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The dynamic susceptibility contrast (DSC) MRI measures of relative cerebral blood volume (rCBV) play a central role in monitoring therapeutic response and disease progression in patients with gliomas. Previous investigations have demonstrated promise of using rCBV in classifying tumor grade, elucidating tumor viability after therapy, and differentiating pseudoprogression and pseudoresponse. However, the quantification and reproducibility of rCBV measurements across patients, devices, and software remain a critical barrier to routine or clinical trial use of longitudinal DSC MRI in patients with gliomas. To address this limitation, the RSNA DSC MRI Biomarker Committee of the Quantitative Imaging Biomarkers Alliance developed a Profile that defines statistics-based claims for the precision of longitudinal measurements. Although rCBV is the clinical marker of interest, the Profile focused on the reproducibility of the measured quantitative imaging biomarker, which is the area under the contrast agent concentration-time curve (AUC) normalized by the mean value of normal-appearing contralateral white matter tissue (tissue-normalized AUC values). Based on previous reports of within-subject coefficient of variation (wCV) in the tissue-normalized AUC values for enhancing gliomas (wCV = 0.31), an increase of 182% or more with respect to the baseline tissue-normalized AUC value indicates that an increase has occurred with 95% confidence. In contrast, a decrease of 64% or more with respect to baseline suggests that a decrease has occurred with 95% confidence. Similarly, an increase of 399% or more in the tissue-normalized AUC values in normal brain gray matter tissue (wCV = 0.40) suggests that an increase has occurred with 95% confidence, whereas a decrease of 80% or more with respect to baseline suggests that a decrease has occurred with 95% confidence. This article provides the rationale for these claims and the compliance activities needed to achieve these claims. Potential updates to incorporate new data based on advances in technology and clinical care in the Profile are also discussed., (© RSNA, 2024 See also the editorial by Peters in this issue.)

Background and Purpose: A national consensus recommendation for the collection of DSC (dynamic susceptibility contrast) MRI perfusion data, used to create maps of relative cerebral blood volume (rCBV), has been recently established for primary and metastatic brain tumors. The goal was to reduce inter-site variability and improve ease of comparison across time and sites, fostering widespread use of this informative measure. To translate this goal into practice the prospective collection of consensus DSC-MRI data and characterization of derived rCBV maps in brain metastases is needed. The purpose of this multi-site study was to determine rCBV in untreated brain metastases in comparison to glioblastoma and normal appearing brain using the national consensus protocol., Materials and Methods: Subjects from three sites with untreated enhancing brain metastases underwent DSC-MRI according to a recommended option that uses a mid-range flip angle, GRE-EPI acquisition and the administration of both a pre-load and 2 nd DSC-MRI dose of 0.1 mmol/kg GBCA. Quantitative maps of standardized rCBV (sRCBV) were generated and enhancing lesion ROIs determined from post-contrast T1-weighted images alone or calibrated difference maps, termed delta T1 (dT1) maps. Mean sRCBV for metastases were compared to normal appearing white matter (NAWM) and glioblastoma (GBM) from a previous study. Comparisons were performed using either the Wilcoxon signed-rank test for paired comparisons or the Mann-Whitney nonparametric test for unpaired comparisons., Results: 49 patients with a primary histology of lung (n=25), breast (n=6), squamous cell carcinoma (SCC) (n=1), melanoma (n=5), gastrointestinal (GI) (n=3) and genitourinary (GU) (n=9) were included in comparison to GBM (n=31). The mean sRCBV of all metastases (1.83+/-1.05) were significantly lower (p=0.0009) than mean sRCBV for GBM (2.67±1.34) with both statistically greater (p<0.0001) than NAWM (0.68 +/- 0.18). Histologically distinct metastases are each statistically greater than NAWM (p<0.0001) with lung (p=0.0002) and GU (p=.02) sRCBV being significantly different than GBM sRCBV., Conclusions: 49 patients with a primary histology of lung (n=25), breast (n=6), squamous cell carcinoma (SCC) (n=1), melanoma (n=5), gastrointestinal (GI) (n=3) and genitourinary (GU) (n=9) were included in comparison to GBM (n=31). The mean sRCBV of all metastases (1.83+/-1.05) were significantly lower (p=0.0009) than mean sRCBV for GBM (2.67+1.34) with both statistically greater (p<0.0001) than NAWM (0.68 +/- 0.18). Histologically distinct metastases are each statistically greater than NAWM (p<0.0001) with lung (p=0.0002) and GU (p=.02) sRCBV being significantly different than GBM sRCBV., Abbreviations: dT1=delta T1; GBCA=gadolinium-based contrast agent; NAWM=normal appearing white matter; normalized relative cerebral blood volume=nRCBV; relative cerebral blood volume=rCBV; standardized relative cerebral blood volume=sRCBV., Competing Interests: Precision Oncology Insights (co-founder L.S.H.); Imaging Biometrics LLC (medical advisory board L.S.H., financial interest (L.S.H., K.M.S.); IQ-AI Ltd. (ownership interest (L.S.H., K.M.S.)); Prism Clinical Imaging (ownership interest K.M.S., board membership K.M.S.). The remaining authors have no conflicts of interest to disclose., (© 2024 by American Journal of Neuroradiology.)

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., (© 2024 by American Journal of Neuroradiology.)

Purpose To develop and validate a deep learning (DL) method to detect and segment enhancing and nonenhancing cellular tumor on pre- and posttreatment MRI scans in patients with glioblastoma and to predict overall survival (OS) and progression-free survival (PFS). Materials and Methods This retrospective study included 1397 MRI scans in 1297 patients with glioblastoma, including an internal set of 243 MRI scans (January 2010 to June 2022) for model training and cross-validation and four external test cohorts. Cellular tumor maps were segmented by two radiologists on the basis of imaging, clinical history, and pathologic findings. Multimodal MRI data with perfusion and multishell diffusion imaging were inputted into a nnU-Net DL model to segment cellular tumor. Segmentation performance (Dice score) and performance in distinguishing recurrent tumor from posttreatment changes (area under the receiver operating characteristic curve [AUC]) were quantified. Model performance in predicting OS and PFS was assessed using Cox multivariable analysis. Results A cohort of 178 patients (mean age, 56 years ± 13 [SD]; 116 male, 62 female) with 243 MRI timepoints, as well as four external datasets with 55, 70, 610, and 419 MRI timepoints, respectively, were evaluated. The median Dice score was 0.79 (IQR, 0.53-0.89), and the AUC for detecting residual or recurrent tumor was 0.84 (95% CI: 0.79, 0.89). In the internal test set, estimated cellular tumor volume was significantly associated with OS (hazard ratio [HR] = 1.04 per milliliter; P < .001) and PFS (HR = 1.04 per milliliter; P < .001) after adjustment for age, sex, and gross total resection (GTR) status. In the external test sets, estimated cellular tumor volume was significantly associated with OS (HR = 1.01 per milliliter; P < .001) after adjustment for age, sex, and GTR status. Conclusion A DL model incorporating advanced imaging could accurately segment enhancing and nonenhancing cellular tumor, distinguish recurrent or residual tumor from posttreatment changes, and predict OS and PFS in patients with glioblastoma. Keywords: Segmentation, Glioblastoma, Multishell Diffusion MRI Supplemental material is available for this article. © RSNA, 2024.

Background and Objectives: Gross-total resection (GTR) and low residual tumor volume (RTV) have been associated with increased survival in glioblastoma. Largely due to the subjectivity involved, the determination of GTR and RTV remains difficult in the postoperative setting. In response, the objective of this study is to evaluate the clinical efficacy of an easy-to-use MRI metric, called delta T1 (dT1), to quantify extent of resection (EOR) and RTV, in comparison to radiologist impression, to predict overall survival (OS) in glioblastoma patients., Methods: 59 patients who underwent resection of glioblastoma were retrospectively identified. Delta T1 (dT1) images, automatically created from the difference between calibrated post- and pre-contrast T1-weighted images, were used to quantify EOR and RTV. Kaplan-Meier survival estimates were determined for EOR categories, an RTV cutoff of 5cm 3 and radiologist interpretation of EOR. Multivariate Cox proportional hazard regression analysis was used to evaluate RTV and EOR along with effects related to sex, KPS, MGMT, and age on OS., Results: Kaplan-Meier analysis revealed a statistically significant difference in median OS for a dT1-determined RTV cutoff of 5 cm 3 (P=.0024, HR=2.18 (1.232-3.856)), but not for radiological impression (P=0.666) or dT1-determined EOR (P=0.0803), which was limited to a comparison between partial and subtotal resections. Furthermore, when covariates were accounted for in multivariate Cox regression, significant differences in OS were retained for dT1-determined RTV. Additionally, a significantly strong yet short-term effect of MGMT methylation status on OS was revealed for each RTV and EOR model., Conclusion: The utility of dT1 maps to quantify EOR and RTV in glioblastoma and predict survival, suggests an emerging role for dT1s with relevance for intraoperative MRI, neuro-navigation and postoperative disease surveillance.

