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1.  Magnetic Resonance Imaging Is the Preferred Method to Assess Treatment-Related Skeletal Changes in Children With Brain Tumors 
Pediatric blood & cancer  2013;60(9):1552-1556.
Purpose
To evaluate the growing skeleton for potential altered skeletalgenesis associated with antiangiogenesis therapy.
Patients and Methods
Knee radiographs and magnetic resonance imaging (MRI) were prospectively obtained on patients enrolled on two consecutive clinical trials using vandetanib, a potent oral (VEGF receptor 2) VEGFR-2 inhibitor alone or combined with dasatinib, a multiple tyrosine kinase inhibitor, in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG).
Results
Fifty-nine patients (32 females) underwent 119 MRIs; 51 patients underwent 89 radiographs of the knees. The median age at enrollment was 6.2 years (range, 2.4–17.6 years). The dose of vandetanib ranged from 50 to 145 mg/m2/day. The median treatment duration was 205 days. Only two patients have not experienced disease progression after 18 and 60 months from diagnosis. MRI identified clinically significant premature physeal fusion in both knees of one patient, focal physeal thickening in one, osteonecrosis in eight patients (present at enrollment in one), and bony spicules crossing the physis in two patients (bilateral in one). MRI follow-up period averaged 5.3 months (range, 0–25.5 months; median, 3.5 months). Radiographs delineated normally fused physes in two patients but no cases of premature physeal fusion, osteonecrosis or bony spicules.
Conclusions
As MRI provided greater information than radiographs, and thus would be a more sensitive test to assess skeletalgenesis in pediatric patients.
doi:10.1002/pbc.24536
PMCID: PMC4309017  PMID: 23526749
antiangiogenesis agents; chemotherapy; magnetic resonance imaging; pediatric brain tumors; skeletalgenesis; VEGF
2.  CARBOPLATIN-BASED PRIMARY CHEMOTHERAPY FOR INFANTS AND YOUNG CHILDREN WITH CNS TUMORS 
Cancer  2009;115(14):3243-3253.
Background
A carboplatin-based chemotherapy regimen was used as primary post-operative therapy in infants with central nervous system tumors to limit renal and ototoxicity and to target systemic exposure.
Patients and Methods
53 patients ≤ age 3 years with embryonal CNS tumor medulloblastoma (MB, n=20), ependymoma (EP, n=21), choroid plexus carcinoma (CPCA, n=5), and primitive embryonal neoplasms including atypical teratoid rhabdoid tumors (n=7) were treated with cyclophosphamide, etoposide, and carboplatin. Radiation therapy was utilized only for residual disease at the end of chemotherapy or disease progression.
Results
The response rate after two cycles of chemotherapy was 34% (complete response [CR] 13.8%, partial response [PR] 20.7%). Myelosuppression was the dominant toxicity; 2 patients had toxic deaths related to thrombocytopenia with trauma. The five-year overall survival (OS) was 49 ± 7%, and the progression-free survival (PFS) was 31 ± 7% with a median follow-up of 11.4 yrs (range: 5.2–15.0 years). For medulloblastoma, the five-year PFS is 26% ± 9%; for EP 33 ± 10%; for CPCA, 80 ± 18%; for PNET and atypical teratoid rhabdoid tumor (ATRT) 0%. Localized ependymoma patients with GTR who did not undergo radiotherapy had a 5-year PFS of 57 ±17% and OS of 71 ± 16%. Two patients developed late second malignancies; one associated with germline p53 mutation.
Conclusion
The results confirm that carboplatin has similar activity to cisplatin in otherwise similar regimens. Five-year survival data are comparable to those reported in other recent studies, including high-dose chemotherapy studies. Of note, is the marked activity in CPCA and gross totally resected ependymoma
doi:10.1002/cncr.24362
PMCID: PMC4307774  PMID: 19484793
Brain tumor; infants; chemotherapy; carboplatin
3.  Efficacy of bevacizumab plus irinotecan in children with recurrent low-grade gliomas—a Pediatric Brain Tumor Consortium study 
Neuro-Oncology  2013;16(2):310-317.
Background
A phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in children with recurrent low-grade glioma to measure sustained response and/or stable disease lasting ≥6 months and progression-free survival.
Methods
Thirty-five evaluable patients received 2 doses (10 mg/kg each) of single-agent BVZ intravenously 2 weeks apart and then BVZ + CPT-11 every 2 weeks until progressive disease, unacceptable toxicity, or a maximum of 2 years of therapy. Correlative studies included neuroimaging and expression of tumor angiogenic markers (vascular endothelial growth factor [VEGF], VEGF receptor 2, hypoxia-inducible factor 2α, and carbonic anhydrase 9).
Results
Thirty-five evaluable patients (median age 8.4 y [range, 0.6–17.6]) received a median of 12 courses of BVZ + CPT-11 (range, 2–26). Twenty-nine of 35 patients (83%) received treatment for at least 6 months. Eight patients progressed on treatment at a median time of 5.4 months (range, 1–17.8). Six patients (17.7%) still in follow-up have had stable disease without receiving additional treatment for a median of 40.1 months (range, 30.6–49.3) from initiating therapy. The 6-month and 2-year progression-free survivals were 85.4% (SE ± 5.96%) and 47.8% (SE ± 9.27%), respectively. The commonest toxicities related to BVZ included grades 1–2 hypertension in 24, grades 1–2 fatigue in 23, grades 1–2 epistaxis in 18, and grades 1–4 proteinuria in 15. The median volume of enhancement decreased significantly between baseline and day 15 (P < .0001) and over the duration of treatment (P < .037).
