Publications by authors named "Whitney B Pope"

109 Publications

Preferential tumor localization in relation to F-FDOPA uptake for lower-grade gliomas.

J Neurooncol 2021 Mar 11. Epub 2021 Mar 11.

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, 924 Westwood Blvd., Suite 615, Los Angeles, CA, 90024, USA.

Purpose: Although tumor localization and 3,4-dihydroxy-6-F-fluoro-L-phenylalanine (FDOPA) uptake may have an association, preferential tumor localization in relation to FDOPA uptake is yet to be investigated in lower-grade gliomas (LGGs). This study aimed to identify differences in the frequency of tumor localization between FDOPA hypometabolic and hypermetabolic LGGs using a probabilistic radiographic atlas.

Methods: Fifty-one patients with newly diagnosed LGG (WHO grade II, 29; III, 22; isocitrate dehydrogenase wild-type, 21; mutant 1p19q non-codeleted,16; mutant codeleted, 14) who underwent FDOPA positron emission tomography (PET) were retrospectively selected. Semiautomated tumor segmentation on FLAIR was performed. Patients with LGGs were separated into two groups (FDOPA hypometabolic and hypermetabolic LGGs) according to the normalized maximum standardized uptake value of FDOPA PET (a threshold of the uptake in the striatum) within the segmented regions. Spatial normalization procedures to build a 3D MRI-based atlas using each segmented region were validated by an analysis of differential involvement statistical mapping.

Results: Superimposition of regions of interest showed a high number of hypometabolic LGGs localized in the frontal lobe, while a high number of hypermetabolic LGGs was localized in the insula, putamen, and temporal lobe. The statistical mapping revealed that hypometabolic LGGs occurred more frequently in the superior frontal gyrus (close to the supplementary motor area), while hypermetabolic LGGs occurred more frequently in the insula.

Conclusion: Radiographic atlases revealed preferential frontal lobe localization for FDOPA hypometabolic LGGs, which may be associated with relatively early detection.
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http://dx.doi.org/10.1007/s11060-021-03730-wDOI Listing
March 2021

Differentiating IDH status in human gliomas using machine learning and multiparametric MR/PET.

Cancer Imaging 2021 Mar 10;21(1):27. Epub 2021 Mar 10.

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA.

Background: The purpose of this study was to develop a voxel-wise clustering method of multiparametric magnetic resonance imaging (MRI) and 3,4-dihydroxy-6-[F]-fluoro-L-phenylalanine (FDOPA) positron emission tomography (PET) images using an unsupervised, two-level clustering approach followed by support vector machine in order to classify the isocitrate dehydrogenase (IDH) status of gliomas.

Methods: Sixty-two treatment-naïve glioma patients who underwent FDOPA PET and MRI were retrospectively included. Contrast enhanced T1-weighted images, T2-weighted images, fluid-attenuated inversion recovery images, apparent diffusion coefficient maps, and relative cerebral blood volume maps, and FDOPA PET images were used for voxel-wise feature extraction. An unsupervised two-level clustering approach, including a self-organizing map followed by the K-means algorithm was used, and each class label was applied to the original images. The logarithmic ratio of labels in each class within tumor regions was applied to a support vector machine to differentiate IDH mutation status. The area under the curve (AUC) of receiver operating characteristic curves, accuracy, and F1-socore were calculated and used as metrics for performance.

Results: The associations of multiparametric imaging values in each cluster were successfully visualized. Multiparametric images with 16-class clustering revealed the highest classification performance to differentiate IDH status with the AUC, accuracy, and F1-score of 0.81, 0.76, and 0.76, respectively.

Conclusions: Machine learning using an unsupervised two-level clustering approach followed by a support vector machine classified the IDH mutation status of gliomas, and visualized voxel-wise features from multiparametric MRI and FDOPA PET images. Unsupervised clustered features may improve the understanding of prioritizing multiparametric imaging for classifying IDH status.
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http://dx.doi.org/10.1186/s40644-021-00396-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944911PMC
March 2021

Relative oxygen extraction fraction (rOEF) MR imaging reveals higher hypoxia in human epidermal growth factor receptor (EGFR) amplified compared with non-amplified gliomas.

Neuroradiology 2020 Oct 26. Epub 2020 Oct 26.

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Purpose: Epidermal growth factor receptor (EGFR) amplification promotes gliomagenesis and is linked to lack of oxygen within the tumor microenvironment. Using hypoxia-sensitive spin-and-gradient echo echo-planar imaging and perfusion MRI, we investigated the influence of EGFR amplification on tissue oxygen availability and utilization in human gliomas.

Methods: This study included 72 histologically confirmed EGFR-amplified and non-amplified glioma patients. Reversible transverse relaxation rate (R'), relative cerebral blood volume (rCBV), and relative oxygen extraction fraction (rOEF) were calculated for the contrast-enhancing and non-enhancing tumor regions. Using Student t test or Wilcoxon rank-sum test, median R', rCBV, and rOEF were compared between EGFR-amplified and non-amplified gliomas. ROC analysis was performed to assess the ability of imaging characteristics to discriminate EGFR amplification status. Overall survival (OS) was determined using univariate and multivariate cox models. Kaplan-Meier survival curves were plotted and compared using the log-rank test.

Results: EGFR amplified gliomas exhibited significantly higher median R' and rOEF than non-amplified gliomas. ROC analysis suggested that R' (AUC = 0.7190; P = 0.0048) and rOEF (AUC = 0.6959; P = 0.0156) could separate EGFR status. Patients with EGFR-amplified gliomas had a significantly shorter OS than non-amplified patients. Univariate cox regression analysis determined both R' and rOEF significantly influence OS. No significant difference was observed in rCBV between patient cohorts nor was rCBV found to be an effective differentiator of EGFR status.

Conclusion: Imaging of tumor oxygen characteristics revealed EGFR-amplified gliomas to be more hypoxic and contribute to shorter patient survival than EGFR non-amplified gliomas.
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http://dx.doi.org/10.1007/s00234-020-02585-8DOI Listing
October 2020

Multiparametric MR-PET measurements in hypermetabolic regions reflect differences in molecular status and tumor grade in treatment-naïve diffuse gliomas.

J Neurooncol 2020 Sep 14;149(2):337-346. Epub 2020 Sep 14.

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, 924 Westwood Blvd, Suite 615, Los Angeles, CA, 90024, USA.

Purpose: To assess whether hypermetabolically-defined regions of interest (ROIs) on 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (FDOPA) positron emission tomography (PET) could be used to evaluate physiological features and whether there are measurable differences between molecular subtypes and tumor grades.

Methods: Sixty-eight treatment-naïve glioma patients who underwent FDOPA PET and magnetic resonance imaging (MRI) were retrospectively included. Fluid-attenuated inversion recovery hyperintense regions (FLAIR) were segmented. FDOPA hypermetabolic regions (FDOPA, tumor-to-striatum ratios > 1) within FLAIR were extracted. Normalized maximum standardized uptake value (nSUV), volume of each ROI, and median relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) within FLAIR or FDOPA were calculated. Imaging metrics were compared using Students t or Mann-Whitney U tests. Area under the curve (AUC) of receiver-operating characteristic curves were used to determine whether imaging metrics within FLAIR or FDOPA can discriminate different molecular statuses or grades.

