Metabolic Profiling of IDH Mutation and Malignant Progression in Infiltrating Glioma.

Infiltrating low grade gliomas (LGGs) are heterogeneous in their behavior and the strategies used for clinical management are highly variable. A key factor in clinical decision-making is that patients with mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) oncogenes are more likely to have a favorable outcome and be sensitive to treatment. Because of their relatively long overall median survival, more aggressive treatments are typically reserved for patients that have undergone malignant progression (MP) to an anaplastic glioma or secondary glioblastoma (GBM). In the current study, ex vivo metabolic profiles of image-guided tissue samples obtained from patients with newly diagnosed and recurrent LGG were investigated using proton high-resolution magic angle spinning spectroscopy (1H HR-MAS). Distinct spectral profiles were observed for lesions with IDH-mutated genotypes, between astrocytoma and oligodendroglioma histologies, as well as for tumors that had undergone MP. Levels of 2-hydroxyglutarate (2HG) were correlated with increased mitotic activity, axonal disruption, vascular neoplasia, and with several brain metabolites including the choline species, glutamate, glutathione, and GABA. The information obtained in this study may be used to develop strategies for in vivo characterization of infiltrative glioma, in order to improve disease stratification and to assist in monitoring response to therapy

Application of MR Spectroscopic Techniques for the Development and Translation of Metabolite Markers Characterizing Infiltrating Glioma

Despite ever more advanced characterization, the family of malignant central nervous system diseases known as infiltrating glioma remain pernicious and resistant to treatment. Because of their molecular and pathologic heterogeneity, they are among the most complex cancers in adults, with tremendous variability in patient outcomes being observed across oncologic subtypes. Over the course of therapy, magnetic resonance imaging (MRI) is critical to evaluating the level of response as the diagnostic standard for clinical management. Conventional MRI, having superior soft tissue contrast, provides a non-invasive means of detecting abnormalities that are embedded within neural anatomy. However, gauging the full extent of tumor is difficult owing to non-specific changes, which may either reflect benign processes in the aftermath of treatment or tumor infiltration. Given the ambiguity associated with anatomical imaging, magnetic resonance spectroscopy (MRS) has emerged as a technique that can add diagnostic value to clinical practice by probing signature chemical species characterizing disease. The primary focus of this work was the development of translatable biomarkers for infiltrating glioma using analogous ex vivo methodology that has greater sensitivity and spectral resolution. By analyzing image-guided tissue samples acquired from a large cohort of patients with pathologically distinct subtypes, it was possible to characterize metabolite expression across diverse swathes of tumor representing natural heterogeneity. Quantified data revealed distinct metabolomic profiles for each of the clinically relevant subtypes that enabled their differential classification. Importantly, classification models were able to predict malignant progression on the basis of these profiles, highlighting the potential to determine pathologic trajectory. Separate analysis of contrast-based radiographic subtypes of the most aggressive form of glioma demonstrated unique metabolite expression in the portion of tumor that fails to exhibit contrast and is therefore masked on standard imaging.Since some of the metabolite markers discovered exhibited features that diminished the lifetime of their signal, technical development of an in vivo MRS sequence was also undertaken. The creation of radiofrequency (RF) pulses with reduced peak power requirements was critical to the design of the sequence and enabled improved signal fidelity over longer acquisition times when incorporated into existing frameworks. Results from this project and those obtained ex vivo support greater clinical integration of spectroscopy

Multiband RF pulses with improved performance via convex optimization.

Selective RF pulses are commonly designed with the desired profile as a low pass filter frequency response. However, for many MRI and NMR applications, the spectrum is sparse with signals existing at a few discrete resonant frequencies. By specifying a multiband profile and releasing the constraint on "don't-care" regions, the RF pulse performance can be improved to enable a shorter duration, sharper transition, or lower peak B1 amplitude. In this project, a framework for designing multiband RF pulses with improved performance was developed based on the Shinnar-Le Roux (SLR) algorithm and convex optimization. It can create several types of RF pulses with multiband magnitude profiles, arbitrary phase profiles and generalized flip angles. The advantage of this framework with a convex optimization approach is the flexible trade-off of different pulse characteristics. Designs for specialized selective RF pulses for balanced SSFP hyperpolarized (HP) (13)C MRI, a dualband saturation RF pulse for (1)H MR spectroscopy, and a pre-saturation pulse for HP (13)C study were developed and tested

Metabolic Profiling of IDH Mutation and Malignant Progression in Infiltrating Glioma.

Infiltrating low grade gliomas (LGGs) are heterogeneous in their behavior and the strategies used for clinical management are highly variable. A key factor in clinical decision-making is that patients with mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) oncogenes are more likely to have a favorable outcome and be sensitive to treatment. Because of their relatively long overall median survival, more aggressive treatments are typically reserved for patients that have undergone malignant progression (MP) to an anaplastic glioma or secondary glioblastoma (GBM). In the current study, ex vivo metabolic profiles of image-guided tissue samples obtained from patients with newly diagnosed and recurrent LGG were investigated using proton high-resolution magic angle spinning spectroscopy (1H HR-MAS). Distinct spectral profiles were observed for lesions with IDH-mutated genotypes, between astrocytoma and oligodendroglioma histologies, as well as for tumors that had undergone MP. Levels of 2-hydroxyglutarate (2HG) were correlated with increased mitotic activity, axonal disruption, vascular neoplasia, and with several brain metabolites including the choline species, glutamate, glutathione, and GABA. The information obtained in this study may be used to develop strategies for in vivo characterization of infiltrative glioma, in order to improve disease stratification and to assist in monitoring response to therapy