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Background: Differentiating treatment-induced injury from recurrent high-grade glioma is an ongoing challenge in neuro-oncology, in part due to lesion heterogeneity. This study aimed to determine whether different MR features were relevant for distinguishing recurrent tumor from the effects of treatment in contrast-enhancing lesions (CEL) and non-enhancing lesions (NEL)., Methods: This prospective study analyzed 291 tissue samples (222 recurrent tumor, 69 treatment-effect) with known coordinates on imaging from 139 patients who underwent preoperative 3T MRI and surgery for a suspected recurrence. 8 MR parameter values were tested from perfusion-weighted, diffusion-weighted, and MR spectroscopic imaging at each tissue sample location for association with histopathological outcome using generalized estimating equation models for CEL and NEL tissue samples. Individual cutoff values were evaluated using receiver operating characteristic curve analysis with 5-fold cross-validation., Results: In tissue samples obtained from CEL, elevated relative cerebral blood volume (rCBV) was associated with the presence of recurrent tumor pathology (P < 0.03), while increases in normalized choline (nCho) and choline-to-NAA index (CNI) were associated with the presence of recurrent tumor pathology in NEL tissue samples (P < 0.008). A mean CNI cutoff value of 2.7 had the highest performance, resulting in mean sensitivity and specificity of 0.61 and 0.81 for distinguishing treatment-effect from recurrent tumor within the NEL., Conclusion: Although our results support prior work that underscores the utility of rCBV in distinguishing the effects of treatment from recurrent tumor within the contrast enhancing lesion, we found that metabolic parameters may be better at differentiating recurrent tumor from treatment-related changes in the NEL of high-grade gliomas., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Glioma is recognized to be a highly heterogeneous CNS malignancy, whose diverse cellular composition and cellular interactions have not been well characterized. To gain new clinical- and biological-insights into the genetically-bifurcated IDH1 mutant (mt) vs wildtype (wt) forms of glioma, we integrated data from protein, genomic and MR imaging from 20 treatment-naïve glioma cases and 16 recurrent GBM cases. Multiplexed immunofluorescence (MxIF) was used to generate single cell data for 43 protein markers representing all cancer hallmarks, Genomic sequencing (exome and RNA (normal and tumor) and magnetic resonance imaging (MRI) quantitative features (protocols were T1-post, FLAIR and ADC) from whole tumor, peritumoral edema and enhancing core vs equivalent normal region were also collected from patients. Based on MxIF analysis, 85,767 cells (glioma cases) and 56,304 cells (GBM cases) were used to generate cell-level data for 24 biomarkers. K-means clustering was used to generate 7 distinct groups of cells with divergent biomarker profiles and deconvolution was used to assign RNA data into three classes. Spatial and molecular heterogeneity metrics were generated for the cell data. All features were compared between IDH mt and IDHwt patients and were finally combined to provide a holistic/integrated comparison. Protein expression by hallmark was generally lower in the IDHmt vs wt patients. Molecular and spatial heterogeneity scores for angiogenesis and cell invasion also differed between IDHmt and wt gliomas irrespective of prior treatment and tumor grade; these differences also persisted in the MR imaging features of peritumoral edema and contrast enhancement volumes. A coherent picture of enhanced angiogenesis in IDHwt tumors was derived from multiple platforms (genomic, proteomic and imaging) and scales from individual proteins to cell clusters and heterogeneity, as well as bulk tumor RNA and imaging features. Longer overall survival for IDH1mt glioma patients may reflect mutation-driven alterations in cellular, molecular, and spatial heterogeneity which manifest in discernable radiological manifestations., Competing Interests: The authors have declared that no competing interests exist.

Noninvasive tools that target tumor cells could improve the management of glioma. Cancer generally has a high demand for Fe(III), an essential nutrient for a variety of biochemical processes. We tested whether 68Ga-citrate, an Fe(III) biomimetic that binds to apo-transferrin in blood, detects glioma in preclinical models and patients using hybrid PET/MRI. Mouse PET/CT studies showed that 68Ga-citrate accumulates in subcutaneous U87MG xenografts in a transferrin receptor-dependent fashion within 4 hours after injection. Seventeen patients with WHO grade III or IV glioma received 3.7-10.2 mCi 68Ga-citrate and were imaged with PET/MR 123-307 minutes after injection to establish that the radiotracer can localize to human tumors. Multiple contrast-enhancing lesions were PET avid, and tumor to adjacent normal white matter ratios were consistently greater than 10:1. Several contrast-enhancing lesions were not PET avid. One minimally enhancing lesion and another tumor with significantly reduced enhancement following bevacizumab therapy were PET avid. Advanced MR imaging analysis of one patient with contrast-enhancing glioblastoma showed that metabolic hallmarks of viable tumor spatially overlaid with 68Ga-citrate accumulation. These early data underscore that high-grade glioma may be detectable with a radiotracer that targets Fe(III) transport.

Background: Rare multicentric lower-grade gliomas (LGGs) represent a unique opportunity to study the heterogeneity among distinct tumor foci in a single patient and to infer their origins and parallel patterns of evolution., Methods: In this study, we integrate clinical features, histology, and immunohistochemistry for 4 patients with multicentric LGG, arising both synchronously and metachronously. For 3 patients we analyze the phylogeny of the lesions using exome sequencing, including one case with a total of 8 samples from the 2 lesions., Results: One patient was diagnosed with multicentric isocitrate dehydrogenase 1 (IDH1) mutated diffuse astrocytomas harboring distinct IDH1 mutations, R132H and R132C; the latter mutation has been associated with Li-Fraumeni syndrome, which was subsequently confirmed in the patient's germline DNA and shown in additional cases with The Cancer Genome Atlas data. In another patient, phylogenetic analysis of synchronously arising grade II and grade III diffuse astrocytomas demonstrated a single shared mutation, IDH1 R132H, and revealed convergent evolution via non-overlapping mutations in ATRX and TP53. In 2 cases, there was divergent evolution of IDH1-mutated and 1p/19q-codeleted oligodendroglioma and IDH1-mutated and 1p/19q-intact diffuse astrocytoma, occurring synchronously in one case and metachronously in a second., Conclusions: Each tumor in multicentric LGG cases may arise independently or may diverge very early in their development, presenting as genetically and histologically distinct tumors. Comprehensive sampling of these lesions can therefore significantly alter diagnosis and management. Additionally, somatic IDH1 R132C mutation in either multicentric or solitary LGG identifies unsuspected germline TP53 mutation, validating the limited number of published cases.

Three-dimensional proton magnetic resonance spectroscopic imaging (MRSI) is a powerful non-invasive tool for characterizing spatial variations in metabolic profiles for patients with glioma. Metabolic parameters obtained using this technique have been shown to predict treatment response, disease progression, and transformation to a more malignant phenotype. The availability of ultra-high-field MR systems has the potential to improve the characterization of metabolites. The purpose of this study was to compare the metabolite profiles acquired with conventional long echo time (TE) MRSI at 3T with those obtained with short TE MRSI at 3T and 7T in patients with glioma. The data acquisition parameters were optimized separately for each echo time and field strength to obtain volumetric coverage within clinically feasible data acquisition times of 5-10 min. While a higher field strength did provide better detection of metabolites with overlapping peaks, spatial coverage was reduced and the use of inversion recovery to reduce lipid precluded the detection of lipid in regions of necrosis. For serial evaluation of large, heterogeneous lesions, the use of 3T short TE MRSI may thus be preferred. Despite the limited number of metabolites that it is able to detect, the use of 3T long TE MRSI gives the best contrast in choline/N-acetyl aspartate between normal appearing brain and tumor and also allows the separate detection of lactate and lipid. It may therefore be preferred for serial evaluation of patients with high-grade glioma and for detection of malignant transformation in patients with low-grade glioma.

