Assessment of Fat Fractions in the Tongue, Soft Palate, Pharyngeal Wall, and Parapharyngeal Fat Pad by the GOOSE and DIXON Methods.

OBJECTIVE: The 2-point DIXON method is widely used to assess fat fractions (FFs) in magnetic resonance images (MRIs) of the tongue, pharyngeal wall, and surrounding tissues in patients with obstructive sleep apnea (OSA). However, the method is semiquantitative and is susceptible to B0 field inhomogeneities and R2* confounding factors. Using the method, although several studies have shown that patients with OSA have increased fat deposition around the pharyngeal cavity, conflicting findings was also reported in 1 study. This discrepancy necessitates that we examine the FF estimation method used in the earlier studies and seek a more accurate method to measure FFs. MATERIALS AND METHODS: We examined the advantages of using the GOOSE (globally optimal surface estimation) method to replace the 2-point DIXON method for quantifying fat in the tongue and surrounding tissues on MRIs. We first used phantoms with known FFs (true FFs) to validate the GOOSE method and examine the errors in the DIXON method. Then, we compared the 2 methods in the tongue, soft palate, pharyngeal wall, and parapharyngeal fat pad of 63 healthy participants to further assess the errors caused by the DIXON method. Six participants were excluded from the comparison of the tongue FFs because of technical failures. Paired Student t tests were performed on FFs to detect significant differences between the 2 methods. All measures were obtained using 3 T Siemens MRI scanners. RESULTS: In the phantoms, the FFs measured by GOOSE agreed with the true FF, with only a 1.2% mean absolute error. However, the same measure by DIXON had a 10.5% mean absolute error. The FFs obtained by DIXON were significantly lower than those obtained by GOOSE (P < 0.0001) in the human participants. We found strong correlations between GOOSE and DIXON in the tongue (R2 = 0.90), soft palate (R2 = 0.66), and parapharyngeal fat pad (R2 = 0.88), but the correlation was weaker in the posterior pharyngeal walls (R2 = 0.32) in participants. CONCLUSIONS: The widely used 2-point DIXON underestimated FFs, relative to GOOSE, in phantom measurements and tissues studied in vivo. Thus, an advanced method, such as GOOSE, that uses multiecho complex data is preferred for estimating FF.

11C-Methionine PET for Identification of Pediatric High-Grade Glioma Recurrence.

Differentiating tumor recurrence or progression from pseudoprogression during surveillance of pediatric high-grade gliomas (PHGGs) using MRI, the primary imaging modality for evaluation of brain tumors, can be challenging. The aim of this study was to evaluate whether 11C-methionine PET, a molecular imaging technique that detects functionally active tumors, is useful for further evaluating MRI changes concerning for tumor recurrence during routine surveillance. Methods: Using 11C-methionine PET during follow-up visits, we evaluated 27 lesions in 26 patients with new or worsening MRI abnormalities for whom tumor recurrence was of concern. We performed quantitative and qualitative assessments of both 11C-methionine PET and MRI data to predict the presence of tumor recurrence. Further, to assess for an association with overall survival (OS), we plotted the time from development of the imaging changes against survival. Results: Qualitative evaluation of 11C-methionine PET achieved 100% sensitivity, 60% specificity, and 93% accuracy to correctly predict the presence of tumors in 27 new or worsening MRI abnormalities. Qualitative MRI evaluation achieved sensitivity ranging from 86% to 95%, specificity ranging from 40% to 60%, and accuracy ranging from 85% to 89%. The interobserver agreement for 11C-methionine PET assessment was 100%, whereas the interobserver agreement was only 50% for MRI (P < 0.01). Quantitative MRI and 11C-methionine PET evaluation using receiver-operating characteristics demonstrated higher specificity (80%) than did qualitative evaluations (40%-60%). Postcontrast enhancement volume, metabolic tumor volume, tumor-to-brain ratio, and presence of tumor as determined by consensus MRI assessment were inversely associated with OS. Conclusion:11C-methionine PET has slightly higher sensitivity and accuracy for correctly predicting tumor recurrence, with excellent interobserver agreement, than does MRI. Quantitative 11C-methionine PET can also predict OS. These findings suggest that 11C-methionine PET can be useful for further evaluation of MRI changes during surveillance of previously treated PHGGs.

