Correlation between Multiparametric MR Imaging and Molecular Genetics in Pontine Pediatric High-Grade Glioma.

BACKGROUND AND PURPOSE: Molecular profiling is a crucial feature in the "integrated diagnosis" of CNS tumors. We aimed to determine whether radiomics could distinguish molecular types of pontine pediatric high-grade gliomas that have similar/overlapping phenotypes on conventional anatomic MR images. MATERIALS AND METHODS: Baseline MR images from children with pontine pediatric high-grade gliomas were analyzed. Retrospective imaging studies included standard precontrast and postcontrast sequences and DTI. Imaging analyses included median, mean, mode, skewness, and kurtosis of the ADC histogram of the tumor volume based on T2 FLAIR and enhancement at baseline. Histone H3 mutations were identified through immunohistochemistry and/or Sanger or next-generation DNA sequencing. The log-rank test identified imaging factors prognostic of survival from the time of diagnosis. Wilcoxon rank-sum and Fisher exact tests compared imaging predictors among groups. RESULTS: Eighty-three patients had pretreatment MR imaging and evaluable tissue sampling. The median age was 6 years (range, 0.7-17 years); 50 tumors had a K27M mutation in H3-3A, and 11, in H3C2/3. Seven tumors had histone H3 K27 alteration, but the specific gene was unknown. Fifteen were H3 wild-type. Overall survival was significantly higher in H3C2/3- compared with H3-3A-mutant tumors (P = .003) and in wild-type tumors compared with any histone mutation (P = .001). Lower overall survival was observed in patients with enhancing tumors (P = .02) compared with those without enhancement. H3C2/3-mutant tumors showed higher mean, median, and mode ADC_total values (P < .001) and ADC_enhancement (P < .004), with lower ADC_total skewness and kurtosis (P < .003) relative to H3-3A-mutant tumors. CONCLUSIONS: ADC histogram parameters are correlated with histone H3 mutation status in pontine pediatric high-grade glioma.

ADC Histogram Analysis of Pediatric Low-Grade Glioma Treated with Selumetinib: A Report from the Pediatric Brain Tumor Consortium.

BACKGROUND AND PURPOSE: Selumetinib is a promising MAP (mitogen-activated protein) kinase (MEK) 1/2 inhibitor treatment for pediatric low-grade gliomas. We hypothesized that MR imaging-derived ADC histogram metrics would be associated with survival and response to treatment with selumetinib. MATERIALS AND METHODS: Children with recurrent, refractory, or progressive pediatric low-grade gliomas who had World Health Organization grade I pilocytic astrocytoma with KIAA1549-BRAF fusion or the BRAF V600E mutation (stratum 1), neurofibromatosis type 1-associated pediatric low-grade gliomas (stratum 3), or sporadic non-neurofibromatosis type 1 optic pathway and hypothalamic glioma (OPHG) (stratum 4) were treated with selumetinib for up to 2 years. Quantitative ADC histogram metrics were analyzed for total and enhancing tumor volumes at baseline and during treatment. RESULTS: Each stratum comprised 25 patients. Stratum 1 responders showed lower values of SD of baseline ADC_total as well as a larger decrease with time on treatment in ADC_total mean, mode, and median compared with nonresponders. Stratum 3 responders showed a greater longitudinal decrease in ADC_total. In stratum 4, higher baseline ADC_total skewness and kurtosis were associated with shorter progression-free survival. When all 3 strata were combined, responders showed a greater decrease with time in ADC_total mode and median. Compared with sporadic OPHG, neurofibromatosis type 1-associated OPHG had lower values of ADC_total mean, mode, and median as well as ADC_enhancement mean and median and higher values of ADC_total skewness and kurtosis at baseline. The longitudinal decrease in ADC_total median during treatment was significantly greater in sporadic OPHG compared with neurofibromatosis type 1-associated OPHG. CONCLUSIONS: ADC histogram metrics are associated with progression-free survival and response to treatment with selumetinib in pediatric low-grade gliomas.

MR Imaging Correlates for Molecular and Mutational Analyses in Children with Diffuse Intrinsic Pontine Glioma.

