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Background In Radiation Therapy Oncology Group (RTOG) 0825, a phase III trial of standard therapy with bevacizumab or without (placebo) in newly diagnosed glioblastoma, 44 patients underwent dynamic contrast enhanced (DCE) and/or dynamic susceptibility contrast (DSC) MRI in the American College of Radiology Imaging Network (ACRIN) trial 6686. The association between early changes in relative cerebral blood volume (rCBV) and volume transfer constant (Ktrans) with overall survival (OS) was evaluated. Methods MRI was performed at postop baseline (S0), immediately before (S1), 1 day after (S2), and 7 weeks after (S3) bevacizumab or placebo initiation. Mean normalized and standardized rCBV (nRCBV, sRCBV) and Ktrans were measured within contrast-enhancing lesion. Wilcoxon rank sum tests compared parameter changes from S1–S2 and S1–S3. Association with OS and progression-free survival (PFS) were determined using Kaplan–Meier and log-rank tests. Treatment response for groups stratified by pretreatment nRCBV (S0, S1) was explored. The intraclass correlation coefficient and repeatability coefficient for the placebo arm (S1–S2) were used to assess repeatability. Results Evaluable were 27–36 datasets per time point. Significant differences between treatment arms were found for changes in nRCBV and sRCBV from S1–S2 and S1–S3, and in Ktrans for S1–S3. Improved PFS (P = 0.05) but not OS (P = 0.46) was observed. High pretreatment rCBV predicted improved OS for bevacizumab-treated patients. Based on the intraclass correlation coefficient, sRCBV (0.92) was more repeatable than nRCBV (0.71) and Ktrans (0.75), consistent with repeatability coefficient values. Conclusions Bevacizumab significantly changes rCBV but not Ktrans as early as 1 day posttreatment in newly diagnosed glioblastoma unrelated to outcomes. Improvements in clinical trial design to maximize rCBV benefit are indicated.

Despite the widespread clinical use of dynamic susceptibility contrast (DSC) MRI, DSC-MRI methodology has not been standardized, hindering its utilization for response assessment in multicenter trials. Recently, the DSC-MRI Standardization Subcommittee of the Jumpstarting Brain Tumor Drug Development Coalition issued an updated consensus DSC-MRI protocol compatible with the standardized brain tumor imaging protocol (BTIP) for high-grade gliomas that is increasingly used in the clinical setting and is the default MRI protocol for the National Clinical Trials Network. After reviewing the basis for controversy over DSC-MRI protocols, this paper provides evidence-based best practices for clinical DSC-MRI as determined by the Committee, including pulse sequence (gradient echo vs spin echo), BTIP-compliant contrast agent dosing (preload and bolus), flip angle (FA), echo time (TE), and post-processing leakage correction. In summary, full-dose preload, full-dose bolus dosing using intermediate (60°) FA and field strength-dependent TE (40–50 ms at 1.5 T, 20–35 ms at 3 T) provides overall best accuracy and precision for cerebral blood volume estimates. When single-dose contrast agent usage is desired, no-preload, full-dose bolus dosing using low FA (30°) and field strength-dependent TE provides excellent performance, with reduced contrast agent usage and elimination of potential systematic errors introduced by variations in preload dose and incubation time.

A recent meeting was held on March 22, 2019, among the FDA, clinical scientists, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocacy groups to discuss challenges and potential solutions for increasing development of therapeutics for central nervous system metastases. A key issue identified at this meeting was the need for consistent tumor measurement for reliable tumor response assessment, including the first step of standardized image acquisition with an MRI protocol that could be implemented in multicenter studies aimed at testing new therapeutics. This document builds upon previous consensus recommendations for a standardized brain tumor imaging protocol (BTIP) in high-grade gliomas and defines a protocol for brain metastases (BTIP-BM) that addresses unique challenges associated with assessment of CNS metastases. The “minimum standard” recommended pulse sequences include: (i) parameter matched pre- and post-contrast inversion recovery (IR)–prepared, isotropic 3D T1-weighted gradient echo (IR-GRE); (ii) axial 2D T2-weighted turbo spin echo acquired after injection of gadolinium-based contrast agent and before post-contrast 3D T1-weighted images; (iii) axial 2D or 3D T2-weighted fluid attenuated inversion recovery; (iv) axial 2D, 3-directional diffusion-weighted images; and (v) post-contrast 2D T1-weighted spin echo images for increased lesion conspicuity. Recommended sequence parameters are provided for both 1.5T and 3T MR systems. An “ideal” protocol is also provided, which replaces IR-GRE with 3D TSE T1-weighted imaging pre- and post-gadolinium, and is best performed at 3T, for which dynamic susceptibility contrast perfusion is included. Recommended perfusion parameters are given.

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Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been correlated with prognosis in head and neck squamous cell carcinoma as well as with changes in normal tissues. These studies implement different software, either commercial or in-house, and different scan protocols. Thus, the generalizability of the results is not confirmed. To assist in the standardization of quantitative metrics to confirm the generalizability of these previous studies, this data descriptor delineates in detail the DCE-MRI digital imaging and communications in medicine (DICOM) files with DICOM radiation therapy (RT) structure sets and digital reference objects (DROs), as well as, relevant clinical data that encompass a data set that can be used by all software for comparing quantitative metrics. Variable flip angle (VFA) with six flip angles and DCE-MRI scans with a temporal resolution of 5.5 s were acquired in the axial direction on a 3T MR scanner with a field of view of 25.6 cm, slice thickness of 4 mm, and 256×256 matrix size.