Background: Activation of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is common in patients with low-grade gliomas (LGGs), but agents that inhibit this pathway, including mTOR inhibitors, have not been studied in this population., Methods: Fifty-eight patients with pathologic evidence of recurrence after they had initially been diagnosed with World Health Organization (WHO) grade II gliomas were enrolled into a prospective phase 2 clinical trial and received daily everolimus (RAD001) for 1 year or until progression. Tissue at the time of enrollment was analyzed for markers of PI3K/mTOR pathway activation. Thirty-eight patients underwent serial multiparametric magnetic resonance imaging, with the tumor volume and the perfusion metrics (the fractional blood volume [fBV] for capillary density and the transfer coefficient [K ps ] for vascular permeability) measured during treatment. The primary endpoint was progression-free survival at 6 months (PFS-6) in patients with WHO II disease at enrollment., Results: For patients with WHO II gliomas at enrollment, the PFS-6 rate was 84%, and this met the primary endpoint (P < .001 for an improvement from the historical rate of 17%). Evidence of PI3K/mTOR activation by immunohistochemistry for phosphorylated ribosomal S6 Ser240/244 (p-S6 Ser240/244 ) was associated with worse progression-free survival (PFS; hazard ratio [HR], 3.03; P = .004) and overall survival (HR, 12.7; P = .01). Tumor perfusion decreased after 6 months (median decrease in fBV, 15%; P = .03; median decrease in K ps , 12%; P = .09), with greater decreases associated with improved PFS (HR for each 10% fBV decrease, 0.71; P = .01; HR for each 10% K ps decrease, 0.82; P = .04)., Conclusions: Patients with recurrent LGGs demonstrated a high degree of disease stability during treatment with everolimus. PI3K/mTOR activation, as measured by immunohistochemistry for p-S6, was associated with a worse prognosis. Tumor vascular changes were observed that were consistent with the antiangiogenic effects of mTOR inhibitors. These results support further study of everolimus for LGGs. Cancer 2017;123:4631-4639. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

IDH1 mutation is the earliest genetic alteration in low-grade gliomas (LGGs), but its role in tumor recurrence is unclear. Mutant IDH1 drives overproduction of the oncometabolite d-2-hydroxyglutarate (2HG) and a CpG island (CGI) hypermethylation phenotype (G-CIMP). To investigate the role of mutant IDH1 at recurrence, we performed a longitudinal analysis of 50 IDH1 mutant LGGs. We discovered six cases with copy number alterations (CNAs) at the IDH1 locus at recurrence. Deletion or amplification of IDH1 was followed by clonal expansion and recurrence at a higher grade. Successful cultures derived from IDH1 mutant, but not IDH1 wild type, gliomas systematically deleted IDH1 in vitro and in vivo, further suggestive of selection against the heterozygous mutant state as tumors progress. Tumors and cultures with IDH1 CNA had decreased 2HG, maintenance of G-CIMP, and DNA methylation reprogramming outside CGI. Thus, while IDH1 mutation initiates gliomagenesis, in some patients mutant IDH1 and 2HG are not required for later clonal expansions., Competing Interests: The authors declare no conflict of interest.

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 ( 1 H 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.

Low-grade gliomas can vary widely in disease course and therefore patient outcome. While current characterization relies on both histological and molecular analysis of tissue resected during surgery, there remains high variability within glioma subtypes in terms of response to treatment and outcome. In this study we hypothesized that parameters obtained from magnetic resonance data would be associated with progression-free survival for patients with recurrent low-grade glioma. The values considered were derived from the analysis of anatomic imaging, diffusion weighted imaging, and 1 H magnetic resonance spectroscopic imaging data. Metrics obtained from diffusion and spectroscopic imaging presented strong prognostic capability within the entire population as well as when restricted to astrocytomas, but demonstrated more limited efficacy in the oligodendrogliomas. The results indicate that multi-parametric imaging data may be applied as a non-invasive means of assessing prognosis and may contribute to developing personalized treatment plans for patients with recurrent low-grade glioma.

Background: Patients with low-grade glioma (LGG) have a relatively long survival, and a balance is often struck between treating the tumor and impacting quality of life. While lesions may remain stable for many years, they may also undergo malignant transformation (MT) at the time of recurrence and require more aggressive intervention. Here we report on a state-of-the-art multiparametric MRI study of patients with recurrent LGG., Methods: One hundred and eleven patients previously diagnosed with LGG were scanned at either 1.5 T or 3 T MR at the time of recurrence. Volumetric and intensity parameters were estimated from anatomic, diffusion, perfusion, and metabolic MR data. Direct comparisons of histopathological markers from image-guided tissue samples with metrics derived from the corresponding locations on the in vivo images were made. A bioinformatics approach was applied to visualize and interpret these results, which included imaging heatmaps and network analysis. Multivariate linear-regression modeling was utilized for predicting transformation., Results: Many advanced imaging parameters were found to be significantly different for patients with tumors that had undergone MT versus those that had not. Imaging metrics calculated at the tissue sample locations highlighted the distinct biological significance of the imaging and the heterogeneity present in recurrent LGG, while multivariate modeling yielded a 76.04% accuracy in predicting MT., Conclusions: The acquisition and quantitative analysis of such multiparametric MR data may ultimately allow for improved clinical assessment and treatment stratification for patients with recurrent LGG., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: Radiotherapy (RT) is an integral component in managing patients with glioma, but the damage it may cause to healthy brain tissue and quality of life is of concern. Susceptibility-weighted imaging (SWI) is highly sensitive to the detection of microbleeds that occur years after RT. This study's goals were to characterize the evolution of radiation-induced microbleeds in normal-appearing brain and determine whether the administration of an anti-angiogenic agent altered this process., Methods: Serial high-resolution SWI was acquired on 17 patients with high-grade glioma between 8 months and 4.5 years posttreatment with RT and adjuvant chemotherapy. Nine of these patients were also treated with the anti-angiogenic agent enzastaurin. Microbleeds were identified as discrete foci of susceptibility not corresponding to vessels, tumor, or postoperative infarct, and counted in normal-appearing brain. Analysis of covariance was performed to compare slopes of regression of individual patients' microbleed counts over time, Wilcoxon rank-sum tests examined significant differences in rates of microbleed formation between groups, and linear and quadratic mixed-effects models were employed., Results: The number of microbleeds increased with time for all patients, with initial onset occurring at 8-22 months. No microbleeds disappeared once formed. The average rate of microbleed formation significantly increased after 2 years post-RT (P < .001). Patients receiving anti-angiogenic therapy exhibited fewer microbleeds overall (P < .05) and a significant reduction in initial rate of microbleed appearance (P = .01)., Conclusions: We have demonstrated a dramatic increase in microbleed formation after 2 years post-RT that was decelerated by the concomitant administration of anti-angiogenic therapy, which may aid in determining brain regions susceptible to RT., (© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Recent technological progress in the multiband echo planer imaging (MB EPI) technique enables accelerated MR diffusion weighted imaging (DWI) and allows whole brain, multi-b-value diffusion imaging to be acquired within a clinically feasible time. However, its applications at 7 T have been limited due to B1 field inhomogeneity and increased susceptibility artifact. It is an ongoing debate whether DWI at 7 T can be performed properly in patients, and a systematic SNR comparison for multiband spin-echo EPI between 3 T and 7 T has not been methodically studied. The goal of this study was to use MB EPI at 7 T in order to obtain 90-directional multi-shell DWI within a clinically feasible acquisition time for patients with glioma. This study included an SNR comparison between 3 T and 7 T, and the application of B1 mapping and distortion correction procedures for reducing the impact of variations in B0 and B1. The optimized multiband sequence was applied in 20 patients with glioma to generate both DTI and NODDI maps for comparison of values in tumor and normal appearing white matter (NAWM). Our SNR analysis showed that MB EPI at 7 T was comparable to that at 3 T, and the data quality acquired in patients was clinically acceptable. NODDI maps provided unique contrast within the T2 lesion that was not seen in anatomical images or DTI maps. Such contrast may reflect the complexity of tissue compositions associated with disease progression and treatment effects. The ability to consistently obtain high quality diffusion data at 7 T will contribute towards the implementation of a comprehensive brain MRI examination at ultra-high field.

Background: The purpose of this study was to evaluate the feasibility of using a short echo time, three-dimensional H-1 magnetic resonance spectroscopic imaging (MRSI) sequence at 7 Tesla (T) to assess the metabolic signature of lesions for patients with glioma., Methods: Twenty-nine patients with glioma were studied. MRSI data were obtained using CHESS water suppression, spectrally selective adiabatic inversion-recovery pulses and automatically prescribed outer-volume-suppression for lipid suppression, and spin echo slice selection (echo time = 30 ms). An interleaved flyback echo-planar trajectory was applied to shorten the total acquisition time (∼10 min). Relative metabolite ratios were estimated in tumor and in normal-appearing white and gray matter (NAWM, GM)., Results: Levels of glutamine, myo-inositol, glycine, and glutathione relative to total creatine (tCr) were significantly increased in the T2 lesions for all tumor grades compared with those in the NAWM (P < 0.05), while N-acetyl aspartate to tCr were significantly decreased (P < 0.05). In grade 2 gliomas, level of total choline-containing-compounds to tCr was significantly increased (P = 0.0137), while glutamate to tCr was significantly reduced (P = 0.0012)., Conclusion: The improved sensitivity of MRSI and the increased number of metabolites that can be evaluated using 7T MR scanners is of interest for evaluating patients with glioma. This study has successfully demonstrated the application of a short-echo spin-echo MRSI sequence to detect characteristic differences in regions of tumor versus normal appearing brain., (© 2014 Wiley Periodicals, Inc.)

