Publications by authors named "Catalina Raymond"

30 Publications

  • Page 1 of 1

Validation of diffusion MRI as a biomarker for efficacy using randomized phase III trial of bevacizumab with or without VB-111 in recurrent glioblastoma.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab082. Epub 2021 Jun 19.

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

Background: Evidence from single and multicenter phase II trials have suggested diffusion MRI is a predictive imaging biomarker for survival benefit in recurrent glioblastoma (rGBM) treated with anti-VEGF therapy. The current study confirms these findings in a large, randomized phase III clinical trial.

Methods: Patients with rGBM were enrolled in a phase III randomized (1:1), controlled trial (NCT02511405) to compare the efficacy and safety of bevacizumab (BV) versus BV in combination with ofranergene obadenovec (BV+VB-111), an anti-cancer viral therapy. In 170 patients with diffusion MRI available, pretreatment enhancing tumor volume and ADC histogram analysis were used to phenotype patients as having high (>1.24 µm/ms) or low (<1.24 µm/ms) ADC, the mean value of the lower peak of the ADC histogram, within the contrast enhancing tumor.

Results: Baseline tumor volume ( = .3460) and ADC ( = .2143) did not differ between treatment arms. Univariate analysis showed patients with high ADC had a significant survival advantage in all patients ( = .0006), as well as BV ( = .0159) and BV+VB-111 individually ( = .0262). Multivariable Cox regression accounting for treatment arm, age, baseline tumor volume, and ADC identified continuous measures of tumor volume ( < .0001; HR = 1.0212) and ADC phenotypes ( = .0012; HR = 0.5574) as independent predictors of OS.

Conclusion: Baseline diffusion MRI and tumor volume are independent imaging biomarkers of OS in rGBM treated with BV or BV+VB-111.
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http://dx.doi.org/10.1093/noajnl/vdab082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350152PMC
June 2021

Characterization of cognitive function in survivors of diffuse gliomas using resting-state functional MRI (rs-fMRI).

Brain Imaging Behav 2021 Aug 5. Epub 2021 Aug 5.

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.

As treatments for diffuse gliomas have advanced, survival for patients with gliomas has also increased. However, there remains limited knowledge on the relationships between brain connectivity and the lasting changes to cognitive function that glioma survivors often experience long after completing treatment. This resting-state functional magnetic resonance imaging (rs-fMRI) study explored functional connectivity (FC) alterations associated with cognitive function in survivors of gliomas. In this pilot study, 22 patients (mean age 43.8 ± 11.9) with diffuse gliomas who completed treatment within the past 10 years were evaluated using rs-fMRI and neuropsychological measures. Novel rs-fMRI analysis methods were used to account for missing brain in the resection cavity. FC relationships were assessed between cognitively impaired and non-impaired glioma patients, along with self-reported cognitive impairment, non-work daily functioning, and time with surgery. In the cognitively non-impaired patients, FC was stronger in the medial prefrontal cortex, rostral prefrontal cortex, and intraparietal sulcus compared to the impaired survivors. When examining non-work daily functioning, a positive correlation with FC was observed between the accumbens and the intracalcarine cortices, while a negative correlation with FC was observed between the parietal operculum cortex and the cerebellum. Additionally, worse self-reported cognitive impairment and worse non-work daily functioning were associated with increased FC between regions involved in cognition and sensorimotor processing. These preliminary findings suggest that neural correlates for cognitive and daily functioning in glioma patients can be revealed using rs-fMRI. Resting-state network alterations may serve as a biomarker for patients' cognition and functioning.
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http://dx.doi.org/10.1007/s11682-021-00497-6DOI Listing
August 2021

Quantification of tumor microenvironment acidity in glioblastoma using principal component analysis of dynamic susceptibility contrast enhanced MR imaging.

Sci Rep 2021 Jul 22;11(1):15011. Epub 2021 Jul 22.

Department of Radiology, Perelman School of Medicine, Hospital of University of Pennsylvania, University of Pennsylvania, Philadelphia, PA, USA.