Conclusion
The combination of BVZ + CPT-11 appears to produce sustained disease control in some children with recurrent low-grade gliomas.
doi:10.1093/neuonc/not154
PMCID: PMC3895377  PMID: 24311632
bevacizumab; CPT-11; children; gliomas; recurrent
4.  Bevacizumab (BVZ)-Associated Toxicities in Children with Recurrent Central Nervous System (CNS) Tumors treated with BVZ and Irinotecan (CPT-11): a Pediatric Brain Tumor Consortium Study (PBTC-022) 
Cancer  2013;119(23):10.1002/cncr.28343.
Background
The incidence and spectrum of acute toxicities related to the use of bevacizumab (BVZ)-containing regimens in children are largely unknown. We report on the adverse events in a recently completed large phase II trial of BVZ plus irinotecan (CPT-11) in children with recurrent central nervous system (CNS) tumors.
Methods
Pediatric Brain Tumor Consortium (PBTC) trial-022 evaluated the efficacy and toxicity of BVZ (10 mg/kg administered intravenously) as a single agent for 2 doses given two weeks apart and then combined with CPT-11 every 2 weeks (1 course = 4 weeks) in children with recurrent CNS tumors. Children were treated until they experienced progressive disease, unacceptable toxicity or completed up to a maximum of two years of therapy. Toxicities were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Patients who received at least one dose of BVZ were included for toxicity assessment.
Results
Between October 2006 and June 2010, 92 patients evaluable for toxicity were enrolled and received 687 treatment courses. The most common toxicities attributable to BVZ included grade I–III hypertension (38% of patients), grade I–III fatigue (30%), grade I–II epistaxis (24%) and grade I–IV proteinuria (22%). Twenty-two patients (24%) stopped therapy due to toxicity.
Conclusions
The combination of BVZ and CPT-11 was fairly well-tolerated, and most severe BVZ-related toxicities were rare, self-limiting and manageable.
doi:10.1002/cncr.28343
PMCID: PMC3835419  PMID: 24104527
pediatric; bevacizumab; toxicity; central nervous system (CNS) tumors; clinical trials
5.  A MOLECULAR BIOLOGY AND PHASE II TRIAL OF LAPATINIB IN CHILDREN WITH REFRACTORY CNS MALIGNANCIES: A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY 
Journal of neuro-oncology  2013;114(2):173-179.
Background
High expression of ERBB2 has been reported in medulloblastoma and ependymoma; EGFR is amplified and over-expressed in brainstem glioma suggesting these proteins as potential therapeutic targets. We conducted a molecular biology (MB) and phase II study to estimate inhibition of tumor ERBB signaling and sustained responses by lapatinib in children with recurrent CNS malignancies.
Patients and Methods
In the MB study, patients with recurrent medulloblastoma, ependymoma, and high-grade glioma (HGG) undergoing resection were stratified and randomized to pre-resection treatment with lapatinib 900 mg/m2/dose bid for 7–14 days or no treatment. Western blot analysis of ERBB expression and pathway activity in fresh tumor obtained at surgery estimated ERBB receptor signaling inhibition in vivo. Drug concentration was simultaneously assessed in tumor and plasma. In the phase II study, patients, stratified by histology, received lapatinib continuously, to assess sustained response.
Results
Eight patients, on the MB trial (4 medulloblastomas, 4 ependymomas), received a median of 2 courses (range: 1–6+). No intratumoral target inhibition by lapatinib was noted in any patient. Tumor-to-plasma ratios of lapatinib were 10–20%. In the 34 patients (14 MB, 10 HGG, 10 ependymoma) in the phase II study, lapatinib was well-tolerated at 900 mg/m2/dose bid. The median number of courses in the phase II trial was 2 (range 1–12). Seven patients (3 medulloblastoma, 4 ependymoma) remained on therapy for at least 4 courses range (4–26).
Conclusion
Lapatinib was well-tolerated in children with recurrent or CNS malignancies, but did not inhibit target in tumor and had little single agent activity.
doi:10.1007/s11060-013-1166-7
PMCID: PMC4246636  PMID: 23836190
Lapatinib; medulloblastoma; high-grade glioma; phase II trial
6.  Phase-I study of vismodegib in children with recurrent or refractory medulloblastoma: a Pediatric Brain Tumor Consortium (PBTC) study 
Purpose
To investigate the safety, dose-limiting toxicities, and pharmacokinetics of the smoothened inhibitor vismodegib in children with refractory or relapsed medulloblastoma.
Patients and Methods
Initially, vismodegib was administered daily at 85 mg/m2 and escalated to 170 mg/m2. The study was then revised to investigate a flat-dosing schedule of 150 mg for patients with small body surface area (BSA, 0.67–1.32 m2) or 300 mg for those who were larger (BSA, 1.33–2.20 m2). Pharmacokinetics were performed during the first course of therapy, and the right knees of all patients were imaged to monitor bone toxicity. Immunohistochemical analysis was done to identify patients with SHH-subtype medulloblastoma.