Progression of central nervous system disease from pediatric to young adulthood in sickle cell anemia.

Silent cerebral infarcts and arteriopathy are common and progressive in individuals with sickle cell anemia. However, most data describing brain lesions in sickle cell anemia are cross-sectional or derive from pediatric cohorts with short follow-up. We investigated the progression of silent cerebral infarct and cerebral vessel stenosis on brain MRI and MRA, respectively, by describing the incidence of new or worsening lesions over a period of up to 25 years among young adults with sickle cell anemia and explored risk factors for progression. Forty-four adults with sickle cell anemia (HbSS or HbSß0thalassemia), exposed to chronic transfusions (n = 12) or hydroxyurea (n = 32), median age 19.2 years (range 18.0-31.5), received a screening brain MRI/MRA and their results were compared with a clinical exam performed during childhood and adolescence. We used exact log-rank test to compare MRI and MRA progression among any two groups. The hazard ratio (HR) and 95% confidence interval (CI) were calculated from Cox regression analyses. Progression of MRI and MRA occurred in 12 (27%) and 4 (9%) young adults, respectively, relative to their pediatric exams. MRI progression risk was high among participants with abnormal pediatric exams (HR: 11.6, 95% CI: 2.5-54.7) and conditional or abnormal transcranial Doppler ultrasound velocities (HR: 3.9, 95% CI: 1.0-15.1). Among individuals treated with hydroxyurea, high fetal hemoglobin measured in childhood was associated with lower hazard of MRI progression (HR: 0.86, 95% CI: 0.76-0.98). MRA progression occurred more frequently among those with prior stroke (HR: 8.6, 95% CI: 1.2-64), abnormal pediatric exam (P = 0.00084), and elevated transcranial Doppler ultrasound velocities (P = 0.004). Brain MRI/MRA imaging in pediatrics can identify high-risk patients for CNS disease progression in young adulthood, prompting consideration for early aggressive treatments.

Effects of hydroxyurea on brain function in children with sickle cell anemia.

INTRODUCTION: Sickle cell anemia (SCA) results in numerous adverse effects on the brain, including neurocognitive dysfunction. Hydroxyurea has been utilized extensively for management of SCA, but its effects on brain function have not been established. METHODS: We examined prospectively the effects of 1 year of treatment with hydroxyurea on brain function in children with SCA (HbSS/HbSß0 -thalassemia) by baseline and exit evaluations, including comprehensive neurocognitive testing, transcranial Doppler ultrasound (TCD), and brain MRI (silent cerebral infarcts [SCI], gray matter cerebral blood flow [GM-CBF], and blood oxygen level-dependent [BOLD] signal from visual stimulation). RESULTS: Nineteen patients with SCA, mean age 12.4 years (range 7.2-17.8), were evaluated. At baseline, subjects had these mean values: full-scale IQ (FSIQ) 82.8, TCD velocity 133 cm/s, GM-CBF 64.4 ml/100 g/min, BOLD signal 2.34% increase, and frequency of SCI 47%. After 1 year of hydroxyurea, there were increases in FSIQ (+2, p = .059) and reading passage comprehension (+4, p = .033), a significant decrease in TCD velocity (-11 cm/s, p = .007), and no significant changes in GM-CBF, BOLD, or SCI frequency. Hemoglobin F (HbF) was associated with passage comprehension, hemoglobin with lower TCD velocity, and lower GM-CBF with greater working memory. Higher BOLD signal was associated with higher processing speed and lower TCD velocity with higher math fluency. DISCUSSION: Improvements in neurocognition and decreased TCD velocity following 1 year of treatment support hydroxyurea use for improving neurocognitive outcomes in SCA. Understanding the mechanisms of benefit, as indicated by relationships of neurocognitive function with HbF, hemoglobin, and CBF, requires further evaluation.

Bithalamic gliomas may be molecularly distinct from their unilateral high-grade counterparts.