Relative cerebral blood volume (rCBV) derived from dynamic susceptibility contrast (DSC) perfusion MR imaging (pMRI) has been shown to be a robust marker of neuroradiological tumor burden. Recent consensus recommendations in pMRI acquisition strategies have provided a pathway for pMRI inclusion in diverse patient care centers, regardless of size or experience. However, even with proper implementation and execution of the DSC-MRI protocol, issues will arise that many centers may not easily recognize or be aware of. Furthermore, missed pMRI issues are not always apparent in the resulting rCBV images, potentiating inaccurate or missed radiological diagnoses. Therefore, we gathered from our database of DSC-MRI datasets, true-to-life examples showcasing the breakdowns in acquisition, postprocessing, and interpretation, along with appropriate mitigation strategies when possible. The pMRI issues addressed include those related to image acquisition and postprocessing with a focus on contrast agent administration, timing, and rate, signal-to-noise quality, and susceptibility artifact. The goal of this work is to provide guidance to minimize and recognize pMRI issues to ensure that only quality data is interpreted., Competing Interests: Imaging Biometrics LLC (KMS-financial interest), IQ-AI Ltd (KMS-ownership interest), Prism Clinical Imaging Inc (KMS-ownership interest, board membership). The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Prah and Schmainda.)

Background: Treatment-resistant glioblastoma (trGBM) is an aggressive brain tumor with a dismal prognosis, underscoring the need for better treatment options. Emerging data indicate that trGBM iron metabolism is an attractive therapeutic target. The novel iron mimetic, gallium maltolate (GaM), inhibits mitochondrial function via iron-dependent and -independent pathways., Methods: In vitro irradiated adult GBM U-87 MG cells were tested for cell viability and allowed to reach confluence prior to stereotactic implantation into the right striatum of male and female athymic rats. Advanced MRI at 9.4T was carried out weekly starting two weeks after implantation. Daily oral GaM (50mg/kg) or vehicle were provided on tumor confirmation. Longitudinal MRI parameters were processed for enhancing tumor ROIs in OsiriX 8.5.1 (lite) with Imaging Biometrics Software (Imaging Biometrics LLC). Statistical analyses included Cox proportional hazards regression models, Kaplan-Meier survival plots, linear mixed model comparisons, and t-statistic for slopes comparison as indicator of tumor growth rate., Results: In this study we demonstrate non-invasively, using longitudinal MRI surveillance, the potent antineoplastic effects of GaM in a novel rat xenograft model of trGBM, as evidenced by extended suppression of tumor growth (23.56 mm 3 /week untreated, 5.76 mm 3 /week treated, P < 0.001), a blunting of tumor perfusion, and a significant survival benefit (median overall survival: 30 days untreated, 56 days treated; P < 0.001). The therapeutic effect was confirmed histologically by the presence of abundant cytotoxic cellular swelling, a significant reduction in proliferation markers ( P < 0.01), and vessel normalization characterized by prominent vessel pruning, loss of branching, and uniformity of vessel lumina. Xenograft tumors in the treatment group were further characterized by an absence of an invasive edge and a significant reduction in both, MIB-1% and mitotic index ( P < 0.01 each). Transferrin receptor and ferroportin expression in GaM-treated tumors illustrated cellular iron deprivation. Additionally, treatment with GaM decreased the expression of pro-angiogenic markers (von Willebrand Factor and VEGF) and increased the expression of anti-angiogenic markers, such as Angiopoietin-2., Conclusion: Monotherapy with the iron-mimetic GaM profoundly inhibits trGBM growth and significantly extends disease-specific survival in vivo ., Competing Interests: KS has ownership interest in IQ-AI Ltd and financial interest in Imaging Biometrics LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Al-Gizawiy, Wujek, Alhajala, Cobb, Prah, Doan, Connelly, Chitambar and Schmainda.)

Background: Neurocysticercosis (NCC) is a parasitic infection of the brain caused by ingesting water or food contaminated with tapeworm eggs. When it presents as a solitary mass, differentiation from a primary brain tumor on imaging can be difficult. Magnetic resonance imaging (MRI)-derived relative cerebral blood volume (rCBV) is a newer imaging technique used to identify areas of neovascularization in tumors, which may advance the differential diagnosis., Observations: A 25-year-old male presented after a seizure. Computed tomography (CT) and MRI demonstrated a partially enhancing lesion with microcalcifications and vasogenic edema. Follow-up rCBV assessment demonstrated mild hyperperfusion and/or small vessels at the lesional margins consistent with either an intermediate grade glioma or infection. Given the radiological equipoise, surgical accessibility, and differential diagnosis including primary neoplasm, metastatic disease, NCC, and abscess, resection was pursued. The calcified mass was excised en bloc and was confirmed as larval-stage NCC., Lessons: CT or MRI may not always provide sufficient information to distinguish NCC from brain tumors. Although reports have suggested that rCBV may aid in identifying NCC, here the authors describe a case of pathologically confirmed NCC in which preoperative, qualitative, standardized rCBV findings raised concern for a primary neoplasm. This case documents the first standardized rCBV values reported in a pathologically confirmed case of NCC in the United States.

Sampling restrictions have hindered the comprehensive study of invasive non-enhancing (NE) high-grade glioma (HGG) cell populations driving tumor progression. Here, we present an integrated multi-omic analysis of spatially matched molecular and multi-parametric magnetic resonance imaging (MRI) profiling across 313 multi-regional tumor biopsies, including 111 from the NE, across 68 HGG patients. Whole exome and RNA sequencing uncover unique genomic alterations to unresectable invasive NE tumor, including subclonal events, which inform genomic models predictive of geographic evolution. Infiltrative NE tumor is alternatively enriched with tumor cells exhibiting neuronal or glycolytic/plurimetabolic cellular states, two principal transcriptomic pathway-based glioma subtypes, which respectively demonstrate abundant private mutations or enrichment in immune cell signatures. These NE phenotypes are non-invasively identified through normalized K2 imaging signatures, which discern cell size heterogeneity on dynamic susceptibility contrast (DSC)-MRI. NE tumor populations predicted to display increased cellular proliferation by mean diffusivity (MD) MRI metrics are uniquely associated with EGFR amplification and CDKN2A homozygous deletion. The biophysical mapping of infiltrative HGG potentially enables the clinical recognition of tumor subpopulations with aggressive molecular signatures driving tumor progression, thereby informing precision medicine targeting., (© 2023. Springer Nature Limited.)

Introduction: 1.5 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., Methods: This 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)., Results: Twenty-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., Conclusion: Our 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., Competing Interests: Author KS was employed IQ-AI Ltd and Imaging Biometrics LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shiroishi, Weinert, Cen, Varghese, Dondlinger, Prah, Mendoza, Nazemi, Ameli, Amini, Shohas, Chen, Bigjahan, Zada, Chen, Neman-Ebrahim, Chang, Chow, Fan, Yang, Attenello, Ye, Kim, Patel, Lerner, Acharya, Hu, Quarles, Boxerman, Wu and Schmainda.)

