MR Imaging Characteristics of Wingless-Type-Subgroup Pediatric Medulloblastoma.
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SUBMITTER: Patay Z
PROVIDER: S-EPMC4827780 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND AND PURPOSE:In addition to the 4 histopathologically defined entities of medulloblastoma, 4 distinct genetically defined subgroups have been included in the World Health Organization classification of 2016. The smallest subgroup is the medulloblastoma with activated wingless pathway. The goal of this study was to identify a typical MR imaging morphology in a larger number of pediatric patients with wingless pathway medulloblastoma. MATERIALS AND METHODS:From January 2001 to October 2017, of 75 patients with histologically confirmed and molecularly subgrouped wingless pathway medulloblastomas recruited to the German Pediatric Brain Tumor (HIT) trials, 38 patients (median age, 12.8 ± 4.6 years at diagnosis; 24 [63.2%] female) had preoperative imaging that passed the entry criteria for this study. Images were rated by the local standardized imaging criteria of the National Reference Center of Neuroradiology. Additionally, a modified laterality score was used to determine tumor localization and extension. RESULTS:Twenty-eight of 38 (73.7%) were primary midline tumors but with a lateral tendency in 39.3%. One extensively eccentric midline tumor was rated by the laterality score as in an off-midline position. Five tumors were found in the cerebellopontine angle; 3, in the deep white matter; and 2, in a cerebellar hemisphere. Leptomeningeal dissemination was rare (11.5%). In 60.5%, intratumoral blood-degradation products were found, and 26.3% showed cysts with blood contents. CONCLUSIONS:According to our observations, wingless pathway medulloblastomas are not preferentially off-midline tumors as postulated in previous studies with smaller wingless pathway medulloblastoma cohorts. Dense intratumoral blood-degradation products and cysts with blood contents are frequently found and might help to differentiate wingless pathway medulloblastoma from other medulloblastoma subtypes.
| S-EPMC6975121 | biostudies-literature
Project description:BackgroundUsing a pathway-focused approach, we aimed to provide a subgroup-specific basis for finding novel therapeutic strategies and further refinement of the risk stratification in pediatric medulloblastoma.MethodBased on genome-wide Cox regression and Gene Set Enrichment Analysis, we investigated prognosis-related signaling pathways and core genes in pediatric medulloblastoma subgroups using 530 patient data from Medulloblastoma Advanced Genomic International Consortium (MAGIC) project. We further examined the relationship between expression of the prognostic core genes and frequent chromosome aberrations using broad range copy number change data.ResultsIn SHH subgroup, relatively high expression of the core genes involved in p53, PLK1, FOXM1, and Aurora B signaling pathways are associated with poor prognosis, and their average expression synergistically increases with co-occurrence of losses of 17p, 14q, or 10q, or gain of 17q. In Group 3, in addition to high MYC expression, relatively elevated expression of PDGFRA, IGF1R, and FGF2 and their downstream genes in PI3K/AKT and MAPK/ERK pathways are related to poor survival outcome, and their average expression is increased with the presence of isochromosome 17q [i(17q)] and synergistically down-regulated with simultaneous losses of 16p, 8q, or 4q. In Group 4, up-regulation of the genes encoding various immune receptors and those involved in NOTCH, NF-κB, PI3K/AKT, or RHOA signaling pathways are associated with worse prognosis. Additionally, the expressions of Notch genes correlate with those of the prognostic immune receptors. Besides the Group 4 patients with previously known prognostic aberration, loss of chromosome 11, those with loss of 8q but without i(17q) show excellent survival outcomes and low average expression of the prognostic core genes whereas those harboring 10q loss, 1q gain, or 12q gain accompanied by i(17q) show bad outcomes. Finally, several metabolic pathways known to be reprogrammed in cancer cells are detected as prognostic pathways including glutamate metabolism in SHH subgroup, pentose phosphate pathway and TCA cycle in Group 3, and folate-mediated one carbon-metabolism in Group 4.ConclusionsThe results underscore several subgroup-specific pathways for potential therapeutic interventions: SHH-GLI-FOXM1 pathway in SHH subgroup, receptor tyrosine kinases and their downstream pathways in Group 3, and immune and inflammatory pathways in Group 4.
