Identification of a Single-Dose, Low-Flip-Angle-Based CBV Threshold for Fractional Tumor Burden Mapping in Recurrent Glioblastoma.

BACKGROUND AND PURPOSE: DSC-MR imaging can be used to generate fractional tumor burden (FTB) maps via application of relative CBV thresholds to spatially differentiate glioblastoma recurrence from posttreatment radiation effects (PTRE). Image-localized histopathology was previously used to validate FTB maps derived from a reference DSC-MR imaging protocol by using preload, a moderate flip angle (MFA, 60°), and postprocessing leakage correction. Recently, a DSC-MR imaging protocol with a low flip angle (LFA, 30°) with no preload was shown to provide leakage-corrected relative CBV (rCBV) equivalent to the reference protocol. This study aimed to identify the rCBV thresholds for the LFA protocol that generate the most accurate FTB maps, concordant with those obtained from the reference MFA protocol. MATERIALS AND METHODS: Fifty-two patients with grade-IV glioblastoma who had prior surgical resection and received chemotherapy and radiation therapy were included in the study. Two sets of DSC-MR imaging data were collected sequentially first by using LFA protocol with no preload, which served as the preload for the subsequent MFA protocol. Standardized relative CBV maps (sRCBV) were obtained for each patient and coregistered with the anatomic postcontrast T1-weighted images. The reference MFA-based FTB maps were computed by using previously published sRCBV thresholds (1.0 and 1.56). A receiver operating characteristics (ROC) analysis was conducted to identify the optimal, voxelwise LFA sRCBV thresholds, and the sensitivity, specificity, and accuracy of the LFA-based FTB maps were computed with respect to the MFA-based reference. RESULTS: The mean sRCBV values of tumors across patients exhibited strong agreement (concordance correlation coefficient = 0.99) between the 2 protocols. Using the ROC analysis, the optimal lower LFA threshold that accurately distinguishes PTRE from tumor recurrence was found to be 1.0 (sensitivity: 87.77%; specificity: 90.22%), equivalent to the ground truth. To identify aggressive tumor regions, the ROC analysis identified an upper LFA threshold of 1.37 (sensitivity: 90.87%; specificity: 91.10%) for the reference MFA threshold of 1.56. CONCLUSIONS: For LFA-based FTB maps, an sRCBV threshold of 1.0 and 1.37 can differentiate PTRE from recurrent tumors. FTB maps aid in surgical planning, guiding pathologic diagnosis and treatment strategies in the recurrent setting. This study further confirms the reliability of single-dose LFA-based DSC-MR imaging.

A 3D dual-echo spiral sequence for simultaneous dynamic susceptibility contrast and dynamic contrast-enhanced MRI with single bolus injection.

PURPOSE: Perfusion MRI reveals important tumor physiological and pathophysiologic information, making it a critical component in managing brain tumor patients. This study aimed to develop a dual-echo 3D spiral technique with a single-bolus scheme to simultaneously acquire both dynamic susceptibility contrast (DSC) and dynamic contrast-enhanced (DCE) data and overcome the limitations of current EPI-based techniques. METHODS: A 3D spiral-based technique with dual-echo acquisition was implemented and optimized on a 3T MRI scanner with a spiral staircase trajectory and through-plane SENSE acceleration for improved speed and image quality, in-plane variable-density undersampling combined with a sliding-window acquisition and reconstruction approach for increased speed, and an advanced iterative deblurring algorithm. Four volunteers were scanned and compared with the standard of care (SOC) single-echo EPI and a dual-echo EPI technique. Two patients were scanned with the spiral technique during a preload bolus and compared with the SOC single-echo EPI collected during the second bolus injection. RESULTS: Volunteer data demonstrated that the spiral technique achieved high image quality, reduced geometric artifacts, and high temporal SNR compared with both single-echo and dual-echo EPI. Patient perfusion data showed that the spiral acquisition achieved accurate DSC quantification comparable to SOC single-echo dual-dose EPI, with the additional DCE information. CONCLUSION: A 3D dual-echo spiral technique was developed to simultaneously acquire both DSC and DCE data in a single-bolus injection with reduced contrast use. Preliminary volunteer and patient data demonstrated increased temporal SNR, reduced geometric artifacts, and accurate perfusion quantification, suggesting a competitive alternative to SOC-EPI techniques for brain perfusion MRI.