Results
Thirteen eligible patients were enrolled on the initial study: 6 received 85 mg/m2 vismodegib, and 7 received 170 mg/m2. Twenty eligible patients were enrolled on the flat-dosing part of the study: 10 at each dosage level. Three dose-limiting toxicities were observed, but no drug-related bone toxicity was documented. The median (range) vismodegib penetration in the cerebrospinal fluid (CSF) was 0.53 (0.26–0.78), when expressed as a ratio of the concentration of vismodegib in the CSF to that of the unbound drug in plasma. Antitumor activity was seen in 1 of 3 patients with SHH-subtype disease whose tumors were evaluable and in none of the patients in the other subgroups.
Conclusions
Vismodegib was well tolerated in children with recurrent or refractory medulloblastoma; only 2 dose-limiting toxicities were observed with flat dosing. The recommended Phase-II study dose is 150 mg or 300 mg, depending on the patient’s BSA.
doi:10.1158/1078-0432.CCR-13-1425
PMCID: PMC3856244  PMID: 24077351
7.  The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma 
Nature genetics  2014;46(5):444-450.
Pediatric high-grade glioma (HGG) is a devastating disease with a two-year survival of less than 20%1. We analyzed 127 pediatric HGGs, including diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGGs (NBS-HGGs) by whole genome, whole exome, and/or transcriptome sequencing. We identified recurrent somatic mutations in ACVR1 exclusively in DIPG (32%), in addition to the previously reported frequent somatic mutations in histone H3, TP53 and ATRX in both DIPG and NBS-HGGs2-5. Structural variants generating fusion genes were found in 47% of DIPGs and NBS-HGGs, with recurrent fusions involving the neurotrophin receptor genes NTRK1, 2, or 3 in 40% of NBS-HGGs in infants. Mutations targeting receptor tyrosine kinase/RAS/PI3K signaling, histone modification or chromatin remodeling, and cell cycle regulation were found in 68%, 73% and 59%, respectively, of pediatric HGGs, including DIPGs and NBS-HGGs. This comprehensive analysis provides insights into the unique and shared pathways driving pediatric HGG within and outside the brainstem.
doi:10.1038/ng.2938
PMCID: PMC4056452  PMID: 24705251
8.  Children's Oncology Group's 2013 Blueprint for Research: Central Nervous System Tumors 
Pediatric blood & cancer  2012;60(6):1022-1026.
In the US, approximately 2,500 children are diagnosed annually with brain tumors. Their survival ranges from >90% to <10%. For children with medulloblastoma, the most common malignant brain tumor, 5-year survival ranges from >80% (standard-risk) to 60% (high-risk). For those with high-grade gliomas (HGGs) including diffuse intrinsic pontine gliomas, 5-year survival remains <10%. Sixty-five percent patients with ependymoma are cured after surgery and radiation therapy depending on the degree of resection and histopathology of the tumor. Phase II trials for brain tumors will investigate agents that act on cMET, PDGFRA, or EZH2 in HGG, DIPG, or medulloblastoma, respectively. Phase III trials will explore risk-based therapy stratification guided by molecular and clinical traits of children with medulloblastoma or ependymoma.
doi:10.1002/pbc.24427
PMCID: PMC4184243  PMID: 23255213
ependymoma; high-grade glioma and diffuse intrinsic pontine glioma; medulloblastoma
9.  Phase II study of cilengitide in the treatment of refractory or relapsed high-grade gliomas in children: A report from the Children's Oncology Group 
Neuro-Oncology  2013;15(10):1438-1444.
Background
Cilengitide, an αv integrin antagonist, has demonstrated activity in recurrent adult glioblastoma (GBM). The Children's Oncology Group ACNS0621 study thus evaluated whether cilengitide is active as a single agent in the treatment of children with refractory high-grade glioma (HGG). Secondary objectives were to investigate the pharmacokinetics and pharmacogenomics of cilengitide in this population.
Methods
Cilengitide (1800 mg/m2/dose intravenous) was administered twice weekly until evidence of disease progression or unacceptable toxicity. Thirty patients (age range, 1.1–20.3 years) were enrolled, of whom 24 were evaluable for the primary response end point.
Results
Toxicity was infrequent and mild, with the exception of one episode of grade 2 pain possibly related to cilengitide. Two intratumoral hemorrhages were reported, but only one (grade 2) was deemed to be possibly related to cilengitide and was in the context of disease progression. One patient with GBM received cilengitide for 20 months and remains alive with continuous stable disease. There were no other responders, with median time to tumor progression of 28 days (range, 11–114 days). Twenty-one of the 24 evaluable patients died, with a median time from enrollment to death of 172 days (range, 28–325 days). The 3 patients alive at the time of this report had a follow-up time of 37, 223, and 1068 days, respectively.
