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PurposeMedulloblastoma is one of the most common malignant brain tumors in children. To date, the treatment of average-risk (non-metastatic, completely resected) medulloblastoma includes craniospinal radiation therapy and adjuvant chemotherapy. Modern treatment modalities and now risk stratification of subgroups have extended the survival of these patients, exposing the long-term morbidities associated with radiation therapy. Prior to advances in molecular subgrouping, we sought to reduce the late effects of radiation in patients with average-risk medulloblastoma.MethodsWe performed a single-arm, multi-institution study, reducing the dose of craniospinal irradiation by 25% to 18 Gray (Gy) with the goal of maintaining the therapeutic efficacy as described in CCG 9892 with maintenance chemotherapy.ResultsTwenty-eight (28) patients aged 3-30 years were enrolled across three institutions between April 2001 and December 2010. Median age at enrollment was 9 years with a median follow-up time of 11.7 years. The 3-year relapse-free (RFS) and overall survival (OS) were 79% (95% confidence interval [CI] 58% to 90%) and 93% (95% CI 74% to 98%), respectively. The 5-year RFS and OS were 71% (95% CI 50% to 85%) and 86% (95% CI 66% to 94%), respectively. Toxicities were similar to those seen in other studies; there were no grade 5 toxicities.ConclusionsGiven the known neurocognitive adverse effects associated with cranial radiation therapy, studies to evaluate the feasibility of dose reduction are needed. In this study, we demonstrate that select patients with average-risk medulloblastoma may benefit from a reduced craniospinal radiation dose of 18 Gy without impacting relapse-free or overall survival.Clinical Trial RegistrationClinicalTrials.gov identifier: NCT00031590

Background: Radiation therapy (RT) plays an important role in management of pediatric central nervous system (CNS) malignancies. Centers are increasingly utilizing pencil beam scanning proton thera...

The treatment of lymphatic anomaly, a rare devastating disease spectrum of mostly unknown etiologies, depends on the patient manifestations1. Identifying the causal genes will allow for developing affordable therapies in keeping with precision medicine implementation2. Here we identified a recurrent gain-of-function ARAF mutation (c.640T>C:p.S214P) in a 12-year-old boy with advanced anomalous lymphatic disease unresponsive to conventional sirolimus therapy and in another, unrelated, adult patient. The mutation led to loss of a conserved phosphorylation site. Cells transduced with ARAF-S214P showed elevated ERK1/2 activity, enhanced lymphangiogenic capacity, and disassembly of actin skeleton and VE-cadherin junctions, which were rescued using the MEK inhibitor trametinib. The functional relevance of the mutation was also validated by recreating a lymphatic phenotype in a zebrafish model, with rescue of the anomalous phenotype using a MEK inhibitor. Subsequent therapy of the lead proband with a MEK inhibitor led to dramatic clinical improvement, with remodeling of the patient's lymphatic system with resolution of the lymphatic edema, marked improvement in his pulmonary function tests, cessation of supplemental oxygen requirements and near normalization of daily activities. Our results provide a representative demonstration of how knowledge of genetic classification and mechanistic understanding guides biologically based medical treatments, which in our instance was life-saving.

Noonan syndrome is a multiorgan system disorder mediated by genetic defects along the RASknown as RASopathies. It is the second most common syndromic cause of congenital heart disease and, in ∼20% of the cases, is associated with severe lymphatic disorders, including chylothorax and protein-losing enteropathy. Recently, we reported on the use of mitogen-activated protein kinase inhibition in a patient with an ARAF mutation and severe lymphatic disorder leading to an abrupt improvement in symptoms and complete remodeling of the central lymphatic system. Here, we present a patient with Noonan syndrome and severe lymphatic abnormality, leading to transfusion-dependent upper gastrointestinal bleeding and protein-losing enteropathy. The patient stopped responding to medical therapy and underwent several lymphatic interventional procedures, which led only to a temporary improvement in symptoms. Because of a lack of other treatment options, an expanded access approval was obtained, and the patient initiated treatment by mitogen-activated protein kinase inhibition using trametinib. This led to resolution of her symptoms, with complete normalization of her electrolyte levels, hemoglobin, and albumin within 3 months of starting the drug. Similar to the previously reported case, she also had complete and generalized remodeling of her lymphatic system. In patients with RAS pathway defects complicated by a severe lymphatic disorder, inhibition of the RAS-MAPK pathway should be considered as a possible treatment option in patients who failed conventional treatment and might be a first-line treatment in the future.