Results: Using either FLAIR or FDOPA, the nSUV and rCBV were significantly higher and the ADC was lower in isocitrate dehydrogenase (IDH) wild-type than mutant gliomas, and in higher-grade gliomas (HGGs) than lower-grade gliomas (LGGs). The FDOPA volume was significantly higher in 1p19q codeleted than non-codeleted gliomas, and in HGGs than LGGs. Although not significant, imaging metrics extracted by FDOPA discriminated molecular status and tumor grade more accurately than those extracted by FLAIR (AUC of IDH status, 0.87 vs. 0.82; 1p19q status, 0.78 vs. 0.73; grade, 0.87 vs. 0.76).

Conclusion: FDOPA hypermetabolic ROI may extract useful imaging features of gliomas, which can illuminate biological differences between different molecular status or tumor grades.
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http://dx.doi.org/10.1007/s11060-020-03613-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682113PMC
September 2020

Decorin expression is associated with predictive diffusion MR phenotypes of anti-VEGF efficacy in glioblastoma.

Sci Rep 2020 09 9;10(1):14819. Epub 2020 Sep 9.

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers (CVIB), Dept. of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, 924 Westwood Blvd, Suite 615, Los Angeles, CA, 90024, USA.

Previous data suggest that apparent diffusion coefficient (ADC) imaging phenotypes predict survival response to anti-VEGF monotherapy in glioblastoma. However, the mechanism by which imaging may predict clinical response is unknown. We hypothesize that decorin (DCN), a proteoglycan implicated in the modulation of the extracellular microenvironment and sequestration of pro-angiogenic signaling, may connect ADC phenotypes to survival benefit to anti-VEGF therapy. Patients undergoing resection for glioblastoma as well as patients included in The Cancer Genome Atlas (TCGA) and IVY Glioblastoma Atlas Project (IVY GAP) databases had pre-operative imaging analyzed to calculate pre-operative ADC values, the average ADC in the lower distribution using a double Gaussian mixed model. ADC values were correlated to available RNA expression from these databases as well as from RNA sequencing from patient derived mouse orthotopic xenograft samples. Targeted biopsies were selected based on ADC values and prospectively collected during resection. Surgical specimens were used to evaluate for DCN RNA and protein expression by ADC value. The IVY Glioblastoma Atlas Project Database was used to evaluate DCN localization and relationship with VEGF pathway via in situ hybridization maps and RNA sequencing data. In a cohort of 35 patients with pre-operative ADC imaging and surgical specimens, DCN RNA expression levels were significantly larger in high ADC tumors (41.6 vs. 1.5; P = 0.0081). In a cohort of 17 patients with prospectively targeted biopsies there was a positive linear correlation between ADC levels and DCN protein expression between tumors (Pearson R = 0.3977; P = 0.0066) and when evaluating different targets within the same tumor (Pearson R = 0.3068; P = 0.0139). In situ hybridization data localized DCN expression to areas of microvascular proliferation and immunohistochemical studies localized DCN protein expression to the tunica adventitia of blood vessels within the tumor. DCN expression positively correlated with VEGFR1 & 2 expression and localized to similar areas of tumor. Increased ADC on diffusion MR imaging is associated with high DCN expression as well as increased survival with anti-VEGF therapy in glioblastoma. DCN may play an important role linking the imaging features on diffusion MR and anti-VEGF treatment efficacy. DCN may serve as a target for further investigation and modulation of anti-angiogenic therapy in GBM.
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http://dx.doi.org/10.1038/s41598-020-71799-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481206PMC
September 2020

Glioblastoma Utilizes Fatty Acids and Ketone Bodies for Growth Allowing Progression during Ketogenic Diet Therapy.

iScience 2020 Aug 13;23(9):101453. Epub 2020 Aug 13.

Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience & Human Behavior, UCLA, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA, USA. Electronic address:

Glioblastoma (GBM) metabolism has traditionally been characterized by a primary dependence on aerobic glycolysis, prompting the use of the ketogenic diet (KD) as a potential therapy. In this study we evaluated the effectiveness of the KD in GBM and assessed the role of fatty acid oxidation (FAO) in promoting GBM propagation. In vitro assays revealed FA utilization throughout the GBM metabolome and growth inhibition in nearly every cell line in a broad spectrum of patient-derived glioma cells treated with FAO inhibitors. In vivo assessments revealed that knockdown of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme for FAO, reduced the rate of tumor growth and increased survival. However, the unrestricted ketogenic diet did not reduce tumor growth and for some models significantly reduced survival. Altogether, these data highlight important roles for FA and ketone body metabolism that could serve to improve targeted therapies in GBM.
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http://dx.doi.org/10.1016/j.isci.2020.101453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471621PMC
August 2020

Human IDH mutant 1p/19q co-deleted gliomas have low tumor acidity as evidenced by molecular MRI and PET: a retrospective study.

Sci Rep 2020 07 17;10(1):11922. Epub 2020 Jul 17.

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, 924 Westwood Blvd., Suite 615, Los Angeles, CA, 90024, USA.

Co-deletion of 1p/19q is a hallmark of oligodendroglioma and predicts better survival. However, little is understood about its metabolic characteristics. In this study, we aimed to explore the extracellular acidity of WHO grade II and III gliomas associated with 1p/19q co-deletion. We included 76 glioma patients who received amine chemical exchange saturation transfer (CEST) imaging at 3 T. Magnetic transfer ratio asymmetry (MTR) at 3.0 ppm was used as the pH-sensitive CEST biomarker, with higher MTR indicating lower pH. To control for the confounder factors, T relaxometry and L-6-F-fluoro-3,4-dihydroxyphenylalnine (F-FDOPA) PET data were collected in a subset of patients. We found a significantly lower MTR in 1p/19q co-deleted gliomas (co-deleted, 1.17% ± 0.32%; non-co-deleted, 1.72% ± 0.41%, P = 1.13 × 10), while FDOPA (P = 0.92) and T (P = 0.61) were not significantly affected. Receiver operating characteristic analysis confirmed that MTR could discriminate co-deletion status with an area under the curve of 0.85. In analysis of covariance, 1p/19q co-deletion status was the only significant contributor to the variability in MTR when controlling for age and FDOPA (P = 2.91 × 10) or T (P = 8.03 × 10). In conclusion, 1p/19q co-deleted gliomas were less acidic, which may be related to better prognosis. Amine CEST-MRI may serve as a non-invasive biomarker for identifying 1p/19q co-deletion status.
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http://dx.doi.org/10.1038/s41598-020-68733-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367867PMC
July 2020

Voxelwise and Patientwise Correlation of F-FDOPA PET, Relative Cerebral Blood Volume, and Apparent Diffusion Coefficient in Treatment-Naïve Diffuse Gliomas with Different Molecular Subtypes.