Conclusions
We conclude that cilengitide is not effective as a single agent for refractory pediatric HGG. However, further study evaluating combination therapy with cilengitide is warranted before a role for cilengitide in the treatment of pediatric HGG can be excluded.
doi:10.1093/neuonc/not058
PMCID: PMC3779033  PMID: 24014381
childhood; cilengitide; high-grade glioma
10.  Processing Speed, Attention, and Working Memory After Treatment for Medulloblastoma: An International, Prospective, and Longitudinal Study 
Journal of Clinical Oncology  2013;31(28):3494-3500.
Purpose
The current study prospectively examined processing speed (PS), broad attention (BA), and working memory (WM) ability of patients diagnosed with medulloblastoma over a 5-year period.
Patients and Methods
The study included 126 patients, ages 3 to 21 years at diagnosis, enrolled onto a collaborative protocol for medulloblastoma. Patients were treated with postsurgical risk-adapted craniospinal irradiation (n = 36 high risk [HR]; n = 90 average risk) followed by four cycles of high-dose chemotherapy with stem-cell support. Patients completed 509 neuropsychological evaluations using the Woodcock-Johnson Tests of Cognitive Abilities Third Edition (median of three observations per patient).
Results
Linear mixed effects models revealed that younger age at diagnosis, HR classification, and higher baseline scores were significantly associated with poorer outcomes in PS. Patients treated as HR and those with higher baseline scores are estimated to have less favorable outcomes in WM and BA over time. Parent education and marital status were significantly associated with BA and WM baseline scores but not change over time.
Conclusion
Of the three key domains, PS was estimated to have the lowest scores at 5 years after diagnosis. Identifying cognitive domains most vulnerable to decline should guide researchers who are aiming to develop efficacious cognitive intervention and rehabilitation programs, thereby improving the quality of survivorship for the pediatric medulloblastoma population.
doi:10.1200/JCO.2012.47.4775
PMCID: PMC3782147  PMID: 23980078
11.  Clinico-radiologic characteristics of long-term survivors of diffuse intrinsic pontine glioma 
Journal of neuro-oncology  2013;114(3):339-344.
Diffuse intrinsic pontine glioma (DIPG) is the deadliest central nervous system tumor in children. The survival of affected children has remained poor despite treatment with radiation therapy (RT) with or without chemotherapy. We reviewed the medical records of all surviving patients with DIPG treated at our institution between October 1, 1992 and May 31, 2011. Blinded central radiologic review of the magnetic resonance imaging at diagnosis of all surviving patients and 15 controls with DIPG was performed. All surviving patients underwent neurocognitive assessment during follow-up. Five (2.6%) of 191 patients treated during the study period were surviving at a median of 9.3 years from their diagnosis (range, 5.3 to 13.2 years). Two patients were younger than 3 years, one lacked signs of pontine cranial nerve involvement, and three had longer duration of symptoms at diagnosis. One patient had a radiologically atypical tumor and one had a tumor originating in the medulla. All five patients received RT. Chemotherapy was variable among these patients. Neurocognitive assessments were obtained after a median interval of 7.1 years. Three of four patients who underwent a detailed evaluation showed cognitive function in the borderline or mental retardation range. Two patients experienced disease progression at 8.8 and 13 years after diagnosis. A minority of children with DIPG experienced long-term survival with currently available therapies. These patients remained at high risk for tumor progression even after long follow-ups. Four of our long-term survivors had clinical and radiologic characteristics at diagnosis associated with improved outcome.
doi:10.1007/s11060-013-1189-0
PMCID: PMC3755743  PMID: 23813229
diffuse; glioma; long-term; neurocognitive; pontine; survivors
12.  C11orf95-RELA fusions drive oncogenic NF-κB signaling in ependymoma 
Nature  2014;506(7489):451-455.
The nuclear factor-κB (NF-κB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-κB signaling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-κB activity in cancer. Here, we show that more than two thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-κB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95-RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95-RELA fusion proteins translocated spontaneously to the nucleus to activate NF-κB target genes, and rapidly transformed neural stem cells—the cell of origin of ependymoma—to form these tumours in mice. Our data identify the first highly recurrent genetic alteration of RELA in human cancer, and the C11orf95-RELA fusion protein as a potential therapeutic target in supratentorial ependymoma.
doi:10.1038/nature13109
PMCID: PMC4050669  PMID: 24553141
13.  The Effects of Propofol on Cerebral Perfusion MRI in Children 
Neuroradiology  2013;55(8):1049-1056.
Introduction
The effects of anesthesia are infrequently considered when interpreting pediatric perfusion MRI. The objectives of this study were to test for measurable differences in MR measures of cerebral blood flow (CBF) and cerebral blood volume (CBV) between non-sedated and propofol-sedated children, and to identify influential factors.
Methods
Supratentorial cortical CBF and CBV measured by dynamic susceptibility contrast perfusion MRI in 37 children (1.8–18 years) treated for infratentorial brain tumors receiving propofol (IV, n=19) or no sedation (NS, n=18) were compared between groups and correlated with age, hematocrit, end-tidal CO2 (ETCO2), dose, weight, and history of radiation therapy (RT). The model most predictive of CBF and CBV was identified by multiple linear regression.