Bithalamic gliomas are rare cancers diagnosed based on poorly defined radiologic criteria. Infiltrative astrocytomas account for most cases. While some previous studies reported dismal outcomes for patients with bithalamic gliomas irrespective of therapy and histologic grade, others described better prognoses even without anticancer therapy. Little is known about their molecular characteristics. We reviewed clinical, radiologic, and histologic features of patients with bithalamic gliomas treated at our institution over 15 years. Targeted sequencing of mutational hotspots in H3F3A, HIST1H3B, IDH1/2, and BRAF, and genome-wide analysis of DNA methylation and copy number abnormalities was performed in available tumors. Eleven patients with bithalamic gliomas were identified. Their median age at diagnosis was 4.8 years (range: 1-15.7). Additional involvement of the brainstem, basal ganglia, and cerebral lobes occurred in 11, 9, and 3 cases, respectively. All patients presented with hydrocephalus. Two-thirds of the patients had a histologic diagnosis of anaplastic astrocytoma. Despite aggressive therapy, our youngest patient, the only one diagnosed before 1 year of age, is the sole long-term survivor. DNA methylation could be performed in seven tumors, all of which clustered with the RTK I 'PDGFRA' subgroup by unsupervised hierarchical analysis of methylation array against a previously published cohort of 59 pediatric high-grade gliomas. Sequencing of hotspots mutations could be done in 10 tumors, none of which harbored H3F3A p.K27 and/or the respective DNA methylation signature, and any other hotspot mutations. Amplification of MDM4 (n = 2), PDGFRA (n = 2), and ID2 combined with MYCN (n = 1) were observed in 7 tumors available for analysis. In comparison with the previously published experience with unilateral high-grade thalamic astrocytomas where H3F3A p.K27 was present in two-thirds of cases, the absence of this molecular subgroup in bithalamic gliomas was striking. This finding suggests that unilateral and bithalamic high-grade gliomas may represent two distinct molecular entities.

Posttreatment DSC-MRI is Predictive of Early Treatment Failure in Children with Supratentorial High-Grade Glioma Treated with Erlotinib.

BACKGROUND AND PURPOSE: The role of perfusion imaging in the management of pediatric high grade glioma is unclear. We evaluated the ability of dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) to determine grade, evaluate post-treatment response and predict treatment failure. MATERIAL AND METHODS: In this study 22 patients with high-grade glioma underwent biopsy and were treated with concurrent and sequential radiotherapy and erlotinib as part of a phase I/II clinical trial (NCT00124657). Preradiotherapy, immediate postradiotherapy, 6­month and treatment failure DSC MR images were reviewed, registered, and processed for the ratio of cerebral blood flow (CBF) and cerebral blood volume (CBV). Processed, derived perfusion, and T1-weighted images (T1WI), T2WI, and fluid attenuation inversion recovery (FLAIR) MRI sequences were used for segmentation and extraction of tumor perfusion parameters at all time points. Patient, tumor, treatment, and outcome data were summarized and related to perfusion data. RESULTS: Regional CBF in tumors increased from diagnosis to postradiotherapy, while they decreased to levels below those at diagnosis from postradiotherapy to 6­month follow-up. At 6 months, the median regional CBF was higher in tumors that progressed (median 1.16) than in those that did not (median, 0.95; P < 0.05). Patients with regional CBF ratios above 1.4 at diagnosis had shorter survival times than did those with regional CBF ratios below 1.4 (P = 0.77). Tumors with a regional CBV above 1.15 at the postradiotherapy (1-3 months) follow-up scan were associated with an earlier time to death than that of tumors with a regional CBV below 1.15 (P < 0.05). CONCLUSION: Posttreatment perfusion characteristics are prognostic and may help predict survival. Overall, perfusion MRI is useful for managing pediatric high-grade glioma and should be incorporated into future clinical trials.

Multiple-response regression analysis links magnetic resonance imaging features to de-regulated protein expression and pathway activity in lower grade glioma.

