- Neurology - Child Neurology
- Pediatric Neuro-Oncology
Pediatric Neuro-Oncology Fellowship Director, Stanford (2012 - Present)
Program Director, Neuro-Oncology Fellowship (UCNS), Stanford (2020 - Present)
Boards, Advisory Committees, Professional Organizations
Member, Executive Committee, Section of Neurology, American Academy of Pediatrics (2012 - 2018)
Treasurer (elect), Brain Tumor Epidemiology Consortium (2012 - 2014)
Medical Education: University of Missouri Kansas City School of Medicine Registrar (2000) MO
Residency: Brown University Hospitals (2002) RI
Residency: Childrens Hospital and Regional Medical Center Fellowships (2006) WA
Fellowship:, Packard Children's & Stanford Hospital, Neuro-Oncology (2007)
Masters:, Stanford University, Epidemiology (2009)
Board Certification: Neurology - Child Neurology, American Board of Psychiatry and Neurology (2007)
Board Certification: Pediatrics, American Board of Pediatrics (2007)
Board Certification: Neuro-Oncology, United Council for Neurologic Subspecialties (2011)
Current Research and Scholarly Interests
My research interests involve the epidemiology, treatment and diagnosis of pediatric and young adult brain tumors. I am also interested in long-term neurologic effects and designing clinical trials to treat brain and spinal cord tumors.
A Clinical and Molecular Risk-Directed Therapy for Newly Diagnosed Medulloblastoma
Historically, medulloblastoma treatment has been determined by the amount of leftover disease present after surgery, also known as clinical risk (standard vs. high risk). Recent studies have shown that medulloblastoma is made up of distinct molecular subgroups which respond differently to treatment. This suggests that clinical risk alone is not adequate to identify actual risk of recurrence. In order to address this, we will stratify medulloblastoma treatment in this phase II clinical trial based on both clinical risk (low, standard, intermediate, or high risk) and molecular subtype (WNT, SHH, or Non-WNT Non-SHH). This stratified clinical and molecular treatment approach will be used to evaluate the following: - To find out if participants with low-risk WNT tumors can be treated with a lower dose of radiation to the brain and spine, and a lower dose of the chemotherapy drug cyclophosphamide while still achieving the same survival rate as past St. Jude studies with fewer side effects. - To find out if adding targeted chemotherapy after standard chemotherapy will benefit participants with SHH positive tumors. - To find out if adding new chemotherapy agents to the standard chemotherapy will improve the outcome for intermediate and high risk Non-WNT Non-SHH tumors. - To define the cure rate for standard risk Non-WNT Non-SHH tumors treated with reduced dose cyclophosphamide and compare this to participants from the past St. Jude study. All participants on this study will have surgery to remove as much of the primary tumor as safely possible, radiation therapy, and chemotherapy. The amount of radiation therapy and type of chemotherapy received will be determined by the participant's treatment stratum. Treatment stratum assignment will be based on the tumor's molecular subgroup assignment and clinical risk. The participant will be assigned to one of three medulloblastoma subgroups determined by analysis of the tumor tissue for tumor biomarkers: - WNT (Strata W): positive for WNT biomarkers - SHH (Strata S): positive for SHH biomarkers - Non-WNT Non-SHH, Failed, or Indeterminate (Strata N): negative for WNT and SHH biomarkers or results are indeterminable Participants will then be assigned to a clinical risk group (low, standard, intermediate, or high) based on assessment of: - How much tumor is left after surgery - If the cancer has spread to other sites outside the brain [i.e., to the spinal cord or within the fluid surrounding the spinal cord, called cerebrospinal fluid (CSF)] - The appearance of the tumor cells under the microscope - Whether or not there are chromosomal abnormalities in the tumor, and if present, what type (also called cytogenetics analysis)
GD2 CAR T Cells in Diffuse Intrinsic Pontine Gliomas(DIPG) & Spinal Diffuse Midline Glioma(DMG)
The primary purpose of this study is to test whether GD2-CAR T cells can be successfully made from immune cells collected from children and young adults with H3K27M-mutant diffuse intrinsic pontine glioma (DIPG) or spinal H3K27M-mutant diffuse midline glioma (DMG). H3K27Mmutant testing will occur as part of standard of care prior to enrollment.
Pembrolizumab in Treating Younger Patients With Recurrent, Progressive, or Refractory High-Grade Gliomas, Diffuse Intrinsic Pontine Gliomas, Hypermutated Brain Tumors, Ependymoma or Medulloblastoma
This phase I trial studies the side effects and best dose of pembrolizumab and to see how well it works in treating younger patients with high-grade gliomas (brain tumors that are generally expected to be fast growing and aggressive), diffuse intrinsic pontine gliomas (brain stem tumors), brain tumors with a high number of genetic mutations, ependymoma or medulloblastoma that have come back (recurrent), progressed, or have not responded to previous treatment (refractory). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may induce changes in the body's immune system, and may interfere with the ability of tumor cells to grow and spread.
Phase 2 Study of Alisertib Therapy for Rhabdoid Tumors
This study incorporates alisertib, the small-molecule inhibitor of Aurora A activity, in the treatment of patients younger than 22 years of age. Patients with recurrent or refractory AT/RT or MRT will receive alisertib as a single agent. Patients with newly diagnosed AT/RT will receive alisertib as part of age- and risk-adapted chemotherapy. Radiation therapy will be given to children ≥12 months of age. Patients with AT/RT and concurrent extra-CNS MRT are eligible. Alisertib will be administered as a single agent on days 1-7 of each 21-day cycle in all recurrent patients enrolled on Stratum A. For the patients on the newly diagnosed strata (B, C or D), alisertib will be administered in sequence with chemotherapy and radiotherapy. This study has 3 primary strata: (A) children with recurrent/progressive AT/RT or extra-CNS MRT, (B) children < 36 months-old with newly diagnosed AT/RT, (C) children > 36 months old with newly diagnosed AT/RT. Children with concurrent MRT will be treated according to age and risk stratification schemes outlined for strata B and C and will have additional treatment for local control. Children with synchronous AT/RT will be treated with age and CNS risk-appropriate therapy, and also receive surgery and/or radiation therapy for local control of the non-CNS tumor. PRIMARY OBJECTIVES - To estimate the sustained objective response rate and disease stabilization in pediatric patients with recurrent or progressive AT/RT (atypical teratoid rhabdoid tumor in the CNS) (Stratum A1) treated with alisertib and to determine if the response is sufficient to merit continued investigation of alisertib in this population. - To estimate the sustained objective response rate and disease stabilization in pediatric patients with recurrent or progressive extra-CNS MRT (malignant rhabdoid tumor outside the CNS) (Stratum A2) treated with alisertib and to determine if the response is sufficient to merit continued investigation of alisertib in this population. - To estimate the 3-year PFS rate of patients with newly diagnosed AT/RT who are younger than 36 months of age at diagnosis with no metastatic disease (Stratum B1) treated with alisertib in sequence with induction and consolidation chemotherapy and radiation therapy (depending on age) and to determine if the rates are sufficient to merit continued investigation of alisertib in this population. - To estimate the 1-year PFS rate of patients with newly diagnosed AT/RT who are younger than 36 months of age at diagnosis, with metastatic disease (Stratum B2) treated with alisertib in sequence with induction and consolidation chemotherapy and to determine if the rates are sufficient to merit continued investigation of alisertib in this population. - To estimate the 3-year PFS rate of patients with newly diagnosed AT/RT who are 3 years of age or greater at diagnosis with no metastatic disease and gross total resection or near total resection (Stratum C1) treated with alisertib in sequence with radiation therapy and consolidation chemotherapy and to determine if the rates are sufficient to merit continued investigation of alisertib in this population. - To estimate the 1-year PFS rate of patients with newly diagnosed AT/RT who are 3 years of age or greater at diagnosis with metastatic or residual disease (Stratum C2) treated with alisertib in sequence with radiation therapy and consolidation chemotherapy and to determine if the rates are sufficient to merit continued investigation of alisertib in this population. - To characterize the pharmacokinetics and pharmacodynamics of alisertib in pediatric patients and to relate drug disposition to toxicity. SECONDARY OBJECTIVES - To estimate the duration of objective response and PFS in patients with recurrent/progressive AT/RT and MRT (Strata A1 and A2). - To estimate PFS and OS distributions in patients with newly diagnosed AT/RT (Strata B1, B2, B3, C1 and C2). - To describe toxicities experienced by patients treated on this trial, specifically any toxicities of alisertib when administered as a single agent or in combination with other therapy over multiple courses and toxicities related to proton or photon radiation therapy. - To describe the patterns of local and distant failure in newly diagnosed patients (Strata B1, B2, B3, C1 and C2). Local control relative to primary-site radiation therapy, with criteria for infield, marginal, or distant failure will also be reported descriptively.
Selumetinib in Treating Young Patients With Recurrent or Refractory Low Grade Glioma
This phase I/II trial studies the side effects and the best dose of selumetinib and how well it works in treating or re-treating young patients with low grade glioma that has come back (recurrent) or does not respond to treatment (refractory). Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Trial of Panobinostat in Children With Diffuse Intrinsic Pontine Glioma
This phase I trial studies the side effects and best dose of panobinostat in treating younger patients with diffuse intrinsic pontine glioma (DIPG). Panobinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Stratum 1 treats patients with DIPG that has returned or gotten worse (progressed). Stratum 2 treats patients with DIPG that has not yet gotten worse. Currently, only Stratum 2 is enrolling patients.
A Study of Pomalidomide Monotherapy for Children and Young Adults With Recurrent or Progressive Primary Brain Tumors
This study will assess the efficacy, safety and tolerability of pomalidomide in children and young adults aged 1 to < 21 years with recurrent or progressive primary brain tumors in one of four primary brain tumor types: high-grade glioma (HGG), medulloblastoma, ependymoma and diffuse intrinsic pontine glioma (DIPG).
