Childhood posterior fossa (PF) ependymomas cause substantial morbidity and mortality. These tumors lack recurrent genetic mutations, but a subset of these ependymomas exhibits CpG island (CpGi) ...hypermethylation PF group A (PFA), implicating epigenetic alterations in their pathogenesis. Further, histological grade does not reliably predict prognosis, highlighting the importance of developing more robust prognostic markers. We discovered global H3K27me3 reduction in a subset of these tumors (PF-ve ependymomas) analogous to H3K27M mutant gliomas. PF-ve tumors exhibited many clinical and biological similarities with PFA ependymomas. Genomic H3K27me3 distribution showed an inverse relationship with CpGi methylation, suggesting that CpGi hypermethylation drives low H3K27me3 in PF-ve ependymomas. Despite CpGi hypermethylation and global H3K27me3 reduction, these tumors showed DNA hypomethylation in the rest of the genome and exhibited increased H3K27me3 genomic enrichment at limited genomic loci similar to H3K27M mutant gliomas. Combined integrative analysis of PF-ve ependymomas with H3K27M gliomas uncovered common epigenetic deregulation of select factors that control radial glial biology, and PF radial glia in early human development exhibited reduced H3K27me3. Finally, H3K27me3 immunostaining served as a biomarker of poor prognosis and delineated radiologically invasive tumors, suggesting that reduced H3K27me3 may be a prognostic indicator in PF ependymomas.
Medulloblastoma in children can be categorized into at least four molecular subgroups, offering the potential for targeted therapeutic approaches to reduce treatment-related morbidities. Little is ...known about the role of tumor microenvironment in medulloblastoma or its contribution to these molecular subgroups. Tumor microenvironment has been shown to be an important source for therapeutic targets in both adult and pediatric neoplasms. In this study, we investigated the hypothesis that expression of genes related to tumor-associated macrophages (TAM) correlates with the medulloblastoma molecular subgroups and contributes to a diagnostic signature.
Gene-expression profiling using human exon array (n = 168) was analyzed to identify medulloblastoma molecular subgroups and expression of inflammation-related genes. Expression of 45 tumor-related and inflammation-related genes was analyzed in 83 medulloblastoma samples to build a gene signature predictive of molecular subgroups. TAMs in medulloblastomas (n = 54) comprising the four molecular subgroups were assessed by immunohistochemistry (IHC).
A 31-gene medulloblastoma subgroup classification score inclusive of TAM-related genes (CD163 and CSF1R) was developed with a misclassification rate of 2%. Tumors in the Sonic Hedgehog (SHH) subgroup had increased expression of inflammation-related genes and significantly higher infiltration of TAMs than tumors in the Group 3 or Group 4 subgroups (P < 0.0001 and P < 0.0001, respectively). IHC data revealed a strong association between location of TAMs and proliferating tumor cells.
These data show that SHH tumors have a unique tumor microenvironment among medulloblastoma subgroups. The interactions of TAMs and SHH medulloblastoma cells may contribute to tumor growth revealing TAMs as a potential therapeutic target.
Malignant rhabdoid tumor (MRT) can occur in the kidney, central nervous system, or extracranial/extrarenal locations and is characterized by alterations in the SMARCB1 gene. The tumors occur in ...infants and young children and confer a poor prognosis requiring aggressive therapeutic interventions to improve the chances for survival. MRTs pose a diagnostic challenge, as they display heterogeneous histopathologic features and differentiate along multiple lineages. The identification of alterations in the SMARCB1 gene in MRT using immunohistochemical (IHC) staining has lead to improved diagnosis of MRT as well as the discovery of the loss of SMARCB1 expression in some non-MRTs. Whether loss of SMARCB1 plays a pathogenic role in nonrhabdoid tumors remains to be determined; however, most of these tumors lack the clinical and other molecular features of MRT. We review the histopathologic features of MRT and the importance and significance of loss of expression of SMARCB1 in both MRT and nonrhabdoid tumors.
Purpose
To develop an MR multitasking‐based dynamic imaging for cerebrovascular evaluation (MT‐DICE) technique for simultaneous quantification of permeability and leakage‐insensitive perfusion with a ...single‐dose contrast injection.
