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1.  A phase II trial of a multi-agent oral antiangiogenic (metronomic) regimen in children with recurrent or progressive cancer 
Pediatric Blood & Cancer  2013;61(4):636-642.
Preclinical models show that an antiangiogenic regimen at low-dose daily (metronomic) dosing may be effective against chemotherapy-resistant tumors. We undertook a prospective, open-label, single-arm, multi-institutional phase II study to evaluate the efficacy of a “5-drug” oral regimen in children with recurrent or progressive cancer.
Patients ≤21 years old with recurrent or progressive tumors were eligible. Treatment consisted of continuous oral celecoxib, thalidomide, and fenofibrate, with alternating 21-day cycles of low-dose cyclophosphamide and etoposide. Primary endpoint was to assess, within eight disease strata, activity of the 5-drug regimen over 27 weeks. Blood and urine angiogenesis markers were assessed.
One hundred one patients were enrolled; 97 began treatment. Median age was 10 years (range: 191 days–21 years); 47 (49%) were female. Disease strata included high-grade glioma (HGG, 21 patients), ependymoma (19), low-grade glioma (LGG, 12), bone tumors (12), medulloblastoma/primitive neuroectodermal tumor (PNET, 8), leukemia (4), neuroblastoma (3), and miscellaneous tumors (18). Treatment was generally well tolerated; most common toxicities were hematologic. Twenty-four (25%) patients completed 27 weeks therapy without progression, including HGG: 1 (5%), ependymoma: 7 (37%), LGG: 7 (58%), medulloblastoma/PNET: 1, neuroblastoma: 1, and miscellaneous tumors: 7 (39%). Best response was complete response (one patient with medulloblastoma), partial response (12), stable disease (36), progressive disease (47), and inevaluable (1). Baseline serum thrombospondin levels were significantly higher in patients successfully completing therapy than in those who progressed (P = 0.009).
The 5-drug regimen was well tolerated. Clinical activity was demonstrated in some but not all tumor strata. Pediatric Blood Cancer 2014;61:636–642. © 2013 The Authors Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.
PMCID: PMC4285784  PMID: 24123865
angiogenesis; drug resistance; pediatric oncology; phase II clinical trials
2.  Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma 
Nature genetics  2014;46(5):462-466.
Midline pediatric high-grade astrocytomas (pHGAs) are incurable with few treatment targets identified. Most tumors harbor K27M mutations on histone 3 variants. In 40 treatment-naïve midline pHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with H3.1 K27M, while FGFR1 mutations/fusions occur in thalamic tumors associated with H3.3 K27M. Hyper-activation of the bone morphogenetic protein (BMP)/ACVR1 developmental pathway in pHGAs harbouring ACVR1 mutations led to increased phospho-SMAD1/5/8 expression and up-regulation of BMP downstream early response genes in tumour cells. Global DNA methylation profiles were significantly associated with the K27M mutation regardless of the mutant H3 variant and irrespective of tumor location, supporting its role in driving the epigenetic phenotype. This significantly expands the potential treatment targets and further justifies pre-treatment biopsy in pHGA as a means to orient therapeutic efforts in this disease.
PMCID: PMC4282994  PMID: 24705250
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.
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.
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).
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).
The combination of BVZ + CPT-11 appears to produce sustained disease control in some children with recurrent low-grade gliomas.
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.
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.
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.
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.
The combination of BVZ and CPT-11 was fairly well-tolerated, and most severe BVZ-related toxicities were rare, self-limiting and manageable.
PMCID: PMC3835419  PMID: 24104527
pediatric; bevacizumab; toxicity; central nervous system (CNS) tumors; clinical trials
Journal of neuro-oncology  2013;114(2):173-179.
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.
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).
Lapatinib was well-tolerated in children with recurrent or CNS malignancies, but did not inhibit target in tumor and had little single agent activity.
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 
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.
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.
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.
PMCID: PMC3856244  PMID: 24077351
7.  Regulatory effects of a Mnk2-eIF4E feedback loop during mTORC1 targeting of human medulloblastoma cells 
Oncotarget  2014;5(18):8442-8451.