The study goal was to determine whether changes in relative cerebral blood volume (rCBV) derived from dynamic susceptibility contrast (DSC) MRI are predictive of overall survival (OS) in patients with recurrent glioblastoma multiforme (GBM) when measured 2, 8, and 16 weeks after treatment initiation.Patients with recurrent GBM (37/123) enrolled in ACRIN 6677/RTOG 0625, a multicenter, randomized, phase II trial of bevacizumab with irinotecan or temozolomide, consented to DSC-MRI plus conventional MRI, 21 with DSC-MRI at baseline and at least 1 postbaseline scan. Contrast-enhancing regions of interest were determined semi-automatically using pre- and postcontrast T1-weighted images. Mean tumor rCBV normalized to white matter (nRCBV) and standardized rCBV (sRCBV) were determined for these regions of interest. The OS rates for patients with positive versus negative changes from baseline in nRCBV and sRCBV were compared using Wilcoxon rank-sum and Kaplan-Meier survival estimates with log-rank tests.Patients surviving at least 1 year (OS-1) had significantly larger decreases in nRCBV at week 2 (P = .0451) and sRCBV at week 16 (P = .014). Receiver operating characteristic analysis found the percent changes of nRCBV and sRCBV at week 2 and sRCBV at week 16, but not rCBV data at week 8, to be good prognostic markers for OS-1. Patients with positive change from baseline rCBV had significantly shorter OS than those with negative change at both week 2 and week 16 (P = .0015 and P = .0067 for nRCBV and P = .0251 and P = .0004 for sRCBV, respectively).Early decreases in rCBV are predictive of improved survival in patients with recurrent GBM treated with bevacizumab.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) provides quantitative metrics (e.g. Ktrans, ve) via pharmacokinetic models. We tested inter-algorithm variability in these quantitative metrics with 11 published DCE-MRI algorithms, all implementing Tofts-Kermode or extended Tofts pharmacokinetic models. Digital reference objects (DROs) with known Ktrans and ve values were used to assess performance at varying noise levels. Additionally, DCE-MRI data from 15 head and neck squamous cell carcinoma patients over 3 time-points during chemoradiotherapy were used to ascertain Ktrans and ve kinetic trends across algorithms. Algorithms performed well (less than 3% average error) when no noise was present in the DRO. With noise, 87% of Ktrans and 84% of ve algorithm-DRO combinations were generally in the correct order. Low Krippendorff’s alpha values showed that algorithms could not consistently classify patients as above or below the median for a given algorithm at each time point or for differences in values between time points. A majority of the algorithms produced a significant Spearman correlation in ve of the primary gross tumor volume with time. Algorithmic differences in Ktrans and ve values over time indicate limitations in combining/comparing data from distinct DCE-MRI model implementations. Careful cross-algorithm quality-assurance must be utilized as DCE-MRI results may not be interpretable using differing software.

RTOG 0625/ACRIN 6677 is a multicenter, randomized, phase II trial of bevacizumab with irinotecan or temozolomide in recurrent glioblastoma (GBM). This study investigated whether early posttreatment progression on FLAIR or postcontrast MRI assessed by central reading predicts overall survival (OS).Of 123 enrolled patients, 107 had baseline and at least 1 posttreatment MRI. Two central neuroradiologists serially measured bidimensional (2D) and volumetric (3D) enhancement on postcontrast T1-weighted images and volume of FLAIR hyperintensity. Progression status on all posttreatment MRIs was determined using Macdonald and RANO imaging threshold criteria, with a third neuroradiologist adjudicating discrepancies of both progression occurrence and timing. For each MRI pulse sequence, Kaplan-Meier survival estimates and log-rank test were used to compare OS between cases with or without radiologic progression.Radiologic progression occurred after 2 chemotherapy cycles (8 weeks) in 9 of 97 (9%), 9 of 73 (12%), and 11 of 98 (11%) 2D-T1, 3D-T1, and FLAIR cases, respectively, and 34 of 80 (43%), 21 of 58 (36%), and 37 of 79 (47%) corresponding cases after 4 cycles (16 weeks). Median OS among patients progressing at 8 or 16 weeks was significantly less than that among nonprogressors, as determined on 2D-T1 (114 vs 278 days and 214 vs 426 days, respectively; P.0001 for both) and 3D-T1 (117 vs 306 days [P.0001] and 223 vs 448 days [P = .0003], respectively) but not on FLAIR (201 vs 276 days [P = .38] and 303 vs 321 days [P = .13], respectively).Early progression on 2D-T1 and 3D-T1, but not FLAIR MRI, after 8 and 16 weeks of anti-vascular endothelial growth factor therapy has highly significant prognostic value for OS in recurrent GBM.

Purpose: Calculation of the precontrast longitudinal relaxation times T10 is an integral part of the Tofts-based pharmacokinetic PK analysis of dynamic contrast enhanced–magnetic resonance images. The purpose of this study was to investigate the interpatient and over time variability of T10 in head and neck primary tumors and involved nodes and to determine the median T10 for primary and nodes T 10 p,n . The authors also looked at the implication of using voxel-based T10 values versus region of interest ROI-based T10 on the calculated values for vascular permeability K trans and extracellular volume fraction ve. Methods: Twenty head and neck cancer patients receiving concurrent chemoradiation and molecularly targeted agents on a prospective trial comprised the study population. Voxel-based T10’s were generated using a gradient echo sequence on a 1.5 T MR scanner using the variable flip angle method with two flip angles J. A. Brookes et al., “Measurement of spin-lattice relaxation times with FLASH for dynamic MRI of the breast,” Br. J. Radiol. 69, 206–214 1996. The voxel-based T10, K trans , and ve were calculated using iCAD’s ® Nashua, NH software. The mean T10’s in muscle and fat ROIs were calculated T10 m,f . To assess reliability of ROI drawing, T10 p,n values from ROIs delineated by 2 users A and B were calculated as the average of the T10’s for 14 patients. For a subset of three patients, the T10 variability from baseline to end of treatment was also investigated. The K trans and ve from primary and node ROIs were calculated using voxel-based T10 values and T 10 p,n and differences reported. Results: The calculated T 10 values for fat and muscle are within the range of values reported in literature for 1.5 T, i.e., T 10 m = 0.958 s and T 10 f = 0.303 s. The average over 14 patients of the T10’s based on drawings by users A and B were T 10 pA = 0.804 s, T 10 nA = 0.760 s, T 10 pB = 0.849 s, and T10 nB = 0.810 s. The absolute percentage difference between K trans and ve calculated with voxelbased T10 versus T 10 p,n ranged from 6% to 81% and from 2% to 24%, respectively. Conclusions: There is a certain amount of variability in the median T10 values between patients, but the differences are not significant. There were also no statistically significant differences between the T10 values for primary and nodes at baseline and the subsequent time points p = 0.94 Friedman test. Voxel-based T10 calculations are essential when quantitative Tofts-based PK analysis in heterogeneous tumors is needed. In the absence of T10 mapping capability, when a relative, qualitative analysis is deemed sufficient, a value of T 10 p,n = 0.800 s can be used as an estimate for T10 for both the primary tumor and the affected nodes in head and neck cancers at all the time points considered. © 2010 American Association of Physicists in Medicine. DOI: 10.1118/1.3427487

