New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine-depleting agent ADI-PEG20 in a non-arginine-auxotrophic cellular background (argininosuccinate synthetase 1 positive). Moreover, this combination led to durable and complete radiological and pathological response, with extended disease-free survival in an orthotopic immune-competent model of GBM, with no significant toxicity. ADI-PEG20 not only enhanced the cellular sensitivity of argininosuccinate synthetase 1–positive GBM to ionizing radiation by elevated production of nitric oxide (˙NO) and hence generation of cytotoxic peroxynitrites, but also promoted glioma-associated macrophage/microglial infiltration into tumors and turned their classical antiinflammatory (protumor) phenotype into a proinflammatory (antitumor) phenotype. Our results provide an effective, well-tolerated, and simple strategy to improve GBM treatment that merits consideration for early evaluation in clinical trials.

BACKGROUND AND PURPOSE: Standard assessment criteria for brain tumors that only include anatomic imaging continue to be insufficient. While numerous studies have demonstrated the value of DSC-MR imaging perfusion metrics for this purpose, they have not been incorporated due to a lack of confidence in the consistency of DSC-MR imaging metrics across sites and platforms. This study addresses this limitation with a comparison of multisite/multiplatform analyses of shared DSC-MR imaging datasets of patients with brain tumors. MATERIALS AND METHODS: DSC-MR imaging data were collected after a preload and during a bolus injection of gadolinium contrast agent using a gradient recalled-echo–EPI sequence (TE/TR = 30/1200 ms; flip angle = 72°). Forty-nine low-grade (n = 13) and high-grade (n = 36) glioma datasets were uploaded to The Cancer Imaging Archive. Datasets included a predetermined arterial input function, enhancing tumor ROIs, and ROIs necessary to create normalized relative CBV and CBF maps. Seven sites computed 20 different perfusion metrics. Pair-wise agreement among sites was assessed with the Lin concordance correlation coefficient. Distinction of low- from high-grade tumors was evaluated with the Wilcoxon rank sum test followed by receiver operating characteristic analysis to identify the optimal thresholds based on sensitivity and specificity. RESULTS: For normalized relative CBV and normalized CBF, 93% and 94% of entries showed good or excellent cross-site agreement (0.8 ≤ Lin concordance correlation coefficient ≤ 1.0). All metrics could distinguish low- from high-grade tumors. Optimum thresholds were determined for pooled data (normalized relative CBV = 1.4, sensitivity/specificity = 90%:77%; normalized CBF = 1.58, sensitivity/specificity = 86%:77%). CONCLUSIONS: By means of DSC-MR imaging data obtained after a preload of contrast agent, substantial consistency resulted across sites for brain tumor perfusion metrics with a common threshold discoverable for distinguishing low- from high-grade tumors.

BACKGROUND AND PURPOSE: DSC-MR imaging using preload, intermediate (60°) flip angle and postprocessing leakage correction has gained traction as a standard methodology. Simulations suggest that DSC-MR imaging with flip angle = 30° and no preload yields relative CBV practically equivalent to the reference standard. This study tested this hypothesis in vivo. MATERIALS AND METHODS: Eighty-four patients with brain lesions were enrolled in this 3-institution study. Forty-three patients satisfied the inclusion criteria. DSC-MR imaging (3T, single-dose gadobutrol, gradient recalled-echo–EPI, TE = 20–35 ms, TR = 1.2–1.63 seconds) was performed twice for each patient, with flip angle = 30°–35° and no preload (P−), which provided preload (P+) for the subsequent intermediate flip angle = 60°. Normalized relative CBV and standardized relative CBV maps were generated, including postprocessing with contrast agent leakage correction (C+) and without (C−) contrast agent leakage correction. Contrast-enhancing lesion volume, mean relative CBV, and contrast-to-noise ratio obtained with 30°/P−/C−, 30°/P−/C+, and 60°/P+/C− were compared with 60°/P+/C+ using the Lin concordance correlation coefficient and Bland-Altman analysis. Equivalence between the 30°/P−/C+ and 60°/P+/C+ protocols and the temporal SNR for the 30°/P− and 60°/P+ DSC-MR imaging data was also determined. RESULTS: Compared with 60°/P+/C+, 30°/P−/C+ had closest mean standardized relative CBV (P = .61), highest Lin concordance correlation coefficient (0.96), and lowest Bland-Altman bias (μ = 1.89), compared with 30°/P−/C− (P = .02, Lin concordance correlation coefficient = 0.59, μ = 14.6) and 60°/P+/C− (P = .03, Lin concordance correlation coefficient = 0.88, μ = −10.1) with no statistical difference in contrast-to-noise ratios across protocols. The normalized relative CBV and standardized relative CBV were statistically equivalent at the 10% level using either the 30°/P−/C+ or 60°/P+/C+ protocols. Temporal SNR was not significantly different for 30°/P− and 60°/P+ (P = .06). CONCLUSIONS: Tumor relative CBV derived from low–flip angle, no-preload DSC-MR imaging with leakage correction is an attractive single-dose alternative to the higher dose reference standard.