The ISMRM Open Science Initiative for Perfusion Imaging (OSIPI): Results from the OSIPI-Dynamic Contrast-Enhanced challenge.

PURPOSE: K trans $$ {K}^{\mathrm{trans}} $$ has often been proposed as a quantitative imaging biomarker for diagnosis, prognosis, and treatment response assessment for various tumors. None of the many software tools for K trans $$ {K}^{\mathrm{trans}} $$ quantification are standardized. The ISMRM Open Science Initiative for Perfusion Imaging-Dynamic Contrast-Enhanced (OSIPI-DCE) challenge was designed to benchmark methods to better help the efforts to standardize K trans $$ {K}^{\mathrm{trans}} $$ measurement. METHODS: A framework was created to evaluate K trans $$ {K}^{\mathrm{trans}} $$ values produced by DCE-MRI analysis pipelines to enable benchmarking. The perfusion MRI community was invited to apply their pipelines for K trans $$ {K}^{\mathrm{trans}} $$ quantification in glioblastoma from clinical and synthetic patients. Submissions were required to include the entrants' K trans $$ {K}^{\mathrm{trans}} $$ values, the applied software, and a standard operating procedure. These were evaluated using the proposed OSIP I gold $$ \mathrm{OSIP}{\mathrm{I}}_{\mathrm{gold}} $$ score defined with accuracy, repeatability, and reproducibility components. RESULTS: Across the 10 received submissions, the OSIP I gold $$ \mathrm{OSIP}{\mathrm{I}}_{\mathrm{gold}} $$ score ranged from 28% to 78% with a 59% median. The accuracy, repeatability, and reproducibility scores ranged from 0.54 to 0.92, 0.64 to 0.86, and 0.65 to 1.00, respectively (0-1 = lowest-highest). Manual arterial input function selection markedly affected the reproducibility and showed greater variability in K trans $$ {K}^{\mathrm{trans}} $$ analysis than automated methods. Furthermore, provision of a detailed standard operating procedure was critical for higher reproducibility. CONCLUSIONS: This study reports results from the OSIPI-DCE challenge and highlights the high inter-software variability within K trans $$ {K}^{\mathrm{trans}} $$ estimation, providing a framework for ongoing benchmarking against the scores presented. Through this challenge, the participating teams were ranked based on the performance of their software tools in the particular setting of this challenge. In a real-world clinical setting, many of these tools may perform differently with different benchmarking methodology.

Identification of single-dose, dual-echo based CBV threshold for fractional tumor burden mapping in recurrent glioblastoma.

Background: Relative cerebral blood volume (rCBV) obtained from dynamic susceptibility contrast (DSC) MRI is widely used to distinguish high grade glioma recurrence from post treatment radiation effects (PTRE). Application of rCBV thresholds yield maps to distinguish between regional tumor burden and PTRE, a biomarker termed the fractional tumor burden (FTB). FTB is generally measured using conventional double-dose, single-echo DSC-MRI protocols; recently, a single-dose, dual-echo DSC-MRI protocol was clinically validated by direct comparison to the conventional double-dose, single-echo protocol. As the single-dose, dual-echo acquisition enables reduction in the contrast agent dose and provides greater pulse sequence parameter flexibility, there is a compelling need to establish dual-echo DSC-MRI based FTB mapping. In this study, we determine the optimum standardized rCBV threshold for the single-dose, dual-echo protocol to generate FTB maps that best match those derived from the reference standard, double-dose, single-echo protocol. Methods: The study consisted of 23 high grade glioma patients undergoing perfusion scans to confirm suspected tumor recurrence. We sequentially acquired single dose, dual-echo and double dose, single-echo DSC-MRI data. For both protocols, we generated leakage-corrected standardized rCBV maps. Standardized rCBV (sRCBV) thresholds of 1.0 and 1.75 were used to compute single-echo FTB maps as the reference for delineating PTRE (sRCBV < 1.0), tumor with moderate angiogenesis (1.0 < sRCBV < 1.75), and tumor with high angiogenesis (sRCBV > 1.75) regions. To assess the sRCBV agreement between acquisition protocols, the concordance correlation coefficient (CCC) was computed between the mean tumor sRCBV values across the patients. A receiver operating characteristics (ROC) analysis was performed to determine the optimum dual-echo sRCBV threshold. The sensitivity, specificity, and accuracy were compared between the obtained optimized threshold (1.64) and the standard reference threshold (1.75) for the dual-echo sRCBV threshold. Results: The mean tumor sRCBV values across the patients showed a strong correlation (CCC = 0.96) between the two protocols. The ROC analysis showed maximum accuracy at thresholds of 1.0 (delineate PTRE from tumor) and 1.64 (differentiate aggressive tumors). The reference threshold (1.75) and the obtained optimized threshold (1.64) yielded similar accuracy, with slight differences in sensitivity and specificity which were not statistically significant (1.75 threshold: Sensitivity = 81.94%; Specificity: 87.23%; Accuracy: 84.58% and 1.64 threshold: Sensitivity = 84.48%; Specificity: 84.97%; Accuracy: 84.73%). Conclusions: The optimal sRCBV threshold for single-dose, dual-echo protocol was found to be 1.0 and 1.64 for distinguishing tumor recurrence from PTRE; however, minimal differences were observed when using the standard threshold (1.75) as the upper threshold, suggesting that the standard threshold could be used for both protocols. While the prior study validated the agreement of the mean sRCBV values between the protocols, this study confirmed that their voxel-wise agreement is suitable for reliable FTB mapping. Dual-echo DSC-MRI acquisitions enable robust single-dose sRCBV and FTB mapping, provide pulse sequence parameter flexibility and should improve reproducibility by mitigating variations in preload dose and incubation time.