Results
Anterior cerebral artery (ACA) and middle cerebral artery (MCA) territory CBF were significantly lower, and MCA territory CBV greater (p=0.03), in IV than NS patients (p=0.01, 0.04). The usual trend of decreasing CBF with age was reversed with propofol in ACA and MCA territories (r=0.53, r=0.47; p<0.05). ACA and MCA CBF (r=0.59, 0.49; p<0.05) and CBV in ACA, MCA and posterior cerebral artery (PCA) territories (r=0.73, 0.80, 0.52; p<0.05) increased with weight in propofol-sedated children, with no significant additional influence from age, ETCO2, hematocrit, or RT.
Conclusion
In propofol-sedated children, usual age-related decreases in CBF were reversed, and increases in CBF and CBV were weight-dependent, not previously described. Weight-dependent increases in propofol clearance may diminish suppression of CBF and CBV. Prospective study is required to establish anesthetic-specific models of CBF and CBV in children.
doi:10.1007/s00234-013-1187-0
PMCID: PMC3720819  PMID: 23673874
magnetic resonance imaging; propofol; perfusion; pediatrics; brain
14.  The Role of Inherited TPMT and COMT Genetic Variation in Cisplatin-induced Ototoxicity in Children with Cancer 
Clinical pharmacology and therapeutics  2013;94(2):10.1038/clpt.2013.121.
Ototoxicity is a debilitating side effect of platinating agents with substantial inter-patient variability. We sought to evaluate the association of TPMT and COMT genetic variations with cisplatin-related hearing damage in the context of frontline pediatric cancer treatment protocols. In 213 children from St. Jude Medulloblastoma-96 and -03 protocols, hearing loss was related to younger age (P=0.013) and craniospinal irradiation (P=0.001), but did not differ by TPMT or COMT variants. Results were similar in an independent cohort of 41 children from solid tumor frontline protocols. Functional hearing loss or hair cell damage was not different in TPMT knockout vs. wildtype mice following cisplatin treatment, and neither TPMT nor COMT variant was associated with cisplatin cytotoxicity in lymphoblastoid cell lines. In conclusion, our results indicated that TPMT or COMT genetic variation was not related to cisplatin ototoxicity in children with cancer and did not influence cisplatin-induced hearing damage in laboratory models.
doi:10.1038/clpt.2013.121
PMCID: PMC3883563  PMID: 23820299
pharmacogenetics; cisplatin; ototoxicity; TPMT; and pediatric cancer
15.  DIFFERENCES IN BRAINSTEM FIBER TRACT RESPONSE TO RADIATION:A LONGITUDINAL DTI STUDY 
Purpose
To determine if radiation-induced changes in white matter tracts are uniform across the brainstem.
Methods and Materials
We analyzed serial diffusion tensor imaging (DTI) data, acquired before radiation therapy and over 48-72 months of follow-up, from 42 pediatric patients (age 6-20 years) with medulloblastoma. FSL software (FMRIB, Oxford, UK) was used to calculate fractional anisotropy (FA) and axial, radial, and mean diffusivities. For a consistent identification of volumes of interest, the parametric maps of each patient were transformed to a standard brain space (MNI152), on which we identified volumes of interest including corticospinal tract (CST), medial lemniscus (ML), transverse pontine fiber (TPF), and middle cerebellar peduncle (MCP) at the level of pons. Temporal changes of DTI parameters in VOIs were compared using a linear mixed effect model.
Results
Radiation-induced white matter injury was marked by a decline in FA after treatment. The decline was often accompanied by decreased axial diffusivity and/or increased radial diffusivity. This implied axonal damage and demyelination. We observed that the magnitude of the changes was not always uniform across substructures of the brainstem. Specifically, the changes in DTI parameters for TPF were more pronounced than in other regions (p<0.001 for FA) despite similarities in the distribution of dose. We did not find a significant difference among CST, ML, and MCP in these patients (p>0.093 for all parameters).
Conclusions
Changes in structural integrity of white matter tracts, assessed by DTI, were not uniform across the brainstem after radiation therapy. These results support a role for tract-based assessment in radiation treatment planning and determination of brainstem tolerance.
doi:10.1016/j.ijrobp.2013.01.028
PMCID: PMC3646932  PMID: 23474114
diffusion tensor imaging (DTI); brainstem; medulloblastoma; white matter injury
16.  Phase I Trial, Pharmacokinetics, and Pharmacodynamics of Vandetanib and Dasatinib in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma 
Purpose
Testing of promising drug combinations is crucial in the treatment of diffuse intrinsic pontine glioma (DIPG). Since the VEGF and PDGF pathways are critical in gliomas, we evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of vandetanib, a VEGFR-2 inhibitor, combined with dasatinib, a potent PDGFR inhibitor, during and after radiotherapy in children with newly diagnosed DIPG.
Experimental Design
Dasatinib was started concurrently with radiotherapy. Vandetanib was started 8 days later. We tested increasing doses of vandetanib (65 and 85 mg/m2 once daily) and dasatinib (65 and 85 mg/m2 twice daily). Dose-limiting toxicities were evaluated during the first six weeks of therapy. Plasma pharmacokinetics was obtained on days 8 and 42±3 in all patients and concomitantly with cerebrospinal fluid (CSF) when possible. Inhibition of targets of dasatinib in peripheral blood mononuclear cells (PBMCs) was evaluated.