Glioblastoma (GBM) has high metabolic demands, which can lead to acidification of the tumor microenvironment. We hypothesize that a machine learning model built on temporal principal component analysis (PCA) of dynamic susceptibility contrast-enhanced (DSC) perfusion MRI can be used to estimate tumor acidity in GBM, as estimated by pH-sensitive amine chemical exchange saturation transfer echo-planar imaging (CEST-EPI). We analyzed 78 MRI scans in 32 treatment naïve and post-treatment GBM patients. All patients were imaged with DSC-MRI, and pH-weighting that was quantified from CEST-EPI estimation of the magnetization transfer ratio asymmetry (MTR) at 3 ppm. Enhancing tumor (ET), non-enhancing core (NC), and peritumoral T2 hyperintensity (namely, edema, ED) were used to extract principal components (PCs) and to build support vector machines regression (SVR) models to predict MTR values using PCs. Our predicted map correlated with MTR values with Spearman's r equal to 0.66, 0.47, 0.67, 0.71, in NC, ET, ED, and overall, respectively (p < 0.006). The results of this study demonstrates that PCA analysis of DSC imaging data can provide information about tumor pH in GBM patients, with the strongest association within the peritumoral regions.
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http://dx.doi.org/10.1038/s41598-021-94560-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298590PMC
July 2021

Worse prognosis for IDH wild-type diffuse gliomas with larger residual biological tumor burden.

Ann Nucl Med 2021 Sep 14;35(9):1022-1029. Epub 2021 Jun 14.

UCLA Brain Tumor Imaging Laboratory (BTIL), David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA.

Objective: The association of overall survival (OS) with tumor burden, including contrast enhanced (CE) volume on CE T1-weighted images, fluid-attenuated inversion recovery (FLAIR) hyperintense volume, and 3, 4-dihydroxy-6-[F]-fluoro-L-phenylalanine (FDOPA) hypermetabolic volume, in isocitrate dehydrogenase (IDH) wild-type gliomas remains unclear. This study aimed to assess the association between biological tumor burden in pre- and post-operative status and OS in IDH wild-type gliomas, and evaluated which volume was the best predictor of OS.

Methods: Thirty-four patients with treatment-naïve IDH wild-type gliomas (WHO grade II 6, III 15, IV 13) were retrospectively included. Three pre-operative tumor regions of interest (ROIs) were segmented based on the CE, FLAIR hyperintense, and FDOPA hypermetabolic regions. Resected ROIs were segmented from the post-operative images. Residual CE, FLAIR hyperintense, and FDOPA hypermetabolic ROIs were created by subtracting resected ROIs from pre-operative ROIs. Cox regression analysis was conducted to investigate the association of OS with the volume of each ROI, and Akaike information criterion was used to assess the fitness.

Results: Residual CE volume had a significant association with OS [hazard ratio (HR) = 1.26, p = 0.039], but this effect disappeared when controlling for tumor grade. Residual FDOPA hypermetabolic volume best fit the regression model and was significantly associated with OS (HR = 1.18, p = 0.008), even when controlling for tumor grade. FLAIR hyperintense volume showed no significant association with OS.

Conclusion: Residual FDOPA hypermetabolic burden predicted OS for IDH wild-type gliomas, regardless of the tumor grade. Furthermore, removing hypermetabolic and CE regions may improve the prognosis.
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http://dx.doi.org/10.1007/s12149-021-01637-0DOI Listing
September 2021

Cortical morphometric correlational networks associated with cognitive deficits in first episode schizophrenia.

Schizophr Res 2021 05 16;231:179-188. Epub 2021 Apr 16.

Dept. of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States of America; Dept. of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States of America; Neuroscience Interdisciplinary Graduate Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States of America. Electronic address:

Schizophrenia (SCZ) is a chronic cognitive and behavioral disorder associated with abnormal cortical activity during information processing. Several brain structures associated with the seven performance domains evaluated using the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive Battery (MCCB) have shown cortical volume loss in first episode schizophrenia (FES) patients. However, the relationship between morphological organization and MCCB performance remains unclear. Therefore, in the current observational study, high-resolution structural MRI scans were collected from 50 FES patients, and the morphometric correlation network (MCN) using cortical volume was established to characterize the cortical pattern associated with poorer MCCB performance. We also investigated topological properties, such as the modularity, the degree and the betweenness centrality. Our findings show structural volume was directly and strongly associated with the cognitive deficits of FES patients in the precuneus, anterior cingulate, and fusiform gyrus, as well as the prefrontal, parietal, and sensorimotor cortices. The medial orbitofrontal, fusiform, and superior frontal gyri were not only identified as the predominant nodes with high degree and betweenness centrality in the MCN, but they were also found to be critical in performance in several of the MCCB domains. Together, these results suggest a widespread cortical network is altered in FES patients and that performance on the MCCB domains is associated with the core pathophysiology of SCZ.
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http://dx.doi.org/10.1016/j.schres.2021.04.001DOI Listing
May 2021

Detection of cerebral reorganization associated with degenerative cervical myelopathy using diffusion spectral imaging (DSI).