Preoperative clinical MRI protocols for gliomas, brain tumors with dismal outcomes due to their infiltrative properties, still rely on conventional structural MRI, which does not deliver information on tumor genotype and is limited in the delineation of diffuse gliomas. The GliMR COST action wants to raise awareness about the state of the art of advanced MRI techniques in gliomas and their possible clinical translation. This review describes current methods, limits, and applications of advanced MRI for the preoperative assessment of glioma, summarizing the level of clinical validation of different techniques. In this second part, we review magnetic resonance spectroscopy (MRS), chemical exchange saturation transfer (CEST), susceptibility-weighted imaging (SWI), MRI-PET, MR elastography (MRE), and MR-based radiomics applications. The first part of this review addresses dynamic susceptibility contrast (DSC) and dynamic contrast-enhanced (DCE) MRI, arterial spin labeling (ASL), diffusion-weighted MRI, vessel imaging, and magnetic resonance fingerprinting (MRF). EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 2., (© 2023 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Progressive enhancement predicted poor survival in ACRIN 6677/RTOG 0625, a multi-center trial of bevacizumab with irinotecan or temozolomide in recurrent glioblastoma, but pseudoresponse likely limited enhancement-based survival prognostication in T1 non-progressors. We aimed to determine whether early change in cerebral blood volume from baseline (ΔCBV) could further stratify the T1 non-progressors according to overall (OS) and progression-free (PFS) survival., Methods: 37/123 enrolled patients had DSC-MRI, including 13, 15, and 8 patients without 2D-T1 progression at 2, 8, and 16 weeks post-treatment initiation, respectively. Mean CBV normalized to white matter (nRCBV) and mean standardized CBV (sRCBV) were extracted from enhancing tumor. ROC curves were derived for ΔCBV using six-month PFS and one-year OS as reference standards. Kaplan-Meier survival estimates and log-rank test compared PFS and OS for both ΔCBV (increase vs. decrease) and T1 response status (stable vs. decreasing enhancement)., Results: PFS and OS were significantly worse for increasing CBV at 2 weeks (p=0.003 and p=0.002 for nRCBV, and p=0.03 and p=0.03 for sRCBV, respectively), but not for 2D-T1 patients with stable vs. decreasing enhancement (p=0.44 and p=0.86, respectively). ΔCBV at week 2 was also a good prognostic marker for OS-1 and PFS-6 using ROC analysis. By contrast, 2D-T1 response status at weeks 2, 8, and 16 was not associated with PFS-6. ΔCBV at 16 weeks (p=0.008 for sRCBV) but not 8 weeks (p=0.74 for nRCBV and p=0.56 for sRCBV) was associated with significant difference in median survival, but no difference in survival was observed for 2D-T1 patients with stable vs. decreasing enhancement at 8 weeks (p=0.69) or 16 weeks (p=0.21). At 16 weeks, OS did not differ significantly between 2D-T1 progressors and 2D-T1 non-progressors with increasing CBV (median survival 3.3 months post week 16 scan vs. 9.2 months, respectively; p=0.13), suggesting that 2D-T1 non-progressors with increasing CBV may have a prognosis like that of 2D-T1 progressors., Conclusion: After 2 weeks of anti-angiogenic therapy, ΔCBV in 2D-T1 non-progressors significantly prognosticated PFS and OS, whereas 2D-T1 response status did not, identifying a subpopulation that benefits from bevacizumab. Combining 2D-T1 progression and ΔCBV may yield a response assessment paradigm with 3-tiered OS stratification., Competing Interests: Author JB is a paid consultant for Neosoma, Inc. Author KS has ownership interest in IQ-AI Ltd and financial interest in Imaging Biometrics LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Boxerman, Snyder, Barboriak and Schmainda.)

Background: Diffusion-weighted imaging (DWI) is commonly used to detect prostate cancer, and a major clinical challenge is differentiating aggressive from indolent disease., Purpose: To compare 14 site-specific parametric fitting implementations applied to the same dataset of whole-mount pathologically validated DWI to test the hypothesis that cancer differentiation varies with different fitting algorithms., Study Type: Prospective., Population: Thirty-three patients prospectively imaged prior to prostatectomy., Field Strength/sequence: 3 T, field-of-view optimized and constrained undistorted single-shot DWI sequence., Assessment: Datasets, including a noise-free digital reference object (DRO), were distributed to the 14 teams, where locally implemented DWI parameter maps were calculated, including mono-exponential apparent diffusion coefficient (MEADC), kurtosis (K), diffusion kurtosis (DK), bi-exponential diffusion (BID), pseudo-diffusion (BID*), and perfusion fraction (F). The resulting parametric maps were centrally analyzed, where differentiation of benign from cancerous tissue was compared between DWI parameters and the fitting algorithms with a receiver operating characteristic area under the curve (ROC AUC)., Statistical Test: Levene's test, P < 0.05 corrected for multiple comparisons was considered statistically significant., Results: The DRO results indicated minimal discordance between sites. Comparison across sites indicated that K, DK, and MEADC had significantly higher prostate cancer detection capability (AUC range = 0.72-0.76, 0.76-0.81, and 0.76-0.80 respectively) as compared to bi-exponential parameters (BID, BID*, F) which had lower AUC and greater between site variation (AUC range = 0.53-0.80, 0.51-0.81, and 0.52-0.80 respectively). Post-processing parameters also affected the resulting AUC, moving from, for example, 0.75 to 0.87 for MEADC varying cluster size., Data Conclusion: We found that conventional diffusion models had consistent performance at differentiating prostate cancer from benign tissue. Our results also indicated that post-processing decisions on DWI data can affect sensitivity and specificity when applied to radiological-pathological studies in prostate cancer., Level of Evidence: 1 TECHNICAL EFFICACY: Stage 3., (© 2021 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

In the follow-up treatment of high-grade gliomas (HGGs), differentiating true tumor progression from treatment-related effects, such as pseudoprogression and radiation necrosis, presents an ongoing clinical challenge. Conventional MRI with and without intravenous contrast serves as the clinical benchmark for the posttreatment surveillance imaging of HGG. However, many advanced imaging techniques have shown promise in helping better delineate the findings in indeterminate scenarios, as posttreatment effects can often mimic true tumor progression on conventional imaging. These challenges are further confounded by the histologic admixture that can commonly occur between tumor growth and treatment-related effects within the posttreatment bed. This review discusses the current practices in the surveillance imaging of HGG and the role of advanced imaging techniques, including perfusion MRI and metabolic MRI., Competing Interests: KSw was co-founder of Precision Oncology Insights, US Patent US8571844B2. KSc: financial interest—Imaging Biometrics LLC; ownership interest—IQ-AQ Ltd; ownership interest—Prism Clinical Imaging, Inc. LH: Imaging Biometrics (Medical Advisory Board); Precision Oncology Insights (co-founder), Bayer Pharmaceutical (paid speaker), US Patent Number 10,909,675. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Malik, Rath, Urcuyo Acevedo, Canoll, Swanson, Boxerman, Quarles, Schmainda, Burns and Hu.)

Background and Purpose: Gliomas have been found to alter iron metabolism and transport in ways that result in an expansion of their intracellular iron compartments to support aggressive tumor growth. This study used deep neural network trained quantitative susceptibility mapping to assess basal ganglia iron concentrations in glioma patients., Materials and Methods: Ninety-two patients with brain lesions were initially enrolled in this study and fifty-nine met the inclusion criteria. Susceptibility-weighted images were collected at 3.0 T and used to construct quantitative susceptibility maps via a deep neural network-based method. The regions of interest were manually drawn within basal ganglia structures and the mean voxel intensities were extracted and averaged across multiple slices. One-way ANCOVA tests were conducted to compare the susceptibility values of groups of patients based on tumor grade while controlling for age, sex, and tumor type., Results: The mean basal ganglia susceptibility for patients with grade IV tumors was higher than that for patients with grade II tumors ( p = 0.00153) and was also higher for patients with grade III tumors compared to patients with grade II tumors ( p = 0.020), after controlling for age, sex, and tumor type. Patient age influenced susceptibility values ( p = 0.00356), while sex ( p = 0.69) and tumor type ( p = 0.11) did not., Conclusions: The basal ganglia iron content increased with glioma severity. Basal ganglia iron levels may thus be a useful biomarker in glioma prognosis and treatment, especially with regard to iron-based cancer therapies.