Results
Twenty-five patients were treated. Treatment was well tolerated. The median duration of treatment was 184 days. Diarrhea was the most significant toxicity. Three patients experienced substantial myelosuppression. The steady-state plasma pharmacokinetics of vandetanib was comparable to previous studies. Although the plasma exposure to dasatinib decreased from days 8 to 42, it remained similar to adult studies. CSF to plasma exposure of vandetanib and dasatinib were approximately 2% in 2 patients. Phosphorylated 70S6K decreased during therapy in PBMCs.
Conclusions
The MTD of vandetanib and dasatinib in combination was 65 mg/m2 for each drug. Other studies are underway to test dasatinib and other PDGFR inhibitors alone or in combination for this deadly cancer.
doi:10.1158/1078-0432.CCR-13-0306
PMCID: PMC3685168  PMID: 23536435
children; dasatinib; glioma; pontine; vandetanib
17.  CNS-PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity 
Acta Neuropathologica  2014;128(2):291-303.
Amplification of the C19MC oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In this study, we sought to evaluate the diagnostic specificity of C19MC and LIN28, and the clinical and biological spectra of C19MC amplified and/or LIN28+ CNS-PNETs. We interrogated 450 pediatric brain tumors using FISH and IHC analyses and demonstrate that C19MC alteration is restricted to a sub-group of CNS-PNETs with high LIN28 expression; however, LIN28 immunopositivity was not exclusive to CNS-PNETs but was also detected in a proportion of other malignant pediatric brain tumors including rhabdoid brain tumors and malignant gliomas. C19MC amplified/LIN28+ group 1 CNS-PNETs arose predominantly in children <4 years old; a majority arose in the cerebrum but 24 % (13/54) of tumors had extra-cerebral origins. Notably, group 1 CNS-PNETs encompassed several histologic classes including embryonal tumor with abundant neuropil and true rosettes (ETANTR), medulloepithelioma, ependymoblastoma and CNS-PNETs with variable differentiation. Strikingly, gene expression and methylation profiling analyses revealed a common molecular signature enriched for primitive neural features, high LIN28/LIN28B and DNMT3B expression for all group 1 CNS-PNETs regardless of location or tumor histology. Our collective findings suggest that current known histologic categories of CNS-PNETs which include ETANTRs, medulloepitheliomas, ependymoblastomas in various CNS locations, comprise a common molecular and diagnostic entity and identify inhibitors of the LIN28/let7/PI3K/mTOR axis and DNMT3B as promising therapeutics for this distinct histogenetic entity.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-014-1291-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s00401-014-1291-1
PMCID: PMC4159569  PMID: 24839957
18.  Sleep Disturbances in Adult Survivors of Childhood Brain Tumors 
Purpose
The aims of this study are to compare self-reported sleep quality in adult survivors of childhood brain tumors and a population-based comparison group, to identify treatment-related factors associated with sleep disturbances, and to identify the impact of post-treatment obesity and depression on sleep scores in adult survivors of childhood brain tumors.
Methods
Randomly selected adult survivors of childhood brain tumors (n = 78) and age, sex and zip code matched population-group members (n = 78) completed the Pittsburgh Sleep Quality Index and the Brief Symptom Inventory. Sleep quality and the effect of demographic, treatment, and post-treatment characteristics were evaluated with linear and logistic regression analyses.
Results
Brain tumor survivors were 2.7 (95% CI: 1.1, 6.0) times more likely than the comparison group to take greater than 30 minutes to fall asleep. Females in both groups reported worse sleep quality and impaired daytime functioning. Among survivors, post-treatment obesity was associated with daytime dysfunction.
Conclusions
These results agree with previous studies associating sleep, sex and obesity and identified longer sleep latency as being a problem among childhood brain tumor survivors. Further study identifying factors contributing to sleep latency, and its impact on quality of life among adult survivors of childhood brain tumors is needed.
doi:10.1007/s11136-012-0208-5
PMCID: PMC3442150  PMID: 22669471
Sleep quality; sleep latency; adult survivors; childhood brain tumors
19.  Restricted Access to the Environment and Quality of Life in Adult Survivors of Childhood Brain Tumors 
Journal of neuro-oncology  2012;111(2):195-203.
Background:
Survivors of pediatric brain tumors are at-risk for late effects which may affect mobility within and access to the physical environment. This study examined the prevalence of and risk factors for restricted environmental access in survivors of childhood brain tumors and investigated the associations between reduced environmental access, health-related quality of life (HRQOL), and survivors’ social functioning.
Methods:
In-home evaluations were completed for 78 brain tumor survivors and 78 population-based controls matched on age, sex, and zip-code. Chi-square tests and multivariable logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI) for poor environmental access and reduced HRQOL.
Results:
The median age of survivors was 22 years at the time of study. Compared to controls, survivors were more likely to report avoiding most dimensions of their physical environment, including a single flight of stairs (p<0.001), uneven surfaces (p<0.001), traveling alone (p=0.01), and traveling to unfamiliar places (p=0.001). Overall, survivors were 4.8 times more likely to report poor environmental access (95% CI, 2.0-11.5, p<0.001). In survivors, poor environmental access was associated with reduced physical function (OR=3.6, 95% CI, 1.0-12.8, p=0.04), general health (OR=6.0, 95% CI, 1.8-20.6, p=0.002), and social functioning (OR=4.3, 95% CI, 1.1-17.3, p=0.03).