BACKGROUND AND PURPOSE: Recent advances in molecular techniques have characterized distinct subtypes of diffuse intrinsic pontine gliomas. Our aim was the identification of MR imaging correlates of these subtypes. MATERIALS AND METHODS: Initial MRIs from subjects with diffuse intrinsic pontine gliomas recruited for a prospective clinical trial before treatment were analyzed. Retrospective imaging analyses included FLAIR/T2 tumor volume, tumor volume enhancing, the presence of cyst and/or necrosis, median, mean, mode, skewness, kurtosis of ADC tumor volume based on FLAIR, and enhancement at baseline. Molecular subgroups based on EGFR and MGMT mutations were established. Histone mutations were also determined (H3F3A, HIST1H3B, HIST1H3C). Univariate Cox proportional hazards regression was used to test the association of imaging predictors with overall and progression-free survival. Wilcoxon rank sum, Kruskal-Wallis, and Fisher exact tests were used to compare imaging measures among groups. RESULTS: Fifty patients had biopsy and MR imaging. The median age at trial registration was 6 years (range, 3.3-17.5 years); 52% were female. On the basis of immunohistochemical results, 48 patients were assigned to 1 of 4 subgroups: 28 in MGMT-/epidermal growth factor receptor (EGFR)-, 14 in MGMT-/EGFR+, 3 in MGMT+/EGFR-, and 3 in MGMT+/EGFR+. Twenty-three patients had histone mutations in H3F3A, 8 in HIST1H3B, and 3 in HIST1H3C. Enhancing tumor volume was near-significantly different across molecular subgroups (P = .04), after accounting for the false discovery rate. Tumor volume enhancing, median, mode, skewness, and kurtosis ADC T2-FLAIR/T2 were significantly different (P ≤ .048) between patients with H3F3A and HIST1H3B/C mutations. CONCLUSIONS: MR imaging features including enhancement and ADC histogram parameters are correlated with molecular subgroups and mutations in children with diffuse intrinsic pontine gliomas.

Advanced ADC Histogram, Perfusion, and Permeability Metrics Show an Association with Survival and Pseudoprogression in Newly Diagnosed Diffuse Intrinsic Pontine Glioma: A Report from the Pediatric Brain Tumor Consortium.

BACKGROUND AND PURPOSE: Diffuse intrinsic pontine glioma is a lethal childhood brain cancer with dismal prognosis and MR imaging is the primary methodology used for diagnosis and monitoring. Our aim was to determine whether advanced diffusion, perfusion, and permeability MR imaging metrics predict survival and pseudoprogression in children with newly diagnosed diffuse intrinsic pontine glioma. MATERIALS AND METHODS: A clinical trial using the poly (adenosine diphosphate ribose) polymerase (PARP) inhibitor veliparib concurrently with radiation therapy, followed by maintenance therapy with veliparib + temozolomide, in children with diffuse intrinsic pontine glioma was conducted by the Pediatric Brain Tumor Consortium. Standard MR imaging, DWI, dynamic contrast-enhanced perfusion, and DSC perfusion were performed at baseline and approximately every 2 months throughout treatment. ADC histogram metrics of T2-weighted FLAIR and enhancing tumor volume, dynamic contrast-enhanced permeability metrics for enhancing tumors, and tumor relative CBV from DSC perfusion MR imaging were calculated. Baseline values, post-radiation therapy changes, and longitudinal trends for all metrics were evaluated for associations with survival and pseudoprogression. RESULTS: Fifty children were evaluable for survival analyses. Higher baseline relative CBV was associated with shorter progression-free survival (P = .02, Q = 0.089) and overall survival (P = .006, Q = 0.055). Associations of higher baseline mean transfer constant from the blood plasma into the extravascular extracellular space with shorter progression-free survival (P = .03, Q = 0.105) and overall survival (P = .03, Q = 0.102) trended toward significance. An increase in relative CBV with time was associated with shorter progression-free survival (P < .001, Q < 0.001) and overall survival (P = .004, Q = 0.043). Associations of longitudinal mean extravascular extracellular volume fraction with progression-free survival (P = .03, Q = 0.104) and overall survival (P = .03, Q = 0.105) and maximum transfer constant from the blood plasma into the extravascular extracellular space with progression-free survival (P = .03, Q = 0.102) trended toward significance. Greater increases with time were associated with worse outcomes. True radiologic progression showed greater post-radiation therapy decreases in mode_ADC_FLAIR compared with pseudoprogression (means, -268.15 versus -26.11, P = .01.) CONCLUSIONS: ADC histogram, perfusion, and permeability MR imaging metrics in diffuse intrinsic pontine glioma are useful in predicting survival and pseudoprogression.

