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1.  Investigating the Relationship between COMT Polymorphisms and Working Memory Performance among Childhood Brain Tumor Survivors 
Pediatric blood & cancer  2013;61(1):40-45.
Background
Survivors of childhood brain tumors are at increased risk for neurocognitive impairments, including deficits in abilities supported by frontal brain regions. Catechol-O-methyltransferase (COMT) metabolizes dopamine in the prefrontal cortex, with the Met allele resulting in greater dopamine availability and better performance on frontally-mediated tasks compared to the Val allele. Given the importance of identifying resiliency factors against the emergence of cognitive late effects, the current study examined the relationship between COMT genotype and working memory performance among childhood brain tumor survivors.
Procedure
Children treated for a brain tumor with conformal radiation therapy (N=50; mean age at irradiation=7.41 ± 3.41; mean age at assessment=13.18 ± 2.88) were administered two computerized measures of working memory (self-ordered search verbal and object tasks). Buccal (cheek) swabs were used to provide tissue from which DNA was extracted.
Results
Findings revealed an association between COMT genotype and performance on the self-ordered verbal (p=0.03) but not object task (p=0.33). Better performance was found for the Met/Val group compared to either Met/Met or Val/Val.
Conclusions
COMT may indicate a potential resiliency factor against neurocognitive effects of cancer and its treatment; however, there is a need for replication with larger samples of childhood brain tumor survivors.
doi:10.1002/pbc.24649
PMCID: PMC4101980  PMID: 23956130
cancer; late effects; genetics; dopamine; prefrontal cortex; working memory
2.  Headaches in Children With Craniopharyngioma 
Journal of child neurology  2012;28(12):1622-1625.
Craniopharyngioma frequently involves intracranial pain-sensitive structures. We retrospectively studied prevalence, associated risk factors, and outcome of headaches in children with craniopharyngioma. Fisher exact test and multivariate analysis were used to study association of study variables. Of the 51 craniopharyngioma patients treated at our institution from January 1994 to December 2005, 40 (78%) reported headaches (35 [68%] before tumor diagnosis). Migraine headaches were diagnosed in 32 (63%) and tension-type headaches in 11 patients (22%). The median follow-up period was 2.7 years. At the last follow-up, 38 (75%) were headache free. Presence of hydrocephalus, distortion of circle of Willis, and large tumor volume were associated with headache, and the last 2 variables were also associated with more severe and frequent headaches. Radiation treatment and insertion of Ommaya reservoir were associated with reduced headache frequency. In conclusion, headaches are common in patients with craniopharyngioma and are likely related to tumor size and volume. In most patients, headaches improve with successful tumor treatment.
doi:10.1177/0883073812464817
PMCID: PMC4264380  PMID: 23143722
brain tumor; craniopharyngioma; headache; migraine; hydrocephalus
3.  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
4.  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
5.  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
6.  Computerized Assessment of Cognitive Late Effects among Adolescent Brain Tumor Survivors 
Journal of neuro-oncology  2013;113(2):333-340.
BACKGROUND
Advantages of computerized assessment of neuropsychological functions include improved standardization and increased reliability of response time variables. ImPACT (Immediate Post-Concussion Assessment and Cognitive Testing) is a computerized battery developed for monitoring recovery following mild brain injuries that assesses attention, memory and processing speed. Despite evidence that core areas of deficit among cancer survivors are those assessed by ImPACT, it has not previously been used with this population.
PROCEDURE
Twenty four childhood brain tumor (BT) survivors treated with conformal radiation therapy (mean age= 15.7±1.6; mean age at irradiation= 9.8±2.5), twenty solid tumor (ST) survivors treated without CNS-directed therapy (mean age= 16.2±1.8) and twenty healthy siblings (mean age= 15.1± 1.6 years) were administered an age modified version of ImPACT. Additional computerized measures of working memory and recognition memory were administered.
RESULTS
Univariate ANOVAs revealed group differences (p< .05) on measures of recognition memory, spatial working memory, processing speed and reaction time, with BT survivors performing significantly worse than ST survivors and siblings. Pearson correlation coefficients revealed significant associations between ImPACT memory tasks and computerized forced choice recognition tasks (rs= .30-.33, p< .05). Multiple surgical resections, hydrocephalus and CSF shunt placement most consistently predicted worse ImPACT performance using linear mixed models (p< .05).