This review explores how the integration of advanced imaging methods with high-quality anatomical images significantly improves the characterization, target definition, assessment of response to therapy, and overall management of patients with high-grade glioma. Metrics derived from diffusion-, perfusion-, and susceptibility-weighted magnetic resonance imaging in conjunction with magnetic resonance spectroscopic imaging, allows us to characterize regions of edema, hypoxia, increased cellularity, and necrosis within heterogeneous tumor and surrounding brain tissue. Quantification of such measures may provide a more reliable initial representation of tumor delineation and response to therapy than changes in the contrast-enhancing or T2 lesion alone and have a significant effect on targeting resection, planning radiation, and assessing treatment effectiveness. In the long term, implementation of these imaging methodologies can also aid in the identification of recurrent tumor and its differentiation from treatment-related confounds and facilitate the detection of radiationinduced vascular injury in otherwise normal-appearing brain tissue.

Mutations of the isocitrate dehydrogenase 1 (IDH1) gene are among the most prevalent in low-grade glioma and secondary glioblastoma, represent an early pathogenic event, and are associated with epigenetically driven modulations of metabolism. Of particular interest is the recently uncovered relationship between the IDH1 mutation and decreased activity of the branched-chain amino acid transaminase 1 (BCAT1) enzyme. Noninvasive imaging methods that can assess BCAT1 activity could therefore improve detection of mutant IDH1 tumors and aid in developing and monitoring new targeted therapies. BCAT1 catalyzes the transamination of branched-chain amino acids while converting α-ketoglutarate (α-KG) to glutamate. Our goal was to use (13)C magnetic resonance spectroscopy to probe the conversion of hyperpolarized [1-(13)C] α-KG to hyperpolarized [1-(13)C] glutamate as a readout of BCAT1 activity. We investigated two isogenic glioblastoma lines that differed only in their IDH1 status and performed experiments in live cells and in vivo in rat orthotopic tumors. Following injection of hyperpolarized [1-(13)C] α-KG, hyperpolarized [1-(13)C] glutamate production was detected both in cells and in vivo, and the level of hyperpolarized [1-(13)C] glutamate was significantly lower in mutant IDH1 cells and tumors compared with their IDH1-wild-type counterparts. Importantly however, in our cells the observed drop in hyperpolarized [1-(13)C] glutamate was likely mediated not only by a drop in BCAT1 activity, but also by reductions in aspartate transaminase and glutamate dehydrogenase activities, suggesting additional metabolic reprogramming at least in our model. Hyperpolarized [1-(13)C] glutamate could thus inform on multiple mutant IDH1-associated metabolic events that mediate reduced glutamate production., (©2014 American Association for Cancer Research.)

Gliomas are routinely graded according to histopathological criteria established by the World Health Organization. Although this classification can be used to understand some of the variance in the clinical outcome of patients, there is still substantial heterogeneity within and between lesions of the same grade. This study evaluated image-guided tissue samples acquired from a large cohort of patients presenting with either new or recurrent gliomas of grades II-IV using ex vivo proton high-resolution magic angle spinning spectroscopy. The quantification of metabolite levels revealed several discrete profiles associated with primary glioma subtypes, as well as secondary subtypes that had undergone transformation to a higher grade at the time of recurrence. Statistical modeling further demonstrated that these metabolomic profiles could be differentially classified with respect to pathological grading and inter-grade conversions. Importantly, the myo-inositol to total choline index allowed for a separation of recurrent low-grade gliomas on different pathological trajectories, the heightened ratio of phosphocholine to glycerophosphocholine uniformly characterized several forms of glioblastoma multiforme, and the onco-metabolite D-2-hydroxyglutarate was shown to help distinguish secondary from primary grade IV glioma, as well as grade II and III from grade IV glioma. These data provide evidence that metabolite levels are of interest in the assessment of both intra-grade and intra-lesional malignancy. Such information could be used to enhance the diagnostic specificity of in vivo spectroscopy and to aid in the selection of the most appropriate therapy for individual patients., (© 2014 The Authors. NMR in Biomedicine published by John Wiley & Sons, Ltd.)

Introduction: Cerebral microbleeds have been observed in normal-appearing brain tissue of patients with glioma years after receiving radiation therapy. The contrast of these paramagnetic lesions varies with field strength due to differences in the effects of susceptibility. The purpose of this study was to compare 3T and 7T MRI as platforms for detecting cerebral microbleeds in patients treated with radiotherapy using susceptibility-weighted imaging (SWI)., Methods: SWI was performed with both 3T and 7T MR scanners on ten patients with glioma who had received prior radiotherapy. Imaging sequences were optimized to obtain data within a clinically acceptable scan time. Both T2*-weighted magnitude images and SWI data were reconstructed, minimum intensity projection was implemented, and microbleeds were manually identified. The number of microbleeds was counted and compared among datasets., Results: Significantly more microbleeds were identified on SWI than magnitude images at both 7T (p = 0.002) and 3T (p = 0.023). Seven-tesla SWI detected significantly more microbleeds than 3T SWI for seven out of ten patients who had tumors located remote from deep brain regions (p = 0.016), but when the additional three patients with more inferior tumors were included, the difference was not significant., Conclusion: SWI is more sensitive for detecting microbleeds than magnitude images at both 3T and 7T. For areas without heightened susceptibility artifacts, 7T SWI is more sensitive to detecting radiation therapy-induced microbleeds than 3T SWI. Tumor location should be considered in conjunction with field strength when selecting the most appropriate strategy for imaging microbleeds.

Tumor recurrence is a leading cause of cancer mortality. Therapies for recurrent disease may fail, at least in part, because the genomic alterations driving the growth of recurrences are distinct from those in the initial tumor. To explore this hypothesis, we sequenced the exomes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients. In 43% of cases, at least half of the mutations in the initial tumor were undetected at recurrence, including driver mutations in TP53, ATRX, SMARCA4, and BRAF; this suggests that recurrent tumors are often seeded by cells derived from the initial tumor at a very early stage of their evolution. Notably, tumors from 6 of 10 patients treated with the chemotherapeutic drug temozolomide (TMZ) followed an alternative evolutionary path to high-grade glioma. At recurrence, these tumors were hypermutated and harbored driver mutations in the RB (retinoblastoma) and Akt-mTOR (mammalian target of rapamycin) pathways that bore the signature of TMZ-induced mutagenesis.

Diffuse gliomas consist of both low- and high-grade varieties, each with distinct morphological and biological features. The often extended periods of relative indolence exhibited by low-grade gliomas (LGG; WHO grade II) differ sharply from the aggressive, rapidly fatal clinical course of primary glioblastoma (GBM; WHO grade IV). Nevertheless, until recently, the molecular foundations underlying this stark biological contrast between glioma variants remained largely unknown. The discoveries of distinctive and highly recurrent genomic and epigenomic abnormalities in LGG have both informed a more accurate classification scheme and pointed to viable avenues for therapeutic development. As such, the field of neuro-oncology now seems poised to capitalize on these gains to achieve significant benefit for LGG patients. This report will briefly recount the proceedings of a workshop held in January 2013 and hosted by Accelerate Brain Cancer Cure (ABC(2)) on the subject of LGG. While much of the meeting covered recent insights into LGG biology, its focus remained on how best to advance the clinical management, whether by improved preclinical modeling, more effective targeted therapeutics and clinical trial design, or innovative imaging technology.