Towards differentiation of brain tumor from radiation necrosis using multi-parametric MRI: Preliminary results at 4.7 T using rodent models.

BACKGROUND: It remains a clinical challenge to differentiate brain tumors from radiation-induced necrosis in the brain. Despite significant improvements, no single MRI method has been validated adequately in the clinical setting. METHODS: Multi-parametric MRI (mpMRI) was performed to differentiate 9L gliosarcoma from radiation necrosis in animal models. Five types of MRI methods probed complementary information on different scales i.e., T2 (relaxation), CEST based APT (probing mobile proteins/peptides) and rNOE (mobile macromolecules), qMT (macromolecules), diffusion based ADC (cell density) and SSIFT iAUC (cell size), and perfusion based DSC (blood volume and flow). RESULTS: For single MRI parameters, iAUC and ADC provide the best discrimination of radiation necrosis and brain tumor. For mpMRI, a combination of iAUC, ADC, and APT shows the best classification performance based on a two-step analysis with the Lasso and Ridge regressions. CONCLUSION: A general mpMRI approach is introduced to choosing candidate multiple MRI methods, identifying the most effective parameters from all the mpMRI parameters, and finding the appropriate combination of chosen parameters to maximize the classification performance to differentiate tumors from radiation necrosis.

Evaluation of single bolus, dual-echo dynamic susceptibility contrast MRI protocols in brain tumor patients.

Relative cerebral blood volume (rCBV) obtained from dynamic susceptibility contrast (DSC) MRI is adversely impacted by contrast agent leakage in brain tumors. Using simulations, we previously demonstrated that multi-echo DSC-MRI protocols provide improvements in contrast agent dosing, pulse sequence flexibility, and rCBV accuracy. The purpose of this study is to assess the in-vivo performance of dual-echo acquisitions in patients with brain tumors (n = 59). To verify pulse sequence flexibility, four single-dose dual-echo acquisitions were tested with variations in contrast agent dose, flip angle, and repetition time, and the resulting dual-echo rCBV was compared to standard single-echo rCBV obtained with preload (double-dose). Dual-echo rCBV was comparable to standard double-dose single-echo protocols (mean (standard deviation) tumor rCBV 2.17 (1.28) vs. 2.06 (1.20), respectively). High rCBV similarity was observed (CCC = 0.96), which was maintained across both flip angle (CCC = 0.98) and repetition time (CCC = 0.96) permutations, demonstrating that dual-echo acquisitions provide flexibility in acquisition parameters. Furthermore, a single dual-echo acquisition was shown to enable quantification of both perfusion and permeability metrics. In conclusion, single-dose dual-echo acquisitions provide similar rCBV to standard double-dose single-echo acquisitions, suggesting contrast agent dose can be reduced while providing significant pulse sequence flexibility and complementary tumor perfusion and permeability metrics.

Development of a spiral spin- and gradient-echo (spiral-SAGE) approach for improved multi-parametric dynamic contrast neuroimaging.

