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1.  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
2.  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
3.  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
4.  Parent-Reported Social Outcomes After Treatment for Pediatric Embryonal Tumors: A Prospective Longitudinal Study 
Journal of Clinical Oncology  2012;30(33):4134-4140.
Purpose
To examine longitudinal parent-reported social outcomes for children treated for pediatric embryonal brain tumors.
Patients and Methods
Patients (N = 220) were enrolled onto a multisite clinical treatment protocol. Parents completed the Child Behavior Checklist/6-18 at the time of their child's diagnosis and yearly thereafter. A generalized linear mixed effects model regression approach was used to examine longitudinal changes in parent ratings of social competence, social problems, and withdrawn/depressed behaviors with demographic and treatment factors as covariates.
Results
During the 5-year period following diagnosis and treatment, few patients were reported to have clinically elevated scores on measures of social functioning. Mean scores differed significantly from population norms, yet remained within the average range. Several factors associated with unfavorable patterns of change in social functioning were identified. Patients with high-risk treatment status had a greater increase in parent-reported social problems (P = .001) and withdrawn/depressed behaviors (P = .01) over time compared with average-risk patients. Patients with posterior fossa syndrome had greater parent-reported social problems over time (P = .03). Female patients showed higher withdrawn/depressed scores over time compared with male patients (P < .001). Patient intelligence, age at diagnosis, and parent education level also contributed to parent report of social functioning.
Conclusion
Results of this study largely suggest positive social adjustment several years after diagnosis and treatment of a pediatric embryonal tumor. However, several factors, including treatment risk status and posterior fossa syndrome, may be important precursors of long-term social outcomes. Future research is needed to elucidate the trajectory of social functioning as these patients transition into adulthood.
doi:10.1200/JCO.2011.40.6702
PMCID: PMC3494836  PMID: 23071220
5.  Lack of efficacy of bevacizumab + irinotecan in cases of pediatric recurrent ependymoma—a Pediatric Brain Tumor Consortium study 
Neuro-Oncology  2012;14(11):1404-1412.
A phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in cases of pediatric recurrent ependymoma (EPN) to estimate sustained objective response rate and progression-free survival (PFS). Eligible patients received 2 doses of single-agent BVZ intravenously (10 mg/kg) 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 diffusion-weighted and T1 dynamic contrast enhanced permeability imaging and tumor immunohistochemistry for vascular endothelial growth factor (VEGF)–A and –B, hypoxia inducible factor–2α, VEGF receptor (R)–2, and carbonic anhydrase (CA)–9. Thirteen evaluable patients received a median of 3 courses (range, 2–12) of BVZ + CPT-11. No sustained response was observed in any patient. Median time to progression in 10 patients was 2.2 months (range, 1.9–6.3). Two patients had stable disease for 10 months and 12 months, respectively. Six-month PFS was 25.7% (SE = 11.1%). Grades I–III toxicities related to BVZ treatment included fatigue in 4 patients, systemic hypertension in 2, epistaxis in 1, headache in 1, and avascular necrosis of bone in 1. Although there was a decrease in the mean diffusion ratio following 2 doses of BVZ, it did not correlate with PFS. BVZ + CPT-11 was well tolerated but had minimal efficacy in cases of recurrent EPN.
doi:10.1093/neuonc/nos213
PMCID: PMC3480265  PMID: 23019233
bevacizumab; CPT-11; efficacy; ependymoma; recurrent
6.  Fanconi Anemia and Biallelic BRCA2 Mutation Diagnosed in a Young Child with an Embryonal CNS Tumor 
Pediatric blood & cancer  2009;53(6):1140-1142.
Medulloblastoma, the most common pediatric malignant brain tumor often arises sporadically; however, in a subgroup of patients, there exist familial conditions such as Fanconi anemia with biallelic BRCA2 mutation that predispose patients to developing medulloblastoma. Biallelic inactivation of BRCA2 in Fanconi anemia has been previously described in only 11 patients with medulloblastoma in the literature to date. Here we report two siblings diagnosed with central nervous system embryonal tumors at an early age in association with biallelic BRCA2 inactivation, including the first reported case of a spinal cord primitive neuroectodermal tumor (PNET) in a BRCA2/FANCD1 kindred.
doi:10.1002/pbc.22139
PMCID: PMC3782106  PMID: 19530235
Brain tumor; Primitive Neuroectodermal tumor; Medulloblastoma; Fanconi Anemia; BRCA2 gene mutation
7.  Isochromosome 17q, MYC Amplification and Large Cell/Anaplastic Phenotype in a Case of Medullomyoblastoma with Extracranial Metastases 
Pediatric blood & cancer  2011;59(3):561-564.
