ADVANCED TRACER KINETIC MODELS FOR IMPROVED TUMOR MARGIN DETECTION AND GUIDING THERAPY
Cancer continues to be the second leading cause of death in the world with one in two individuals suffering from some form of cancer within their lifetimes . The main objective in most cancer therapies is to achieve a complete resection of the cancerous cells, which in surgical approaches is evident from the diagnosis of positive resection margins during postoperative pathology. However, pathological analysis is performed after the patient has been discharged. Thus technologies capable of identifying tumor margins in resected samples intraoperatively could substantially reduce the psychological and economical burden of “call-back” surgeries. As a step in this direction, a wide-field Raman spectroscopy system was employed, which has the capacity to discriminate between tumor and healthy tissue through a “dual-tracer” staining approach within the surgical window. The approach entails dipping the resected tissue in two tracers: one targeted to a cancer specific cell-surface receptor, and another left “untargeted”. In this experiment human glioma (U251) and human epidermoid (A431) tumors were grown subcutaneously in ten nude athymic mice. The data obtained from the Raman spectra of different tissue specimens were then analyzed through tracer kinetic modeling to quantify cancer molecule abundance as a surrogate of cancer presence. The salient finding in this study was that the model was able to predict the expected differences in EGFR concentration amongst the healthy tissue, U251, and A431. Kinetic model estimation of the ratio of EGFR concentration in U251 and A431 cell lines were in the ratio of 2:1, which correlates, with the expected ratio of EGFR concentration determined by flow cytometry which was close to 4:1. This technology not only promises to xii highlight tumor margins on a molecular level but can also be leveraged to analyze the molecular environment of the tumor to guide adjuvant precision therapies. Tracer kinetic modeling approaches were also applied to a guided precision therapy called Photodynamic therapy. Not only could the analysis of data provide parameter values for the tracer kinetics but an approach was also developed which with only a few initial data points could predict the time optimal for therapy in advance of the drug concentration maximum.