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Methylation profiling has radically transformed our understanding of tumors previously called central nervous system primitive neuro-ectodermal tumors (CNS-PNET). While this marks a momentous step toward defining key differences, reclassification has thrown treatment into disarray. To shed light on response to therapy and guide clinical decision-making, we report outcomes and molecular features of children with CNS-PNETs from two multi-center risk-adapted studies (SJMB03 for patients ≥ 3 years; SJYC07 for patients 3 years) complemented by a non-protocol institutional cohort. Seventy patients who had a histological diagnosis of CNS-PNET or CNS embryonal tumor from one of the new categories that has supplanted CNS-PNET were included. This cohort was molecularly characterized by DNA methylation profiling (n = 70), whole-exome sequencing (n = 53), RNA sequencing (n = 20), and germline sequencing (n = 28). Clinical characteristics were detailed, and treatment was divided into craniospinal irradiation (CSI)-containing (SJMB03 and SJMB03-like) and CSI-sparing therapy (SJYC07 and SJYC07-like). When the cohort was analyzed in its entirety, no differences were observed in the 5-year survival rates even when CSI-containing therapy was compared to CSI-sparing therapy. However, when analyzed by DNA methylation molecular grouping, significant survival differences were observed, and treatment particulars provided suggestions of therapeutic response. Patients with CNS neuroblastoma with FOXR2 activation (CNS-NB-FOXR2) had a 5-year event-free survival (EFS)/overall survival (OS) of 66.7% ± 19.2%/83.3% ± 15.2%, and CIC rearranged sarcoma (CNS-SARC-CIC) had a 5-year EFS/OS both of 57.1% ± 18.7% with most receiving regimens that contained radiation (focal or CSI) and multidrug chemotherapy. Patients with high-grade neuroepithelial tumor with BCOR alteration (HGNET-BCOR) had abysmal responses to upfront chemotherapy-only regimens (5-year EFS = 0%), but survival extended with salvage radiation after progression [5-year OS = 53.6% ± 20.1%]. Patients with embryonal tumor with multilayered rosettes (ETMR) or high-grade glioma/glioblastoma multiforme (HGG/GBM) did not respond favorably to any modality (5-year EFS/OS = 10.7 ± 5.8%/17.9 ± 7.2%, and 10% ± 9.0%/10% ± 9.0%, respectively). As an accompaniment, we have assembled this data onto an interactive website to allow users to probe and query the cases. By reporting on a carefully matched clinical and molecular cohort, we provide the needed insight for future clinical management.

Cerebral edema from brain tumors can cause neurological impairment. Steroids treat edema but with possible adverse effects. We surveyed providers regarding steroid use in newly diagnosed patients with brain tumors to determine if practices are standard or markedly variable. An anonymous voluntary online survey was sent to members of neuro-oncology consortiums. Four clinical scenarios were provided and questions regarding initiation of steroids, type, dose, formulation, and duration were asked. Demographic information was collected. 369 providers received the survey, 76 responded (20.6% response rate). The proportion of providers who would start steroids significantly differed among scenarios (scenario 1 vs 2, p

PURPOSE: Survivors of pediatric embryonal brain tumors (BT) are at high risk for sensorineural hearing loss (SNHL) associated with neurocognitive decline. However, previous studies have not assessed the relationship between SNHL and adaptive functioning. We examined neurocognitive and adaptive functioning in patients with and without SNHL. METHODS: Participants included 36 patients treated for an embryonal BT with craniospinal irradiation (CSI) and cisplatin chemotherapy who were assessed 6.7 years post-treatment on average. The impact of SNHL on neurocognitive performance and parent-rated adaptive functioning was assessed in univariate and multivariate analyses. RESULTS: There were 17 cases with SNHL (mean age at evaluation = 14.4) and 19 cases with NH (mean age at evaluation = 13.8). After accounting for age at diagnosis and additional covariates in multivariable analyses, SNHL was associated with worse overall intellectual functioning (p = 0.027) and perceptual reasoning (p = 0.016) performance. There was no effect of SNHL on adaptive functioning in multivariable models. Age at diagnosis and sex were associated with performance on neurocognitive measures. CONCLUSIONS: SNHL in pediatric embryonal BT is associated with increased risk for neurocognitive deficits in conjunction with other demographic and treatment-related factors.

