Esophageal adenocarcinoma (EAC) has one of the fastest rising rates of incidence in the US. Unfortunately, the five-year-survival for patients diagnosed with EAC is only 10%. EAC develops primarily in patients with Barrett's esophagus (BE). Endoscopic screening and biopsy is recommended for at-risk individuals. However, standard white-light endoscopic examination frequently misses areas of early neoplasia, which are often clinically indistinguishable from normal mucosa and/or inflammatory changes. Studies have shown that as many as 43-57% of early cancers can be missed by this method. Thus, there is an important need for new endoscopic technologies which improve the ability of clinicians to identify precancerous lesions and early cancers with high sensitivity and specificity. The goal of this proposal is to develop, optimize and validate novel multi-modal, multi-scale optical imaging platforms for non-invasive, early detection of esophageal neoplasia based on optical imaging. We will collaborate with colleagues at Pentax, Inc. to design and test multi-modal endoscopic imaging systems for early detection of neoplasia in Barrett's esophagus. Widefield endoscopic imaging will be used initially to screen the surface area at risk to identify abnormal sites with high sensitivity; suspicious areas will then be imaged with much higher spatial resolution to achieve high diagnostic specificity. Both wide field and high resolution technologies will be integrated into a single endoscopic platform to increase the ease and accuracy of endoscopic cancer screening and surveillance. In sequential clinical studies, we will first separately optimize the performance of wide field endoscopic imaging and high resolution imaging. We will then integrate the wide field and high resolution imaging systems and validate their accuracy for the detection of neoplasia in subjects with Barrett's esophagus, the precursor to esophageal adenocarcinoma. Lastly, we will develop an image atlas of typical wide-field and high-resolution images, interpretation criteria, and histopathology to train future users and serve as an educational resource.