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Infiltrating low-grade gliomas (LGGs) are a class of terminal central nervous system tumors that comprise malignant neuroglia. Histopathological diagnosis of tumor grade is performed using criteria set by the World Health Organization (WHO) and is based on factors that include nuclear atypia, proliferative capacity, tumor neovascularization, and necrosis.1 The clinical outcome for patients with LGG is variable, with some lesions following a more indolent disease course, while others recur more rapidly and often after undergoing malignant transformation (MT) to a higher grade.2 Lesions that have thus transformed to a grade III anaplastic glioma or grade IV secondary glioblastoma multiforme (GBM) are managed with additional, more aggressive treatments. To date, little is known regarding the nature of recurrent disease, and the most significant prognostic factors for patients diagnosed with LGG are the presence of somatic driver mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) oncogenes and the codeletion of the 1p and 19q chromosomal arms, which have been associated with increased survival and sensitivity to the treatment given.2–5 IDH mutations have been implicated as an initiating event in gliomagenesis and are key to reprogramming the tumor epigenome and metabolome, largely through neomorphic production and accumulation of 2-hydroxyglutarate.6 Given uncertainties regarding the effectiveness of options available for treating LGGs, IDH mutations have garnered significant attention as a targetable therapeutic pathway, and there are several novel therapies on the horizon.7–9 Until these therapeutics become available, the clinical mainstay of treatment for patients with LGG consists of surgical resection, with radiation therapy and alkylating chemotherapy being typically reserved for recurrences that were either subtotally resected or have undergone MT. MRI is an integral component of brain tumor diagnosis and monitoring. Recent advances in state-of-the-art techniques have enabled the noninvasive assessment of tumor morphology and physiology, with primary GBM having been studied most extensively. Although the ability to noninvasively detect MT would be of significant clinical interest for diagnosis and treatment planning, few studies have focused on addressing this question. Multiparametric MRI holds significant promise for comprehensively characterizing the structural and physiological properties of the tumor. We hypothesize that these advanced imaging techniques may also provide improved characterization of MT in patients with recurrent LGG. The objective of this study was to establish multiparametric MRI profiles of patients with tumors prior to image-guided surgery in order to relate metrics obtained from these methodologies to histopathological grade. Volumetric regions with abnormal imaging features were calculated to provide a robust assessment of the entire recurrent tumor lesion. Regions of viable tumor were targeted for image-guided tissue sampling in order to associate in vivo parameters with histopathological features and to strengthen our understanding of the link between glioma tumor biology and parameters from noninvasive imaging.

Interpretation of changes in the T1- and T2-weighted MR images from patients with newly diagnosed glioblastoma (GBM) treated with standard of care in conjunction with anti-angiogenic agents is complicated by pseudoprogression and pseudoresponse. The hypothesis being tested in this study was that 3D H-1 magnetic resonance spectroscopic imaging (MRSI) provides estimates of levels of choline, creatine, N-acetylaspartate (NAA), lactate and lipid that change in response to treatment and that metrics describing these characteristics are associated with survival. Thirty-one patients with newly diagnosed GBM and being treated with radiation therapy (RT), temozolomide, erlotinib and bevacizumab were recruited to receive serial MR scans that included 3-D lactate edited MRSI at baseline, mid-RT, post-RT and at specific follow-up time points. The data were processed to provide estimates of metrics representing changes in metabolite levels relative to normal appearing brain. Cox proportional hazards analysis was applied to examine the relationship of these parameters with progression free survival (PFS) and overall survival (OS). There were significant reductions in parameters that describe relative levels of choline to NAA and creatine, indicating that the treatment caused a decrease in tumor cellularity. Changes in the levels of lactate and lipid relative to the NAA from contralateral brain were consistent with vascular normalization. Metabolic parameters from the first serial follow-up scan were associated with PFS and OS, when accounting for age and extent of resection. Integrating metabolic parameters into the assessment of patients with newly diagnosed GBM receiving therapies that include anti-angiogenic agents may be helpful for tracking changes in tumor burden, resolving ambiguities in anatomic images caused by non-specific treatment effects and for predicting outcome.