(1/1038) Multiple target sites of allelic imbalance on chromosome 17 in Barrett's oesophageal cancer.
Twelve Barrett's adenocarcinomas have been analysed for the occurrence of allelic imbalance (LOH) on chromosome 17 using 41 microsatellite markers. This study provides evidence for 13 minimal regions of LOH, six on 17p and seven on 17q. Four of these centre in the vicinity of the known tumour suppressor genes (TSGs) TP53 (17p13.1), NFI (17q11.2), BRCA1 (17q21.1), and a putative TSG (17p13.3). The tumours all displayed relatively small regions of LOH (1-10 cM), and in several tumours extensive regions of LOH were detected. One tumour displayed only two very small regions of LOH; 17p11.2 and 17p13.1. The frequency of allelic imbalance has been calculated based on the LOH encompassing only one minimal region, and based on all the LOH observations. By both evaluations the highest LOH frequencies were found for regions II (p53), III (17p13.1 centromeric to p53), IV (17p12), V (17p11.2) and VII (NF1, 17q11.2). Our data supports the existence of multiple TSGs on chromosome 17 and challenges the view that p53 is the sole target of LOH on 17p in Barrett's adenocarcinoma. (+info)
(2/1038) Differential expression of Hsp27 in normal oesophagus, Barrett's metaplasia and oesophageal adenocarcinomas.
The protein expression patterns of normal, metaplastic and malignant oesophageal tissues were analysed by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) to identify changes associated with Barrett's metaplasia and transformation to oesophageal adenocarcinoma. Heat-shock protein 27 (Hsp27), a small heat-shock protein which is protective against cytotoxic stresses, was abundant in normal oesophagus. However, Hsp27 expression was markedly lower in Barrett's metaplasia and oesophageal adenocarcinomas. This was confirmed by immunohistochemical analysis. Hsp27 protein was most highly expressed in the upper layers of squamous epithelium and exhibited a pattern of expression that corresponded with the degree of squamous maturation. Northern and Southern analysis demonstrated Hsp27 to be regulated at the level of mRNA transcription or abundance. Normal oesophageal tissues were examined for gender differences in Hsp27 expression. Women expressed fourfold higher levels of Hsp27 mRNA, however, this difference was not appreciable in protein expression. Hsp27 protein was inducible by heat shock in Barrett's adenocarcinoma cell lines and an immortalized oesophageal epithelial cell line (HET-1A), but not by oestradiol. These results demonstrate abundant constitutive expression of the stress-response protein Hsp27 in the normal oesophagus, and suggest that low-level expression in Barrett's metaplasia may be one factor which may influence susceptibility to oesophageal adenocarcinoma development. (+info)
(3/1038) Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma.
BACKGROUND: The causes of adenocarcinomas of the esophagus and gastric cardia are poorly understood. We conducted an epidemiologic investigation of the possible association between gastroesophageal reflux and these tumors. METHODS: We performed a nationwide, population-based, case-control study in Sweden. Case ascertainment was rapid, and all cases were classified uniformly. Information on the subjects' history of gastroesophageal reflux was collected in personal interviews. The odds ratios were calculated by logistic regression, with multivariate adjustment for potentially confounding variables. RESULTS: Of the patients interviewed, the 189 with esophageal adenocarcinoma and the 262 with adenocarcinoma of the cardia constituted 85 percent of the 529 patients in Sweden who were eligible for the study during the period from 1995 through 1997. For comparison, we interviewed 820 control subjects from the general population and 167 patients with esophageal squamous-cell carcinoma. Among persons with recurrent symptoms of reflux, as compared with persons without such symptoms, the odds ratios were 7.7 (95 percent confidence interval, 5.3 to 11.4) for esophageal adenocarcinoma and 2.0 (95 percent confidence interval, 1.4 to 2.9) for adenocarcinoma of the cardia. The more frequent, more severe, and longer-lasting the symptoms of reflux, the greater the risk. Among persons with long-standing and severe symptoms of reflux, the odds ratios were 43.5 (95 percent confidence interval, 18.3 to 103.5) for esophageal adenocarcinoma and 4.4 (95 percent confidence interval, 1.7 to 11.0) for adenocarcinoma of the cardia. The risk of esophageal squamous-cell carcinoma was not associated with reflux (odds ratio, 1.1; 95 percent confidence interval, 0.7 to 1.9). CONCLUSIONS: There is a strong and probably causal relation between gastroesophageal reflux and esophageal adenocarcinoma. The relation between reflux and adenocarcinoma of the gastric cardia is relatively weak. (+info)
(4/1038) Review article: Helicobacter pylori and gastro-oesophageal reflux disease-clinical implications and management.