The mTOR pathway controls mRNA translation of mitogenic proteins and is a central regulator of metabolism in malignant cells. Development of malignant cell resistance is a limiting factor to the effects of mTOR inhibitors, but the mechanisms accounting for such resistance are not well understood. We provide evidence that mTORC1 inhibition by rapamycin results in engagement of a negative feedback regulatory loop in malignant medulloblastoma cells, involving phosphorylation of the eukaryotic translation-initiation factor eIF4E. This eIF4E phosphorylation is Mnk2- mediated, but Mnk1-independent, and acts as a survival mechanism for medulloblastoma cells. Pharmacological targeting of Mnk1/2 or siRNA-mediated knockdown of Mnk2 sensitizes medulloblastoma cells to mTOR inhibition and promotes suppression of malignant cell proliferation and anchorage-independent growth. Altogether, these findings provide evidence for the existence of a Mnk2-controlled feedback loop in medulloblastoma cells that accounts for resistance to mTOR inhibitors, and raise the potential for combination treatments of mTOR and Mnk inhibitors for the treatment of medulloblastoma.
PMCID: PMC4226695  PMID: 25193863
TOR; Mnk; rapamycin; medulloblastoma
8.  A prognostic gene expression signature in infratentorial ependymoma 
Acta neuropathologica  2012;123(5):727-738.
Patients with ependymoma exhibit a wide range of clinical outcomes that is currently unexplained by clinical or histological factors. Little is known regarding molecular biomarkers that could predict clinical behavior. Since recent data suggests that these tumors display biological characteristics according to their location (cerebral vs. infratentorial vs. spinal cord), rather than explore a broad spectrum of ependymoma, we focused on molecular alterations in ependymomas arising in the infratentorial compartment. Unsupervised clustering of available gene expression microarray data revealed two major subgroups of infratentorial ependymoma. Group 1 tumors over expressed genes that were associated with mesenchyme, Group 2 tumors showed no distinct gene ontologies. To assess the prognostic significance of these gene expression subgroups, real-time reverse-transcriptase polymerase chain reaction assays were performed on genes defining the subgroups in a training set. This resulted in a 10-gene prognostic signature. Multivariate analysis showed that the 10-gene signature was an independent predictor of recurrence-free survival after adjusting for clinical factors. Evaluation of an external dataset describing subgroups of infratentorial ependymomas showed concordance of subgroup definition, including validation of the mesenchymal subclass. Importantly, the 10-gene signature was validated as a predictor of recurrence-free survival in this dataset. Taken together, the results indicate a link between clinical outcome and biologically-identified subsets of infratentorial ependymoma and offer the potential for prognostic testing to estimate clinical aggressiveness in these tumors.
PMCID: PMC4013829  PMID: 22322993
Infratentorial ependymoma; Expression profiling; Gene expression signature; Prognostic genes; Microarray; Biomarker
9.  A Phase 1 Pharmacokinetic Optimal Dosing Study of Intraventricular Topotecan for Children with Neoplastic Meningitis: A Pediatric Brain Tumor Consortium Study 
Pediatric blood & cancer  2012;60(4):627-632.
We performed a phase 1 pharmacokinetic optimal dosing study of intraventricular topotecan (IT), administered daily × 5, to determine whether the maximum tolerated dose of IT topotecan was also the pharmacokinetic optimal dose.
Patients and Methods
Patients received topotecan administered through an intraventricular access device (0.1 or 0.2 mg/dose), daily × 5 every other week × 2 (Induction); every 3 weeks × 2 (Consolidation); then every 4 weeks for up to 11 courses (Maintenance). Ventricular CSF pharmacokinetic studies were performed on day 1, week 1 of induction, and in a subset of patients after a single intralumbar topotecan dose on day 1, week 3.
Nineteen patients were enrolled. All were evaluable for toxicity and 18 were assessable for pharmacokinetics. Arachnoiditis requiring corticosteroid therapy occurred in 1/3 patients at the 0.1 mg dose level and 2 of the initial 3 patients enrolled at the 0.2 mg dose level. All subsequent patients were therefore treated with concomitant dexamethasone. Pharmacokinetic evaluation after accrual of the first 7 patients revealed that a topotecan lactone concentration > 1 ng/ml for 8 hours was attained in all patients and thus further dose escalation was not pursued. Results of simulation studies showed that at the dose levels evaluated, >99.9% of patients are expected to achieve CSF topotecan lactone concentrations > 1 ng/mL for at least 8 h.