Two major difficulties encountered in implementing Magnetic Resonance Spectroscopic Imaging (MRSI) in a clinical setting are limited coverage and difficulty in prescription. The goal of this project was to automate completely the process of 3D PRESS MRSI prescription, including placement of the selection box, saturation bands and shim volume, while maximizing the coverage of the brain. The automated prescription technique included acquisition of an anatomical MRI image, optimization of the oblique selection box parameters, optimization of the placement of outer-volume suppression saturation bands, and loading of the calculated parameters into a customized 3D MRSI pulse sequence. To validate the technique and compare its performance with existing protocols, 3D MRSI data were acquired from six exams from three healthy volunteers. To assess the performance of the automated 3D MRSI prescription for patients with brain tumors, the data were collected from 16 exams from 8 subjects with gliomas. This technique demonstrated robust coverage of the tumor, high consistency of prescription and very good data quality within the T2 lesion., (Copyright © 2012 Wiley Periodicals, Inc.)

Gain-of-function mutations of the isocitrate dehydrogenase 1 (IDH1) gene are among the most prevalent in low-grade gliomas and secondary glioblastoma. They lead to intracellular accumulation of the oncometabolite 2-hydroxyglutarate, represent an early pathogenic event and are considered a therapeutic target. Here we show, in this proof-of-concept study, that [1-(13)C] α-ketoglutarate can serve as a metabolic imaging agent for non-invasive, real-time, in vivo monitoring of mutant IDH1 activity, and can inform on IDH1 status. Using (13)C magnetic resonance spectroscopy in combination with dissolution dynamic nuclear polarization, the metabolic fate of hyperpolarized [1-(13)C] α-ketoglutarate is studied in isogenic glioblastoma cells that differ only in their IDH1 status. In lysates and tumours that express wild-type IDH1, only hyperpolarized [1-(13)C] α-ketoglutarate can be detected. In contrast, in cells that express mutant IDH1, hyperpolarized [1-(13)C] 2-hydroxyglutarate is also observed, both in cell lysates and in vivo in orthotopic tumours.

Objective: The objective of this study was to determine whether metabolic parameters derived from ex vivo analysis of tissue samples are predictive of biologic characteristics of recurrent low grade gliomas (LGGs). This was achieved by exploring the use of multivariate pattern recognition methods to generate statistical models of the metabolic characteristics of recurrent LGGs that correlate with aggressive biology and poor clinical outcome., Methods: Statistical models were constructed to distinguish between patients with recurrent gliomas that had undergone malignant transformation to a higher grade and those that remained grade 2. The pattern recognition methods explored in this paper include three filter-based feature selection methods (chi-square, gain ratio, and two-way conditional probability), a genetic search wrapper-based feature subset selection algorithm, and five classification algorithms (linear discriminant analysis, logistic regression, functional trees, support vector machines, and decision stump logit boost). The accuracy of each pattern recognition framework was evaluated using leave-one-out cross-validation and bootstrapping., Materials: The population studied included fifty-three patients with recurrent grade 2 gliomas. Among these patients, seven had tumors that transformed to grade 4, twenty-four had tumors that transformed to grade 3, and twenty-two had tumors that remained grade 2. Image-guided tissue samples were obtained from these patients using surgical navigation software. Part of each tissue sample was examined by a pathologist for histological features and for consistency with the tumor grade diagnosis. The other part of the tissue sample was analyzed with ex vivo nuclear magnetic resonance (NMR) spectroscopy., Results: Distinguishing between recurrent low grade gliomas that transformed to a higher grade and those that remained grade 2 was achieved with 96% accuracy, using areas of the ex vivo NMR spectrum corresponding to myoinositol, 2-hydroxyglutarate, hypo-taurine, choline, glycerophosphocholine, phosphocholine, glutathione, and lipid. Logistic regression and decision stump boosting models were able to distinguish between recurrent gliomas that transformed to a higher grade and those that did not with 100% training accuracy (95% confidence interval [93-100%]), 96% leave-one-out cross-validation accuracy (95% confidence interval [87-100%]), and 96% bootstrapping accuracy (95% confidence interval [95-97%]). Linear discriminant analysis, functional trees, and support vector machines were able to achieve leave-one-out cross-validation accuracy above 90% and bootstrapping accuracy above 85%. The three feature ranking methods were comparable in performance., Conclusions: This study demonstrates the feasibility of using quantitative pattern recognition methods for the analysis of metabolic data from brain tissue obtained during the surgical resection of gliomas. All pattern recognition techniques provided good diagnostic accuracies, though logistic regression and decision stump boosting slightly outperform the other classifiers. These methods identified biomarkers that can be used to detect malignant transformations in individual low grade gliomas, and can lead to a timely change in treatment for each patient., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Purpose: To evaluate the intermediate- and long-term imaging manifestations of radiotherapy on normal-appearing brain tissue in patients with treated gliomas using 7T susceptibility-weighted imaging (SWI)., Methods and Materials: SWI was performed on 25 patients with stable gliomas on a 7 Tesla magnet. Microbleeds were identified as discrete foci of susceptibility that did not correspond to vessels. The number of microbleeds was counted within and outside of the T2-hyperintense lesion. For 3 patients, radiation dosimetry maps were reconstructed and fused with the 7T SWI data., Results: Multiple foci of susceptibility consistent with microhemorrhages were observed in patients 2 years after chemoradiation. These lesions were not present in patients who were not irradiated. The prevalence of microhemorrhages increased with the time since completion of radiotherapy, and these lesions often extended outside the boundaries of the initial high-dose volume and into the contralateral hemisphere., Conclusions: High-field SWI has potential for visualizing the appearance of microbleeds associated with long-term effects of radiotherapy on brain tissue. The ability to visualize these lesions in normal-appearing brain tissue may be important in further understanding the utility of this treatment in patients with longer survival., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Recent studies have indicated that a significant survival advantage is conferred to patients with gliomas whose lesions harbor mutations in the genes isocitrate dehydrogenase 1 and 2 (IDH1/2). IDH1/2 mutations result in aberrant enzymatic production of the potential oncometabolite D-2-hydroxyglutarate (2HG). Here, we report on the ex vivo detection of 2HG in IDH1-mutated tissue samples from patients with recurrent low-grade gliomas using the nuclear magnetic resonance technique of proton high-resolution magic angle spinning spectroscopy. Relative 2HG levels from pathologically confirmed mutant IDH1 tissues correlated with levels of other ex vivo metabolites and histopathology parameters associated with increases in mitotic activity, relative tumor content, and cellularity. Ex vivo spectroscopic measurements of choline-containing species and in vivo magnetic resonance measurements of diffusion parameters were also correlated with 2HG levels. These data provide extensive characterization of mutant IDH1 lesions while confirming the potential diagnostic value of 2HG as a surrogate marker of patient survival. Such information may augment the ability of clinicians to monitor therapeutic response and provide criteria for stratifying patients to specific treatment regimens.

The purpose of this study was to implement a new lactate-edited 3D 1H magnetic resonance spectroscopic imaging (MRSI) sequence at 3 T and demonstrate the feasibility of using this sequence for measuring lactate in patients with gliomas. A 3D PRESS MRSI sequence incorporating shortened, high bandwidth 180° pulses, new dual BASING lactate-editing pulses, high bandwidth very selective suppression (VSS) pulses and a flyback echo-planar readout was implemented at 3 T. Over-prescription factor of PRESS voxels was optimized using phantom to minimize chemical shift artifacts. The lactate-edited flyback sequence was compared with lactate-edited MRSI using conventional elliptical k-space sampling in a phantom and volunteers, and then applied to patients with gliomas. The results demonstrated the feasibility of detecting lactate within a short scan time of 9.5 min in both phantoms and patients. Over-prescription of voxels gave less chemical shift artifacts allowing detection of lactate on the majority of the selected volume. The normalized SNR of brain metabolites using the flyback encoding were comparable to the SNR of brain metabolites using conventional phase encoding MRSI. The specialized lactate-edited 3D MRSI sequence was able to detect lactate in brain tumor patients at 3 T. The implementation of this technique means that brain lactate can be evaluated in a routine clinical setting to study its potential as a marker for prognosis and response to therapy.