MR Imaging-Based Radiomic Signatures of Distinct Molecular Subgroups of Medulloblastoma.

BACKGROUND AND PURPOSE: Distinct molecular subgroups of pediatric medulloblastoma confer important differences in prognosis and therapy. Currently, tissue sampling is the only method to obtain information for classification. Our goal was to develop and validate radiomic and machine learning approaches for predicting molecular subgroups of pediatric medulloblastoma. MATERIALS AND METHODS: In this multi-institutional retrospective study, we evaluated MR imaging datasets of 109 pediatric patients with medulloblastoma from 3 children's hospitals from January 2001 to January 2014. A computational framework was developed to extract MR imaging-based radiomic features from tumor segmentations, and we tested 2 predictive models: a double 10-fold cross-validation using a combined dataset consisting of all 3 patient cohorts and a 3-dataset cross-validation, in which training was performed on 2 cohorts and testing was performed on the third independent cohort. We used the Wilcoxon rank sum test for feature selection with assessment of area under the receiver operating characteristic curve to evaluate model performance. RESULTS: Of 590 MR imaging-derived radiomic features, including intensity-based histograms, tumor edge-sharpness, Gabor features, and local area integral invariant features, extracted from imaging-derived tumor segmentations, tumor edge-sharpness was most useful for predicting sonic hedgehog and group 4 tumors. Receiver operating characteristic analysis revealed superior performance of the double 10-fold cross-validation model for predicting sonic hedgehog, group 3, and group 4 tumors when using combined T1- and T2-weighted images (area under the curve = 0.79, 0.70, and 0.83, respectively). With the independent 3-dataset cross-validation strategy, select radiomic features were predictive of sonic hedgehog (area under the curve = 0.70-0.73) and group 4 (area under the curve = 0.76-0.80) medulloblastoma. CONCLUSIONS: This study provides proof-of-concept results for the application of radiomic and machine learning approaches to a multi-institutional dataset for the prediction of medulloblastoma subgroups.

Multiparametric Analysis of Permeability and ADC Histogram Metrics for Classification of Pediatric Brain Tumors by Tumor Grade.

BACKGROUND AND PURPOSE: Accurate tumor grading is essential for treatment planning of pediatric brain tumors. We hypothesized that multiparametric analyses of a combination of permeability metrics and ADC histogram metrics would differentiate high- and low-grade tumors with high accuracy. MATERIALS AND METHODS: DTI and dynamic contrast-enhanced MR imaging using T1-mapping with flip angles of 2°, 5°, 10°, and 15°, followed by a 0.1-mmol/kg body weight gadolinium-based bolus was performed on all patients in addition to standard MR imaging. Permeability data were processed and transfer constant from the blood plasma into the extracellular extravascular space, rate constant from the extracellular extravascular space back into blood plasma, extravascular extracellular volume fraction, and fractional blood plasma volume were calculated from 3D tumor volumes. Apparent diffusion coefficient histogram metrics were calculated for 3 separate tumor volumes derived from T2-FLAIR sequences, T1 contrast-enhanced sequences, and permeability maps, respectively. RESULTS: Results from 41 patients (0.3-16.76 years of age; mean, 6.22 years) with newly diagnosed contrast-enhancing brain tumors (16 low-grade; 25 high-grade) were included in the institutional review board-approved retrospective analysis. Wilcoxon tests showed a higher transfer constant from blood plasma into extracellular extravascular space and rate constant from extracellular extravascular space back into blood plasma, and lower extracellular extravascular volume fraction (P < .001) in high-grade tumors. The mean ADCs of FLAIR and enhancing tumor volumes were significantly lower in high-grade tumors (P < .001). ROC analysis showed that a combination of extravascular volume fraction and mean ADC of FLAIR volume differentiated high- and low-grade tumors with high accuracy (area under receiver operating characteristic curve = 0.918). CONCLUSIONS: ADC histogram metrics combined with permeability metrics differentiate low- and high-grade pediatric brain tumors with high accuracy.

Automated Processing of Dynamic Contrast-Enhanced MRI: Correlation of Advanced Pharmacokinetic Metrics with Tumor Grade in Pediatric Brain Tumors.

