Short-interval estimation of proliferation rate using serial diffusion MRI predicts progression-free survival in newly diagnosed glioblastoma treated with radiochemotherapy

Cell invasion, motility, and proliferation level estimate (CIMPLE) mapping is a new imaging technique that provides parametric maps of microscopic invasion and proliferation rate estimates using serial diffusion MRI data. However, a few practical constraints have limited the use of CIMPLE maps as a tool for estimating these dynamic parameters, particularly during short-interval follow-up times. The purpose of the current study was to develop an approximation for the CIMPLE map solution for short-interval scanning involving the assumption that net intervoxel tumor invasion does not occur within sufficiently short time frames. Proliferation rate maps created using the “no invasion” approximation were found to be increasingly similar to maps created from full solution during increasingly longer follow-up intervals (3D cross correlation, R ² = 0.5298, P = 0.0001). Results also indicate proliferation rate maps from the “no invasion” approximation had significantly higher sensitivity (82 vs. 64 %) and specificity (90 vs. 80 %) for predicting 6 month progression free survival and was a better predictor of time to progression during standard radiochemotherapy compared to the full CIMPLE solution (log-rank; no invasion estimation, P = 0.0134; full solution, P = 0.0555). Together, results suggest the “no invasion” approximation allows for quick estimation of proliferation rate using diffusion MRI data obtained from multiple scans obtained daily or biweekly for use in quantifying early treatment response.     

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

Journal of Neuro-Oncology - 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...     

Regional and Voxel‐Wise Comparisons of Blood Flow Measurements Between Dynamic Susceptibility Contrast Magnetic Resonance Imaging (DSC‐MRI) and Arterial Spin Labeling (ASL) in Brain Tumors

The objective of the current study was to evaluate the regional and voxel‐wise correlation between dynamic susceptibility contrast (DSC) and arterial spin labeling (ASL) perfusion magnetic resonance imaging (MRI) measurement of cerebral blood flow (CBF) in patients with brain tumors. Thirty patients with histologically verified brain tumors were evaluated in the current study. DSC‐MRI was performed by first using a preload dose of gadolinium contrast, then collecting a dynamic image acquisition during a bolus of contrast, followed by posthoc contrast agent leakage correction. Pseudocontinuous ASL was collected using 30 pairs of tag and control acquisition using a 3‐dimensional gradient‐echo spin‐echo (GRASE) acquisition. All images were registered to a high‐resolution anatomical atlas. Average CBF measurements within regions of contrast‐enhancement and T2 hyperintensity were evaluated between the two modalities. Additionally, voxel‐wise correlation between CBF measurements obtained with DSC and ASL were assessed. Results demonstrated a positive linear correlation between DSC and ASL measurements of CBF when regional average values were compared; however, a statistically significant voxel‐wise correlation was only observed in around 30‐40% of patients. These results suggest DSC and ASL may provide regionally similar, but spatially different measurements of CBF.     

Nonlinear registration of diffusion‐weighted images improves clinical sensitivity of functional diffusion maps in recurrent glioblastoma treated with bevacizumab

Diffusion‐weighted imaging estimates of apparent diffusion coefficient (ADC) have shown sensitivity to brain tumor cellularity as well as response to therapy. Functional diffusion maps (fDMs) exploit these principles by examining voxelwise changes in ADC within the same patient over time. Currently, the fDM technique involves linear image registration of ADC maps from subsequent follow‐up times to pretreatment ADC maps; however, misregistration of ADC maps due to geometric distortions as well as mass effect from growing tumor can confound fDM measurements. In this study, we compare the use of a nonlinear registration scheme to the current linear fDM technique in 70 patients with recurrent glioblastoma multiforme treated with bevacizumab. Results suggest that nonlinear registration of pretreatment ADC maps to post‐treatment ADC maps improves the clinical predictability, sensitivity, and specificity of fDMs for both progression‐free and overall survival. Magn Reson Med, 2011. © 2011 Wiley‐Liss, Inc.     

Comparison between intensity normalization techniques for dynamic susceptibility contrast (DSC)-MRI estimates of cerebral blood volume (CBV) in human gliomas

Purpose:

To compare “standardization,” “Gaussian normalization,” and “Z‐score normalization” intensity transformation techniques in dynamic susceptibility contrast magnetic resonance imaging (DSC‐MRI) estimates of cerebral blood volume (CBV) in human gliomas. DSC‐MRI is a well‐established biomarker for CBV in brain tumors; however, DSC‐MRI estimates of CBV are semiquantitative. The use of image intensity transformation algorithms provides a mechanism for obtaining quantitatively similar CBV maps with the same intensity scaling.