A significant proportion of patients with gastro-oesophageal reflux disease (GERD) have Helicobacter pylori infection, but it is unclear whether or not H. pylori should be treated in this clinical setting. The aim of this review was to critically assess the relationship between H. pylori and GERD and its potential implications for the management of GERD. Data for this review were gathered from the following sources up to April 1998-the biomedical database MEDLINE, a detailed review of medical journals, and a review of abstracts submitted to relevant international meetings. On average, 40% of GERD patients carry H. pylori infection, with a reported infection prevalence ranging from 16% to 88%. To date, there has been no reported controlled trial of effective H. pylori therapy in GERD. GERD has been reported to develop de novo following the cure of H. pylori in peptic ulcer disease. In the presence of H. pylori, proton pump inhibitor therapy appears to accelerate the development of atrophic corpus gastritis, a potentially precancerous condition. Conversely, proton pump inhibitor therapy seems to become less effective after cure of H. pylori. The mechanisms underlying these important contrasting phenomena are poorly understood. The relationship between H. pylori and GERD is complex, and it is difficult to give definitive guidelines on the management of H. pylori infection in GERD. Controlled trials of H. pylori therapy in GERD are urgently needed, as well as further long-term data on both the natural history of gastric histopathological changes in the H. pylori-positive GERD patient treated with proton pump inhibitors, and the impact of H. pylori status on the clinical efficacy of antisecretory therapy. Pending these data, it is perhaps advisable to advocate cure of H. pylori in young patients with proton pump inhibitor-dependent GERD who, in the absence of anti-reflux surgery, are faced with the likelihood of long-term medical therapy. (+info)
(5/1038) Impact of endoscopic biopsy surveillance of Barrett's oesophagus on pathological stage and clinical outcome of Barrett's carcinoma.
BACKGROUND: The efficacy of endoscopic biopsy surveillance of Barrett's oesophagus in reducing mortality from oesophageal cancer has not been confirmed. AIMS: To investigate the impact of endoscopic biopsy surveillance on pathological stage and clinical outcome of Barrett's carcinoma. METHODS: A clinicopathological comparison was made between patients who initially presented with oesophageal adenocarcinoma (n = 54), and those in whom the cancer had been detected during surveillance of Barrett's oesophagus (n = 16). RESULTS: The surveyed patients were known to have Barrett's oesophagus for a median period of 42 months (range 6-144 months). Prior to the detection of adenocarcinoma or high grade dysplasia, 13 to 16 patients (81%) were previously found to have low grade dysplasia. Surgical pathology showed that surveyed patients had significantly earlier stages than non-surveyed patients (p = 0.0001). Only one surveyed patient (6%) versus 34 non-surveyed patients (63%) had nodal involvement (p = 0.0001). Two year survival was 85.9% for surveyed patients and 43.3% for non-surveyed patients (p = 0.0029). CONCLUSIONS: The temporal course of histological progression in our surveyed patients supports the theory that adenocarcinoma in Barrett's oesophagus develops through stages of increasing severity of dysplasia. Endoscopic biopsy surveillance of Barrett's oesophagus permits detection of malignancy at an early and curable stage, thereby potentially reducing mortality from oesophageal adenocarcinoma. (+info)
(6/1038) Barrett's oesophagus.