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
Adult Study: ABT-414 Alone or ABT-414 Plus Temozolomide vs. Lomustine or Temozolomide for Recurrent Glioblastoma Pediatric Study: Evaluation of ABT-414 in Children With High Grade Gliomas
This study was conducted to evaluate the efficacy and safety of depatuxizumab mafodotin (ABT-414) alone or with temozolomide versus temozolomide or lomustine alone in adult participants with recurrent glioblastoma. The study also included a substudy to evaluate safety, tolerability and pharmacokinetics of ABT-414 in a pediatric population.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
An Open-label Safety and Tolerability Study of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy Who Previously Participated in ISIS 396443-CS1 (NCT01494701)
The primary objective of this study is to examine the safety and tolerability of nusinersen (ISIS 396443) administered intrathecally to participants with Spinal Muscular Atrophy (SMA) who previously participated in ISIS 396443-CS1 (NCT02865109). The secondary objective was to examine the plasma pharmacokinetics of a single dose of ISIS 396443 administered intrathecally to participants with SMA who previously participated in ISIS 396443-CS1.
Stanford is currently not accepting patients for this trial. For more information, please contact Shirley Paulose, 650-724-3792.
DNA Analysis of Tumor Tissue Samples From Patients With Diffuse Brain Stem Glioma
This multi-institutional study will prospectively collect tumor and constitutional tissue samples from patients with diffuse brainstem glioma and other types of brainstem gliomas either during therapy or at autopsy to perform an extensive analysis of genetic and molecular abnormalities in these tumors.
Stanford is currently not accepting patients for this trial.
Everolimus for Children With Recurrent or Progressive Ependymoma
The purpose of this study is to evaluate the anti-tumor activity of Everolimus among children with recurrent or progressive ependymoma. Recurrent or progressive ependymoma is incurable and has very limited treatment options. The rationale for this study is based upon both pre-clinical and clinical considerations: Immunohistochemistry studies have demonstrated that 20 out of 23 (87%) pediatric ependymomas are immunoreactive for phosphorylated S6, a biomarker that often predicts response to mTOR pathway-targeted therapy. Furthermore, children with with multiply recurrent ependymomas have had objective and durable responses to the mTOR inhibitor, Sirolimus (Rapamune, Pfizer). As a result of this pre-clinical and clinical data, this study will further investigate the activity of an mTOR pathway inhibitor, Everolimus, against children with recurrent or progressive ependymomas. In this study, Everolimus will be administered at a dose and schedule that have previously been demonstrated as safe and effective in children. Children may take Everolimus for up to 2 years on this study, until tumor progression or unacceptable toxicity.
Stanford is currently not accepting patients for this trial. For more information, please contact Sonia Partap, MD, 650-723-6841.
Palbociclib Isethionate in Treating Younger Patients With Recurrent, Progressive, or Refractory Central Nervous System Tumors
This phase I trial studies the side effects and best dose of palbociclib isethionate in treating younger patients with central nervous system tumors that have grown, come back, or not responded to treatment. Palbociclib isethionate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Stanford is currently not accepting patients for this trial. For more information, please contact Prianka Kumar, 650-724-3866.
The effect of insurance status on overall survival among children and adolescents with cancer.
International journal of epidemiology
BACKGROUND: Differences in access, delivery and utilisation of health care may impact childhood and adolescent cancer survival. We evaluated whether insurance coverage impacts survival among US children and adolescents with cancer diagnoses, overall and by age group, and explored potential mechanisms.METHODS: Data from 58421 children (aged ≤14years) and adolescents (15-19years), diagnosed with cancer from 2004 to 2010, were obtained from the National Cancer Database. We examined associations between insurance status at initial diagnosis or treatment and diagnosis stage; any treatment received; and mortality using logistic regression, Cox proportional hazards (PH) regression, restricted mean survival time (RMST) and mediation analyses.RESULTS: Relative to privately insured individuals, the hazard of death (all-cause) was increased and survival months were decreased in those with Medicaid [hazard ratio (HR) = 1.27, 95% confidence interval (CI): 1.22 to 1.33; and -1.73months, 95% CI: -2.07 to -1.38] and no insurance (HR = 1.32, 95% CI: 1.20 to 1.46; and -2.13months, 95% CI: -2.91 to -1.34). The HR for Medicaid vs. private insurance was larger (pinteraction <0.001) in adolescents (HR = 1.52, 95% CI: 1.41 to 1.64) than children (HR = 1.16, 95% CI: 1.10 to 1.23). Despite statistical evidence violation of the PH assumption, RMST results supported all interpretations. Earlier diagnosis for staged cancers in the Medicaid and uninsured populations accounted for an estimated 13% and 19% of the survival deficit, respectively, vs. the privately insured population. Any treatment received did not account for insurance-associated survival differences in children and adolescents with cancer.CONCLUSIONS: Children and adolescents without private insurance had a higher risk of death and shorter survival within 5 years following cancer diagnosis. Additional research is needed to understand underlying mechanisms.
View details for DOI 10.1093/ije/dyaa079
View details for PubMedID 32572489
ACR Appropriateness Criteria Cerebrovascular Disease-Child.
Journal of the American College of Radiology : JACR
2020; 17 (5S): S36–S54
Stroke is an uncommon but an important and under-recognized cause of morbidity and mortality in children. Strokes may be due to either brain ischemia or intracranial hemorrhage. Common symptoms of pediatric acute stroke include headache, vomiting, focal weakness, numbness, visual disturbance, seizures, and altered consciousness. Most children presenting with an acute neurologic deficit do not have an acute stroke, but have symptoms due to stroke mimics which include complicated migraine, seizures with postictal paralysis, and Bell palsy. Because of frequency of stroke mimics, in children and the common lack of specificity in symptoms, the diagnosis of a true stroke may be delayed. There are a relatively large number of potential causes of stroke mimic and true stroke. Consequently, imaging plays a critical role in the assessment of children with possible stroke and especially in children who present with acute onset of stroke symptoms. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
View details for DOI 10.1016/j.jacr.2020.01.036
View details for PubMedID 32370977
ACR Appropriateness Criteria Head Trauma-Child.
Journal of the American College of Radiology : JACR
2020; 17 (5S): S125–S137
Head trauma is a frequent indication for cranial imaging in children. The majority of accidental pediatric head trauma is minor and sustained without intracranial injury. Well-validated pediatric-specific clinical decision guidelines should be used to identify very low-risk children who can safely forgo imaging. In those who require acute imaging, CT is considered the first-line imaging modality for suspected intracranial injury because of the short duration of the examination and its high sensitivity for acute hemorrhage. MRI can accurately detect traumatic complications, but often necessitates sedation in children, owing to the examination length and motion sensitivity, which limits rapid assessment. There is a paucity of literature regarding vascular injuries in pediatric blunt head trauma and imaging is typically guided by clinical suspicion. Advanced imaging techniques have the potential to identify changes that are not seen by standard imaging, but data are currently insufficient to support routine clinical use. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
View details for DOI 10.1016/j.jacr.2020.01.026
View details for PubMedID 32370957
- Germline Elongator mutations in Sonic Hedgehog medulloblastoma NATURE 2020
Phase II study of peginterferon alpha-2b for patients with unresectable or recurrent craniopharyngiomas: a Pediatric Brain Tumor Consortium report.
Craniopharyngiomas account for approximately 1.2-4% of all CNS tumors. They are typically treated with a combination of surgical resection and focal radiotherapy. Unfortunately, treatment can lead to permanent deleterious effects on behavior, learning, and endocrine function.The Pediatric Brain Tumor Consortium performed a multicenter phase 2 study in children and young adults with unresectable or recurrent craniopharyngioma (PBTC-039). Between December 2013 and November 2017, 19 patients (median age at enrollment, 13.1 years, range 2-25 years) were enrolled in one of two strata: patients previously treated with surgery alone (stratum 1), or who received radiation (stratum 2).Eighteen eligible patients (8 male, 10 female) were treated with weekly subcutaneous pegylated interferon alpha-2b for up to 18 courses (108 weeks). Therapy was well-tolerated with no grade 4 or 5 toxicities. Two of the 7 eligible patients (28.6%) in stratum 1 had a partial response, but only one response was sustained for more than three months. None of the 11 stratum 2 patients had an objective radiographic response, although the median progression-free survival was 19.5 months.Pegylated interferon alpha-2b treatment, in lieu of or following radiotherapy, was well-tolerated in children and young adults with recurrent craniopharyngiomas. Although objective responses were limited, progression free survival results are encouraging warranting further studies.
View details for DOI 10.1093/neuonc/noaa119
View details for PubMedID 32393959
- A Review of Chronic Leukoencephalopathy among Survivors of Childhood Cancer PEDIATRIC NEUROLOGY 2019; 101: 2–10
- Molecular grouping and outcomes of young children with newly diagnosed ependymoma treated on the multi-institutional SJYC07 trial NEURO-ONCOLOGY 2019; 21 (10): 1319–30
ACR Appropriateness Criteria Sinusitis-Child.