PURPOSE: The purpose of this study was to develop a spiral-based combined spin- and gradient-echo (spiral-SAGE) method for simultaneous dynamic contrast-enhanced (DCE-MRI) and dynamic susceptibility contrast MRI (DSC-MRI). METHODS: Using this sequence, we obtained gradient-echo TEs of 1.69 and 26 ms, a SE TE of 87.72 ms, with a TR of 1663 ms. Using an iterative SENSE reconstruction followed by deblurring, spiral-induced image artifacts were minimized. Healthy volunteer images are shown to demonstrate image quality using the optimized reconstruction, as well as for comparison with EPI-based SAGE. A bioreactor phantom was used to compare dynamic-contrast time courses with both spiral-SAGE and EPI-SAGE. A proof-of-concept cohort of patients with brain tumors shows the range of hemodynamic maps available using spiral-SAGE. RESULTS: Comparison of spiral-SAGE images with conventional EPI-SAGE images illustrates substantial reductions of image distortion and artifactual image intensity variations. Bioreactor phantom data show similar dynamic contrast time courses between standard EPI-SAGE and spiral-SAGE for the second and third echoes, whereas first-echo data show improvements in quantifying T1 changes with shorter echo times. In a cohort of patients with brain tumors, spiral-SAGE-based perfusion and permeability maps are shown with comparison with the standard single-echo EPI perfusion map. CONCLUSION: Spiral-SAGE provides a substantial improvement for the assessment of perfusion and permeability by mitigating artifacts typically encountered with EPI and by providing a shorter echo time for improved characterization of permeability. Spiral-SAGE enables quantification of perfusion, permeability, and vessel architectural parameters, as demonstrated in brain tumors.

Uncertainty quantification in the radiogenomics modeling of EGFR amplification in glioblastoma.

Radiogenomics uses machine-learning (ML) to directly connect the morphologic and physiological appearance of tumors on clinical imaging with underlying genomic features. Despite extensive growth in the area of radiogenomics across many cancers, and its potential role in advancing clinical decision making, no published studies have directly addressed uncertainty in these model predictions. We developed a radiogenomics ML model to quantify uncertainty using transductive Gaussian Processes (GP) and a unique dataset of 95 image-localized biopsies with spatially matched MRI from 25 untreated Glioblastoma (GBM) patients. The model generated predictions for regional EGFR amplification status (a common and important target in GBM) to resolve the intratumoral genetic heterogeneity across each individual tumor-a key factor for future personalized therapeutic paradigms. The model used probability distributions for each sample prediction to quantify uncertainty, and used transductive learning to reduce the overall uncertainty. We compared predictive accuracy and uncertainty of the transductive learning GP model against a standard GP model using leave-one-patient-out cross validation. Additionally, we used a separate dataset containing 24 image-localized biopsies from 7 high-grade glioma patients to validate the model. Predictive uncertainty informed the likelihood of achieving an accurate sample prediction. When stratifying predictions based on uncertainty, we observed substantially higher performance in the group cohort (75% accuracy, n = 95) and amongst sample predictions with the lowest uncertainty (83% accuracy, n = 72) compared to predictions with higher uncertainty (48% accuracy, n = 23), due largely to data interpolation (rather than extrapolation). On the separate validation set, our model achieved 78% accuracy amongst the sample predictions with lowest uncertainty. We present a novel approach to quantify radiogenomics uncertainty to enhance model performance and clinical interpretability. This should help integrate more reliable radiogenomics models for improved medical decision-making.

Analysis of postprocessing steps for residue function dependent dynamic susceptibility contrast (DSC)-MRI biomarkers and their clinical impact on glioma grading for both 1.5 and 3T.