J Nucl Med 2021 Mar 9;62(3):319-325. Epub 2020 Jul 9.

UCLA Brain Tumor Imaging Laboratory, Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, UCLA, Los Angeles, California

Our purpose was to identify correlations between F-fluorodihydroxyphenylalanine (F-FDOPA) uptake and physiologic MRI, including relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC), in gliomas with different molecular subtypes and to evaluate their prognostic values. Sixty-eight treatment-naïve glioma patients who underwent F-FDOPA PET and physiologic MRI were retrospectively selected (36 with isocitrate dehydrogenase wild-type [IDH], 16 with mutant 1p/19q noncodeleted [IDH], and 16 with mutant codeleted [IDH]). Fluid-attenuated inversion recovery hyperintense areas were segmented and used as regions of interest. For voxelwise and patientwise analyses, Pearson correlation coefficients ( and ) between the normalized SUV (nSUV), rCBV, and ADC were evaluated. Cox regression analysis was performed to investigate the associations between overall survival and , maximum or median nSUV, median rCBV, or median ADC. For IDH and IDH gliomas, nSUV demonstrated significant positive correlations with rCBV ( = 0.25 and 0.31, respectively; = 0.50 and 0.70, respectively) and negative correlations with ADC ( = -0.19 and -0.19, respectively; = -0.58 and -0.61, respectively) in both voxelwise and patientwise analyses. IDH gliomas demonstrated a significant positive correlation between nSUV and ADC only in voxelwise analysis ( = 0.18). In Cox regression analysis, between nSUV and rCBV (hazard ratio, 28.82) or ADC (hazard ratio, 0.085) had significant associations with overall survival for only IDH gliomas. IDH gliomas showed distinctive patterns of correlations between amino acid PET and physiologic MRI. Stronger correlations between nSUV and rCBV or ADC may result in a worse prognosis for IDH gliomas.
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http://dx.doi.org/10.2967/jnumed.120.247411DOI Listing
March 2021

Diffusion Magnetic Resonance Imaging Phenotypes Predict Overall Survival Benefit From Bevacizumab or Surgery in Recurrent Glioblastoma With Large Tumor Burden.

Neurosurgery 2020 10;87(5):931-938

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.

Background: Diffusion magnetic resonance (MR) characteristics are a predictive imaging biomarker for survival benefit in recurrent glioblastoma treated with anti-vascular endothelial growth factor (VEGF) therapy; however, its use in large volume recurrence has not been evaluated.

Objective: To determine if diffusion MR characteristics can predict survival outcomes in patients with large volume recurrent glioblastoma treated with bevacizumab or repeat resection.

Methods: A total of 32 patients with large volume (>20 cc or > 3.4 cm diameter) recurrent glioblastoma treated with bevacizumab and 35 patients treated with repeat surgery were included. Pretreatment tumor volume and apparent diffusion coefficient (ADC) histogram analysis were used to phenotype patients as having high (>1.24 μm2/ms) or low (<1.24 μm2/ms) ADCL, the mean value of the lower peak in a double Gaussian model of the ADC histogram within the contrast enhancing tumor.

Results: In bevacizumab and surgical cohorts, volume was correlated with overall survival (Bevacizumab: P = .009, HR = 1.02; Surgical: P = .006, HR = 0.96). ADCL was an independent predictor of survival in the bevacizumab cohort (P = .049, HR = 0.44), but not the surgical cohort (P = .273, HR = 0.67). There was a survival advantage of surgery over bevacizumab in patients with low ADCL (P = .036, HR = 0.43) but not in patients with high ADCL (P = .284, HR = 0.69).

Conclusion: Pretreatment diffusion MR imaging is an independent predictive biomarker for overall survival in recurrent glioblastoma with a large tumor burden. Large tumors with low ADCL have a survival benefit when treated with surgical resection, whereas large tumors with high ADCL may be best managed with bevacizumab.
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http://dx.doi.org/10.1093/neuros/nyaa135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566341PMC
October 2020

Diffusion MRI changes in the anterior subventricular zone following chemoradiation in glioblastoma with posterior ventricular involvement.

J Neurooncol 2020 May 1;147(3):643-652. Epub 2020 Apr 1.

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Introduction: There is growing evidence that the subventricular zone (SVZ) plays a key role in glioblastoma (GBM) tumorigenesis. However, little is known regarding how the SVZ, which is a harbor for adult neural stem cells, may be influenced by chemoradiation. The current diffusion-weighted imaging (DWI) study explored ipsilateral and contralateral alterations in the anterior SVZ in GBM patients with posterior enhancing lesions following chemoradiation.

Methods: Forty GBM patients with tumor involvement in the posterior SVZ (mean age = 57 ± 10; left-hemisphere N = 25; right-hemisphere N = 15) were evaluated using DWI before and after chemoradiation. Regions-of-interest were drawn on the ipsilesional and contralesional anterior SVZ on apparent diffusion coefficient (ADC) maps for both timepoints. ADC histogram analysis was performed by modeling a bimodal, double Gaussian distribution to obtain ADC, defined as the mean of the lower Gaussian distribution.

Results: The ipsilesional SVZ had lower ADC values compared to the contralesional SVZ before treatment (mean difference = 0.025 μm/ms; P = 0.007). Following chemoradiation, these changes were no longer observed (mean difference = 0.0025 μm/ms; P > 0.5), as ADC values of the ipsilesional SVZ increased (mean difference = 0.026 μm/ms; P = 0.037). An increase in ipsilesional ADC was associated with shorter progression-free (P = 0.0119) and overall survival (P = 0.0265).

Conclusions: These preliminary observations suggest baseline asymmetry as well as asymmetric changes in the SVZ proximal (ipsilesional) to the tumor with respect to contralesional SVZ regions may be present in GBM, potentially implicating this region in tumorigenesis and/or treatment resistance.
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http://dx.doi.org/10.1007/s11060-020-03460-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769136PMC
May 2020

Rate of change in maximum F-FDOPA PET uptake and non-enhancing tumor volume predict malignant transformation and overall survival in low-grade gliomas.

J Neurooncol 2020 Mar 24;147(1):135-145. Epub 2020 Jan 24.

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Purpose: To examine whether the rate of change in maximum F-FDOPA PET uptake and the rate of change in non-enhancing tumor volume could predict malignant transformation and residual overall survival (OS) in low grade glioma (LGG) patients who received serial F-FDOPA PET and MRI scans.

Methods: 27 LGG patients with ≥ 2 F-FDOPA PET and MRI scans between 2003 and 2016 were included. The rate of change in FLAIR volume (uL/day) and maximum normalized F-FDOPA specific uptake value (nSUV/month), were compared between histological and molecular subtypes. General linear models (GLMs) were used to integrate clinical information with MR-PET measurements to predict malignant transformation. Cox univariate and multivariable regression analyses were performed to identify imaging and clinical risk factors related to OS.