This article describes methods and issues that are specific to the assessment of change in tumor characteristics as measured using quantitative magnetic resonance (MR) techniques and how this relates to the establishment of quantitative MR imaging (MRI) biomarkers of patient response to therapy. The initial focus is on the various sources of bias and variance in the measurement of microvascular parameters and diffusion parameters as such parameters are being used relatively commonly as secondary or exploratory end points in current phase 1/2 clinical trails of conventional and targeted therapies. Several ongoing initiatives that seek to identify the magnitude of some of the sources of measurement variations are then discussed. Finally, resources being made available through the National Cancer Institute Reference Image Database to Evaluate Response (RIDER) project that might be of use in investigations of quantitative MRI biomarker change analysis are described. These resources include 1) data from phantom-based assessment of system response, including short-term (1 hour) and moderate-term (1 week) contrast response and relaxation time measurement, 2) data obtained from repeated dynamic contrast agent-enhanced MRI studies in intracranial tumors, and 3) data obtained from repeated diffusion MRI studies in both breast and brain. A concluding section briefly discusses issues that must be addressed to allow the transition of MR-based imaging biomarker measures from their current role as secondary/exploratory end points in clinical trials to primary/surrogate markers of response and, ultimately, in clinical application.

To compare the performance of three physiologically-based pharmacokinetic (PBPK) models for predicting gadolinium contrast agent concentration-time curves (Gd-CTCs) obtained in superior sagittal sinus (SSS), cerebral cortex, and psoas muscle.Three published whole-body PBPK models were modified to predict Gd-CTCs in normal-appearing tissue. The models differed in the number of organs modeled and total number of compartments, and were designated as the "well-mixed," "delay," and "dispersion" models. The suitability of the three models to predict Gd-CTC was studied using data from dynamic contrast-enhanced MR perfusion imaging obtained at 1.5T from 10 patients with glioblastoma multiforme and at 3.0T from five patients with liver metastases.The dispersion model produced better fits than the delay model in the SSS (P0.0001) and cerebral cortex (P0.0001), and better fits than the well-mixed model in psoas muscle (P0.005). No model produced better fits than the dispersion model at any of the three locations.In this evaluation, the dispersion model was most robust for prediction of Gd-CTCs derived from dynamic contrast-enhanced (DCE)-MRI. This represents a preliminary step in the development of a PBPK model useful for predicting Gd-CTCs at a time resolution appropriate for dynamic MRI applications.

Purpose: Structural and functional alterations in tumor vasculature are thought to contribute to tumor hypoxia which is a primary driver of malignancy through its negative impact on the efficacy of radiation, immune surveillance, apoptosis, genomic stability, and accelerated angiogenesis. We performed a prospective, multicenter study to test the hypothesis that abnormal tumor vasculature and hypoxia, as measured with MRI and PET, will negatively impact survival in patients with newly diagnosed glioblastoma. Experimental Design: Prior to the start of chemoradiation, patients with glioblastoma underwent MRI scans that included dynamic contrast enhanced and dynamic susceptibility contrast perfusion sequences to quantitate tumor cerebral blood volume/flow (CBV/CBF) and vascular permeability (ktrans) as well as 18F-Fluoromisonidazole (18F-FMISO) PET to quantitate tumor hypoxia. ROC analysis and Cox regression models were used to determine the association of imaging variables with progression-free and overall survival. Results: Fifty patients were enrolled of which 42 had evaluable imaging data. Higher pretreatment 18F-FMISO SUVpeak (P = 0.048), mean ktrans (P = 0.024), and median ktrans (P = 0.045) were significantly associated with shorter overall survival. Higher pretreatment median ktrans (P = 0.021), normalized RCBV (P = 0.0096), and nCBF (P = 0.038) were significantly associated with shorter progression-free survival. SUVpeak [AUC = 0.75; 95% confidence interval (CI), 0.59–0.91], nRCBV (AUC = 0.72; 95% CI, 0.56–0.89), and nCBF (AUC = 0.72; 95% CI, 0.56–0.89) were predictive of survival at 1 year. Conclusions: Increased tumor perfusion, vascular volume, vascular permeability, and hypoxia are negative prognostic markers in newly diagnosed patients with gioblastoma, and these important physiologic markers can be measured safely and reliably using MRI and 18F-FMISO PET. Clin Cancer Res; 22(20); 5079–86. ©2016 AACR.

A recent joint meeting was held on January 30, 2014, with the US Food and Drug Administration (FDA), National Cancer Institute (NCI), clinical scientists, imaging experts, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocate groups to discuss imaging endpoints for clinical trials in glioblastoma. This workshop developed a set of priorities and action items including the creation of a standardized MRI protocol for multicenter studies. The current document outlines consensus recommendations for a standardized Brain Tumor Imaging Protocol (BTIP), along with the scientific and practical justifications for these recommendations, resulting from a series of discussions between various experts involved in aspects of neuro-oncology neuroimaging for clinical trials. The minimum recommended sequences include: (i) parameter-matched precontrast and postcontrast inversion recovery-prepared, isotropic 3D T1-weighted gradient-recalled echo; (ii) axial 2D T2-weighted turbo spin-echo acquired after contrast injection and before postcontrast 3D T1-weighted images to control timing of images after contrast administration; (iii) precontrast, axial 2D T2-weighted fluid-attenuated inversion recovery; and (iv) precontrast, axial 2D, 3-directional diffusion-weighted images. Recommended ranges of sequence parameters are provided for both 1.5 T and 3 T MR systems.