BACKGROUND AND PURPOSE: Lower grade gliomas (LGGs), lesions of WHO grades II and III, comprise 10-15% of primary brain tumors. In this first-of-a-kind study, we aim to carry out a radioproteomic characterization of LGGs using proteomics data from the TCGA and imaging data from the TCIA cohorts, to obtain an association between tumor MRI characteristics and protein measurements. The availability of linked imaging and molecular data permits the assessment of relationships between tumor genomic/proteomic measurements with phenotypic features. MATERIALS AND METHODS: Multiple-response regression of the image-derived, radiologist scored features with reverse-phase protein array (RPPA) expression levels generated correlation coefficients for each combination of image-feature and protein or phospho-protein in the RPPA dataset. Significantly-associated proteins for VASARI features were analyzed with Ingenuity Pathway Analysis software. Hierarchical clustering of the results of the pathway analysis was used to determine which feature groups were most strongly correlated with pathway activity and cellular functions. RESULTS: The multiple-response regression approach identified multiple proteins associated with each VASARI imaging feature. VASARI features were found to be correlated with expression of IL8, PTEN, PI3K/Akt, Neuregulin, ERK/MAPK, p70S6K and EGF signaling pathways. CONCLUSION: Radioproteomics analysis might enable an insight into the phenotypic consequences of molecular aberrations in LGGs.

Leukoencephalopathy and long-term neurobehavioural, neurocognitive, and brain imaging outcomes in survivors of childhood acute lymphoblastic leukaemia treated with chemotherapy: a longitudinal analysis.

BACKGROUND: Leukoencephalopathy is observed in some children undergoing chemotherapy for acute lymphoblastic leukaemia, although its effects on long-term outcomes is unknown. This study examines the associations between acute leukoencephalopathy and neurobehavioural, neurocognitive, and brain white matter imaging outcomes in long-term survivors of childhood acute lymphoblastic leukaemia treated with chemotherapy without cranial radiation. METHODS: In this longitudinal analysis, we used data of children with acute lymphoblastic leukaemia at St Jude Children's Research Hospital (Memphis, TN, USA) who had been treated between June 1, 2000, and Oct 31, 2010. Eligible patients were diagnosed with non-B-cell acute lymphoblastic leukaemia, aged at least 8 years, and survivors with at least 5 years since their initial diagnosis. Brain MRIs obtained during active therapy were systematically coded for leukoencephalopathy using Common Terminology Criteria for Adverse Event version 4. At least 5 years after their diagnosis, survivors completed neurocognitive testing, another brain MRI, and their parents completed neurobehavioural ratings of their child (Behavior Rating Inventory of Executive Function [BRIEF]). Follow-up MRI included diffusion tensor imaging to assess white matter integrity, with indices of fractional anisotropy, axial diffusivity, and radial diffusivity from frontal lobes, parietal lobes, and in the frontostriatal tract. The neuroradiologist, who assessed abnormal MRIs, was masked to both group assignment of survivors and the neurobehavioural and neurocognitive outcomes. The primary outcomes were neurobehavioural function, assessed from completed BRIEF, and neurocognitive performance, measured by direct neurocognitive tests (Delis-Kaplan Executive Function System, Wechsler Intelligence Scale for Children-IV/Wechsler Adult Intelligence Scale-III, Rey-Osterrieth Complex Figure Test, and Lafayette Grooved Pegboard Test). This study had completed enrolment in October, 2014, and is registered as an observational study at ClinicalTrials.gov, number NCT01014195. FINDINGS: Between Feb 18, 2010, and Oct 22, 2014, 210 (70%) of 301 eligible survivors participated in our study of whom 190 were evaluable, 162 had an MRI. 56 participants had quantitative brain imaging data and were included in evaluable population analyses. 51 (27%) of the 190 evaluable participants had acute leukoencephalopathy. Compared with population norms, survivors were reported to have more neurobehavioural problems with working memory, organisation, initiation, and planning (p<0·001 for all). Survivors had worse scores than the general population on direct measures of memory span, processing speed, and executive function (p<0·05 for all). Survivors with a history of acute leukoencephalopathy had more neurobehavioural problems than survivors with no history of leukoencephalopathy on organisation (adjusted T-score 56·2 [95% CI 53·3-59·1] vs 52·2 [50·4-53·9], p=0·020) and initiation (55·5 [52·7-58·3] vs 52·1 [50·4-53·8], p=0·045). Survivors with acute leukoencephalopathy also had reduced white matter integrity in the frontostriatal tract at follow-up: lower fractional anisotropy (p=0·069), higher axial diffusivity (p=0·020), and higher radial diffusivity (p=0·0077). A one-unit change in the radial diffusivity index corresponded with a 15·0 increase in raw score points on initiation, 30·3 on planning, and 28·0 on working memory (p<0·05 for all). INTERPRETATION: Acute leukoencephalopathy during chemotherapy treatment, without cranial radiation, for childhood acute lymphoblastic leukaemia predicted higher risk for long-term neurobehavioural problems and reduced white matter integrity in frontal brain regions. Survivors of childhood acute lymphoblastic leukaemia might benefit from preventive cognitive or behavioural interventions, particularly those who develop acute leukoencephalopathy. FUNDING: National Institute of Mental Health, National Cancer Institute, American Lebanese Syrian Associated Charities.

