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  • 1
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 14, No. 1 ( 2023-09-28)
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2553671-0
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  • 2
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 19, No. 1 ( 2017-01-01), p. 128-137
    Abstract: Glioblastoma (GBM) exhibits profound intratumoral genetic heterogeneity. Each tumor comprises multiple genetically distinct clonal populations with different therapeutic sensitivities. This has implications for targeted therapy and genetically informed paradigms. Contrast-enhanced (CE)-MRI and conventional sampling techniques have failed to resolve this heterogeneity, particularly for nonenhancing tumor populations. This study explores the feasibility of using multiparametric MRI and texture analysis to characterize regional genetic heterogeneity throughout MRI-enhancing and nonenhancing tumor segments. Methods We collected multiple image-guided biopsies from primary GBM patients throughout regions of enhancement (ENH) and nonenhancing parenchyma (so called brain-around-tumor, [BAT]). For each biopsy, we analyzed DNA copy number variants for core GBM driver genes reported by The Cancer Genome Atlas. We co-registered biopsy locations with MRI and texture maps to correlate regional genetic status with spatially matched imaging measurements. We also built multivariate predictive decision-tree models for each GBM driver gene and validated accuracies using leave-one-out-cross-validation (LOOCV). Results We collected 48 biopsies (13 tumors) and identified significant imaging correlations (univariate analysis) for 6 driver genes: EGFR, PDGFRA, PTEN, CDKN2A, RB1, and TP53. Predictive model accuracies (on LOOCV) varied by driver gene of interest. Highest accuracies were observed for PDGFRA (77.1%), EGFR (75%), CDKN2A (87.5%), and RB1 (87.5%), while lowest accuracy was observed in TP53 (37.5%). Models for 4 driver genes (EGFR, RB1, CDKN2A, and PTEN) showed higher accuracy in BAT samples (n = 16) compared with those from ENH segments (n = 32). Conclusion MRI and texture analysis can help characterize regional genetic heterogeneity, which offers potential diagnostic value under the paradigm of individualized oncology.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2017
    detail.hit.zdb_id: 2094060-9
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  • 3
    In: Tomography, MDPI AG, Vol. 3, No. 2 ( 2017-06-01), p. 89-95
    Abstract: With DSC-MRI, contrast agent leakage effects in brain tumors can either be leveraged for percent signal recovery (PSR) measurements or be adequately resolved for accurate relative cerebral blood volume (rCBV) measurements. Leakage effects can be dimished by administration of a preload dose before imaging and/or specific postprocessing steps. This study compares the consistency of both PSR and rCBV measurements as a function of varying preload doses in a retrospective analysis of 14 subjects with high-grade gliomas. The scans consisted of 6 DSC-MRI scans during 6 sequential bolus injections (0.05 mmol/kg). Mean PSR was calculated for tumor and normal-appearing white matter regions of interest. DSC-MRI data were corrected for leakage effects before computing mean tumor rCBV. Statistical differences were seen across varying preloads for tumor PSR (P value = 4.57E-24). Tumor rCBV values did not exhibit statistically significant differences across preloads (P value = .14) and were found to be highly consistent for clinically relevant preloads (intraclass correlation coefficient = 0.93). For a 0.05 mmol/kg injection bolus and pulse sequence parameters used, the highest PSR contrast between normal-appearing white matter and tumor occurs when no preload is used. This suggests that studies using PSR as a biomarker should acquire DSC-MRI data without preload. The finding that leakage-corrected rCBV values do not depend on the presence or dose of preload contradicts that of previous studies with dissimilar acquisition protocols. This further confirms the sensitivity of rCBV to preload dosing schemes and pulse sequence parameters and highlights the importance of standardization efforts for achieving multisite rCBV consistency.
    Type of Medium: Online Resource
    ISSN: 2379-139X
    Language: English
    Publisher: MDPI AG
    Publication Date: 2017
    detail.hit.zdb_id: 2857000-5
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  • 4
    In: Frontiers in Radiology, Frontiers Media SA, Vol. 2 ( 2022-4-15)
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 2673-8740
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 3106354-8
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  • 5
    In: Tomography, MDPI AG, Vol. 5, No. 1 ( 2019-03-01), p. 110-117
    Abstract: The use of rCBV as a response metric in clinical trials has been hampered, in part, due to variations in the biomarker consistency and associated interpretation across sites, stemming from differences in image acquisition and post-processing methods. 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).