Intraventricular topotecan, 0.2 mg, administered daily for 5 days with concomitant dexamethasone is well tolerated and was defined to be the pharmacokinetic optimal dose in this trial.
PMCID: PMC3573253  PMID: 23002039
topotecan; intraventricular; neoplastic meningitis; leptomeningeal; pharmacokinetic
11.  Parent-perceived child cognitive function: results from a sample drawn from the US general population 
This paper reports the development and evaluation of a perceived cognitive function (pedsPCF) item bank reported by parents of the pediatric US general population.
Based on feedback from clinicians, parents, and children, we developed a scale sampling concerns related to children’s cognitive functioning. We administered the scale to 1,409 parents of children aged 7–17 years; of them, 319 had a neurological diagnosis. Dimensionality of the pedsPCF was evaluated via factor analyses and its clinical utility studied by comparing parent ratings in patient groups and symptom cluster defined by the Child Behavior Checklist (CBCL).
Forty-four of 45 items met criteria for unidimensionality. The pedsPCF significantly differentiated samples defined by medication use, repeated grades, special education status, neurologic diagnosis, and relevant symptom clusters with large effect sizes (>0.8). It can predicted children symptoms with the correction rates ranging 79–89%.
We have provided empirical support for the unidimensionality of the pedsPCF item bank and evidence for its potential clinical utility. The pedsPCF is a promising measurement tool to screen children for further comprehensive cognitive tests.
PMCID: PMC3885608  PMID: 20652814
Perceived cognitive function; Children; Brain tumor; Neuro-oncology; Item bank
12.  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.
PMCID: PMC3480265  PMID: 23019233
bevacizumab; CPT-11; efficacy; ependymoma; recurrent
13.  The Deubiquitylase USP37 Links REST to the Control of p27 Stability and Cell Proliferation 
Oncogene  2012;32(13):1691-1701.
The RE1 Silencing Transcription Factor (REST) is a repressor of neuronal differentiation and its elevated expression in neural cells blocks neuronal differentiation. In the present study, we demonstrate a role for REST in the control of proliferation of medulloblastoma cells. REST expression decreased the levels of CDKNIB/p27, a cyclin-dependent kinase inhibitor and a brake of cell proliferation in these cells. The reciprocal relationship between REST and p27 was validated in human tumor samples. REST knockdown in medulloblastoma cells derepessed a novel REST-target gene encoding the deubiquitylase ubiquitin-specific peptidase 37 (USP37). Ectopically expressed wild type USP37 formed a complex with p27, promoted its deubiquitination and stabilization and blocked cell proliferation. Knockdown of REST and USP37 prevented p27 stabilization and blocked the diminution in proliferative potential that normally accompanied REST loss. Unexpectedly, wild type USP37 expression also induced the expression of REST-target neuronal differentiation genes even though REST levels were unaffected. In contrast, a mutant of USP37 carrying a site-directed change in a conserved cysteine failed to rescue REST-mediated p27 destabilization, maintenance of cell proliferation and blockade to neuronal differentiation. Consistent with these findings, a significant correlation between USP37 and p27 was observed in patient tumors. Collectively, these findings provide a novel connection between REST and the proteasomal machinery in the control of p27 and cell proliferation in medulloblastoma cells.
PMCID: PMC3435483  PMID: 22665064
REST; proliferation; p27; USP37; deubiquitylase
14.  REST is a Novel Prognostic Factor and Therapeutic Target for Medulloblastoma 
Molecular cancer therapeutics  2012;11(8):1713-1723.