A combinatorial radiographic phenotype may stratify patient survival and be associated with invasion and proliferation characteristics in glioblastoma.

OBJECTIVE: Individual MRI characteristics (e.g., volume) are routinely used to identify survival-associated phenotypes for glioblastoma (GBM). This study investigated whether combinations of MRI features can also stratify survival. Furthermore, the molecular differences between phenotype-induced groups were investigated. METHODS: Ninety-two patients with imaging, molecular, and survival data from the TCGA (The Cancer Genome Atlas)-GBM collection were included in this study. For combinatorial phenotype analysis, hierarchical clustering was used. Groups were defined based on a cutpoint obtained via tree-based partitioning. Furthermore, differential expression analysis of microRNA (miRNA) and mRNA expression data was performed using GenePattern Suite. Functional analysis of the resulting genes and miRNAs was performed using Ingenuity Pathway Analysis. Pathway analysis was performed using Gene Set Enrichment Analysis. RESULTS: Clustering analysis reveals that image-based grouping of the patients is driven by 3 features: volume-class, hemorrhage, and T1/FLAIR-envelope ratio. A combination of these features stratifies survival in a statistically significant manner. A cutpoint analysis yields a significant survival difference in the training set (median survival difference: 12 months, p = 0.004) as well as a validation set (p = 0.0001). Specifically, a low value for any of these 3 features indicates favorable survival characteristics. Differential expression analysis between cutpoint-induced groups suggests that several immune-associated (natural killer cell activity, T-cell lymphocyte differentiation) and metabolism-associated (mitochondrial activity, oxidative phosphorylation) pathways underlie the transition of this phenotype. Integrating data for mRNA and miRNA suggests the roles of several genes regulating proliferation and invasion. CONCLUSIONS: A 3-way combination of MRI phenotypes may be capable of stratifying survival in GBM. Examination of molecular processes associated with groups created by this combinatorial phenotype suggests the role of biological processes associated with growth and invasion characteristics.

Assessing the Effects of Software Platforms on Volumetric Segmentation of Glioblastoma.

BACKGROUND: Radiological assessments of biologically relevant regions in glioblastoma have been associated with genotypic characteristics, implying a potential role in personalized medicine. Here, we assess the reproducibility and association with survival of two volumetric segmentation platforms and explore how methodology could impact subsequent interpretation and analysis. METHODS: Post-contrast T1- and T2-weighted FLAIR MR images of 67 TCGA patients were segmented into five distinct compartments (necrosis, contrast-enhancement, FLAIR, post contrast abnormal, and total abnormal tumor volumes) by two quantitative image segmentation platforms - 3D Slicer and a method based on Velocity AI and FSL. We investigated the internal consistency of each platform by correlation statistics, association with survival, and concordance with consensus neuroradiologist ratings using ordinal logistic regression. RESULTS: We found high correlations between the two platforms for FLAIR, post contrast abnormal, and total abnormal tumor volumes (spearman's r(67) = 0.952, 0.959, and 0.969 respectively). Only modest agreement was observed for necrosis and contrast-enhancement volumes (r(67) = 0.693 and 0.773 respectively), likely arising from differences in manual and automated segmentation methods of these regions by 3D Slicer and Velocity AI/FSL, respectively. Survival analysis based on AUC revealed significant predictive power of both platforms for the following volumes: contrast-enhancement, post contrast abnormal, and total abnormal tumor volumes. Finally, ordinal logistic regression demonstrated correspondence to manual ratings for several features. CONCLUSION: Tumor volume measurements from both volumetric platforms produced highly concordant and reproducible estimates across platforms for general features. As automated or semi-automated volumetric measurements replace manual linear or area measurements, it will become increasingly important to keep in mind that measurement differences between segmentation platforms for more detailed features could influence downstream survival or radio genomic analyses.