Objective: Summarize evidence for use of advanced MRI techniques as monitoring biomarkers in the clinic, and highlight the latest bench-to-bedside developments., Methods: Experts in advanced MRI techniques applied to high-grade glioma treatment response assessment convened through a European framework. Current evidence regarding the potential for monitoring biomarkers in adult high-grade glioma is reviewed, and individual modalities of perfusion, permeability, and microstructure imaging are discussed (in Part 1 of two). In Part 2, we discuss modalities related to metabolism and/or chemical composition, appraise the clinic readiness of the individual modalities, and consider post-processing methodologies involving the combination of MRI approaches (multiparametric imaging) or machine learning (radiomics)., Results: High-grade glioma vasculature exhibits increased perfusion, blood volume, and permeability compared with normal brain tissue. Measures of cerebral blood volume derived from dynamic susceptibility contrast-enhanced MRI have consistently provided information about brain tumor growth and response to treatment; it is the most clinically validated advanced technique. Clinical studies have proven the potential of dynamic contrast-enhanced MRI for distinguishing post-treatment related effects from recurrence, but the optimal acquisition protocol, mode of analysis, parameter of highest diagnostic value, and optimal cut-off points remain to be established. Arterial spin labeling techniques do not require the injection of a contrast agent, and repeated measurements of cerebral blood flow can be performed. The absence of potential gadolinium deposition effects allows widespread use in pediatric patients and those with impaired renal function. More data are necessary to establish clinical validity as monitoring biomarkers. Diffusion-weighted imaging, apparent diffusion coefficient analysis, diffusion tensor or kurtosis imaging, intravoxel incoherent motion, and other microstructural modeling approaches also allow treatment response assessment; more robust data are required to validate these alone or when applied to post-processing methodologies., Conclusion: Considerable progress has been made in the development of these monitoring biomarkers. Many techniques are in their infancy, whereas others have generated a larger body of evidence for clinical application., Competing Interests: Author KS has ownership interest in IQ-AI Ltd and financial interest in Imaging Biometrics LLC. Author TB has participated in a speaker’s bureau for AbbVie and Siemens Healthineers. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Henriksen, del Mar Álvarez-Torres, Figueiredo, Hangel, Keil, Nechifor, Riemer, Schmainda, Warnert, Wiegers and Booth.)

Objective: To summarize evidence for use of advanced MRI techniques as monitoring biomarkers in the clinic, and to highlight the latest bench-to-bedside developments., Methods: The current evidence regarding the potential for monitoring biomarkers was reviewed and individual modalities of metabolism and/or chemical composition imaging discussed. Perfusion, permeability, and microstructure imaging were similarly analyzed in Part 1 of this two-part review article and are valuable reading as background to this article. We appraise the clinic readiness of all the individual modalities and consider methodologies involving machine learning (radiomics) and the combination of MRI approaches (multiparametric imaging)., Results: The biochemical composition of high-grade gliomas is markedly different from healthy brain tissue. Magnetic resonance spectroscopy allows the simultaneous acquisition of an array of metabolic alterations, with choline-based ratios appearing to be consistently discriminatory in treatment response assessment, although challenges remain despite this being a mature technique. Promising directions relate to ultra-high field strengths, 2-hydroxyglutarate analysis, and the use of non-proton nuclei. Labile protons on endogenous proteins can be selectively targeted with chemical exchange saturation transfer to give high resolution images. The body of evidence for clinical application of amide proton transfer imaging has been building for a decade, but more evidence is required to confirm chemical exchange saturation transfer use as a monitoring biomarker. Multiparametric methodologies, including the incorporation of nuclear medicine techniques, combine probes measuring different tumor properties. Although potentially synergistic, the limitations of each individual modality also can be compounded, particularly in the absence of standardization. Machine learning requires large datasets with high-quality annotation; there is currently low-level evidence for monitoring biomarker clinical application., Conclusion: Advanced MRI techniques show huge promise in treatment response assessment. The clinical readiness analysis highlights that most monitoring biomarkers require standardized international consensus guidelines, with more facilitation regarding technique implementation and reporting in the clinic., Competing Interests: KS: Ownership interest in IQ-AI Ltd and financial interest in Imaging Biometrics LLC. TB speaker’s bureau for AbbVie and Siemens Healthineers. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Booth, Wiegers, Warnert, Schmainda, Riemer, Nechifor, Keil, Hangel, Figueiredo, Álvarez-Torres and Henriksen.)

Background and Importance: Distinction of brain tumor progression from treatment effect on postcontrast magnetic resonance imaging (MRI) is an ongoing challenge in the management of brain tumor patients. A newly emerging MRI biomarker called fractional tumor burden (FTB) has demonstrated the ability to spatially distinguish high-grade brain tumor from treatment effect with important implications for surgical management and pathological diagnosis., Clinical Presentation: A 58-yr-old male with glioblastoma was treated with standard concurrent chemoradiotherapy (CRT) after initial resection. Throughout follow-up imaging, the distinction of tumor progression from treatment effect was of concern. The surgical report from a redo resection indicated recurrent glioblastoma, while the tissue sent for pathological diagnosis revealed no tumor. Presurgical FTB maps confirmed the spatial variation of tumor and treatment effect within the contrast-agent enhancing lesion. Unresected lesion, shown to be an active tumor on FTB, was the site of substantial tumor growth postresection., Conclusion: This case report introduces the idea that a newly developed MRI biomarker, FTB, can provide information of tremendous benefit for surgical management, pathological diagnosis as well as subsequent treatment management decisions in high-grade glioma., (Copyright © The Author(s) 2021. Published by Oxford University Press on behalf of the Congress of Neurological Surgeons.)

Tumoral hypoxia correlates with worse outcomes in glioblastoma (GBM). While bevacizumab is routinely used to treat recurrent GBM, it may exacerbate hypoxia. Evofosfamide is a hypoxia-targeting prodrug being tested for recurrent GBM. To characterize resistance to bevacizumab and identify those with recurrent GBM who may benefit from evofosfamide, we ascertained MRI features and hypoxia in patients with GBM progression receiving both agents. Thirty-three patients with recurrent GBM refractory to bevacizumab were enrolled. Patients underwent MR and 18 F-FMISO PET imaging at baseline and 28 days. Tumor volumes were determined, MRI and 18 F-FMISO PET-derived parameters calculated, and Spearman correlations between parameters assessed. Progression-free survival decreased significantly with hypoxic volume [hazard ratio (HR) = 1.67, 95% confidence interval (CI) 1.14 to 2.46, P = 0.009] and increased significantly with time to the maximum value of the residue (Tmax) (HR = 0.54, 95% CI 0.34 to 0.88, P = 0.01). Overall survival decreased significantly with hypoxic volume (HR = 1.71, 95% CI 1.12 to 12.61, p = 0.01), standardized relative cerebral blood volume (srCBV) (HR = 1.61, 95% CI 1.09 to 2.38, p = 0.02), and increased significantly with Tmax (HR = 0.31, 95% CI 0.15 to 0.62, p < 0.001). Decreases in hypoxic volume correlated with longer overall and progression-free survival, and increases correlated with shorter overall and progression-free survival. Hypoxic volume and volume ratio were positively correlated (r s  = 0.77, P < 0.0001), as were hypoxia volume and T1 enhancing tumor volume (r s  = 0.75, P < 0.0001). Hypoxia is a key biomarker in patients with bevacizumab-refractory GBM. Hypoxia and srCBV were inversely correlated with patient outcomes. These radiographic features may be useful in evaluating treatment and guiding treatment considerations.

