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Background and Objective: Reflux esophagitis (RE) is characterized by inflammation of the squamous epithelium (SQ) of the esophagus and may progress to Barrett’s esophagus (BE) characterized by intestinal metaplasia. The role of inflammation in this transition has been postulated but lacks experimental evidence. Here, the inflammatory responses in the esophagus of these patients were investigated. Patients and Methods: Fifty-one esophageal biopsies from with patients BE (n = 19), RE (n = 8) and controls (n = 23) were analyzed. T-cells were analyzed before and after ex vivo expansion (14 days) by multicolor flow cytometric analysis. The following markers were studied: CD3, CD4, CD8 (T-cell markers), Granzyme B (marker of cytotoxicity), CD103 (αE/epithelial integrin) and NKg2a (inhibitory receptor on T-cells and NK-cells). Results: Analysis of ex vivo cultures from normal looking SQ from controls, RE patients, and BE patients revealed no significant differences in the number and phenotypes of T-cells. In contrast, tissue from RE was different to normal SQ in four aspects: 1) higher percentages of CD3+CD4+-cells (72±7% vs 48±6%, p = 0.01) and 2) CD8+GranzymeB+ -cells (53±11% vs 26±4%, p<0.05), while 3) lower percentages of CD4+CD103+-cells (45±19% vs 80±3%, p = 0.02) and 4) CD8+NKg2a+- cells (31±12% vs 44±5%). Conclusion: Despite the fact that both tissues are exposed to the same reflux associated inflammatory triggers, the immune response observed in RE is clearly distinct from that in SQ of BE. The differences in immune responses in BE tissue might contribute to its susceptibility for transformation into intestinal metaplasia. [ABSTRACT FROM AUTHOR]

Objective. Esophageal cancer development is a sequence that starts with reflux esophagitis (RE), followed by Barrett's esophagitis (BE), dysplasia, and finally esophageal adenocarcinoma (EAC). Tumor necrosis factor (TNF) is a potent anti-neoplastic agent, hence DNA polymorphisms that reduce TNF levels potentially enhance the development of BE and EAC. The aim of the study was to determine the impact of TNF gene variation on the RE-BE-EAC cascade. Methods. DNA from 887 Caucasian participants (197 controls, 305 RE, 257 BE, 128 EAC) was tested for the gene polymorphism TNF-β NcoI, and TNF production was determined by TNF-α specific immunohistochemistry on esophageal biopsies from these BE ( n == 31) and EAC ( n == 4) patients. Results. As compared with healthy controls, the TNF-β NcoI A/A genotype was significantly more prevalent in BE ( p == 0.04) and EAC patients ( p == 0.02), but not in RE patients ( p == 0.1). While TNF-α protein levels were invariably high in esophageal biopsies from EAC patients, most esophageal BE samples showed low to moderate TNF levels. Conclusions. Chronic inflammation, like in BE, markedly increase the risk of malignant transformation. In this study, the significantly higher frequency of the TNF-β NcoI A/A genotype and the local TNF expression indicate that the pro-inflammatory cytokine TNF plays a role in the development of BE and EAC. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Barrett's esophagus (BE) is a premalignant condition of the esophagus. It is a consequence of mucosal injury from chronic gastroesophageal reflux in which bile acids are an important toxic component. The farnesoid X receptor (FXR) is a nuclear receptor involved in the regulation of bile acid synthesis, transport, and absorption. FXR activation is also involved in the induction of the innate immune response. This suggests that FXR is involved in the pathogenesis and the inflammation seen in BE. METHODS: mRNA levels of FXR and the FXR-regulated genes, ileal bile acid-binding protein (IBABP), small heterodimer partner (SHP), and chemokines interleukin (IL)-8 and macrophage inflammatory protein 3α (MIP3α), were determined by real time-polymerase chain reaction (RT-PCR). Protein expression was determined by immunohistochemistry. RESULTS: FXR was not expressed in squamous epithelium of healthy subjects (N = 7), but was present in both squamous and columnar epithelium of BE patients. Compared to the squamous epithelium of BE patients, their columnar epithelium displayed a 2.3-fold ( P= 0.02) increase in FXR mRNA. Also, IBABP (2.2-fold; P= 0.0029), SHP (2.7-fold; P= 0.007), IL-8 (1.5-fold; P= 0.04), and MIP3α (1.7-fold; P= 0.019) transcription levels were increased. Exposure of esophageal cell line TE7 to deoxycholic acid (DCA) resulted in a similar induction. The induction was abolished by the FXR antagonist guggulsterone. CONCLUSIONS: Expression levels of the bile acid receptor FXR, the bile acid metabolism genes IBABP and SHP, and the chemokines IL-8 and MIP3α are increased in Barrett's epithelium. The in vitro induction of FXR by DCA suggests that bile acids can actively induce the inflammatory response in BE by recruiting immune cells. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

