Project description:The remarkable heterogeneity of glioblastoma, across patients and over time, is one of the main challenges in precision diagnostics and treatment planning. Non-invasive in vivo characterization of this heterogeneity using imaging could assist in understanding disease subtypes, as well as in risk-stratification and treatment planning of glioblastoma. The current study leveraged advanced imaging analytics and radiomic approaches applied to multi-parametric MRI of de novo glioblastoma patients (n?=?208 discovery, n?=?53 replication), and discovered three distinct and reproducible imaging subtypes of glioblastoma, with differential clinical outcome and underlying molecular characteristics, including isocitrate dehydrogenase-1 (IDH1), O6-methylguanine-DNA methyltransferase, epidermal growth factor receptor variant III (EGFRvIII), and transcriptomic subtype composition. The subtypes provided risk-stratification substantially beyond that provided by WHO classifications. Within IDH1-wildtype tumors, our subtypes revealed different survival (p?<?0.001), thereby highlighting the synergistic consideration of molecular and imaging measures for prognostication. Moreover, the imaging characteristics suggest that subtype-specific treatment of peritumoral infiltrated brain tissue might be more effective than current uniform standard-of-care. Finally, our analysis found subtype-specific radiogenomic signatures of EGFRvIII-mutated tumors. The identified subtypes and their clinical and molecular correlates provide an in vivo portrait of phenotypic heterogeneity in glioblastoma, which points to the need for precision diagnostics and personalized treatment.
Project description:BACKGROUND AND PURPOSE:Damage to the blood-brain barrier with subsequent contrast enhancement is a hallmark of glioblastoma. Non-enhancing tumor invasion into the peritumoral edema is, however, not usually visible on conventional magnetic resonance imaging. New quantitative techniques using relaxometry offer additional information about tissue properties. The aim of this study was to evaluate longitudinal relaxation R1, transverse relaxation R2, and proton density in the peritumoral edema in a group of patients with malignant glioma before surgery to assess whether relaxometry can detect changes not visible on conventional images. METHODS:In a prospective study, 24 patients with suspected malignant glioma were examined before surgery. A standard MRI protocol was used with the addition of a quantitative MR method (MAGIC), which measured R1, R2, and proton density. The diagnosis of malignant glioma was confirmed after biopsy/surgery. In 19 patients synthetic MR images were then created from the MAGIC scan, and ROIs were placed in the peritumoral edema to obtain the quantitative values. Dynamic susceptibility contrast perfusion was used to obtain cerebral blood volume (rCBV) data of the peritumoral edema. Voxel-based statistical analysis was performed using a mixed linear model. RESULTS:R1, R2, and rCBV decrease with increasing distance from the contrast-enhancing part of the tumor. There is a significant increase in R1 gradient after contrast agent injection (P < .0001). There is a heterogeneous pattern of relaxation values in the peritumoral edema adjacent to the contrast-enhancing part of the tumor. CONCLUSION:Quantitative analysis with relaxometry of peritumoral edema in malignant gliomas detects tissue changes not visualized on conventional MR images. The finding of decreasing R1 and R2 means shorter relaxation times closer to the tumor, which could reflect tumor invasion into the peritumoral edema. However, these findings need to be validated in the future.
Project description:INTRODUCTION: Our purpose was to determine whether perfusion MR imaging can be used to differentiate benign and malignant meningiomas on the basis of the differences in perfusion of tumor parenchyma and/or peritumoral edema. METHODS: A total of 33 patients with preoperative meningiomas (25 benign and 8 malignant) underwent conventional and dynamic susceptibility contrast perfusion MR imaging. Maximal relative cerebral blood volume (rCBV) and the corresponding relative mean time to enhance (rMTE) (relative to the contralateral normal white matter) in both tumor parenchyma and peritumoral edema were measured. The independent samples t-test was used to determine whether there was a statistically significant difference in the mean rCBV and rMTE ratios between benign and malignant meningiomas. RESULTS: The mean maximal rCBV values of benign and malignant meningiomas were 7.16+/-4.08 (mean+/-SD) and 5.89+/-3.86, respectively, in the parenchyma, and 1.05+/-0.96 and 3.82+/-1.39, respectively, in the peritumoral edema. The mean rMTE values were 1.16+/-0.24 and 1.30+/-0.32, respectively, in the parenchyma, and 0.91+/-0.25 and 1.24+/-0.35, respectively, in the peritumoral edema. The differences in rCBV and rMTE values between benign and malignant meningiomas were not statistically significant (P>0.05) in the parenchyma, but both were statistically significant (P<0.05) in the peritumoral edema. CONCLUSION: Perfusion MR imaging can provide useful information on meningioma vascularity which is not available from conventional MRI. Measurement of maximal rCBV and corresponding rMTE values in the peritumoral edema is useful in the preoperative differentiation between benign and malignant meningiomas.