Medulloblastoma is a malignant pediatric brain tumor. Current treatment following patient stratification into standard and high-risk groups using clinical features, has improved survival. However, a subset of patients with standard-risk features have unanticipated aggressive disease, underscoring the need for a better understanding of tumor biology and development of novel treatments. Poor differentiation, a hallmark of medulloblastomas is associated with elevated expression levels of the repressor of neuronal differentiation REST. Here, we assessed if elevated REST expression levels had prognostic significance and if its pharmacological manipulation would promote neurogenesis and block tumor cell growth. REST levels in patient tumors were measured by immunohistochemistry (IHC) and stratified into low/moderate- (+/++/+++) and high-REST (+++++) groups. Kaplan-Meier curves revealed that patients with high-REST tumors had worse overall and event-free survival compared to patients with REST-negative or REST-low tumors. Since histone deacetylases (HDACs), are required for REST-dependent repression of neurogenesis, we evaluated a panel of HDAC inhibitors (HDACIs) for their effects on growth and differentiation of established and primary REST-positive cell lines. MS-275, trichostatin-A (TSA), valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) upregulated expression of the REST-target neuronal differentiation gene, Syn1, suggesting a potential effect of these HDACIs on REST function. Interestingly, VPA and TSA substantially increased histone acetylation at the REST promoter and activated its transcription, whereas SAHA unexpectedly promoted its proteasomal degradation. A REST-dependent decrease in cell growth was also observed following SAHA treatment. Thus, our studies suggest that HDACIs may have therapeutic potential for patients with REST-positive tumors. This warrants further investigation.
PMCID: PMC3763747  PMID: 22848092
REST; medulloblastoma; HDAC inhibitor; prognosis; differentiation
15.  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.
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.
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.
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.
PMCID: PMC3529096  PMID: 22790443
mafosfamide; intrathecal; infant brain tumor; embryonal CNS tumor; conformal radiation therapy
16.  A Phase II Study of O6-Benzylguanine and Temozolomide in Pediatric Patients with Recurrent or Progressive High Grade Gliomas and Brainstem Gliomas: A Pediatric Brain Tumor Consortium Study 
Journal of neuro-oncology  2011;106(3):643-649.
To estimate the sustained (≥8 weeks) objective response rate in pediatric patients with recurrent or progressive high-grade gliomas (HGG, Stratum A) or brainstem gliomas (BSG, Stratum B) treated with the combination of O6-benzylguanine (O6BG) and temozolomide® (TMZ).
Patients and Methods
Patients received O6BG 120 mg/m2/d IV followed by TMZ 75 mg/m2/d orally daily for 5 consecutive days of each 28-day course. The target objective response rate to consider the combination active was 17%. A two-stage design was employed.
Forty-three patients were enrolled; 41 were evaluable for response, including 25 patients with HGG and 16 patients with BSG. The combination of O6BG and TMZ was tolerable, and the primary toxicities were myelosuppression and gastrointestinal symptoms. One sustained (≥8 weeks) partial response was observed in the HGG cohort; no sustained objective responses were observed in the BSG cohort. Long-term (≥6 courses) stable disease (SD) was observed in 4 patients in Stratum A and 1 patient in Stratum B. Of the 5 patients with objective response or long-term SD, 3 underwent central review with 2 reclassified as low-grade gliomas.
The combination of O6BG and TMZ did not achieve the target response rate for activity in pediatric patients with recurrent or progressive HGG and BSG.
PMCID: PMC3518022  PMID: 21968943
glioma; pediatric; resistance; alkylating agent; brainstem glioma; AGT; MGMT
17.  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.
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.
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.
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.
PMCID: PMC3179253  PMID: 21825264
18.  Development of a Parent-Report Cognitive Function Item Bank Using Item Response Theory and Exploration of its Clinical Utility in Computerized Adaptive Testing 
Journal of Pediatric Psychology  2011;36(7):766-779.
Objective The purpose of this study is to report the reliability, validity, and clinical utility of a parent-report perceived cognitive function (pedsPCF) item bank. Methods From the U.S. general population, 1,409 parents of children aged 7–17 years completed 45 pedsPCF items. Their psychometric properties were evaluated using Item Response Theory (IRT) approaches. Receiver operating characteristic (ROC) curves and discriminant function analysis were used to predict clinical problems on child behavior checklist (CBCL) scales. A computerized adaptive testing (CAT) simulation was used to evaluate clinical utility. Results The final 43-item pedsPCF item bank demonstrates no item bias, has acceptable IRT parameters, and provides good prediction of related clinical problems. CAT simulation resulted in correlations of 0.98 between CAT and the full-length pedsPCF. Conclusions The pedsPCF has sound psychometric properties, U.S. general population norms, and a brief-yet-precise CAT version is available. Future work will evaluate pedsPCF in other clinical populations in which cognitive function is important.