J Clin Neurosci 2021 Apr 5;86:164-173. Epub 2021 Feb 5.

Dept. of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Neuroscience Interdisciplinary Graduate Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Dept. of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Degenerative Cervical Myelopathy (DCM) is a spinal cord disorder that causes significant physical disabilities in older patients. While most DCM research focuses on the spinal cord, widespread reorganization of the brain may occur to compensate for functional impairment. This observational study used diffusion spectrum imaging (DSI) to examine reorganization of cerebral white matter associated with neurological impairment as measured by the modified Japanese Orthopedic Association (mJOA), and severity of neck disability as measured by the Neck Disability Index (NDI) score. A total of 47 patients were included in the cervical spondylosis (CS) cohort: 38 patients with DCM (mean mJOA = 14.6, and mean NDI = 12.0), and 9 neurologically asymptomatic patients with spinal cord compression (mJOA = 18, and mean NDI = 7.0). 28 healthy volunteers (HCs) served as the control group. Lower generalized fractional anisotropy (GFA) was observed throughout much of the brain in patients compared to HCs (p < 0.05). Fiber pathways associated with somatosensory functions, such as the corpus callosum and corona radiata, showed increased quantitative anisotropy (QA) in patients compared to HCs. Correlation analyses further suggested that structural connectivity was enhanced to compensate for neurological dysfunction within sensorimotor regions, where fibers such as the posterior corona radiata had NQA values that were negatively associated with mJOA (p = 0.0020, R = 0.2935) and positively associated with NDI score (p = 0.0164, R = 0.1889). Altogether, these results suggest that DCM and neurologically asymptomatic spinal cord compression patients tend to have long-term reorganization within the brain, particularly in those regions responsible for the perception and integration of sensory information, motor regulation, and pain modulation.
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http://dx.doi.org/10.1016/j.jocn.2021.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007933PMC
April 2021

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

J Neurooncol 2021 May 11;152(3):573-582. 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221401PMC
May 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

A physical phantom for amine chemical exchange saturation transfer (CEST) MRI.

MAGMA 2021 Aug 23;34(4):569-580. Epub 2021 Jan 23.

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

Objective: To develop a robust amine chemical exchange saturation transfer (CEST) physical phantom, validate the temporal stability, and create a supporting software for automatic image processing and quality assurance.

Materials And Methods: The phantom was designed as an assembled laser-cut acrylic rack and 18 vials of phantom solutions, prepared with different pHs, glycine concentrations, and gadolinium concentrations. We evaluated glycine concentrations using ultraviolet absorbance for 70 days and measured the pH, relaxation rates, and CEST contrast for 94 days after preparation. We used Spearman's correlation to determine if glycine degraded over time. Linear regression and Bland-Altman analysis were performed between baseline and follow-up measurements of pH and MRI properties.

Results: No degradation of glycine was observed (p > 0.05). The pH and MRI measurements stayed stable for 3 months and showed high consistency across time points (R = 1.00 for pH, R, R, and CEST contrast), which was further validated by the Bland-Altman plots. Examples of automatically generated reports are provided.

Discussion: We designed a physical phantom for amine CEST-MRI, which is easy to assemble and transfer, holds 18 different solutions, and has excellent short-term chemical and MRI stability. We believe this robust phantom will facilitate the development of novel sequences and cross-scanners validations.
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http://dx.doi.org/10.1007/s10334-020-00902-zDOI Listing
August 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 2021 Jun 26;63(6):857-868. 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071834PMC
June 2021

Maximum Uptake and Hypermetabolic Volume of 18F-FDOPA PET Estimate Molecular Status and Overall Survival in Low-Grade Gliomas: A PET and MRI Study.

Clin Nucl Med 2020 Dec;45(12):e505-e511

Department of Radiological Science, David Geffen School of Medicine.

Purpose: We evaluated F-FDOPA PET and MRI characteristics in association with the molecular status and overall survival (OS) in a large number of low-grade gliomas (LGGs).

