, decreased apoptosis, and increased angiogenesis. Increased cardiovascular toxicity associated with prolonged use of selective COX-2 inhibitors tempers enthusiasm for any further investigation of this agent class in this context. Results of ongoing studies investigating effect of aspirin with PPI therapy on neoplastic progression in BE are awaited. Other agents that have shown promising initial results include troglitazone, a peroxisome proliferators-activated receptor gamma ligand that reduces ornithine decarboxylase activity; telomerase inhibitors that induce apoptosis; and all transretinoic acid that induces apoptosis as well. Large randomized controlled prospective clinical studies are needed to validate the effect of chemopreventive strategies in high-risk populations; results of which could profoundly change the natural history and management of this disease.

Biomarkers for Risk Stratification of Neoplastic Progression in Barrett Esophagus

Barrett esophagus (BE) is caused by chronic gastroesophageal reflux and predisposes to the development of esophageal adenocarcinoma through different grades of dysplasia. Only a subset of BE patients will finally develop esophageal adenocarcinoma. The majority will therefore not benefit from an endoscopic surveillance program, based on the histological identification of dysplasia. Several studies have been performed to find additional biomarkers that can be used to detect the subgroup of patients with an increased risk of developing malignancy in BE. In this review, we will summarize the most promising tissue biomarkers, i.e. proliferation/cell cycle proteins, tumor suppressor genes, adhesion molecules, DNA ploidy status and inflammation associated markers, that can be used for risk stratification in BE, and discuss their respective clinical application.