BACKGROUND AND PURPOSE: For more widespread clinical use advanced imaging methods such as relative cerebral blood volume must be both accurate and repeatable. The aim of this study was to determine the repeatability of relative CBV measurements in newly diagnosed glioblastoma multiforme by using several of the most commonly published estimation techniques. MATERIALS AND METHODS: The relative CBV estimates were calculated from dynamic susceptibility contrast MR imaging in double-baseline examinations for 33 patients with treatment-naive and pathologically proved glioblastoma multiforme (men = 20; mean age = 55 years). Normalized and standardized relative CBV were calculated by using 6 common postprocessing methods. The repeatability of both normalized and standardized relative CBV, in both tumor and contralateral brain, was examined for each method with metrics of repeatability, including the repeatability coefficient and within-subject coefficient of variation. The minimum sample size required to detect a parameter change of 10% or 20% was also determined for both normalized relative CBV and standardized relative CBV for each estimation method. RESULTS: When ordered by the repeatability coefficient, methods using postprocessing leakage correction and ΔR2*(t) techniques offered superior repeatability. Across processing techniques, the standardized relative CBV repeatability in normal-appearing brain was comparable with that in tumor ( P = .31), yet inferior in tumor for normalized relative CBV ( P = .03). On the basis of the within-subject coefficient of variation, tumor standardized relative CBV estimates were less variable (13%–20%) than normalized relative CBV estimates (24%–67%). The minimum number of participants needed to detect a change of 10% or 20% is 118–643 or 30–161 for normalized relative CBV and 109–215 or 28–54 for standardized relative CBV. CONCLUSIONS: The ΔR2* estimation methods that incorporate leakage correction offer the best repeatability for relative CBV, with standardized relative CBV being less variable and requiring fewer participants to detect a change compared with normalized relative CBV.

Diffusion-weighted magnetic resonance (MR) imaging and perfusion MR imaging are advanced techniques that provide information not available from conventional MR imaging. In particular, these techniques have a number of applications with regard to characterization of tumors and assessment of tumor response to therapy. In this review, the authors describe the fundamental principles of diffusion-weighted and perfusion MR imaging and provide an overview of the ways in which these techniques are being used to characterize tumors by helping distinguish tumor types, assess tumor grade, and attempt to determine tumor margins. In addition, the role of these techniques for evaluating response to tumor therapy is outlined.

The purpose of our study was to determine the degree to which carotid canal fracture and other CT findings are associated with internal carotid artery (ICA) injury in patients with head trauma.Three neuroradiologists retrospectively evaluated CT scans and cerebral angiograms of 43 patients who underwent cerebral angiography within 7 days after blunt cranial trauma over a 5-year period. Seventeen patients underwent unilateral and 26 had bilateral carotid angiography. Angiograms were evaluated for ICA injury and CT scans were evaluated for carotid canal fracture, brain contusion, subarachnoid hemorrhage, basilar skull fracture, subdural hematoma, soft-tissue swelling, sphenoid sinus air-fluid level, and other skull fracture. We recorded the number of true-positive (+CT, +angiogram), true-negative (-CT, -angiogram), false-positive (+CT, -angiogram), and false-negative (-CT, +angiogram) studies. We determined the sensitivity, specificity, positive predictive value, and negative predictive value for each CT finding.We identified 21 carotid canal fractures in 17 patients. Eleven ICA injuries were seen in 10 patients. Six patients with ICA injury had a carotid canal fracture. The presence of a carotid canal fracture had a sensitivity of 60% and specificity of 67% for detection of injury to the ICA passing through that canal. These values were similar to those for other CT findings.Sensitivity, specificity, positive predictive value, and negative predictive value of carotid canal fracture were only moderately good for determining the presence of ICA injury and were similar to other CT findings not typically associated with ICA injury.

To compare fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) with the current standard, magnetic resonance (MR) imaging, to determine the sensitivity and specificity of FDG PET for detection of cerebral metastases and to determine the factors that may affect lesion conspicuity.Forty patients underwent brain PET and contrast material-enhanced brain MR imaging, with a maximum of 30 days between examinations. PET and MR images were each retrospectively reviewed by two independent readers who were blinded to the clinical history and results of the other technique. Presence of metastatic disease was recorded for each modality. Sensitivity and specificity of FDG PET were determined with MR imaging as the standard. Statistical analysis was performed with the Fisher exact test and the logistic regression model.Sixteen patients had cerebral metastases at MR imaging, and in 12 of these, PET scans were interpreted as showing metastatic disease (in four, scans were false-negative). Twenty-four patients had no cerebral metastases at MR imaging, and 20 of these had PET scans interpreted as normal (in four, scans were false-positive). For identification of patients with cerebral metastases, FDG PET had a sensitivity of 75% (12 of 16) and a specificity of 83% (20 of 24). Thirty-eight metastatic lesions were seen at MR imaging; 23 (61%) of these were identified at PET. Size was a statistically significant factor that influenced lesion detection at PET (P.001).Only 61% of metastatic lesions in the brain were identified at PET. In particular, detection of small lesions was difficult.

© 2015, Spandidos Publications. All rights reserved. Functional diffusion mapping (fDM) is a cancer imaging technique that quantifies voxelwise changes in apparent diffusion coefficient (ADC). Previous studies have shown value of fDMs in bevacizumab therapy for recurrent glioblastoma multiforme (GBM). The aim of the present study was to implement explicit criteria for diffusion MRI quality control and independently evaluate fDM performance in a multicenter clinical trial (RTOG 0625/ACRIN 6677). A total of 123 patients were enrolled in the current multicenter trial and signed institutional review board-approved informed consent at their respective institutions. MRI was acquired prior to and 8 weeks following therapy. A 5-point QC scoring system was used to evaluate DWI quality. fDM performance was evaluated according to the correlation of these metrics with PFS and OS at the first follow-up time-point. Results showed ADC variability of 7.3% in NAWM and 10.5% in CSF. A total of 68% of patients had usable DWI data and 47% of patients had high quality DWI data when also excluding patients that progressed before the first follow-up. fDM performance was improved by using only the highest quality DWI. High pre-treatment contrast enhancing tumor volume was associated with shorter PFS and OS. A high volume fraction of increasing ADC after therapy was associated with shorter PFS, while a high volume fraction of decreasing ADC was associated with shorter OS. In summary, DWI in multicenter trials are currently of limited value due to image quality. Improvements in consistency of image quality in multicenter trials are necessary for further advancement of DWI biomarkers.