Central nervous system (CNS) tumors are the most common solid tumors in children. Findings on the role of maternal and perinatal factors on the susceptibility or outcome of these tumors are inconclusive. Therefore, we investigated the association between these early-life factors, risk, and survival of pediatric CNS tumors, using data from one of the world’s largest and most diverse cancer registries. Information on pediatric CNS tumor cases (n = 1950) for the period 1995–2011 was obtained from the Texas Cancer Registry. Birth certificate controls were frequency-matched on birth year at a ratio of 10:1 for the same period. Evaluated maternal and perinatal variables were obtained from birth records. Unconditional logistic regression was used to generate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for etiological factors. Additionally, Cox proportional hazards regression was employed to assess adjusted hazard ratios (HRs) and 95% CIs for survival factors. The results indicated that Hispanic and non-Hispanic black mothers were less likely to have children with CNS tumors compared to non-Hispanic white mothers (OR 0.88 [95% CI 0.78–0.98] P-value = 0.019; OR 0.79 [95% CI 0.67–0.93 P-value = 0.004], respectively). Infants born large for gestational age (OR 1.26 [95% CI 1.07–1.47] P-value = 0.004) and those delivered pre-term (OR 1.19 [95% CI 1.04–1.38] P-value = 0.013) showed an increased risk of CNS tumors. Infants born by vaginal forceps or vacuum delivery had a higher risk of CNS tumors compared to those born by spontaneous vaginal delivery (OR 1.35 [95% CI 1.12–1.62] P-value = 0.002). Additionally, offspring of Hispanic and non-Hispanic black mothers showed a higher risk of death (HR 1.45 [95% CI 1.16–1.80] P-value = 0.001; HR 1.53 [95% CI 1.12–2.09] P-value = 0.008, respectively). Infants born by cesarean had a higher risk of death compared to those delivered vaginally (HR 1.28 [95% CI 1.05–1.57] P-value = 0.016). These findings indicate the important role of maternal and perinatal characteristics in the etiology and survival of these clinically significant malignancies.

The incidence of high-grade gliomas (HGGs) in children is significantly lower than in adults, with less than 400 children diagnosed every year in the USA. While the histopathology of HGGs in children is very similar to those in adults, their biology is very different. Recent studies have led to an exponential increase in our understanding of the biology of these tumors, with the identification of distinct epigenetic subtypes, each with characteristic clinical and molecular profiles. The 2016 WHO classification of central nervous system tumors has recognized the most common subtype, with the poorest prognosis—“diffuse midline glioma H3 K27M-mutant”—marking a shift towards the integration of molecular features with the traditional histopathological diagnosis. Like adults, children with HGGs have a very poor prognosis overall, with treatment consisting of maximal safe surgical resection followed by radiation therapy. However, the role of temozolomide, which is a well-established adjuvant therapy for MGMT-methylated HGGs in adults, is less clear in children. In this review, we outline the epidemiology, recent advances in our understanding of biology, past landmark clinical trials, and promising therapeutic strategies for pediatric HGG.

Immunobiology of medulloblastoma (MB), the most common malignant brain tumor in children, is poorly understood. Although tumor cells in some MBs were recently shown to express CD1d and be susceptible to Vα24-invariant natural killer T (NKT)-cell cytotoxicity, the clinical relevance of CD1d expression in MB patients remains unknown. We investigated the expression of CD1d in pediatric MBs and correlated with molecular and clinical characteristics. Specifically, we explored if NKT cell therapy can be targeted at a subset of pediatric MBs with poorer prognosis. Particularly, infantile MBs have a worse outcome because radiotherapy is delayed to avoid neurocognitive sequelae. Immunohistochemistry for CD1d was performed on a screening set of 38 primary pediatric MBs. Gene expression of the membrane form of M2 macrophage marker, CD163, was studied in an expanded cohort of 60 tumors. Outcome data was collected prospectively. Thirteen of 38 MBs (34.2 %) expressed CD1d on immunohistochemistry. CD1d was expressed mainly on MB tumor cells, and on some tumor-associated macrophages. Majority (18/22, 82 %) of non sonic-hedgehog/Wingless-activated MBs (group 3 and 4) were CD1d-negative (p = 0.05). A subset of infantile MBs (4/9, 44.4 %) expressed CD1d. Macrophages infiltrating MB expressed CD163 apart from CD1d. Molecular subtypes demonstrated statistical differences in CD163 expression, SHH-tumors were the most enriched (p = 0.006). Molecular and clinical subtypes of pediatric MB exhibit distinct differences in CD1d expression, which have important therapeutic implications. High CD1d expression in infantile MBs offers potential new immunotherapeutic treatment with NKT cell therapy in infants, where treatment is suboptimal due delayed radiotherapy.

Objective Myxopapillary ependymoma (MPE) is a rare tumor, accounting for 10–20 % of pediatric intramedullary spinal cord tumors. Our objective was to study the patterns of dissemination and failure in pediatric MPE.