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., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Dismal prognosis and limited treatment options for recurrent high-grade glioma have provoked interest in various forms of reirradiation. Pulsed reduced dose rate radiation therapy (pRDR) is a promising technique that exploits low-dose hyper-radiosensitivity of proliferating tumor cells while sparing adjacent nonproliferating normal brain tissue. Large radiation treatment volumes can thus be used to target both contrast-enhancing and FLAIR abnormalities thought to harbor recurrent gross and microscopic disease, respectively. The aim of this retrospective study was to determine whether the addition of pRDR to bevacizumab improves survival over bevacizumab alone for recurrent high-grade glioma., Methods and Materials: Eighty patients with recurrent high-grade glioma were included in this study; 47 patients received bevacizumab monotherapy (BEV), and 33 patients received pRDR with bevacizumab (BEV/pRDR). Progression-free survival (PFS) and overall survival were compared between the BEV and BEV/pRDR groups. Regression analysis was performed to identify and control for confounding influences on survival analyses., Results: Significant (P < .05) advantages in PFS (12 vs 4 months; hazard ratio = 2.37) and OS (16 vs. 9 months; hazard ratio = 1.68) were observed with BEV/pRDR compared with BEV alone., Conclusions: This retrospective analysis suggests that treatment with pRDR in addition to bevacizumab could significantly prolong PFS and overall survival compared with bevacizumab alone for recurrent high-grade glioma., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We have previously characterized the reproducibility of brain tumor relative cerebral blood volume (rCBV) using a dynamic susceptibility contrast magnetic resonance imaging digital reference object across 12 sites using a range of imaging protocols and software platforms. As expected, reproducibility was highest when imaging protocols and software were consistent, but decreased when they were variable. Our goal in this study was to determine the impact of rCBV reproducibility for tumor grade and treatment response classification. We found that varying imaging protocols and software platforms produced a range of optimal thresholds for both tumor grading and treatment response, but the performance of these thresholds was similar. These findings further underscore the importance of standardizing acquisition and analysis protocols across sites and software benchmarking., (© 2020 The Authors. Published by Grapho Publications, LLC.)

New drugs are needed for glioblastoma, an aggressive brain tumor with a dismal prognosis. We recently reported that gallium maltolate (GaM) retards the growth of glioblastoma in a rat orthotopic brain tumor model by inhibiting mitochondrial function and iron-dependent ribonucleotide reductase (RR). However, GaM's mechanism of action at the mitochondrial level is not known. Given the interaction between gallium and iron metabolism, we hypothesized that gallium might target iron-sulfur (Fe-S) cluster-containing mitochondrial proteins. Using Extracellular Flux Analyzer technology, we confirmed that after a 24-h incubation, GaM 50 μmol/L inhibited glioblastoma cell growth by <10% but inhibited cellular oxygen consumption rate by 44% and abrogated mitochondrial reserve capacity. GaM blocked mitochondrial complex I activity and produced a 2.9-fold increase in cellular ROS. NMR spectroscopy revealed that gallium binds to IscU, the bacterial scaffold protein for Fe-S cluster assembly and stabilizes its folded state. Gallium inhibited the rate of in vitro cluster assembly catalyzed by bacterial cysteine desulfurase in a reaction mixture containing IscU, Fe (II), DTT, and L-cysteine. Metformin, a complex I inhibitor, enhanced GaM's inhibition of complex I, further increased cellular ROS levels, and synergistically enhanced GaM's cytotoxicity in glioblastoma cells in 2-D and 3-D cultures. Metformin did not affect GaM action on cellular iron uptake or transferrin receptor1 expression nor did it enhance the cytotoxicity of the RR inhibitor Didox. Our results show that GaM inhibits complex I by disrupting iron-sulfur cluster assembly and that its cytotoxicity can be synergistically enhanced by metformin through combined action on complex I., Competing Interests: CONFLICTS OF INTEREST None., (Copyright: © 2020 Alhajala et al.)

Background and Purpose: Perfusion MR imaging measures of relative CBV can distinguish recurrent tumor from posttreatment radiation effects in high-grade gliomas. Currently, relative CBV measurement requires normalization based on user-defined reference tissues. A recently proposed method of relative CBV standardization eliminates the need for user input. This study compares the predictive performance of relative CBV standardization against relative CBV normalization for quantifying recurrent tumor burden in high-grade gliomas relative to posttreatment radiation effects., Materials and Methods: We recruited 38 previously treated patients with high-grade gliomas (World Health Organization grades III or IV) undergoing surgical re-resection for new contrast-enhancing lesions concerning for recurrent tumor versus posttreatment radiation effects. We recovered 112 image-localized biopsies and quantified the percentage of histologic tumor content versus posttreatment radiation effects for each sample. We measured spatially matched normalized and standardized relative CBV metrics (mean, median) and fractional tumor burden for each biopsy. We compared relative CBV performance to predict tumor content, including the Pearson correlation ( r ), against histologic tumor content (0%-100%) and the receiver operating characteristic area under the curve for predicting high-versus-low tumor content using binary histologic cutoffs (≥50%; ≥80% tumor)., Results: Across relative CBV metrics, fractional tumor burden showed the highest correlations with tumor content (0%-100%) for normalized ( r  = 0.63, P  < .001) and standardized ( r = 0.66, P  < .001) values. With binary cutoffs (ie, ≥50%; ≥80% tumor), predictive accuracies were similar for both standardized and normalized metrics and across relative CBV metrics. Median relative CBV achieved the highest area under the curve (normalized = 0.87, standardized = 0.86) for predicting ≥50% tumor, while fractional tumor burden achieved the highest area under the curve (normalized = 0.77, standardized = 0.80) for predicting ≥80% tumor., Conclusions: Standardization of relative CBV achieves similar performance compared with normalized relative CBV and offers an important step toward workflow optimization and consensus methodology., (© 2020 by American Journal of Neuroradiology.)

Since the U.S. Supreme Court issued its landmark decision in 1973 to legalize abortion, over 60 million preborn have been killed by elective abortion. While alive in the womb, these preborn are abandoned and not protected under current law. But once aborted, their body parts are a highly esteemed and prized commodity amongst certain members of the scientific community. Moral discourse is disregarded for the sake of science. The public have been lulled and lured into believing that this practice must continue in order to understand and develop cures for some of the most debilitating diseases of our day. But they are mistaken. This practice is not necessary, especially in light of numerous noncontroversial alternatives. Here, we expose and consider the false and misleading claims regarding human fetal tissue (HFT) in research from scientific, legal, and ethical points of view. We endeavor deeply to understand the depth of the injustice in this practice and what forces promote and maintain it; and by revealing and understanding these forces, we set forth how these inhumane practices can be ended. An accurate portrayal of the history of HFT use in research is provided, along with a close examination of the current state of this practice under existing laws. The serious societal implications are also discussed, which will worsen beyond comprehension if these practices are allowed to continue. The timeliness of this information cannot be overstated, and a thorough understanding is paramount for anyone who desires to know the facts about HFT in research and medicine and its detrimental impact for humanity., (Copyright © 2020 by the National Legal Center for the Medically Dependent and Disabled, Inc.)

Background and Purpose: Brain tumor clinical trials requiring solid tumor assessment typically rely on the 2D manual delineation of enhancing tumors by ≥2 expert readers, a time-consuming step with poor interreader agreement. As a solution, we developed quantitative dT1 maps for the delineation of enhancing lesions. This retrospective analysis compares dT1 with 2D manual delineation of enhancing tumors acquired at 2 time points during the post therapeutic surveillance period of the American College of Radiology Imaging Network 6677/Radiation Therapy Oncology Group 0625 (ACRIN 6677/RTOG 0625) clinical trial., Materials and Methods: Patients enrolled in ACRIN 6677/RTOG 0625, a multicenter, randomized Phase II trial of bevacizumab in recurrent glioblastoma, underwent standard MR imaging before and after treatment initiation. For 123 patients from 23 institutions, both 2D manual delineation of enhancing tumors and dT1 datasets were evaluable at weeks 8 ( n = 74) and 16 ( n = 57). Using dT1, we assessed the radiologic response and progression at each time point. Percentage agreement with adjudicated 2D manual delineation of enhancing tumor reads and association between progression status and overall survival were determined., Results: For identification of progression, dT1 and adjudicated 2D manual delineation of enhancing tumor reads were in perfect agreement at week 8, with 73.7% agreement at week 16. Both methods showed significant differences in overall survival at each time point. When nonprogressors were further divided into responders versus nonresponders/nonprogressors, the agreement decreased to 70.3% and 52.6%, yet dT1 showed a significant difference in overall survival at week 8 ( P = .01), suggesting that dT1 may provide greater sensitivity for stratifying subpopulations., Conclusions: This study shows that dT1 can predict early progression comparable with the standard method but offers the potential for substantial time and cost savings for clinical trials., (© 2019 by American Journal of Neuroradiology.)

