Performance of Standardized Relative CBV for Quantifying Regional Histologic Tumor Burden in Recurrent High-Grade Glioma: Comparison against Normalized Relative CBV Using Image-Localized Stereotactic Biopsies.

BACKGROUND AND PURPOSE: Perfusion MR imaging measures of relative CBV can distinguish recurrent tumor from posttreatment radiation effects in high-grade gliomas. Currently, relative CBV measurement requires normalization based on user-defined reference tissues. A recently proposed method of relative CBV standardization eliminates the need for user input. This study compares the predictive performance of relative CBV standardization against relative CBV normalization for quantifying recurrent tumor burden in high-grade gliomas relative to posttreatment radiation effects. MATERIALS AND METHODS: We recruited 38 previously treated patients with high-grade gliomas (World Health Organization grades III or IV) undergoing surgical re-resection for new contrast-enhancing lesions concerning for recurrent tumor versus posttreatment radiation effects. We recovered 112 image-localized biopsies and quantified the percentage of histologic tumor content versus posttreatment radiation effects for each sample. We measured spatially matched normalized and standardized relative CBV metrics (mean, median) and fractional tumor burden for each biopsy. We compared relative CBV performance to predict tumor content, including the Pearson correlation (r), against histologic tumor content (0%-100%) and the receiver operating characteristic area under the curve for predicting high-versus-low tumor content using binary histologic cutoffs (≥50%; ≥80% tumor). RESULTS: Across relative CBV metrics, fractional tumor burden showed the highest correlations with tumor content (0%-100%) for normalized (r = 0.63, P < .001) and standardized (r = 0.66, P < .001) values. With binary cutoffs (ie, ≥50%; ≥80% tumor), predictive accuracies were similar for both standardized and normalized metrics and across relative CBV metrics. Median relative CBV achieved the highest area under the curve (normalized = 0.87, standardized = 0.86) for predicting ≥50% tumor, while fractional tumor burden achieved the highest area under the curve (normalized = 0.77, standardized = 0.80) for predicting ≥80% tumor. CONCLUSIONS: Standardization of relative CBV achieves similar performance compared with normalized relative CBV and offers an important step toward workflow optimization and consensus methodology.

Utility of Percentage Signal Recovery and Baseline Signal in DSC-MRI Optimized for Relative CBV Measurement for Differentiating Glioblastoma, Lymphoma, Metastasis, and Meningioma.

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.

Moving Toward a Consensus DSC-MRI Protocol: Validation of a Low-Flip Angle Single-Dose Option as a Reference Standard for Brain 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.

Optimization of Acquisition and Analysis Methods for Clinical Dynamic Susceptibility Contrast MRI Using a Population-Based Digital Reference Object.

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.

Multisite Concordance of DSC-MRI Analysis for Brain Tumors: Results of a National Cancer Institute Quantitative Imaging Network Collaborative Project.

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.

Optimization of DSC MRI Echo Times for CBV Measurements Using Error Analysis in a Pilot Study of High-Grade Gliomas.

BACKGROUND AND PURPOSE: The optimal TE must be calculated to minimize the variance in CBV measurements made with DSC MR imaging. Simulations can be used to determine the influence of the TE on CBV, but they may not adequately recapitulate the in vivo heterogeneity of precontrast T2*, contrast agent kinetics, and the biophysical basis of contrast agent-induced T2* changes. The purpose of this study was to combine quantitative multiecho DSC MRI T2* time curves with error analysis in order to compute the optimal TE for a traditional single-echo acquisition. MATERIALS AND METHODS: Eleven subjects with high-grade gliomas were scanned at 3T with a dual-echo DSC MR imaging sequence to quantify contrast agent-induced T2* changes in this retrospective study. Optimized TEs were calculated with propagation of error analysis for high-grade glial tumors, normal-appearing white matter, and arterial input function estimation. RESULTS: The optimal TE is a weighted average of the T2* values that occur as a contrast agent bolus transverses a voxel. The mean optimal TEs were 30.0 ± 7.4 ms for high-grade glial tumors, 36.3 ± 4.6 ms for normal-appearing white matter, and 11.8 ± 1.4 ms for arterial input function estimation (repeated-measures ANOVA, P < .001). CONCLUSIONS: Greater heterogeneity was observed in the optimal TE values for high-grade gliomas, and mean values of all 3 ROIs were statistically significant. The optimal TE for the arterial input function estimation is much shorter; this finding implies that quantitative DSC MR imaging acquisitions would benefit from multiecho acquisitions. In the case of a single-echo acquisition, the optimal TE prescribed should be 30-35 ms (without a preload) and 20-30 ms (with a standard full-dose preload).

