Publications by authors named "Benjamin M Ellingson"

174 Publications

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40644-021-00396-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944911PMC
March 2021

Consensus Recommendations for MRI and PET Imaging of Primary Central Nervous System Lymphoma: Guideline Statement from the International Primary CNS Lymphoma Collaborative Group (IPCG).

Neuro Oncol 2021 Feb 9. Epub 2021 Feb 9.

Department of Radiology, Neuroradiology Division, Mayo Clinic, Phoenix, AZ USA.

Advanced molecular and pathophysiologic characterization of Primary Central Nervous System Lymphoma (PCNSL) has revealed insights into promising targeted therapeutic approaches. Medical imaging plays a fundamental role in PCNSL diagnosis, staging, and response assessment. Institutional imaging variation and inconsistent clinical trial reporting diminishes the reliability and reproducibility of clinical response assessment. In this context, we aimed to: 1) critically review the use of advanced PET and MRI in the setting of PCNSL; 2) provide results from an international survey of clinical sites describing the current practices for routine and advanced imaging, and 3) provide biologically based recommendations from the International PCNSL Collaborative Group (IPCG) on adaptation of standardized imaging practices. The IPCG provides PET and MRI consensus recommendations built upon previous recommendations for standardized brain tumor imaging protocols (BTIP) in primary and metastatic disease. A biologically integrated approach is provided to addresses the unique challenges associated with the imaging assessment of PCNSL. Detailed imaging parameters facilitate the adoption of these recommendations by researchers and clinicians. To enhance clinical feasibility, we have developed both "ideal" and "minimum standard" protocols at 3T and 1.5T MR systems that will facilitate widespread adoption.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noab020DOI Listing
February 2021

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

MAGMA 2021 Jan 23. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10334-020-00902-zDOI Listing
January 2021

Intravoxel incoherent motion (IVIM) modeling of diffusion MRI during chemoradiation predicts therapeutic response in IDH wildtype glioblastoma.

Radiother Oncol 2021 Mar 5;156:258-265. Epub 2021 Jan 5.

Department of Radiation Oncology, Sunnybrook Health Sciences Center, University of Toronto, Canada.

Background: Prediction of early progression in glioblastoma may provide an opportunity to personalize treatment. Simplified intravoxel incoherent motion (IVIM) MRI offers quantitative estimates of diffusion and perfusion metrics. We investigated whether these metrics, during chemoradiation, could predict treatment outcome.

Methods: 38 patients with newly diagnosed IDH-wildtype glioblastoma undergoing 6-week/30-fraction chemoradiation had standardized post-operative MRIs at baseline (radiation planning), and at the 10th and 20th fractions. Non-overlapping T1-enhancing (T1C) and non-enhancing T2-FLAIR hyperintense regions were independently segmented. Apparent diffusion coefficient (ADC, ADC) and perfusion fraction (f, f) maps were generated with simplified IVIM modelling. Parameters associated with progression before or after 6.9 months (early vs late progression, respectively), overall survival (OS) and progression-free survival (PFS) were investigated.

Results: Higher ADC at baseline [Odds Ratio (OR) = 1.06, 95% CI 1.01-1.15, p = 0.025], lower f at fraction 10 (OR = 2.11, 95% CI 1.04-4.27, p = 0.018), and lack of increase in ADC at fraction 20 compared to baseline (OR = 1.12, 95% CI 1.02-1.22, p = 0.02) were associated with early progression. Combining ADC at baseline, f at fraction 10, ECOG and MGMT promoter methylation status significantly improved AUC to 90.3% compared to a model with only ECOG and MGMT promoter methylation status (p = 0.001). Using multivariable analysis, neither IVIM metrics were associated with OS but higher f at fraction 10 (HR = 0.72, 95% CI 0.56-0.95, p = 0.018) was associated with longer PFS.

Conclusion: ADC at baseline, its lack of increase from baseline to fraction 20, or f at fraction 10 significantly predicted early progression. f at fraction 10 was associated with PFS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.radonc.2020.12.037DOI Listing
March 2021

Unique challenges for glioblastoma immunotherapy-discussions across neuro-oncology and non-neuro-oncology experts in cancer immunology. Meeting Report from the 2019 SNO Immuno-Oncology Think Tank.

Neuro Oncol 2021 Mar;23(3):356-375

Department of Neurological Surgery, UCSF, San Francisco, California.