Methods: Eighty-six patients who underwent F-FDOPA PET and MRI and were diagnosed with new or recurrent LGGs were retrospectively evaluated with respect to their isocitrate dehydrogenase (IDH) and 1p19q status (10 IDH wild type, 57 mutant, 19 unknown; 1p19q status in IDH mutant: 20 noncodeleted, 37 codeleted). After segmentation of the hyperintense area on fluid-attenuated inversion recovery image (FLAIRROI), the following were calculated: normalized SUVmax (nSUVmax) of F-FDOPA relative to the striatum, F-FDOPA hypermetabolic volume (tumor-to-striatum ratios >1), FLAIRROI volume, relative cerebral blood volume, and apparent diffusion coefficient within FLAIRROI. Receiver operating characteristic curve and Cox regression analyses were performed.

Results: PET and MRI metrics combined with age predicted the IDH mutation and 1p19q codeletion statuses with sensitivities of 73% and 76% and specificities of 100% and 94%, respectively. Significant correlations were found between OS and the IDH mutation status (hazard ratio [HR] = 4.939), nSUVmax (HR = 2.827), F-FDOPA hypermetabolic volume (HR = 1.048), and FLAIRROI volume (HR = 1.006). The nSUVmax (HR = 151.6) for newly diagnosed LGGs and the F-FDOPA hypermetabolic volume (HR = 1.038) for recurrent LGGs demonstrated significant association with OS.

Conclusions: Combining F-FDOPA PET and MRI with age proved useful for predicting the molecular status in patients with LGGs, whereas the nSUVmax and F-FDOPA hypermetabolic volume may be useful for prognostication.
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http://dx.doi.org/10.1097/RLU.0000000000003318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950323PMC
December 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

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 03 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049346PMC
March 2021

Association between cortical volume and gray-white matter contrast with second generation antipsychotic medication exposure in first episode male schizophrenia patients.

Schizophr Res 2020 08 31;222:397-410. Epub 2020 May 31.

Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States of America; Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States of America. Electronic address:

This cross-sectional study examines the differences in cortical volume and gray-to-white matter contrast (GWC) in first episode schizophrenia patients (SCZ) compared to healthy control participants (HC) and in SCZ patients as a function of exposure to second generation antipsychotic medication. We hypothesize 1) SCZ exhibit regionally lower cortical volumes relative to HCs, 2) cortical volume will be greater with longer exposure to second generation antipsychotics prior to the MRI scan, and 3) lower GWC with longer exposure to second generation antipsychotics prior to the MRI scan, suggesting more blurring from greater intracortical myelin. To accomplish this, MRI scans from 71 male SCZ patients treated with second generation oral risperidone and 42 male HCs were examined. 3D T1-weighted MPRAGE images collected at 1.5T were used to estimate cortical volume and GWC by sampling signal intensity at 30% within the cortical ribbon. Average cortical volume and GWC were calculated and compared between SCZ and HC. Cortical volume and GWC in SCZ patients were correlated with duration of medication exposure for the time period prior to the scan. First-episode SCZ patients had significantly lower cortical volume compared to HCs in bilateral temporal, superior and rostral frontal, postcentral gyral, and parahippocampal regions. In SCZ patients, greater cortical volume was associated with (log-transformed) duration of second-generation antipsychotic medication exposure in bilateral precuneus, right lingual, and right superior parietal regions. Lower GWC was correlated with longer duration of medication exposure bilaterally in the superior frontal lobes. In summary, second generation antipsychotics may increase cortical volume and decrease GWC in first episode SCZ patients.
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http://dx.doi.org/10.1016/j.schres.2020.03.073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572538PMC
August 2020

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

Multiparametric MR-PET Imaging Predicts Pharmacokinetics and Clinical Response to GDC-0084 in Patients with Recurrent High-Grade Glioma.

Clin Cancer Res 2020 07 8;26(13):3135-3144. Epub 2020 Apr 8.

Center for Neuro-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Purpose: GDC-0084 is an oral, brain-penetrant small-molecule inhibitor of PI3K and mTOR. Because these two targets alter tumor vascularity and metabolism, respectively, we hypothesized multiparametric MR-PET could be used to quantify the response, estimate pharmacokinetic (PK) parameters, and predict progression-free survival (PFS) in patients with recurrent malignant gliomas.

Patients And Methods: Multiparametric advanced MR-PET imaging was performed to evaluate physiologic response in a first-in-man, multicenter, phase I, dose-escalation study of GDC-0084 (NCT01547546) in 47 patients with recurrent malignant glioma.

