The goal of this proposal is to demonstrate that brain tumors which harbor isocitrate dehydrogenases (IDH) gene mutations can be distinguished from IDH wild-type (WT) tumors intraoperatively and in real-time, based on their autofluorescence emission properties. Mutation of the IDH1/2 genes is common in low-grade gliomas (LGG) and occur infrequently in glioblastoma multiforme (GBM). The presence of IDH mutations is the greatest prognostic marker for GBM patients. Patients with IDH mutant gliomas have improved survival compared to their grade matched, WT counterparts. Importantly, recent studies suggest that the benefit of aggressive surgical resection differs between IDH-WT and IDH-mutant tumors; thus, intraoperative identification of IDH mutations will change the operative goals. Subsequently, there is a considerable interest in developing rapid, intraoperative methods to identify IDH mutations. IDH mutations cause global changes in cellular metabolism by impairing the conversion alpha-ketoglutarate (?KG) to isocitrate, which normally reduces NADP+ to NADPH. Instead, ?KG is converted to 2-hydroxyglutarate, consuming NADPH to produce NADP+. Brain autofluorescence properties are highly interlinked with changes in cellular metabolism. In particular, the variation in autofluorescence emission intensity of brain tissue has been attributed to differences in NAD(P)H concentration and redox state. Also, differences in the lifetime (or decay) of autofluorescent intensities between glioma and normal brain tissues have been attributed to disparities between free- and bound-NAD(P)H. Therefore, we hypothesize that optical parameters derived from autofluorescence lifetime measurements of gliomas can be correlated to changes in cellular metabolism caused by IDH mutations. This proposal will build on previous clinical studies that demonstrate gliomas of distinct phenotypes have distinct fluorescence lifetime characteristics and our expertise with moving fluorescence lifetime imaging (FLIm) techniques into clinical settings. To accomplish our goal, we propose 2 specific aims.
Aim 1 : Conduct FLIm intraoperative measurements in LLG and HGG patients (N=80) undergoing conventional neurosurgical procedures. This will provide an extensive database of FLIm parameters (retrieved from both in vivo and ex vivo measurements) correlated with tissue pathology including IDH mutation status.
Aim 2 : Validate the utilization of FLIm as a means for real-time detection of IDH mutations. This will demonstrate the predictive value of FLIm for detection of IDH mutation status and for potential guidance during brain tumor surgery. In summary, this study will demonstrate the clinical utility of FLIm for intraoperative, real-time assessment of IDH mutation status to improve surgical outcomes. Since the FLIm apparatus is characterized by simple, fast and flexible data acquisition and display, and allows for seamless integration with existing imaging techniques used in neurosurgery, the findings are immediately translational. For GBM patients, identification of IDH mutations during surgery will alter goals concerning the extent of resection, leading to less aggressive tissue removal and decreased morbidity while ensuring limited impact on survival. For LGG patients, where extent of resection has been associated with a near doubling in overall survival, identification of IDH mutant tissue in real-time will allow differentiation between tumor and normal brain, thereby maximizing the extent of resection while decreasing the risk of neurologic injury.
IDH mutation status is a critical prognostic factor for brain cancer patients and the ability to identify/visualize IDH- mutated tissue intraoperatively may improve surgical outcome and patient survival. Our novel optical imaging FLIm system captures and analyzes tissue autofluorescence and may be sensitive to alterations in tissue autofluorescence that arise from IDH mutation. The successful validation of FLIm as an intraoperative method for IDH mutation identification may improve patient outcomes by facilitating more appropriate surgical goals and enhancing the surgeon's ability to visual tumor margins.