Cancer immunotherapy has made remarkable advances with over 50 separate Food and Drug Administration (FDA) approvals as first- or second-line indications since 2015. These include immune checkpoint blocking antibodies, chimeric antigen receptor-transduced T cells, and bispecific T-cell-engaging antibodies. While multiple cancer types now benefit from these immunotherapies, notable exceptions thus far include brain tumors, such as glioblastoma. As such, it seems critical to gain a better understanding of unique mechanistic challenges underlying the resistance of malignant gliomas to immunotherapy, as well as to acquire insights into the development of future strategies. An Immuno-Oncology Think Tank Meeting was held during the 2019 Annual Society for Neuro-Oncology Scientific Conference. Discussants in the fields of neuro-oncology, neurosurgery, neuro-imaging, medical oncology, and cancer immunology participated in the meeting. Sessions focused on topics such as the tumor microenvironment, myeloid cells, T-cell dysfunction, cellular engineering, and translational aspects that are critical and unique challenges inherent with primary brain tumors. In this review, we summarize the discussions and the key messages from the meeting, which may potentially serve as a basis for advancing the field of immune neuro-oncology in a collaborative manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noaa277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992879PMC
March 2021

Minimizing echo and repetition times in magnetic resonance imaging using a double half-echo k-space acquisition and low-rank reconstruction.

NMR Biomed 2021 Apr 9;34(4):e4458. Epub 2020 Dec 9.

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

Sampling k-space asymmetrically (ie, partial Fourier sampling) in the readout direction is a common way to reduce the echo time (TE) during magnetic resonance image acquisitions. This technique requires overlap around the center of k-space to provide a calibration region for reconstruction, which limits the minimum fractional echo to ~60% before artifacts are observed. The present study describes a method for reconstructing images from exact half echoes using two separate acquisitions with reversed readout polarity, effectively providing a full line of k-space without additional data around central k-space. This approach can benefit sequences or applications that prioritize short TE, short inter-echo spacing or short repetition time. An example of the latter is demonstrated to reduce banding artifacts in balanced steady-state free precession.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/nbm.4458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935763PMC
April 2021

Novel tonometer device distinguishes brain stiffness in epilepsy surgery.

Sci Rep 2020 12 1;10(1):20978. Epub 2020 Dec 1.

Department of Neurosurgery, David Geffen School of Medicine at UCLA, 300 Stein Plaza, Suite 525, Los Angeles, CA, 90095-6901, USA.

Complete surgical resection of abnormal brain tissue is the most important predictor of seizure freedom following surgery for cortical dysplasia. While lesional tissue is often visually indiscernible from normal brain, anecdotally, it is subjectively stiffer. We report the first experience of the use of a digital tonometer to understand the biomechanical properties of epilepsy tissue and to guide the conduct of epilepsy surgery. Consecutive epilepsy surgery patients (n = 24) from UCLA Mattel Children's Hospital were recruited to undergo intraoperative brain tonometry at the time of open craniotomy for epilepsy surgery. Brain stiffness measurements were corrected with abnormalities on neuroimaging and histopathology using mixed-effects multivariable linear regression. We collected 249 measurements across 30 operations involving 24 patients through the pediatric epilepsy surgery program at UCLA Mattel Children's Hospital. On multivariable mixed-effects regression, brain stiffness was significantly associated with the presence of MRI lesion (β = 32.3, 95%CI 16.3-48.2; p < 0.001), severity of cortical disorganization (β = 19.8, 95%CI 9.4-30.2; p = 0.001), and recent subdural grid implantation (β = 42.8, 95%CI 11.8-73.8; p = 0.009). Brain tonometry offers the potential of real-time intraoperative feedback to identify abnormal brain tissue with millimeter spatial resolution. We present the first experience with this novel intraoperative tool for the conduct of epilepsy surgery. A carefully designed prospective study is required to elucidate whether the clinical application of brain tonometry during resective procedures could guide the area of resection and improve seizure outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-77888-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708453PMC
December 2020

Radiographic read paradigms and the roles of the central imaging laboratory in neuro-oncology clinical trials.

