Inherent in early detection and guided resection of malignancy is the need for high sensitivity, since both early lesions and residual disease consist of small numbers of cancer cells, and both are diagnosed and defined using molecular markers and morphologic features. In the present paradigm these methods are typically performed on excised tissues that are sent to pathology; as such, the diagnostic event is separated from the patient by significant time and distance. Reducing this time and distance will hasten and refine intervention as well as relieve stress to the patient. However, it will require the development of technologies that image, or sense, rapidly over a range of scales and hence will require integrated multimodality approaches. We addressed this problem by combining novel molecular probes with endomicroscopes that enable point-of-care microscopy. We also combined these high-resolution devices with integrated wide-FOV optical systems and endoscopic ultrasound instruments. The core technology that formed the foundation for instrumentation development was a dual-axis confocal (DAC) fluorescence-based endomicroscope. A 5-mm OD DAC endomicroscope was evaluated for its safety and robustness for clinical use and then integrated with a fluorescence-based widefield microendoscope. Initially the dye ICG was used as a contrast agent to provide anatomic information; since this dye is a both a chromogen and a fluorophore, it can be visualized with a standard endoscope (chromogen), with the fluorescence imaging devices providing a range of scales and multiple levels of information. We advanced the use of flurocoxib, a molecular probe designed to detect early and small lesions, since it targets COX-2 that is expressed in inflammatory lesions, dysplasia, and malignant neoplasia, as an early marker of malignancy. Initial clinical testing informed, through a feedback loop, the next-generation designs for both devices and molecular probes, resulting in more robust approaches for improved integration. Results from these studies led to a robust, clinically useful miniaturized multimodality imaging device and improved molecular probes, both of which have utility for early detection and guided resection for a wide variety of cancers.
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