Medullomyoblastoma is a rare variant of medulloblastoma, a member of the family of central nervous system (CNS) embryonal tumors. The outcome of standard therapy for CNS embryonal tumors is often unpredictable in the setting of medullomyoblastoma. Here, we present the clinical course and treatment of an almost 4-year-old girl with medullomyoblastoma that was characterized by MYC amplification, isochromosome 17q and large cell/anaplastic histopathology.
doi:10.1002/pbc.24002
PMCID: PMC3392450  PMID: 22147345
medullomyoblastoma; MYC amplification; isochromosome 17q; central nervous system embryonal tumors
8.  White matter integrity is associated with cognitive processing in patients treated for a posterior fossa brain tumor 
Neuro-Oncology  2012;14(9):1185-1193.
Children treated for posterior fossa tumors experience reduced cognitive processing speed and, after imaging, show damage to white matter (WM) tracts in the brain. This study explores relationships between white matter microstructure, assessed by fractional anisotropy (FA), and speed of cognitive processing using tract-based spatial statistics (TBSS). At 36 months after treatment with radiotherapy and chemotherapy, 40 patients completed an MRI examination and neuropsychological evaluation. Patients were matched with healthy control subjects based on age, sex, and race. Individual FA values were extracted from examinations for all voxels identified as having significant association between processing speed and FA using TBSS. The regions were labeled anatomically, and fiber tracts were grouped into larger fiber bundle categories based on their anatomical and functional associations. Analyses were performed between mean skeletal FA values in each of the fiber bundles and each of the cognitive processing scores controlling for age. Children 3 years after treatment for posterior fossa brain tumors demonstrate significantly lower processing speed associated with decreased FA, compared with their healthy peers. Commissural fibers in the corpus callosum were negatively affected by disease and therapy with detrimental consequence on patients' cognitive processing. Diffusion tensor imaging of the white matter tracts in the brain is relevant to determining potential mechanisms underlying clinically meaningful change in cognitive performance. Neuroprotective strategies are needed to preserve critical functions.
doi:10.1093/neuonc/nos154
PMCID: PMC3424215  PMID: 22898373
diffusion tensor imaging; FA; medulloblastoma; processing speed; TBSS
9.  Pilot Study of Systemic and Intrathecal Mafosfamide followed by Conformal Radiation for Infants with Intracranial Central Nervous System Tumors: A Pediatric Brain Tumor Consortium Study (PBTC-001) 
Journal of neuro-oncology  2012;109(3):565-571.
Purpose
A pilot study to investigate the feasibility of the addition of intrathecal (IT) mafosfamide to a regimen of concomitant multi-agent systemic chemotherapy followed by conformal radiation therapy (RT) for children <3 years with newly diagnosed embryonal CNS tumors was performed.
Patients and Methods
Ninety-three newly diagnosed infants and children (<3 years) with embryonal CNS tumors were enrolled. Twenty weeks of systemic multi-agent chemotherapy commenced within 35 days of surgery. Patients without CSF flow obstruction (n=71) received IT mafosfamide (14 mg) with chemotherapy. Localized (M0) patients with SD or better subsequently received RT followed by 20 additional weeks of chemotherapy. Second look surgery was encouraged prior to RT if there was an incomplete surgical resection at diagnosis.
Results
71 evaluable patients with normal CSF flow received IT Mafosfamide with systemic chemotherapy; patients with M+ disease were removed from protocol therapy at 20 weeks and those with PD at the time of progression. One and 5-year progression free survival (PFS) and overall survival (OS) for the cohort of 71 evaluable patients were 52±6.5% and 33±13%, and 67±6.2% and 51±11%, respectively. The 1-year Progression Free Survival (PFS) for M0 patients with medulloblastoma (MB, n=20), supratentorial primitive neuroectodermal tumor (PNET, n=9), and atypical teratoid rhabdoid tumor (ATRT, n=12) was 80±7%, 67±15% and 27±13% and 5-year PFS was 65± 19%, 37±29%, and 0±0%, respectively.
Conclusion
The addition of IT mafosfamide to systemic chemotherapy in infants with embryonal CNS tumors was feasible. The PFS for M0 patients appears comparable to or better than most prior historical comparisons and was excellent for those receiving conformal radiotherapy.
doi:10.1007/s11060-012-0929-x
PMCID: PMC3529096  PMID: 22790443
mafosfamide; intrathecal; infant brain tumor; embryonal CNS tumor; conformal radiation therapy
10.  NECROSIS AFTER CRANIOSPINAL IRRADIATION: RESULTS FROM A PROSPECTIVE SERIES OF CHILDREN WITH CNS EMBRYONAL TUMORS 
PURPOSE
Necrosis of the CNS is a known complication of craniospinal irradiation (CSI) in children with medulloblastoma and similar tumors. We reviewed the incidence of necrosis in our prospective treatment series.