Neuro Oncol 2021 02;23(2):189-198

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

Determination of therapeutic benefit in intracranial tumors is intimately dependent on serial assessment of radiographic images. The Response Assessment in Neuro-Oncology (RANO) criteria were established in 2010 to provide an updated framework to better characterize tumor response to contemporary treatments. Since this initial update a number of RANO criteria have provided some basic principles for the interpretation of changes on MR images; however, the details of how to operationalize RANO and other criteria for use in clinical trials are ambiguous and not standardized. In this review article designed for the neuro-oncologist or treating clinician, we outline essential steps for performing radiographic assessments by highlighting primary features of the Imaging Charter (referred to as the Charter for the remainder of this article), a document that describes the clinical trial imaging methodology and methods to ensure operationalization of the Charter into the workings of a clinical trial. Lastly, we provide recommendations for specific changes to optimize this methodology for neuro-oncology, including image registration, requirement of growing tumor for eligibility in trials of recurrent tumor, standardized image acquisition guidelines, and hybrid reader paradigms that allow for both unbiased measurements and more comprehensive interpretation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noaa253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906061PMC
February 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00234-020-02585-8DOI Listing
October 2020

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/RLU.0000000000003318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950323PMC
December 2020

Compensatory brainstem functional and structural connectivity in patients with degenerative cervical myelopathy by probabilistic tractography and functional MRI.

Brain Res 2020 12 17;1749:147129. Epub 2020 Sep 17.

Dept. of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States. Electronic address:

Degenerative cervical myelopathy (DCM) is the most common cause of spinal cord impairment in adults. Previous supraspinal investigations have primarily focused on cortical changes in this patient population. As the nexus between the brain and the spinal cord, the brainstem has been understudied in patients with DCM. The current study examined the structural and functional connectivity between the brainstem and cortex in DCM patients using probabilistic tractography and resting-state functional MRI. A total of 26 study patients and 32 neurologically intact, healthy volunteers (HCs) participated in this prospective analysis. The study cohort included DCM patients (n = 18), as well as neurologically asymptomatic patients with evidence of cervical spine degenerative changes and spinal cord compression (n = 8). Results of the study demonstrated significant differences in fiber density (FD), fiber cross-section (FDC), and the functional connectivity (FC) between the study cohort and HCs. Through seeding the brainstem, the study cohort showed reductions in FD and FDC along the corticospinal tract, including regions extending through the corona radiata and internal capsule. By correlating FD and FDC with the Neck Disability Index (NDI), and the modified Japanese Orthopaedic Association (mJOA), we identified increasing total volume of projections to the thalamus, basal ganglia, and internal capsule, and increased functional connectivity to visual network and the posterior parietal cortices. These results support our hypothesis that DCM patients tend to have long-term FC reorganization not only localized to sensorimotor regions, but also to regulatory and visual processing regions, designed to ultimately preserve neurological function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brainres.2020.147129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606789PMC
December 2020

Influence of phosphate concentration on amine, amide, and hydroxyl CEST contrast.

Magn Reson Med 2021 02 16;85(2):1062-1078. Epub 2020 Sep 16.

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

Purpose: To evaluate the influence of phosphate on amine, amide, and hydroxyl CEST contrast using Bloch-McConnell simulations applied to physical phantom data.

Methods: Phantom solutions of 4 representative metabolites with exchangeable protons-glycine (α-amine protons), Cr (η-amine protons), egg white protein (amide protons), and glucose (hydroxyl protons)-were prepared at different pH levels (5.6 to 8.9) and phosphate concentrations (5 to 80 mM). CEST images of the phantom were collected with CEST-EPI sequence at 3 tesla. The CEST data were then fitted to full Bloch-McConnell equation simulations to estimate the exchange rate constants. With the fitted parameters, simulations were performed to evaluate the intracellular and extracellular contributions of CEST signals in normal brain tissue and brain tumors, as well as in dynamic glucose-enhanced experiments.

Results: The exchange rates of α-amine and hydroxyl protons were found to be highly dependent on both pH and phosphate concentrations, whereas the exchange rates of η-amine and amide protons were pH-dependent, albeit not catalyzed by phosphate. With phosphate being predominantly intracellular, CEST contrast of α-amine exhibited a higher sensitivity to changes in the extracellular microenvironment. Simulations of dynamic glucose-enhanced signals demonstrated that the contrast between normal and tumor tissue was mostly due to the extracellular CEST effect.

Conclusion: The proton exchange rates in some metabolites can be greatly catalyzed by the presence of phosphate at physiological concentrations, which substantially alters the CEST contrast. Catalytic agents should be considered as confounding factors in future CEST-MRI research. This new dimension may also benefit the development of novel phosphate-sensitive imaging methods.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mrm.28481DOI Listing
February 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-71799-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481206PMC
September 2020

Focal cortical dysplasia imaging discrepancies between MRI and FDG-PET: Unique association with temporal lobe location.

Seizure 2020 Oct 17;81:180-185. Epub 2020 Aug 17.

Department of Radiological Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.

Purpose: Although magnetic resonance imaging (MRI) and F-2-fluorodeoxyglucose-positron emission tomography (FDG-PET) are used for pre-surgical assessment of focal cortical dysplasia (FCD), they often disagree. This study aimed to identify factors that contribute to discrepancies in FCD imaging between MRI and FDG-PET.