CONCLUSIONS
The ImPACT test battery demonstrated sensitivity to cognitive late effects experienced by some BT survivors with clinical predictors of performance consistent with the pediatric oncology literature. Correlations with measures of similar constructs provide evidence for convergent validity. Findings offer initial support for the utility of ImPACT for monitoring of cognitive late effects.
doi:10.1007/s11060-013-1123-5
PMCID: PMC3679205  PMID: 23525951
pediatric; cancer; ImPACT
7.  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
8.  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
9.  Clinical controversies: Pediatric tumors 
Seminars in radiation oncology  2013;23(2):97-108.
Despite the claim in the published literature, the introduction of proton therapy for children is not analogous to the evolution of conformal photon irradiation relying on the understanding of the impact of altered dose distributions. The differences in radiobiological effect when comparing photons to protons means that we are comparing a known entity to an unknown entity: the dose-volume histogram for proton therapy might mean something substantially different than the dose-volume histogram for photon therapy. The multifaceted difference between the two modalities supports the argument for careful evaluation, follow-up and clinical trials with adverse event monitoring when using proton therapy in children. We review the current data on the outcome of proton therapy in a range of pediatric tumours and compare them to the often excellent results of photon therapy in the setting of multidisciplinary management of childhood cancer.
It is hoped that the apparent dosimetric advantage of proton therapy over photons will lead to improved indications for therapy, disease control and functional outcomes. While physical dose distribution is of clear importance, the multimodality management of children by an expert pediatric oncology team and the availability of ancillary measures that improve the quality of treatment delivery may be more important than the actual beam. In addition, current estimates of the benefit of proton therapy over photon therapy based on toxicity reduction will only be realized when survivorship has been achieved. Once substantive data proton therapy data become available, it will be necessary to demonstrate benefit in clinically relevant outcome measures in comparison to best existing photon outcome data. Such an effort will require improved funding and appreciation for late effects research. Only real clinical outcome data combined with better understanding of the radiobiological differences between protons and photons will help us to further reduce side effects in children and exploit the full curative potential of this relatively new modality.
doi:10.1016/j.semradonc.2012.11.008
PMCID: PMC3595134  PMID: 23473686
10.  Evaluation of children with craniopharyngioma using carbon-11 methionine PET prior to proton therapy 
Neuro-Oncology  2013;15(4):506-510.
Background
Fluorine-18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET) is limited in its evaluation of brain tumors due to the high basal activity of the cerebral cortex and white matter. Carbon-11 methionine (11C MET) has little uptake under normal conditions. We prospectively investigated the uptake of 18F FDG and 11C MET PET in patients with craniopharyngioma prior to proton therapy.
Methods
Ten patients newly diagnosed with craniopharyngioma underwent PET imaging using 18F FDG and 11C MET. PET and MRI studies were registered to help identify tumor volume. Measurements of maximum standardized uptake value (SUVmax) were taken of the tumor and compared with noninvolved left frontal background white matter using a paired t-test. Uptake was graded using a 4-point scale.
Results
Median patient age was 9 years (range 5–19). Seven patients were diagnosed by pathology, 1 by cyst fluid aspiration, and 2 by neuroimaging. Median FDG SUVmax for tumor and background were 2.65 and 3.2, respectively. Median MET SUVmax for tumor and background were 2.2 and 1, respectively. There was a significant difference between MET tumor SUVmax and MET background SUVmax (P = .0001). The difference between FDG tumor SUVmax and FDG background SUVmax was not significant (P = .3672).
Conclusion
11C MET PET uptake is significantly greater within the tumor compared with noninvolved background white matter, making it more useful than FDG PET in identifying active tumor in patients with craniopharyngioma. Future work will focus on using 11C MET PET to discriminate between active and inactive tumor after irradiation.
doi:10.1093/neuonc/nos321
PMCID: PMC3607263  PMID: 23408862
craniopharyngioma; fluorodeoxyglucose; FDG; methionine; positron emission tomography; proton therapy
11.  A multi-disciplinary consensus statement concerning surgical approaches to low-grade, high-grade astrocytomas and diffuse intrinsic pontine gliomas in childhood (CPN Paris 2011) using the Delphi method 
Neuro-Oncology  2013;15(4):462-468.
