Improved Leakage Correction for Single-Echo Dynamic Susceptibility Contrast Perfusion MRI Estimates of Relative Cerebral Blood Volume in High-Grade Gliomas by Accounting for Bidirectional Contrast Agent Exchange

Background and purposeContrast agent extravasation through a disrupted blood-brain barrier potentiates inaccurate DSC MR imaging estimation of relative CBV. We explored whether incorporation of an interstitial washout rate in a leakage-correction model for single-echo, gradient-echo DSC MR imaging improves relative CBV estimates in high-grade gliomas.Materials and methodsWe modified the traditional model-based postprocessing leakage-correction algorithm, assuming unidirectional contrast agent extravasation (Boxerman-Weisskoff model) to account for bidirectional contrast agent exchange between intra- and extravascular spaces (bidirectional model). For both models, we compared the goodness of fit with the parent leakage-contaminated relaxation rate curves by using the Akaike Information Criterion and the difference between modeled interstitial relaxation rate curves and dynamic contrast-enhanced MR imaging by using Euclidean distance in 21 patients with glioblastoma multiforme.ResultsThe bidirectional model had improved Akaike Information Criterion versus the bidirectional model in >50% of enhancing tumor voxels in all 21 glioblastoma multiformes (77% ± 9%; P < .0001) and had reduced the Euclidean distance in >50% of enhancing tumor voxels for 17/21 glioblastoma multiformes (62% ± 17%; P = .0041). The bidirectional model and dynamic contrast-enhanced-derived kep demonstrated a strong correlation (r = 0.74 ± 0.13). On average, enhancing tumor relative CBV for the Boxerman-Weisskoff model exceeded that for the bidirectional model by 16.6% ± 14.0%.ConclusionsInclusion of the bidirectional exchange in leakage-correction models for single-echo DSC MR imaging improves the model fit to leakage-contaminated DSC MR imaging data and significantly improves the estimation of relative CBV in high-grade gliomas

Epidermal Growth Factor Receptor Activation in Glioblastoma through Novel Missense Mutations in the Extracellular Domain

Background: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy. Methods and Findings: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/ 8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors. Conclusions: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma

Epidermal Growth Factor Receptor Activation in Glioblastoma through Novel Missense Mutations in the Extracellular Domain

BACKGROUND: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy. METHODS AND FINDINGS: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors. CONCLUSIONS: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma

Quantitative volumetric analysis of conventional MRI response in recurrent glioblastoma treated with bevacizumab

Although the effects of bevacizumab on magnetic resonance images (MRIs) of recurrent glioblastoma multiforme (GBM) are well documented, to our knowledge, no studies have explicitly quantified the volumetric changes resulting from initial treatment, nor have there been studies examining the ability for volumetric changes in conventional MRI to predict progression-free survival (PFS) and overall survival (OS). In the current study, we retrospectively examined volumetric changes on conventional MRI scans in 84 patients with recurrent GBM. MRIs were obtained before (mean, 11 days) and after (mean, 42 days) treatment with bevacizumab. The volume of abnormal fluid-attenuated inversion recovery (FLAIR) signal intensity, the volume of contrast enhancement, and the ratio of the 2 were quantified for each patient before and after initial treatment. Results demonstrated that initial treatment with bevacizumab resulted in a significant decrease in both the volume of abnormal FLAIR signal and the volume of contrast enhancement. Initial, residual, and change in FLAIR volume were not predictive of PFS or OS. Initial contrast-enhancing volume was predictive of PFS but not OS. The pretreatment relative nonenhancing tumor ratio, defined as the ratio of FLAIR to contrast-enhancing volume, was found to be predictive of both PFS and OS

Clinical aggressiveness of malignant gliomas is linked to augmented metabolism of amino acids.

Glutamine, glutamate, asparagine, and aspartate are involved in an enzyme-network that controls nitrogen metabolism. Branched-chain-amino-acid aminotransferase-1 (BCAT1) promotes proliferation of gliomas with wild-type IDH1 and is closely connected to the network. We hypothesized that metabolism of asparagine, glutamine, and branched-chain-amino-acids is associated with progression of malignant gliomas. Gene expression for asparagine synthetase (ASNS), glutaminase (GLS), and BCAT1 were analyzed in 164 gliomas from 156 patients [33-anaplastic gliomas (AG) and 131-glioblastomas (GBM), 64 of which were recurrent GBMs]. ASNS and GLS were twofold higher in GBMs versus AGs. BCAT1 was also higher in GBMs. ASNS expression was twofold higher in recurrent versus new GBMs. Five patients had serial samples: 4-showed higher ASNS and 3-higher GLS at recurrence. We analyzed grade and treatment in 4 groups: (1) low ASNS, GLS, and BCAT1 (n = 96); (2) low ASNS and GLS, but high BCAT1 (n = 26); (3) high ASNS or GLS, but low BCAT1 (n = 25); and (4) high ASNS or GLS and high BCAT1 (n = 17). Ninety-one  % of patients (29/32) with grade-III lesions were in group 1. In contrast, 95 % of patients (62/65) in groups 2-4 had GBMs. Treatment was similar in 4 groups (radiotherapy-80 %; temozolomide-30 %; other chemotherapy-50 %). High expression of ASNS, GLS, and BCAT1 were each associated with poor survival in the entire group. The combination of lower ASNS, GLS, and BCAT1 levels correlated with better survival for newly diagnosed GBMs (66 patients; P = 0.0039). Only tumors with lower enzymes showed improved outcome with temozolomide. IDH1(WT) gliomas had higher expression of these genes. Manipulation of amino acid metabolism in malignant gliomas may be further studied for therapeutics development