Methods: Sixty-two patients (mean age, 18.9 years) with a FCD type I or II were retrospectively selected. These patients were visually categorized into two groups: 1) extent of PET abnormality larger than MRI abnormality and 2) vice versa or equivalent. Predictive factors of these two groups were analyzed by multivariate logistic regression. The extent of hypometabolic transient zone surrounding FCDs and their mean standardized uptake values were measured and compared by the Mann-Whitney U-test.

Results: FCDs were detected on MRI and PET in 46 and 55 patients, respectively, whereas no abnormality was detected in 4 patients. The PET hypometabolic areas were larger than the MRI abnormal areas in 26 patients (88 % in the temporal lobe), whereas the PET hypometabolic areas were equivalent or smaller than the MRI abnormal areas in 32 patients (69 % in the frontal lobe). The temporal lobe location was an independent predictor for differentiating the two groups (OR = 35.2, 95 % CI = 6.81-168.0, P < .001). The temporal lobe lesions had significantly wider transient zones and lower standardized uptake values than those in the other lobes (P < .001, both).

Conclusion: The discrepancies between MRI and FDG-PET findings of FCD were associated with temporal lobe location.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.seizure.2020.08.017DOI Listing
October 2020

Response to Letter to Editor.

Neuro Oncol 2020 11;22(11):1706-1707

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, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noaa202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690353PMC
November 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.120.247411DOI Listing
March 2021

Pathophysiology, classification, and MRI parallels in microvascular disease of the heart and brain.

Microcirculation 2020 11 26;27(8):e12648. Epub 2020 Jul 26.

Division of Cardiology, David Geffen School of Medicine at, UCLA and VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.

Diagnostic imaging technology in vascular disease has long focused on large vessels and the pathologic processes that impact them. With improved diagnostic techniques, investigators are now able to uncover many underlying mechanisms and prognostic factors for microvascular disease. In the heart and brain, these pathologic entities include coronary microvascular disease and cerebral small vessel disease, both of which have significant impact on patients, causing angina, myocardial infarction, heart failure, stroke, and dementia. In the current paper, we will discuss parallels in pathophysiology, classification, and diagnostic modalities, with a focus on the role of magnetic resonance imaging in microvascular disease of the heart and brain. Novel approaches for streamlined imaging of the cardiac and central nervous systems including the use of intravascular contrast agents such as ferumoxytol are presented, and unmet research gaps in diagnostics are summarized.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/micc.12648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680357PMC
November 2020

Ivosidenib in Isocitrate Dehydrogenase 1Mutated Advanced Glioma.

J Clin Oncol 2020 10 12;38(29):3398-3406. Epub 2020 Jun 12.

Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Purpose: Diffuse gliomas are malignant brain tumors that include lower-grade gliomas (LGGs) and glioblastomas. Transformation of low-grade glioma into a higher tumor grade is typically associated with contrast enhancement on magnetic resonance imaging. Mutations in the isocitrate dehydrogenase 1 () gene occur in most LGGs (> 70%). Ivosidenib is an inhibitor of mutant IDH1 (mIDH1) under evaluation in patients with solid tumors.

Methods: We conducted a multicenter, open-label, phase I, dose escalation and expansion study of ivosidenib in patients with m solid tumors. Ivosidenib was administered orally daily in 28-day cycles.

Results: In 66 patients with advanced gliomas, ivosidenib was well tolerated, with no dose-limiting toxicities reported. The maximum tolerated dose was not reached; 500 mg once per day was selected for the expansion cohort. The grade ≥ 3 adverse event rate was 19.7%; 3% (n = 2) were considered treatment related. In patients with nonenhancing glioma (n = 35), the objective response rate was 2.9%, with 1 partial response. Thirty of 35 patients (85.7%) with nonenhancing glioma achieved stable disease compared with 14 of 31 (45.2%) with enhancing glioma. Median progression-free survival was 13.6 months (95% CI, 9.2 to 33.2 months) and 1.4 months (95% CI, 1.0 to 1.9 months) for the nonenhancing and enhancing glioma cohorts, respectively. In an exploratory analysis, ivosidenib reduced the volume and growth rates of nonenhancing tumors.

Conclusion: In patients with m advanced glioma, ivosidenib 500 mg once per day was associated with a favorable safety profile, prolonged disease control, and reduced growth of nonenhancing tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.19.03327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527160PMC
October 2020

Consensus recommendations for a dynamic susceptibility contrast MRI protocol for use in high-grade gliomas.