Astrocytic tumors account for 42% of childhood brain tumors, arising in all anatomical regions and associated with neurofibromatosis type 1 (NF1) in 15%. Anatomical site determines the degree and risk of resectability; the more complete resection, the better the survival rates. New biological markers and modern radiotherapy techniques are altering the risk assessments of clinical decisions for tumor resection and biopsy. The increasingly distinct pediatric neuro-oncology multidisciplinary team (PNMDT) is developing a distinct evidence base.
A multidisciplinary consensus conference on pediatric neurosurgery was held in February 2011, where 92 invited participants reviewed evidence for clinical management of hypothalamic chiasmatic glioma (HCLGG), diffuse intrinsic pontine glioma (DIPG), and high-grade glioma (HGG). Twenty-seven statements were drafted and subjected to online Delphi consensus voting by participants, seeking >70% agreement from >60% of respondents; where <70% consensus occurred, the statement was modified and resubmitted for voting.
Twenty-seven statements meeting consensus criteria are reported. For HCLGG, statements describing overall therapeutic purpose and indications for biopsy, observation, or treatment aimed at limiting the risk of visual damage and the need for on-going clinical trials were made. Primary surgical resection was not recommended. For DIPG, biopsy was recommended to ascertain biological characteristics to enhance understanding and targeting of treatments, especially in clinical trials. For HGG, biopsy is essential, the World Health Organization classification was recommended; selection of surgical strategy to achieve gross total resection in a single or multistep process should be discussed with the PNMDT and integrated with trials based drug strategies for adjuvant therapies.
doi:10.1093/neuonc/nos330
PMCID: PMC3607269  PMID: 23502427
low-grade astrocytoma
12.  The Utility of Parent Report in the Assessment of Working Memory among Childhood Brain Tumor Survivors 
Childhood brain tumor survivors are at increased risk for neurocognitive impairments, including working memory (WM) problems. WM is typically assessed using performance measures. Little is known about the value of parent ratings for identifying WM difficulties, the relationship between rater and performance measures, or predictors of parent-reported WM problems in this population. Accordingly, the current study examined the utility of parent report in detecting WM difficulties among childhood brain tumor survivors treated with conformal radiation therapy (n=50) relative to siblings (n=40) and solid tumor survivors not receiving CNS-directed therapy (n=40). Parents completed the Behavior Rating Inventory of Executive Function (BRIEF). Participants were administered WM measures (digit span, self-ordered search tasks). Findings revealed parents rated brain tumor survivors as having significantly more WM problems (p<.01) compared to controls. However, the BRIEF-WM scale demonstrated poor sensitivity and specificity for detecting performance-based problems. Significant, albeit modest, correlations were found between the BRIEF-WM scale and performance measures (r=−.24 −.22; p<.05) for the combined group. Age at testing, socioeconomic status, and IQ were significant predictors of parent reported WM problems. Rater and performance measures offer complimentary yet different information in assessing WM, which reiterates the importance of utilizing both within the context of clinical assessment.
doi:10.1017/S1355617712001567
PMCID: PMC3630283  PMID: 23351399
cancer; cognitive late effects; pediatrics; BRIEF; rater-based measures; executive functions
13.  Longitudinal Investigation of Adaptive Functioning following Conformal Irradiation for Pediatric Craniopharyngioma and Low-Grade Glioma 
Purpose
Children treated for brain tumors with conformal radiation therapy experience preserved cognitive outcomes. Early evidence suggests that adaptive functions or independent living skills may be spared. This longitudinal investigation prospectively examined intellectual and adaptive functioning during the first 5 years following irradiation for childhood craniopharyngioma and low-grade glioma (LGG). The effect of visual impairment on adaptive outcomes was investigated.
Methods and Materials
Children with craniopharyngioma (n=62) and LGG (n=77) were treated using conformal or intensity-modulated radiation therapy. The median age was 8.05 years (3.21 years –17.64 years) and 8.09 years (2.20 years–19.27 years), respectively. Serial cognitive evaluations including measures of intelligence quotient (IQ) and the Vineland Adaptive Behavior Scales (VABS) were conducted at pre-irradiation baseline, 6 months after treatment, and annually through 5 years. A total of 588 evaluations were completed during the follow-up period.