PMCID: PMC3146757  PMID: 21378106
assessment; cancer and oncology; cognitive assessment; computer applications/eHealth; neuropsychology; quality of life
19.  Medical radiation exposure and risk of retinoblastoma resulting from new germline RB1 mutation 
Although ionizing radiation induces germline mutations in animals, human studies of radiation-exposed populations have not detected an effect. We conducted a case-control study of sporadic bilateral retinoblastoma, which results from a new germline RB1 mutation, to investigate gonadal radiation exposure of parents from medical sources before their child's conception. Parents of 206 cases from 9 North American institutions and 269 controls participated; fathers of 184 cases and 223 friend and relative controls and mothers of 204 cases and 260 controls provided information in telephone interviews on their medical radiation exposure. Cases provided DNA for RB1 mutation testing. Of common procedures, lower GI series conferred the highest estimated dose to testes and ovaries. Paternal history of lower GI series was associated with increased risk of retinoblastoma in the child (matched odds ratio (OR)=3.6, 95% confidence interval (CI) 1.2, 11.2, 2-sided P=0.02), as was estimated total testicular dose from all procedures combined (OR for highest dose=3.9, 95% CI 1.2, 14.4, P =0.02). Maternal history of lower GI series was also associated with increased risk (OR=7.6, 95% CI 2.8, 20.7, P <0.001) as was estimated total dose (OR for highest dose=3.0, 95% CI 1.4, 7.0, P =0.005). The RB1 mutation spectrum in cases of exposed parents did not differ from that of other cases. Some animal and human data support our findings of an association of gonadal radiation exposure in men and women with new germline RB1 mutation detectable in their children, although bias, confounding, and/or chance may also explain the results.
PMCID: PMC3124307  PMID: 20648557
germline mutation; ionizing radiation; retinoblastoma; case-control studies; pediatric cancer
20.  Phase I Trial of Lenalidomide in Pediatric Patients With Recurrent, Refractory, or Progressive Primary CNS Tumors: Pediatric Brain Tumor Consortium Study PBTC-018 
Journal of Clinical Oncology  2010;29(3):324-329.
A phase I trial of lenalidomide was performed in children with recurrent, refractory, or progressive primary CNS tumors to estimate the maximum-tolerated dose (MTD) and to describe the toxicity profile and pharmacokinetics.
Patients and Methods
Lenalidomide was administered by mouth daily for 21 days, repeated every 28 days. The starting dose was 15 mg/m2/d orally, and the dose was escalated according to a modified continuous reassessment method. Correlative studies included pharmacokinetics obtained from consenting patients on course 1, day 1, and at steady-state (between days 7 and 21).
Fifty-one patients (median age, 10 years; range, 2 to 21 years) were enrolled. Forty-four patients were evaluable for dose finding, and 49 patients were evaluable for toxicity. The primary toxicity was myelosuppression, but the MTD was not defined because doses up to 116 mg/m2/d were well-tolerated during the dose-finding period. Two objective responses were observed (one in thalamic juvenile pilocytic astrocytoma and one in optic pathway glioma) at dose levels of 88 and 116 mg/m2/d. Twenty-three patients, representing all dose levels, received ≥ six cycles of therapy. Pharmacokinetic analysis demonstrated that the lenalidomide area under the concentration-time curve from 0 to 24 hours and maximum plasma concentration increased with dosage over the range studied.
Lenalidomide was tolerable in children with CNS tumors at doses of 116 mg/m2/d during the initial dose-finding period. The primary toxicity is myelosuppression. Antitumor activity, defined by both objective responses and long-term stable disease, was observed, primarily in patients with low-grade gliomas.
PMCID: PMC3056466  PMID: 21149652
21.  Identification of MicroRNAs as Potential Prognostic Markers in Ependymoma 
PLoS ONE  2011;6(10):e25114.
We have examined expression of microRNAs (miRNAs) in ependymomas to identify molecular markers of value for clinical management. miRNAs are non-coding RNAs that can block mRNA translation and affect mRNA stability. Changes in the expression of miRNAs have been correlated with many human cancers.