Results: A GLM using patient age, treatment, the rate of change in FLAIR and F-FDOPA nSUV could predict malignant transformation with > 67% sensitivity and specificity (AUC = 0.7556, P = 0.0248). A significant association was observed between OS and continuous rates of change in PET uptake (HR = 1.0212, P = 0.0034). Cox multivariable analysis confirmed that continuous measures of the rate of change in PET uptake was an independent predictor of OS (HR = 1.0242, P = 0.0033); however, stratification of patients based on increasing or decreasing rate of change in FLAIR (HR = 2.220, P = 0.025), PET uptake (HR = 2.148, P = 0.0311), or both FLAIR and PET (HR = 2.354, P = 0.0135) predicted OS.

Conclusions: The change in maximum normalized F-FDOPA PET uptake, with or without clinical information and rate of change in tumor volume, may be useful for predicting the risk of malignant transformation and estimating residual survival in patients with LGG.
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http://dx.doi.org/10.1007/s11060-020-03407-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080591PMC
March 2020

Imaging challenges of immunotherapy and targeted therapy in patients with brain metastases: response, progression, and pseudoprogression.

Neuro Oncol 2020 01;22(1):17-30

Institute of Neuroscience and Medicine, Research Center Juelich, Juelich, Germany.

The advent of immunotherapy using immune checkpoint inhibitors (ICIs) and targeted therapy (TT) has dramatically improved the prognosis of various cancer types. However, following ICI therapy or TT-either alone (especially ICI) or in combination with radiotherapy-imaging findings on anatomical contrast-enhanced MRI can be unpredictable and highly variable, and are often difficult to interpret regarding treatment response and outcome. This review aims at summarizing the imaging challenges related to TT and ICI monotherapy as well as combined with radiotherapy in patients with brain metastases, and to give an overview on advanced imaging techniques which potentially overcome some of these imaging challenges. Currently, major evidence suggests that imaging parameters especially derived from amino acid PET, perfusion-/diffusion-weighted MRI, or MR spectroscopy may provide valuable additional information for the differentiation of treatment-induced changes from brain metastases recurrence and the evaluation of treatment response.
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http://dx.doi.org/10.1093/neuonc/noz147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954406PMC
January 2020

Metabolic characterization of human IDH mutant and wild type gliomas using simultaneous pH- and oxygen-sensitive molecular MRI.

Neuro Oncol 2019 09;21(9):1184-1196

UCLA Brain Tumor Imaging Laboratory, Center for Computer Vision and Imaging Biomarkers, University of California Los Angeles, Los Angeles, California.

Background: Isocitrate dehydrogenase 1 (IDH1) mutant gliomas are thought to have distinct metabolic characteristics, including a blunted response to hypoxia and lower glycolytic flux. We hypothesized that non-invasive quantification of abnormal metabolic behavior in human IDH1 mutant gliomas could be performed using a new pH- and oxygen-sensitive molecular MRI technique.

Methods: Simultaneous pH- and oxygen-sensitive MRI was obtained at 3T using amine CEST-SAGE-EPI. The pH-dependent measure of the magnetization transfer ratio asymmetry (MTRasym) at 3 ppm and oxygen-sensitive measure of R2' were quantified in 90 patients with gliomas. Additionally, stereotactic, image-guided biopsies were performed in 20 patients for a total of 52 samples. The association between imaging measurements and hypoxia-inducible factor 1 alpha (HIF1α) expression was identified using Pearson correlation analysis.

Results: IDH1 mutant gliomas exhibited significantly lower MTRasym at 3 ppm, R2', and MTRasymxR2' (P = 0.007, P = 0.003, and P = 0.001, respectively). MTRasymxR2' could identify IDH1 mutant gliomas with a high sensitivity (81.0%) and specificity (81.3%). HIF1α was positively correlated with MTRasym at 3 ppm, R2' and MTRasymxR2' in IDH1 wild type (r = 0.610, P = 0.003; r = 0.667, P = 0.008; r = 0.635, P = 0.006), but only MTRasymxR2' in IDH1 mutant gliomas (r = 0.727, P = 0.039).

Conclusions: IDH1 mutant gliomas have distinct metabolic and microenvironment characteristics compared with wild type gliomas. An imaging biomarker combining tumor acidity and hypoxia (MTRasymxR2') can differentiate IDH1 mutation status and is correlated with tumor acidity and hypoxia.
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http://dx.doi.org/10.1093/neuonc/noz078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594567PMC
September 2019

Validation of vessel size imaging (VSI) in high-grade human gliomas using magnetic resonance imaging, image-guided biopsies, and quantitative immunohistochemistry.

Sci Rep 2019 02 26;9(1):2846. Epub 2019 Feb 26.

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

To evaluate the association between a vessel size index (VSI) derived from dynamic susceptibility contrast (DSC) perfusion imaging using a custom spin-and-gradient echo echoplanar imaging (SAGE-EPI) sequence and quantitative estimates of vessel morphometry based on immunohistochemistry from image-guided biopsy samples. The current study evaluated both relative cerebral blood volume (rCBV) and VSI in eleven patients with high-grade glioma (7 WHO grade III and 4 WHO grade IV). Following 26 MRI-guided glioma biopsies in these 11 patients, we evaluated tissue morphometry, including vessel density and average radius, using an automated procedure based on the endothelial cell marker CD31 to highlight tumor vasculature. Measures of rCBV and VSI were then compared to histological measures. We demonstrate good agreement between VSI measured by MRI and histology; VSI = 13.67 μm and VSI = 12.60 μm, with slight overestimation of VSI in grade III patients compared to histology. rCBV showed a moderate but significant correlation with vessel density (r = 0.42, p = 0.03), and a correlation was also observed between VSI and VSI (r = 0.49, p = 0.01). The current study supports the hypothesis that vessel size measures using MRI accurately reflect vessel caliber within high-grade gliomas, while traditional measures of rCBV are correlated with vessel density and not vessel caliber.
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http://dx.doi.org/10.1038/s41598-018-37564-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391482PMC
February 2019

pH-weighted amine chemical exchange saturation transfer echoplanar imaging (CEST-EPI) as a potential early biomarker for bevacizumab failure in recurrent glioblastoma.

J Neurooncol 2019 May 26;142(3):587-595. Epub 2019 Feb 26.

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, Los Angeles, CA, USA.

Purpose: The objective of the current study was to explore the efficacy of using pH-weighted amine CEST-EPI as a potential non-invasive imaging biomarker for treatment response and/or failure in recurrent GBM patients treated with bevacizumab.

Method: A total of 11 patients with recurrent GBM treated with bevacizumab were included in this prospective study. CEST-EPI, perfusion MRI, and standardized anatomic MRI were obtained in patients before and after bevacizumab administration. CEST-EPI measures of magnetization transfer ratio asymmetry (MTR) at 3 ppm were used for pH-weighted imaging contrast. Multiple measures were examined for their association with progression-free survival (PFS).