The purpose of this study is to determine whether the use of helical tomotherapy can reduce dose to the heart, breast tissue, and thyroid gland in children receiving whole lung irradiation (WLI). Computed tomography simulation scans from nine pediatric patients previously treated with WLI were used for this dosimetry study. Each scan was alternatively planned using helical tomotherapy to minimize dose to surrounding critical structures. The clinical target volume (CTV) included both lungs. The ribs and spine in proximity to the lungs were included in the CTV to minimize bone asymmetry resulting from partial irradiation. The planning target volume (PTV) included the CTV with a 0.8-cm margin. The following structures were contoured: right atrium, left atrium, right ventricle, left ventricle, right and left breast, thyroid gland, and the humeral heads. Median dose (D med), minimum dose (D min), and maximum dose (D max) for the PTV, CTV, heart chambers, thyroid gland, right and left breast as well as right and left humeral heads were also obtained. The median PTV receiving the prescription dose was 97 %, with PTVs ranging from 95 to 99 %. The average D med for each of the four chambers of the heart ranged from 37 to 55 % of the prescription dose. The average D med for the breasts ranged from 88 to 95 % while for the thyroid gland was 10 % of the prescription dose. Helical tomotherapy can minimize the radiation dose delivered to nontarget organs such as the heart, breasts, and thyroid gland.

The growth pattern of pilocytic astrocytoma (PAs) is unpredictable. Gene expression profiling has recently demonstrated an inverse relationship between myelin basic protein (MBP) expression and progression free survival (PFS) in PAs. We present here the pattern of expression of oligodendroglial differentiation markers (ODMs) in PAs by immunohistochemistry and their correlation with PI and PFS. Sixty-four cases of PA were reviewed and representative sections were stained for Ki-67 and ODMs, including MBP, platelet-derived growth factor receptor-α (PDGFR-α), Olig-1, and Olig-2. Sections were graded semi-quantitatively for intensity (I: 0–3+) and extent (E: 0–4+) of staining. PI was expressed as a percentage of Ki-67 positive cells. Immunoreactivity of MBP, PDGFR-α, Olig-1, and Olig-2 was observed in 84, 56, 97, and 75% of cases, respectively. There was a statistically significant inverse correlation between MBP expression and PI (r 2 = .696, p = .014). A positive correlation was observed between PDGFR-α and PI (r 2 = .727, p = .011). Further analysis showed a significant difference in PFS between low expressors [I + E score ≤ 3] and high expressors (I + E score ≥ 4) for PDGFR-α with p

Medulloblastomas represent 20% of malignant brain tumors of childhood. Although, they show multiple, non-random genomic alterations, no common, early genetic event involving all histologic types of medulloblastomas have been described. Nineteen medulloblastomas were analyzed using chromosomal comparative genomic hybridization (cCGH). Nine tumors with the most frequent number of genetic changes were further analyzed using bacterial artificial chromosome array CGH (aCGH). With aCGH, the frequency of gains and losses were higher than with cCGH. Chromosome 2p gains spanning 2p11-2p25 including N-myc locus, 2p24.1 were detected in 5/9 (55%) tumors while 14q12 gains were detected in 6/9 (67%) tumors. The 14q12 locus overlapped with the FOXGI gene locus. Quantitative real time PCR showed a 2-7-fold copy gain for FOXG1 in all the nine tumors. Protein expression was demonstrated by immunohistochemistry in all histologic types. The expression of FOXG1 and p21cip1 showed an inverse relationship. FOXG1 copy gain (2 to 21 folds) was seen in 93% (55/59) of a validating set of tumors and showed a positive correlation with protein expression (Spearman's rank order correlation coefficient = 0.276; P = 0.038) representing the first report of FOXG1 dysregulation in medulloblastoma. Modulation of FOXG1 expression in DAOY cell line using siRNA showed a modest decrease in proliferation with a 2-fold upregulation of p21cip1. Current reports indicate that FOXG1 represses TGF-beta induced expression of p21cip1 and cytostasis, and forms a transcriptional repressor complex with Notch signaling induced hes1. Our findings are consistent with a role for FOXG1 in the inhibition of TGF-beta induced cytostasis in medulloblastoma.

The X-linked BCL-6 co-repressor (BCOR) gene encodes a key constituent of a variant polycomb repressive complex (PRC) that is mutated or translocated in human cancers. Here we report on the identification of somatic internal tandem duplications (ITDs) clustering in the C terminus of BCOR in 23 of 27 (85%) pediatric clear cell sarcomas of the kidney (CCSK) from two independent cohorts. We profile CCSK tumours using a combination of whole-exome, transcriptome and targeted sequencing. Identical ITD mutations are found in primary and relapsed tumour pairs but not in adjacent normal kidney or blood. Mutant BCOR transcripts and proteins are markedly upregulated in ITD-positive tumours. Transcriptome analysis of ITD-positive CCSKs reveals enrichment for PRC2-regulated genes and similarity to undifferentiated sarcomas harbouring BCOR–CCNB3 fusions. The discovery of recurrent BCOR ITDs defines a major oncogenic event in this childhood sarcoma with significant implications for diagnostic and therapeutic approaches to this tumour.