Conclusions:
Adult survivors of pediatric brain tumors were more likely to avoid their physical environment than matched controls. Restricted environmental access was associated with reduced HRQOL and diminished social functioning. Interventions directed at improving physical mobility may have significant impact on survivor quality of life.
doi:10.1007/s11060-012-1001-6
PMCID: PMC3995451  PMID: 23143294
CNS malignancies; survivorship; quality of life; environmental access
20.  Complete clinical regression of a BRAF V600E-mutant pediatric glioblastoma multiforme after BRAF inhibitor therapy 
BMC Cancer  2014;14:258.
Background
Standard therapies for high grade glioma have failed to substantially improve survival and are associated with significant morbidity. At relapse, high grade gliomas, such as glioblastoma multiforme, are refractory to therapy and universally fatal. BRAF V600E-mutations have been described in a modest 6% to 7% of primary central nervous system (CNS) tumors, but with increased prevalence in the pediatric population and in certain brain tumor subtypes. The use of BRAF inhibitors have transformed melanoma therapy however their use in brain tumors remains unproven.
Case presentation
We describe the pediatric case of a now 12 year old Caucasian male who originally presented at age 9 with a right fronto-parietal glioblastoma multiforme that recurred 2 ½ years from diagnosis. Molecular analysis of the primary tumor revealed a BRAF V600E mutation and the patient was placed on the BRAF inhibitor vemurafenib. A complete response was observed after 4 months of therapy and remains sustained at 6 months.
Conclusion
This is the first report of a complete response of relapsed glioblastoma multiforme to targeted BRAF inhibitor therapy. While not a predominant mutation in glioblastoma multiforme, the increased prevalence of BRAF V600 mutations in pediatric CNS tumors and certain subtypes marks a population to whom this therapy could be applied. Response to this therapy suggests that BRAF inhibitors can affect primary CNS lesions when a documented and targetable mutation is present.
doi:10.1186/1471-2407-14-258
PMCID: PMC3996187  PMID: 24725538
High-grade glioma; Glioblastoma multiforme; BRAF mutations; V600E; Pediatric brain tumor; BRAF inhibitors
21.  IMAGING CHANGES IN VERY YOUNG CHILDREN WITH BRAIN TUMORS TREATED WITH PROTON THERAPY AND CHEMOTHERAPY 
PT promises to reduce side effects in children with brain tumors by sparing normal tissue when compared to 3-dimensional conformal or intensity-modulated radiation therapy. Information is lacking about the combined effects of PT and chemotherapy in young children. We describe imaging changes in eight very young children with localized brain tumors who received PT after chemotherapy. Mostly transient signal abnormalities and enhancement in brain parenchyma were observed by serial MR imaging that were consistent with radiation-induced effects on normal appearing tissue. Correlation with PT planning data revealed that the areas of imaging abnormality were located within or adjacent to the volume that received the highest radiation dose. Radiologists should be aware of these findings in children who receive PT after chemotherapy. In this report we describe the time course of these PT-related imaging findings and correlate with treatment and clinical outcomes.
doi:10.3174/ajnr.A3219
PMCID: PMC3573244  PMID: 22821924
22.  Survival and secondary tumors in children with medulloblastoma receiving radiotherapy and adjuvant chemotherapy: results of Children's Oncology Group trial A9961 
Neuro-Oncology  2012;15(1):97-103.
The purpose of the trial was to determine the survival and incidence of secondary tumors in children with medulloblastoma receiving radiotherapy plus chemotherapy. Three hundred seventy-nine eligible patients with nondisseminated medulloblastoma between the ages of 3 and 21 years were treated with 2340 cGy of craniospinal and 5580 cGy of posterior fossa irradiation. Patients were randomized between postradiation cisplatin and vincristine plus either CCNU or cyclophosphamide. Survival, pattern of relapse, and occurrence of secondary tumors were assessed. Five- and 10-year event-free survivals were 81 ± 2% and 75.8 ± 2.3%; overall survivals were 87 ± 1.8% and 81.3 ± 2.1%. Event-free survival was not impacted by chemotherapeutic regimen, sex, race, age at diagnosis, or gender. Seven patients had disease relapse beyond 5 years after diagnosis; relapse was local in 4 patients, local plus supratentorial in 2, and supratentorial alone in 1. Fifteen patients experienced secondary tumors as a first event at a median time of 5.8 years after diagnosis (11 >5 y postdiagnosis). All non-CNS solid secondary tumors (4) occurred in regions that had received radiation. Of the 6 high-grade gliomas, 5 occurred >5 years postdiagnosis. The estimated cumulative 10-year incidence rate of secondary malignancies was 4.2% (1.9%–6.5%). Few patients with medulloblastoma will relapse ≥5 years postdiagnosis; relapse will occur predominantly at the primary tumor site. Patients are at risk for development of secondary tumors, many of which are malignant gliomas. This may become an increasing issue as more children survive.
doi:10.1093/neuonc/nos267
PMCID: PMC3534419  PMID: 23099653
chemotherapy; medulloblastoma; radiotherapy; secondary tumors
23.  Phase II Trial of Erlotinib during and after Radiotherapy in Children with Newly Diagnosed High-Grade Gliomas 
Background: Epidermal growth factor receptor is overexpressed in most pediatric high-grade gliomas (HGG). Since erlotinib had shown activity in adults with HGG, we conducted a phase II trial of erlotinib and local radiotherapy (RT) in children with newly diagnosed HGG.