METHODS AND MATERIALS
Between 1996 and 2009, 236 children with medulloblastoma (n = 185) or other CNS embryonal tumors (n=51) received post-operative CSI followed by dose-intense cyclophosphamide, vincristine, and cisplatin. Average-risk cases (n = 148) received 23.4 Gy CSI, 36 Gy posterior fossa, and 55.8 Gy primary; after 2003, the treatment was 23.4 Gy CSI and 55.8 Gy primary. All high-risk cases (n = 88) received 36–39.6 Gy CSI and 55.8 Gy primary. The primary site clinical target volume margin was 2-cm (pre-2003) or 1-cm (post-2003). With competing risk of death by any cause, we determined the cumulative incidence of necrosis.
RESULTS
With a median follow-up of 52 months (range, 4–163 months), eight cases of necrosis were documented. One death was attributed. The median time to the imaging evidence was 4.8 months and symptoms 6.0 months. The cumulative incidence at 5 years was 3.7% ± 1.3% (n = 236) for the entire cohort, and 4.4% ± 1.5% (n = 196) for infratentorial tumor location. The mean relative volume of infratentorial brain receiving high-dose irradiation was significantly greater for patients with necrosis compared to those without: ≥ 50 Gy (92.12% ± 4.58 vs. 72.89% ± 1.96, p = 0.0337), ≥ 52 Gy (88.95% ± 5.50 vs. 69.16% ± 1.97, p = 0.0275), and ≥ 54 Gy (82.28% ± 7.06 vs. 63.37% ± 1.96, p = 0.0488).
CONCLUSIONS
Necrosis in patients with CNS embryonal tumors is uncommon. When competing risks are considered, the incidence is 3.7% at 5 years. The volume of infratentorial brain receiving greater than 50, 52, and 54 Gy is predictive for necrosis.
doi:10.1016/j.ijrobp.2012.01.061
PMCID: PMC3529413  PMID: 22768993
necrosis; medulloblastoma; craniospinal irradiation; pediatrics
11.  Distinct disease-risk groups in pediatric supratentorial and posterior fossa ependymomas 
Acta neuropathologica  2012;124(2):247-257.
Purpose
No reliable classification exists for the therapeutic stratification of children with ependymoma, such that disease-risk might be identified and patients treated to ensure a combination of maximal cure rates and minimal adverse therapeutic effects. This study examined associations between clinicopathological and cytogenetic variables and outcome in a trial cohort of children with ependymoma, with the aim of defining a practical scheme for grading this heterogeneous tumor.
Methods
Intracranial ependymomas (n=146) from children treated on the RT1 trial at St. Jude Children’s Research Hospital were evaluated for the status of multiple pathological features. Interphase FISH (iFISH) defined the status of chromosomes 1q, 6q (LATS1), and 9p21 (CDKN2A). Data relating to these variables were compared with survival data in order to model disease-risk groups.
Results
Extent of surgical resection was a significant determinant of outcome. Tumor cell density and mitotic count were associated with outcome among children with posterior fossa ependymomas (n=119). Among pathologic factors, only brain invasion was associated with outcome in children with supratentorial ependymomas (n=27). Gain of 1q was independently associated with outcome and in combination with clinicopathological variables defined a three-tier system of disease-risk for posterior fossa tumors.
Conclusions
Among children developing posterior fossa ependymomas treated with maximal surgical resection and conformal radiotherapy, key clinicopathological variables and chromosome 1q status can be used to define tiers of disease-risk. In contrast, risk factors for pediatric supratentorial tumors are limited to subtotal resection and brain invasion.
doi:10.1007/s00401-012-0981-9
PMCID: PMC3554251  PMID: 22526017
12.  Diagnostic Utility and Correlation of Tumor Markers in the Serum and Cerebrospinal Fluid of Children with Intracranial Germ Cell Tumors 
Purpose
In order to predict whether tumor markers assist in the histopathologic diagnosis of germ cell tumors (GCTs), we analyzed the correlation of beta human chorionic gonadotropin (bHCG) and alpha-fetoprotein (AFP) in serum and cerebrospinal fluid (CSF) samples at baseline and subsequent follow-up examinations.
Method
A retrospective study of patients diagnosed with intracranial GCTs between July 1985 and February 2011 at our institution was conducted to review clinical, surgical, radiological, laboratory and histopathologic data.