Journal of the American College of Radiology : JACR
2018; 15 (11S): S403–S412
Sinusitis is common in children that usually resolves spontaneously. Imaging is not part of the standard of care for initial diagnosis, however may be necessary in cases with persistent or chronic sinusitis to guide surgical intervention, or to rule out intracranial and vascular complications of sinusitis. Computed tomography (CT) and magnetic resonance imaging (MRI) are the leading imaging modalities. In this article, appropriateness in use of imaging modalities are discussed under common/clinically relevant scenarios. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
View details for PubMedID 30392608
A phase 1/2 dose-finding, safety, and activity study of cabazitaxel in pediatric patients with refractory solid tumors including tumors of the central nervous system
PEDIATRIC BLOOD & CANCER
2018; 65 (9): e27217
This phase 1/2 study (NCT01751308) evaluated cabazitaxel in pediatric patients. Phase 1 determined the maximum tolerated dose (MTD) in patients with recurrent/refractory solid tumors, including central nervous system (CNS) tumors. Phase 2 evaluated activity in pediatric recurrent high-grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG).In phase 1, a 3 + 3 dose-escalation study design was followed. Cabazitaxel was administered at a starting dose of 20 mg/m2 . Dose-limiting toxicities (DLTs) during cycle 1 were assessed to determine the MTD. Tumor response and cabazitaxel pharmacokinetics were also assessed. In phase 2, patients received cabazitaxel at the MTD determined in phase 1. Tumor responses were assessed every 9 weeks (modified Response Assessment in Neuro-oncology criteria). Progression-free survival and cabazitaxel pharmacokinetics were evaluated, and overall survival was estimated.In phase 1, 23 patients were treated, including 19 with CNS tumors. One patient had a partial response; five had stable disease for >3 cycles. Common adverse events included fatigue, diarrhea, nausea and vomiting, febrile neutropenia, and hypersensitivity reactions. Two of three DLTs (febrile neutropenia) occurred with a dose of 35 mg/m2 ; the MTD was 30 mg/m2 . Slightly higher cabazitaxel clearance was observed compared with adult trials. In phase 2, 16 patients (eight HGG and eight DIPG) were enrolled; 11 were evaluable for response and five withdrew (three due to anaphylaxis). All 11 patients progressed within four cycles. No responses were observed; the study was stopped due to futility.The safety profile of cabazitaxel was consistent with previous studies. The MTD (30 mg/m2 ) was higher than the adult MTD. Cabazitaxel did not demonstrate activity in recurrent/refractory HGG or DIPG.
View details for PubMedID 29750396
Cerebrospinal fluid vasopressin and symptom severity in children with autism.
Annals of neurology
Autism is a brain disorder characterized by social impairments. Progress in understanding autism has been hindered by difficulty in obtaining brain-relevant tissues [e.g., cerebrospinal fluid (CSF)] by which to identify markers of disease and targets for treatment. Here we overcome this barrier by providing evidence that mean CSF concentration of the "social" neuropeptide arginine vasopressin (AVP) is lower in children with autism versus controls. CSF AVP concentration also significantly differentiates individual cases from controls and is associated with greater social symptom severity in children with autism. These findings indicate that AVP may be a promising CSF marker of autism's social deficits. This article is protected by copyright. All rights reserved.
View details for PubMedID 30152888
THE MOLECULAR AND CLINICAL LANDSCAPE OF INFANT MEDULLOBLASTOMA (IMB): RESULTS AND MOLECULAR ANALYSIS FROM A PROSPECTIVE, MULTICENTER PHASE II TRIAL (SJYC07)
OXFORD UNIV PRESS INC. 2018: 126–27
View details for Web of Science ID 000438339000442
Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial
2018; 19 (6): 768–84
Young children with medulloblastoma have a poor overall survival compared with older children, due to use of radiation-sparing therapy in young children. Radiotherapy is omitted or reduced in these young patients to spare them from debilitating long-term side-effects. We aimed to estimate event-free survival and define the molecular characteristics associated with progression-free survival in young patients with medulloblastoma using a risk-stratified treatment strategy designed to defer, reduce, or delay radiation exposure.In this multicentre, phase 2 trial, we enrolled children younger than 3 years with newly diagnosed medulloblastoma at six centres in the USA and Australia. Children aged 3-5 years with newly diagnosed, non-metastatic medulloblastoma without any high-risk features were also eligible. Eligible patients were required to start therapy within 31 days from definitive surgery, had a Lansky performance score of at least 30, and did not receive previous radiotherapy or chemotherapy. Patients were stratified postoperatively by clinical and histological criteria into low-risk, intermediate-risk, and high-risk treatment groups. All patients received identical induction chemotherapy (methotrexate, vincristine, cisplatin, and cyclophosphamide), with high-risk patients also receiving an additional five doses of vinblastine. Induction was followed by risk-adapted consolidation therapy: low-risk patients received cyclophosphamide (1500 mg/m2 on day 1), etoposide (100 mg/m2 on days 1 and 2), and carboplatin (area under the curve 5 mg/mL per min on day 2) for two 4-week cycles; intermediate-risk patients received focal radiation therapy (54 Gy with a clinical target volume of 5 mm over 6 weeks) to the tumour bed; and high-risk patients received chemotherapy with targeted intravenous topotecan (area under the curve 120-160 ng-h/mL intravenously on days 1-5) and cyclophosphamide (600 mg/m2 intravenously on days 1-5). After consolidation, all patients received maintenance chemotherapy with cyclophosphamide, topotecan, and erlotinib. The coprimary endpoints were event-free survival and patterns of methylation profiling associated with progression-free survival. Outcome and safety analyses were per protocol (all patients who received at least one dose of induction chemotherapy); biological analyses included all patients with tissue available for methylation profiling. This trial is registered with ClinicalTrials.gov, number NCT00602667, and was closed to accrual on April 19, 2017.Between Nov 27, 2007, and April 19, 2017, we enrolled 81 patients with histologically confirmed medulloblastoma. Accrual to the low-risk group was suspended after an interim analysis on Dec 2, 2015, when the 1-year event-free survival was estimated to be below the stopping rule boundary. After a median follow-up of 5·5 years (IQR 2·7-7·3), 5-year event-free survival was 31·3% (95% CI 19·3-43·3) for the whole cohort, 55·3% (95% CI 33·3-77·3) in the low-risk cohort (n=23) versus 24·6% (3·6-45·6) in the intermediate-risk cohort (n=32; hazard ratio 2·50, 95% CI 1·19-5·27; p=0·016) and 16·7% (3·4-30·0) in the high-risk cohort (n=26; 3·55, 1·66-7·59; p=0·0011; overall p=0·0021). 5-year progression-free survival by methylation subgroup was 51·1% (95% CI 34·6-67·6) in the sonic hedgehog (SHH) subgroup (n=42), 8·3% (95% CI 0·0-24·0%) in the group 3 subgroup (n=24), and 13·3% (95% CI 0·0-37·6%) in the group 4 subgroup (n=10). Within the SHH subgroup, two distinct methylation subtypes were identified and named iSHH-I and iSHH-II. 5-year progression-free survival was 27·8% (95% CI 9·0-46·6; n=21) for iSHH-I and 75·4% (55·0-95·8; n=21) for iSHH-II. The most common adverse events were grade 3-4 febrile neutropenia (48 patients [59%]), neutropenia (21 [26%]), infection with neutropenia (20 [25%]), leucopenia (15 [19%]), vomiting (15 [19%]), and anorexia (13 [16%]). No treatment-related deaths occurred.The risk-adapted approach did not improve event-free survival in young children with medulloblastoma. However, the methylation subgroup analyses showed that the SHH subgroup had improved progression-free survival compared with the group 3 subgroup. Moreover, within the SHH subgroup, the iSHH-II subtype had improved progression-free survival in the absence of radiation, intraventricular chemotherapy, or high-dose chemotherapy compared with the iSHH-I subtype. These findings support the development of a molecularly driven, risk-adapted, treatment approach in future trials in young children with medulloblastoma.American Lebanese Syrian Associated Charities, St Jude Children's Research Hospital, NCI Cancer Center, Alexander and Margaret Stewart Trust, Sontag Foundation, and American Association for Cancer Research.
View details for PubMedID 29778738
Arginine vasopressin in cerebrospinal fluid is a marker of sociality in nonhuman primates
SCIENCE TRANSLATIONAL MEDICINE
2018; 10 (439)
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by core social impairments. ASD remains poorly understood because of the difficulty in studying disease biology directly in patients and the reliance on mouse models that lack clinically relevant, complex social cognition abilities. We use ethological observations in rhesus macaques to identify male monkeys with naturally occurring low sociality. These monkeys showed differences in specific neuropeptide and kinase signaling pathways compared to socially competent male monkeys. Using a discovery and replication design, we identified arginine vasopressin (AVP) in cerebrospinal fluid (CSF) as a key marker of group differences in monkey sociality; we replicated these findings in an independent monkey cohort. We also confirmed in an additional monkey cohort that AVP concentration in CSF is a stable trait-like measure. Next, we showed in a small pediatric cohort that CSF AVP concentrations were lower in male children with ASD compared to age-matched male children without ASD (but with other medical conditions). We demonstrated that CSF AVP concentration was sufficient to accurately distinguish ASD cases from medical controls. These data suggest that AVP and its signaling pathway warrant consideration in future research studies investigating new targets for diagnostics and drug development in ASD.
View details for PubMedID 29720452
Pediatric neuro-oncology survival disparities in California
JOURNAL OF NEURO-ONCOLOGY
2018; 138 (1): 83–97
The objective of this study was to investigate racial/ethnic differences in survival for pediatric high-grade glioma (HGG) and medulloblastoma in the state of California. We obtained data from the California Cancer Registry on 552 high-grade glioma patients (110 brainstem, 442 non-brainstem) and 648 medulloblastoma patients ages 0-19 years from 1988 to 2012. Using multivariate Cox proportional hazards regression, we examined the impact of individual and neighborhood characteristics on survival. Socioeconomic quintile and insurance status differed significantly by race for both diagnoses. Hispanic children with non-brainstem HGG had worse survival than non-Hispanic white children: hazard ratio (HR) 1.62; 95% confidence interval (CI) 1.24-2.11, but the difference was mitigated some by accounting for socioeconomic status (HR 1.48, CI 1.10-1.99). Racial/ethnic differences in survival exist for children with high-grade glioma, particularly Hispanic children with non-brainstem high-grade glioma, and are likely related to sociologic factors.
View details for PubMedID 29417400
ACR Appropriateness Criteria® Headache-Child.