Results
Baseline assessment revealed no deficits in IQ and VABS indices for children with craniopharyngioma, with significant (p < .05) longitudinal decline in VABS Communication and Socialization indices. Clinical factors associated with more rapid decline included females and pre-irradiation chemotherapy (interferon). The only change in VABS Daily Living Skills correlated with IQ change (r = .34; p = .01) in children with craniopharyngioma. Children with LGG performed below population norms (p < .05) at baseline on VABS Communication, Daily Living Indices, and the Adaptive Behavior Composite, with significant (p < .05) longitudinal decline limited to VABS Communication. Older age at irradiation was a protective factor against longitudinal decline. Severe visual impairment did not independently correlate with poorer adaptive outcomes for either tumor group.
Conclusions
There was relative sparing of post-irradiation functional outcomes over time in this sample. Baseline differences in functional abilities prior to the initiation of irradiation suggested that other factors influence functional outcomes above and beyond the effects of irradiation.
doi:10.1016/j.ijrobp.2012.10.031
PMCID: PMC3685870  PMID: 23245284
Conformal radiation; craniopharyngioma; low-grade glioma; adaptive functioning; neurocognitive outcomes
14.  DISEASE CONTROL AFTER REDUCED VOLUME CONFORMAL AND INTENSITY-MODULATED RADIATION THERAPY FOR CHILDHOOD CRANIOPHARYNGIOMA 
PURPOSE
To estimate the rate of disease control after conformal radiation therapy using reduced clinical target volume (CTV) margins and determine factors that predict for tumor progression.
METHODS AND MATERIALS
Eighty-eight children (median age 8.5 years, range 3.2–17.6 years) received conformal or intensity-modulated radiation therapy between 1998 and 2009. This included those prospectively treated from 1998 to 2003 using a 10 mm CTV, defined as the margin surrounding the solid and cystic tumor targeted to receive the prescription dose of 54 Gy. The CTV margin was subsequently reduced after 2003 yielding two groups of patients: those treated with a CTV margin greater than 5 mm (n=26) and those treated with a CTV margin less than or equal to 5 mm (n=62). Disease progression was estimated on the basis of additional variables including sex, race, extent of resection, tumor interventions, target volume margins, and the frequency of weekly surveillance MR imaging during radiation therapy. The median follow-up was 5 years.
RESULTS
There was no difference comparing progression-free survival based on CTV margin (>5mm vs. ≤ 5mm) at 5 years, 88.1 + 6.3% vs. 96.2 + 4.4% (P=0.6386). There was no difference based on the planning target volume (PTV) margin (or combined CTV+PTV). The PTV was systematically reduced from 5 to 3mm during the time period of the study. Factors predictive of superior progression-free survival included Caucasian race (P=0.0175), absent CSF shunting requirement (P=0.0066), and the number of surveillance imaging studies during treatment (P=0.0216). Patients whose treatment protocol included a higher number of weekly surveillance MR imaging evaluations had a lower rate of tumor progression.
CONCLUSIONS
These results suggest that targeted volume reductions for radiation therapy using smaller margins are feasible and safe but require careful monitoring. We are currently investigating the differences in outcome based on host factors to explain the results.
doi:10.1016/j.ijrobp.2012.10.030
PMCID: PMC3594571  PMID: 23245282
Radiotherapy; Pediatrics; Brain Tumor; Craniopharyngioma; Adaptive Therapy
15.  Supratentorial Ependymoma: Disease Control, Complications and Functional Outcomes after Irradiation 
Purpose
Ependymoma is less commonly found in the supratentorial brain and has known clinical and molecular features that are unique. Our single institution series provides valuable information about disease control for supratentorial ependymoma and the complications of supratentorial irradiation in children.
Methods and Materials
A total of 50 children with newly diagnosed supratentorial ependymoma were treated with adjuvant radiation therapy (RT); 36 were using conformal methods after 1996. The median age at RT was 6.5 years (range, 1–18.9). The entire group was characterized according to sex (girls = 27), race (Caucasian = 43), extent of resection (gross-total = 46), and tumor grade (anaplastic = 28). The conformal RT group was prospectively evaluated for neurological, endocrine and cognitive effects.
Results
With a median follow-up of 9.1 years from the start of RT for survivors (range 0.2–23.2), the 10-year progression-free and overall survival were 73% + 7% and 76% + 6%, respectively. None of the evaluated factors was prognostic for disease control. Local and distant failures were evenly divided among the 16 patients who experienced progression. Eleven patients died from disease and one from CNS necrosis. Seizure disorders were present in 17 patients and 4 were considered to be clinically disabled. Clinically significant cognitive effects were limited to children with difficult to control seizures. Average values for IQ and academic achievement (reading, spelling, and math) were within the range of normal through 10 years of follow-up. Central hypothyroidism was the most commonly treated endocrinopathy.