Results
Of 67 patients eligible for the study, 42 had germinomas and 25 non germinomatous GCTs. At baseline, serum and CSF AFP agreed in 97.9% of patients (Cohen’s Kappa 0.93). Baseline bHCG samples agreed in only 72.5% of patients (Cohen’s Kappa 0.46). In most cases, values were higher in serum for AFP and in CSF for bHCG. ROC curves estimated from logistic regression model indicated that CSF and serum samples had almost equal diagnostic utility, and the DeLong test showed that the difference in area under curves was not statistically significant. During follow-up (185 paired CSF and serum values from 43 patients), 90.3% of AFP values correlated between CSF and serum (Cohen’s Kappa 0.22, showing fair agreement). For bHCG, 96.2% of values agreed in serum and CSF (Cohen’s Kappa 0.61).
Conclusions
In some patients, intracranial GCTs can be diagnosed based solely upon positive serum AFP values. In addition, marker values from serum only may be sufficient to predict tumor relapse at interval follow-up examinations.
doi:10.1007/s00381-012-1762-4
PMCID: PMC3526807  PMID: 22547227
germ cell tumors; tumor markers; beta human chorionic gonadotropin; alpha-fetoprotein; correlation of markers; diagnostic utility
13.  Treatment Outcomes in Black and White Children With Cancer: Results From the SEER Database and St Jude Children's Research Hospital, 1992 Through 2007 
Journal of Clinical Oncology  2012;30(16):2005-2012.
Purpose
Treatment outcome for black patients with cancer has been significantly worse than for their white counterparts. We determined whether recent improved treatment had narrowed the gap in outcome between black and white pediatric patients.
Patients and Methods
In a parallel comparison, we analyzed survival by disease category between black and white patients with childhood cancer registered in one of the 17 cancer registries of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program or treated at St Jude Children's Research Hospital, which provides comprehensive treatment to all patients regardless of their ability to pay, from 1992 to 2000 and from 2001 to 2007.
Results
Analysis of the SEER data indicated that in both study periods, black patients had significantly poorer rates of survival than did white patients, with the exception of a few types of cancer. Despite significantly improved treatment outcomes for patients who were treated from 2001 to 2007, the racial difference in survival has actually widened for acute myeloid leukemia and neuroblastoma. By contrast, in the cohorts treated at St Jude Children's Research Hospital, there were no significant differences in survival between black and white patients in either study period, regardless of the cancer type. Importantly, the outcome of treatment for acute lymphoblastic leukemia, acute myeloid leukemia, and retinoblastoma has improved in parallel for both races during the most recent study period.
Conclusion
With equal access to comprehensive treatment, black and white children with cancer can achieve the same high cure rates.
doi:10.1200/JCO.2011.40.8617
PMCID: PMC3383176  PMID: 22547602
14.  Hemodynamic Responses to Visual Stimulation in Children with Sickle Cell Anemia 
Brain imaging and behavior  2011;5(4):295-306.
Blood oxygenation level- dependent (BOLD) and cerebral blood flow (CBF)-based functional magnetic resonance imaging (fMRI) were used to measure primary visual cortex responses to photic stimulation in 23 children (12.4 ± 0.7 years old) with sickle cell anemia (SCA) and 21 clinical controls (11 ± 1.0 years old). The objectives were to investigate the effect of SCA on detection of brain activation with fMRI and to explore the relationship between fMRI responses and global cognitive function. The BOLD responses were diminished in children with SCA. Clinical indicators of disease severity were greatest in patients without detectable visual cortex activation, but blood hemoglobin concentration and resting CBF were not predictive of BOLD signal amplitude in the SCA patients. Unexpectedly, the BOLD signal amplitude was positively associated (rs≥0.8, p≤0.05) with Wechsler Abbreviated Scale of Intelligence scores, suggesting that fMRI may help clarify medical, hemodynamic, and neural factors that mediate adverse effects of SCA on neurocognitive function.
doi:10.1007/s11682-011-9133-4
PMCID: PMC3620037  PMID: 21881848
sickle cell anemia; functional magnetic resonance imaging; brain activation; cognitive function; blood oxygenation level- dependent; cerebral blood flow
15.  Integrative genomic analyses identify LIN28 and OLIG2 as markers of survival and metastatic potential in childhood central nervous system primitive neuro-ectodermal brain tumours 
The lancet oncology  2012;13(8):838-848.
Background
Childhood Central Nervous System Primitive Neuro-Ectodermal brain Tumours (CNS-PNETs) are highly aggressive brain tumours for which molecular features and best therapeutic strategy remains unknown. We interrogated a large cohort of these rare tumours in order to identify molecular markers that will enhance clinical management of CNS-PNET.