Methods
MT‐DICE builds on a saturation‐recovery prepared multi‐echo fast low‐angle shot sequence. The k‐space is randomly sampled for 7.6 min, with single‐dose contrast agent injected 1.5 min into the scan. MR multitasking is used to model the data into six dimensions, including three spatial dimensions for whole‐brain coverage, a saturation‐recovery time dimension, and a TE dimension for dynamic and quantification, respectively, and a contrast dynamics dimension for capturing contrast kinetics. The derived pixel‐wise time series are converted into contrast concentration‐time curves for calculation of kinetic metrics. The technique was assessed for its agreement with reference methods in and measurements in eight healthy subjects and, in three of them, inter‐session repeatability of permeability and leakage‐insensitive perfusion parameters. Its feasibility was also demonstrated in four patients with brain tumors.
Results
MT‐DICE values of normal gray matter and white matter were in excellent agreement with reference values (intraclass correlation coefficients = 0.860/0.962 for gray matter and 0.925/0.975 for white matter ). Both permeability and perfusion parameters demonstrated good to excellent intersession agreement with the lowest intraclass correlation coefficients at 0.694. Contrast kinetic parameters in all healthy subjects and patients were within the literature range.
Conclusion
Based on dynamic mapping, MT‐DICE allows for simultaneous quantification of permeability and leakage‐insensitive perfusion metrics with a single‐dose contrast injection.
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Background
Germ cell tumors (GCT) arising from non‐midline structures (basal ganglia, thalamus, and posterior fossa) are rare. Although patients with midline (pineal and suprasellar) germinoma have ...excellent survival with chemotherapy and whole ventricular irradiation (WVI), germinoma in non‐midline locations have traditionally been treated with craniospinal irradiation (CSI) or whole brain irradiation (WBI) to achieve similar outcomes. However, CSI and WBI are associated with significant long‐term neuropsychological sequelae.
Methods
We describe the clinical and neuropsychological outcomes of patients with non‐midline germinoma treated at the Children's Hospital Los Angeles between 1990 and 2015.
Results
Nine patients had basal ganglia/thalamic germinoma and one patient had a cerebellar primary. Eight patients received chemotherapy followed by reduced dose/volume irradiation, whereas two patients received chemotherapy alone as upfront therapy. One patient in the chemotherapy alone group relapsed after 4.3 years and was salvaged with CSI plus boost. The overall survival for the entire cohort was 100% at a median follow‐up of 8.5 years. Neuropsychological data were available for six patients at a median of five months (baseline) and 4.2 years (follow‐up) post‐diagnosis. At four‐year follow‐up, data available revealed intact overall cognitive ability, verbal memory, and executive functioning, but persistent deficits in fine motor function. Comparison of baseline to follow‐up suggests a downward trend in working memory, planning/problem‐solving, verbal memory, and visuospatial integration.
Conclusion
Chemotherapy followed by reduced dose/volume of irradiation is an effective strategy resulting in long‐term survival in patients with non‐midline germinoma. Neuropsychological data suggest relatively minimal morbidity over time.
The prognosis for patients with pediatric high-grade glioma (pHGG) is poor despite aggressive multimodal therapy. Objective responses to targeted therapy with BRAF inhibitors have been reported in ...some patients with recurrent BRAF-mutant pHGG but are rarely sustained.
We performed a retrospective, multi-institutional review of patients with BRAF-mutant pHGG treated with off-label BRAF +/- MEK inhibitors as part of their initial therapy.
Nineteen patients were identified, with a median age of 11.7 years (range, 2.3-21.4). Histologic diagnoses included HGG (n = 6), glioblastoma (n = 3), anaplastic ganglioglioma (n = 4), diffuse midline glioma (n = 3), high-grade neuroepithelial tumor (n = 1), anaplastic astrocytoma (n = 1), and anaplastic astroblastoma (n = 1). Recurrent concomitant oncogenic alterations included CDKN2A/B loss, H3 K27M, as well as mutations in ATRX, EGFR, and TERT. Eight patients received BRAF inhibitor monotherapy. Eleven patients received combination therapy with BRAF and MEK inhibitors. Most patients tolerated long-term treatment well with no grade 4-5 toxicities. Objective and durable imaging responses were seen in the majority of patients with measurable disease. At a median follow-up of 2.3 years (range, 0.3-6.5), three-year progression-free and overall survival for the cohort were 65% and 82%, respectively, and superior to a historical control cohort of BRAF-mutant pHGG patients treated with conventional therapies.
