Biomedical subjects
Publications and source records attributed to George Triadafilopoulos.
Although medical and surgical treatments are available for gastroesophageal reflux disease, endoscopic therapies for this condition are relatively new. This review describes the principles behind such treatments as well as the individual procedures themselves, focusing on mechanisms of action, safety and tolerability, and efficacy in animal and human clinical trials. Future trends in endoscopic therapy are discussed.
BACKGROUND & AIMS: Cyclooxygenase 2 (COX-2) is overexpressed in Barrett's esophagus and adenocarcinoma and up-regulated by acid or bile salt exposure. COX-2 inhibition with the selective inhibitor rofecoxib may be important in chemoprevention of esophageal adenocarcinoma by decreasing cell proliferation. METHODS: Biopsy specimens of esophagus, Barrett's esophagus, and duodenum were obtained at baseline from 12 patients and were compared with biopsy specimens obtained after 10 days of therapy with rofecoxib 25 mg orally daily. All patients were maintained asymptomatic on their proton pump inhibitor therapy throughout the study. COX-2 expression, proliferating cell nuclear antigen (PCNA) expression (proliferation marker), and prostaglandin E2 (PGE2) biopsy content (marker of COX activity) were assessed by immunoblotting and enzyme immunoabsorbence assays. RESULTS: At baseline, COX-2 expression was 3-fold higher in Barrett's esophagus than esophagus and duodenum (P < 0.05). After rofecoxib therapy, COX-2 expression in Barrett's esophagus decreased by 77% (P < 0.005). Similarly at baseline, PGE2 content was 2-fold higher in Barrett's esophagus than esophagus or duodenum. After rofecoxib therapy, PGE2 content decreased in Barrett's esophagus by 59% (P < 0.005). At baseline, PCNA expression was also 2-fold higher in Barrett's esophagus than squamous esophagus and duodenum (P < 0.005). After rofecoxib therapy, PCNA expression in Barrett's esophagus decreased by 62.5% (P < 0.005). CONCLUSIONS: Rofecoxib 25 mg orally once daily reduces COX-2 expression, PGE2 release, and cell proliferation in Barrett's esophagus. Together with acid suppressive therapy, rofecoxib may be a promising chemoprevention agent against dysplasia and esophageal adenocarcinoma.
BACKGROUND & AIMS: The incidence of esophageal adenocarcinoma in the western world has been linked to chronic heartburn, regurgitation, and the development of the premalignant epithelium of Barrett's esophagus (BE). However, up to 40% of esophageal adenocarcinomas occur in patients without prior reflux symptoms. We prospectively screened for the presence of BE in asymptomatic subjects older than 50 years of age undergoing screening sigmoidoscopy for colorectal cancer. METHODS: Subjects undergoing sigmoidoscopy for colorectal cancer (CRC) screening were invited to undergo upper endoscopy. Exclusion criteria included symptoms of gastroesophageal reflux disease (GERD) more than once a month, use of medications for GERD, or previous endoscopy. BE was classified as long-segment BE (LSBE), short-segment BE (SSBE), and microscopic specialized intestinal metaplasia of the esophagogastric junction (SIM-EGJ). RESULTS: Of 408 potential study candidates, 110 subjects were screened; 9 were women. The mean (+/-SD) age was 61 +/- 9.3 (range, 50-80) years, most of them (73%) Caucasian. Intestinal metaplasia (IM) extending above the EGJ was detected in 27 (25%) subjects; 8 (7%) had LSBE, and 19 (17%) had SSBE. Patients with BE were no more likely to be obese, consumers of tobacco or alcohol, report a family history of GERD, show association with toxic exposure, or use antacids more than once a month, compared with those without BE. CONCLUSIONS: BE was detected in 25% of asymptomatic male veterans older than 50 years of age undergoing screening sigmoidoscopy for CRC.
BACKGROUND: This multicenter prospective study investigated the longer-term (12 month) safety and efficacy of radiofrequency energy delivery for the treatment of GERD. METHODS: A prospective study was conducted of 118 patients with chronic heartburn and/or regurgitation who required antisecretory medication daily and had demonstrated pathologic esophageal acid exposure, a sliding hiatal hernia (<or=2 cm), and esophagitis (<or= grade 2). RF energy was delivered with the Stretta catheter and thermocouple-controlled generator to create thermal lesions below the mucosa at the gastroesophageal junction. GERD symptom scores, quality of life (SF-36), and medication use were assessed at 0, 1, 4, 6, and 12 months; esophageal acid exposure, motility, and endoscopy were assessed at 0 and 6 months. RESULTS: Seventy-two men and 46 women were treated. At 12 months, 94 patients were available for follow-up. There were improvements after 12 months in the median heartburn score (4 to 1, p = 0.0001), GERD score (27 to 9, p = 0.0001), satisfaction (1 to 4, p = 0.0001), mental SF-36 (46.3 to 55.4, p < 0.0001), and physical SF-36 (40.9 to 53.1, p = 0.0001); proton pump inhibitor requirement fell from 88.1% to 30% of patients. Esophageal acid exposure improved significantly (10.2% to 6.4%, p = 0.0001). There were 10 (8.6%) complications, none of which required therapeutic intervention. CONCLUSION: The Stretta procedure significantly improves GERD symptoms, quality of life, and esophageal acid exposure and eliminates the need for antisecretory medication in the majority of patients at 12 months.
Barrett's esophagus (BE) results from acid and bile reflux and predisposes to cancer. To further understand the mechanisms of acid- and bile-induced hyperproliferation in BE, we investigated the release of PGE(2) in response to acid or bile salt exposure. Biopsies of esophagus, BE, and duodenum were exposed to a bile salt mixture as a 1-h pulse and compared with exposure to pH 7.4 for up to 24 h, and PGE(2) release, cyclooxygenase-2 (COX-2), and protein kinase C (PKC) expression were compared. Similar experiments were also performed with acidified media (pH 3.5) alone, in the presence or absence of bisindolylmaleimide (BIM), a selective PKC inhibitor, and NS-398, a COX-2 inhibitor. One-hour pulses of bile salts or acid significantly enhanced proliferation, COX-2 expression, and PGE(2) release in BE. In contrast, the combination pulse of acid and bile salts had no such effect. Treatment with either BIM or NS-398 led to a dramatic decrease in PGE(2) release in BE explants and a suppression of proliferation. The acid- or bile salt-mediated hyperproliferation is related to PGE(2) release. Acid- and bile salt-induced induction of COX-2 and PKC may explain, at least in part, the tumor-promoting effects of acid and bile in BE.
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