Journal of the American College of Radiology : JACR
2018; 15 (5S): S78–S90
Headaches in children are not uncommon and have various causes. Proper neuroimaging of these children is very specific to the headache type. Care must be taken to choose and perform the most appropriate initial imaging examination in order to maximize the ability to properly determine the cause with minimum risk to the child. This evidence-based report discusses the different headache types in children and provides appropriate guidelines for imaging these children. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
View details for PubMedID 29724429
Biomarker Discovery for Social Impairments: Translation From a Novel Monkey Model to Patients With Autism
NATURE PUBLISHING GROUP. 2017: S501–S502
View details for Web of Science ID 000416846303041
Irreversible growth plate fusions in children with medulloblastoma treated with a targeted hedgehog pathway inhibitor
2017; 8 (41): 69295–302
The permanent defects in bone growth observed in preclinical studies of hedgehog (Hh) pathway inhibitors were not substantiated in early phase clinical studies of vismodegib in children. Consequently, vismodegib advanced into pediatric trials for malignancies suspected of being driven by aberrant activation of the Hh pathway. In one multicenter phase II trial, vismodegib was added to the therapy regimen for newly diagnosed Hh pathway activated medulloblastoma. Herein, we report on 3 children (2 on trial and one off trial) treated with vismodegib who developed widespread growth plate fusions that persist long after cessation of therapy. Currently, all 3 patients exhibit profound short stature and disproportionate growth, and 2 subsequently developed precocious puberty. Notably, the growth plate fusions only developed after a prolonged exposure to the drug (> 140 days). These findings resulted in a major trial amendment to restrict the agent to skeletally mature patients as well as a product label warning and update. Moreover, these findings alter the risk-benefit ratio of Hh inhibitors and underscore the importance of careful study of targeted agents in children.
View details for PubMedID 29050204
Pediatric cancer risk in association with birth defects: A systematic review
2017; 12 (7): e0181246
Many epidemiological studies have examined associations between birth defects (BDs) and pediatric malignancy over the past several decades. Our objective was to conduct a systematic literature review of studies reporting on this association.We used librarian-designed searches of the PubMed Medline and Embase databases to identify primary research articles on pediatric neoplasms and BDs. English language articles from PubMed and Embase up to 10/12/2015, and in PubMed up to 5/12/2017 following an updated search, were eligible for inclusion if they reported primary epidemiological research results on associations between BDs and pediatric malignancies. Two reviewers coded each article based on the title and abstract to identify eligible articles that were abstracted using a structured form. Additional articles were identified through reference lists and other sources. Results were synthesized for pediatric cancers overall and for nine major pediatric cancer subtypes.A total of 14,778 article citations were identified, of which 80 met inclusion criteria. Pediatric cancer risk was increased in most studies in association with BDs overall with some notable specific findings, including increased risks for CNS tumors in association with CNS abnormalities and positive associations between rib anomalies and several pediatric cancer types.Some children born with BDs may be at increased risk for specific pediatric malignancy types. This work provides a foundation for future investigations that are needed to clarify specific BD types predisposing toward malignancy and possible underlying causes of both BDs and malignancy.
View details for PubMedID 28749971
AN ANALYSIS OF IMMUNOPHENOTYPE, INCLUDING PD-L1 AND PD1 EXPRESSION, IN PEDIATRIC CNS MALIGNANCIES: A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY
OXFORD UNIV PRESS INC. 2017: 29
View details for Web of Science ID 000402766800123
Suspected Physical Abuse-Child.
Journal of the American College of Radiology
2017; 14 (5S): S338-S349
The youngest children, particularly in the first year of life, are the most vulnerable to physical abuse. Skeletal survey is the universal screening examination in children 24 months of age and younger. Fractures occur in over half of abused children. Rib fractures may be the only abnormality in about 30%. A repeat limited skeletal survey after 2 weeks can detect additional fractures and can provide fracture dating information. The type and extent of additional imaging for pediatric patients being evaluated for suspected physical abuse depends on the age of the child, the presence of neurologic signs and symptoms, evidence of thoracic or abdominopelvic injuries, and social considerations. Unenhanced CT of the head is the initial study for suspected intracranial injury. Clinically occult abusive head trauma can occur, especially in young infants. Therefore, head CT should be performed in selected neurologically asymptomatic physical abuse patients. Contrast-enhanced CT of the abdomen/pelvis is utilized for suspected intra-abdominal or pelvic injury. Particular attention should be paid to discrepancies between the patterns of injury and the reported clinical history. Making the diagnosis of child abuse also requires differentiation from anatomical and developmental variants and possible underlying metabolic and genetic conditions. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
View details for DOI 10.1016/j.jacr.2017.01.036
View details for PubMedID 28473090
Journal of the American College of Radiology
2017; 14 (5S): S13-S24
It is now generally accepted that nontraumatic back pain in the pediatric population is common. The presence of isolated back pain in a child has previously been an indication for imaging; however, recently a more conservative approach has been suggested using clinical criteria. The presence of constant pain, night pain, and radicular pain, alone or in combination, lasting for 4 weeks or more, constitute clinical red flags that should prompt further imaging. Without these clinical red flags, imaging is likely not indicated. Exceptions include an abnormal neurologic examination or clinical and laboratory findings suggesting an infectious or neoplastic etiology, and when present should prompt immediate imaging. Initial imaging should consist of spine radiographs limited to area of interest, with spine MRI without contrast to evaluate further if needed. CT of the spine, limited to area of interest, and Tc-99m bone scan whole body with single-photon emission computed tomography may be useful in some patients. The addition of intravenous contrast is also recommended for evaluation of a potential neoplastic or infectious process. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
View details for DOI 10.1016/j.jacr.2017.01.039
View details for PubMedID 28473069
JOURNAL OF CHILD NEUROLOGY
2016; 31 (12): 1354-1366
Over the past 150 years since Virchow's initial characterization of ependymoma, incredible efforts have been made in the classification of these tumors and in the care of pediatric patients with this disease. While the advent of modern neurosurgery and the optimization of radiation have provided significant gains, a more complex but incomplete picture of pediatric ependymomas has begun to form through a combination of international collaborations and detailed genetic and histologic characterizations. This review includes and synthesizes the clinical understanding of pediatric ependymoma and their developing molecular insight into what is truly a family of malignancies in which distinct members require different surgical approaches, radiation plans, and targeted therapies.
View details for DOI 10.1177/0883073815610428
View details for Web of Science ID 000384470800002
View details for PubMedID 26503805
CHILDREN WITH MEDULLOBLASTOMA AND HIGH-GRADE GLIOMA: RACIAL/ETHNIC AND SOCIOECONOMIC DISPARITIES IN SURVIVAL OUTCOME
OXFORD UNIV PRESS INC. 2016: 40
View details for Web of Science ID 000379749000153
CHILDREN WITH MEDULLOBLASTOMA AND HIGH-GRADE GLIOMA: RACIAL/ETHNIC AND SOCIOECONOMIC DISPARITIES IN SURVIVAL OUTCOME
WILEY-BLACKWELL. 2016: S69
View details for Web of Science ID 000374306900245
Cerebrospinal fluid and plasma oxytocin concentrations are positively correlated and negatively predict anxiety in children
2015; 20 (9): 1085-1090
The neuropeptide oxytocin (OXT) exerts anxiolytic and prosocial effects in the central nervous system of rodents. A number of recent studies have attempted to translate these findings by investigating the relationships between peripheral (e.g., blood, urinary and salivary) OXT concentrations and behavioral functioning in humans. Although peripheral samples are easy to obtain in humans, whether peripheral OXT measures are functionally related to central OXT activity remains unclear. To investigate a possible relationship, we quantified OXT concentrations in concomitantly collected cerebrospinal fluid (CSF) and blood samples from child and adult patients undergoing clinically indicated lumbar punctures or other CSF-related procedures. Anxiety scores were obtained in a subset of child participants whose parents completed psychometric assessments. Findings from this study indicate that plasma OXT concentrations significantly and positively predict CSF OXT concentrations (r=0.56, P=0.0064, N=27). Moreover, both plasma (r=-0.92, P=0.0262, N=10) and CSF (r=-0.91, P=0.0335, N=10) OXT concentrations significantly and negatively predicted trait anxiety scores, consistent with the preclinical literature. Importantly, plasma OXT concentrations significantly and positively (r=0.96, P=0.0115, N=10) predicted CSF OXT concentrations in the subset of child participants who provided behavioral data. This study provides the first empirical support for the use of blood measures of OXT as a surrogate for central OXT activity, validated in the context of behavioral functioning. These preliminary findings also suggest that impaired OXT signaling may be a biomarker of anxiety in humans, and a potential target for therapeutic development in individuals with anxiety disorders.Molecular Psychiatry advance online publication, 4 November 2014; doi:10.1038/mp.2014.132.
View details for DOI 10.1038/mp.2014.132
View details for Web of Science ID 000360175500009
Arginine Vasopressin Is a Blood-Based Biomarker of Social Functioning in Children with Autism
2015; 10 (7)
Brain arginine vasopressin (AVP) critically regulates normative social behavior in mammals, and experimental disruption of the AVP signaling pathway produces social impairments in rodent models. We therefore hypothesized that AVP signaling deficits may contribute to social impairments in children with autism spectrum disorder (ASD). Since blood measures (which are far easier to obtain than brain measures) of AVP are most meaningful if they are related to brain AVP activity, Study 1 tested the relationship between AVP concentrations in concomitantly collected blood and CSF samples from children and adults (N = 28) undergoing clinical procedures. Study 2 tested whether blood AVP concentrations: 1) differed between children with ASD (N = 57), their ASD discordant siblings (N = 47), and neurotypical controls (N = 55); and 2) predicted social functioning (using the NEPSY-II Theory of Mind and Affect Recognition tasks and the Social Responsiveness Scale) in this large, well-characterized child cohort. Blood AVP concentrations significantly and positively predicted CSF AVP concentrations (F1,26 = 7.17, r = 0.46, p = 0.0127) in Study 1. In Study 2, blood AVP concentrations did not differ between groups or by sex, but significantly and positively predicted Theory of Mind performance, specifically in children with ASD, but not in non-ASD children (F1,144 = 5.83, p = 0.017). Blood AVP concentrations can be used: 1) as a surrogate for brain AVP activity in humans; and 2) as a robust biomarker of theory of mind ability in children with ASD. These findings also suggest that AVP biology may be a promising therapeutic target by which to improve social cognition in individuals with ASD.