Conclusion
RT may be administered with acceptable risks for complications in children with supratentorial ependymoma. These results suggest that outcomes for these children are improving and that complications may be limited by use of focal irradiation methods.
doi:10.1016/j.ijrobp.2012.10.033
PMCID: PMC3705553  PMID: 23245280
16.  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
17.  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
18.  Topotecan and vincristine combination is effective against advanced bilateral intraocular retinoblastoma and has manageable toxicity 
Cancer  2012;118(22):5663-5670.
Background
New, effective chemotherapeutic agents are needed for intraocular retinoblastoma.
Methods
Our institutional clinical trial sought to estimate the rate of response to 2 courses of vincristine and topotecan (VT) window therapy in patients with bilateral retinoblastoma and advanced disease (Reese-Ellsworth Group IV or V) in at least one eye. The topotecan dose started at 3 mg/m2/day for 5 days, and was adjusted to target a systemic exposure of 140 ± 20 ng/ml*hr. The vincristine dose was 0.05 mg/kg for patients < 12 months of age and 1.5 mg/m2 for those > 12 months of age at diagnosis.
Results
From February 2005 to June 2010, 27 patients received VT window therapy. Median age at enrollment was 8.1 months (range, 0.7–22.1 months). Twenty-four patients (88.9%) responded to window therapy (95% CI, 71.3%–96.9%). Hematologic toxicity comprised grade 4 neutropenia (n=27), grade 3 anemia (n=19), and grade 3/4 thrombocytopenia (n=16). Thirteen patients had grade 3 non-hematologic toxicity. G-CSF support was added after 10 patients had been treated and significantly reduced the duration of grade 4 neutropenia (median, 7 vs. 24 days; P <0.001). Pharmacokinetic studies showed rapid changes in topotecan clearance rates during the first year of life.
Conclusions
The combination of topotecan and vincristine is effective for the treatment of advanced intraocular retinoblastoma. G-CSF treatment alleviates the duration of grade 4 neutropenia. Appropriate topotecan starting doses for patients 0–3, 3–6, 6–9, 9–12, and >12 months of age are specified.
doi:10.1002/cncr.27563
PMCID: PMC3413782  PMID: 22516936
Retinoblastoma; topotecan; pharmakokinetic; first year of life; toxicity
19.  Predicting the Probability of Abnormal Stimulated Growth Hormone Response in Children After Radiotherapy for Brain Tumors 
Purpose
To develop a mathematical model utilizing more readily available measures than stimulation tests that identifies brain tumor survivors with high likelihood of abnormal growth hormone secretion after radiotherapy (RT), to avoid late recognition and a consequent delay in growth hormone replacement therapy.
Methods and Materials
We analyzed 191 prospectively collected post-RT evaluations of peak growth hormone level (arginine tolerance/levodopa stimulation test), serum insulin-like growth factor 1 (IGF-1), IGF-binding protein 3, height, weight, growth velocity, and body mass index in 106 children and adolescents treated for ependymoma (n = 72), low-grade glioma (n = 28) or craniopharyngioma (n = 6), who had normal growth hormone levels before RT. Normal level in this study was defined as the peak growth hormone response to the stimulation test ≥7 ng/mL.
Results
Independent predictor variables identified by multivariate logistic regression with high statistical significance (p < 0.0001) included IGF-1 z score, weight z score, and hypothalamic dose. The developed predictive model demonstrated a strong discriminatory power with an area under the receiver operating characteristic curve of 0.883. At a potential cutoff point of probability of 0.3 the sensitivity was 80% and specificity 78%.
Conclusions
Without unpleasant and expensive frequent stimulation tests, our model provides a quantitative approach to closely follow the growth hormone secretory capacity of brain tumor survivors. It allows identification of high-risk children for subsequent confirmatory tests and in-depth workup for diagnosis of growth hormone deficiency.
doi:10.1016/j.ijrobp.2012.01.049
PMCID: PMC3554243  PMID: 22483696
Pediatric brain tumor; Radiotherapy; Growth hormone; Insulin-like growth factor; Stimulation test
20.  Learning and Memory Following Conformal Radiation Therapy for Pediatric Craniopharyngioma and Low-Grade Glioma 
Purpose
The primary objective of this study was to examine whether children with low-grade glioma (LGG) or craniopharyngioma had impaired learning and memory after conformal radiation therapy (CRT). A secondary objective was to determine whether children who received chemotherapy before CRT, a treatment often used to delay radiation therapy in younger children with LGG, received any protective benefit with respect to learning.