Results: Measured maximum concentration ( ) was associated with a decrease in enhancing tumor volume ( = 0.0287) and an increase in fractional anisotropy (FA; = 0.0418). Posttreatment tumor volume, F-FDG uptake, K, and relative cerebral blood volume (rCBV) were all correlated with . A linear combination of change in F-FDG PET uptake, apparent diffusion coefficient (ADC), FA, K, v, and rCBV was able to estimate both ( = 0.4113; < 0.0001) and drug exposure (AUC; = 0.3481; < 0.0001). Using this composite multiparametric MR-PET imaging response biomarker to predict PK, patients with an estimated > 0.1 μmol/L and AUC > 1.25 μmol/L*hour demonstrated significantly longer PFS compared with patients with a lower estimated concentration and exposure ( = 0.0039 and = 0.0296, respectively).

Conclusions: Results from this study suggest composite biomarkers created from multiparametric MR-PET imaging targeting metabolic and/or physiologic processes specific to the drug mechanism of action may be useful for subsequent evaluation of treatment efficacy for larger phase II-III studies.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204664PMC
July 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

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

Probabilistic independent component analysis of dynamic susceptibility contrast perfusion MRI in metastatic brain tumors.

Cancer Imaging 2019 Mar 18;19(1):14. Epub 2019 Mar 18.

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

Purpose: To identify clinically relevant magnetic resonance imaging (MRI) features of different types of metastatic brain lesions, including standard anatomical, diffusion weighted imaging (DWI) and dynamic susceptibility contrast (DSC) perfusion MRI.

Methods: MRI imaging was retrospectively assessed on one hundred and fourteen (N = 114) brain metastases including breast (n = 27), non-small cell lung cancer (NSCLC, n = 43) and 'other' primary tumors (n = 44). Based on 114 patient's MRI scans, a total of 346 individual contrast enhancing tumors were manually segmented. In addition to tumor volume, apparent diffusion coefficients (ADC) and relative cerebral blood volume (rCBV) measurements, an independent component analysis (ICA) was performed with raw DSC data in order to assess arterio-venous components and the volume of overlap (AVOL) relative to tumor volume, as well as time to peak (TTP) of T* signal from each component.

Results: Results suggests non-breast or non-NSCLC ('other') tumors had higher volume compare to breast and NSCLC patients (p = 0.0056 and p = 0.0003, respectively). No differences in median ADC or rCBV were observed across tumor types; however, breast and NSCLC tumors had a significantly higher "arterial" proportion of the tumor volume as indicated by ICA (p = 0.0062 and p = 0.0018, respectively), while a higher "venous" proportion were prominent in breast tumors compared with NSCLC (p = 0.0027) and 'other' lesions (p = 0.0011). The AVOL component was positively related to rCBV in all groups, but no correlation was found for arterial and venous components with respect to rCBV values. Median time to peak of arterial and venous components were 8.4 s and 12.6 s, respectively (p < 0.0001). No difference was found in arterial or venous TTP across groups.

Conclusions: Advanced ICA-derived component analysis demonstrates perfusion differences between metastatic brain tumor types that were not observable with classical ADC and rCBV measurements. These results highlight the complex relationship between brain tumor vasculature characteristics and the site of primary tumor diagnosis.
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http://dx.doi.org/10.1186/s40644-019-0201-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423873PMC
March 2019

pH-weighted molecular MRI in human traumatic brain injury (TBI) using amine proton chemical exchange saturation transfer echoplanar imaging (CEST EPI).

Neuroimage Clin 2019 25;22:101736. Epub 2019 Feb 25.

Dept. of Neurosurgery, UCLA Brain Injury Research Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Cerebral acidosis is a consequence of secondary injury mechanisms following traumatic brain injury (TBI), including excitotoxicity and ischemia, with potentially significant clinical implications. However, there remains an unmet clinical need for technology for non-invasive, high resolution pH imaging of human TBI for studying metabolic changes following injury. The current study examined 17 patients with TBI and 20 healthy controls using amine chemical exchange saturation transfer echoplanar imaging (CEST EPI), a novel pH-weighted molecular MR imaging technique, on a clinical 3T MR scanner. Results showed significantly elevated pH-weighted image contrast (MTR at 3 ppm) in areas of T2 hyperintensity or edema (P < 0.0001), and a strong negative correlation with Glasgow Coma Scale (GCS) at the time of the MRI exam (R = 0.4777, P = 0.0021), Glasgow Outcome Scale - Extended (GOSE) at 6 months from injury (R = 0.5334, P = 0.0107), and a non-linear correlation with the time from injury to MRI exam (R = 0.6317, P = 0.0004). This evidence suggests clinical feasibility and potential value of pH-weighted amine CEST EPI as a high-resolution imaging tool for identifying tissue most at risk for long-term damage due to cerebral acidosis.
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http://dx.doi.org/10.1016/j.nicl.2019.101736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396390PMC
December 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

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

F-FDOPA PET and MRI characteristics correlate with degree of malignancy and predict survival in treatment-naïve gliomas: a cross-sectional study.

