Volume 122, Issue 4, Pages 1101-1112 (April 2002) Chemoprevention of esophageal adenocarcinoma by COX-2 inhibitors in an animal model of Barrett's esophagus  Navtej S. Buttar, Kenneth K. Wang, Olga Leontovich, Jay Y. Westcott, Rodney J. Pacifico, Marlys A. Anderson, Krishnawatie K. Krishnadath, Lori S. Lutzke, Lawrence J. Burgart  Gastroenterology  Volume 122, Issue 4, Pages 1101-1112 (April 2002) DOI: 10.1053/gast.2002.32371 Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 1 Surgical interventions to create an animal model of Barrett's esophagus. The steps in creating an esophagoenteric anastomosis are shown. (A) The gastroesophageal junction (vertical arrow) was identified to transect esophagus just above it. The vagus trunk (horizontal arrow) was preserved during transection. (B) Eight polypropylene sutures were applied at the lower end of the esophagus for esophagoenteric anastomosis. (C) A 5-mm jejunostomy was created just distal to the ligament of Treitz on the antimesenteric border using electrocautery. (D) While carefully maintaining the orientation and patency of the lumen, an end-to-side esophagoenterostomy was performed. Gastroenterology 2002 122, 1101-1112DOI: (10.1053/gast.2002.32371) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 2 Study design. A flow diagram showing the randomization process and study follow-up. Gastroenterology 2002 122, 1101-1112DOI: (10.1053/gast.2002.32371) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 3 Incidence of esophageal adenocarcinoma. The rate of esophageal cancer (%) is represented by solid bars. The risk of esophageal cancer is significantly lower in the MF-tricyclic–treated group (P = 0.013) and the Sulindac-treated group (P < 0.001) than in the control group. There is no significant difference in the risk of esophageal cancer between the MF-tricyclic– and the Sulindac–treated groups (P = 0.205). Gastroenterology 2002 122, 1101-1112DOI: (10.1053/gast.2002.32371) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 4 Autopsy. (A, B) Carcinoma infiltrating and extending beyond the esophageal wall. (C) The esophageal lumen was opened by longitudinally cutting the non–tumor-bearing esophageal wall. The luminal view shows an ulcerated tumor (vertical arrow). The ulceration extends proximally for 4 mm. The black horizontal arrow and a zigzag line represent the location of the esophagoenteric anastomosis. Gastroenterology 2002 122, 1101-1112DOI: (10.1053/gast.2002.32371) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 5 Adenocarcinoma of the esophagus. (A) A photomicrograph showing well-differentiated adenocarcinoma of the esophagus, which is approaching the muscularis layer, but not invading it (original magnification, 10×). (B) An invasive adenocarcinoma of the esophagus extending beyond the muscularis propria is shown by an arrow (original magnification, 10×). (C) A higher-magnification photomicrograph of invasive cancer with desmoid reaction is shown (original magnification, 20×). Gastroenterology 2002 122, 1101-1112DOI: (10.1053/gast.2002.32371) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 6 Barrett's metaplasia. (A) A short segment of columnar metaplasia is shown by a horizontal white arrow (original magnification, 10×). This segment is surrounded both proximally and distally by squamous epithelium of the esophagus (vertical black arrows). (B) A high-magnification (30×) photomicrograph of Figure 6A is showing transition (horizontal black arrow) from squamous (vertical black arrow) to columnar metaplasia (horizontal white arrow). Gastroenterology 2002 122, 1101-1112DOI: (10.1053/gast.2002.32371) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 7 Effect of enteroesophageal reflux on COX expression and activity. (A) COX-1 and COX-2 protein expression (Western blot test) in the esophageal tissue is shown from 2 representative animals without surgical intervention (columns 1 and 2) and 2 representative animals that underwent surgical intervention to induce esophageal reflux (columns 3 and 4). COX-1 expression remains the same, but esophageal reflux induced a heterogenous COX-2 expression. (B) COX activity as assessed by PGE2 levels is shown by solid bars. The PGE2 level in the esophageal tissue after surgical intervention to induce reflux was significantly increased to 264.2 ± 65 ng/g, compared with 4.8 ± 6.8 ng/g in rats without surgical intervention (P < 0.001). Gastroenterology 2002 122, 1101-1112DOI: (10.1053/gast.2002.32371) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 8 Effect of study drugs on enteroesophageal reflux–induced COX-2 activity of the esophageal tissue: Animals in the MF-tricyclic and sulindac groups had PGE2 levels of 175.5 ± 21.4 and 131.9 ± 42 ng/g, respectively, compared with 264.2 ± 65 ng/g in the control group. Rats in the sulindac group had significantly lower levels of PGE2 than rats in the control group (P = 0.03). No significant difference in PGE2 level was noted between the sulindac and MF-tricyclic groups. Gastroenterology 2002 122, 1101-1112DOI: (10.1053/gast.2002.32371) Copyright © 2002 American Gastroenterological Association Terms and Conditions