BACKGROUND: Neoplastic progression of BE towards EAC is associated with increased expression of COX-2. Increased COX-2 expression and enzyme activity is linked to the COX-2 CA haplotype, which consists of two gene polymorphisms in the COX-2 promoter. AIM: To study the impact of COX-2 haplotypes on the risk of developing EAC in patients with different forms of gastroesophageal reflux disease including BE. METHODS: DNA was obtained from a total of 635 Dutch white patients comprised of 140 patients with EAC, 255 with BE, and 240 with reflux esophagitis. COX-2 haplotypes were based on the gene polymorphisms at −765C/G and −1195A/G, as determined by PCR-RFLP. RESULTS: The tested population contained 170 (14%) CA- (−765C and −1195A) haplotypes, 829 (65%) GA and 271 (21%) GG-haplotypes, and no GC-haplotypes. The haplotype distribution in patients with reflux esophagitis and BE was similar (CA 12%, GA 68%, GG 21%), but differed significantly from that in patients with EAC (CA 21%, GA 58%, GG 20%). Particularly, the CA-haplotype was more common ( P < 0.001) in EAC patients. CA-carriership was associated with EAC (OR 2.8, 95% CI 1.3–6.2, P= 0.008), with homozygosity for the CA-allele being statistically most significantly associated (OR 6.1, 95% CI 1.6–24.2, P= 0.01). CONCLUSION: The COX-2 CA-haplotype is more frequently observed in patients with EAC than in patients with BE and reflux esophagitis. These data suggest a direct link between COX-2 activity and neoplastic progression in patients with BE and reflux esophagitis. [ABSTRACT FROM AUTHOR]

Background. Barrett's oesophagus (BO), a premalignant condition associated with the development of oesophageal adenocarcinoma (OAC), is thought to be a consequence of chronic duodeno-gastro-oesophageal reflux. Of the refluxates, bile acids, either alone or in combination with acid, are probably the most important. Methods. Analysis of the literature on the role played by bile acids in inducing BO and/or progression to OAC. Results. Combined pH and Bilitec™ 2000 (as a measure of bile reflux) monitoring and oesophageal aspiration studies in humans suggest a combined role for bile acids, particularly taurine conjugated bile acids, in causing oesophageal mucosal injury. Evidence from animal models has demonstrated that duodenal juice alone is also able to induce BO and/or OAC. Likewise, ex vivo studies with biopsies from BO patients show that increased proliferation and cyclo-oxygenase-2 expression are present after a pulsed exposure to acid or conjugated bile acids, but not if acid and bile acids are combined. Proton-pump inhibitors (PPIs) have been shown to decrease the biliary component of the refluxate. There is some evidence that PPIs are able to reduce neoplastic progression in BO. On the other hand, chronic PPIs can also stimulate bacterial overgrowth, which can result in increased production of secondary bile acids, particularly deoxycholic acid, in the stomach. Deoxycholic acid has been demonstrated to have a tumour-promoting capacity. Conclusions. It is unknown what factors of the refluxate (acid and/or bile) induce BO and/or promote carcinogenesis, but there is evidence that secondary bile acids play a role. A better understanding of the molecular steps involved in the induction of BO, and the role of bile acids herein, may identify targets at which preventive therapies can be directed. [ABSTRACT FROM AUTHOR]

: ObjectivesRecent studies indicate that colonization with cagA-positive Helicobacter pylori (H. pylori) strains may protect against gastroesophageal reflux disease (GERD) and its complications, but the role of cagA in the etiology of Barrett’s esophagus has so far been poorly investigated. The pathogenesis of intestinal metaplasia (IM) at an endoscopically normal esophagogastric junction (EGJ) is still unclear, and the role of the H. pylori virulence factor cagA in it has not been investigated. The aim of our study was to assess the relationship between H. pylori and cagA-positive H. pylori in particular and IM at an endoscopically normal EGJ and Barrett’s esophagus.: MethodsSerum samples were obtained from 62 patients without IM, 43 patients with IM at an endoscopically normal junction, and 51 patients with Barrett’s esophagus. IM was defined as presence of goblet cells with positive staining with Alcian blue. The prevalence of H. pylori and cagA was investigated by assessment of IgG antibody levels as determined by ELISA.: ResultsThe overall H. pylori prevalence was 59% (92/156), and the cagA prevalence was 29% (46/156). Although 63% (39/62) of IM negative subjects and 74% (32/43) of those with IM at the junction were H. pylori positive, only 41% (21/51) of Barrett’s patients tested positive. The differences between the IM negative and the Barrett’s group (p = 0.02) and between IM at the junction and Barrett’s were significant (p = 0.002). The relative cagA prevalence (percentage with cagA positivity and H. pylori positivity) was 56% (22/39) in patients who were IM negative, 59% (19/32) in those with IM at the junction, and 24% (5/21) in those with Barrett’s. The prevalence of anti-CagA was significantly lower in patients with Barrett’s esophagus compared with patients who were IM negative (p = 0.002) and those who had IM at the junction (p < 0.001). No difference in cagA prevalence was seen between the latter groups.: ConclusionsThese findings are in line with the concept that H. pylori and cagA-positive strains in particular protect against the development of Barrett’s esophagus. In contrast, our findings do not support the theory that IM at an endoscopically normal esophagogastric junction is associated with H. pylori or cagA-positive strains. IM at the junction and Barrett’s esophagus seem to have different etiologies. [Copyright &y& Elsevier]

A letter to the editor in response to the article "Prediction of malignant potential in reflux disease: Are cytokine polymorphisms important?" by M. D. Gough, R. Ackroyd and A. W. Majeed in the previous issue is presented.