Materials and Methods
We have utilized TaqMan Low Density Arrays to evaluate the expression of 365 miRNAs in ependymomas and normal brain tissue. We first demonstrated the similarity of expression profiles of paired frozen tissue (FT) and paraffin-embedded specimens (FFPE). We compared the miRNA expression profiles of 34 FFPE ependymoma samples with 8 microdissected normal brain tissue specimens enriched for ependymal cells. miRNA expression profiles were then correlated with tumor location, histology and other clinicopathological features.
We have identified miRNAs that are over-expressed in ependymomas, such as miR-135a and miR-17-5p, and down-regulated, such as miR-383 and miR-485-5p. We have also uncovered associations between expression of specific miRNAs which portend a worse prognosis. For example, we have identified a cluster of miRNAs on human chromosome 14q32 that is associated with time to relapse. We also found that miR-203 is an independent marker for relapse compared to the parameters that are currently used. Additionally, we have identified three miRNAs (let-7d, miR-596 and miR-367) that strongly correlate to overall survival.
We have identified miRNAs that are differentially expressed in ependymomas compared with normal ependymal tissue. We have also uncovered significant associations of miRNAs with clinical behavior. This is the first report of clinically relevant miRNAs in ependymomas.
PMCID: PMC3203863  PMID: 22053178
22.  High-dose carboplatin, thiotepa, and etoposide with autologous stem cell rescue for patients with previously irradiated recurrent medulloblastoma† 
Neuro-Oncology  2010;12(3):297-303.
Recurrent medulloblastoma is highly lethal in previously irradiated patients. Previously irradiated patients with M-0–M-3 recurrences who achieved a minimal disease state prior to protocol enrollment received carboplatin (Calvert formula with area under the curve = 7 mg/mL min, maximum 500 mg/m2/day) on days −8 to −6, and thiotepa (300 mg/m2/day) and etoposide (250 mg/m2/day) on days −5 to −3, followed by autologous stem cell rescue (ASCR) on day 0. Twenty-five patients, aged 7.6–44.7 years (median 13.8 years) at ASCR, were treated. Three (12%) died of treatment-related toxicities within 30 days of ASCR, due to multiorgan system failure (n = 2) and aspergillus infection with veno-occlusive disease (n = 1). Tumor recurred in 16 at a median of 8.5 months (range 2.3–58.5 months). Six are event-free survivors at a median of 151.2 months post-ASCR (range 127.2–201.6 months). The Kaplan–Meier estimate of median overall survival is 26.8 months (95% CI: 11.9–51.1 months) and of event-free survival (EFS) and overall survival are both 24% (95% CI: 9.8%–41.7%) at 10 years post-ASCR. M-0 (vs M-1 + ) recurrence prior to protocol, lack of tissue confirmation of relapse, and initial therapy of radiation therapy (RT) alone (vs RT + chemotherapy) were not significantly associated with better EFS (P = .33, .34, and .27, respectively). Trends toward better EFS were noted in patients (n = 5) who received additional RT as part of their retrieval therapy (P = .07) and whose recurrent disease was demonstrated to be sensitive to reinduction chemotherapy (P = .09). This retrieval strategy provides long-term EFS for some patients with previously irradiated recurrent medulloblastoma. The use of additional RT may be associated with better outcome.
PMCID: PMC2940591  PMID: 20167818
chemotherapy; hematopoietic stem cell transplantation; medulloblastoma
23.  Genome-wide quantitative assessment of variation in DNA methylation patterns 
Nucleic Acids Research  2011;39(10):4099-4108.
Genomic DNA methylation contributes substantively to transcriptional regulations that underlie mammalian development and cellular differentiation. Much effort has been made to decipher the molecular mechanisms governing the establishment and maintenance of DNA methylation patterns. However, little is known about genome-wide variation of DNA methylation patterns. In this study, we introduced the concept of methylation entropy, a measure of the randomness of DNA methylation patterns in a cell population, and exploited it to assess the variability in DNA methylation patterns of Alu repeats and promoters. A few interesting observations were made: (i) within a cell population, methylation entropy varies among genomic loci; (ii) among cell populations, the methylation entropies of most genomic loci remain constant; (iii) compared to normal tissue controls, some tumors exhibit greater methylation entropies; (iv) Alu elements with high methylation entropy are associated with high GC content but depletion of CpG dinucleotides and (v) Alu elements in the intronic regions or far from CpG islands are associated with low methylation entropy. We further identified 12 putative allelic-specific methylated genomic loci, including four Alu elements and eight promoters. Lastly, using subcloned normal fibroblast cells, we demonstrated the highly variable methylation patterns are resulted from low fidelity of DNA methylation inheritance.