To measure mean cerebral blood flow (CBF) in ischemic and nonischemic territories and in low-attenuation regions in patients with acute stroke by using deconvolution-derived hemodynamic imaging.Twelve patients with acute middle cerebral artery stroke and 12 control patients were examined by using single-section computed tomography (CT) perfusion scanning. Analysis was performed with a deconvolution-based algorithm. Comparisons of mean CBF, cerebral blood volume (CBV), and mean transit time (MTT) were determined between hemispheres in all patients and between low- and normal-attenuation regions in patients with acute stroke. Two independent readers examined the images for extent of visually apparent regional perfusion abnormalities. The data were compared with extent of final infarct in seven patients with acute stroke who underwent follow-up CT or magnetic resonance imaging.Significant decreases in CBF (-50%, P =.001) were found in the affected hemispheres of patients with acute stroke. Significant changes in CBV (-26%, P =.03) and MTT (+111%, P =.004) were also seen. Significant alterations in perfusion were also seen in low- compared with normal-attenuation areas. Pearson correlation between readers for extent of CBF abnormality was 0.94 (P =.001). Intraobserver variation was 8.9% for CBF abnormalities.Deconvolution analysis of CT perfusion data is a promising method for evaluation of cerebral hemodynamics in patients with acute stroke.

Purpose: Glioblastoma is the most common malignant brain tumor. It is characterized by low median survival time and high survival variability. Survival prognosis for glioblastoma is very important for optimized treatment planning. Imaging features observed in magnetic resonance (MR) images were shown to be a good predictor of survival. However, manual assessment of MR features is time-consuming and can be associated with a high inter-reader variability as well as inaccuracies in the assessment. In response to this limitation, the authors proposed and evaluated a computer algorithm that extracts important MR image features in a fully automatic manner. Methods: The algorithm first automatically segmented the available volumes into a background region and four tumor regions. Then, it extracted ten features from the segmented MR imaging volumes, some of which were previously indicated as predictive of clinical outcomes. To evaluate the algorithm, the authors compared the extracted features for 73 glioblastoma patients to the reference standard established by manual segmentation of the tumors. Results: The experiments showed that their algorithm was able to extract most of the image features with moderate to high accuracy. High correlation coefficients between the automatically extracted value and reference standard were observed for the tumor location, minor and major axis length as well as tumor volume. Moderately high correlation coefficients were also observed for proportion of enhancing tumor, proportion of necrosis, and thickness of enhancing margin. The correlation coefficients for all these features were statistically significant (p < 0.0001). Conclusions: The authors proposed and evaluated an algorithm that, given a set of MR volumes of a glioblastoma patient, is able to extract MR image features that correlate well with their reference standard. Future studies will evaluate how well the computer-extracted features predict survival.

Purpose: Our purpose was to show the computed tomography (CT) and magnetic resonance (MR) imaging features of vertex epidural hematomas (EDHs) and emphasize pitfalls in the diagnosis of this entity. Subjects and methods: The neuroradiologic studies of four patients (CT in four, MR imaging and MR venography in one) were evaluated for EDH shape, size and appearance. Results: EDHs were biconvex in three patients and crescentic in one patient. CT appearances included a collection that was hyperdense (two patients), generally isodense with a few regions of hyperdensity (one patient) and mixed hyperdense and hypodense (one patient). MR imaging findings in one patient consisted of hyperintense signal on T1-weighted images and hypointense signal on T2-weighted images. Inferior displacement of the superior sagittal sinus was seen in two patients. Diagnosis of a small vertex EDH was difficult on routine axial CT in one patient, but apparent on MR imaging and MR venography. Conclusions: Small vertex EDHs can be difficult to diagnose on routine CT. MR imaging or thin section CT should be performed to exclude the diagnosis in patients with trauma to the skull vertex.

Article abstract Hippocampal sulcal cavities are usually considered incidental findings on brain MRI. In a group of 92 elderly volunteers, the authors graded the number and size of hippocampal sulcal cavities with brain MRI to obtain a cavity score. Cavity scores increased with age, and were higher in subjects carrying the APOE ε4 or ε2 alleles than in subjects with the ε3/3 genotype. Age-related morphologic changes in the hippocampus may be mediated by the APOE genotype.

We read with interest Whitney Pope's recent editorial1 in Neuro-Oncology on the paper by Kickingereder et al2 addressing the utility of relative cerebral blood volume (rCBV) derived from susceptibility-contrast perfusion-weighted MRI for determining therapeutic response in bevacizumab-treated recurrent glioblastoma multiforme (GBM). Kickingereder and Pope contend that although pretreatment rCBV may be a predictive marker of overall survival (OS), there is no evidence supporting post-bevacizumab change in rCBV from baseline as an early response marker. We caution against premature dismissal of rCBV change as an early predictor of treatment response.

A recent joint meeting was held on January 30, 2014, with the US Food and Drug Administration (FDA), National Cancer Institute (NCI), clinical scientists, imaging experts, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocate groups to discuss imaging endpoints for clinical trials in glioblastoma. This workshop developed a set of priorities and action items including the creation of a standardized MRI protocol for multicenter studies. The current document outlines consensus recommendations for a standardized Brain Tumor Imaging Protocol (BTIP), along with the scientific and practical justifications for these recommendations, resulting from a series of discussions between various experts involved in aspects of neuro-oncology neuroimaging for clinical trials. The minimum recommended sequences include: (i) parameter-matched precontrast and postcontrast inversion recovery-prepared, isotropic 3D T1-weighted gradient-recalled echo; (ii) axial 2D T2-weighted turbo spin-echo acquired after contrast injection and before postcontrast 3D T1-weighted images to control timing of images after contrast administration; (iii) precontrast, axial 2D T2-weighted fluid-attenuated inversion recovery; and (iv) precontrast, axial 2D, 3-directional diffusion-weighted images. Recommended ranges of sequence parameters are provided for both 1.5 T and 3 T MR systems.

To assess the patterns of abnormal neuroradiologic findings in patients with a hypercoagulable state related to activated protein C (APC) resistance.Records in 23 patients with a hypercoagulable state related to APC resistance (18 women, five men; average age, 44.5 years) were reviewed for cerebrovascular disease risk factors and other causes of a hypercoagulable state. Computed tomographic scans, magnetic resonance (MR) images, angiograms, and transesophageal echocardiograms were also reviewed.Stroke risk factors or other causes of a hypercoagulable state were found in 12 patients. Arterial infarcts were seen in 18 patients. Hyperintense white matter foci were seen on MR images in six patients. Dural sinus thrombosis was found in four patients. Angiograms of intracranial circulation in six patients showed major artery occlusions in four. MR angiograms in four patients showed internal carotid artery occlusion in one. No major abnormalities were seen in extracranial cerebral vasculature in 15 patients. Transesophageal echocardiograms in 11 patients showed a patent foramen ovale in one patient but no systemic source of embolism. Seven patients had non-central nervous system thrombotic events.Patients with APC resistance and stroke appear to differ from the general stroke population in terms of age and frequency of extracranial sources of cerebrovascular disease.