Materials and Methods:

The coefficient of variance (CV) in normal‐appearing white matter and relative contrast between tumor regions and normal tissue was compared between the three CBV transformations across five different MR scanners in 96 patients with gliomas.

Results:

The results suggest all normalization techniques improved variability and relative tumor contrast of CBV measurements compared with nonnormalized CBV maps. The results suggest Gaussian normalization of CBV maps provided slightly lower CV in normal white matter and provided slightly higher tumor contrast for glioblastomas (WHO grade IV) compared with other techniques.

Conclusion:

The results suggest Gaussian normalization of leakage‐corrected CBV maps may be the best choice for image intensity correction for use in large‐scale, multicenter clinical trials where MR scanners and protocols vary widely due to ease of implementation, lowest variability, and highest tumor to normal tissue contrast. J. Magn. Reson. Imaging 2012;35:1472–1477. © 2012 Wiley Periodicals, Inc.     

Incidence,survival, pathology,and genetics of adult Latino Americans with glioblastoma

Latino Americans are a rapidly growing ethnic group in the United States but studies of glioblastoma in this population are limited. We have evaluated characteristics of 21,184 glioblastoma patients from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. This SEER data from 2001 to 2011 draws from 28% of the U.S. population. Latinos have a lower incidence of GBM and present slightly younger than non-Latino Whites. Cubans present at an older age than other Latino sub-populations. Latinos have a higher incidence of giant cell glioblastoma than non-Latino Whites while the incidence of gliosarcoma is similar. Despite lower rates of radiation therapy and greater rates of sub-total resection than non-Latino Whites, Latinos have better 1 and 5 year survival rates. SEER does not record chemotherapy data. Survivals of Latino sub-populations are similar with each other. Age, extent of resection, and the use of radiation therapy are associated with improved survival but none of these variables are sufficient in a multivariate analysis to explain the improved survival of Latinos relative to non-Latino Whites. As molecular data is not available in SEER records, we studied the MGMT and IDH status of 571 patients from a UCLA database. MGMT methylation and IDH1 mutation rates are not statistically significantly different between non-Latino Whites and Latinos. For UCLA patients with available information, chemotherapy and radiation rates are similar for non-Latino White and Latino patients, but the latter have lower rates of gross total resection and present at a younger age.     

Pretreatment ADC Histogram Analysis Is a Predictive Imaging Biomarker for Bevacizumab Treatment but Not Chemotherapy in Recurrent Glioblastoma

BACKGROUND AND PURPOSE:Pre-treatment ADC characteristics have been shown to predict response to bevacizumab in recurrent glioblastoma multiforme. However, no studies have examined whether ADC characteristics are specific to this particular treatment. The purpose of the current study was to determine whether ADC histogram analysis is a bevacizumab-specific or treatment-independent biomarker of treatment response in recurrent glioblastoma multiforme.MATERIALS AND METHODS:Eighty-nine bevacizumab-treated and 43 chemotherapy-treated recurrent glioblastoma multiformes never exposed to bevacizumab were included in this study. In all patients, ADC values in contrast-enhancing ROIs from MR imaging examinations performed at the time of recurrence, immediately before commencement of treatment for recurrence, were extracted and the resulting histogram was fitted to a mixed model with a double Gaussian distribution. Mean ADC in the lower Gaussian curve was used as the primary biomarker of interest. The Cox proportional hazards model and log-rank tests were used for survival analysis.RESULTS:Cox multivariate regression analysis accounting for the interaction between bevacizumab- and non-bevacizumab-treated patients suggested that the ability of the lower Gaussian curve to predict survival is dependent on treatment (progression-free survival, P = .045; overall survival, P = .003). Patients with bevacizumab-treated recurrent glioblastoma multiforme with a pretreatment lower Gaussian curve > 1.2 μm²/ms had a significantly longer progression-free survival and overall survival compared with bevacizumab-treated patients with a lower Gaussian curve < 1.2 μm²/ms. No differences in progression-free survival or overall survival were observed in the chemotherapy-treated cohort. Bevacizumab-treated patients with a mean lower Gaussian curve > 1.2 μm²/ms had a significantly longer progression-free survival and overall survival compared with chemotherapy-treated patients.CONCLUSIONS:The mean lower Gaussian curve from ADC histogram analysis is a predictive imaging biomarker for bevacizumab-treated, not chemotherapy-treated, recurrent glioblastoma multiforme. Patients with recurrent glioblastoma multiforme with a mean lower Gaussian curve > 1.2 μm²/ms have a survival advantage when treated with bevacizumab.