Improving Perfusion Measurement in DSC-MR Imaging with Multiecho Information for Arterial Input Function Determination.

BACKGROUND AND PURPOSE: Clinical measurements of cerebral perfusion have been increasingly performed with multiecho dynamic susceptibility contrast-MR imaging techniques due to their ability to remove confounding T1 effects of contrast agent extravasation from perfusion quantification. However, to this point, the extra information provided by multiecho techniques has not been used to improve the process of estimating the arterial input function, which is critical to accurate perfusion quantification. The purpose of this study is to investigate methods by which multiecho DSC-MRI data can be used to automatically avoid voxels whose signal decreases to the level of noise when calculating the arterial input function. MATERIALS AND METHODS: Here we compare postprocessing strategies for clinical multiecho DSC-MR imaging data to test whether arterial input function measures could be improved by automatically identifying and removing voxels exhibiting signal attenuation (truncation) artifacts. RESULTS: In a clinical pediatric population, we found that the Pearson correlation coefficient between ΔR2* time-series calculated from each TE individually was a valuable criterion for automated estimation of the arterial input function, resulting in higher peak arterial input function values while maintaining smooth and reliable arterial input function shapes. CONCLUSIONS: This work is the first to demonstrate that multiecho information may be useful in clinically important automatic arterial input function estimation because it can be used to improve automatic selection of voxels from which the arterial input function should be measured.

On the Use of DSC-MRI for Measuring Vascular Permeability.

BACKGROUND AND PURPOSE: Contrast agent extravasation has been shown to confound brain tumor perfusion measurements with DSC-MR imaging, necessitating the use of correction techniques (eg, Weisskoff, Bjornerud). Leakage parameters (K2 and K(a)) postulated to reflect vessel permeability can be extracted from these correction methods; however, the biophysical interpretation of these parameters and their relationship to commonly used MR imaging measures of vascular permeability (eg, contrast agent volume transfer constant, [K(trans)]) remain unclear. Given that vascular density, as assessed by blood volume, and vascular permeability, as reflected by K(trans) (and potentially K2 or K(a)), report on unique and clinically informative vascular characteristics, there is a compelling interest to simultaneously assess these features. MATERIALS AND METHODS: We acquired multiecho DSC-MR imaging data, allowing the simultaneous computation and voxelwise comparison of single- and dual-echo derived measures of K2, K(a) and K(trans) in patients with glioma. This acquisition enabled the investigation of competing T1 and T2* leakage effects and TE dependency on these parameters. RESULTS: K2 and K(a) displayed nonsignificant (P = .150 and P = .060, respectively) voxelwise linear correlations with K(trans), while a significant (P < .001) inverse relationship was observed between K2 and Ka (coefficient of determination [r(2)] = 0.466-0.984). Significantly different (P < .005) mean estimates were found between voxels exhibiting predominately T1 and T2* effects for K2 and K(a). K(trans), however, was observed to be similar between these voxels (0.109 versus 0.092 minutes(-1)). Significant differences (P < .001) in extracellular-extravascular volume fraction (v(e)) (0.285 versus 0.167) were also observed between cohorts. Additionally, K2 and K(a) were found to have a significant quadratic relationship (P = .031 and P = .005, respectively) with v(e). CONCLUSIONS: Estimates of vascular permeability in brain tumors may be simultaneously acquired from multiple-echo DSC-MR imaging via K(trans); however, caution should be used in assuming a similar relationship for K2 and K(a).