Background and Purpose: DSC-MR imaging using preload, intermediate (60°) flip angle and postprocessing leakage correction has gained traction as a standard methodology. Simulations suggest that DSC-MR imaging with flip angle = 30° and no preload yields relative CBV practically equivalent to the reference standard. This study tested this hypothesis in vivo., Materials and Methods: Eighty-four patients with brain lesions were enrolled in this 3-institution study. Forty-three patients satisfied the inclusion criteria. DSC-MR imaging (3T, single-dose gadobutrol, gradient recalled-echo-EPI, TE = 20-35 ms, TR = 1.2-1.63 seconds) was performed twice for each patient, with flip angle = 30°-35° and no preload (P-), which provided preload (P+) for the subsequent intermediate flip angle = 60°. Normalized relative CBV and standardized relative CBV maps were generated, including postprocessing with contrast agent leakage correction (C+) and without (C-) contrast agent leakage correction. Contrast-enhancing lesion volume, mean relative CBV, and contrast-to-noise ratio obtained with 30°/P-/C-, 30°/P-/C+, and 60°/P+/C- were compared with 60°/P+/C+ using the Lin concordance correlation coefficient and Bland-Altman analysis. Equivalence between the 30°/P-/C+ and 60°/P+/C+ protocols and the temporal SNR for the 30°/P- and 60°/P+ DSC-MR imaging data was also determined., Results: Compared with 60°/P+/C+, 30°/P-/C+ had closest mean standardized relative CBV ( P = .61), highest Lin concordance correlation coefficient (0.96), and lowest Bland-Altman bias (μ = 1.89), compared with 30°/P-/C- ( P = .02, Lin concordance correlation coefficient = 0.59, μ = 14.6) and 60°/P+/C- ( P = .03, Lin concordance correlation coefficient = 0.88, μ = -10.1) with no statistical difference in contrast-to-noise ratios across protocols. The normalized relative CBV and standardized relative CBV were statistically equivalent at the 10% level using either the 30°/P-/C+ or 60°/P+/C+ protocols. Temporal SNR was not significantly different for 30°/P- and 60°/P+ ( P = .06)., Conclusions: Tumor relative CBV derived from low-flip angle, no-preload DSC-MR imaging with leakage correction is an attractive single-dose alternative to the higher dose reference standard., (© 2019 by American Journal of Neuroradiology.)

Relative cerebral blood volume (rCBV) cannot be used as a response metric in clinical trials, in part, because of variations in biomarker consistency and associated interpretation across sites, stemming from differences in image acquisition and postprocessing methods (PMs). This study leveraged a dynamic susceptibility contrast magnetic resonance imaging digital reference object to characterize rCBV consistency across 12 sites participating in the Quantitative Imaging Network (QIN), specifically focusing on differences in site-specific imaging protocols (IPs; n = 17), and PMs (n = 19) and differences due to site-specific IPs and PMs (n = 25). Thus, high agreement across sites occurs when 1 managing center processes rCBV despite slight variations in the IP. This result is most likely supported by current initiatives to standardize IPs. However, marked intersite disagreement was observed when site-specific software was applied for rCBV measurements. This study's results have important implications for comparing rCBV values across sites and trials, where variability in PMs could confound the comparison of therapeutic effectiveness and/or any attempts to establish thresholds for categorical response to therapy. To overcome these challenges and ensure the successful use of rCBV as a clinical trial biomarker, we recommend the establishment of qualifying and validating site- and trial-specific criteria for scanners and acquisition methods (eg, using a validated phantom) and the software tools used for dynamic susceptibility contrast magnetic resonance imaging analysis (eg, using a digital reference object where the ground truth is known).

Pediatric glioblastoma (GBM) is a relatively rare brain tumor in children that has a dismal prognosis. Surgery followed by radiotherapy is the main treatment protocol used for older patients. The benefit of adjuvant chemotherapy is still limited due to a poor understanding of the underlying molecular and genetic changes that occur with irradiation of the tumor. In this study, we performed total RNA sequencing on an established stable radioresistant pediatric GBM cell line to identify mRNA expression changes following radiation. The expression of many genes was altered in the radioresistant pediatric GBM model. These genes have never before been reported to be associated with the development of radioresistant GBM. In addition to exhibiting an accelerated growth rate, radioresistant GBM cells also have overexpression of the DNA synthesis-rate-limiting enzyme ribonucleotide reductase, and pro-cathepsin B. These newly identified genes should be concertedly studied to better understand their role in pediatric GBM recurrence and progression after radiation. It was observed that the changes in multiple biological pathways protected GBM cells against radiation and transformed them to a more malignant form. These changes emphasize the importance of developing a treatment regimen that consists of a multiple-agent cocktail that acts on multiple implicated pathways to effectively target irradiated pediatric GBM. An alternative to radiation or a novel therapy that targets differentially expressed genes, such as metalloproteases, growth factors, and oncogenes and aim to minimize oncogenic changes following radiation is necessary to improve recurrent GBM survival., Competing Interests: CONFLICTS OF INTEREST None declared.

Background and Purpose: Standard assessment criteria for brain tumors that only include anatomic imaging continue to be insufficient. While numerous studies have demonstrated the value of DSC-MR imaging perfusion metrics for this purpose, they have not been incorporated due to a lack of confidence in the consistency of DSC-MR imaging metrics across sites and platforms. This study addresses this limitation with a comparison of multisite/multiplatform analyses of shared DSC-MR imaging datasets of patients with brain tumors., Materials and Methods: DSC-MR imaging data were collected after a preload and during a bolus injection of gadolinium contrast agent using a gradient recalled-echo-EPI sequence (TE/TR = 30/1200 ms; flip angle = 72°). Forty-nine low-grade ( n = 13) and high-grade ( n = 36) glioma datasets were uploaded to The Cancer Imaging Archive. Datasets included a predetermined arterial input function, enhancing tumor ROIs, and ROIs necessary to create normalized relative CBV and CBF maps. Seven sites computed 20 different perfusion metrics. Pair-wise agreement among sites was assessed with the Lin concordance correlation coefficient. Distinction of low- from high-grade tumors was evaluated with the Wilcoxon rank sum test followed by receiver operating characteristic analysis to identify the optimal thresholds based on sensitivity and specificity., Results: For normalized relative CBV and normalized CBF, 93% and 94% of entries showed good or excellent cross-site agreement (0.8 ≤ Lin concordance correlation coefficient ≤ 1.0). All metrics could distinguish low- from high-grade tumors. Optimum thresholds were determined for pooled data (normalized relative CBV = 1.4, sensitivity/specificity = 90%:77%; normalized CBF = 1.58, sensitivity/specificity = 86%:77%)., Conclusions: By means of DSC-MR imaging data obtained after a preload of contrast agent, substantial consistency resulted across sites for brain tumor perfusion metrics with a common threshold discoverable for distinguishing low- from high-grade tumors., (© 2018 by American Journal of Neuroradiology.)

Gallium, a metal with antineoplastic activity, binds transferrin (Tf) and enters tumor cells via Tf receptor1 (TfR1); it disrupts iron homeostasis leading to cell death. We hypothesized that TfR1 on brain microvascular endothelial cells (BMEC) would facilitate Tf-Ga transport into the brain enabling it to target TfR-bearing glioblastoma. We show that U-87 MG and D54 glioblastoma cell lines and multiple glioblastoma stem cell (GSC) lines express TfRs, and that their growth is inhibited by gallium maltolate (GaM) in vitro After 24 hours of incubation with GaM, cells displayed a loss of mitochondrial reserve capacity followed by a dose-dependent decrease in oxygen consumption and a decrease in the activity of the iron-dependent M2 subunit of ribonucleotide reductase (RRM2). IHC staining of rat and human tumor-bearing brains showed that glioblastoma, but not normal glial cells, expressed TfR1 and RRM2, and that glioblastoma expressed greater levels of H- and L-ferritin than normal brain. In an orthotopic U-87 MG glioblastoma xenograft rat model, GaM retarded the growth of brain tumors relative to untreated control ( P = 0.0159) and reduced tumor mitotic figures ( P = 0.045). Tumors in GaM-treated animals displayed an upregulation of TfR1 expression relative to control animals, thus indicating that gallium produced tumor iron deprivation. GaM also inhibited iron uptake and upregulated TfR1 expression in U-87 MG and D54 cells in vitro We conclude that GaM enters the brain via TfR1 on BMECs and targets iron metabolism in glioblastoma in vivo, thus inhibiting tumor growth. Further development of novel gallium compounds for brain tumor treatment is warranted. Mol Cancer Ther; 17(6); 1240-50. ©2018 AACR ., (©2018 American Association for Cancer Research.)