Methods
Transcriptional and copy number profiles from primary hemispheric CNS-PNETs were examined using clustering, gene and pathways enrichment analyses to discover tumour sub-groups and group-specific molecular markers. Immuno-histochemical and/or gene expression analyses were used to validate and examine the clinical significance of novel sub-group markers in 123 primary CNS-PNETs.
Findings
Three molecular sub-groups of CNS-PNETs distinguished by primitive neural (Group 1), oligo-neural (Group 2) and mesenchymal lineage (Group 3) gene expression signature were identified. Tumour sub-groups exhibited differential expression of cell lineage markers, LIN28 and OLIG2, and correlated with distinct demographics, survival and metastatic incidence. Group 1 tumours affected primarily younger females; male: female ratios were respectively 0.61 (median age 2.9 years; 95% CI: 2.4–5.2; p≤ 0.005), 1.25 (median age 7.9 years; 95% CI: 6–9.7) and 1.63 (median age 5.9 years; 95% CI: 4.9–7.8) for group 1, 2 and 3 patients. Overall outcome was poorest in group 1 patients which had a median survival of 0.8 years (95% CI: 0.47–1.2; p=0.019) as compared to 1.8 years (95% CI: 1.4–2.3) and 4.3 years; (95% CI: 0.82–7.8) respectively for group 2 and 3 patients. Group 3 tumours had the highest incidence of metastases at diagnosis; M0: M+ ratio were respectively 0.9 and 3.9 for group 3, versus group 1 and 2 tumours combined (p=0.037).
Interpretation
LIN28 and OLIG2 represent highly promising, novel diagnostic and prognostic molecular markers for CNS PNET that warrants further evaluation in prospective clinical trials.
doi:10.1016/S1470-2045(12)70257-7
PMCID: PMC3615440  PMID: 22691720
16.  BRAIN TUMOR THERAPY-INDUCED CHANGES IN NORMAL-APPEARING BRAINSTEM MEASURED WITH LONGITUDINAL DIFFUSION TENSOR IMAGING 
Purpose
To characterize therapy-induced changes in normal-appearing brainstems of childhood brain tumor patients by serial diffusion tensor imaging (DTI).
Methods and Materials
We analyzed 109 DTI studies from 20 brain tumor patients, aged 4-23 years, with normal-appearing brainstems included in the treatment fields. Those with medulloblastomas, supratentorial primitive neuroectodermal tumors and atypical teratoid rhabdoid tumors (n=10) received postoperative craniospinal irradiation (23.4-39.6 Gy) and a cumulative dose of 55.8 Gy to the primary site, followed by 4 cycles of high-dose chemotherapy. Patients with high-grade gliomas (n=10) received erlotinib during and after irradiation (54-59.4 Gy). Parametric maps of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were computed and spatially registered to three-dimensional radiation dose data. Volumes of interest included corticospinal tracts, medial lemnisci, and the pons. Serving as an age-related benchmark for comparison, 37 DTI studies from 20 healthy volunteers, aged 6-25 years, were included in the analysis.
Results
The median DTI follow-up was 3.5 years (range, 1.6-5.0 years). The median mean dose to the pons was 56 Gy (range, 7-59 Gy). Three patterns were seen in longitudinal FA and ADC changes: (1) a stable or normal developing time trend, (2) initial deviation from normal with subsequent recovery, and (3) progressive deviation without evidence of complete recovery. The maximal decline in FA often occurred 1.5 to 3.5 years after the start of radiation therapy. A full recovery time trend could be observed within 4 years. Patients with incomplete recovery often had a larger decline in FA within the first year. Radiation dose alone did not predict long-term recovery patterns.
Conclusions
Variation existed among individual patients after therapy in longitudinal evolution of brainstem white matter injury and recovery. Early response in brainstem anisotropy may serve as an indicator of the recovery time trend over 5 years following radiation therapy.
doi:10.1016/j.ijrobp.2011.03.057
PMCID: PMC3181276  PMID: 21664060
Diffusion tensor imaging; Brainstem; Radiation therapy
17.  SEQUENCING OF LOCAL THERAPY AFFECTS THE PATTERN OF TREATMENT FAILURE AND SURVIVAL IN CHILDREN WITH ATYPICAL TERATOID RHABDOID TUMORS OF THE CENTRAL NERVOUS SYSTEM 
Purpose
To assess the pattern of treatment failure associated with current therapeutic paradigms for childhood atypical teratoid rhabdoid tumors (AT/RT).