Project description:Identification of the epidermal growth factor receptor variant III (EGFRvIII) mutation in glioblastoma has become increasingly relevant in the optimization of therapy. Traditionally, determination of tumor EGFRvIII-expression has relied on tissue-based diagnostics. Here, we assess the accuracy of magnetic resonance perfusion-weighted imaging (MR-PWI) in discriminating the EGFRvIII-expressing glioblastoma subtype. We analyzed RNA from 132 primary human glioblastoma tissue samples by reverse-transcription polymerase chain reaction (RT-PCR) for the EGFRvIII and EGFR wild-type mutations and by quantitative RT-PCR for expression of vascular endothelial growth factor (VEGF). Concurrently, 3 independent observers reviewed preoperative 1.5-Tesla (T)/SE or 3.0-Tesla (T)/GE MR perfusion images to determine the maximum relative tumor blood volume (rTBV) of each of these tumors. EGFRvIII-expressing glioblastomas showed significantly higher rTBV, compared with those tumors lacking EGFRvIII expression. This association was observed in both the 1.5T/SE (P = .000) and 3.0T/GE (P = .001) cohorts. By logistic regression analysis, combining the 2 MR system cohorts, rTBV was a very strong predictor of EGFRvIII mutation (odds ratio [rTBV] = 2.70; P = .000; McFadden's ?(2) = 0.23). Furthermore, by receiver-operating characteristic curve analysis, rTBV discriminated EGFRvIII with very high accuracy (A(z) = 0.81). In addition, we found that VEGF upregulation was associated, although without reaching statistical significance, with EGFRvIII expression (P = .16) and with increased rTBV (F-ratio = 2.71; P = .102). These trends suggest that VEGF-mediated angiogenesis may be a potential mediator of angiogenesis to increase perfusion in EGFRvIII-expressing glioblastomas, but there are likely several other contributing factors. This study demonstrates the potential to use rTBV, a MR-PWI-derived parameter, as a noninvasive surrogate of the EGFRvIII mutation.
Project description:<h4>Background</h4>Epidermal growth factor receptor variant III (EGFRvIII) is a driver mutation and potential therapeutic target in glioblastoma. Non-invasive in vivo EGFRvIII determination, using clinically acquired multiparametric MRI sequences, could assist in assessing spatial heterogeneity related to EGFRvIII, currently not captured via single-specimen analyses. We hypothesize that integration of subtle, yet distinctive, quantitative imaging/radiomic patterns using machine learning may lead to non-invasively determining molecular characteristics, and particularly the EGFRvIII mutation.<h4>Methods</h4>We integrated diverse imaging features, including the tumor's spatial distribution pattern, via support vector machines, to construct an imaging signature of EGFRvIII. This signature was evaluated in independent discovery (n = 75) and replication (n = 54) cohorts of de novo glioblastoma, and compared with the EGFRvIII status obtained through an assay based on next-generation sequencing.<h4>Results</h4>The cross-validated accuracy of the EGFRvIII signature in classifying the mutation status in individual patients of the independent discovery and replication cohorts was 85.3% (specificity = 86.3%, sensitivity = 83.3%, area under the curve [AUC] = 0.85) and 87% (specificity = 90%, sensitivity = 78.6%, AUC = 0.86), respectively. The signature was consistent with EGFRvIII+ tumors having increased neovascularization and cell density, as well as a distinctive spatial pattern involving relatively more frontal and parietal regions compared with EGFRvIII- tumors.<h4>Conclusions</h4>An imaging signature of EGFRvIII was found, revealing a complex, yet distinct macroscopic glioblastoma phenotype. By non-invasively capturing the tumor in its entirety, the proposed methodology can assist in evaluating the tumor's spatial heterogeneity, hence overcoming common spatial sampling limitations of tissue-based analyses. This signature can preoperatively stratify patients for EGFRvIII-targeted therapies, and potentially monitor dynamic mutational changes during treatment.
Project description:BACKGROUND AND PURPOSE:Genetic classifications are crucial for understanding the heterogeneity of glioblastoma. Recently, perfusion MRI techniques have demonstrated associations molecular alterations. In this work, we investigated whether perfusion markers within infiltrated peripheral edema were associated with proneural, mesenchymal, classical and neural subtypes. MATERIALS AND METHODS:ONCOhabitats open web services were used to obtain the cerebral blood volume at the infiltrated peripheral edema for MRI studies of 50 glioblastoma patients from The Cancer Imaging Archive: TCGA-GBM. ANOVA and Kruskal-Wallis tests were carried out in order to assess the association between vascular features and the Verhaak subtypes. For assessing specific differences, Mann-Whitney U-test was conducted. Finally, the association of overall survival with molecular and vascular features was assessed using univariate and multivariate Cox models. RESULTS:ANOVA and Kruskal-Wallis tests for the maximum cerebral blood volume at the infiltrated peripheral edema between the four subclasses yielded false discovery rate corrected p-values of <0.001 and 0.02, respectively. This vascular feature was significantly higher (p = 0.0043) in proneural patients compared to the rest of the subtypes while conducting Mann-Whitney U-test. The multivariate Cox model pointed to redundant information provided by vascular features at the peripheral edema and proneural subtype when analyzing overall survival. CONCLUSIONS:Higher relative cerebral blood volume at infiltrated peripheral edema is associated with proneural glioblastoma subtype suggesting underlying vascular behavior related to molecular composition in that area.