View details for DOI 10.1371/journal.pone.0132224
View details for Web of Science ID 000358597100030
View details for PubMedCentralID PMC4511760
IMPACT OF MOLECULAR SUB-TYPE AND CRANIOSPINAL IRRADIATION (CSI) DOSE ON RELAPSE OF MEDULLOBLASTOMA
OXFORD UNIV PRESS INC. 2015: 22
View details for Web of Science ID 000361304800088
Decreased tumor apparent diffusion coefficient correlates with objective response of pediatric low-grade glioma to bevacizumab
JOURNAL OF NEURO-ONCOLOGY
2015; 122 (3): 491-496
Recent small, retrospective series suggest bevacizumab may be a therapeutic option for recurrent pediatric low-grade glioma (LGG). Assessment of therapeutic responses is complicated by the unpredictable natural history of these tumors. Because diffusion-weighted imaging quantifies microscopic water motion affected by cellular density and histologic features, we hypothesized that it may be helpful in monitoring therapeutic response of LGG to bevacizumab. We retrospectively reviewed eight consecutive patients, median age 4.8 (range 2.3-12.3) years at initiation of bevacizumab therapy for recurrent or refractory LGG. Patients received 10 mg/kg/dose every 2 weeks (median 16 doses/therapy course). Mean apparent diffusion coefficient (ADC) was measured and analyzed in respect to tumor volume. Following the first treatment course, seven of eight patients had reduced tumor volume (≥25 %) and ADC. The median decrease in tumor volume was 47% (range -6 to 78 %) and the median decrease in ADC was 14 % (range -5 to 30 %). The ADC was significantly decreased during therapy, whereas the decrease in volume was seen only after therapy completion. There was a positive correlation between percent change in tumor volume and ADC (p < 0.05). We report a decrease in tumor ADC during initial bevacizumab therapy that is accompanied by a decrease in volume following therapy. Imaging changes in microscopic water motion associated with histology may be useful in monitoring the therapeutic response of LGG to bevacizumab.
View details for DOI 10.1007/s11060-015-1754-9
View details for Web of Science ID 000354717800008
View details for PubMedID 25758812
Clinical course and progression-free survival of adult intracranial and spinal ependymoma patients
2015; 17 (3): 440-447
Ependymomas are rare CNS tumors. Previous studies describing the clinical course of ependymoma patients were restricted to small sample sizes, often with patients at a specific institution.Clinically annotated ependymoma tissue samples from 19 institutions were centrally reviewed. Patients were all adults aged 18 years or older at the time of diagnosis. Potential prognostic clinical factors identified on univariate analysis were included in a multivariate Cox proportional hazards model with backwards selection to model progression-free survival.The 282 adult ependymoma patients were equally male and female with a mean age of 43 years (range, 18-80y) at diagnosis. The majority were grade II (78%) with the tumor grade for 20 cases being reclassified on central review (half to higher grade). Tumor locations were spine (46%), infratentorial (35%), and supratentorial (19%). Tumor recurrence occurred in 26% (n = 74) of patients with a median time to progression of 14 years. A multivariate Cox proportional hazards model identified supratentorial location (P < .01), grade III (anaplastic; P < .01), and subtotal resection, followed or not by radiation (P < .01), as significantly increasing risk of early progression.We report findings from an ongoing, multicenter collaboration from a collection of clinically annotated adult ependymoma tumor samples demonstrating distinct predictors of progression-free survival. This unique resource provides the opportunity to better define the clinical course of ependymoma for clinical and translational studies.
View details for DOI 10.1093/neuonc/nou162
View details for Web of Science ID 000352479700016
View details for PubMedID 25121770
Sports and childhood brain tumors: Can I play?
2014; 1 (4): 158-165
It is unknown whether children with brain tumors have a higher risk of complications while participating in sports. We sought to estimate the prevalence of such events by conducting a systematic review of the literature, and we surveyed providers involved with pediatric central nervous system (CNS) tumor patients.A systematic review of the literature in the PubMed, Scopus, and Cochrane databases was conducted for original articles addressing sport-related complications in the brain-tumor population. An online questionnaire was created to survey providers involved with pediatric CNS tumor patients about their current recommendations and experience regarding sports and brain tumors.We retrieved 32 subjects, including 19 pediatric cases from the literature. Most lesions associated with sport complications were arachnoid cysts (n = 21), followed by glioma (n = 5). The sports in which symptom onset most commonly occurred were soccer (n = 7), football (n = 5), and running (n = 5). We surveyed 111 pediatric neuro-oncology providers. Sport restriction varied greatly from none to 14 sports. Time to return to play in sports with contact also varied considerably between providers. Rationales for limiting sports activities were partly related to subspecialty. Responders reported 9 sport-related adverse events in patients with brain tumor.Sport-related complications are uncommon in children with brain tumors. Patients might not be at a significantly higher risk and should not need to be excluded from most sports activities.
View details for PubMedID 26034627
Childhood Brain Tumor Epidemiology: A Brain Tumor Epidemiology Consortium Review
CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION
2014; 23 (12): 2716-2736
Childhood brain tumors are the most common pediatric solid tumor and include several histological subtypes. Although progress has been made in improving survival rates for some subtypes, understanding of risk factors for childhood brain tumors remains limited to a few genetic syndromes and ionizing radiation to the head and neck. In this report, we review descriptive and analytical epidemiology childhood brain tumor studies from the past decade and highlight priority areas for future epidemiology investigations and methodological work that is needed to advance our understanding of childhood brain tumor causes. Specifically, we summarize the results of a review of studies published since 2004 that have analyzed incidence and survival in different international regions and that have examined potential genetic, immune system, developmental and birth characteristics, and environmental risk factors.
View details for DOI 10.1158/1055-9965.EPI-14-0207
View details for Web of Science ID 000345967300014
MRI surrogates for molecular subgroups of medulloblastoma.
AJNR. American journal of neuroradiology
2014; 35 (7): 1263-1269
Recently identified molecular subgroups of medulloblastoma have shown potential for improved risk stratification. We hypothesized that distinct MR imaging features can predict these subgroups.All patients with a diagnosis of medulloblastoma at one institution, with both pretherapy MR imaging and surgical tissue, served as the discovery cohort (n = 47). MR imaging features were assessed by 3 blinded neuroradiologists. NanoString-based assay of tumor tissues was conducted to classify the tumors into the 4 established molecular subgroups (wingless, sonic hedgehog, group 3, and group 4). A second pediatric medulloblastoma cohort (n = 52) from an independent institution was used for validation of the MR imaging features predictive of the molecular subtypes.Logistic regression analysis within the discovery cohort revealed tumor location (P < .001) and enhancement pattern (P = .001) to be significant predictors of medulloblastoma subgroups. Stereospecific computational analyses confirmed that group 3 and 4 tumors predominated within the midline fourth ventricle (100%, P = .007), wingless tumors were localized to the cerebellar peduncle/cerebellopontine angle cistern with a positive predictive value of 100% (95% CI, 30%-100%), and sonic hedgehog tumors arose in the cerebellar hemispheres with a positive predictive value of 100% (95% CI, 59%-100%). Midline group 4 tumors presented with minimal/no enhancement with a positive predictive value of 91% (95% CI, 59%-98%). When we used the MR imaging feature-based regression model, 66% of medulloblastomas were correctly predicted in the discovery cohort, and 65%, in the validation cohort.Tumor location and enhancement pattern were predictive of molecular subgroups of pediatric medulloblastoma and may potentially serve as a surrogate for genomic testing.
View details for DOI 10.3174/ajnr.A3990
View details for PubMedID 24831600
UNRAVELING THE TALE OF MEDULLOBLASTOMA: IMPACT OF MOLECULAR SUB-TYPE AND CRANIOSPINAL IRRADIATION (CSI) DOSE ON RELAPSE
OXFORD UNIV PRESS INC. 2014: 82–83
View details for Web of Science ID 000337924200313
Time-dependent structural changes of the dentatothalamic pathway in children treated for posterior fossa tumor.
AJNR. American journal of neuroradiology
2014; 35 (4): 803-807
Injury to the dentatothalamic pathway that originates in the cerebellum has been suggested as a mechanism for neurologic complications in children treated for posterior fossa tumors. We hypothesized that time-dependent changes occur in the dentatothalamic pathway.Diffusion tensor evaluation was performed in 14 children (median age, 4.1 years; age range, 1-20 years) who underwent serial MR imaging at 3T as part of routine follow-up after posterior fossa tumor resection with or without adjuvant therapy. Tensor metrics were obtained in the acute (≤1 week), subacute (1 to <6 months), and chronic (≥6 months) periods after surgery. We evaluated the following dentatothalamic constituents: bilateral dentate nuclei, cerebellar white matter, and superior cerebellar peduncles. Serial dentate nuclei volumes were also obtained and compared with the patient's baseline.The most significant tensor changes to the superior cerebellar peduncles and cerebellar white matter occurred in the subacute period, regardless of the tumor pathology or therapy regimen, with signs of recovery in the chronic period. However, chronic volume loss and reduced mean diffusivity were observed in the dentate nuclei and did not reverse. This atrophy was associated with radiation therapy and symptoms of ataxia.Longitudinal diffusion MR imaging in children treated for posterior fossa tumors showed time-dependent tensor changes in components of the dentatothalamic pathway that suggest evolution of structural damage with inflammation and recovery of tissue directionality. However, the dentate nuclei did not show tensor or volumetric recovery, suggesting that the injury may be chronic.
View details for DOI 10.3174/ajnr.A3735
View details for PubMedID 24052507
Surveillance imaging in children with malignant CNS tumors: low yield of spine MRI.
