Whole Genome Methylation Analysis of Nondysplastic Barrett Esophagus that Progresses to Invasive Cancer.

OBJECTIVE: To investigate differences in methylation between patients with nondysplastic Barrett esophagus who progress to invasive adenocarcinoma and those who do not. BACKGROUND: Identifying patients with nondysplastic Barrett esophagus who progress to invasive adenocarcinoma remains a challenge. Previous studies have demonstrated the potential utility of epigenetic markers for identifying this group. METHODS: A whole genome methylation interrogation using the Illumina HumanMethylation 450 array of patients with nondysplastic Barrett esophagus who either develop adenocarcinoma or remain static, with validation of findings by bisulfite pyrosequencing. RESULTS: In all, 12 patients with "progressive" versus 12 with "nonprogressive" nondysplastic Barrett esophagus were analyzed via methylation array. Forty-four methylation markers were identified that may be able to discriminate between nondysplastic Barrett esophagus that either progress to adenocarcinoma or remain static. Hypomethylation of the recently identified tumor suppressor OR3A4 (probe cg09890332) validated in a separate cohort of samples (median methylation in progressors 67.8% vs 96.7% in nonprogressors; P = 0.0001, z = 3.85, Wilcoxon rank-sum test) and was associated with the progression to adenocarcinoma. There were no differences in copy number between the 2 groups, but a global trend towards hypomethylation in the progressor group was observed. CONCLUSION: Hypomethylation of OR3A4 has the ability to risk stratify the patient with nondysplastic Barrett esophagus and may form the basis of a future surveillance program.

Outcome of index upper gastrointestinal endoscopy in patients presenting with dysphagia in a tertiary care hospital-A 10 years review.

BACKGROUND: Patients with malignant tumours of the upper gastrointestinal tract tumours exhibit important alarm symptoms such as dysphagia that warrant clinical investigations. An endoscopic examination of the upper gastrointestinal tract will be required in most cases. This study evaluates the diagnostic potential of index endoscopy in a random population of patients with dysphagia. METHODS: This is a retrospective analysis of prospectively collected data over 10 years. Patients with previous endoscopic evaluation or upper gastrointestinal pathology were excluded from the study. Data was analysed to see the number and frequency of abnormal findings in upper gastrointestinal tract, and their significance in relation to the presenting symptoms. RESULTS: Total number of index endoscopies was 13, 881. 913 patients were included in the study including 465 males (age range: 17-92 years, median: 55 years) and 448 females (age range: 18-100, median: 59 years), with male to female ratio of 1.04: 1. Oesophagus was abnormal in 678 cases (74%) and biopsies were taken in 428 patients (47%). Superficial oesophagitis, Barrett's oesophagus, oesophageal cancer, and oesophageal ulcer were main histological findings. Age more than 50 years and weight loss were significant predictors of oesophageal cancer (p < 0.0001). Male gender, heartburn, epigastric pain, weight loss and vomiting were significantly related to Barrett's oesophagus. A total of 486 gastric and 56 duodenal biopsies were also taken. There were 20 cases of gastric adenocarcinoma. CONCLUSION: OGD is an effective initial investigation to assess patients with dysphagia, especially males above the age of 50 years. Patients may be started on treatment or referred for further investigations, for example, a barium meal in the absence of any anatomical abnormality.

Identification of FGF receptor-binding peptides for cancer gene therapy.

Linear FGF receptor-binding heptapeptides were identified by phage display using sequential rounds of biopanning against cells with displacement of phage by FGF2. The consensus motif MXXP was iterated after four to five rounds and the peptide MQLPLAT was studied in depth. Phage bearing MQLPLAT showed high levels of binding to FGF receptor positive cells, with over 90% of phage bound being eluted competitively by adding free FGF2. MQLPLAT phage showed only limited binding to Cos7 cells deficient in receptors for FGF. MQLPLAT phage bound to SKOV3 cells with a K(d) of 2.51 x 10(-10) M. Although binding could be blocked by preincubation with free FGF2, heparin could not displace the phage. Use of MQLPLAT to target polyelectrolyte gene delivery vectors in vitro in the presence of serum achieved up to 40-fold greater transgene transduction than nontargeted vectors. MQLPLAT phage were administered into gastric carcinomas via the tumor-feeding artery immediately following resection from patients. The phage showed up to 9-fold more accumulation in the tumor than in adjacent regions of normal tissue, whereas control phage showed less than 2-fold. These peptides should provide useful ligands for specific delivery of gene therapy vectors to clinically relevant targets.