Project description:Glioblastoma is the most deadly primary brain tumor in adults and has long represented a therapeutic challenge. Disease recurrence is inevitable, and the management of recurrent disease is complicated by spontaneous or induced tumor heterogeneity which confers resistance to therapy and increased oncogenicity. EGFR and the tumor-specific mutation EGFRvIII is commonly altered in glioblastoma making it an appealing therapeutic target. Immunotherapy is an emerging and promising therapeutic approach to glioma and the EGFRvIII vaccine, rindopepimut, is the first immunotherapeutic drug to enter Phase III clinical trials for glioblastoma. Rindopepimut activates a specific immune response against tumor cells harboring the EGFRvIII protein. This review evaluates the recently completed ReACT Phase II trial using rindopepimut plus bevacizumab in the setting of EGFRvIII-positive recurrent glioblastoma (Clinical Trials identifier: NCT01498328).
Project description:Epidermal growth factor receptor (EGFR) and EGFRvIII analysis is of current interest in glioblastoma - the most common malignant primary CNS tumor, because of new EGFRvIII vaccine trials underway. EGFR activation in glioblastoma promotes cellular proliferation via activation of MAPK and PI3K-Akt pathways, and EGFRvIII is the most common variant, leading to constitutively active EGFR. This review explains EGFR and EGFRvIII signaling in GBM; describes targeted therapy approaches to date including tyrosine kinase inhibitor, antibody-based therapies, vaccines and pre-clinical RNA-based therapies, and discusses the difficulties encountered with these approaches including pathway redundancy and intratumoral heterogeneity.
Project description:Measures of tumor vascularity and hypoxia have been correlated with glioma grade and outcome. Dynamic contrast-enhanced (DCE) MRI can noninvasively map tumor blood flow, vascularity, and permeability. In this prospective observational cohort pilot study, preoperative imaging was correlated with molecular markers of hypoxia, vascularity, proliferation, and progression-free and overall patient survival.Pharmacokinetic modeling methods were used to generate maps of tumor blood flow, extraction fraction, permeability-surface area product, transfer constant, washout rate, interstitial volume, blood volume, capillary transit time, and capillary heterogeneity from preoperative DCE-MRI data in human glioma patients. Tissue was obtained from areas of peritumoral edema, active tumor, hypoxic penumbra, and necrotic core and evaluated for vascularity, proliferation, and expression of hypoxia-regulated molecules. DCE-MRI parameter values were correlated with hypoxia-regulated protein expression at tissue sample sites.Patient survival correlated with DCE parameters in 2 cases: capillary heterogeneity in active tumor and interstitial volume in areas of peritumoral edema. Statistically significant correlations were observed between several DCE parameters and tissue markers. In addition, MIB-1 index was predictive of overall survival (P = .044) and correlated with vascular endothelial growth factor expression in hypoxic penumbra (r = 0.7933, P = .0071) and peritumoral edema (r = 0.4546). Increased microvessel density correlated with worse patient outcome (P = .026).Our findings suggest that DCE-MRI may facilitate noninvasive preoperative predictions of areas of tumor with increased hypoxia and proliferation. Both imaging and hypoxia biomarkers are predictive of patient outcome. This has the potential to allow unprecedented prognostic decisions and to guide therapies to specific tumor areas.
Project description:Cerebral edema associated with brain tumors is an important source of morbidity. Its type depends largely on the capillary ultra-structures of the histopathologic subtype of underlying brain tumor. The purpose of our study was to differentiate vasogenic edema associated with brain metastases and infiltrative edema related to diffuse gliomas using quantitative 3D T1 rho (T1ρ) imaging.Preoperative MR examination including whole brain 3D T1ρ imaging was performed in 23 patients with newly diagnosed brain tumors (9 with metastasis, 8 with lower grade glioma, LGG, 6 with glioblastoma, GBM). Mean T1ρ values were measured in regions of peritumoral non-enhancing T2 signal hyperintensity, excluding both enhancing and necrotic or cystic component, and normal-appearing white matter.Mean T1ρ values were significantly elevated in the vasogenic edema surrounding intracranial metastases when compared to the infiltrative edema associated with either LGG or GBM (p=0.02 and <0.01, respectively). No significant difference was noted between T1ρ values of infiltrative edema between LGG and GBM (p=0.84 and 0.96, respectively).Our study demonstrates the feasibility and potential diagnostic role of T1ρ in the quantitative differentiation between edema related to intracranial metastases and gliomas and as a potentially complementary tool to standard MR techniques in further characterizing pathophysiology of vasogenic and infiltrative edema.