Result: Tumor acidity, measured with MTR at 3 ppm, was significantly reduced in both contrast enhancing and non-enhancing tumor after bevacizumab (p = 0.0002 and p < 0.00001, respectively). The reduction in tumor acidity in both contrast enhancing and non-enhancing tumor was linearly correlated with PFS (p = 0.044 and p = 0.00026, respectively). In 9 of the 11 patients, areas of residual acidity were localized to areas of tumor recurrence, typically around 2 months prior to radiographic progression. Univariate (p = 0.006) and multivariate Cox regression controlling for age (p = 0.009) both indicated that change in tumor acidity (ΔMTR at 3 ppm) was a significant predictor of PFS.

Conclusions: This pilot study suggests pH-weighted amine CEST MRI may have value as a non-invasive, early imaging biomarker for bevacizumab treatment response and failure. Early decreases MTR at 3.0 ppm in recurrent GBM after bevacizumab may be associated with better PFS. Residual or emerging regions of acidity may colocalize to the site of tumor recurrence.
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http://dx.doi.org/10.1007/s11060-019-03132-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482078PMC
May 2019

Longitudinal MRI findings in patients with newly diagnosed glioblastoma after intraoperative radiotherapy.

J Neuroradiol 2020 Mar 16;47(2):166-173. Epub 2019 Jan 16.

Department of Radiation Oncology, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany.

Background And Purpose: Post-radiation treatment effects (pseudoprogression/radionecrosis) may bias MRI-based tumor response evaluation. To understand these changes specifically after high doses of radiotherapy, we analyzed MRIs of patients enrolled in the INTRAGO study (NCT02104882), a phase I/II dose-escalation trial of intraoperative radiotherapy (20-40 Gy) in glioblastoma.

Methods: INTRAGO patients were evaluated and compared to control patients who received standard therapy with focus on contrast enhancement patterns/volume, T2 lesion volume, and mean rCBV.

Results: Overall, 11/15 (73.3%) INTRAGO patients (median age 60 years) were included. Distant failure was observed in 7/11 (63.6%) patients, local tumor recurrence in one patient (9.1%). On the first follow-up MRI all but one patient demonstrated enhancement of varying patterns around the resection cavity which were: in 2/11 (18.2%) patients thin and linear, in 7/11 (63.6%) combined linear and nodular, and in 1/11 (9.1%) voluminous, indistinct, and mesh-like. In the course of treatment, most patients developed the latter two patterns (8/11 [72.7%]). INTRAGO patients demonstrated more often combined linear and nodular and/or voluminous, indistinct, mesh-like components (8/11 [72.7%]) in comparison to control patients (3/12 [25%], P = 0.02). INTRAGO patients demonstrated significantly increasing enhancing lesion (P = 0.001) and T2 lesion volumes (P < 0.001) in the longitudinal non-parametric analysis in comparison to the control group. rCBV showed no significant differences between both groups.

Conclusions: High doses of radiotherapy to the tumor cavity result in more pronounced enhancement patterns/volumes and T2 lesion volumes. These results will be useful for the response evaluation of patients exposed to high doses of radiotherapy in future studies.
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http://dx.doi.org/10.1016/j.neurad.2019.01.090DOI Listing
March 2020

Improving B Correction for pH-Weighted Amine Proton Chemical Exchange Saturation Transfer (CEST) Imaging by Use of k-Means Clustering and Lorentzian Estimation.

Tomography 2018 Sep;4(3):123-137

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.

Amine chemical exchange saturation transfer (CEST) echoplanar imaging (EPI) provides unique pH and amino acid MRI contrast, enabling sensitive detection of altered microenvironment properties in various diseases. However, CEST contrast is sensitive to static magnetic field (B) inhomogeneities. Here we propose 2 new B correction algorithms for use in correcting pH-weighted amine CEST EPI based on k-means clustering and Lorentzian fitting of CEST data: the iterative downsampling estimation using Lorentzian fitting and the 2-stage Lorentzian estimation with 4D polynomial fitting. Higher quality images of asymmetric magnetization transfer ratio (MTR) at 3.0 ppm could be obtained with the proposed algorithms than with the existing B correction methods. In particular, the proposed methods are shown to improve the intertissue consistency, interpatient consistency, and tumor region signal-to-noise ratio of MTR at 3.0 ppm images, with nonexcessive computation time.
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http://dx.doi.org/10.18383/j.tom.2018.00017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173788PMC
September 2018

Post-chemoradiation volumetric response predicts survival in newly diagnosed glioblastoma treated with radiation, temozolomide, and bevacizumab or placebo.

Neuro Oncol 2018 10;20(11):1525-1535

UCLA Brain Research Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.

Background: In the current study we used contrast-enhanced T1 subtraction maps to test whether early changes in enhancing tumor volume are prognostic for overall survival (OS) in newly diagnosed glioblastoma (GBM) patients treated with chemoradiation with or without bevacizumab (BV).

Methods: Seven hundred ninety-eight patients (404 BV and 394 placebo) with newly diagnosed GBM in the AVAglio trial (NCT00943826) had baseline MRI scans available, while 337 BV-treated and 269 placebo-treated patients had >4 MRI scans for response evaluation. The volume of contrast-enhancing tumor was quantified and used for subsequent analyses.

Results: A decrease in tumor volume during chemoradiation was associated with a longer OS in the placebo group (hazard ratio [HR] = 1.578, P < 0.0001) but not BV-treated group (HR = 1.135, P = 0.4889). Results showed a higher OS in patients on the placebo arm with a sustained decrease in tumor volume using a post-chemoradiation baseline (HR = 1.692, P = 0.0005), and a trend toward longer OS was seen in BV-treated patients (HR = 1.264, P = 0.0724). Multivariable Cox regression confirmed that sustained response or stable disease was prognostic for OS (HR = 0.7509, P = 0.0127) when accounting for age (P = 0.0002), KPS (P = 0.1516), postsurgical tumor volume (P < 0.0001), O6-methylguanine-DNA methyltransferase status (P < 0.0001), and treatment type (P = 0.7637) using the post-chemoradiation baseline.

Conclusions: The post-chemoradiation timepoint is a better baseline for evaluating efficacy in newly diagnosed GBM. Early progression during the maintenance phase is consequential in predicting OS, supporting the use of progression-free survival rates as a meaningful surrogate for GBM.
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http://dx.doi.org/10.1093/neuonc/noy064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6178278PMC
October 2018

Mono-exponential, diffusion kurtosis and stretched exponential diffusion MR imaging response to chemoradiation in newly diagnosed glioblastoma.

J Neurooncol 2018 Sep 31;139(3):651-659. Epub 2018 May 31.

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, Los Angeles, CA, USA.

Purpose: To quantify changes and prognostic value of diffusion MRI measurements obtained using mono-exponential, diffusion kurtosis imaging (DKI) and stretched exponential (SE) models prior and after chemoradiation in newly diagnosed glioblastoma (GBM).

Methods: Diffusion-weighted images (DWIs) were acquired in twenty-three patients following surgery, prior chemoradiation and within 7 days following completion of treatment, using b-values ranging from 0 to 5000s/mm. Mono-exponential diffusion (apparent diffusion coefficient: ADC), isotropic (non-directional) DKI model with apparent diffusivity (Dapp) and kurtosis (Kapp) estimates as well as SE model with distributed-diffusion coefficient (DDC) and mean intra-voxel heterogeneity (α) were computed for all patients prior and after chemoradiation. Median values were calculated for normal appearing white matter (NAWM) and contrast-enhancing tumor (CET). The magnitudes of diffusion change prior and after chemoradiation were used to predict overall survival (OS).