| S-EPMC6560914 | biostudies-literature
Project description:Medulloblastoma (MB) is the most common malignant central nervous system tumor in pediatric patients. Mainstay of therapy remains surgical resection followed by craniospinal radiation and chemotherapy, although limitations to this therapy are applied in the youngest patients. Clinically, tumors are divided into average and high-risk status on the basis of age, metastasis at diagnosis, and extent of surgical resection. However, technological advances in high-throughput screening have facilitated the analysis of large transcriptomic datasets that have been used to generate the current classification system, dividing patients into four primary subgroups, i.e., WNT (wingless), SHH (sonic hedgehog), and the non-SHH/WNT subgroups 3 and 4. Each subgroup can further be subdivided on the basis of a combination of cytogenetic and epigenetic events, some in distinct signaling pathways, that activate specific phenotypes impacting patient prognosis. Here, we delve deeper into the genetic basis for each subgroup by reviewing the extent of cytogenetic events in key genes that trigger neoplastic transformation or that exhibit oncogenic properties. Each of these discussions is further centered on how these genetic aberrations can be exploited to generate novel targeted therapeutics for each subgroup along with a discussion on challenges that are currently faced in generating said therapies. Our future hope is that through better understanding of subgroup-specific cytogenetic events, the field may improve diagnosis, prognosis, and treatment to improve overall quality of life for these patients.
| S-EPMC8774967 | biostudies-literature
Project description: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.
| S-EPMC6330121 | biostudies-literature
Project description:PurposeTo develop a method that combines parallel imaging and compressed sensing to enable faster and/or higher spatial resolution magnetic resonance (MR) imaging and show its feasibility in a pediatric clinical setting.Materials and methodsInstitutional review board approval was obtained for this HIPAA-compliant study, and informed consent or assent was given by subjects. A pseudorandom k-space undersampling pattern was incorporated into a three-dimensional (3D) gradient-echo sequence; aliasing then has an incoherent noiselike pattern rather than the usual coherent fold-over wrapping pattern. This k-space-sampling pattern was combined with a compressed sensing nonlinear reconstruction method that exploits the assumption of sparsity of medical images to permit reconstruction from undersampled k-space data and remove the noiselike aliasing. Thirty-four patients (15 female and 19 male patients; mean age, 8.1 years; range, 0-17 years) referred for cardiovascular, abdominal, and knee MR imaging were scanned with this 3D gradient-echo sequence at high acceleration factors. Obtained k-space data were reconstructed with both a traditional parallel imaging algorithm and the nonlinear method. Both sets of images were rated for image quality, radiologist preference, and delineation of specific structures by two radiologists. Wilcoxon and symmetry tests were performed to test the hypothesis that there was no significant difference in ratings for image quality, preference, and delineation of specific structures.ResultsCompressed sensing images were preferred more often, had significantly higher image quality ratings, and greater delineation of anatomic structures (P < .001) than did images obtained with the traditional parallel reconstruction method.ConclusionA combination of parallel imaging and compressed sensing is feasible in a clinical setting and may provide higher resolution and/or faster imaging, addressing the challenge of delineating anatomic structures in pediatric MR imaging.