J Neurooncol 2018 Sep 20;139(2):399-409. Epub 2018 Apr 20.

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

Introduction: To report the potential value of pre-operative F-FDOPA PET and anatomic MRI in diagnosis and prognosis of glioma patients.

Methods: Forty-five patients with a pathological diagnosis of glioma with pre-operative F-FDOPA PET and anatomic MRI were retrospectively examined. The volume of contrast enhancement and T2 hyperintensity on MRI images along with the ratio of maximum F-FDOPA SUV in tumor to normal tissue (T/N SUV) were measured and used to predict tumor grade, molecular status, and overall survival (OS).

Results: A significant correlation was observed between WHO grade and: the volume of contrast enhancement (r = 0.67), volume of T2 hyperintensity (r = 0.42), and F-FDOPA uptake (r = 0.60) (P < 0.01 for each correlation). The volume of contrast enhancement and F-FDOPA T/N SUV were significantly higher in glioblastoma (WHO IV) compared with lower grade gliomas (WHO I-III), as well as for high-grade gliomas (WHO III-IV) compared with low-grade gliomas (WHO I-II). Receiver-operator characteristic (ROC) analyses confirmed the volume of contrast enhancement and F-FDOPA T/N SUV could each differentiate patient groups. No significant differences in F-FDOPA uptake were observed by IDH or MGMT status. Multivariable Cox regression suggested age (HR 1.16, P = 0.0001) and continuous measures of F-FDOPA PET T/N SUV (HR 4.43, P = 0.016) were significant prognostic factors for OS in WHO I-IV gliomas.

Conclusions: Current findings suggest a potential role for the use of pre-operative F-FDOPA PET in suspected glioma. Increased F-FDOPA uptake may not only predict higher glioma grade, but also worse OS.
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http://dx.doi.org/10.1007/s11060-018-2877-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092195PMC
September 2018

Volumetric response quantified using T1 subtraction predicts long-term survival benefit from cabozantinib monotherapy in recurrent glioblastoma.

Neuro Oncol 2018 09;20(10):1411-1418

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

Background: To overcome challenges with traditional response assessment in anti-angiogenic agents, the current study uses T1 subtraction maps to quantify volumetric radiographic response in monotherapy with cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2), hepatocyte growth factor receptor (MET), and AXL, in an open-label, phase II trial in patients with recurrent glioblastoma (GBM) (NCT00704288).

Methods: A total of 108 patients with adequate imaging data and confirmed recurrent GBM were included in this retrospective study from a phase II multicenter trial of cabozantinib monotherapy (XL184-201) at either 100 mg (N = 87) or 140 mg (N = 21) per day. Contrast enhanced T1-weighted digital subtraction maps were used to define volume of contrast-enhancing tumor at baseline and subsequent follow-up time points. Volumetric radiographic response (>65% reduction in contrast-enhancing tumor volume from pretreatment baseline tumor volume sustained for more than 4 wk) was tested as an independent predictor of overall survival (OS).

Results: Volumetric response rate for all therapeutic doses was 38.9% (41.4% and 28.6% for 100 mg and 140 mg doses, respectively). A log-linear association between baseline tumor volume and OS (P = 0.0006) and a linear correlation between initial change in tumor volume and OS (P = 0.0256) were observed. A significant difference in OS was observed between responders (median OS = 20.6 mo) and nonresponders (median OS = 8.0 mo) (hazard ratio [HR] = 0.3050, P < 0.0001). Multivariable analyses showed that continuous measures of baseline tumor volume (HR = 1.0233, P < 0.0001) and volumetric response (HR = 0.2240, P < 0.0001) were independent predictors of OS.

Conclusions: T1 subtraction maps provide value in determining response in recurrent GBM treated with cabozantinib and correlated with survival benefit.
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http://dx.doi.org/10.1093/neuonc/noy054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120362PMC
September 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

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
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