Ependymomas are a heterogeneous group of neuroepithelial tumors of children and adults. In pediatric cases, the standard of care has long consisted of neurosurgical resection to the greatest extent acceptable followed by adjuvant involved field irradiation. Complete macroscopic surgical resection has remained the only consistent clinical variable known to improve survival. Adjuvant chemotherapy has yet to predictably affect outcome, possibly due to the molecular heterogeneity of histologically similar tumors. The administration of chemotherapy subsequently remains limited to clinical trials. However, recent comprehensive genomic, transcriptomic, and epigenetic interrogations of ependymomas have uncovered unique molecular characteristics and subtypes that correlated with clinical features such as age, neuroanatomical location, and prognosis. These findings represent a potential paradigm shift and provide a biologic rationale for targeted therapeutic strategies and risk-adapted administration of conventional treatment modalities. In this review, we focus on intracranial WHO grade II and III ependymoma of children and discuss conventional management strategies, followed by recent biologic findings and novel therapeutics currently under investigation.

Chemotherapy is commonly used in the treatment of children with high-grade glioma, although its usefulness is uncertain. We conducted a multi-institutional study to evaluate the efficacy of temozolomide given after radiotherapy in children with newly diagnosed high-grade glioma and unfavorable low-grade glioma (gliomatosis cerebri or bithalamic involvement). Optional window therapy of intravenous irinotecan (10 doses of 20 mg/m2 per cycle x 2) was given over 6 weeks. The 5-day schedule of temozolomide (200 mg/m2 per day) started 4 weeks after the completion of radiotherapy and continued for a total of 6 cycles. Thirty-one eligible patients (median age: 12.3 years) participated. Tumors most commonly involved cerebral hemispheres (n = 13, 42%) and thalamus (n = 14, 45%). Whereas six patients underwent radical resection, the remainder had limited surgery, including biopsy (n = 14, 45%). The predominant histologic diagnoses were glioblastoma multiforme (n = 15, 48%) and anaplastic astrocytoma (n = 10, 32%). Two patients had bithalamic grade II astrocytoma. Twenty-seven patients received radiotherapy (median dose: 59.4 Gy), including craniospinal irradiation in 3 because of leptomeningeal spread. Four patients did not receive radiotherapy in this study because of consent withdrawn (n = 2), toxicity during window therapy (n = 1), or at the physician's discretion (n = 1). Twenty-three patients received 112 cycles of temozolomide therapy. The 2-year progression-free and overall survival estimates were 11 +/- 5% and 21 +/- 7%, respectively. Although the heterogeneity of prognostic factors in our patients made assessment of treatment outcome more difficult, the addition of 6 cycles of temozolomide after radiotherapy did not seem to alter the poor outcome of these patients.

Background Effectively educating families about the risks and benefits of genomic tests such as whole exome sequencing (WES) offers numerous challenges, including the complexity of test results and potential loss of privacy. Research on best practices for obtaining informed consent (IC) in a variety of clinical settings is needed. The BASIC3 study of clinical tumor and germline WES in an ethnically diverse cohort of newly diagnosed pediatric cancer patients offers the opportunity to study the IC process in the setting of critical illness. We report on our experience for the first 100 families enrolled, including study participation rates, reasons for declining enrollment, assessment of clinical and demographic factors that might impact study enrollment, and preferences of parents for participation in optional genomics study procedures. Methods A specifically trained IC team offered study enrollment to parents of eligible children for procedures including clinical tumor and germline WES with results deposited in the medical record and disclosure of both diagnostic and incidental results to the family. Optional study procedures were also offered, such as receiving recessive carrier status and deposition of data into research databases. Stated reasons for declining participation were recorded. Clinical and demographic data were collected and comparisons made between enrolled and non-enrolled patients. Results Over 15 months, 100 of 121 (83%) eligible families elected to enroll in the study. No significant differences in enrollment were detected based on factors such as race, ethnicity, use of Spanish interpreters and Spanish consent forms, and tumor features (central nervous system versus non-central nervous system, availability of tumor for WES). The most common reason provided for declining enrollment (10% of families) was being overwhelmed by the new cancer diagnosis. Risks specific to clinical genomics, such as privacy concerns, were less commonly reported (5.5%). More than 85% of parents consented to each of the optional study procedures. Conclusions An IC process was developed that utilizes a specialized IC team, active communication with the oncology team, and an emphasis on scheduling flexibility. Most parents were willing to participate in a clinical germline and tumor WES study as well as optional procedures such as genomic data sharing independent of race, ethnicity or language spoken. Electronic supplementary material The online version of this article (doi:10.1186/s13073-014-0069-3) contains supplementary material, which is available to authorized users.

Corrigendum: Common variants in ACYP2 influence susceptibility to cisplatin-induced hearing loss