Barrett's oesophagus represents the replacement of stratified squamous epithelium by metaplastic columnar epithelium for 3 cm of the distal oesophagus. Gastro-oesophageal reflux, which affects 40% of the adult population, is the principal aetiological factor. This results in predominantly acid but also bile reflux (due to duodenogastrooesophageal reflux) through the lower oesophageal sphincter, transient relaxation of which accounts for the main mechanism of reflux. Conventional Barrett's oesophagus is reported in 11-13% of patients with symptomatic reflux and short segment Barrett's oesophagus (< 3.0 cm) in 18%. Approximately 50% of these patients have recognised complications on presentation, eg, carcinoma (15%). The disparity between clinical symptoms and endoscopic severity is due to reduced oesophageal mucosal sensitivity as a consequence of prolonged mucosal acid exposure. These rather alarming figures combined with the knowledge that Barrett's oesophagus is a pre-malignant condition (the diagnosis is associated with a 25-130-fold increase of malignancy) may account for the substantial increase in junctional gastrooesophageal malignancies. Symptomatic Barrett's oesophagus should be managed with full-dose proton pump inhibitors, eg, lansoprazole. Anti-reflux surgery should be reserved for the medically fit patient with recurrent symptomatic relapse in the histological absence of premalignant change. There is no evidence suggesting that surgery can be used as a prophylactic measure against malignancy. Encouraging short-term results have been obtained with photodynamic therapy in the management of high-grade dysplasia. However, columnar epithelium has been found underlying the regenerated squamous epithelium, suggesting that life-long surveillance is warranted. (+info)
(7/1038) Toxic bile acids in gastro-oesophageal reflux disease: influence of gastric acidity.
BACKGROUND: Bile acid toxicity has been shown in the gastric, colonic, and hepatic tissues; the effect on oesophageal mucosa is less well known. AIMS: To determine the spectrum of bile acids refluxing in patients with gastro-oesophageal reflux disease and its relation to oesophageal pH using a new technique of combined oesophageal aspiration and pH monitoring. METHODS: Ten asymptomatic subjects and 30 patients with symptoms of gastro-oesophageal reflux disease (minimal mucosal injury, erosive oesophagitis (grade 2 or 3 Savary-Miller), Barrett's oesophagus/stricture; n=10 in each group) underwent 15 hour continuous oesophageal aspiration with simultaneous pH monitoring. Bile acid assay of the oesophageal samples was performed using modified high performance liquid chromatography. RESULTS: The peak bile acid concentration and DeMeester acid scores were significantly higher in the patients with oesophagitis (median bile acid concentration 124 micromol/l; acid score 20.2) and Barrett's oesophagus/stricture (181 micromol/l; 43. 3) than patients with minimal injury (14 micromol/l; 12.5) or controls (0 micromol/l; 11.1). The predominant bile acids detected were cholic, taurocholic, and glycocholic acids but there was a significantly greater proportion of secondary bile acids, deoxycholic and taurodeoxycholic acids, in patients with erosive oesophagitis and Barrett's oesophagus/stricture. Although bile acid reflux episodes occurred at variable pH, a temporal relation existed between reflux of taurine conjugates and oesophageal acid exposure (r=0.58, p=0.009). CONCLUSION: Toxic secondary bile acid fractions have been detected in patients with extensive mucosal damage. Mixed reflux is more harmful than acid reflux alone with possible toxic synergism existing between the taurine conjugates and acid. (+info)
(8/1038) Hypothesis: the changing relationships of Helicobacter pylori and humans: implications for health and disease.
Helicobacter pylori has apparently colonized the human stomach since time immemorial and is superbly adapted for persistence. Several genotypes, including cag+, are associated with increased risk of gastric and duodenal diseases. With modern life, for probably the first time in human history, there are large numbers of noncolonized persons. Duodenal ulceration has been present essentially for only 200 years; that its incidence rose just as H. pylori was waning is best explained by changes in gastric microecology. As H. pylori is disappearing, duodenal ulceration and gastric cancer rates are falling. However, more proximal diseases, gastroesophageal reflux (GERD), Barrett's esophagus, and adenocarcinomas of the gastric cardia and lower esophagus, are increasing; colonization with cag+ H. pylori strains appears protective against these diseases. Thus, in the 21st century, the continuing decline in H. pylori may lead to the disappearance of duodenal ulcers and distal gastric cancers and toward a marked increase in GERD, Barrett's esophagus, and esophageal adenocarcinoma. (+info)