Journal of neuro-oncology
2014; 116 (3): 617-623
Magnetic resonance imaging (MRI) is routinely obtained in patients with central nervous system (CNS) tumors, but few studies have been conducted to evaluate this practice. We assessed the benefits of surveillance MRI and more specifically spine MRI in a contemporary cohort. We evaluated MRI results of children diagnosed with CNS tumors from January 2000 to December 2011. Children with at least one surveillance MRI following the diagnosis of medulloblastoma (MB), atypical teratoid rhabdoid tumor (ATRT), pineoblastoma (PB), supratentorial primitive neuroectodermal tumor, supratentorial high-grade glioma (World Health Organization grade III-IV), CNS germ cell tumors or ependymoma were included. A total of 2,707 brain and 1,280 spine MRI scans were obtained in 258 patients. 97 % of all relapses occurred in the brain and 3 % were isolated to the spine. Relapse was identified in 226 (8 %) brain and 48 (4 %) spine MRI scans. The overall rate of detecting isolated spinal relapse was 9/1,000 and 7/1,000 for MB patients. MRI performed for PB showed the highest rate for detecting isolated spinal recurrence with 49/1,000. No initial isolated spinal relapse was identified in patients with glioma, supratentorial primitive neuroectodermal tumor and ATRT. Isolated spinal recurrences are infrequent in children with malignant CNS tumors and the yield of spine MRI is very low. Tailoring surveillance spine MRI to patients with higher spinal relapse risk such as PB, MB with metastatic disease and within 3 years of diagnosis could improve allocation of resources without compromising patient care.
View details for DOI 10.1007/s11060-013-1347-4
View details for PubMedID 24401959
Relapse patterns in pediatric embryonal central nervous system tumors
JOURNAL OF NEURO-ONCOLOGY
2013; 115 (2): 209-215
Embryonal tumors of the central nervous system (CNS) share histological features and were therefore initially grouped as primitive neuroectodermal tumors (PNET) and treated similarly. We sought to determine the relapse patterns of specific embryonal CNS tumors. We conducted a historical cohort study of children diagnosed with CNS embryonal tumors from January 2000 to December 2011 in two pediatric neuro-oncology centers. Patients of 21 years of age or younger at time of presentation with a diagnosis of medulloblastoma, supratentorial PNET, pineoblastoma or atypical teratoid/rhabdoid tumor (ATRT) and at least one surveillance MRI were included. A total of 133 patients met inclusion criteria and 49 (37 %) patients relapsed during the observation period. The majority (79 %) of sPNET relapses were local, whereas all (100 %) PB relapses were associated with diffuse leptomeningeal disease. Relapse patterns for MB were more diverse with local recurrence in 27 %, distant recurrence in 35 % and diffuse leptomeningeal disease in 38 %. The frequency of relapses involving the spine differed (p < 0.001) between tumor types (MB 28/55 [51 %], sPNET 3/33 [9 %], ATRT 3/7 [43 %] and PB 12/12 [100 %]). No sPNET patients had isolated spinal relapse (0/14). Embryonal tumors were found to have divergent patterns of recurrence. While medulloblastoma has variable relapse presentations, sPNET relapses locally and pineoblastoma recurs with diffuse leptomeningeal disease involving the spine. These results point toward possibly new upfront treatment stratification among embryonal tumors in accordance with relapse pattern.
View details for DOI 10.1007/s11060-013-1213-4
View details for PubMedID 23921420
MEDULLOBLASTOMA IN THE OPERATIVE THEATER: ARE THEY PLAYING ACCORDING TO THEIR SUBTYPES?
OXFORD UNIV PRESS INC. 2013: 168
View details for Web of Science ID 000327456200666
Increased focal hemosiderin deposition in pediatric medulloblastoma patients receiving radiotherapy at a later age Clinical article
JOURNAL OF NEUROSURGERY-PEDIATRICS
2013; 12 (5): 444-451
Object Focal hemosiderin deposition (FHD) is commonly observed on brain MRI scans of patients treated for childhood medulloblastoma (MB). The authors sought to determine the clinical significance of FHD and its relationship to patient age, radiation dose, and cognitive outcomes. Methods A single-institution retrospective study of 93 MB patients at Lucile Packard Children's Hospital at Stanford from 1998 to 2011 identified 41 patients with a negative baseline MRI scan and at least 2 posttreatment MRI scans obtained with T2* gradient recalled echo (GRE). The number and cumulative rate of FHDs detectable by GRE were compared between patients aged 6 years and younger (early age) and aged 7-21 years (late age) at the time of radiotherapy (RT) and between low-dose (1800-2340 cGy) and high-dose (2920-3960 cGy) RT. Results The median age at MB diagnosis was 7.3 years (range 0.9-21.0 years), the median clinical follow-up period was 5.8 years (range 0.8-13.4 years), and the median 5-year overall survival was 81% ± 7%. Of 30 school-aged children with MB, 21 (70%) required special education, and the median IQ of 10 tested patients was 100 (range 50-118). Thirty-three patients (80%) had FHD after a median latency of 1.9 years (range 0.1-5.9 years). Ninety-four percent (436 of 466) of the lesions arose in the supratentorial region of the brain, whereas 29 (6%) resided in the brainstem or the cerebellum. No spinal lesions were observed on routine spine MRI scans using T2 fast spin echo imaging. The mean cumulative lesion rate per year was 2.23 ± 3.05, and this rate was higher in older children at the time of RT compared with younger children (3.23 vs 0.67 per year, p = 0.002) but did not differ among different RT doses (p = 0.395). A child's IQ or need for special education showed no significant correlation with the rate of lesion development or number of lesions. None of the lesions resulted in symptomatic hemorrhage that required surgical intervention. Conclusions More FHD was observed in children treated for MB at the older ages than in those treated at the younger ages. There was no significant association of the incidence of FHD with radiation dose or cognitive outcomes, and none of the lesions required surgical intervention.
View details for DOI 10.3171/2013.7.PEDS1330
View details for Web of Science ID 000325956400005
Histological Predictors of Outcome in Ependymoma are Dependent on Anatomic Site Within the Central Nervous System
2013; 23 (5): 584-594
Ependymomas originate in posterior fossa (PF), supratentorial (ST) or spinal cord (SC) compartments. At present, grading schemes are applied independent of anatomic site. We performed detailed histological examination on 238 World Health Organization grade II and III ependymomas. Among PF ependymomas, the presence of hypercellular areas, necrosis, microvascular proliferation and elevated mitotic rate (all P < 0.01) were significantly associated with worse progression-free survival (PFS), while extensive ependymal canal formation was not (P = 0.89). Similar to the PF tumors, microvascular proliferation (P = 0.01) and elevated mitotic rate (P = 0.03) were significantly associated with worse PFS in the ST tumors. However, in contrast to PF tumors, extensive ependymal canals (P = 0.03) were associated with worse clinical outcome in ST ependymomas, but hypercellularity (P = 0.57) and necrosis (P = 0.47) were not. On multivariate Cox regression, after adjusting for relevant clinical variables, individual histological factors and a composite histological score remained significant among ST and PF ependymoma. In contrast to both PF and ST ependymoma, histological features were not found to be associated with PFS in SC tumors. Taken together, the clinical relevance of specific histological features in ependymoma appears to be related to the anatomic site of origin and suggests that site-specific grading criteria be considered in future classification systems.
View details for DOI 10.1111/bpa.12050
View details for Web of Science ID 000329280700009
View details for PubMedID 23452038
Prognostic role for diffusion-weighted imaging of pediatric optic pathway glioma.
Journal of neuro-oncology
2013; 113 (3): 479-483
Optic pathway glioma (OPG) has an unpredictable course, with poor correlation between conventional imaging features and tumor progression. We investigated whether diffusion-weighted MRI (DWI) predicts the clinical behavior of these tumors. Twelve children with OPG (median age 2.7 years; range 0.4-6.2 years) were followed for a median 4.4 years with DWI. Progression-free survival (time to requiring therapy) was compared between tumors stratified by apparent diffusion coefficient (ADC) from initial pre-treatment scans. Tumors with baseline ADC greater than 1,400 × 10(-6) mm(2)/s required treatment earlier than those with lower ADC (log-rank p = 0.002). In some cases, ADC increased leading up to treatment, and declined following treatment with surgery, chemotherapy, or radiation. Baseline ADC was higher in tumors that eventually required treatment (1,562 ± 192 × 10(-6) mm(2)/s), compared with those conservatively managed (1,123 ± 114 × 10(-6) mm(2)/s) (Kruskal-Wallis test p = 0.013). Higher ADC predicted earlier tumor progression in this cohort and in some cases declined after therapy. Evaluation of OPG with DWI may therefore be useful for predicting tumor behavior and assessing treatment response.
View details for DOI 10.1007/s11060-013-1140-4
View details for PubMedID 23673514
Distinctive MRI Features of Pediatric Medulloblastoma Subtypes
AMERICAN JOURNAL OF ROENTGENOLOGY
2013; 200 (4): 895-903
We hypothesized that the apparent diffusion coefficient (ADC) and other MRI features can be used to predict medulloblastoma histologic subtypes, as defined by the World Health Organization (WHO) in WHO Classification of Tumours of the Central Nervous System.A retrospective review of pediatric patients with medulloblastoma between 1989 and 2011 identified 38 patients with both pretreatment MRI and original pathology slides. The mean and minimum tumor ADC values and conventional MRI features were compared among medulloblastoma histologic subtypes.The cohort of 38 patients included the following histologic subtypes: 24 classic medulloblastomas, nine large cell (LC) or anaplastic medulloblastomas, four desmoplastic medulloblastomas, and one medulloblastoma with extensive nodularity. The median age at diagnosis was 8 years (range, 1-21 years) and the median follow-up time was 33 months (range, 0-150 months). The mean ADC (× 10(-3) mm(2)/s) was lower in classic medulloblastoma (0.733 ± 0.046 [SD]) than in LC or anaplastic medulloblastoma (0.935 ± 0.127) (Mann-Whitney test, p = 0.004). Similarly, the minimum ADC was lower in classic medulloblastoma (average ± SD, 0.464 ± 0.056) than in LC or anaplastic medulloblastoma (0.630 ± 0.053) (p = 0.004). The MRI finding of focal cysts correlated with the classic and desmoplastic subtypes (Fisher exact test, p = 0.026). Leptomeningeal enhancement positively correlated with the LC or anaplastic medulloblastoma subtype and inversely correlated with the classic medulloblastoma and desmoplastic medulloblastoma subtypes (p = 0.04). Ring enhancement correlated with tumor necrosis (p = 0.022) and with the LC or anaplastic medulloblastoma histologic subtype (p < 0.001).The LC or anaplastic medulloblastoma subtype was associated with increased ADC and with ring enhancement, the latter of which correlated with tumor necrosis. These features could be considered in the evaluation of high-risk medulloblastoma subtypes.