The absence of major progress in the treatment of glioblastoma (GBM) is partly attributable to our poor understanding of both GBM tumor biology and the acquirement of treatment resistance in recurrent GBMs. Recurrent GBMs are characterized by their resistance to radiation. In this study, we used an established stable U87 radioresistant GBM model and total RNA sequencing to shed light on global mRNA expression changes following irradiation. We identified many genes, the expressions of which were altered in our radioresistant GBM model, that have never before been reported to be associated with the development of radioresistant GBM and should be concertedly further investigated to understand their roles in radioresistance. These genes were enriched in various biological processes such as inflammatory response, cell migration, positive regulation of epithelial to mesenchymal transition, angiogenesis, apoptosis, positive regulation of T-cell migration, positive regulation of macrophage chemotaxis, T-cell antigen processing and presentation, and microglial cell activation involved in immune response genes. These findings furnish crucial information for elucidating the molecular mechanisms associated with radioresistance in GBM. Therapeutically, with the global alterations of multiple biological pathways observed in irradiated GBM cells, an effective GBM therapy may require a cocktail carrying multiple agents targeting multiple implicated pathways in order to have a chance at making a substantial impact on improving the overall GBM survival., Competing Interests: CONFLICTS OF INTEREST None declared.

The goal of this study is to spatially discriminate tumor from treatment effect (TE), within the contrast-enhancing lesion, for brain tumor patients at all stages of treatment. To this end, the diagnostic accuracy of MRI-derived diffusion and perfusion parameters to distinguish pure TE from pure glioblastoma (GBM) was determined utilizing spatially-correlated biopsy samples. From July 2010 through June 2015, brain tumor patients who underwent pre-operative DWI and DSC-MRI and stereotactic image-guided biopsy were considered for inclusion in this IRB-approved study. MRI-derived parameter maps included apparent diffusion coefficient (ADC), normalized cerebral blood flow (nCBF), normalized and standardized relative cerebral blood volume (nRCBV, sRCBV), peak signal-height (PSR) and percent signal-recovery (PSR). These were co-registered to the Stealth MRI and median values extracted from the spatially-matched biopsy regions. A ROC analysis accounting for multiple subject samples was performed, and the optimal threshold for distinguishing TE from GBM determined for each parameter. Histopathologic diagnosis of pure TE (n = 10) or pure GBM (n = 34) was confirmed in tissue samples from 15 consecutive subjects with analyzable data. Perfusion thresholds of sRCBV (3575; SN/SP% = 79.4/90.0), nRCBV (1.13; SN/SP% = 82.1/90.0), and nCBF (1.05; SN/SP% = 79.4/80.0) distinguished TE from GBM (P < 0.05), whereas ADC, PSR, and PH could not (P > 0.05). The thresholds for CBF and CBV can be applied to lesions with any admixture of tumor or treatment effect, enabling the identification of true tumor burden within enhancing lesions. This approach overcomes current limitations of averaging values from both tumor and TE for quantitative assessments.

Diffusion weighted MRI has become ubiquitous in many areas of medicine, including cancer diagnosis and treatment response monitoring. Reproducibility of diffusion metrics is essential for their acceptance as quantitative biomarkers in these areas. We examined the variability in the apparent diffusion coefficient (ADC) obtained from both postprocessing software implementations utilized by the NCI Quantitative Imaging Network and online scan time-generated ADC maps. Phantom and in vivo breast studies were evaluated for two ([Formula: see text]) and four ([Formula: see text]) [Formula: see text]-value diffusion metrics. Concordance of the majority of implementations was excellent for both phantom ADC measures and in vivo [Formula: see text], with relative biases [Formula: see text] ([Formula: see text]) and [Formula: see text] (phantom [Formula: see text]) but with higher deviations in ADC at the lowest phantom ADC values. In vivo [Formula: see text] concordance was good, with typical biases of [Formula: see text] to 3% but higher for online maps. Multiple b -value ADC implementations were separated into two groups determined by the fitting algorithm. Intergroup mean ADC differences ranged from negligible for phantom data to 2.8% for [Formula: see text] in vivo data. Some higher deviations were found for individual implementations and online parametric maps. Despite generally good concordance, implementation biases in ADC measures are sometimes significant and may be large enough to be of concern in multisite studies.

Glioblastoma remains the most common, malignant primary cancer of the central nervous system with a low life expectancy and an overall survival of less than 1.5 years. The treatment options are limited and there is no cure. Moreover, almost all patients develop recurrent tumors, which typically are more aggressive. Therapeutically resistant glioblastoma or glioblastoma stem-like cells (GSCs) are hypothesized to cause this inevitable recurrence. Identifying prognostic biomarkers of glioblastoma will potentially advance knowledge about glioblastoma tumorigenesis and enable discovery of more effective therapies. Proteomic analysis of more than 600 glioblastoma-specific proteins revealed, for the first time, that expression of acid ceramidase (ASAH1) is associated with poor glioblastoma survival. CD133+ GSCs express significantly higher ASAH1 compared to CD133- GSCs and serum-cultured glioblastoma cell lines, such as U87MG. These findings implicate ASAH1 as a plausible independent prognostic marker, providing a target for a therapy tailored toward GSCs. We further demonstrate that ASAH1 inhibition increases cellular ceramide level and induces apoptosis. Strikingly, U87MG cells, and three different patient-derived glioblastoma stem-like cancer cell lines were efficiently killed, through apoptosis, by three different known ASAH1 inhibitors with IC50's ranging from 11-104 μM. In comparison, the standard glioblastoma chemotherapy agent, temozolomide, had minimal GSC-targeted effects at comparable or even higher concentrations (IC50 > 750 μM against GSCs). ASAH1 is identified as a de novo glioblastoma drug target, and ASAH1 inhibitors, such as carmofur, are shown to be highly effective and to specifically target glioblastoma GSCs. Carmofur is an ASAH1 inhibitor that crosses the blood-brain barrier, a major bottleneck in glioblastoma treatment. It has been approved in Japan since 1981 for colorectal cancer therapy. Therefore, it is poised for repurposing and translation to glioblastoma clinical trials., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Glioblastoma multiforme (GBM) is the most common primary, intracranial malignancy of the central nervous system. The standard treatment protocol, which involves surgical resection, and concurrent radiation with adjuvant temozolomide (TMZ), still imparts a grim prognosis. Ultimately, all GBMs exhibit recurrence or progression, developing resistance to standard treatment. This study demonstrates that GBMs acquire resistance to radiation via upregulation of acid ceramidase (ASAH1) and sphingosine‑1-phosphate (Sph-1P). Moreover, inhibition of ASAH1 and Sph-1P, either with humanized monoclonal antibodies, small molecule drugs (i.e. carmofur), or a combination of both, led to suppression of GBM cell growth. These results suggest that ASAH1 and Sph-1P may be excellent targets for the treatment of new GBMs and recurrent GBMs, especially since the latter overexpresses ASAH1.

Background and Purpose: The optimal TE must be calculated to minimize the variance in CBV measurements made with DSC MR imaging. Simulations can be used to determine the influence of the TE on CBV, but they may not adequately recapitulate the in vivo heterogeneity of precontrast T2*, contrast agent kinetics, and the biophysical basis of contrast agent-induced T2* changes. The purpose of this study was to combine quantitative multiecho DSC MRI T2* time curves with error analysis in order to compute the optimal TE for a traditional single-echo acquisition., Materials and Methods: Eleven subjects with high-grade gliomas were scanned at 3T with a dual-echo DSC MR imaging sequence to quantify contrast agent-induced T2* changes in this retrospective study. Optimized TEs were calculated with propagation of error analysis for high-grade glial tumors, normal-appearing white matter, and arterial input function estimation., Results: The optimal TE is a weighted average of the T2* values that occur as a contrast agent bolus transverses a voxel. The mean optimal TEs were 30.0 ± 7.4 ms for high-grade glial tumors, 36.3 ± 4.6 ms for normal-appearing white matter, and 11.8 ± 1.4 ms for arterial input function estimation (repeated-measures ANOVA, P < .001)., Conclusions: Greater heterogeneity was observed in the optimal TE values for high-grade gliomas, and mean values of all 3 ROIs were statistically significant. The optimal TE for the arterial input function estimation is much shorter; this finding implies that quantitative DSC MR imaging acquisitions would benefit from multiecho acquisitions. In the case of a single-echo acquisition, the optimal TE prescribed should be 30-35 ms (without a preload) and 20-30 ms (with a standard full-dose preload)., (© 2017 by American Journal of Neuroradiology.)