Upfront targeted therapy for patients with BRAF-mutant pHGG is feasible and effective, with superior clinical outcomes compared to historical data. This promising treatment paradigm is currently being evaluated prospectively in the Children's Oncology Group ACNS1723 clinical trial.
Background
For several types of cancer, biological differences and outcome disparities have been documented in adolescents/young adults (AYAs, 15–39 years old) versus children. This study compared ...clinicopathological features and survival between younger AYAs and children with low-grade glioma (LGG), a common brain tumor among AYAs.
Methods
This was a secondary analysis of Children’s Oncology Group legacy study CCG-9891/POG-9130, which enrolled participants 0–21 years of age with newly-diagnosed LGG treated with surgery alone. For analysis, participants were categorized as children (0–14 years old) or early AYAs (eAYAs, 15–21 years old) and compared on demographics, clinical presentation, tumor characteristics, surgical outcomes, progression-free survival (PFS) and overall survival (OS).
Results
Among 468 children and 50 eAYAs, more eAYAs presented with seizures (34.0% vs. 19.2%; p = 0.015), without other significant differences in clinicopathological features. 5-year PFS rates for children and eAYA were 80.2% (95% confidence interval 95% CI, 76.1–83.7) and 83.0% (95% CI 68.8–91.1), respectively; 5-year OS rates were 97.3% (95% CI 95.2–98.5) and 95.4% (95% CI 82.7–98.8), respectively. Multivariable analysis including all participants showed presence of residual tumor to be an independent predictor of PFS (< 1.5 cm
3
, hazard ratio HR 5.93 95% CI 3.45–10.18) and (≥ 1.5 cm
3
, HR 8.38 95% CI 4.75–14.79) (p < 0.001), while midline-chiasmatic location (HR 9.69 95% CI 3.05–30.75, p < 0.001) and non-pilocytic astrocytoma histology (HR 6.77 95% CI 2.35–19.49, p < 0.001) were independent predictors of OS.
Conclusion
Unlike several other cancers, LGG has similar presenting features and survival for both eAYAs and children. This support continuing a unified treatment approach and enrollment of eAYAs in pediatric clinical trials for LGGs.
Purpose
Irradiation-avoiding strategies have been used with relative success in the treatment of infants and young children with medulloblastoma. While advances in cancer genomics have significantly ...improved our understanding of the tumor biology of medulloblastoma allowing for improved prognostication and risk-stratification, the molecular subgroup-specific outcomes of infants and young children with medulloblastoma treated with irradiation-avoiding strategies remains unknown.
Methods
Molecular and clinical features of children with medulloblastoma treated with irradiation-avoiding strategies at Children’s Hospital Los Angeles were analyzed. Molecular subgrouping of these patients was determined using a 31-gene
Taq
Man Low Density Array signature. Survival analyses were conducted based on 3 molecular subgroups (SHH, Group 3, and Group 4).
Results
Twenty-eight patients with medulloblastoma received irradiation-sparing regimens and were included in this analysis. Patients were divided into SHH (n = 16), Group 3 (n = 3) and Group 4 subgroups (n = 9). Subgroup specific 5-year progression-free and overall survival was 81.2% (95% CI 52.5–93.5) and 93.7% (95% CI 63.2–99.1) for SHH, 0% and 0% for Group 3 and 0% and 44.4% (95% CI 13.6–71.9) for Group 4.
Conclusion
The majority of young children with SHH-subgroup medulloblastoma can be treated effectively with irradiation-sparing regimens. Our results support the use of chemotherapy-only strategies for upfront treatment of young children with SHH medulloblastoma, while demonstrating the urgent need for intensification/augmentation of treatment for patients with group 3/4 medulloblastoma.
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