BACKGROUND AND PURPOSE: The percentage signal recovery in non-leakage-corrected (no preload, high flip angle, intermediate TE) DSC-MR imaging is known to differ significantly for glioblastoma, metastasis, and primary CNS lymphoma. Because the percentage signal recovery is influenced by preload and pulse sequence parameters, we investigated whether the percentage signal recovery can still differentiate these common contrast-enhancing neoplasms using a DSC-MR imaging protocol designed for relative CBV accuracy (preload, intermediate flip angle, low TE). MATERIALS AND METHODS: We retrospectively analyzed DSC-MR imaging of treatment-naïve, pathology-proved glioblastomas (n = 14), primary central nervous system lymphomas (n = 7), metastases (n = 20), and meningiomas (n = 13) using a protocol designed for relative CBV accuracy (a one-quarter-dose preload and single-dose bolus of gadobutrol, TR/TE = 1290/40 ms, flip angle = 60° at 1.5T). Mean percentage signal recovery, relative CBV, and normalized baseline signal intensity were compared within contrast-enhancing lesion volumes. Classification accuracy was determined by receiver operating characteristic analysis. RESULTS: Relative CBV best differentiated meningioma from glioblastoma and from metastasis with areas under the curve of 0.84 and 0.82, respectively. The percentage signal recovery best differentiated primary central nervous system lymphoma from metastasis with an area under the curve of 0.81. Relative CBV and percentage signal recovery were similar in differentiating primary central nervous system lymphoma from glioblastoma and from meningioma. Although neither relative CBV nor percentage signal recovery differentiated glioblastoma from metastasis, mean normalized baseline signal intensity achieved 86% sensitivity and 50% specificity. CONCLUSIONS: Similar to results for non-preload-based DSC-MR imaging, percentage signal recovery for one-quarter-dose preload-based, intermediate flip angle DSC-MR imaging differentiates most pair-wise comparisons of glioblastoma, metastasis, primary central nervous system lymphoma, and meningioma, except for glioblastoma versus metastasis. Differences in normalized post-preload baseline signal for glioblastoma and metastasis, reflecting a snapshot of dynamic contrast enhancement, may motivate the use of single-dose multiecho protocols permitting simultaneous quantification of DSC-MR imaging and dynamic contrast-enhanced MR imaging parameters.

BACKGROUND AND PURPOSE: The accuracy of DSC-MR imaging CBV maps in glioblastoma depends on acquisition and analysis protocols. Multisite protocol heterogeneity has challenged standardization initiatives due to the difficulties of in vivo validation. This study sought to compare the accuracy of routinely used protocols using a digital reference object. MATERIALS AND METHODS: The digital reference object consisted of approximately 10,000 simulated voxels recapitulating typical signal heterogeneity encountered in vivo. The influence of acquisition and postprocessing methods on CBV reliability was evaluated across 6912 parameter combinations, including contrast agent dosing schemes, pulse sequence parameters, field strengths, and postprocessing methods. Accuracy and precision were assessed using the concordance correlation coefficient and coefficient of variation. RESULTS: Across all parameter space, the optimal protocol included full-dose contrast agent preload and bolus, intermediate (60°) flip angle, 30-ms TE, and postprocessing with a leakage-correction algorithm (concordance correlation coefficient = 0.97, coefficient of variation = 6.6%). Protocols with no preload or fractional dose preload and bolus using these acquisition parameters were generally less robust. However, a protocol with no preload, full-dose bolus, and low (30°) flip angle performed very well (concordance correlation coefficient = 0.93, coefficient of variation = 8.7% at 1.5T and concordance correlation coefficient = 0.92, coefficient of variation = 8.2% at 3T). CONCLUSIONS: Schemes with full-dose preload and bolus maximize CBV accuracy and reduce variability, which could enable smaller sample sizes and more reliable detection of CBV changes in clinical trials. When a lower total contrast agent dose is desired, use of a low flip angle, no preload, and full-dose bolus protocol may provide an attractive alternative.