Purpose: The goal of this study was to implement time efficient data acquisition and reconstruction methods for 3D magnetic resonance spectroscopic imaging (MRSI) of gliomas at a field strength of 3T using parallel imaging techniques., Methods: The point spread functions, signal to noise ratio (SNR), spatial resolution, metabolite intensity distributions and Cho:NAA ratio of 3D ellipsoidal, 3D sensitivity encoding (SENSE) and 3D combined ellipsoidal and SENSE (e-SENSE) k-space sampling schemes were compared with conventional k-space data acquisition methods., Results: The 3D SENSE and e-SENSE methods resulted in similar spectral patterns as the conventional MRSI methods. The Cho:NAA ratios were highly correlated (P<.05 for SENSE and P<.001 for e-SENSE) with the ellipsoidal method and all methods exhibited significantly different spectral patterns in tumor regions compared to normal appearing white matter. The geometry factors ranged between 1.2 and 1.3 for both the SENSE and e-SENSE spectra. When corrected for these factors and for differences in data acquisition times, the empirical SNRs were similar to values expected based upon theoretical grounds. The effective spatial resolution of the SENSE spectra was estimated to be same as the corresponding fully sampled k-space data, while the spectra acquired with ellipsoidal and e-SENSE k-space samplings were estimated to have a 2.36-2.47-fold loss in spatial resolution due to the differences in their point spread functions., Conclusion: The 3D SENSE method retained the same spatial resolution as full k-space sampling but with a 4-fold reduction in scan time and an acquisition time of 9.28 min. The 3D e-SENSE method had a similar spatial resolution as the corresponding ellipsoidal sampling with a scan time of 4:36 min. Both parallel imaging methods provided clinically interpretable spectra with volumetric coverage and adequate SNR for evaluating Cho, Cr and NAA.

Purpose: To use normalized apparent diffusion coefficient (nADC) histograms from patients with grade II oligodendroglioma (OD) and astrocytoma (AC) to generate RGB color maps that emphasize the differences between normal-appearing white matter (NAWM), oligo-like, and astro-like regions., Materials and Methods: NAWM and nonenhancing lesion (NEL) ADC values from 19 ODs and 11 ACs were summed to generate oligo-like (red), NAWM (green), and astro-like (blue) nADC histograms. These nADC histograms were then used to map nADC values to an RGB matrix., Results: Color maps of oligodendroglial tumor regions were generally visualized in pink, while color maps of astrocytic tumor regions showed various shades of blue. This technique was also applied to 23 patients with the more mixed subtype, oligoastrocytoma (OA), which showed a mixture of both blue and pink, which in many cases appeared to bleed into each other and were blotchy., Conclusion: This technique allows for the visualization of biologically different regions within the whole tumor mass, which may aid in directing image-guided biopsies. This can be used to ensure that the biopsy is directed to regions that can more accurately define the dominant tumor characteristics., ((c) 2009 Wiley-Liss, Inc.)

Distinguishing between low-grade oligodendrogliomas (ODs) and astrocytomas (AC) is of interest for defining prognosis and stratifying patients to specific treatment regimens. The purpose of this study was to determine if the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) from diffusion imaging can help to differentiate between newly diagnosed grade II OD and AC subtypes and to evaluate the ADC and FA values for the mixed population of oligoastrocytomas (OA). Fifty-three patients with newly diagnosed grade II gliomas were studied using a 1.5T whole body scanner (23 ODs, 16 ACs, and 14 OAs). The imaging protocol included post-gadolinium T1-weighted images, T2-weighted images, and either three and/or six directional diffusion imaging sequence with b = 1000 s/mm(2). Diffusion-weighted images were analyzed using in-house software to calculate maps of ADC and for six directional acquisitions, FA. The intensity values were normalized by values from normal appearing white matter (NAWM) to generate maps of normalized apparent diffusion coefficient (nADC) and normalized fractional anisotropy (nFA). The hyperintense region in the T2 weighted image was defined as the T2All region. A Mann-Whitney rank-sum test was performed on the 25th, median, and 75th nADC and nFA among the three subtypes. Logistic regression was performed to determine how well the nADC and nFA predict subtype. Lesions diagnosed as being OD had significantly lower nADC and significantly higher nFA, compared to AC. The nADC and nFA values individually classified the data with an accuracy of 87%. Combining the two did not enhance the classification. The patients with OA had nADC and nFA values between those of OD and AC. This suggests that ADC and FA may be helpful in directing tissue sampling to the most appropriate regions for taking biopsies in order to make a definitive diagnosis.

Purpose: To measure T(1) and T(2) relaxation times of metabolites in glioma patients at 3T and to investigate how these values influence the observed metabolite levels., Materials and Methods: A total of 23 patients with gliomas and 10 volunteers were studied with single-voxel two-dimensional (2D) J-resolved point-resolved spectral selection (PRESS) using a 3T MR scanner. Voxels were chosen in normal appearing white matter (WM) and in regions of tumor. The T(1) and T(2) of choline containing compounds (Cho), creatine (Cr), and N-acetyl aspartate (NAA) were estimated., Results: Metabolite T(1) relaxation values in gliomas were not significantly different from values in normal WM. The T(2) of Cho and Cr were statistically significantly longer for grade 4 gliomas than for normal WM but the T(2) of NAA was similar. These differences were large enough to impact the corrections of metabolite levels for relaxation times with tumor grade in terms of metabolite ratios (P < 0.001)., Conclusion: The differential increase in T(2) for Cho and Cr relative to NAA means that the ratios of Cho/NAA and Cr/NAA are higher in tumor at longer echo times (TEs) relative to values in normal appearing brain. Having this information may be useful in defining the acquisition parameters for optimizing contrast between tumor and normal tissue in MR spectroscopic imaging (MRSI) data, in which limited time is available and only one TE can be used., ((c) 2008 Wiley-Liss, Inc.)

Purpose: To examine the relationship between apparent diffusion coefficients (ADC) from diffusion weighted imaging (DWI) and choline levels from proton magnetic resonance spectroscopic imaging (MRSI) in newly diagnosed Grade II and IV gliomas within distinct anatomic regions., Materials and Methods: A total of 37 patients with Grade II and 28 patients with Grade IV glioma were scanned on a 1.5T system with 3D MRSI and DWI. Region level analysis included Spearman rank correlation between median normalized ADC and choline for each patient per grade within each distinct abnormal anatomical region. Voxel level analysis calculated a Spearman rank correlation per region, per patient., Results: Grade II lesions showed no evidence of a correlation between normalized ADC and choline using either the region or voxel level analysis. Region level analysis of Grade IV lesions did not appear to correlate in the contrast enhancement or necrotic core, but did suggest a significant negative correlation in the more heterogeneous nonenhancing and combined regions., Conclusion: There appears to be differences in the relationship between ADC and choline levels in Grade II and Grade IV gliomas. Correlation within these regions in Grade IV lesions was strongest when all regions were included, suggesting heterogeneity may be driving the relationship., ((c) 2008 Wiley-Liss, Inc.)

Previous studies have shown that metabolic information provided by 3D Magnetic Resonance Spectroscopy Imaging (MRSI) could affect the definition of target volumes for radiation treatments (RT). This study aimed to (i) investigate the effect of incorporating spectroscopic volumes as determined by MRSI on target volume definition, patient selection eligibility, and dose prescription for stereotactic radiosurgery treatment planning; (ii) correlate the spatial extent of pre-SRS spectroscopic abnormality and treatment volumes with areas of focal recurrence as defined by changes in contrast enhancement; and (iii) examine the metabolic changes following SRS to assess treatment response. Twenty-six patients treated with Gamma Knife radiosurgery for recurrent glioblastoma multiforme (GBM) were retrospectively evaluated. All patients underwent both MRI and MRSI studies prior to SRS. Follow-up MRI exams were available for all 26 patients, with MRI/MRSI available in only 15/26 patients. We observed that the initial CNI 2 contours extended beyond the pre-SRS CE in 25/26 patients ranging in volume from 0.8 cc to 18.8 cc (median 5.6 cc). The inclusion of the volume of CNI 2 extending beyond the CE would have increased the SRS target volume by 5-165% (median 23.4%). This would have necessitated decreasing the SRS prescription dose in 19/26 patients to avoid increased toxicity; the resultant treatment volume would have exceeded 20cc in five patients, thus possibly excluding those from RS treatment per our institutional practice. MRSI follow-up studies showed a decrease in Choline, stable Creatine, and increased NAA indicative of response to SRS in the majority of patients. When combined with patient survival data, metabolic information obtained during follow-up MRSI studies seemed to indicate the potential to help to distinguish necrosis from new/recurrent tumor; however, this should be further verified by biopsy studies.