As intracranial MR angiography becomes more widely used and spatial resolution improves, anomalies at the Circle of Willis which have been previously well described on angiographic studies and anatomic dissections will become more frequently appreciated by MR angiography. Recognition of these variants is important to avoid confusion of the anomalies with aneurysms, evaluate collateral pathways in the intracerebral circulation, and enhance pre-operative planning in patients undergoing surgery at the skull base. In this review, we illustrate several of the more common types of anomalies at the Circle of Willis and discuss the possible clinical significance of each.

Objective Our goal was to demonstrate the spectrum of neuroradiologic (CT, MR, and angiographic) findings in craniocervical arterial dissection (CAD) related to exercise or sporting activities and compare the diagnostic utility of CT, MRI, and MR angiography (MRA). Materials and methods The neuroradiologic examinations of 11 patients with CAD was performed: CT was performed in 10 patients, cranial MRI in 9, cranial and cervical MRA in 4, and contrast angiography in 10. The CT examinations were assessed for the presence of an infarction or a hyperdense artery (consistent with intraluminal thrombus), MRI examinations for the presence of infarction or abnormal periarterial signal, and contrast angiograms for arterial stenosis or occlusion, luminal irregularity, pseudoaneurysm, intimal flap, or distal branch occlusions. Results Computed tomography demonstrated infarction in four patients. At contrast angiography, a dissection was found in the artery supplying the region of infarction in all cases. A hyperdense artery was found by CT in two patients, which correlated with dissection of the artery or its parent artery on contrast angiography. Cranial MRI findings were seen in six patients (infarction in five, periarterial signal abnormality in five). Dissection was confirmed in all four patients with abnormal periarterial signal who underwent contrast angiography. Two patients with abnormal intracranial periarterial signal had corresponding abnormalities on MRA. False-negative cranial and cervical MRI and MRA studies were performed in one patient because the imaging volumes used for the cervical and intracranial MR examinations did not overlap. Four patients with normal intracranial arterial signal had dissection in the neck demonstrated by contrast angiography. Conclusion Neuroradiologic findings of CAD can include infarction, a hyperdense artery on CT, abnormal periarterial signal on MRI, and a narrowed arterial signal column on MRA. Computed tomography is an insensitive screening examination. Proper use of MRI and MRA involves examination of both the head and the neck with overlapping imaging volumes of the two regions.

The aim of this study was to determine the prognostic significance of the volume and intensity of abnormal (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) accumulation within areas of contrast enhancement on post-therapeutic volumetric MRI.A total of 10 patients with Grade III or IV glioma were treated with resection followed by intracavitary radiation therapy with (131)I-labelled antitenascin monoclonal antibody. Patients underwent serial FDG-PET and 1.5 T MR imaging. For each patient, MR and FDG-PET image volumes at each time point were aligned using a rigid-body normalised mutual information algorithm. Contrast-enhancing regions of interest (ROIs) were defined using a semi-automated k-means clustering technique. Activity within the ROI on the co-registered PET scan was calculated as a ratio (mean activity ratio; MAR) to activity in contralateral normal-appearing white matter (NAWM). The PET lesion was defined as the portion of the ROI associated with activity greater than two standard deviations above the mean in NAWM. Survival was assessed using the logrank test.Larger contrast-enhancing ROIs were strongly associated with an increased MAR (r = 0.51; p0.002). Enhancing lesions with an MAR1.2 were associated with decreased survival (p0.016). In nine patients who died, the MAR on PET correlated inversely with survival duration (r = -0.43; p0.01), whereas PET lesion volume did not.Following intracavitary radiation therapy, the development of contrast-enhancing lesions that are associated with high mean FDG-PET accumulation suggests poor prognosis.

Rationale and Objectives To estimate the gain in signal-to-noise ratio (SNR) in first-pass contrast-enhanced (CE) abdominal magnetic resonance angiography (MRA) at 3.0 T compared with 1.5 T. Materials and Methods Three protocols were simulated using six contrast agents: gadopentetate dimeglumine (Magnevist, Berlex, Wayne, NJ), gadoteridol (Prohance, Bracco, Princeton, NJ), gadobenate dimeglumine (Multihance, Bracco, Princeton, NJ), gadodiamide (Omniscan, Amersham Health, Princeton, NJ), gadoversetamide (Optimark, Mallinckrodt, St. Louis, MO), and gadofosveset trisodium (MS-325, EPIX Medical, Cambridge, MA). Contrast concentrations were calculated for five abdominal vessels. Based on these data, the gain in SNR during CE abdominal MRA at 3.0 T over 1.5 T was estimated. Results In these simulations, peak concentrations in all five target vessels were about 5 mM, 10 mM, and 0.7 mM for protocol 1, protocol 2, and protocol 3, respectively. A gain in SNR at 3 T over 1.5 T during CE abdominal MRA of at least 94% in all five target vessels could be achieved by applying protocol 1 or protocol 2, whereas protocol 3 provided a gain in SNR of 70%. Conclusions Although five of the contrast agents studied fulfill the expectation of providing approximately twice the SNR at 3.0 T versus 1.5 T during CE abdominal MRA, MS-325 offers a gain in SNR of 70% only.