| S-EPMC2909438 | biostudies-literature
Project description:Purpose To evaluate the effects of histologic features and anatomic magnetic resonance (MR) imaging characteristics of brain tumors on the functional MR imaging signal in the primary motor cortex (PMC), as false-negative blood oxygen level-dependent (BOLD) functional MR imaging activation can limit the accurate localization of eloquent cortices. Materials and Methods Institutional review board approval was obtained, and informed consent was waived for this HIPAA-compliant retrospective study. It comprised 63 patients referred between 2006 and 2014 for preoperative functional MR imaging localization of the Rolandic cortex. The patients had glioblastoma multiforme (GBM) (n = 20), metastasis (n = 21), or meningioma (n = 22). The volumes of functional MR imaging activation were measured during performance of a bilateral hand motor task. Ratios of functional MR imaging activation were normalized to PMC volume. Statistical analysis was performed for the following: (a) differences between hemispheres within each histologic tumor type (paired Wilcoxon test), (b) differences across tumor types (Kruskal-Wallis and Fisher tests), (c) pairwise tests between tumor types (Mann-Whitney U test), (d) relationships between fast fluid-attenuated inversion recovery (FLAIR) data and enhancement volume with activation (Spearman rank correlation coefficient), and (e) differences in activation volumes by tumor location (Mann-Whitney U test). Results A significant interhemispheric difference was found between the activation volumes in GBMs (mean, 511.43 voxels ± 307.73 [standard deviation] and 330.78 voxels ± 278.95; P < .01) but not in metastases (504.68 voxels ± 220.98 and 460.22 voxels ± 276.83; P = .15) or meningiomas (424.07 voxels ± 247.58 and 415.18 voxels ± 222.36; P = .85). GBMs showed significantly lower activation ratios (median, 0.49; range, 0.04-1.15) than metastases (median, 0.79; range, 0.28-1.66; P = .043) and meningiomas (median, 0.91; range, 0.52-2.05; P < .01). There was a moderate correlation with the volumes of FLAIR abnormality in metastases (ρ = -0.50) and meningiomas (ρ = -0.55). Enhancement volume (ρ = -0.11) and tumor distance from the PMC (median, 0.73 and range, 0.04-2.05 for near and median, 0.82 and range, 0.39-1.66 for far; P = .14) did not influence activation. Conclusion BOLD functional MR imaging activation in the ipsilateral PMC is influenced by tumor type and is significantly reduced in GBMs. FLAIR abnormality correlates moderately with the activation ratios in metastases and meningiomas. © RSNA, 2016 Online supplemental material is available for this article.
| S-EPMC5410952 | biostudies-literature
Project description:ObjectivesTo quantify the brain maturation process during childhood using combined amide proton transfer (APT) and conventional magnetization transfer (MT) imaging at 3 Tesla.MethodsEighty-two neurodevelopmentally normal children (44 males and 38 females; age range, 2-190 months) were imaged using an APT/MT imaging protocol with multiple saturation frequency offsets. The APT-weighted (APTW) and MT ratio (MTR) signals were quantitatively analyzed in multiple brain areas. Age-related changes in MTR and APTW were evaluated with a non-linear regression analysis.ResultsThe APTW signals followed a decreasing exponential curve with age in all brain regions measured (R(2) = 0.7-0.8 for the corpus callosum, frontal and occipital white matter, and centrum semiovale). The most significant changes appeared within the first year. At maturation, larger decreases in APTW and lower APTW values were found in the white matter. On the contrary, the MTR signals followed an increasing exponential curve with age in the same brain regions measured, with the most significant changes appearing within the initial 2 years. There was an inverse correlation between the MTR and APTW signal intensities during brain maturation.ConclusionsTogether with MT imaging, protein-based APT imaging can provide additional information in assessing brain myelination in the paediatric population.Key points• APTW signals followed a decreasing exponential curve with age. • The most significant APTW changes appeared within the first year • At maturation, larger APTW decreases and lower APTW appeared in white matter • MTR signals followed an increasing exponential curve with age.