Background and Purpose: MR spectroscopic imaging (MRSI) and dynamic susceptibility-contrast MR imaging (DSC-MR imaging) are functional in vivo techniques for assessing tumor metabolism and vasculature characteristics. Because tumor hypoxia is influenced by tortuous, degraded, swollen, and angiogenic tumor vasculature, regions of abnormal perfusion parameters should coexist with changes in lactate and creatine metabolite levels., Materials and Methods: DSC-MR imaging and lactate-edited MRSI were performed on 38 treatment-naive patients with high-grade gliomas (17 grade III, 21 grade IV) before surgical diagnosis. Regions of abnormal perfusion were determined from peak height and percent recovery maps for each voxel within the spectroscopic imaging volume. Choline, creatine, and lactate levels within voxels experiencing only abnormal peak height (aPH), only abnormal recovery (aRec), and both abnormal peak height and recovery (aPH+aRec) were determined and compared to the surrounding T2 hyperintensity (T2h) and normal-appearing white matter., Results: There were decreasing trends in volume from aPH to aRec to aPH+aRec regions for both grade III and grade IV gliomas. Grade IV gliomas exhibited significantly elevated choline in all abnormal perfusion regions, with reduced creatine and increased lactate in the aRec region relative to the surrounding T2h. Grade III gliomas showed trends toward increased creatine within the aPH region and reduced levels within the aRec region., Conclusion: Depressed creatine and elevated lactate levels confirmed the lack of oxygenation within regions of compromised vascular integrity. Identification of regions with leaky or dense vasculature and metabolic markers of hypoxia and cellular proliferation could be useful in determining the more aggressive part of the tumor for targeting, monitoring, and assessing effects of treatment.

Object: The accurate diagnosis of World Health Organization Grades II and III gliomas is crucial for the effective treatment of patients with such lesions. Increased cell density and mitotic activity are histological features that distinguish Grade III from Grade II gliomas. Because increased cellular proliferation and density both contribute to the in vivo magnetic resonance (MR) spectroscopic peak corresponding to choline-containing compounds (Cho), the authors hypothesized that multivoxel MR spectroscopy might help identify the tumor regions with the most aggressive growth characteristics, which would be optimal locations for biopsy. They investigated the ability to use one or more MR spectroscopic parameters to predict the MIB-1 cell proliferation index (PI), the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling cell death index (DI), the cell density, and the ratio of proliferation to cell death (PI/DI) within different regions of the same tumor., Methods: Patients with presumed Grades II or III glioma underwent 3D MR spectroscopic imaging prior to surgery, and two or three regions within the tumor were targeted for biopsy retrieval based on their spectroscopic features. Biopsy specimens were extracted from the tumor during image-guided resection, and the PI, DI, and cell density were assessed in the specimens using immunohistochemical methods., Conclusions: The authors found that the relative levels of Cho and N-acetylaspartate (NAA) correlated with the cell density, PI, and PI/DI ratio within different regions of the same tumor and that the association held for the subpopulation of nonenhancing tumors. The association was stronger in tumors with large ranges of Cho/NAA values, irrespective of the presence of contrast enhancement. The findings demonstrate the validity of using MR spectroscopy to identify regions of aggressive growth in presumed Grade II or III gliomas that would be suitable targets for retrieving diagnostic biopsy specimens.

Purpose: To evaluate perfusion, diffusion, and spectroscopy values in enhancing and non-enhancing lesions for patients with newly diagnosed gliomas of different grades., Materials and Methods: Sixty-seven patients with newly diagnosed glioma were entered into the study 20 grade II, 26 grade III and 21 grade IV. MR data were acquired at 1.5T and included diffusion weighted images (59/67 patients), dynamic perfusion weighted images (30/67 patients) and 3D H-1 MR spectroscopy (64/67 patients). Enhancing and non-enhancing lesions were delineated by a neuroradiologist and applied to maps of relative cerebral blood volume (rCBV), apparent diffusion coefficient (ADC), relative anisotropy (RA) and metabolite intensities., Results: The median rCBV within enhancing regions of grade IV gliomas was significantly elevated relative to enhancing regions in grade III gliomas and normal brain. ADC was elevated relative to normal brain, but was not significantly different between grades or between enhancing and non-enhancing regions. The RA was higher in the non-enhancing region of grade IV gliomas relative to grade II and grade III. Levels of lactate plus lipid were significantly elevated in grade IV relative to grade II and grade III gliomas. Both enhancing and non-enhancing regions in grade IV gliomas showed significant correlations between CBV, ADC and choline levels., Conclusion: The data were consistent with grade IV gliomas having higher membrane turnover, increased cell density and increased vascularity within enhancing lesions. Analysis of the correlations among parameters within grade IV gliomas suggested that high vascularity (high rCBV) was correlated with increased cellularity (low ADC) and increased membrane turnover (high choline) in these lesions. The non-enhancing region of grades II and III gliomas had MR parameters consistent with increased cellularity and/or membrane turnover., (Copyright 2006 John Wiley & Sons, Ltd.)

3D magnetic resonance spectroscopic imaging (MRSI) has been successfully employed to extract information about brain tumor metabolism, such as cell membrane breakdown, cellular energetics, and neuronal integrity, through its ability to differentiate signals coming from choline (Cho), creatine (Cr), and N-acetyl aspartate (NAA) molecules. The additional presence of lipids within subregions of the tumor may indicate cellular membrane breakdown due to cell death. Another potential source of lipids is subcutaneous fat, which may be excited with point-resolved spectroscopy (PRESS) volume selection and aliased into the spectral field of view (FOV) due to the chemical shift artifact and the low bandwidth of the selection pulses. The purpose of our study was to employ a postprocessing method for unaliasing lipid resonances originating from in-slice subcutaneous lipids from the 3D MRSI of gliomas at 3T, using an eight-channel phased-array coil and sensitivity encoding (SENSE)., (Copyright (c) 2006 Wiley-Liss, Inc.)

Purpose: To model the partial voluming of gray matter (GM) and white matter (WM) in perfusion imaging, and to use this model to estimate the cerebral blood volume (CBV) of pure WM and GM, which could then be used to normalize data across patients in preparation for analyzing tumor perfusion., Materials and Methods: Dynamic susceptibility contrast (DSC) perfusion imaging was performed on 20 glioma patients. The perfusion data were registered to the T1 image using rigid-body and non-rigid algorithms. The rCBV for each voxel was computed by gamma-variate fitting and then fit as a linear function of the estimated fractional WM content. The estimated CBV of pure WM was used to normalize across patients, and the resulting tumor CBV values were compared with expectations., Results: Rigid registration improved the correlation between the fractional WM content and CBV for all patients, with non-rigid registration yielding further improvements for all but two patients. The mean GM-to-WM CBV ratio was estimated at 2.15 +/- 0.33 (mean +/- SD). Voxels that exhibited both T1-Gd contrast enhancement and an abnormal proton spectrum were found to have a CBV 2.53 +/- 0.89 times higher than that in the WM., Conclusion: A partial-volume model is demonstrated for estimating pure WM and GM CBV. It is also shown that the relationship between the tumor CBV as estimated with this model is generally consistent with expectations based on spectroscopy and imaging., ((c) 2006 Wiley-Liss, Inc.)

Magnetic resonance spectroscopic imaging (MRSI) has been used to more accurately diagnose, localize, and assess progression and treatment response for gliomas. The main limitation of the MRSI is the long data acquisition times. A current approach is to reduce the amount of k-space data sampled by limiting the data acquisition to a central elliptical portion of k-space. This study investigated the feasibility of reducing the data acquisition time further for the MRSI data using two parallel imaging techniques and investigating the relative performance of sensitivity encoding (SENSE) and generalized autocalibrating partially parallel acquisitions (GRAPPA).

Background and Purpose: The advent of new anti-angiogenic therapies has created the need for better defining regions of abnormal vascularity in order to add specificity to the classification of high-grade gliomas. This study investigated MR imaging parameters corresponding to the peak height and percent recovery of the T2* relaxivity curve to characterize angiogenesis and microvascular leakage within the T2 and contrast-enhancing abnormalities in high-grade gliomas., Methods: Dynamic susceptibility-weighted MR imaging was performed in 41 patients with untreated high-grade glioma during the first pass and recirculation phase of a gadolinium bolus injection. Normalized peak height and percent recovery of the post-bolus signal were calculated on a voxel by voxel basis within the T2 and contrast-enhancing lesions (T2L, CEL) and compared between grade III and grade IV gliomas., Results: Grade IV gliomas showed significantly larger volumes of abnormal peak height and recovery compared to grade III patients (P < .01). Within the CEL, grade IV gliomas exhibited significantly higher peak height values than grade III patients (P < .05). Enhancing grade III patients (n = 7) demonstrated higher minimum values of percent recovery within both regions compared to grade IV patients. Non-enhancing grade III gliomas (n = 11) had significantly elevated minimum percent recovery values when compared to the T2L-CEL region in grade IV patients (n = 23; P < .05)., Conclusion: Direct measurement of the spatial distribution of tumor microvasculature characteristics has shown considerable heterogeneity within different regions of grade III and grade IV gliomas. Peak height and percent recovery parameters help to improve the specificity for characterization of the degree of angiogenesis and microvascular leakage in these tumors and may be useful in evaluating response to treatment.