BACKGROUND AND PURPOSE: Pharmacokinetic parameters from dynamic contrast-enhanced MR imaging have proved useful for differentiating brain tumor grades in adults. In this study, we retrospectively reviewed dynamic contrast-enhanced perfusion data from children with newly diagnosed brain tumors and analyzed the pharmacokinetic parameters correlating with tumor grade. MATERIALS AND METHODS: Dynamic contrast-enhanced MR imaging data from 38 patients were analyzed by using commercially available software. Subjects were categorized into 2 groups based on pathologic analyses consisting of low-grade (World Health Organization I and II) and high-grade (World Health Organization III and IV) tumors. Pharmacokinetic parameters were compared between the 2 groups by using linear regression models. For parameters that were statistically distinct between the 2 groups, sensitivity and specificity were also estimated. RESULTS: Eighteen tumors were classified as low-grade, and 20, as high-grade. Transfer constant from the blood plasma into the extracellular extravascular space (Ktrans), rate constant from extracellular extravascular space back into blood plasma (Kep), and extracellular extravascular volume fraction (Ve) were all significantly correlated with tumor grade; high-grade tumors showed higher Ktrans, higher Kep, and lower Ve. Although all 3 parameters had high specificity (range, 82%-100%), Kep had the highest specificity for both grades. Optimal sensitivity was achieved for Ve, with a combined sensitivity of 76% (compared with 71% for Ktrans and Kep). CONCLUSIONS: Pharmacokinetic parameters derived from dynamic contrast-enhanced MR imaging can effectively discriminate low- and high-grade pediatric brain tumors.

The Neuroimaging Center of the Pediatric Brain Tumor Consortium-collaborative neuroimaging in pediatric brain tumor research: a work in progress.

As an essential part of the National Cancer Institute (NCI)-funded Pediatric Brain Tumor Consortium (PBTC), the Neuroimaging Center (NIC) is dedicated to infusing the study of pediatric brain tumors with imaging "best practice" by producing a correlative research plan that 1) resonates with novel therapeutic interventions being developed by the wider PBTC, 2) ensures that every PBTC protocol incorporates an imaging "end point" among its objectives, 3) promotes the widespread implementation of standardized technical protocols for neuroimaging, and 4) facilitates a quality assurance program that complies with the highest standards for image data transfer, diagnostic image quality, and data integrity. To accomplish these specific objectives, the NIC works with the various PBTC sites (10 in all, plus NCI/ National Institute of Neurological Diseases and Stroke representation) to ensure that the overarching mission of the consortium--to better understand tumor biology and develop new therapies for central nervous system tumors in children--is furthered by creating a uniform body of imaging techniques, technical protocols, and standards. Since the inception of the NIC in 2003, this broader mandate has been largely accomplished through a series of site visits and meetings aimed at assessing prevailing neuroimaging practices against NIC-recommended protocols, techniques, and strategies for achieving superior image quality and executing the secure transfer of data to the central PBTC. These ongoing evaluations periodically examine investigations into targeted drug therapies. In the future, the NIC will concentrate its efforts on improving image analysis for MR imaging and positron-emission tomography (PET) and on developing new ligands for PET; imaging markers for radiation therapy; and novel systemic, intrathecal, and intralesional therapeutic interventions.

Prolonged T*2 values in newborn versus adult brain: Implications for fMRI studies of newborns.

The neonatal brain possesses higher water content, lower macromolecular concentration, and reduced synaptic density than is found in the brain of a 1-year-old child. Changes in MRI characteristics of brain such as relaxation times accompany rapid changes in brain during early postnatal development. It was hypothesized that T(*)(2) values found in newborns would be significantly higher than those found in 9-month-old children and adults as measured at 1.5 T. Spoiled gradient echo measurements of T(*)(2) within the brains of newborns, 9-month-olds, and adults confirmed this hypothesis. The results have implications with regard to functional MRI studies in newborns since, in general, BOLD signal optimization is achieved when echo times TE are set equal to the T(*)(2) values of the tissue of interest. Since significantly longer T(*)(2) values are found in newborns, it is suggested that the TE values employed for fMRI studies of newborns should be increased to maximize BOLD signal intensity changes and improve the overall reliability of fMRI results in newborns.