Background Lymphedema is an abnormal accumulation of interstitial fluid within the tissues. Primary lymphedema is caused by aberrant lymphangiogenesis and it has been historically classified based on age at presentation. Although most cases are sporadic, primary lymphedema may be familial or present in association with chromosomal abnormalities and syndromic disorders. To the best of our knowledge, primary lymphedema has never been described in patients with 22q11.2 deletion syndrome. Methods and results We identified 4 patients with 22q11.2 deletion syndrome and primary lymphedema via our International 22q11.2 Deletion Syndrome Consortium. All patients underwent comprehensive clinical, laboratory and imaging assessments to rule out other causes of lymphedema. All patients had de novo typical deletions and family histories were negative for lymphedema. Conclusions We report the novel association of primary lymphedema with 22q11.2 deletion syndrome. Importantly, animal models demonstrated Tbx1 playing a critical role in lymphangiogenesis by reducing Vegfr3 expression in lymphatic endothelial cells. Moreover, the VEGFR3 pathway is essential for lymphangiogenesis with mutations identified in hereditary primary lymphedema. Accordingly, our findings provide a new insight into understanding cellular mechanisms of lymphangiogenesis disorders.

The treatment of lymphatic anomaly, a rare devastating disease spectrum of mostly unknown etiologies, depends on the patient manifestations

Background: Prolonged cis-retinoic acid (RA) exposure contributes to premature epiphyseal closure. cis-RA is administered in various treatment regimens for pediatric cancers, thus increasing the risk for bone deformities and compromised growth. Results: We present a case of premature epiphyseal closure in a 9-year-old female with a history of medulloblastoma and treatment with a multimodal regimen including cis-RA. She was subsequently diagnosed with radiation-induced endocrine late effects including hypothyroidism and growth hormone deficiency (GHD). Seven months after initiation of GH therapy, an increased prominence of the wrists and knees combined with a deceleration in growth velocity prompted further evaluation; radiographs revealed bilateral premature closure of the distal femur and proximal tibia growth plates despite normal left wrist bone age. Conclusion: High doses of vitamin A and its analogs are linked to premature closure of the lower-extremity growth plates in animals and children. Pediatric brain tumor patients are at increased risk of growth failure due to concurrent radiation-induced GHD, damage to the spinal bones, and cis-RA-associated premature closure of the lower-extremity growth plates, with significant reduction in adult stature. A better appreciation of the detrimental effect of cis-RA on the growing skeleton is needed to monitor at-risk patients and to provide timely interventions.

Patients with neurofibromatosis type 1 (NF1) are at increased risk for both benign and malignant tumours, and distinguishing the malignant potential of an individual tumour is a common clinical problem in these patients. Here, we review two cases of uncommon malignancies (Hodgkin lymphoma and mediastinal germ-cell tumour) in patients with nf1. Although 18F-fluorodeoxyglucose positron-emission tomography (FDG-PET) has been used to differentiate benign neurofibromas from malignant peripheral nerve sheath tumours, FDG-PET characteristics for more rare tumours have been poorly described in children with NF1. Here, we report the role of PET imaging in clinical decision-making in each case. In NF1, FDG-PET might be useful in the clinical management of unusual tumour presentations and might help to provide information about the malignant potential of uncommon tumours.

Effective medical therapies are lacking for the treatment of neurofibromatosis type 1-related plexiform neurofibromas, which are characterized by elevated RAS-mitogen-activated protein kinase (MAPK) signaling.We conducted a phase 1 trial of selumetinib (AZD6244 or ARRY-142886), an oral selective inhibitor of MAPK kinase (MEK) 1 and 2, in children who had neurofibromatosis type 1 and inoperable plexiform neurofibromas to determine the maximum tolerated dose and to evaluate plasma pharmacokinetics. Selumetinib was administered twice daily at a dose of 20 to 30 mg per square meter of body-surface area on a continuous dosing schedule (in 28-day cycles). We also tested selumetinib using a mouse model of neurofibromatosis type 1-related neurofibroma. Response to treatment (i.e., an increase or decrease from baseline in the volume of plexiform neurofibromas) was monitored by using volumetric magnetic resonance imaging analysis to measure the change in size of the plexiform neurofibroma.A total of 24 children (median age, 10.9 years; range, 3.0 to 18.5) with a median tumor volume of 1205 ml (range, 29 to 8744) received selumetinib. Patients were able to receive selumetinib on a long-term basis; the median number of cycles was 30 (range, 6 to 56). The maximum tolerated dose was 25 mg per square meter (approximately 60% of the recommended adult dose). The most common toxic effects associated with selumetinib included acneiform rash, gastrointestinal effects, and asymptomatic creatine kinase elevation. The results of pharmacokinetic evaluations of selumetinib among the children in this trial were similar to those published for adults. Treatment with selumetinib resulted in confirmed partial responses (tumor volume decreases from baseline of ≥20%) in 17 of the 24 children (71%) and decreases from baseline in neurofibroma volume in 12 of 18 mice (67%). Disease progression (tumor volume increase from baseline of ≥20%) has not been observed to date. Anecdotal evidence of decreases in tumor-related pain, disfigurement, and functional impairment was observed.Our early-phase data suggested that children with neurofibromatosis type 1 and inoperable plexiform neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803 .).