View details for DOI 10.2214/AJR.12.9249
View details for PubMedID 23521467
Concurrent cyclophosphamide and craniospinal radiotherapy for pediatric high-risk embryonal brain tumors
JOURNAL OF NEURO-ONCOLOGY
2012; 110 (2): 287-291
Embryonal tumors are an aggressive subtype of high-grade, pediatric central nervous system (CNS) tumors often with dismal survival rates. The 5-year survival for highest-risk embryonal tumors may be as low as 10 %. We report feasibility and efficacy from our experience using intravenous (IV) cyclophosphamide concurrently with craniospinal radiation (CSI) in high-risk embryonal CNS tumors of childhood. Ten consecutive children (aged: 3.5-15.5 years, median: 10.2 years, six male) with high-risk embryonal tumors, including: large cell/anaplastic medulloblastoma (6), atypical teratoid rhabdoid tumor (1), and leptomeningeal primitive neuroectodermal tumor (3), were treated with IV cyclophosphamide 1 g/M(2) on days 1 and 2 of CSI. Following a median of 36 Gy CSI plus tumor boosts, adjuvant treatment consisted of 21 doses of oral etoposide (7) and alkylator based chemotherapy from five to eight cycles in all. Of the ten patients thus treated, six remain alive with no evidence of disease and four are deceased. Median survival was 3.3 years, with a 3-year progression-free survival of 50 % (5/10). Median follow-up was: 3.3 years (range: 5 months-12.9 years) in the five patients with progression, median time-to-progression was: 1.3 years (range: 1 month-3 years). Median follow-up in the patients without progression is 8.8 years (range: 3-12.9 years). Complications due to adjuvant chemotherapy were typical and included myelosupression (10), necessitating shortened duration of chemotherapy in three, and hemorrhagic cystitis (1). In high-risk embryonal CNS tumors, cyclophosphamide given concurrently with CSI is well tolerated. Early results suggest that a phase II trial is warranted.
View details for DOI 10.1007/s11060-012-0969-2
View details for Web of Science ID 000311208100017
View details for PubMedID 22941430
DIFFERENT RELAPSE PATTERNS IN EMBRYONAL CNS TUMORS
OXFORD UNIV PRESS INC. 2012: 123
View details for Web of Science ID 000310971300486
SHOULD WE EXPECT SYMPTOMS AT RELAPSE?
OXFORD UNIV PRESS INC. 2012: 127
View details for Web of Science ID 000310971300505
INJURY TO DENTATE NUCLEI AND EFFERENT FIBERS BY PEDIATRIC POSTERIOR FOSSA TUMORS
OXFORD UNIV PRESS INC. 2012: 132–33
View details for Web of Science ID 000308394400499
Aggressive Cerebellar Neuroepithelial Tumor in a 10 Year Old Boy
LIPPINCOTT WILLIAMS & WILKINS. 2012: 572
View details for Web of Science ID 000304589600100
SURVEILLANCE SPINE MRIS TO DETECT TUMOR RELAPSE IN PATIENTS WITH MEDULLOBLASTOMA
OXFORD UNIV PRESS INC. 2012: 143
View details for Web of Science ID 000308394400542
Stroke and Cerebrovascular Complications in Childhood Cancer Survivors
SEMINARS IN PEDIATRIC NEUROLOGY
2012; 19 (1): 18-24
The outcomes for childhood cancer have drastically improved over the last several decades. Previously, irradiation was commonly used for blood-borne (leukemia, lymphoma) cancers and neck and brain tumors. Radiation therapy remains the mainstay of treatment for highly malignant cancers of head and neck and for some primary central nervous system tumors. Unfortunately, radiation therapy has been implicated as a contributor to many late effects of treatment, including cerebrovascular disease from large-vessel vascular injury, stroke, moyamoya, mineralizing microangiopathy, to stroke-like migraine. This review summarizes the pathophysiology of these disorders in relationship to treatment with and without radiation as well as the relevant manifestations of radiation-induced cerebrovascular disease. Patient populations at highest risk and current recommendations for health providers and patient education are emphasized when possible.
View details for DOI 10.1016/j.spen.2012.02.012
View details for Web of Science ID 000305263900004
View details for PubMedID 22641072
PROGNOSTIC ROLE OF DIFFUSION-WEIGHTED MRI IN PEDIATRIC OPTIC PATHWAY GLIOMA
OXFORD UNIV PRESS INC. 2011: 139–40
View details for Web of Science ID 000297026600547
Birth Anomalies and Obstetric History as Risks for Childhood Tumors of the Central Nervous System
2011; 128 (3): E652-E657
The causes of childhood central nervous system (CNS) tumors are largely unknown. Birth characteristics have been examined as possible risk factors for childhood CNS tumors, although the studies have been underpowered and inconclusive. We hypothesized that birth anomalies and a mother's history of previous pregnancy losses, as a proxy for genetic defects, increase the risk for CNS tumors.From the California Cancer Registry, we identified 3733 patients aged 0 to 14 years with CNS tumors, diagnosed from 1988 through 2006 and linked to a California birth certificate. Four controls were matched to each patient. We calculated odds ratios (ORs) for the reported presence of a birth defect and for history of pregnancy losses by using logistic regression, adjusted for race, Hispanic ethnicity, maternal age, birth weight, and birth order.Offspring from mothers who had ≥ 2 fetal losses after 20 weeks' gestation had a threefold risk for CNS tumors (OR: 3.13 [95% confidence interval (CI): 1.32-7.41]) and a 14-fold risk for high-grade glioma (OR: 14.28 [95% CI: 1.56-130.65]). Birth defects increased risk for the CNS cancers medulloblastoma (OR: 1.70 [95% CI: 1.12-2.57]), primitive neuroectodermal tumor (OR: 3.64 [95% CI: 1.54-8.56]), and germ cell tumors (OR: 6.40 [95% CI: 2.09-19.56]).Multiple pregnancy losses after 20 weeks' gestation and birth defects increase the risk of a childhood CNS tumor. Previous pregnancy losses and birth defects may be surrogate markers for gene defects in developmental pathways that lead to CNS tumorigenesis.
View details for DOI 10.1542/peds.2010-3637
View details for Web of Science ID 000295406100022
View details for PubMedID 21824884
View details for PubMedCentralID PMC3164097
Liposomal cytarabine for central nervous system embryonal tumors in children and young adults
JOURNAL OF NEURO-ONCOLOGY
2011; 103 (3): 561-566
To assess the tolerability and efficacy of liposomal cytarabine (LC), an encapsulated, sustained-release, intrathecal (IT) formulation of cytosine arabinoside, in de novo and relapsed central nervous system (CNS) embryonal tumors in children and young adults. We studied retrospectively all patients less than age 30 at our institution treated consecutively with LC for medulloblastoma (MB), primitive neuroectodermal tumor (PNET), and atypical teratoid rhabdoid tumor (ATRT). Seventeen patients received LC (2 mg/kg up to 50 mg, every 2 weeks to monthly) at diagnosis of high-risk CNS embryonal tumor (2 PNET, 3 ATRT) or relapse of MB (12 MB; 9 had leptomeningeal metastases). Sixteen patients received concurrent systemic chemotherapy. A total of 108 doses were administered (IT 82, intraventricular 26) with a mean of six (range 1-16) treatments per patient. Only three administrations were associated with adverse effects of arachnoiditis or headache. None developed malignant cerebrospinal fluid (CSF) cytology while receiving LC. All the six evaluable patients with malignant CSF cytology and treated with at least two doses cleared their CSF (mean 3 doses, range 1-5). Median overall survival in relapse patients was 9.1 months. Five patients (4 de novo and 1 relapsed) remain alive in complete remission for a median 26.8 months from first LC. Liposomal cytarabine is an easily administered, well-tolerated, and active drug in patients with high-risk embryonal neoplasms. One-third of our cohort remains in remission from otherwise fatal diagnoses. Our findings warrant a phase II trial of LC in newly diagnosed or recurrent CNS embryonal tumors.
View details for DOI 10.1007/s11060-010-0419-y
View details for PubMedID 20859651
Effect of chronic red cell transfusion therapy on vasculopathies and silent infarcts in patients with sickle cell disease
AMERICAN JOURNAL OF HEMATOLOGY
2011; 86 (1): 104-106
Regular, chronic red cell transfusions (CTX) have been shown to be effective prophylaxis against stroke in sickle cell disease (SCD) in those at risk. Because serial brain imaging is not routinely performed, little is known about the impact of CTX on silent infarcts (SI) and cerebral vascular pathology. Thus, we retrospectively evaluated the magnetic resonance imaging reports of a cohort of SCD patients who were prescribed CTX for either primary or secondary stroke prophylaxis. Seventeen patients with Hb SS were included (mean age 15 years, mean follow-up 4.3 years). Eight patients were on CTX for primary prophylaxis. New SI occurred in 17.6% of patients corresponding to an SI rate of 5.42 per 100 patient-years. Vasculopathy of the cerebral arteries was present in 65% of patients and progressed in 63% of these patients. Those who developed progressive vasculopathy were on CTX for an average of 8 years before lesions progressed. Patients on CTX for secondary prophylaxis had more SIs and evidence of progressive vascular disease than patients on CTX for primary prophylaxis. We conclude that adherence to CTX does not necessarily prevent SI or halt cerebral vasculopathy progression, especially in those with a history of overt stroke.