A theoretical framework to model DSC-MRI data acquired in the presence of contrast agent extravasation.

Dynamic susceptibility contrast (DSC) MRI methods rely on compartmentalization of the contrast agent such that a susceptibility gradient can be induced between the contrast-containing compartment and adjacent spaces, such as between intravascular and extravascular spaces. When there is a disruption of the blood-brain barrier, as is frequently the case with brain tumors, a contrast agent leaks out of the vasculature, resulting in additional T(1), T(2) and T*(2) relaxation effects in the extravascular space, thereby affecting the signal intensity time course and reducing the reliability of the computed hemodynamic parameters. In this study, a theoretical model describing these dynamic intra- and extravascular T(1), T(2) and T*(2) relaxation interactions is proposed. The applicability of using the proposed model to investigate the influence of relevant MRI pulse sequences (e.g. echo time, flip angle), and physical (e.g. susceptibility calibration factors, pre-contrast relaxation rates) and physiological parameters (e.g. permeability, blood flow, compartmental volume fractions) on DSC-MRI signal time curves is demonstrated. Such a model could yield important insights into the biophysical basis of contrast-agent-extravasation-induced effects on measured DSC-MRI signals and provide a means to investigate pulse sequence optimization and appropriate data analysis methods for the extraction of physiologically relevant imaging metrics.

Assessment of the morphological and functional effects of the anti-angiogenic agent SU11657 on 9L gliosarcoma vasculature using dynamic susceptibility contrast MRI.

To investigate the influence of anti-angiogenic agents on tumor perfusion, we employed a dynamic susceptibility contrast (DSC)-MRI method that utilizes a simultaneous gradient-echo (GE) and spin-echo (SE) imaging sequence to derive perfusion parameters (blood flow, blood volume, and mean transit time (MTT)). These parameters are sensitive to both the total vasculature (from the GE data) and the microvasculature (from the SE data), and can also provide a measure of the mean vessel diameter (mVD). This approach was used to evaluate the response of a 9L rat brain tumor model to 20 mg/kg and 40 mg/kg of the anti-angiogenic agent SU11657. The 20-mg/kg dose significantly decreased mVD by 29.9% (P = 0.02). The 40-mg/kg dose significantly decreased mVD by 30.4% (P = 0.0007), SE blood volume by 31.8% (P = 0.03), GE and SE MTT by 46.9% (P = 0.03) and 62.0% (P = 0.0005), and increased GE and SE blood flow by 36.6% (P = 0.04) and 52.6% (P = 0.02). These findings demonstrate that DSC-MRI perfusion methods can play a key role in the noninvasive evaluation of morphological and functional changes in tumor vasculature in response to therapy.

Improving the reliability of obtaining tumor hemodynamic parameters in the presence of contrast agent extravasation.

A new approach to improve the reliability of dynamic susceptibility contrast MRI for the evaluation of brain tumor hemodynamics in the presence of contrast agent extravasation is described. This model-based technique simultaneously estimates the voxel-wise tumor residue function and the temporal extravascular T(1) changes following contrast agent leakage. With these estimates the model corrects the measured MRI signal, which is then used to calculate tumor hemodynamic parameters. The feasibility of this technique is demonstrated with computer simulations that cover a wide range of hemodynamic conditions and by application to eight tumor-bearing rats. The simulations demonstrate that the corrected hemodynamic parameters precisely matched the actual values with a maximum percentage error of 4.2% compared to 68.6% for the uncorrected parameters. The corrected parameters are also essentially independent of the tumor hemodynamic state and degree of contrast extravasation. Consistent with these improvements, significant differences between corrected and uncorrected parameters, calculated from a gradient-echo sequence, are shown in a rat 9L gliosarcoma model. This method combined with the hemodynamic parameters derived from GE and SE sequences shows promise as a new tool to evaluate tumor angiogenesis and its therapy.