PMCID: PMC3105398  PMID: 21278160
24.  BTECH: A Platform to Integrate Genomic, Transcriptomic and Epigenomic Alterations in Brain Tumors 
Neuroinformatics  2011;9(1):59-67.
The identification of molecular signatures predictive of clinical behavior and outcome in brain tumors has been the focus of many studies in the recent years. Despite the wealth of data that are available in the public domain on alterations in the genome, epigenome and transcriptome of brain tumors, the underlying molecular mechanisms leading to tumor initiation and progression remain largely unknown. Unfortunately, most of these data are scattered in multiple databases and supplementary materials of publications, thus making their retrieval, evaluation, comparison and visualization a rather arduous task. Here we report the development and implementation of an open access database (BTECH), a community resource for the deposition of a wide range of molecular data derived from brain tumor studies. This comprehensive database integrates multiple datasets, including transcript profiles, epigenomic CpG methylation data, DNA copy number alterations and structural chromosomal rearrangements, tumor-associated gene lists, SNPs, genomic features concerning Alu repeats and general genomic annotations. A genome browser has also been developed that allows for the simultaneous visualization of the different datasets and the various annotated features. Besides enabling an integrative view of diverse datasets through the genome browser, we also provide links to the original references for users to have a more accurate understanding of each specific dataset. This integrated platform will facilitate uncovering interactions among genetic and epigenetic factors associated with brain tumor development. BTECH is freely available at
Electronic supplementary material
The online version of this article (doi:10.1007/s12021-010-9091-9) contains supplementary material, which is available to authorized users.
PMCID: PMC3063551  PMID: 21210251
Database; Brain tumor; Genome browser; Genomics; Epigenomics; DNA methylation; Gene expression
25.  Phase II Study of Clofarabine in Pediatric Patients With Refractory or Relapsed Acute Myeloid Leukemia 
Journal of Clinical Oncology  2009;27(26):4392-4397.
To determine the efficacy and safety of clofarabine in pediatric patients with refractory or relapsed acute myeloid leukemia (AML).
Patients and Methods
A phase II, open-label, multicenter study was conducted with single-agent clofarabine in pediatric patients with refractory or relapsed AML. Clofarabine was administered intravenously over 2 hours at the pediatric maximum-tolerated dose (MTD) of 52 mg/m2 daily for 5 consecutive days. Cycles were repeated every 2 to 6 weeks. Responses determined by an independent response review panel.
The 42 patients treated on the study had a median age of 13 years (range, 2 to 22 years) and had received a median number of two (range, one to five) prior regimens. The response rate was 26% and included one complete response without platelet recovery and 10 partial responses. The median duration of response was 20 weeks (range, 2 to ≥ 156 weeks). Six of 28 patients who were refractory to the immediately preceding therapy achieved response. Thirteen patients (31%), including seven responders, proceeded to hematopoietic stem-cell transplantation (HSCT) after treatment with clofarabine and survived between 24 to ≥ 160 weeks. Five patients (12%) remain alive post-transplantation at ≥ 63, ≥ 71, ≥ 86, ≥ 114, and ≥ 130 weeks. The most common grade 3 or greater adverse events without regard to causality were febrile neutropenia, catheter-related infection, epistaxis, hypotension, nausea, and fever. Transient elevation of liver enzymes and hypokalemia occurred frequently. Five patients died within 30 days of clofarabine administration secondary to progressive disease, and another five died as a result of an adverse event.
Clofarabine is active in pediatric patients with multiply relapsed or refractory AML. Responses allowed several refractory patients to proceed to HSCT. The toxicity profile was expected in this patient population.
PMCID: PMC2744276  PMID: 19652076

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