BACKGROUND: Dynamic susceptibility contrast (DSC)-MRI analysis pipelines differ across studies and sites, potentially confounding the clinical value and use of the derived biomarkers. PURPOSE/HYPOTHESIS: To investigate how postprocessing steps for computation of cerebral blood volume (CBV) and residue function dependent parameters (cerebral blood flow [CBF], mean transit time [MTT], capillary transit heterogeneity [CTH]) impact glioma grading. STUDY TYPE: Retrospective study from The Cancer Imaging Archive (TCIA). POPULATION: Forty-nine subjects with low- and high-grade gliomas. FIELD STRENGTH/SEQUENCE: 1.5 and 3.0T clinical systems using a single-echo echo planar imaging (EPI) acquisition. ASSESSMENT: Manual regions of interest (ROIs) were provided by TCIA and automatically segmented ROIs were generated by k-means clustering. CBV was calculated based on conventional equations. Residue function dependent biomarkers (CBF, MTT, CTH) were found by two deconvolution methods: circular discretization followed by a signal-to-noise ratio (SNR)-adapted eigenvalue thresholding (Method 1) and Volterra discretization with L-curve-based Tikhonov regularization (Method 2). STATISTICAL TESTS: Analysis of variance, receiver operating characteristics (ROC), and logistic regression tests. RESULTS: MTT alone was unable to statistically differentiate glioma grade (P > 0.139). When normalized, tumor CBF, CTH, and CBV did not differ across field strengths (P > 0.141). Biomarkers normalized to automatically segmented regions performed equally (rCTH AUROC is 0.73 compared with 0.74) or better (rCBF AUROC increases from 0.74-0.84; rCBV AUROC increases 0.78-0.86) than manually drawn ROIs. By updating the current deconvolution steps (Method 2), rCTH can act as a classifier for glioma grade (P < 0.007), but not if processed by current conventional DSC methods (Method 1) (P > 0.577). Lastly, higher-order biomarkers (eg, rCBF and rCTH) along with rCBV increases AUROC to 0.92 for differentiating tumor grade as compared with 0.78 and 0.86 (manual and automatic reference regions, respectively) for rCBV alone. DATA CONCLUSION: With optimized analysis pipelines, higher-order perfusion biomarkers (rCBF and rCTH) improve glioma grading as compared with CBV alone. Additionally, postprocessing steps impact thresholds needed for glioma grading. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;51:547-553.

Systematic assessment of multi-echo dynamic susceptibility contrast MRI using a digital reference object.

PURPOSE: Brain tumor dynamic susceptibility contrast (DSC) MRI is adversely impacted by T1 and T2∗ contrast agent leakage effects that result in inaccurate hemodynamic metrics. While multi-echo acquisitions remove T1 leakage effects, there is no consensus on the optimal set of acquisition parameters. Using a computational approach, we systematically evaluated a wide range of acquisition strategies to determine the optimal multi-echo DSC-MRI perfusion protocol. METHODS: Using a population-based DSC-MRI digital reference object (DRO), we assessed the influence of preload dosing (no preload and full dose preload), field strength (1.5 and 3T), pulse sequence parameters (echo time, repetition time, and flip angle), and leakage correction on relative cerebral blood volume (rCBV) and flow (rCBF) accuracy. We also compared multi-echo DSC-MRI protocols with standard single-echo protocols. RESULTS: Multi-echo DSC-MRI is highly consistent across all protocols, and multi-echo rCBV (with or without use of a preload dose) had higher accuracy than single-echo rCBV. Regression analysis showed that choice of repetition time and flip angle had minimal impact on multi-echo rCBV and rCBV, indicating the potential for significant flexibility in acquisition parameters. The echo time combination had minimal impact on rCBV, though longer echo times should be avoided, particularly at higher field strengths. Leakage correction improved rCBV accuracy in all cases. Multi-echo rCBF was less biased than single-echo rCBF, although rCBF accuracy was reduced overall relative to rCBV. CONCLUSIONS: Multi-echo acquisitions were more robust than single-echo, essentially decoupling both repetition time and flip angle from rCBV accuracy. Multi-echo acquisitions obviate the need for preload dosing, although leakage correction to remove residual T2∗ leakage effects remains compulsory for high rCBV accuracy.

Imaging vascular and hemodynamic features of the brain using dynamic susceptibility contrast and dynamic contrast enhanced MRI.