Pediatric brain tumors are the most common solid tumors in children and are also a leading culprit of cancer-related fatalities in children. Pediatric brain tumors remain hard to treat. In this study, we demonstrated that medulloblastoma, pediatric glioblastoma, and atypical teratoid rhabdoid tumors express significant levels of acid ceramidase, where levels are highest in the radioresistant tumors, suggesting that acid ceramidase may confer radioresistance. More importantly, we also showed that acid ceramidase inhibitors are highly effective at targeting these pediatric brain tumors with low IC50 values (4.6-50 μM). This data suggests acid ceramidase as a novel drug target for adjuvant pediatric brain tumor therapies. Of these acid ceramidase inhibitors, carmofur has seen clinical use in Japan since 1981 for colorectal cancers and is a promising drug to undergo further animal studies and subsequently a clinical trial as a treatment for pediatric patients with brain tumors.

Dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) are the perfusion imaging techniques most frequently used to probe the angiogenic character of brain neoplasms. With these methods, T 1 - and T 2 / T 2 *-weighted imaging sequences are used to image the distribution of gadolinium (Gd)-based contrast agents. However, it is well known that Gd exhibits combined T 1 , T 2 , and T 2 * shortening effects in tissue, and therefore, the results of both DCE- and DSC-MRI can be confounded by these opposing effects. In particular, residual susceptibility effects compete with T 1 shortening, which can confound DCE-MRI parameters, whereas dipolar T 1 and T 2 leakage and residual susceptibility effects can confound DSC-MRI parameters. We introduce here a novel perfusion imaging acquisition and postprocessing method termed Spiral Perfusion Imaging with Consecutive Echoes (SPICE) that can be used to simultaneously acquire DCE- and DSC-MRI data, which requires only a single dose of the Gd contrast agent, does not require the collection of a precontrast T 1 map for DCE-MRI processing, and eliminates the confounding contrast agent effects due to contrast extravasation. A detailed mathematical description of SPICE is provided here along with a demonstration of its utility in patients with high-grade glioma., Competing Interests: Kathleen M. Schmainda has ownership interest in Imaging Biometrics, LLC.

Background and Purpose: Patients with recurrent glioblastoma often exhibit regions of diffusion restriction following the initiation of bevacizumab therapy. Studies suggest that these regions represent either diffusion-restricted necrosis or hypercellular tumor. This study explored postmortem brain specimens and a population analysis of overall survival to determine the identity and implications of such lesions., Materials and Methods: Postmortem examinations were performed on 6 patients with recurrent glioblastoma on bevacizumab with progressively growing regions of diffusion restriction. ADC values were extracted from regions of both hypercellular tumor and necrosis. A receiver operating characteristic analysis was performed to define optimal ADC thresholds for differentiating tissue types. A retrospective population study was also performed comparing the overall survival of 64 patients with recurrent glioblastoma treated with bevacizumab. Patients were separated into 3 groups: no diffusion restriction, diffusion restriction that appeared and progressed within 5 months of bevacizumab initiation, and delayed or stable diffusion restriction. An additional analysis was performed assessing tumor O 6 -methylguanine-DNA-methyltransferase methylation., Results: The optimal ADC threshold for differentiation of hypercellularity and necrosis was 0.736 × 10 -3 mm 2 /s. Progressively expanding diffusion restriction was pathologically confirmed to be coagulative necrosis surrounded by viable tumor. Progressive lesions were associated with the worst overall survival, while stable lesions showed the greatest overall survival (P < .05). Of the 40% of patients with O 6 -methylguanine-DNA-methyltransferase methylated tumors, none developed diffusion-restricted lesions., Conclusions: Progressive diffusion-restricted lesions were pathologically confirmed to be coagulative necrosis surrounded by viable tumor and associated with decreased overall survival. Stable lesions were, however, associated with increased overall survival. All lesions were associated with O 6 -methylguanine-DNA-methyltransferase unmethylated tumors., (© 2016 by American Journal of Neuroradiology.)

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 (k trans ) as well as 18 F-Fluoromisonidazole ( 18 F-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 18 F-FMISO SUV peak (P = 0.048), mean k trans (P = 0.024), and median k trans (P = 0.045) were significantly associated with shorter overall survival. Higher pretreatment median k trans (P = 0.021), normalized RCBV (P = 0.0096), and nCBF (P = 0.038) were significantly associated with shorter progression-free survival. SUV peak [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 18 F-FMISO PET. Clin Cancer Res; 22(20); 5079-86. ©2016 AACR., Competing Interests: Dr. Sorensen reports stock ownership and employment with Siemens and patents/royalties/intellectual property with General Electric. Dr Schmainda reports ownership interest in Imaging Biometrics LLC. All other authors report no conflict of interest., (©2016 American Association for Cancer Research.)

Magnetic resonance imaging (MRI) is used to diagnose and monitor brain tumors. Extracting additional information from medical imaging and relating it to a clinical variable of interest is broadly defined as radiomics. Here, multiparametric MRI radiomic profiles (RPs) of de novo glioblastoma (GBM) brain tumors is related with patient prognosis. Clinical imaging from 81 patients with GBM before surgery was analyzed. Four MRI contrasts were aligned, masked by margins defined by gadolinium contrast enhancement and T2/fluid attenuated inversion recovery hyperintensity, and contoured based on image intensity. These segmentations were combined for visualization and quantification by assigning a 4-digit numerical code to each voxel to indicate the segmented RP. Each RP volume was then compared with overall survival. A combined classifier was then generated on the basis of significant RPs and optimized volume thresholds. Five RPs were predictive of overall survival before therapy. Combining the RP classifiers into a single prognostic score predicted patient survival better than each alone ( P < .005). Voxels coded with 1 RP associated with poor prognosis were pathologically confirmed to contain hypercellular tumor. This study applies radiomic profiling to de novo patients with GBM to determine imaging signatures associated with poor prognosis at tumor diagnosis. This tool may be useful for planning surgical resection or radiation treatment margins.

Brain tumor cells invade adjacent normal brain along white matter (WM) bundles of axons. We therefore hypothesized that the location of tumor intersecting WM tracts would be associated with differing survival. This study introduces a method, voxel-wise survival analysis (VSA), to determine the relationship between the location of brain tumor intersecting WM tracts and patient prognosis. 113 primary glioblastoma (GBM) patients were retrospectively analyzed for this study. Patient specific tumor location, defined by contrast-enhancement, was combined with diffusion tensor imaging derived tractography to determine the location of axons intersecting tumor enhancement (AXITEs). VSA was then used to determine the relationship between the AXITE location and patient survival. Tumors intersecting the right anterior thalamic radiation (ATR), right inferior fronto-occipital fasciculus (IFOF), right and left cortico-spinal tract (CST), and corpus callosum (CC) were associated with decreased overall survival. Tumors intersecting the CST, body of the CC, right ATR, posterior IFOF, and inferior longitudinal fasciculus are associated with decreased progression-free survival (PFS), while tumors intersecting the right genu of the CC and anterior IFOF are associated with increased PFS. Patients with tumors intersecting the ATR, IFOF, CST, or CC had significantly improved survival prognosis if they were additionally treated with bevacizumab. This study demonstrates the usefulness of VSA by locating AXITEs associated with poor prognosis in GBM patients. This information should be included in patient-physician conversations, therapeutic strategy, and clinical trial design.

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-naïve 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., (© 2015 by American Journal of Neuroradiology.)

Background: 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., Methods: 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., Results: 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)., Conclusions: Early decreases in rCBV are predictive of improved survival in patients with recurrent GBM treated with bevacizumab., (© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)