Methods and Materials
Learning and memory in 57 children with LGG and 44 children with craniopharyngioma were assessed with the California Verbal Learning Test–Children’s Version and the Visual-Auditory Learning tests. Learning measures were administered before CRT, 6 months later, and then yearly for a total of 5 years.
Results
No decline in learning scores after CRT was observed when patients were grouped by diagnosis. For children with LGG, chemotherapy before CRT did not provide a protective effect on learning. Multiple regression analyses, which accounted for age and tumor volume and location, found that children treated with chemotherapy before CRT were at greater risk of decline on learning measures than those treated with CRT alone. Variables predictive of learning and memory decline included hydrocephalus, shunt insertion, younger age at time of treatment, female gender, and pre-CRT chemotherapy.
Conclusions
This study did not reveal any impairment or decline in learning after CRT in over-all aggregate learning scores. However, several important variables were found to have a significant effect on neurocognitive outcome. Specifically, chemotherapy before CRT was predictive of worse outcome on verbal learning in LGG patients. In addition, hydrocephalus and shunt insertion in craniopharyngioma were found to be predictive of worse neurocognitive outcome, suggesting a more aggressive natural history for those patients.
doi:10.1016/j.ijrobp.2012.03.066
PMCID: PMC3534785  PMID: 22867897
21.  Dosimetric Impact of Intrafractional Patient Motion in Pediatric Brain Tumor Patients 
The purpose of this study was to determine the dosimetric consequences of intrafractional patient motion on the clinical target volume (CTV), spinal cord, and optic nerves for non-sedated pediatric brain tumor patients. The patients were immobilized for treatment using a customized thermoplastic full-face mask and bite-block attached to an array of reflectors. The array was optically tracked by infra-red cameras at a frequency of 10 Hz. Patients were localized based on skin/mask marks and weekly films were taken to ensure proper setup. Before each noncoplanar field was delivered, the deviation from baseline of the array was recorded. The systematic error (SE) and random error (RE) were calculated. Direct simulation of the intrafractional motion was used to quantify the dosimetric changes to the targets and critical structures. Nine patients utilizing the optical tracking system were evaluated. The patient cohort had a mean of 31 ± 1.5 treatment fractions; motion data were acquired for a mean of 26 ± 6.2 fractions. The mean age was 15.6 ± 4.1 years. The SE and RE were 0.4 and 1.1 mm in the posterior-anterior, 0.5 and 1.0 mm in left-right, and 0.6 and 1.3 mm in superior-inferior directions, respectively. The dosimetric effects of the motion on the CTV were negligible; however, the dose to the critical structures was increased. Patient motion during treatment does affect the dose to critical structures, therefore, planning risk volumes are needed to properly assess the dose to normal tissues. Because the motion did not affect the dose to the CTV, the 3-mm PTV margin used is sufficient to account for intrafractional motion, given the patient is properly localized at the start of treatment.
doi:10.1016/j.meddos.2009.01.004
PMCID: PMC3800030  PMID: 19931014
Pediatric brain tumor; intra-fraction motion; target localization
22.  Induction Chemotherapy and Conformal Radiation Therapy for Very Young Children With Nonmetastatic Medulloblastoma: Children's Oncology Group Study P9934 
Journal of Clinical Oncology  2012;30(26):3181-3186.
Purpose
P9934 was a prospective trial of systemic chemotherapy, second surgery, and conformal radiation therapy (CRT) limited to the posterior fossa and primary site for children between 8 months and 3 years old with nonmetastatic medulloblastoma. The study was open from June 2000 until June 2006.
Patients and Methods
After initial surgery, children received four cycles of induction chemotherapy, followed by age- and response-adjusted CRT to the posterior fossa (18 or 23.4 Gy) and tumor bed (cumulative 50.4 or 54 Gy) and maintenance chemotherapy. Neurodevelopmental outcomes were evaluated and event-free survival (EFS) results were directly compared with a previous study of multiagent chemotherapy without irradiation (Pediatric Oncology Group [POG] trial 9233).