In the context of neurologic disorders, dynamic susceptibility contrast (DSC) and dynamic contrast enhanced (DCE) MRI provide valuable insights into cerebral vascular function, integrity, and architecture. Even after two decades of use, these modalities continue to evolve as their biophysical and kinetic basis is better understood, with improvements in pulse sequences and accelerated imaging techniques and through application of more robust and automated data analysis strategies. Here, we systematically review each of these elements, with a focus on how their integration improves kinetic parameter accuracy and the development of new hemodynamic biomarkers that provide sub-voxel sensitivity (e.g., capillary transit time and flow heterogeneity). Regarding contrast mechanisms, we discuss the dipole-dipole interactions and susceptibility effects that give rise to simultaneous T1, T2 and T2∗ relaxation effects, including their quantification, influence on pulse sequence parameter optimization, and use in methods such as vessel size and vessel architectural imaging. The application of technologic advancements, such as parallel imaging, simultaneous multi-slice, undersampled k-space acquisitions, and sliding window strategies, enables improved spatial and/or temporal resolution of DSC and DCE acquisitions. Such acceleration techniques have also enabled the implementation of, clinically feasible, simultaneous multi-echo spin- and gradient echo acquisitions, providing more comprehensive and quantitative interrogation of T1, T2 and T2∗ changes. Characterizing these relaxation rate changes through different post-processing options allows for the quantification of hemodynamics and vascular permeability. The application of different biophysical models provides insight into traditional hemodynamic parameters (e.g., cerebral blood volume) and more advanced parameters (e.g., capillary transit time heterogeneity). We provide insight into the appropriate selection of biophysical models and the necessary post-processing steps to ensure reliable measurements while minimizing potential sources of error. We show representative examples of advanced DSC- and DCE-MRI methods applied to pathologic conditions affecting the cerebral microcirculation, including brain tumors, stroke, aging, and multiple sclerosis. The maturation and standardization of conventional DSC- and DCE-MRI techniques has enabled their increased integration into clinical practice and use in clinical trials, which has, in turn, spurred renewed interest in their technological and biophysical development, paving the way towards a more comprehensive assessment of cerebral hemodynamics.

Characterizing the Influence of Preload Dosing on Percent Signal Recovery (PSR) and Cerebral Blood Volume (CBV) Measurements in a Patient Population With High-Grade Glioma Using Dynamic Susceptibility Contrast MRI.

With DSC-MRI, contrast agent leakage effects in brain tumors can either be leveraged for percent signal recovery (PSR) measurements or be adequately resolved for accurate relative cerebral blood volume (rCBV) measurements. Leakage effects can be dimished by administration of a preload dose before imaging and/or specific postprocessing steps. This study compares the consistency of both PSR and rCBV measurements as a function of varying preload doses in a retrospective analysis of 14 subjects with high-grade gliomas. The scans consisted of 6 DSC-MRI scans during 6 sequential bolus injections (0.05 mmol/kg). Mean PSR was calculated for tumor and normal-appearing white matter regions of interest. DSC-MRI data were corrected for leakage effects before computing mean tumor rCBV. Statistical differences were seen across varying preloads for tumor PSR (P value = 4.57E-24). Tumor rCBV values did not exhibit statistically significant differences across preloads (P value = .14) and were found to be highly consistent for clinically relevant preloads (intraclass correlation coefficient = 0.93). For a 0.05 mmol/kg injection bolus and pulse sequence parameters used, the highest PSR contrast between normal-appearing white matter and tumor occurs when no preload is used. This suggests that studies using PSR as a biomarker should acquire DSC-MRI data without preload. The finding that leakage-corrected rCBV values do not depend on the presence or dose of preload contradicts that of previous studies with dissimilar acquisition protocols. This further confirms the sensitivity of rCBV to preload dosing schemes and pulse sequence parameters and highlights the importance of standardization efforts for achieving multisite rCBV consistency.

A Population-Based Digital Reference Object (DRO) for Optimizing Dynamic Susceptibility Contrast (DSC)-MRI Methods for Clinical Trials.

The standardization and broad-scale integration of dynamic susceptibility contrast (DSC)-magnetic resonance imaging (MRI) have been confounded by a lack of consensus on DSC-MRI methodology for preventing potential relative cerebral blood volume inaccuracies, including the choice of acquisition protocols and postprocessing algorithms. Therefore, we developed a digital reference object (DRO), using physiological and kinetic parameters derived from in vivo data, unique voxel-wise 3-dimensional tissue structures, and a validated MRI signal computational approach, aimed at validating image acquisition and analysis methods for accurately measuring relative cerebral blood volume in glioblastomas. To achieve DSC-MRI signals representative of the temporal characteristics, magnitude, and distribution of contrast agent-induced T1 and changes observed across multiple glioblastomas, the DRO's input parameters were trained using DSC-MRI data from 23 glioblastomas (>40 000 voxels). The DRO's ability to produce reliable signals for combinations of pulse sequence parameters and contrast agent dosing schemes unlike those in the training data set was validated by comparison with in vivo dual-echo DSC-MRI data acquired in a separate cohort of patients with glioblastomas. Representative applications of the DRO are presented, including the selection of DSC-MRI acquisition and postprocessing methods that optimize CBV accuracy, determination of the impact of DSC-MRI methodology choices on sample size requirements, and the assessment of treatment response in clinical glioblastoma trials.