Methods and Materials
Pediatric patients with AT/RT of the central nervous system treated at our institution between 1987 and 2007 were retrospectively evaluated. Overall survival (OS), progression-free survival, and cumulative incidence of local failure were correlated with age, sex, tumor location, extent of disease, and extent of surgical resection. Radiotherapy (RT) sequencing, chemotherapy, dose, timing, and volume administered after resection were also evaluated.
Results
Thirty-one patients at a median age of 2.3 years at diagnosis (range, 0.45–16.87 years) were enrolled into protocols that included risk- and age-stratified RT. Craniospinal irradiation with focal tumor bed boost (median dose, 54 Gy) was administered to 18 patients. Gross total resection was achieved in 16. Ten patients presented with metastases at diagnosis. RT was delayed more than 3 months in 20 patients and between 1 and 3 months in 4; 7 patients received immediate postoperative irradiation preceding high-dose alkylator-based chemotherapy. At a median follow-up of 48 months, the cumulative incidence of local treatment failure was 37.5% ± 9%; progression-free survival was 33.2% ± 10%; and OS was 53.5% ± 10%. Children receiving delayed RT (≥1 month postoperatively) were more likely to experience local failure (hazard ratio [HR] 1.23, p = 0.007); the development of distant metastases before RT increased the risk of progression (HR 3.49, p = 0.006); and any evidence of disease progression before RT decreased OS (HR 20.78, p = 0.004). Disease progression occurred in 52% (11/21) of children with initially localized tumors who underwent gross total resection, and the progression rate increased proportionally with increasing delay from surgery to RT.
Conclusions
Delayed RT is associated with a higher rate of local and metastatic disease progression in children with AT/RT. Current treatment regimens for pediatric patients with AT/RT are distinctly age stratified; novel protocols investigating RT volumes and sequencing are needed.
doi:10.1016/j.ijrobp.2011.02.059
PMCID: PMC3530399  PMID: 21601374
Atypical teratoid rhabdoid tumor; Local failure; Radiation therapy; Therapeutic sequencing; Pattern of failure
18.  Novel mutations target distinct subgroups of medulloblastoma 
Nature  2012;488(7409):43-48.
Summary
Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. To identify mutations that drive medulloblastoma we sequenced the entire genomes of 37 tumours and matched normal blood. One hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma: several target distinct components of the epigenetic machinery in different disease subgroups, e.g., regulators of H3K27 and H3K4 trimethylation in subgroup-3 and 4 (e.g., KDM6A and ZMYM3), and CTNNB1-associated chromatin remodellers in WNT-subgroup tumours (e.g., SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours, identified genes that maintain this cell lineage (DDX3X) as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumourigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.
doi:10.1038/nature11213
PMCID: PMC3412905  PMID: 22722829
19.  Dysembryoplastic Neuroepithelial Tumors and Cognitive Outcome: cure at a price? 
Cancer  2010;116(23):5461-5469.
Background
Dysembryoplastic neuroepithelial tumors (DNETs) are benign glioneuronal tumors that occur in children. These tumors are characterized by seizures, lack of neurologic deficits, and a seemingly benign course after resection.
Methods
We conducted a retrospective review of data relating to 11 children diagnosed with DNET between January 1988 and December 2007 at St. Jude Children's Research Hospital. This report documents the clinical features, neurocognitive function, and treatment outcomes in our institutional series.
Results
Our patient cohort included 8 boys and 3 girls (median age at diagnosis, 10 years); all patients presented with seizures: 4 complex partial, 3 generalized tonic clonic, 2 absence, 1 partial simple, and 1 not classified. Of the 11 patients, 1 died of cardiac fibrosis, and tumors recurred or progressed in 4 (36%). Seizure control was achieved in all patients but 1. Of the 9 patients who completed neuropsychologic testing, only 3 (23%) functioned at or above the expected level of same-age peers.
Conclusion
The high recurrence and progression rates of DNETs and the high rate of abnormal neurocognitive test results in this study highlight the need for regular follow-up and appropriate academic counseling of children with these tumors.
doi:10.1002/cncr.25528
PMCID: PMC3556450  PMID: 20672357
Dysembryoplastic neuroepithelial tumors (DNETs); pediatric; recurrence; neuropsychologic outcome
20.  Physical performance limitations among adult survivors of childhood brain tumors 
Cancer  2010;116(12):3034-3044.
Background
Young adult survivors of childhood brain tumors (BT) may have late-effects that compromise physical performance and everyday task participation.
Objective
To evaluate muscle strength, fitness, physical performance, and task participation among adult survivors of childhood BT.
Design/Method
In-home evaluations and interviews were conducted for 156 participants (54% male). Results on measures of muscle strength, fitness, physical performance, and participation were compared between survivors and population-group members with chi-squared statistics and two-sample t-tests. Associations between late effects and physical performance, and physical performance and participation, were evaluated in regression models.
