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Multiphoton Endoscopy for Diagnosis of Barrett’s Esophagus
Michael Nathanson, Section Chief of Digestive Diseases, Internal Medicine, Yale University School of Medicine.
Funding: P30 DK34989, R01 DK45710 (01/01/95-03/31/10).

Cancers of the digestive system account for a significant fraction of cancer deaths – 1 of every 4 cancer deaths in the US are due to digestive system neoplasms. Unique opportunities exist to screen patients for these common but deadly forms of cancer, since endoscopy can be used to directly visualize the esophagus, stomach, duodenum, and colon. Although premalignant changes in the gastrointestinal mucosa are evident by microscopic examination of biopsy specimens, these changes typically are not evident upon endoscopic examination. Confocal endoscopy has the potential to permit microscopic examination of the gastrointestinal mucosa in situ, but this approach is limited by the types of fluorescent dyes that can be used in patients. In contrast, multiphoton excited tissue imaging has the potential to reveal important cellular and subcellular details without the use of fluorescent labels. The objective of this project is to evaluate the potential of using intrinsic tissue emissions for detection of Barrett’s Esophagus, a condition that can lead to esophageal adenocarcinoma.

We have had several productive collaborations with Dr. Nathanson in the past in a variety of different areas (Echevarría, 2003 and O’Neill, 2002). This project began a few years ago when DRBIO collaborated with the Nathanson group to retrofit the Yale Zeiss 510 NLO system with improved blue detectors, which enabled a systematic examination of human biopsy samples from all areas of the GI tract (Rogart, et al, 2008). Histological patterns observed by MPM were characterized in normal and dysplastic tissues from the esophagus, stomach, colon, and rectum. Although MPM images from all areas showed diagnostic potential, one easily accessible region that would only require only a minimal region to be imaged would be a screen for Barrett’s esophagus. Results from this preliminary examination of the esophageal epithelium are shown in Figure 1. The usefulness of multiphoton endomicroscopy as a cancer screening tool will be assessed in patients with Barrett’s esophagus. This project would establish a novel paradigm for translation of state-of-the-art microscopic imaging techniques to situations that would have an immediate and high impact on clinical care of cancer patients.


Echevarria, W., M. F. Leite, M. T. Guerra, W. R. Zipfel, and M. H. Nathanson. 2003. Regulation of calcium signals in the nucleus by a nucleoplasmic reticulum. Nat Cell Biol 5:440-446.

O'Neill, A. F., R. E. Hagar, W. R. Zipfel, M. H. Nathanson, and B. E. Ehrlich. 2002. Regulation of the type III InsP(3) receptor by InsP(3) and calcium. Biochem Biophys Res Commun 294:719-725.

Rogart, J. N., J. Nagata, C. S. Loeser, R. D. Roorda, H. Aslanian, M. E. Robert, W. R. Zipfel, and M. H. Nathanson. 2008. Multiphoton imaging can be used for microscopic examination of intact human gastrointestinal mucosa ex vivo. Clin Gastroenterol Hepatol 6:95-101.





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