Multicenter imaging outcomes study of The Cancer Genome Atlas glioblastoma patient cohort: imaging predictors of overall and progression-free survival.

BACKGROUND: Despite an aggressive therapeutic approach, the prognosis for most patients with glioblastoma (GBM) remains poor. The aim of this study was to determine the significance of preoperative MRI variables, both quantitative and qualitative, with regard to overall and progression-free survival in GBM. METHODS: We retrospectively identified 94 untreated GBM patients from the Cancer Imaging Archive who had pretreatment MRI and corresponding patient outcomes and clinical information in The Cancer Genome Atlas. Qualitative imaging assessments were based on the Visually Accessible Rembrandt Images feature-set criteria. Volumetric parameters were obtained of the specific tumor components: contrast enhancement, necrosis, and edema/invasion. Cox regression was used to assess prognostic and survival significance of each image. RESULTS: Univariable Cox regression analysis demonstrated 10 imaging features and 2 clinical variables to be significantly associated with overall survival. Multivariable Cox regression analysis showed that tumor-enhancing volume (P = .03) and eloquent brain involvement (P < .001) were independent prognostic indicators of overall survival. In the multivariable Cox analysis of the volumetric features, the edema/invasion volume of more than 85 000 mm(3) and the proportion of enhancing tumor were significantly correlated with higher mortality (Ps = .004 and .003, respectively). CONCLUSIONS: Preoperative MRI parameters have a significant prognostic role in predicting survival in patients with GBM, thus making them useful for patient stratification and endpoint biomarkers in clinical trials.

Successive distinct high-grade gliomas in L-2-hydroxyglutaric aciduria.

Patients with L-2-hydroxyglutaric aciduria are at risk for developing cerebral neoplasms, particularly gliomas, as one of the optical isomers of the known oncometabolite, 2-hydroxyglutarate is produced in L-2-hydroxyglutaric aciduria. To illustrate the concept of sustained oncogenic potential in permanent exposure to L-2-hydroxyglutarate in brain tissue, we present the medical history of a patient with L-2-hydroxyglutaric aciduria who underwent surgery to remove a right temporal anaplastic astrocytoma and developed an anatomically distinct, but histopathologically similar, tumor in the left frontal region 40 months later. This is the first reported case of successive distinct gliomas in a patient with L-2-hydroxyglutaric aciduria. While this implies a significant, cumulative lifetime risk for cerebral neoplasms in patients with this rare organic aciduria, it also allows further insight into a unique mechanism of tumorigenesis in the brain.

Addition of MR imaging features and genetic biomarkers strengthens glioblastoma survival prediction in TCGA patients.

PURPOSE: The purpose of our study was to assess whether a model combining clinical factors, MR imaging features, and genomics would better predict overall survival of patients with glioblastoma (GBM) than either individual data type. METHODS: The study was conducted leveraging The Cancer Genome Atlas (TCGA) effort supported by the National Institutes of Health. Six neuroradiologists reviewed MRI images from The Cancer Imaging Archive (http://cancerimagingarchive.net) of 102 GBM patients using the VASARI scoring system. The patients' clinical and genetic data were obtained from the TCGA website (http://www.cancergenome.nih.gov/). Patient outcome was measured in terms of overall survival time. The association between different categories of biomarkers and survival was evaluated using Cox analysis. RESULTS: The features that were significantly associated with survival were: (1) clinical factors: chemotherapy; (2) imaging: proportion of tumor contrast enhancement on MRI; and (3) genomics: HRAS copy number variation. The combination of these three biomarkers resulted in an incremental increase in the strength of prediction of survival, with the model that included clinical, imaging, and genetic variables having the highest predictive accuracy (area under the curve 0.679±0.068, Akaike's information criterion 566.7, P<0.001). CONCLUSION: A combination of clinical factors, imaging features, and HRAS copy number variation best predicts survival of patients with GBM.