Results
BT survivors were a median age of 22 (18–58), and 14.7 (6.5–45.9) years from diagnosis. Survivors had lower estimates of grip strength (Female: 24.7±9.2 vs. 31.5±5.8, Male: 39.0±12.2 vs. 53.0±10.1 kilograms), knee extension strength (Female: 246.6±95.5 vs. 331.5±5.8, Male: 304.7±116.4 vs. 466.6±92.1 Newtons) and peak oxygen uptake (Female: 25.1±8.8 vs. 31.3±5.1, Male: 24.6±9.5 vs. 33.2±3.4 milliliters/kilogram/minute) than population-group members. Physical performance was lower among survivors and associated with not living independently (OR=5.0, 95% CI=2.0–12.2) and not attending college (OR=2.3, 95% CI 1.2–4.4).
Conclusion
Muscle strength and fitness values among BT survivors are similar to those among persons 60+ years, and are associated with physical performance limitations. Physical performance limitations are associated with poor outcomes in home and school environments. These data indicate an opportunity for interventions targeted at improving long-term physical function in this survivor population.
doi:10.1002/cncr.25051
PMCID: PMC3554250  PMID: 20564409
physical performance; disability; brain tumor; cancer survivor; pediatric
21.  How parents cope with their child’s diagnosis and treatment of an embryonal tumor: Results of a prospective and longitudinal study 
Journal of neuro-oncology  2011;105(2):253-259.
Purpose
The current study reports longitudinal coping responses among parents of children diagnosed with an embryonal brain tumor.
Patients and Methods
Patients (n=219) were enrolled on a treatment protocol for a pediatric embryonal brain tumor. Their parents (n=251) completed the Coping Response Inventory at time of their child’s diagnosis and yearly thereafter, resulting in 502 observations. Outcomes were examined with patient and parent age at diagnosis, patient risk, parent gender and education as covariates.
Results
At the time of diagnosis, the highest observed coping method was seeking guidance with well above average scores (T=61.6). Over time, younger parents were found to seek guidance at a significantly higher rate than older parents (p=.016) and the use of acceptance resignation and seeking alternative results by all parents significantly increased (p=.011 and p<.0001 respectively). The use of emotional discharge was also observed above average at time of diagnosis (T= 55.4) with younger fathers being more likely to exhibit emotional discharge than older fathers (p=.002). Differences in coping according to age of the patient and parent education level are also discussed.
Discussion
Results show a high need for guidance, and above average emotional discharge, especially among younger parents. It is imperative for the healthcare team to lead with accurate information so that these parents may make informed decisions about the care of their child. This need remains high years after diagnosis. Therefore it is critical to continue a consistent level of effective communication and support, even following treatment.
doi:10.1007/s11060-011-0574-9
PMCID: PMC3537225  PMID: 21499990
pediatric; brain tumor; medulloblastoma; psychological sequelae
22.  Regional white matter anisotropy and reading ability in patients treated for embryonal tumors 
Brain imaging and behavior  2010;4(2):132-140.
Purpose
Children treated with cranial irradiation for brain tumors have reduced white matter volume and deficits in reading ability. This study prospectively examined the relationship between reading and white matter integrity within this patient group.
Methods
Patients (n=54) were treated with post-surgical radiation followed by 4 cycles of high-dose chemotherapy with stem cell support. At 12 months post-diagnosis, all patients completed a neuropsychology evaluation and a diffusion tensor imaging (DTI) exam. White matter integrity was determined through measures of fractional anisotropy (FA).
Results
Significant group differences in FA were found between above average readers and below average readers within the left and right posterior limb of the internal capsule, and right knee of the internal capsule with a trend within the left temporal-occipital region.
Conclusions
The integrity of the white matter in these regions may affect communication among visual, auditory, and language cortical areas that are engaged during reading.
doi:10.1007/s11682-010-9092-1
PMCID: PMC3521043  PMID: 20502994
diffusion tensor imaging; reading; pediatric brain tumors
23.  Genome-Wide Analyses Identify Recurrent Amplifications of Receptor Tyrosine Kinases and Cell-Cycle Regulatory Genes in Diffuse Intrinsic Pontine Glioma 
Journal of Clinical Oncology  2011;29(30):3999-4006.
Purpose
Long-term survival for children with diffuse intrinsic pontine glioma (DIPG) is less than 10%, and new therapeutic targets are urgently required. We evaluated a large cohort of DIPGs to identify recurrent genomic abnormalities and gene expression signatures underlying DIPG.