Results
Seventy-four patients met eligibility requirements. The 4-year EFS and overall survival probabilities were 50% ± 6% and 69% ± 5.5%, respectively, which compared favorably to the results from POG 9233. Analysis showed that the desmoplastic/nodular subtype was a favorable factor in predicting survival. Our 4-year EFS rate was 58% ± 8% for patients with desmoplasia. Whereas seven of 10 patients who had disease progression before CRT had primary-site failure, 15 of 19 patients who progressed after CRT had distant-site failure. Neurodevelopmental assessments did not show a decline in cognitive or motor function after protocol-directed chemotherapy and CRT.
Conclusion
The addition of CRT to postoperative chemotherapy in young children with nonmetastatic medulloblastoma increased event-free survival compared with the use of postoperative chemotherapy alone. Future studies will use histopathologic typing (desmoplastic/nodular versus nondesmoplastic/nodular) to stratify patients for therapy by risk of relapse.
doi:10.1200/JCO.2010.34.4341
PMCID: PMC3434977  PMID: 22851568
23.  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
24.  A 5-Year Investigation of Children’s Adaptive Functioning Following Conformal Radiation Therapy for Localized Ependymoma 
Purpose
Conformal and intensity modulated radiation therapies have the potential to preserve cognitive outcomes in children with ependymoma; however, functional behavior remains uninvestigated. This longitudinal investigation prospectively examined intelligence quotient (IQ) and adaptive functioning during the first 5 years after irradiation in children diagnosed with ependymoma.
Methods and Materials
The study cohort consisted of 123 children with intracranial ependymoma. Mean age at irradiation was 4.60 years (95% confidence interval [CI], 3.85–5.35). Serial neurocognitive evaluations, including an age-appropriate IQ measure and the Vineland Adaptive Behavior Scales (VABS), were completed before irradiation, 6 months after treatment, and annually for 5 years. A total of 579 neurocognitive evaluations were included in these analyses.
Results
Baseline IQ and VABS were below normative means (P<.05), although within the average range. Linear mixed models revealed stable IQ and VABS across the follow-up period, except for the VABS Communication Index, which declined significantly (P=.015). Annual change in IQ (−.04 points) did not correlate with annual change in VABS (−.90 to +.44 points). Clinical factors associated with poorer baseline performance (P<.05) included preirradiation chemotherapy, cerebrospinal fluid shunt placement, number and extent of surgical resections, and younger age at treatment. No clinical factors significantly affected the rate of change in scores.
Conclusions
Conformal and intensity modulated radiation therapies provided relative sparing of functional outcomes including IQ and adaptive behaviors, even in very young children. Communication skills remained vulnerable and should be the target of preventive and rehabilitative interventions.
doi:10.1016/j.ijrobp.2011.10.043
PMCID: PMC3534783  PMID: 22541967
25.  Visual Outcomes in Pediatric Optic Pathway Glioma After Conformal Radiation Therapy 
Purpose
To assess visual outcome prospectively after conformal radiation therapy (CRT) in children with optic pathway glioma.
Methods and Materials
We used CRT to treat optic pathway glioma in 20 children (median age 9.3 years) between July 1997 and January 2002. We assessed changes in visual acuity using the logarithm of the minimal angle of resolution after CRT (54 Gy) with a median follow-up of 24 months. We included in the study children who underwent chemotherapy (8 patients) or resection (9 patients) before CRT.
Results
Surgery played a major role in determining baseline (pre-CRT) visual acuity (better eye: P=.0431; worse eye: P=.0032). The visual acuity in the worse eye was diminished at baseline (borderline significant) with administration of chemotherapy before CRT (P=.0726) and progression of disease prior to receiving CRT (P=.0220). In the worse eye, improvement in visual acuity was observed in patients who did not receive chemotherapy before CRT (P=.0289).
Conclusions
Children with optic pathway glioma initially treated with chemotherapy prior to receiving radiation therapy have decreased visual acuity compared with those who receive primary radiation therapy. Limited surgery before radiation therapy may have a role in preserving visual acuity.
doi:10.1016/j.ijrobp.2011.10.067
PMCID: PMC3554252  PMID: 22607912
Vision; Pediatrics; Glioma; Radiotherapy

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