Imaging genomic mapping of an invasive MRI phenotype predicts patient outcome and metabolic dysfunction: a TCGA glioma phenotype research group project.

BACKGROUND: Invasion of tumor cells into adjacent brain parenchyma is a major cause of treatment failure in glioblastoma. Furthermore, invasive tumors are shown to have a different genomic composition and metabolic abnormalities that allow for a more aggressive GBM phenotype and resistance to therapy. We thus seek to identify those genomic abnormalities associated with a highly aggressive and invasive GBM imaging-phenotype. METHODS: We retrospectively identified 104 treatment-naïve glioblastoma patients from The Cancer Genome Atlas (TCGA) whom had gene expression profiles and corresponding MR imaging available in The Cancer Imaging Archive (TCIA). The standardized VASARI feature-set criteria were used for the qualitative visual assessments of invasion. Patients were assigned to classes based on the presence (Class A) or absence (Class B) of statistically significant invasion parameters to create an invasive imaging signature; imaging genomic analysis was subsequently performed using GenePattern Comparative Marker Selection module (Broad Institute). RESULTS: Our results show that patients with a combination of deep white matter tracts and ependymal invasion (Class A) on imaging had a significant decrease in overall survival as compared to patients with absence of such invasive imaging features (Class B) (8.7 versus 18.6 months, p < 0.001). Mitochondrial dysfunction was the top canonical pathway associated with Class A gene expression signature. The MYC oncogene was predicted to be the top activation regulator in Class A. CONCLUSION: We demonstrate that MRI biomarker signatures can identify distinct GBM phenotypes associated with highly significant survival differences and specific molecular pathways. This study identifies mitochondrial dysfunction as the top canonical pathway in a very aggressive GBM phenotype. Thus, imaging-genomic analyses may prove invaluable in detecting novel targetable genomic pathways.

Outcome prediction in patients with glioblastoma by using imaging, clinical, and genomic biomarkers: focus on the nonenhancing component of the tumor.

PURPOSE: To correlate patient survival with morphologic imaging features and hemodynamic parameters obtained from the nonenhancing region (NER) of glioblastoma (GBM), along with clinical and genomic markers. MATERIALS AND METHODS: An institutional review board waiver was obtained for this HIPAA-compliant retrospective study. Forty-five patients with GBM underwent baseline imaging with contrast material-enhanced magnetic resonance (MR) imaging and dynamic susceptibility contrast-enhanced T2*-weighted perfusion MR imaging. Molecular and clinical predictors of survival were obtained. Single and multivariable models of overall survival (OS) and progression-free survival (PFS) were explored with Kaplan-Meier estimates, Cox regression, and random survival forests. RESULTS: Worsening OS (log-rank test, P = .0103) and PFS (log-rank test, P = .0223) were associated with increasing relative cerebral blood volume of NER (rCBVNER), which was higher with deep white matter involvement (t test, P = .0482) and poor NER margin definition (t test, P = .0147). NER crossing the midline was the only morphologic feature of NER associated with poor survival (log-rank test, P = .0125). Preoperative Karnofsky performance score (KPS) and resection extent (n = 30) were clinically significant OS predictors (log-rank test, P = .0176 and P = .0038, respectively). No genomic alterations were associated with survival, except patients with high rCBVNER and wild-type epidermal growth factor receptor (EGFR) mutation had significantly poor survival (log-rank test, P = .0306; area under the receiver operating characteristic curve = 0.62). Combining resection extent with rCBVNER marginally improved prognostic ability (permutation, P = .084). Random forest models of presurgical predictors indicated rCBVNER as the top predictor; also important were KPS, age at diagnosis, and NER crossing the midline. A multivariable model containing rCBVNER, age at diagnosis, and KPS can be used to group patients with more than 1 year of difference in observed median survival (0.49-1.79 years). CONCLUSION: Patients with high rCBVNER and NER crossing the midline and those with high rCBVNER and wild-type EGFR mutation showed poor survival. In multivariable survival models, however, rCBVNER provided unique prognostic information that went above and beyond the assessment of all NER imaging features, as well as clinical and genomic features.