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The clinical management of glioma remains a challenge. The prognosis is poor—for glioblastoma multiforme, the most virulent of these brain cancers, survival is only ~1 year. Surgical resection of the tumor is the first line of defense. Several studies demonstrate a survival advantage in patients who undergo near-complete tumor resection; however, achieving complete resection is limited by the difficulty of visualizing residual tumor after de-bulking. Intraoperative fluorescence guidance is a promising candidate to better visualize residual tumor. The most clinically developed form uses protoporphyrin IX fluorescence, the precursor to heme in its biosynthesis which preferentially accumulates in tumor cells after the administration of 5-aminolevulinic acid. Challenges remain in quantitatively assessing the fluorescence to reduce variability of outcome and improve tumor detection specificity, and in observing sub-surface tumor fluorescence. To these ends, this work outlines the development of intraoperative techniques to 1) quantify tissue fluorescence using a handheld fiberoptic probe and 2) improve detection by reconstructing the depth-resolved fluorescence topography of sub-surface tumor. As a critical component to achieve these objectives, a technique to measure the tissue optical properties was developed. This technique used diffuse reflectance measurements mediated by a handheld fiberoptic probe to derive the tissue optical properties. The handheld fiberoptic probe was further developed to include fluorescence spectroscopy. A novel algorithm to combine the fluorescence measurement and the tissue optical properties was derived in order to extract the quantitative fluorescence spectrum, i.e. fluorescence without confounding effects of tissue optical properties. The concentration of fluorescent tumor biomarker can then be extracted. The quantitative fluorescence work culminated in deployment of the fiberoptic probe in clinical trials for the resection of intracranial tumors. The quantitative fluorescence probe out-performed a state-of-the-art fluorescence surgical microscope for a broad range of brain tumor pathologies. A novel technique for depth-resolved fluorescence detection was developed utilizing multi-excitation fluorescence imaging. An algorithm to extract depth information from the multi-excitation images was derived, with validation in phantoms and a rat brain tumor model. This demonstrates the potential for depth-resolved fluorescence imaging, which there is a clear need for in tumor resection guidance. |