| S-EPMC5747245 | biostudies-literature
Project description:We evaluated the potential effects of ATO in different pediatric SHH-MB cell lines (ONS-76: TP53-wild type; DAOY and UW402: TP53-mutated). MB cell lines molecular subgroup was confirmed and TP53 mutations were validated. Cell viability, clonogenicity and apoptosis were evaluated after ATO treatment at different concentrations (1-16 µM) alone or combined with irradiation doses (0.5, 1, 2 and 4 Gy). Rad51 and Ku86 proteins were evaluated by WB. ATO treatment reduced cell viability for all SHH-MB cell lines. Significant decrease of clonogenic capacity and higher apoptosis rates were also observed after ATO exposure, being cell death more pronounced (>70%) for the SHH-MB TP53-mutated. Combined treatment of ATO with irradiation also reduced colonies formation in UW402 tumor cells, which was independent of DNA damage repair proteins Rad51 and Ku86. In silico analyses suggested that a set of genes from cell cycle and p53 pathways are differentially expressed in SHH tumor subtypes, suggesting that cell lines may respond to therapies according to the gene expression profiles. Herein, we showed ATO cytotoxicity in pediatric SHH cell lines, with marked radiosensitizing effect for the MB-SHH TP53-mutated cells. These results highlight the potential of ATO, alone or in combination with radiotherapy, supporting further clinical investigations.
| S-EPMC7176640 | biostudies-literature
Project description:Medulloblastoma comprises four distinct molecular variants: WNT, SHH, Group 3, and Group 4. We analyzed alternative splicing usage in 14 normal cerebellar samples and 103 medulloblastomas of known subgroup. Medulloblastoma samples have a statistically significant increase in alternative splicing as compared to normal fetal cerebella (2.3-times; P < 6.47E-8). Splicing patterns are distinct and specific between molecular subgroups. Unsupervised hierarchical clustering of alternative splicing events accurately assigns medulloblastomas to their correct subgroup. Subgroup-specific splicing and alternative promoter usage was most prevalent in Group 3 (19.4%) and SHH (16.2%) medulloblastomas, while observed less frequently in WNT (3.2%), and Group 4 (9.3%) tumors. Functional annotation of alternatively spliced genes reveals overrepresentation of genes important for neuronal development. Alternative splicing events in medulloblastoma may be regulated in part by the correlative expression of antisense transcripts, suggesting a possible mechanism affecting subgroup-specific alternative splicing. Our results identify additional candidate markers for medulloblastoma subgroup affiliation, further support the existence of distinct subgroups of the disease, and demonstrate an additional level of transcriptional heterogeneity between medulloblastoma subgroups.
| S-EPMC3984840 | biostudies-literature
Project description:Medulloblastoma is a heterogeneous disease with at least four distinct molecular subgroups: wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4. Recently there has been considerable progress defining the molecular drivers and prognostic factors of each subgroup. However, this information has only rarely been used to stratify risk or impact treatment. The purpose of this work is to provide an update on current clinical trials that provide molecularly stratified treatment paradigms. A search was conducted on ClinicalTrials.gov using the following search terms: "medulloblastoma and subgroup", "medulloblastoma and SHH", "medulloblastoma and WNT", and "medulloblastoma and Non-WNT/Non-SHH". This search resulted in nine distinct clinical trials, five for newly diagnosed medulloblastoma and four for recurrent medulloblastoma. Four trials for newly diagnosed medulloblastoma had a component of craniospinal irradiation reduction for patients with WNT medulloblastoma. Molecularly stratified trials for recurrent medulloblastoma largely focus on SHH. As these trials are ongoing, there are limited data available. A trial in which newly-diagnosed WNT patients received modest chemotherapy without radiation has been closed to accrual due to several early failures. Phase II trials evaluating vismodegib for SHH medulloblastoma in children and adults have been disappointing. In conclusion, although there is an expanding array of clinical trials which incorporate molecular data in prescribing treatment for newly-diagnosed and recurrent medulloblastoma, treatments for these diseases are fairly uniform, with craniospinal radiation dose being the main variable. As the drivers of the distinct subgroups and their associated prognoses are better elucidated, future clinical trials and novel targeted agents are needed to improve outcomes and reduce toxicity where feasible.
| S-EPMC7237968 | biostudies-literature