Methods: Following maximum surgical resection, patients between 3 and 21 years with non-metastatic HGG received local RT at 59.4 Gy (54 Gy for spinal tumors and those with ≥70% brain involvement). Erlotinib started on day 1 of RT (120 mg/m2 per day) and continued for 2 years unless there was tumor progression or intolerable toxicities. The 2-year progression-free survival (PFS) was estimated for patients with intracranial anaplastic astrocytoma (AA) and glioblastoma (GBM).
Results: Median age at diagnosis for 41 patients with intracranial tumors (21 with GBM and 20 with AA) was 10.9 years (range, 3.3–19 years). The 2-year PFS for patients with AA and GBM was 15 ± 7 and 19 ± 8%, respectively. Only five patients remained alive without tumor progression. Twenty-six patients had at least one grade 3 or 4 toxicity irrespective of association with erlotinib; only four required dose modifications. The main toxicities were gastrointestinal (n = 11), dermatologic (n = 5), and metabolic (n = 4). One patient with gliomatosis cerebri who required prolonged corticosteroids died of septic shock associated with pancreatitis.
Conclusion: Although therapy with erlotinib was mostly well-tolerated, it did not change the poor outcome of our patients. Our results showed that erlotinib is not a promising medication in the treatment of children with intracranial AA and GBM.
doi:10.3389/fonc.2014.00067
PMCID: PMC3978340  PMID: 24744992
erlotinib; epidermal growth factor receptor; high-grade glioma; pediatric; phase II; radiotherapy
24.  Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas 
Nature genetics  2013;45(6):602-612.
The commonest pediatric brain tumors are low-grade gliomas (LGGs). We utilized whole genome sequencing to discover multiple novel genetic alterations involving BRAF, RAF1, FGFR1, MYB, MYBL1 and genes with histone-related functions, including H3F3A and ATRX, in 39 LGGs and low-grade glioneuronal tumors (LGGNTs). Only a single non-silent somatic alteration was detected in 24/39 (62%) tumors. Intragenic duplications of the FGFR1 tyrosine kinase domain (TKD) and rearrangements of MYB were recurrent and mutually exclusive in 53% of grade II diffuse LGGs. Transplantation of Trp53-null neonatal astrocytes containing TKD-duplicated FGFR1 into brains of nude mice generated high-grade astrocytomas with short latency and 100% penetrance. TKD-duplicated FGFR1 induced FGFR1 autophosphorylation and upregulation of the MAPK/ERK and PI3K pathways, which could be blocked by specific inhibitors. Focusing on the therapeutically challenging diffuse LGGs, our study of 151 tumors has discovered genetic alterations and potential therapeutic targets across the entire range of pediatric LGGs/LGGNTs.
doi:10.1038/ng.2611
PMCID: PMC3727232  PMID: 23583981
25.  Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group 
Acta Neuropathologica  2013;127(2):189-201.
Medulloblastoma is curable in approximately 70 % of patients. Over the past decade, progress in improving survival using conventional therapies has stalled, resulting in reduced quality of life due to treatment-related side effects, which are a major concern in survivors. The vast amount of genomic and molecular data generated over the last 5–10 years encourages optimism that improved risk stratification and new molecular targets will improve outcomes. It is now clear that medulloblastoma is not a single-disease entity, but instead consists of at least four distinct molecular subgroups: WNT/Wingless, Sonic Hedgehog, Group 3, and Group 4. The Medulloblastoma Down Under 2013 meeting, which convened at Bunker Bay, Australia, brought together 50 leading clinicians and scientists. The 2-day agenda included focused sessions on pathology and molecular stratification, genomics and mouse models, high-throughput drug screening, and clinical trial design. The meeting established a global action plan to translate novel biologic insights and drug targeting into treatment regimens to improve outcomes. A consensus was reached in several key areas, with the most important being that a novel classification scheme for medulloblastoma based on the four molecular subgroups, as well as histopathologic features, should be presented for consideration in the upcoming fifth edition of the World Health Organization’s classification of tumours of the central nervous system. Three other notable areas of agreement were as follows: (1) to establish a central repository of annotated mouse models that are readily accessible and freely available to the international research community; (2) to institute common eligibility criteria between the Children’s Oncology Group and the International Society of Paediatric Oncology Europe and initiate joint or parallel clinical trials; (3) to share preliminary high-throughput screening data across discovery labs to hasten the development of novel therapeutics. Medulloblastoma Down Under 2013 was an effective forum for meaningful discussion, which resulted in enhancing international collaborative clinical and translational research of this rare disease. This template could be applied to other fields to devise global action plans addressing all aspects of a disease, from improved disease classification, treatment stratification, and drug targeting to superior treatment regimens to be assessed in cooperative international clinical trials.
doi:10.1007/s00401-013-1213-7
PMCID: PMC3895219  PMID: 24264598

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