Results: Diffusivity in NAWM was consistent for all diffusion measures during chemoradiation, while diffusivity measurements (ADC, Dapp and DDC) within CET changed significantly. A strong positive correlation existed between ADC, Dapp, and DDC measurements prior to chemoradiation; however, this association was weak following chemoradiation, suggesting a more complex microstructural environment after cytotoxic therapy. When combined with baseline tumor volume and MGMT status, age and ADC changes added significant prognostic values, whereas more complex diffusion models did not show significant value in predicting OS.

Conclusions: Despite increased tissue complexity following chemoradiation, advanced diffusion models have longer acquisition times, provide largely comparable measures of diffusivity, and do not appear to provide additional prognostic value compared to mono-exponential ADC maps.
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http://dx.doi.org/10.1007/s11060-018-2910-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126989PMC
September 2018

Gadolinium deposition within the paediatric brain: no increased intrinsic T1-weighted signal intensity within the dentate nucleus following the administration of a minimum of four doses of the macrocyclic agent gadobutrol.

Eur Radiol 2018 Nov 9;28(11):4882-4889. Epub 2018 May 9.

Department of Radiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Objectives: To determine whether repeated administration of the macrocyclic gadolinium-based contrast agent (GBCA) gadobutrol in children is associated with T1-weighted hyperintensity within the dentate nucleus, an imaging surrogate for gadolinium deposition.

Methods: With institutional review board approval, we identified a cohort of eight patients aged 18 years or younger who underwent at least four gadobutrol-enhanced magnetic resonance imaging (MRI) examinations of the brain from 2013 to 2017. For comparison, we identified a cohort of 19 patients who underwent at least four gadopentetate dimeglumine-enhanced MRI examinations. For each examination, both dentate nuclei were contoured on unenhanced images; the mean dentate-to-pons signal intensity (DN-P SI) ratio was calculated. DN-P SI ratios from the first and last MRI exams were compared using Wilcoxon signed ranks tests and linear regression analyses.

Results: In the gadobutrol cohort, there was no significant change in the mean DN-P SI ratio from the first to the last scan (1.02 vs 1.02, p = 1.00). In the gadopentetate dimeglumine cohort, there was a significant increase in the mean DN-P SI ratio from the first to the last scan (1.05 vs 1.13, p = 0.003). After controlling for potentially confounding variables, the change in DN-P SI ratio from the first to the last scan was significantly lower for patients in the gadobutrol group than in the gadopentetate dimeglumine group (β = -0.08, p = 0.04).

Conclusions: Repeated administration of the macrocyclic GBCA gadobutrol in children was not associated with T1-weighted dentate hyperintensity, while the repeated administration of the linear GBCA gadopentetate dimeglumine was associated with T1-weighted dentate hyperintensity, presumably due to gadolinium deposition.

Key Points: • Gadolinium-based contrast agents are routinely used in magnetic resonance imaging. • Repeated administration of the macrocyclic agent gadobutrol in children was not associated with T1-weighted dentate hyperintensity.
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http://dx.doi.org/10.1007/s00330-018-5464-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226378PMC
November 2018

Phase 2 Study of Bortezomib Combined With Temozolomide and Regional Radiation Therapy for Upfront Treatment of Patients With Newly Diagnosed Glioblastoma Multiforme: Safety and Efficacy Assessment.

Int J Radiat Oncol Biol Phys 2018 04 6;100(5):1195-1203. Epub 2018 Jan 6.

Department of Neurology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California. Electronic address:

Purpose: To assess the safety and efficacy of upfront treatment using bortezomib combined with standard radiation therapy (RT) and temozolomide (TMZ), followed by adjuvant bortezomib and TMZ for ≤24 cycles, in patients with newly diagnosed glioblastoma multiforme (GBM).

Methods And Materials: Twenty-four patients with newly diagnosed GBM were enrolled. The patients received standard external beam regional RT with concurrent TMZ beginning 3 to 6 weeks after surgery, followed by adjuvant TMZ and bortezomib for ≤24 cycles or until tumor progression. During RT, bortezomib was given at 1.3 mg/m on days 1, 4, 8, 11, 29, 32, 36, and 39. After RT, bortezomib was given at 1.3 mg/m on days 1, 4, 8, and 11 every 4 weeks.

Results: No unexpected adverse events occurred from the addition of bortezomib. The efficacy analysis showed a median progression-free survival (PFS) of 6.2 months (95% confidence interval [CI] 3.7-8.8), with promising PFS rates at ≥18 months compared with historical norms (25.0% at 18 and 24 months; 16.7% at 30 months). In terms of overall survival (OS), the median OS was 19.1 months (95% CI 6.7-31.4), with improved OS rates at ≥12 months (87.5% at 12, 50.0% at 24, 34.1% at 36-60 months) compared with the historical norms. The median PFS was 24.7 months (95% CI 8.5-41.0) in 10 MGMT methylated and 5.1 months (95% CI 3.9-6.2) in 13 unmethylated patients. The estimated median OS was 61 months (95% CI upper bound not reached) in the methylated and 16.4 months (95% CI 11.8-21.0) in the unmethylated patients.

Conclusions: The addition of bortezomib to current standard radiochemotherapy in newly diagnosed GBM patients was tolerable. The PFS and OS rates appeared promising, with more benefit to MGMT methylated patients. Further clinical investigation is warranted in a larger cohort of patients.
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http://dx.doi.org/10.1016/j.ijrobp.2018.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277207PMC
April 2018

Conventional and advanced magnetic resonance imaging in patients with high-grade glioma.

Q J Nucl Med Mol Imaging 2018 Sep 26;62(3):239-253. Epub 2018 Apr 26.

Department of Radiological Sciences, David Geffen School of Medicine, University of California - Los Angeles, Los Angeles, CA, USA.

Magnetic resonance imaging is integral to the care of patients with high-grade gliomas. Anatomic detail can be acquired with conventional structural imaging, but newer approaches also add capabilities to interrogate image-derived physiologic and molecular characteristics of central nervous system neoplasms. These advanced imaging techniques are increasingly employed to generate biomarkers that better reflect tumor burden and therapy response. The following is an overview of current strategies based on advanced magnetic resonance imaging that are used in the assessment of high-grade glioma patients with an emphasis on how novel imaging biomarkers can potentially advance patient care.
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http://dx.doi.org/10.23736/S1824-4785.18.03086-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123261PMC
September 2018

Validation of postoperative residual contrast-enhancing tumor volume as an independent prognostic factor for overall survival in newly diagnosed glioblastoma.

Neuro Oncol 2018 08;20(9):1240-1250

UCLA Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.