Purpose: To identify radiation-induced changes in the cerebral vasculature of healthy tissue in the first four months following radiotherapy through the analysis of dynamic-susceptibility contrast perfusion imaging., Materials and Methods: Dynamic gradient-echo imaging was performed on 22 patients during injection of a bolus of Gd-DTPA contrast. The relative cerebral blood volume (rCBV), maximum DeltaR2* of the first passage of the bolus, and a recirculation parameter were derived from gamma-variate fits of the dynamic data. The white matter (WM) rCBV and peak heights were estimated through correlation with segmented T1-weighted images. A percent recovery to baseline was also computed to further describe the recirculation phase., Results: A significant elevation of the recirculation phase was observed at doses>15 Gy at two months following radiotherapy. This was reflected in an increased recirculation parameter in the fitted curves in the 15-30, 30-45, and >45 Gy dose groups to 2.8%, 3.8%, and 2.4% above the <15 Gy voxels, as well as in a decline in percent recovery to baseline. A trend toward lower rCBV and peak heights was observed at that same time point., Conclusion: The observed results suggest a dose-dependent decline in vessel density and increase in vascular permeability and/or tortuosity in irradiated normal-appearing brain tissue at two months following radiotherapy., (Copyright (c) 2005 Wiley-Liss, Inc.)

Background and Purpose: Gliomas are heterogeneous tumors with increased microvasculature, hypoxia, and necrosis. The purpose of this study was to examine the distribution and relationship of the MR-derived relative cerebral blood volume (rCBV), lactate (Lac), and mobile lipids (Lip), which have been proposed as markers for these phenomena of gliomas in vivo., Methods: Twenty-three patients with newly diagnosed gliomas were examined before surgical biopsy and/or resection (seven grade II, five grade III, and 11 grade IV), and 27 patients were studied after surgery but before radiation treatment and/or chemotherapy (11 grade II, two grade III, and 14 grade IV gliomas). Lac and Lip were estimated from Lac-edited three-dimensional MR spectroscopic images. Dynamic susceptibility-contrast MR imaging was applied to obtain perfusion-weighted images and rCBV maps., Results: Before surgical biopsy/resection, one low-grade and 12 of 16 high-grade gliomas had significantly elevated Lac. No low-grade and 10 of 16 high-grade gliomas had significantly elevated Lip. In presurgical high-grade gliomas, volumes of elevated Lip and macronecrosis were significantly correlated. rCBV was significantly increased in regions with elevated Lac. After we excluded macronecrosis, the rCBV for regions with elevated Lip but no Lac was significantly higher than rCBV in regions with elevated Lac but no Lip. After surgical biopsy/resection, more low-grade patients showed significantly elevated Lac and Lip than before., Conclusion: The in vivo distribution of rCBV, Lac, and Lip, as evaluated with three-dimensional MR spectroscopic imaging, may help in the diagnosis and selection of the most appropriate therapy for patients with gliomas.

Purpose: To identify radiation-induced changes in healthy white-matter spectra in the first six months following radiotherapy, and assess the impact of these changes on an automated algorithm for detecting spectral abnormalities., Materials and Methods: 1H-MRSI was performed on 10 patients with grade IV gliomas who were to undergo radiation therapy. Choline (Cho), creatine (Cr), and N-acetylaspartate (NAA) ratios were studied as a function of dose and time. The impact of these spectral changes on a spectral analysis algorithm was evaluated., Results: The Cho/NAA ratios rose to values of 0.66 +/- 0.15, 0.75 +/- 0.21, and 0.73 +/- 0.15 two months after therapy, compared to immediate post-therapy values of 0.56 +/- 0.15, 0.60 +/- 0.16, and 0.61 +/- 0.15 for the < 25, 25-50, and > 50 Gy dose groups, respectively. These maxima were followed by a dose-dependent recovery. A similar trend was found in the Cho/Cr ratio. The automated spectral analysis system incorporated the changing Cho/NAA ratio into a global redefinition of healthy tissue, but did not account for dose-dependent spatial variations in Cho/NAA ratios., Conclusion: Radiation significantly alters the spectra of healthy tissues in the first six months after radiotherapy. This suggests that the radiation dose distribution should be considered during analysis of post-therapy spectra., (Copyright 2004 Wiley-Liss, Inc.)

Although MR imaging (MRI) and MR spectroscopic imaging (MRSI) have been applied in the diagnosis and treatment planning for brain tumors, their prognostic significance has not yet been determined. The goal of this study was to identify pre-treatment MRI and MRSI parameters for patients with malignant glioma that may be useful in predicting survival. Two populations of patients with newly-diagnosed malignant glioma were examined with MRI and three-dimensional proton ((1)H) MRSI. Thirty-nine patients (22 grade 3 and 17 glioblastoma multiforme, GBM) were studied prior to surgery, and 33 GBM patients were studied after surgery but prior to treatment with radiation and chemotherapy. Signal intensities of choline (Cho), creatine (Cr), N-acetyl aspartate (NAA), and lactate/lipid (LL) were estimated from the spectra. Recursive partitioning methods were applied to parameters that included age, histological grade, MRI and MRSI variables to generate survival trees. Patients were grouped into high and low risk categories and the corresponding Kaplan-Meier curves were plotted for comparison between groups. The parameters that were selected by recursive partitioning as being predictive of poor outcome were older age, larger contrast enhancement, higher Cho-to-Cr, higher Cho-to-NAA, higher LL and lower Cr-to-NAA abnormalities. The survival functions were significantly different between the sub-groups of patients obtained from the survival tree for both pre-surgery and post-surgery data. The results of this study suggest that pre-treatment MRI and three-dimensional (1)H-MRSI provide information that predicts outcome for patients with malignant gliomas and have drawn attention to variables that should be examined prospectively in future studies using these techniques., (Copyright 2004 John Wiley & Sons, Ltd.)

Although there are trends in the morphologic, metabolic, hemodynamic, and structural properties of untreated gliomas that are reflected in MR measurements, there is considerable heterogeneity both within and between lesions of the same histologic grade. The spatial extent of the abnormality in ADC and RA images is similar to the T2 lesion, but there is no obvious difference in intensity between grades. The rCBV is significantly increased in the enhancing volume of grade 4 lesions but is similar or reduced in intensity for most grade 3 lesions. There are clear differences between the enhancing volumes and the regions with increased Cho that may be highly significant for planning focal therapy. The location and intensity of the Lac/Lip peaks are consistent with those representing regions of necrosis for grade 4 lesions. The fact that small Lac/Lip peaks can also be seen in grade 2 and grade 3 lesions suggests that their presence may be indicative of regions that are likely to progress to a higher grade. If this were the case, it would be valuable for directing biopsies. The correlations between rCBV, Cho, and ADC suggest that cellularity, membrane turnover, and vascularity are linked in grade 4 lesions. It is not clear whether there is any relationship between these parameters regions in grade 2 or grade 3 gliomas. While further work is required to optimize the methodology associated with these MR parameters, it seems likely that combining the information from such measurements may be valuable for predicting outcome and tailoring therapy to individual patients.

Object: Data obtained preoperatively from three-dimensional (3D)/proton magnetic resonance (MR) spectroscopy were compared with the results of histopathological assays of tissue biopsies obtained during surgery to verify the sensitivity and specificity of a choline-containing compound-N-acetylaspartate index (CNI) used to distinguish tumor from nontumorous tissue within T2-hyperintense and contrast-enhancing lesions of patients with untreated gliomas. The information gleaned from the biopsy correlation study was used to test the hypothesis that there is metabolically active tumor in nonenhancing regions of the T2-hyperintense lesion that can be detected using MR spectroscopy., Methods: Patients suspected of harboring a glioma underwent 3D MR spectroscopy during their preoperative MR imaging examination. Surgical navigation techniques were used to record the location of tissue biopsies collected during open resection of the tumor. A receiver operating curve analysis of the CNI and histological characteristics of specimens at each biopsy location was performed to determine the optimal threshold of the CNI required to separate tumor from nontumorous tissue. Histograms of the CNIs within enhancing and nonenhancing regions of lesions appearing on MR images were generated to determine the spatial distribution of CNIs consistent with tumor., Conclusions: Biopsy samples containing tumor were distinguished from those containing a mixture of normal, edematous, gliotic, and necrotic tissue with 90% sensitivity and 86% specificity by using a CNI threshold of 2.5. The CNIs of nontumorous specimens were significantly different from those of biopsy specimens containing Grade II (p < 0.03), Grade III (p < 0.005), and Grade IV (p < 0.01) tumors. On average, one third to one half of the T2-hyperintense lesion outside the contrast-enhancing lesion contained CNI greater than 2.5.