To determine prospectively the diffusibility of water in normal lumbar disks in adults by using the mean apparent diffusion coefficient (ADC) and to determine if a relationship exists between disk ADC and magnetic resonance (MR) findings of disk degeneration.The study was approved by the Institutional Review Board, and all participants gave written informed consent prior to enrollment. Diffusion-weighted MR imaging of the lumbar spine was performed in 39 patients (all men; mean age, 53 years) and five volunteers (all men; mean age, 31 years). ADC values were recorded for each disk. All disks were visually graded by two independent observers as being normal or as showing at least one of three MR findings of degeneration on sagittal T2-weighted images. Mean ADC values of normal disks were compared with those of degenerated disks and were correlated with age and anatomic location. Data were analyzed by using Kendall correlation statistics, Mantel-Haenszel statistics, and a paired two-tailed Student t test.The mean ADC value was 2.27 x 10(-3) mm(2)/sec +/- 0.58 (+/- standard deviation) in normal disks and 2.06 x 10(-3) mm(2)/sec +/- 0.47 in abnormal disks (9% reduction, P = .006). A statistically significant dependence of lumbar disk ADC on anatomic location was reported (analysis of variance, P.001), with lower ADC values seen in more caudal disks. There was no association between age and mean disk ADC.A statistically significant decrease was seen in the ADC values of degenerated lumbar disks when compared with ADC values of normal disks. More caudal disks, even when normal, showed lower ADC values than more cephalic disks.

Signal intensity (SI) values of gray- and white-matter brain regions of interest (ROIs) were obtained from T 2 - and proton density-weighted magnetic resonance (MR) images of 58 normal subjects aged 22–82 years (31 females, 52.3±18.8 years; 27 males, 54.1±18.1 years). Sampled ROIs included the caudate, putamen, thalamus, orbitofrontal gyrus, gyrus rectus, uncus, frontal white matter, anterior and posterior corpus callosum, cranial–cervical junction fat, and retroorbital fat. Effects of age and sex on SI were examined using repeated-measures analysis of covariance. For both T 2 - and proton density-weighted acquisitions, a significant inverse relationship between age and SI was observed for the ratio of all summed gray-matter ROIs divided by summed white-matter ROIs. This relationship was additionally observed for ratios of both subcortical gray/white matter and cortical gray/white matter. Females compared with males had significantly lower cortical gray/white matter ratios on T 2 -weighted scans. Differences in SI were observed between cranial–cervical junction fat and retroorbital fat on both acquisitions, with females showing significantly higher values for cranial–cervical junction fat and males showing higher values for retroorbital fat. Implications for brain morphometry, the use of fat as a reference standard, and other issues in neuroimaging are discussed.

We evaluated commercially available software that rapidly and automatically registers brain MR images on a clinical workstation, and we studied the accuracy of these registrations.Ten patients with a diagnosis of glioblastoma multiforme underwent contrast-enhanced inversion recovery prepared three-dimensional (3D) volumetric spoiled gradient-recalled acquisition in the steady state (SPGR) MR imaging (contiguous 1.5-mm slice thickness, 96-104 slices). After this imaging sequence, each patient was brought out of the head coil into a sitting position and then repositioned in the coil. The inversion recovery prepared 3D SPGR sequence was then repeated. A commercially available software program operating on a clinical workstation was used to automatically register the second inversion recovery prepared SPGR series to the first. The speed of registration was recorded. The accuracy of each registration was estimated by recording the coordinates of eight anatomic landmarks on the registered and reference series and by calculating the mean error among matching landmarks.In nine of 10 patients, the registration software produced a visually satisfactory registration. In one patient, a second registration was necessary to produce a satisfactory registration. The processing time for each iteration was 48.3 +/- 3.8 sec (mean +/- SD). The mean error in aligning matching anatomic landmarks ranged from 0.67 to 1.41 mm, with an overall mean of 1.18 mm. The largest error among matching landmarks was 2.3 mm.Commercially available registration software can automatically register 3D imaging volumes in less than 1 min. The mean error in registration was approximately equivalent to the dimensions of a single voxel.

The purpose of this study was to examine the frequency of change in size of pineal cysts on serial MR studies.Thirty-two patients (19 females, 13 males) with a diagnosis of pineal cyst at any time who underwent brain MR imaging more than once in a period of at least 6 months were identified by computerized search of radiology reports. Four patients underwent MR imaging to follow up pineal cysts, whereas the remaining patients were imaged for a variety of indications, including intracerebral neoplasms. Measurements of maximal cyst dimension on both initial and latest follow-up studies were obtained in all patients, and cyst volumes were calculated in 23 patients.Length of follow-up ranged from 6 months to 9 years. All cysts were considered incidental and none were treated. Maximal cyst dimensions ranged from 0.5 to 2.2 cm. On average, there was no significant change in cyst volume. The maximal dimension of the cyst did not change in 24 (75%) of 32 patients. Two cysts resolved completely on follow-up, three cysts decreased by 2-4 mm, two cysts enlarged by 2-3 mm, and one cyst formed and grew to 1.2 cm.Whereas the size of pineal cysts as a whole remained unchanged on serial MR studies, cysts may either form or involute in individual patients. Small increases in cyst size did occur but were not associated with specific clinical findings. These findings suggest that typical pineal cysts may be followed up on a clinical basis alone rather than on imaging.

The purpose of this study was to compare MR imaging features of gangliogliomas in children less than 10 years old with those seen in patients at least 10 years old.Our study population consisted of 15 female patients and 10 male patients with a mean age of 20 years. The early childhood group was composed of six children with a mean age of 5.5 years. The older group was composed of 19 patients with a mean age of 25.6 years. We assessed tumor volume, tumor location, percentage of tumor that was cystic, pattern of contrast enhancement, and degree of edema.The temporal lobe was the most common tumor location in both groups. Mean tumor volume in the early childhood group was 83 cm3, which was significantly larger than the mean tumor volume (9.78 cm3) for the older group (p = 0.001). Cystic tumors were more common in the early childhood group (83%) than in the older group (63%), and the average percentage of cysts in the cystic tumors was much higher in the early childhood group (67%) than in the older group (30%). Contrast enhancement was seen in five of six early childhood tumors and 13 of 16 tumors in older patients. Four of six tumors in the early childhood group and five of 19 tumors in the older patient group had associated edema.The mean tumor volume of gangliogliomas in the early childhood group was significantly larger than that of the older patient group. This finding may be indicative of differences in tumor growth patterns in the two groups, ability of the hemicranium to adjust to mass effect in childhood, or sampling error as a result of a relatively small sample size.