Biexponential apparent diffusion coefficient parametrization in adult vs newborn brain.

The decay of brain water signal with b-factor in adult and newborn brains has been measured over an extended b-factor range. Measurements of the apparent diffusion coefficient (ADC) decay curves were made at 16 b-factors from 100 to 5000 s/mm(2) along three orthogonal directions using a line scan diffusion imaging (LSDI) sequence to acquire data from 0.09 ml voxels in a mid-brain axial slice. Regions-of-interest (ROIs) in cortical gray (CG) and white matter in the internal capsule (IC) were selected for ADC decay curve analyses using a biexponential fitting model over this extended b-factor range. Measures of the fast and slow ADC component amplitudes and the traces of the fast and slow diffusion coefficients were obtained from CG and IC ROIs in both adults and newborns. The ADC decay curves from the newborn brain regions were found to have a significantly higher fraction of the fast diffusion ADC component than corresponding regions in the adult brain. The results demonstrate that post-natal brain development has a profound affect on the biexponential parameters which characterize the decay of water signal over an extended b-factor range in both gray and white matter.

Childhood moyamoya disease: hemodynamic MRI.

BACKGROUND: Childhood moyamoya disease is a rare progressive cerebrovascular disease. OBJECTIVE: To evaluate cerebral hemodynamics using dynamic Gd-DTPA-enhanced imaging in children with moyamoya disease. MATERIALS AND METHODS: Eight children (2-11 years of age) with the clinical and angiographic findings typical of moyamoya disease, before and/or after surgical intervention (pial synangiosis), underwent conventional MR imaging (MRI) and hemodynamic MR imaging (HMRI). HMRI used a spoiled gradient-echo with low flip angle (10 deg) and long TE (TR/TE = 24/15 ms) to minimize T 1 effects and emphasize T 2* weighting. Raw and calculated hemodynamic images were reviewed. Three-dimensional time-of-flight MR angiography (MRA) and perfusion brain single photon emission computed tomography (SPECT) were also performed. RESULTS: Abnormal hemodynamic maps resulting from vascular stenosis or occlusion and basal collaterals were observed in six patient studies. HMRI depicted perfusion dynamics of affected cerebrovascular territories, detected cortical perfusion deficits, and complemented conventional MRI and MRA. HMRI findings were consistent with those of catheter angiography and perfusion SPECT. CONCLUSION: Our preliminary experience suggests that HMRI may be of value in the preoperative and postoperative evaluation of surgical interventions in moyamoya disease.

Multivoxel proton MR spectroscopy and hemodynamic MR imaging of childhood brain tumors: preliminary observations.

PURPOSE: To assess multivoxel proton MR spectroscopy combined with MR imaging and hemodynamic MR imaging in the evaluation of brain tumors in children and young adults. METHODS: Fifteen patients with brain tumors and 10 healthy children underwent MR imaging and MR spectroscopy on a 1.5-T system. Ten patients with tumors had both MR spectroscopy and hemodynamic MR imaging. MR spectroscopy data sets with 1 cm3 to 3.4 cm3 resolution were acquired within 8.5 minutes by using a point-resolved spectroscopic, chemical-shift imaging technique in two dimensions with volume preselection. MR imaging was performed using fast spin-echo techniques. Hemodynamic MR imaging data were acquired every 2.5 seconds at one anatomic level using a spoiled gradient-echo sequence during intravenous bolus administration of contrast material. RESULTS: Assessment with multivoxel MR spectroscopy and hemodynamic MR imaging added about 30 minutes to the total MR examination time. Normal tissue exhibited spectral peaks from biologically significant compounds such as N-acetylaspartate (NAA), choline-containing compounds (Cho), and total creatine (tCr). Twelve biopsy-proved tumors exhibited prominent Cho, reduced NAA, variable tCr, and/or lactate or lipids, and two showed increased hemodynamic parameters. Three of the tumors treated with radiation did not reveal prominent levels of Cho. Tissue necrosis had no Cho, NAA, or tCr, and reduced hemodynamics. CONCLUSIONS: Preliminary findings by MR spectroscopy combined with MR imaging and hemodynamic MR imaging suggest that regions of active tumor may be differentiated from areas of normal tissue and areas of necrosis. These findings may enable metabolic and hemodynamic characterization of childhood brain tumors as well as suggest their response to therapy.