View details for DOI 10.1002/ajh.21901
View details for PubMedID 21117059
Birth Weight and Order as Risk Factors for Childhood Central Nervous System Tumors
JOURNAL OF PEDIATRICS
2010; 157 (3): 450-455
To determine whether birth characteristics related to maternal-fetal health in utero are associated with the development of childhood central nervous system tumors.We identified, from the California Cancer Registry, 3733 children under age 15 diagnosed with childhood central nervous system tumors between 1988 and 2006 and linked these cases to their California birth certificates. Four controls per case, matched on birth date and sex, were randomly selected from the same birth files. We evaluated associations of multiple childhood CNS tumor subtypes with birth weight and birth order.Low birth weight was associated with a reduced risk of low-grade gliomas (OR=0.67; 95% CI, 0.46 to 0.97) and high birth weight was associated with increased risk of high-grade gliomas (OR=1.57; 95% CI, 1.16 to 2.12). High birth order (fourth or higher) was associated with decreased risk of low-grade gliomas (OR=0.75; 95% CI, 0.56 to 0.99) and increased risk of high-grade gliomas (OR=1.32; 95% CI, 1.01 to 1.72 for second order).Factors that drive growth in utero may increase the risk of low-grade gliomas. There may be a similar relationship in high-grade gliomas, although other factors, such as early infection, may modify this association. Additional investigation is warranted to validate and further define these findings.
View details for DOI 10.1016/j.jpeds.2010.04.006
View details for Web of Science ID 000281116100023
View details for PubMedID 20553692
- Embryonal Tumors PEDIATRIC CNS TUMORS, SECOND EDITION 2010: 89–114
Cerebrovascular disease in childhood cancer survivors A Children's Oncology Group Report
2009; 73 (22): 1906-1913
Curative therapy for childhood cancer has dramatically improved over past decades. Therapeutic radiation has been instrumental in this success. Unfortunately, irradiation is associated with untoward effects, including stroke and other cerebrovascular disease (CVD). The Children's Oncology Group (COG) has developed guidelines for screening survivors at risk for persistent or late sequelae of cancer therapy.This review summarizes the pathophysiology and relevant manifestations of radiation-induced CVD and outlines the specific patient groups at risk for early-onset stroke. The reader will be alerted to the availability of the COG recommendations for monitoring, and, when applicable, specific screening and treatment recommendations will be highlighted.A multidisciplinary task force critically reviewed the existing literature and scored the evidence to establish the current COG guidelines for monitoring health of survivors treated with head and neck irradiation.Previous head and neck exposure to therapeutic radiation is associated with latent CVD and increased risk for stroke in some patient groups. Common manifestations of radiation-induced CVD includes steno-occlusive disease, moyamoya, aneurysm, mineralizing microangiopathy, vascular malformations, and strokelike migraines.Risk for stroke is increased in survivors of pediatric CNS tumors, Hodgkin lymphoma, and acute lymphoblastic leukemia who received radiation to the brain and/or neck. As the population of survivors ages, vigilance for stroke and cerebrovascular disease needs to continue based on specific exposures during curative cancer therapy.
View details for DOI 10.1212/WNL.0b013e3181c17ea8
View details for Web of Science ID 000272205200015
View details for PubMedID 19812380
View details for PubMedCentralID PMC2788797
Medulloblastoma Incidence has not Changed Over Time A CBTRUS Study
JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY
2009; 31 (12): 970-971
Earlier studies have reported changes in the incidence of medulloblastoma (MB) but have conflicted, likely because of small sample size or misclassification of MB with primitive neuroectodermal tumor (PNET). The incidence of MB and PNET from 1985 to 2002 was determined from the Central Brain Tumor Registry of the United States, a large population-based cancer registry, using strict histologic and site codes. No statistically significant change in MB incidence was observed over the last 2 decades, but there was an increase in MB and PNET combined.
View details for Web of Science ID 000272658700019
View details for PubMedID 19887963
Levetiracetam For Seizures in Children With Brain Tumors and Other Cancers
PEDIATRIC BLOOD & CANCER
2009; 52 (2): 288-289
Children with brain tumors and other cancers can suffer from seizures. Unfortunately, most antiepileptic therapies are metabolized by the hepatic cytochrome P450 (CYP) system. Levetiracetam, a newer anticonvulsant, does not undergo CYP metabolism and does not alter the pharmacokinetics of chemotherapy, antiemetics, and corticosteroids, which are metabolized by the liver. We studied 23 patients with cancer and seizures treated with levetiracetam. Over 95% of patients had fewer seizures, with 65.2% becoming seizure free; only one patient experienced an adverse reaction. Levetiracetam is effective and well tolerated in children with brain tumors and other cancers, who are often on multiple enzyme-inducing drugs.
View details for DOI 10.1002/pbc.21772
View details for Web of Science ID 000261796000032
View details for PubMedID 18831033
- Neurological complications in children. Cancer treatment and research 2009; 150: 133-143
Epidemiology of Pediatric Central Nervous System Germ Cell Tumors: A California Cancer Registry Study
WILEY-LISS. 2008: S152
View details for Web of Science ID 000262112100044
GENDER, BIRTH SEASONALITY, AND BIRTH DEFECTS AS RISK FACTORS FOR PEDIATRIC BRAIN TUMORS: A CALIFORNIA CANCER REGISTRY STUDY
OXFORD UNIV PRESS INC. 2008: 779–80
View details for Web of Science ID 000259854500088
Perinatal risk factors for childhood brain tumors: A California case-control study
DUKE UNIV PRESS. 2008: 415
View details for Web of Science ID 000256974900172
- 50 years ago in The Journal of Pediatrics - Jacksonian seizures in infancy and childhood JOURNAL OF PEDIATRICS 2008; 152 (6): 800
Epidemiology of pediatric CNS germ cell tumors: A California Cancer Registry study
DUKE UNIV PRESS. 2008: 413
View details for Web of Science ID 000256974900165
Update on new treatments and developments in childhood brain tumors
CURRENT OPINION IN PEDIATRICS
2007; 19 (6): 670-674
Childhood primary central nervous system tumors remain a therapeutic conundrum. As the second most common pediatric cancer, brain tumors lead to significantly worse survival and long-term effects compared with those seen with hematologic malignancies and other solid tumors. This review discusses current management strategies in three pediatric brain tumors, the long-term effects of therapy, as well as novel laboratory findings that may alter future treatment strategies.The current literature focuses on tactics to predict those at risk of treatment failure and long-term effects. By analyzing tumors at a molecular genetics level rather than traditional histology, new data have begun to emerge on methods to begin to consider targeted therapies, tailored to the individual child. Furthermore, as survivorship has improved with current radiation and chemotherapy regimens, long-term effects have been identified and merit clinical attention.Even though long-term survival for children with a brain tumor approaches 70%, the need for improved treatment regimens is striking. Secondary malignancies, neurocognitive deficits and treatment failure continue to afflict these children and young adults. The current review will inform clinicians of the challenges faced by basic scientists and clinicians when treating brain tumors, and point to future research directions.
View details for Web of Science ID 000251347800010
View details for PubMedID 18025934
- 50 Years Ago in The Journal of Pediatrics: Agenesis of the corpus callosum: report of eight cases in infancy. JOURNAL OF PEDIATRICS 2007; 150 (4): 399
- 50 Years Ago in The Journal of Pediatrics: Low cerebrospinal fluid glucose associated with meningeal neoplasia JOURNAL OF PEDIATRICS 2007; 151 (2): 177
Spontaneously relapsing and remitting primary CNS lymphoma in an immunocompetent 45-year-old man
JOURNAL OF NEURO-ONCOLOGY
2006; 80 (3): 305-307
A 45-year-old immunocompetent man with primary central nervous system lymphoma (PCNSL) presented with multiple spontaneous relapses and remissions in the absence of steroid treatment. Because of the fluctuations with improvement in both the clinical course and MRI findings, alternative disorders were considered that led to delay of diagnosis and treatment prior to brain biopsy. This case and a handful of others with single remissions emphasize that PCNSL cannot be reliably ruled out by improving or disappearing symptoms, signs or traditional MR imaging abnormalities.
View details for DOI 10.1007/s11060-006-9192-3
View details for Web of Science ID 000243002600011
View details for PubMedID 16794747
Complications of a temozolomide overdose: a case report
JOURNAL OF NEURO-ONCOLOGY
2006; 80 (1): 57-61
This is a report of a 53 year-old man with a glioblastoma multiforme (GBM) treated with an excessive dose of temozolomide (TMZ).This is a single case review of all clinically relevant records. O6-methylguanine-DNA methyltransferase activity was determined by a biochemical assay.Following conventional radiotherapy (RT) without concurrent chemotherapy, the patient received 5,500 mg of TMZ over 2 days. At the standard dose of 200 mg/m2/day his total 5-day dose should have been 1,940 mg. Acutely he had nausea, vomiting and diarrhea for 2 days which cleared. The dominant severe toxicity was pancytopenia between one and four weeks after TMZ which was complicated by secondary infections that were successfully managed. Transient transaminitis occurred but there were no significant pulmonary, renal or other systemic toxicities. His progression free survival was 22 months and overall survival 24 months.His outcome suggests that TMZ may prove to be a good agent for dose-escalation trials with hematopoietic stem cell rescue.
View details for DOI 10.1007/s11060-006-9152-y
View details for Web of Science ID 000240802300009
View details for PubMedID 16645714
Prolonged but reversible migraine-like episodes long after cranial irradiation
2006; 66 (7): 1105-1107
The authors describe three patients with prolonged but reversible episodes of severe headaches and focal neurologic deficits developing years after irradiation for cranial neoplasms. Despite extensive evaluations, etiology of episodes in these three and eight other previously reported patients remains undetermined. Whether they all have the same condition is uncertain. Although some had cortical gadolinium enhancement on MRI, all 11 patients returned to baseline over hours to weeks.
View details for Web of Science ID 000236673300030
View details for PubMedID 16606929