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

BackgroundRelative 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.MethodsThe 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.ResultsThe 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%).ConclusionsThe 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

Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumors

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.Fondo de Desarrollo Regional (FEDER). Programa Operativo Epiro 2014-2020National Strategic Reference Frameworks de la Unión Europea. NSRF 2014-2020-5033092Ministerio de Ciencia, Innovación y Universidades de España y fondos FEDER. RTI2018-098645-B-100Consejería de Economía y Conocimiento de la Junta de Andalucía y fondos FEDER. P18- RT-1372Universidad de Sevilla. US-126480

Toward Uniform Implementation Of Parametric Map Digital Imaging And Communication In Medicine Standard In Multisite Quantitative Diffusion Imaging Studies

This paper reports on results of a multisite collaborative project launched by the MRI subgroup of Quantitative Imaging Network to assess current capability and provide future guidelines for generating a standard parametric diffusion map Digital Imaging and Communication in Medicine (DICOM) in clinical trials that utilize quantitative diffusion-weighted imaging (DWI). Participating sites used a multivendor DWI DICOM dataset of a single phantom to generate parametric maps (PMs) of the apparent diffusion coefficient (ADC) based on two models. The results were evaluated for numerical consistency among models and true phantom ADC values, as well as for consistency of metadata with attributes required by the DICOM standards. This analysis identified missing metadata descriptive of the sources for detected numerical discrepancies among ADC models. Instead of the DICOM PM object, all sites stored ADC maps as DICOM MR objects, generally lacking designated attributes and coded terms for quantitative DWI modeling. Source-image reference, model parameters, ADC units and scale, deemed important for numerical consistency, were either missing or stored using nonstandard conventions. Guided by the identified limitations, the DICOM PM standard has been amended to include coded terms for the relevant diffusion models. Open-source software has been developed to support conversion of site-specific formats into the standard representation

A cross-sectional study to test equivalence of low- versus intermediate-flip angle dynamic susceptibility contrast MRI measures of relative cerebral blood volume in patients with high-grade gliomas at 1.5 Tesla field strength

Introduction1.5 Tesla (1.5T) remain a significant field strength for brain imaging worldwide. Recent computer simulations and clinical studies at 3T MRI have suggested that dynamic susceptibility contrast (DSC) MRI using a 30° flip angle (“low-FA”) with model-based leakage correction and no gadolinium-based contrast agent (GBCA) preload provides equivalent relative cerebral blood volume (rCBV) measurements to the reference-standard acquisition using a single-dose GBCA preload with a 60° flip angle (“intermediate-FA”) and model-based leakage correction. However, it remains unclear whether this holds true at 1.5T. The purpose of this study was to test this at 1.5T in human high-grade glioma (HGG) patients.MethodsThis was a single-institution cross-sectional study of patients who had undergone 1.5T MRI for HGG. DSC-MRI consisted of gradient-echo echo-planar imaging (GRE-EPI) with a low-FA without preload (30°/P-); this then subsequently served as a preload for the standard intermediate-FA acquisition (60°/P+). Both normalized (nrCBV) and standardized relative cerebral blood volumes (srCBV) were calculated using model-based leakage correction (C+) with IBNeuro™ software. Whole-enhancing lesion mean and median nrCBV and srCBV from the low- and intermediate-FA methods were compared using the Pearson’s, Spearman’s and intraclass correlation coefficients (ICC).ResultsTwenty-three HGG patients composing a total of 31 scans were analyzed. The Pearson and Spearman correlations and ICCs between the 30°/P-/C+ and 60°/P+/C+ acquisitions demonstrated high correlations for both mean and median nrCBV and srCBV.ConclusionOur study provides preliminary evidence that for HGG patients at 1.5T MRI, a low FA, no preload DSC-MRI acquisition can be an appealing alternative to the reference standard higher FA acquisition that utilizes a preload

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

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

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 T 1 , T 2 and T 2∗ 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 T 1 , T 2 and T 2∗ 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