Patients and Methods
Single-nucleotide polymorphism arrays were used to compare the frequencies of genomic copy number abnormalities in 43 DIPGs and eight low-grade brainstem gliomas with data from adult and pediatric (non-DIPG) glioblastomas, and expression profiles were evaluated using gene expression arrays for 27 DIPGs, six low-grade brainstem gliomas, and 66 nonbrainstem low-grade gliomas.
Results
Frequencies of specific large-scale and focal imbalances varied significantly between DIPGs and nonbrainstem pediatric glioblastomas. Focal amplifications of genes within the receptor tyrosine kinase–Ras–phosphoinositide 3-kinase signaling pathway were found in 47% of DIPGs, the most common of which involved PDGFRA and MET. Thirty percent of DIPGs contained focal amplifications of cell-cycle regulatory genes controlling retinoblastoma protein (RB) phosphorylation, and 21% had concurrent amplification of genes from both pathways. Some tumors showed heterogeneity in amplification patterns. DIPGs showed distinct gene expression signatures related to developmental processes compared with nonbrainstem pediatric high-grade gliomas, whereas expression signatures of low-grade brainstem and nonbrainstem gliomas were similar.
Conclusion
DIPGs comprise a molecularly related but distinct subgroup of pediatric gliomas. Genomic studies suggest that targeted inhibition of receptor tyrosine kinases and RB regulatory proteins may be useful therapies for DIPG.
doi:10.1200/JCO.2011.35.5677
PMCID: PMC3209696  PMID: 21931021
24.  An integrated in vitro and in vivo high throughput screen identifies treatment leads for ependymoma 
Cancer cell  2011;20(3):384-399.
Summary
Using a mouse model of ependymoma—a chemoresistant brain tumor—we combined multi-cell high-throughput screening (HTS), kinome-wide binding assays, and in vivo efficacy studies, to identify potential treatments with predicted toxicity against neural stem cells (NSC). We identified kinases within the insulin signaling pathway and centrosome cycle as regulators of ependymoma cell proliferation, and their corresponding inhibitors as potential therapies. FDA approved drugs not currently used to treat ependymoma were also identified that posses selective toxicity against ependymoma cells relative to normal NSCs both in vitro and in vivo e.g., 5-fluoruracil. Our comprehensive approach advances understanding of the biology and treatment of ependymoma including the discovery of several treatment leads for immediate clinical translation.
doi:10.1016/j.ccr.2011.08.013
PMCID: PMC3172881  PMID: 21907928
25.  Phase I Trial of MK-0752 in Children With Refractory CNS Malignancies: A Pediatric Brain Tumor Consortium Study 
Journal of Clinical Oncology  2011;29(26):3529-3534.
Purpose
To estimate the maximum-tolerated dose (MTD), describe dose-limiting toxicities (DLTs), and characterize pharmacokinetic properties of MK-0752, a gamma secretase inhibitor, in children with refractory or recurrent CNS malignancies.
Patients and Methods
MK-0752 was administered once daily for 3 consecutive days of every 7 days at escalating dosages starting at 200 mg/m2. The modified continual reassessment method was used to estimate the MTD. A course was 28 days in duration. Pharmacokinetic analysis was performed during the first course. Expression of NOTCH and hairy enhancer of split (HES) proteins was assessed in peripheral-blood mononuclear cells (PBMCs) before and following treatment with MK-0752.
Results
Twenty-three eligible patients were enrolled: 10 males (median age, 8.1 years; range, 2.6 to 17.7 years) with diagnoses of brainstem glioma (n = 6), ependymoma (n = 8), medulloblastoma/primitive neuroectodermal tumor (n = 4), glioblastoma multiforme (n = 2), atypical teratoid/rhabdoid tumor (n = 1), malignant glioma (n = 1), and choroid plexus carcinoma, (n = 1). Seventeen patients were fully evaluable for toxicity. No DLTs occurred in the three patients enrolled at 200 mg/m2/dose. At 260 mg/m2/dose, DLTs occurred in two of six patients, both of whom experienced grade 3 ALT and AST. There were no grade 4 toxicities; non–dose-limiting grade 3 toxicities included hypokalemia and lymphopenia. Population pharmacokinetic values (% coefficient of variation) for MK-0752 were apparent oral clearance, 0.444 (38%) L/h/m2; apparent volume of distribution, 7.36 (24%) L/m2; and ka, 0.358 (99%) hr−1.
Conclusion
MK-0752 is well-tolerated in children with recurrent CNS malignancies. The recommended phase II dose using the 3 days on followed by 4 days off schedule is 260 mg/m2/dose once daily.
doi:10.1200/JCO.2011.35.7806
PMCID: PMC3179253  PMID: 21825264

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