Task Specific Project 3

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In Specific Aim 3c, we would like to demonstrate the use of fluorescent-labeled peptides to guide tissue biopsy 'of flat dysplasia in the setting of Barrett's esophagus on wide area endoscopy. While we could continue our efforts in colon, the large surface area in this organ renders flat dysplasia difficult to find for this demonstration. Instead flat dysplasia is much more readily accessible in the setting of Barrett's esophagus. This is an important pre-malignant condition for esophageal adenocarcinoma that is associated with gastroesophageal reflux disease.90 This cancer is the most rapidly increasing cancer in Caucasian males when incidence rates are normalized to incidence.91 Unfortunately, Barrett's esophagus is a common condition diagnosed in 7% of patients undergoing screening colonoscopy for colon cancer with 6% prevalence even in those who have not had gastroesophageal reflux type symptoms.92 However, only a small minority of cases of Barrett's esophagus progress to cancer. This condition is found in as high as 25% of asymptomatic patients undergoing routine endoscopy.93 It has been suggested that the most effective approach to these patients should be based on the histological evidence of dysplasia which is the only clinically utilized biomarker for progression to cancer. Dysplasia is used by all of the clinical guidelines to determine therapy and surveillance in patients yet it is recognized that dysplasia is difficult to find within the Barrett's segment as well as difficult to standardize its interpretation. In fact, dysplasia does not well fit NIH criteria for a biomarker as it really cannot be objectively measured as demonstrated in a study that assessed agreement among the leading gastrointestinal pathologists in the United States and found a kappa score of 0.42 for each grade of dysplasia.72 This metaplastic conversion of normal squamous epithelium into columnar epithelium can be seen endoscopically as an extension of the gastroesophageal junction. Similar to the colon, screening of patients with Barrett's requires detection and localization of dysplasia, which is flat and endoscopically indistinct from Barrett's esophagus on white light. Currently, extensive biopsies performed randomly in 4 quadrants at 1 to 2 cm intervals using jumbo biopsy forceps (Seattle protocol) are recommended.94 However, because the technique is labor-intensive and requires a therapeutic endoscope, it is used by less than 20% of U.S. gastroenterologists.95 Furthermore, this method of screening has not been shown to reduce the rate of progression of Barrett's esophagus to adenocarcinoma.96 Thus, a new method for detecting and localizing dysplasia in the setting of Barrett's esophagus is needed.