Background: In the current study, we pooled imaging data in newly diagnosed glioblastoma (GBM) patients from international multicenter clinical trials, single institution databases, and multicenter clinical trial consortiums to identify the relationship between postoperative residual enhancing tumor volume and overall survival (OS).

Methods: Data from 1511 newly diagnosed GBM patients from 5 data sources were included in the current study: (i) a single institution database from UCLA (N = 398; Discovery); (ii) patients from the Ben and Cathy Ivy Foundation for Early Phase Clinical Trials Network Radiogenomics Database (N = 262 from 8 centers; Confirmation); (iii) the chemoradiation placebo arm from an international phase III trial (AVAglio; N = 394 from 120 locations in 23 countries; Validation); (iv) the experimental arm from AVAglio examining chemoradiation plus bevacizumab (N = 404 from 120 locations in 23 countries; Exploratory Set 1); and (v) an Alliance (N0874) phase I/II trial of vorinostat plus chemoradiation (N = 53; Exploratory Set 2). Postsurgical, residual enhancing disease was quantified using T1 subtraction maps. Multivariate Cox regression models were used to determine influence of clinical variables, O6-methylguanine-DNA methyltransferase (MGMT) status, and residual tumor volume on OS.

Results: A log-linear relationship was observed between postoperative, residual enhancing tumor volume and OS in newly diagnosed GBM treated with standard chemoradiation. Postoperative tumor volume is a prognostic factor for OS (P < 0.01), regardless of therapy, age, and MGMT promoter methylation status.

Conclusion: Postsurgical, residual contrast-enhancing disease significantly negatively influences survival in patients with newly diagnosed GBM treated with chemoradiation with or without concomitant experimental therapy.
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http://dx.doi.org/10.1093/neuonc/noy053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071654PMC
August 2018

Simultaneous pH-sensitive and oxygen-sensitive MRI of human gliomas at 3 T using multi-echo amine proton chemical exchange saturation transfer spin-and-gradient echo echo-planar imaging (CEST-SAGE-EPI).

Magn Reson Med 2018 11 6;80(5):1962-1978. Epub 2018 Apr 6.

UCLA Brain Tumor Imaging Laboratory, Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.

Purpose: To introduce a new pH-sensitive and oxygen-sensitive MRI technique using amine proton CEST echo spin-and-gradient echo (SAGE) EPI (CEST-SAGE-EPI).

Methods: pH-weighting was obtained using CEST estimations of magnetization transfer ratio asymmetry (MTR ) at 3 ppm, and oxygen-weighting was obtained using R2' measurements. Glutamine concentration, pH, and relaxation rates were varied in phantoms to validate simulations and estimate relaxation rates. The values of MTR and R2' in normal-appearing white matter, T hyperintensity, contrast enhancement, and macroscopic necrosis were measured in 47 gliomas.

Results: Simulation and phantom results confirmed an increase in MTR with decreasing pH. The CEST-SAGE-EPI estimates of R , R2*, and R2' varied linearly with gadolinium diethylenetriamine penta-acetic acid concentration (R  = 6.2 mM ·sec and R2* = 6.9 mM ·sec ). The CEST-SAGE-EPI and Carr-Purcell-Meiboom-Gill estimates of R (R  = 0.9943) and multi-echo gradient-echo estimates of R2* (R  = 0.9727) were highly correlated. T lesions had lower R2' and higher MTR compared with normal-appearing white matter, suggesting lower hypoxia and high acidity, whereas contrast-enhancement tumor regions had elevated R2' and MTR , indicating high hypoxia and acidity.

Conclusion: The CEST-SAGE-EPI technique provides simultaneous pH-sensitive and oxygen-sensitive image contrasts for evaluation of the brain tumor microenvironment. Advantages include fast whole-brain acquisition, in-line B correction, and simultaneous estimation of CEST effects, R , R2*, and R2' at 3 T.
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http://dx.doi.org/10.1002/mrm.27204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107417PMC
November 2018

Brain metastases: neuroimaging.

Authors:
Whitney B Pope

Handb Clin Neurol 2018 ;149:89-112

Department of Radiological Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA, United States. Electronic address:

Magnetic resonance imaging (MRI) is the cornerstone for evaluating patients with brain masses such as primary and metastatic tumors. Important challenges in effectively detecting and diagnosing brain metastases and in accurately characterizing their subsequent response to treatment remain. These difficulties include discriminating metastases from potential mimics such as primary brain tumors and infection, detecting small metastases, and differentiating treatment response from tumor recurrence and progression. Optimal patient management could be benefited by improved and well-validated prognostic and predictive imaging markers, as well as early response markers to identify successful treatment prior to changes in tumor size. To address these fundamental needs, newer MRI techniques including diffusion and perfusion imaging, MR spectroscopy, and positron emission tomography (PET) tracers beyond traditionally used 18-fluorodeoxyglucose are the subject of extensive ongoing investigations, with several promising avenues of added value already identified. These newer techniques provide a wealth of physiologic and metabolic information that may supplement standard MR evaluation, by providing the ability to monitor and characterize cellularity, angiogenesis, perfusion, pH, hypoxia, metabolite concentrations, and other critical features of malignancy. This chapter reviews standard and advanced imaging of brain metastases provided by computed tomography, MRI, and amino acid PET, focusing on potential biomarkers that can serve as problem-solving tools in the clinical management of patients with brain metastases.
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http://dx.doi.org/10.1016/B978-0-12-811161-1.00007-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118134PMC
July 2018

Application of arterial spin labeling perfusion MRI to differentiate benign from malignant intracranial meningiomas.

Eur J Radiol 2017 Dec 7;97:31-36. Epub 2017 Oct 7.

Department of Radiological Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. Electronic address:

Purpose: Differentiating WHO grade I-III of meningioma by non-invasive imaging is challenging. This study investigated the potential of MR arterial spin labeling (ASL) to establish tumor grade in meningioma patients.

Material And Methods: Pseudo-continuous ASL with 3D background suppressed gradient and spin echo (GRASE) was acquired on 54 patients with newly diagnosed or recurrent intracranial meningioma. Perfusion patterns characterized in CBF color maps were independently evaluated by three neuroradiologists blinded to patient history, and correlated with tumor grade from histo-pathological review.

Results: Three perfusion patterns could be discerned by visual evaluation of CBF maps. Pattern 1 consisted of homogeneous hyper-perfusion of the entire tumor; pattern 2 demonstrated heterogeneous hyper-perfusion; pattern 3 showed no substantial hyper-perfusion. Evaluation of the perfusion patterns was highly concordant among the three readers (Kendall W=0.9458, P<0.0001). Pattern 1 was associated with WHO Grade I meningioma of (P<0.0001). Patterns 2 and 3 were predictive of WHO Grade II and III meningioma (P<0.0001), with an odds ratio (OR, versus pattern 1) of 49.6 (P<0.01) in a univariate analysis, and an OR of 186.4 (P<0.01) in a multivariate analysis.