Malignant gliomas, including anaplastic astrocytomas, anaplastic oligodendrogliomas, anaplastic mixed oligoastrocytomas, and glioblastoma multiforme (GBM), account for almost 80% of malignant primary brain tumors.¹ GBM, the most aggressive and malignant type of primary brain tumor, has a mean survival of only 12–14 months under the current standard of care of radiotherapy combined with concurrent temozolomide, along with adjuvant temozolomide.^2,3 GBMs are highly vascular tumors, recruiting existing vasculature and generating neovasculature from excessive levels of circulating angiogenic growth factors, including vascular endothelial growth factor (VEGF). The highly vascular nature of these tumors has led to a new class of antiangogenic agents, for which there are many ongoing clinical trials in GBM.^4–6Standard imaging techniques are limited in their ability to evaluate the effectiveness of antiangiogenic therapy in malignant gliomas due to a reduction in contrast enhancement. These limitations have resulted in a surge of more advanced imaging biomarkers aimed at predicting response to therapy, as summarized in various review articles.^7,8 Among these new imaging biomarkers showing promise are diffusion MR imaging techniques,^9–18 including ADC histogram analysis. Previous results have shown that pretreatment ADC histogram analysis performed within the contrast-enhancing tumor regions can stratify patients with recurrent GBM into high- and low-risk groups. When using a double Gaussian mixed model to represent the ADC histogram, previous studies have shown that a lower mean value of the Gaussian curve (ADC_L) results in a significantly shorter progression-free survival (PFS) and overall survival (OS) in both single-institution⁹ and multicenter clinical trial data¹⁹ when evaluating bevacizumab in malignant gliomas. An important question remains as to whether ADC histogram analysis is a predictive biomarker specific to antiangiogenic therapy in recurrent GBM or whether it is a predictive biomarker independent of the particular treatment administered. In the current study, we performed ADC histogram analysis in patients with recurrent GBM from the University of California, Los Angeles (UCLA) treated with bevacizumab and those with recurrent GBM from the University of Toronto treated with a variety of chemotherapies and never exposed to bevacizumab, to determine whether ADC histogram analysis performed before treatment in recurrent GBM is a bevacizumab-specific or treatment-independent biomarker of treatment response.     

Altered functional connectivity of the default mode network in diffuse gliomas measured with pseudo-resting state fMRI

The purpose of the current study was to explore whether brain tumors disrupt the integrity of the default mode network (DMN), a well-characterized resting-state fMRI network. We evaluated whether tumor grade, volume, post-surgical/clinical status, or location decreased the functional connectivity within the DMN in patients with gliomas. Task-based fMRI data was obtained from 68 diffuse glioma patients and 12 healthy volunteers. Pseudo-resting state fMRI data was calculated from task-based fMRI data using standard techniques. Data was preprocessed and DMN integrity was compared across WHO grade, tumor volume surgical status (new vs. recurrent tumors), age, and KPS using univariate and multivariate linear models. WHO grade was the most significant predictor of DMN integrity (P = 0.004), whereas T2 hyperintense lesion volume was not a predictor (P = 0.154). DMN integrity was lower in high-grade (WHO III–IV) compared with low-grade (WHO II) patients (P = 0.020). Tumors in the left parietal lobe showed a more impaired DMN compared with tumors in the frontal lobe, while tumors within and outside the network nodes did not differ significantly. Results suggest higher tumor grade along with prior surgery and/or treatment cause the largest reduction in DMN functional connectivity in patients with primary gliomas, and that tumor location has an impact on connectivity.     

<Superscript>18</Superscript>F-FDOPA PET and MRI characteristics correlate with degree of malignancy and predict survival in treatment-naïve gliomas: a cross-sectional study

Introduction

To report the potential value of pre-operative ¹⁸F-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 ¹⁸F-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 ¹⁸F-FDOPA SUV in tumor to normal tissue (T/N SUV_max) 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 ¹⁸F-FDOPA uptake (r?=?0.60) (P?<?0.01 for each correlation). The volume of contrast enhancement and ¹⁸F-FDOPA T/N SUV_max 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 ¹⁸F-FDOPA T/N SUV_max could each differentiate patient groups. No significant differences in ¹⁸F-FDOPA uptake were observed by IDH or MGMT status. Multivariable Cox regression suggested age (HR 1.16, P?=?0.0001) and continuous measures of ¹⁸F-FDOPA PET T/N SUV_max (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 ¹⁸F-FDOPA PET in suspected glioma. Increased ¹⁸F-FDOPA uptake may not only predict higher glioma grade, but also worse OS.