    Type of Medium: Online Resource
    ISSN: 2379-139X
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2857000-5
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  • 6
    In: Tomography, MDPI AG, Vol. 6, No. 2 ( 2020-06-01), p. 203-208
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 2379-139X
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2857000-5
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  • 7
    In: Frontiers in Oncology, Frontiers Media SA, Vol. 13 ( 2023-1-17)
    Abstract: Relative cerebral blood volume (rCBV) obtained from dynamic susceptibility contrast (DSC) MRI is widely used to distinguish high grade glioma recurrence from post treatment radiation effects (PTRE). Application of rCBV thresholds yield maps to distinguish between regional tumor burden and PTRE, a biomarker termed the fractional tumor burden (FTB). FTB is generally measured using conventional double-dose, single-echo DSC-MRI protocols; recently, a single-dose, dual-echo DSC-MRI protocol was clinically validated by direct comparison to the conventional double-dose, single-echo protocol. As the single-dose, dual-echo acquisition enables reduction in the contrast agent dose and provides greater pulse sequence parameter flexibility, there is a compelling need to establish dual-echo DSC-MRI based FTB mapping. In this study, we determine the optimum standardized rCBV threshold for the single-dose, dual-echo protocol to generate FTB maps that best match those derived from the reference standard, double-dose, single-echo protocol. Methods The study consisted of 23 high grade glioma patients undergoing perfusion scans to confirm suspected tumor recurrence. We sequentially acquired single dose, dual-echo and double dose, single-echo DSC-MRI data. For both protocols, we generated leakage-corrected standardized rCBV maps. Standardized rCBV (sRCBV) thresholds of 1.0 and 1.75 were used to compute single-echo FTB maps as the reference for delineating PTRE (sRCBV & lt; 1.0), tumor with moderate angiogenesis (1.0 & lt; sRCBV & lt; 1.75), and tumor with high angiogenesis (sRCBV & gt; 1.75) regions. To assess the sRCBV agreement between acquisition protocols, the concordance correlation coefficient (CCC) was computed between the mean tumor sRCBV values across the patients. A receiver operating characteristics (ROC) analysis was performed to determine the optimum dual-echo sRCBV threshold. The sensitivity, specificity, and accuracy were compared between the obtained optimized threshold (1.64) and the standard reference threshold (1.75) for the dual-echo sRCBV threshold. Results The mean tumor sRCBV values across the patients showed a strong correlation (CCC = 0.96) between the two protocols. The ROC analysis showed maximum accuracy at thresholds of 1.0 (delineate PTRE from tumor) and 1.64 (differentiate aggressive tumors). The reference threshold (1.75) and the obtained optimized threshold (1.64) yielded similar accuracy, with slight differences in sensitivity and specificity which were not statistically significant (1.75 threshold: Sensitivity = 81.94%; Specificity: 87.23%; Accuracy: 84.58% and 1.64 threshold: Sensitivity = 84.48%; Specificity: 84.97%; Accuracy: 84.73%). Conclusions The optimal sRCBV threshold for single-dose, dual-echo protocol was found to be 1.0 and 1.64 for distinguishing tumor recurrence from PTRE; however, minimal differences were observed when using the standard threshold (1.75) as the upper threshold, suggesting that the standard threshold could be used for both protocols. While the prior study validated the agreement of the mean sRCBV values between the protocols, this study confirmed that their voxel-wise agreement is suitable for reliable FTB mapping. Dual-echo DSC-MRI acquisitions enable robust single-dose sRCBV and FTB mapping, provide pulse sequence parameter flexibility and should improve reproducibility by mitigating variations in preload dose and incubation time.
    Type of Medium: Online Resource
    ISSN: 2234-943X
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2649216-7
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  • 8
    In: Frontiers in Oncology, Frontiers Media SA, Vol. 13 ( 2023-9-20)
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 2234-943X
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2649216-7
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