Neuro Oncol 2020 09;22(9):1262-1275

Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

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

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noaa141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523451PMC
September 2020

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuros/nyaa135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566341PMC
October 2020

Volumetric analysis of IDH-mutant lower-grade glioma: a natural history study of tumor growth rates before and after treatment.

Neuro Oncol 2020 12;22(12):1822-1830

Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.

Background: Lower-grade gliomas (LGGs) with isocitrate dehydrogenase 1 and/or 2 (IDH1/2) mutations have long survival times, making evaluation of treatment efficacy difficult. We investigated the volumetric growth rate of IDH mutant gliomas before and after treatment with established glioma therapies to determine whether a significant change in growth rate could be documented and perhaps be used in the future to evaluate treatment response to investigational agents in LGG trials.

Methods: In this multicenter retrospective study, 230 adult patients with IDH1/2 mutated LGGs (World Health Organization grade II or III) undergoing surgery, radiation, or chemotherapy for progressive non-enhancing tumor were identified. Subjects were required to have 3 MRI scans containing T2/fluid attenuated inversion recovery imaging spanning a minimum of 6 months prior to treatment. A mixed-effect model was used to estimate tumor growth prior to treatment. A subset of 95 patients who received chemotherapy, radiotherapy, or chemoradiotherapy and had 2 posttreatment imaging time points available were evaluated for change in pre- and posttreatment volumetric growth rates using a piecewise mixed model.

Results: The pretreatment volumetric growth rate across all 230 patients was 27.37%/180 days (95% CI: [23.36%, 31.51%]). In the 95 patients with both pre- and posttreatment scans available, there was a significant difference in volumetric growth rates before (26.63%/180 days, 95% CI: [19.31%, 34.40%]) and after treatment (-15.24% /180 days, 95% CI: [-21.37%, -8.62%]) (P < 0.0001). The growth rates for patient subgroup with 1p/19q codeletion (N = 118) was significantly slower than the rate of the 1p/19q non-codeleted group (N = 68) (22.84% vs 35.49%, P = 0.0108).

Conclusion: In this study, we evaluated the growth rates of IDH mutant gliomas before and after standard therapy. Further study is needed to establish whether a change in growth rate is associated with patient survival and its use as a surrogate endpoint in clinical trials for IDH mutant LGGs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noaa105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746936PMC
December 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-3817DOI Listing
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11060-020-03460-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769136PMC
May 2020

Multiparametric MRI for early identification of therapeutic response in recurrent glioblastoma treated with immune checkpoint inhibitors.

Neuro Oncol 2020 11;22(11):1658-1666

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

Background: Physiologic changes quantified by diffusion and perfusion MRI have shown utility in predicting treatment response in glioblastoma (GBM) patients treated with cytotoxic therapies. We aimed to investigate whether quantitative changes in diffusion and perfusion after treatment by immune checkpoint inhibitors (ICIs) would determine 6-month progression-free survival (PFS6) in patients with recurrent GBM.

Methods: Inclusion criteria for this retrospective study were: (i) diagnosis of recurrent GBM treated with ICIs and (ii) availability of diffusion and perfusion in pre and post ICI MRI (iii) at ≥6 months follow-up from treatment. After co-registration, mean values of the relative apparent diffusion coefficient (rADC), Ktrans (volume transfer constant), Ve (extravascular extracellular space volume) and Vp (plasma volume), and relative cerebral blood volume (rCBV) were calculated from a volume-of-interest of the enhancing tumor. Final assignment of stable/improved versus progressive disease was determined on 6-month follow-up using modified Response Assessment in Neuro-Oncology criteria.

Results: Out of 19 patients who met inclusion criteria and follow-up (mean ± SD: 7.8 ± 1.4 mo), 12 were determined to have tumor progression, while 7 had treatment response after 6 months of ICI treatment. Only interval change of rADC was suggestive of treatment response. Patients with treatment response (6/7: 86%) had interval increased rADC, while 11/12 (92%) with tumor progression had decreased rADC (P = 0.001). Interval change in rCBV, Ktrans, Vp, and Ve were not indicative of treatment response within 6 months.

Conclusions: In patients with recurrent GBM, interval change in rADC is promising in assessing treatment response versus progression within the first 6 months following ICI treatment.

Key Points: • In recurrent GBM treated with ICIs, interval change in rADC suggests early treatment response.• Interval change in rADC can be used as an imaging biomarker to determine PFS6.• Interval change in MR perfusion and permeability measures do not suggest ICI treatment response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noaa066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846197PMC
November 2020