Hypoxia Imaging With PET Correlates With Antitumor Activity of the Hypoxia-Activated Prodrug Evofosfamide (TH-302) in Rodent Glioma Models.

High-grade gliomas are often characterized by hypoxia, which is associated with both poor long-term prognosis and therapy resistance. The adverse role hypoxia plays in treatment resistance and disease progression has led to the development of hypoxia imaging methods and hypoxia-targeted treatments. Here, we determined the tumor hypoxia and vascular perfusion characteristics of 2 rat orthotopic glioma models using 18-fluoromisonidozole positron emission tomography. In addition, we determined tumor response to the hypoxia-activated prodrug evofosfamide (TH-302) in these rat glioma models. C6 tumors exhibited more hypoxia and were less perfused than 9L tumors. On the basis of these differences in their tumor hypoxic burden, treatment with evofosfamide resulted in 4- and 2-fold decreases in tumor growth rates of C6 and 9L tumors, respectively. This work shows that imaging methods sensitive to tumor hypoxia and perfusion are able to predict response to hypoxia-targeted agents. This has implications for improved patient selection, particularly in clinical trials, for treatment with hypoxia-activated cytotoxic prodrugs, such as evofosfamide.

Assessment of a simplified spin and gradient echo (sSAGE) approach for human brain tumor perfusion imaging.

The goal of this study was to validate a simplified spin- and gradient-echo (sSAGE) approach to obtain T1-corrected dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) data in a clinical brain tumor population. A five-echo SAGE sequence was used to acquire DSC-MRI data (n=8 patients, 3 primary glioma, and 5 brain metastases). The ΔR2⁎ and ΔR2 time series obtained from a nonlinear fit of all echoes (SAGE) were compared to ΔR2⁎ and ΔR2 time series obtained analytically (sSAGE) using three echoes (two GEs and one SE). Through the use of multiple echoes, both methods removed T1 leakage effects from the ΔR2⁎ and ΔR2 time series, and the sSAGE ΔR2⁎ and ΔR2 time series were highly correlated with those from SAGE, with average correlations of 0.9. The resulting hemodynamic parameters included GE and SE cerebral blood volume (CBV), cerebral blood flow (CBF), mean vessel diameter (mVD), volume transfer constant (Ktrans), and volume fraction of the extravascular extracellular space (ve). For each metric, there was good correlation (>0.86) between sSAGE and SAGE, with no significant differences. The sSAGE method provides T1-corrected GE and SE DSC-MRI parameters in an efficient and clinically feasible manner.

Influence of water compartmentation and heterogeneous relaxation on quantitative magnetization transfer imaging in rodent brain tumors.

PURPOSE: The goal of this study was to investigate the influence of water compartmentation and heterogeneous relaxation properties on quantitative magnetization transfer (qMT) imaging in tissues, and in particular whether a two-pool model is sufficient to describe qMT data in brain tumors. METHODS: Computer simulations and in vivo experiments with a series of qMT measurements before and after injection of Gd-DTPA were performed. Both off-resonance pulsed saturation (pulsed) and on-resonance selective inversion recovery (SIR) qMT methods were used, and all data were fit with a two-pool model only. RESULTS: Simulations indicated that a two-pool fitting of four-pool data yielded accurate measures of pool size ratio (PSR) of macromolecular versus free water protons when there were fast transcytolemmal exchange and slow R1 recovery. The fitted in vivo PSR of both pulsed and SIR qMT methods showed no dependence on R1 variations caused by different concentrations of Gd-DTPA during wash-out, whereas the fitted kex (magnetization transfer exchange rate) changed significantly with R1 . CONCLUSION: A two-pool model provides reproducible estimates of PSR in brain tumors independent of relaxation properties in the presence of relatively fast transcytolemmal exchange, whereas estimates of kex are biased by relaxation variations. In addition, estimates of PSR in brain tumors using the pulsed and SIR qMT methods agree well with one another. Magn Reson Med 76:635-644, 2016. © 2015 Wiley Periodicals, Inc.

Validation of a T1 and T2* leakage correction method based on multiecho dynamic susceptibility contrast MRI using MION as a reference standard.