L imbic encephalitis is a rare neurologic disorder characterized clinically by behavioral changes and memory loss [I]. Patients with limbic encephalitis typically (but not always) have an underlying malignancy, most commonly small cell carcinoma of the lung [I 1. In this setting, the neurologic changes represent a paraneoplastic syndrome. The MR imaging findings of limbic encephalitis have been well described in a number of case reports 12-61 and during the acute phase of the illness include hyperintense signal abnormality on T2-weighted images within medial temporal lobe structures such as the hippocampi and amygdalae and, on occasion, the hypothalamus. We report the 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) findings oflimbic encephalitis during the acute phase of the illness.

The causes of stroke in young adults differ substantially from those in older adults. In many instances, the diagnosis can be made by taking a clinical history and performing laboratory studies (e.g., in patients who have multiple thromboses associated with anti-phospholipid antibodies). In other circumstances, clues to the diagnosis can be found on routine CT and MR studies. However, in many circumstances, imaging tailored to a specific diagnosis is important (e.g., MR imaging of the neck in patients with suspected arterial dissection). In yet other cases, additional studies (e.g., echocardiography in suspected cardiogenic embolism) are important to establish the cause.

and OS for the entire cohort were 88.0%, 69.5%, and 78.4%, respectively. Of the 85 patients, there were 7 locoregional failures (LRF), 13 distant failures (DF), 4 LRF and DF, and 4 deaths from intercurrent illness. Among the 16 patients with locoregional ordistantfailure,mediantimefromendofradiotherapytofirstfailurewas9.8months.OnCoxproportionalhazardsregressionanalysis, an increase in integrated SUV of 209.2 SUV$ml (difference between the 75th and 25th percentiles) was associated with a statistically significant increased hazard of recurrence (2.2-fold, p\0.0001), even after controlling for Karnofsky performance status (2.0-fold, p = 0.0007), and of death (1.7-fold, p = 0.0037). An increase in MTV was also associated with increased hazard of progression (1.9-fold, p = 0.002) and of death (2.1-fold, p = 0.001). We did not find a significant relationship between maximum SUV and DFS or OS. Conclusions: High metabolic tumor burden as measured by MTV or integrated SUV are adverse prognostic factors for disease recurrence and death in head and neck cancer. MTV and integrated SUV retained significance after controlling for KPS, another significant adverse prognostic factor in this cohort. These metabolic parameters are potentially valuable tools for risk stratification and guiding treatment in future clinical trials.

2026 Background: DCE-MRI can determine vascular permeability using Ktrans, a volume transfer constant of contrast agent between blood plasma and the extravascular extracellular space. We report a p...

2029 Background: Significant responses seen in GBM patients treated with BEV and CPT-11 generated the need to develop ways to predict clinical benefit. DCE-MRI can be used to evaluate the microvasculature within tumors. DCE-MRI uses Ktrans, a volume transfer constant of contrast agent between blood plasma and the extravascular extracellular space, to determine vascular permeability. A 50% reduction in Ktrans is clinically meaningful. We report a phase II trial to determine the correlation between vascular permeability and radiographic response in GBM patients treated with the combination. Methods: Eligibility included patients with recurrent GBM. Both agents were given every 14 days. All patients received BEV at 10 mg/kg IV. CPT-11 was dosed at 340 mg/m2 for patients on enzyme inducing antiepileptic drugs (EIAED) and 125 mg/m2 for patients not on EIAED. Radiographic responses were assessed every 6 weeks. DCE-MRIs were performed before administration of chemotherapy, one day after treatment and after the first cycle. The primary endpoint was to examine the effect of BEV and CPT-11 treatment on vascular permeability as measured by percent change from baseline in Ktrans. Results: Twenty patients were enrolled, with a median age of 49.5 years. Fifteen patients are assessable for response. Best responses include one patient with complete response, 8 with partial response (response rate=60%), six patients with stable disease, and one with disease progression. Ktrans values are available for 13 patients; data are not available for seven patients (too early: 4, technical difficulty: 3). A reduction in Ktrans by 50% was observed in 6 patients one day after treatment and in 12 patients at the end of cycle 1. Changes in Ktrans value were highly correlated with the percentage decline in tumor volume from baseline to end of cycle one (Pearson correlation = 0.82; p=0.0006). Fifteen patients are still on study. Five patients came off due to disease progression. Conclusions: The utilization of DCE-MRI to determine a reduction in vascular permeability following a combination of BEV and CPT-11 is feasible and correlates significantly with the degree of tumor volume decrease. No significant financial relationships to disclose.

Purpose: To evaluate the use of DCE‐MRI to measure changes in tumorphysiology in LAHN cancer patients receiving TT and cisplatin based concurrent chemoradiation (ChemoRT). Material and Methods: Eligible patients with LAHN were enrolled on an IRB approved clinical trial to establish the safety and efficacy of adding TT (bevacizumab and erlotinib) to ChemoRT. To quantify this efficacy, DCE‐MR images were acquired on a 1.5T GE Signa Exite scanner before treatment started, at the end of the lead‐in phase (2 weeks of TT alone), at the end of week 1 of ChemoRT, and at the end of the ChemoRT (70 Gy). The images were analyzed using a full Time Point (fTP) pharmacokinetic analysis implemented by CAD Sciences® (White Plains, NY) that measures the vascular permeability (PERM) and extracellular volume fraction (EVF). The T10 for the primary and nodes was determined from series acquired with varying TRs. A dynamic 3D spoiled gradient echo sequence was used before and after bolus injection of Gd DTPA (Magnevist®). Regions of interest (ROIs) were defined over the entire extent of the tumor and LN, respectively. Enhancement curve analysis, PERM and EVF statistics and ROI volume comparisons were performed. Results: The T10 for tumor was 1500 msec, and 2000 msec for LN. All the fTP analyses used these values. Fifteen patients have been imaged to date. We found that coronal imaging allows better ROI selection without vascular averaging for this type of subjects.. Detailed analyses of all time points have been completed on three patients, all with clinical complete response. Combined PERM and EVF analyses showed marked decreases with treatment (p

B, Unenhanced CT scan shows multiple low-attenuation round splenic lesions, some with central high attenuation (arrow). C, Low-power (x 2.5) micrograph of abscess shows serpiginous fibrotic layer (arrow) surrounding pus (P) and fungus ball (F). D, Higher-power (x 125) micrograph of abscess wall shows normal spleen at bottom and layers of fibrosis (F), chronic inflammatory cells, and histiocytes (H). Pus (P) is at top.