Gliomas are infiltrative lesions that typically have poorly defined margins on conventional magnetic resonance (MR) and computed tomography (CT) images. This presents a considerable challenge for planning radiation and other forms of focal therapy, and introduces the possibility of both under-treating macroscopic tumor, and over-treating regions of normal brain tissue. New therapy systems are able to deliver radiation more precisely and accurately to irregular three-dimensional target volumes, and have placed a premium on definition of the spatial extent of the lesion. Proton MR spectroscopic imaging (H-MRSI) has been proposed as an in vivo molecular imaging technique that assists in targeting and predicts response to radiation therapy for patients with gliomas. The evidence that supports the use of H-MRSI for planning radiation treatment is reviewed, together with the technical requirements for implementing data acquisition and analysis procedures in a clinical setting. Although there is room for improvement in the spatial resolution and chemical specificity obtained at the conventional field strength of 1.5 T, there are clear benefits to integrating H-MRSI into treatment planning and follow-up examinations. Further work is required to integrate the results of the H-MRSI examination into the treatment planning workstation, and to improve the quality of the data using more sensitive phased array coils and higher field strength magnets., (Copyright 2002 Wiley-Liss, Inc.)

Purpose: To evaluate the role of 3D MR spectroscopic imaging (MRSI) as a tool for characterizing heterogeneity within a lesion in glioma patients., Materials and Methods: Forty-nine patients with newly diagnosed glioma were studied with 3D water-suppressed proton (1-H) MRSI. Signal intensities from choline (Cho), creatine (Cr), N-acytel aspartate (NAA), and lactate/lipid (LL) were estimated from the spectra. Regions of interest (ROIs) corresponding to the metabolic abnormalities were defined and compared with the anatomic lesions., Results: This study showed that the tumor burden measured with either the volumes of the metabolic abnormalities or the metabolic levels in the most abnormal voxels was correlated with the degree of malignancy of the tumor. The volumes of elevated Cho and decreased NAA were useful for distinguishing low-grade from high-grade lesions. The volume of abnormal LL was correlated with the existence of necrosis and with the volume of contrast-enhancing lesions in high-grade lesions. The differences in the volume of abnormal LL were also statistically significant between patients in each grade., Conclusion: These 3D-MRSI data provide important additional information to conventional MRI for evaluating and characterizing gliomas., (Copyright 2002 Wiley-Liss, Inc.)

Purpose: The role of radiotherapy (RT) seems established for patients with low-grade gliomas with poor prognostic factors. Three-dimensional (3D) magnetic resonance spectroscopy imaging (MRSI) has been reported to be of value in defining the extent of glioma infiltration. We performed a study examining the impact MRSI would have on the routine addition of 2-3-cm margins around MRI T2-weighted hyperintensity to generate the treatment planning clinical target volume (CTV) for low-grade gliomas., Methods and Materials: Twenty patients with supratentorial gliomas WHO Grade II (7 astrocytomas, 6 oligoastrocytomas, 7 oligodendrogliomas) underwent MRI and MRSI before surgery. The MRI was contoured manually; the regions of interest included T2 hyperintensity and, if present, regions of contrast enhancement on T1-weighted images. The 3D-MRSI peak parameters for choline and N-acetyl-aspartate, acquired voxel-by-voxel, were categorized using a choline/N-acetyl-aspartate index (CNI), a tool for quantitative assessment of tissue metabolite levels, with CNI 2 being the lowest value corresponding to tumor. CNI data were aligned to MRI and displayed as 3D contours. The relationship between the anatomic and metabolic information on tumor extent was assessed by comparing the CNI contours and other MRSI-derived metabolites to the MRI T2 volume., Results: The limitations in the size of the region "excited" meant that MRSI could be used to evaluate only a median 68% of the T2 volume (range 38-100%), leaving the volume T2c. The CNI 2 volume (median 29 cm(3), range 10-73) was contained totally within the T2c in 55% of patients. In the remaining patients, the volume of CNI 2 extending beyond the T2c was quite small (median 2.3 cm(3), range 1.4-5.2), but was not distributed uniformly about the T2c, extending up to 22 mm beyond it. Two patients demonstrated small regions of contrast enhancement corresponding to the regions of highest CNI. Other metabolites, such as creatine and lactate, seem useful for determining less and more radioresistant areas, respectively., Conclusion: Metabolically active tumor, as detected by MRSI, is restricted mainly to the T2 hyperintensity in low-grade gliomas, but can extend outside it in a limited and nonuniform fashion up to 2 cm. Therefore, a CTV including T2 and areas of CNI extension beyond the T2 hyperintensity would result in a reduction in the size and a change in the shape of the standard clinical target volumes generated by adding uniform margins of 2-3 cm to the T2 hyperintensity.

Background and Purpose: The diagnosis of brain tumors after high-dose radiation therapy is frequently limited by the lack of metabolic discrimination available with conventional imaging methods. The purpose of this study was to use proton MR spectroscopy to investigate serial changes in recurrent malignant gliomas after gamma knife radiosurgery to characterize tissue response to high-dose radiation., Methods: Eighteen patients with recurrent gliomas were studied with MR imaging and 3D proton MR spectroscopic imaging at the time of radiosurgery and at regular time points thereafter. Choline (Cho) and N-acetyl aspartate levels were calculated on a voxel-by-voxel basis and compared with levels found in normal tissue and with levels observed at previous time points. The results of the spectral analysis were then compared with the radiologic findings. Statistical comparisons were precluded by the small sample sizes involved., Results: Response within the gamma knife target was observed as a reduction of Cho levels and an increase in lactate/lipid levels, typically within 6 months of treatment. Increases in Cho correlated with poor radiologic response and suggested tumor recurrence, confirmed histologically in six cases. The development of a spectral abnormality preceded a coincident increase in contrast enhancement by 1 to 2 months in nine cases., Conclusion: Proton MR spectroscopic imaging provided diagnostic and monitoring information before and after radiosurgery. Evaluation of metabolic changes with proton MR spectroscopy and structural changes with MR imaging improved tissue discrimination and provided correlation with histologic findings.

Background and Purpose: Tumor progression is often difficult to distinguish from nonneoplastic treatment response on the basis of MR images alone. This study correlates metabolite levels measured by preoperative MR spectroscopic (MRS) imaging with histologic findings of biopsies, obtained during image-guided resections of brain mass lesions, to clarify the potential role of MRS in making this distinction., Methods: Twenty-nine patients with brain tumors underwent high-resolution (0.2-1 cc) 3D proton MRS imaging and MR imaging before undergoing surgery; 11 had a newly diagnosed neoplasm, and 18 had recurrent disease. Surgical biopsies were obtained from locations referenced on MR images by guidance with a surgical navigation system. MR spectral voxels were retrospectively centered on each of 79 biopsy locations, and metabolite levels were correlated with histologic examination of each specimen., Results: All mass lesions studied, whether attributable to tumor or noncancerous effects of previous therapy, showed abnormal MR spectra compared with normal parenchyma. When the pattern of MRS metabolites consisted of abnormally increased choline and decreased N-acetyl aspartate (NAA) resonances, histologic findings of the biopsy specimen invariably was positive for tumor. When choline and NAA resonances were below the normal range, histologic findings were variable, ranging from radiation necrosis, astrogliosis, and macrophage infiltration to mixed tissues that contained some low-, intermediate-, and high-grade tumor., Conclusion: This study demonstrated that 3D MRS imaging can identify regions of viable cancer, which may be valuable for guiding surgical biopsies and focal therapy. Regions manifesting abnormal MR spectra had a mixture of histologic findings, including astrogliosis, necrosis, and neoplasm.