Conclusion: Qualitative evaluation of ASL CBF maps can help differentiate benign (WHO Grade I) from higher grade (WHO Grade II and III) intracranial meningiomas, potentially impacting therapeutic strategy.
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http://dx.doi.org/10.1016/j.ejrad.2017.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165628PMC
December 2017

Diffusion MRI Phenotypes Predict Overall Survival Benefit from Anti-VEGF Monotherapy in Recurrent Glioblastoma: Converging Evidence from Phase II Trials.

Clin Cancer Res 2017 Oct 27;23(19):5745-5756. Epub 2017 Jun 27.

UCLA Neuro Oncology Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.

Anti-VEGF therapies remain controversial in the treatment of recurrent glioblastoma (GBM). In the current study, we demonstrate that recurrent GBM patients with a specific diffusion MR imaging signature have an overall survival (OS) advantage when treated with cediranib, bevacizumab, cabozantinib, or aflibercept monotherapy at first or second recurrence. These findings were validated using a separate trial comparing bevacizumab with lomustine. Patients with recurrent GBM and diffusion MRI from the monotherapy arms of 5 separate phase II clinical trials were included: (i) cediranib (NCT00035656); (ii) bevacizumab (BRAIN Trial, AVF3708g; NCT00345163); (iii) cabozantinib (XL184-201; NCT00704288); (iv) aflibercept (VEGF Trap; NCT00369590); and (v) bevacizumab or lomustine (BELOB; NTR1929). Apparent diffusion coefficient (ADC) histogram analysis was performed prior to therapy to estimate "ADC," the mean of the lower ADC distribution. Pretreatment ADC, enhancing volume, and clinical variables were tested as independent prognostic factors for OS. The coefficient of variance (COV) in double baseline ADC measurements was 2.5% and did not significantly differ ( = 0.4537). An ADC threshold of 1.24 μm/ms produced the largest OS differences between patients (HR ∼ 0.5), and patients with an ADC > 1.24 μm/ms had close to double the OS in all anti-VEGF therapeutic scenarios tested. Training and validation data confirmed that baseline ADC was an independent predictive biomarker for OS in anti-VEGF therapies, but not in lomustine, after accounting for age and baseline enhancing tumor volume. Pretreatment diffusion MRI is a predictive imaging biomarker for OS in patients with recurrent GBM treated with anti-VEGF monotherapy at first or second relapse. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-2844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626594PMC
October 2017

Perfusion and diffusion MRI signatures in histologic and genetic subtypes of WHO grade II-III diffuse gliomas.

J Neurooncol 2017 Aug 25;134(1):177-188. Epub 2017 May 25.

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, Los Angeles, CA, USA.

The value of perfusion and diffusion-weighted MRI in differentiating histological subtypes according to the 2007 WHO glioma classification scheme (i.e. astrocytoma vs. oligodendroglioma) and genetic subtypes according to the 2016 WHO reclassification (e.g. 1p/19q co-deletion and IDH1 mutation status) in WHO grade II and III diffuse gliomas remains controversial. In the current study, we describe unique perfusion and diffusion MR signatures between histological and genetic glioma subtypes. Sixty-five patients with 2007 histological designations (astrocytomas and oligodendrogliomas), 1p/19q status (+ = intact/- = co-deleted), and IDH1 mutation status (MUT/WT) were included in this study. In all patients, median relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) were estimated within T2 hyperintense lesions. Bootstrap hypothesis testing was used to compare subpopulations of gliomas, separated by WHO grade and 2007 or 2016 glioma classification schemes. A multivariable logistic regression model was also used to differentiate between 1p19q and 1p19q WHO II-III gliomas. Neither rCBV nor ADC differed significantly between histological subtypes of pure astrocytomas and pure oligodendrogliomas. ADC was significantly different between molecular subtypes (p = 0.0016), particularly between IDH and IDH/1p19q (p = 0.0013). IDH/1p19q grade III gliomas had higher median ADC; IDH grade III gliomas had higher rCBV with lower ADC; and IDH/1p19q had intermediate rCBV and ADC values, similar to their grade II counterparts. A multivariable logistic regression model was able to differentiate between IDH and IDH WHO II and III gliomas with an AUC of 0.84 (p < 0.0001, 74% sensitivity, 79% specificity). Within IDH WHO II-III gliomas, a separate multivariable logistic regression model was able to differentiate between 1p19q and 1p19q WHO II-III gliomas with an AUC of 0.80 (p = 0.0015, 64% sensitivity, 82% specificity). ADC better differentiated between genetic subtypes of gliomas according to the 2016 WHO guidelines compared to the classification scheme outlined in the 2007 WHO guidelines based on histological features of the tissue. Results suggest a combination of rCBV, ADC, T2 hyperintense volume, and presence of contrast enhancement together may aid in non-invasively identifying genetic subtypes of diffuse gliomas.
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http://dx.doi.org/10.1007/s11060-017-2506-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927357PMC
August 2017

Pseudoprogression, radionecrosis, inflammation or true tumor progression? challenges associated with glioblastoma response assessment in an evolving therapeutic landscape.

J Neurooncol 2017 Sep 5;134(3):495-504. Epub 2017 Apr 5.

Department of Radiology, Mayo Clinic, Rochester, MN, USA.

The wide variety of treatment options that exist for glioblastoma, including surgery, ionizing radiation, anti-neoplastic chemotherapies, anti-angiogenic therapies, and active or passive immunotherapies, all may alter aspects of vascular permeability within the tumor and/or normal parenchyma. These alterations manifest as changes in the degree of contrast enhancement or T2-weighted signal hyperintensity on standard anatomic MRI scans, posing a potential challenge for accurate radiographic response assessment for identifying anti-tumor effects. The current review highlights the challenges that remain in differentiating true disease progression from changes due to radiation therapy, including pseudoprogression and radionecrosis, as well as immune or inflammatory changes that may occur as either an undesired result of cytotoxic therapy or as a desired consequence of immunotherapies.
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http://dx.doi.org/10.1007/s11060-017-2375-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893814PMC
September 2017

The use of amino acid PET and conventional MRI for monitoring of brain tumor therapy.

Neuroimage Clin 2017 18;13:386-394. Epub 2016 Dec 18.

Institute of Neuroscience and Medicine, Forschungszentrum Jülich, Jülich, Germany; Dept. of Nuclear Medicine, University of Aachen, Aachen, Germany.

Routine diagnostics and treatment monitoring of brain tumors is usually based on contrast-enhanced MRI. However, the capacity of conventional MRI to differentiate tumor tissue from posttherapeutic effects following neurosurgical resection, chemoradiation, alkylating chemotherapy, radiosurgery, and/or immunotherapy may be limited. Metabolic imaging using PET can provide relevant additional information on tumor metabolism, which allows for more accurate diagnostics especially in clinically equivocal situations. This review article focuses predominantly on the amino acid PET tracers C-methyl-l-methionine (MET), -(2-[F]fluoroethyl)-l-tyrosine (FET) and 3,4-dihydroxy-6-[F]-fluoro-l-phenylalanine (FDOPA) and summarizes investigations regarding monitoring of brain tumor therapy.
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http://dx.doi.org/10.1016/j.nicl.2016.12.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226808PMC
November 2017