PURPOSE: A combined biophysical- and pharmacokinetic-based method is proposed to separate, quantify, and correct for both T1 and T2* leakage effects using dual-echo dynamic susceptibility contrast (DSC) acquisitions to provide more accurate hemodynamic measures, as validated by a reference intravascular contrast agent (CA). THEORY AND METHODS: Dual-echo DSC-MRI data were acquired in two rodent glioma models. The T1 leakage effects were removed and also quantified to subsequently correct for the remaining T2* leakage effects. Pharmacokinetic, biophysical, and combined biophysical and pharmacokinetic models were used to obtain corrected cerebral blood volume (CBV) and cerebral blood flow (CBF), and these were compared with CBV and CBF from an intravascular CA. RESULTS: T1 -corrected CBV was significantly overestimated compared with MION CBV, while T1 + T2*-correction yielded CBV values closer to the reference values. The pharmacokinetic and simplified biophysical methods showed similar results and underestimated CBV in tumors exhibiting strong T2* leakage effects. The combined method was effective for correcting T1 and T2* leakage effects across tumor types. CONCLUSION: Correcting for both T1 and T2* leakage effects yielded more accurate measures of CBV. The combined correction method yields more reliable CBV measures than either correction method alone, but for certain brain tumor types (e.g., gliomas), the simplified biophysical method may provide a robust and computationally efficient alternative. Magn Reson Med 76:613-625, 2016. © 2015 Wiley Periodicals, Inc.

A simplified spin and gradient echo approach for brain tumor perfusion imaging.

PURPOSE: In this study, we propose a simplified acquisition and analysis approach for spin and gradient echo (SAGE)-based dynamic susceptibility-contrast MRI (DSC-MRI) data that is free of contrast agent T1 leakage effects. METHODS: A five-echo SAGE sequence was used to acquire DSC-MRI data in rat C6 tumors (n = 7). Nonlinear fitting of all echoes was performed to obtain T1-insensitive ΔR2* and ΔR2 time series. The simplified approach, which includes two gradient echoes and one spin echo, was also used to analytically compute T1-insensitive ΔR2* using the two gradient echoes and ΔR2 using all three echoes. The blood flow, blood volume, and vessel size values derived from each method were compared. RESULTS: In all cases, the five-echo and simplified SAGE ΔR2* and ΔR2 were in excellent agreement and demonstrated significant T1 leakage correction compared with the uncorrected single-echo data. The derived hemodynamic parameters for blood volume, blood flow, and vessel size were not significantly different between the two methods. CONCLUSIONS: The proposed simplified SAGE technique enables the acquisition of gradient and spin echo DSC-MRI data corrected for T1 leakage effects yields parameters that are in agreement with the five-echo SAGE approach and does not require nonlinear fitting to extract ΔR2* and ΔR2 time series.

MR Imaging Biomarkers in Oncology Clinical Trials.

The authors discuss eight areas of quantitative MR imaging that are currently used (RECIST, DCE-MR imaging, DSC-MR imaging, diffusion MR imaging) in clinical trials or emerging (CEST, elastography, hyperpolarized MR imaging, multiparameter MR imaging) as promising techniques in diagnosing cancer and assessing or predicting response of cancer to therapy. Illustrative applications of the techniques in the clinical setting are summarized before describing the current limitations of the methods.

Assessment of a combined spin- and gradient-echo (SAGE) DSC-MRI method for preclinical neuroimaging.

The goal of this study was to optimize and validate a combined spin- and gradient-echo (SAGE) sequence for dynamic susceptibility-contrast magnetic resonance imaging to obtain hemodynamic parameters in a preclinical setting. The SAGE EPI sequence was applied in phantoms and in vivo rat brain (normal, tumor, and stroke tissue). Partial and full Fourier encoding schemes were implemented and characterized. Maps of cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT), vessel size index (VSI), volume transfer constant (K(trans)), and volume fraction of the extravascular extracellular space (ve) were obtained. Partial Fourier encoding provided shortened echo times with acceptable signal-to-noise ratio and temporal stability, thus enabling reliable characterization of T2, T2(*) and T1 in both phantoms and rat brain. The hemodynamic parameters CBV, CBF, and MTT for gradient-echo and spin-echo contrast were determined in tumor and stroke; VSI, K(trans), and ve were also computed in tumor tissue. The SAGE EPI sequence allows the acquisition of multiple gradient- and spin-echoes, from which measures of perfusion, permeability, and vessel size can be obtained in a preclinical setting. Partial Fourier encoding can be used to minimize SAGE echo times and reliably quantify dynamic T2 and T2(*) changes. This acquisition provides a more comprehensive assessment of hemodynamic status in brain tissue with vascular and perfusion abnormalities.