The authors present the case of en bloc resection of a clival-C2 atypical teratoid/rhabdoid tumor. These aggressive lesions of early childhood generally occur in the cerebellum or cerebral hemispheres. This 7-year-old boy presented with pain on turning his head and was found to have a clival-C2 mass. A metastatic workup was negative for disseminated disease. A transoral biopsy procedure revealed an atypical teratoid/rhabdoid tumor on histological examination. The tumor was resected via a transoral approach, and the patient's spine was stabilized with posterior instrumented fusion from the occiput to C-5. Postoperatively, the patient underwent 16 months of chemotherapy along with 6 weeks of overlapping radiation therapy. Twenty-seven months after the initial surgery he presented with leg pain and was found to have a solitary metastatic lesion at the conus medullaris. There was no local recurrence at the clivus. The conus tumor was resected and found to be consistent with the primary tumor. Several months later the patient presented with disseminated intrathecal disease and ultimately died 42 months after the initial resection.

BACKGROUND Because few large studies of pediatric ependymoma treatment are available, the authors believed that a retrospective review of treatment outcomes from a single institution would yield potentially valuable information regarding potential prognostic factors. In this article, they report their 20-year institutional experience with this disease. METHODS Medical records were reviews of patients with intracranial ependymoma who received their initial treatment at the Children's Hospital of Philadelphia (CHOP)/Hospital of the University of Pennsylvania (HUP) between January 1980 and December 2000. Of the 61 patients who were identified, 49 patients underwent primary therapy at CHOP/HUP and formed the basis for the study. Actuarial overall survival (OS) and progression-free survival (PFS) were determined by the Kaplan-Meier method. Univariate and multivariate analyses were performed using the log-rank test and Cox proportional-hazards models. RESULTS With median follow-up of 110.2 months, the 5-year OS and PFS rates were 66.2% and 40.7%, respectively. Older age and higher radiation dose significantly predicted for improved OS. Anaplastic histology predicted for decreased PFS. Cervical spinal cord extension resulted in decreased OS primarily caused by failures outside the primary site. Patients who had a favorable prognosis (aged ≥3 years, no dissemination or cord extension, complete resection, and radiation dose ≥54 grays [Gy]) had 5-year OS and PFS rates of 83.1% and 60.6%, respectively. CONCLUSIONS In this study of patients with pediatric intracranial ependymoma, OS and PFS rates were concordant with the rates published in other modern series. The finding of a dose response up to 54 Gy supported the current trend toward dose escalation. Tumor extension to the cervical spine was identified as a predictor for failure outside of the primary site. Although the survival rates were encouraging, there is still significant room for improvement in the management of this disease. Cancer 2007. © 2007 American Cancer Society.

Recurrence of malignant brain tumors results in a poor prognosis with limited treatment options. High-dose chemotherapy with autologous hematopoietic cell rescue (AHCR) has been used in patients with recurrent malignant brain tumors and has shown improved outcomes compared with standard chemotherapy. Temozolomide is standard therapy for glioblastoma and has also shown activity in patients with medulloblastoma/primitive neuro-ectodermal tumor (PNET), particularly those with recurrent disease. Temozolomide was administered twice daily on days -10 to -6, followed by thiotepa 300 mg/m(2) per day and carboplatin dosed using the Calvert formula or body surface area on days -5 to -3, with AHCR day 0. Twenty-seven patients aged 3-46 years were enrolled. Diagnoses included high-grade glioma (n=12); medulloblastoma/PNET (n=9); central nervous system (CNS) germ cell tumor (n=4); ependymoma (n=1) and spinal cord PNET (n=1). Temozolomide doses ranged from 100 mg/m(2) per day to 400 mg/m(2) per day. There were no toxic deaths. Prolonged survival was noted in several patients including those with recurrent high-grade glioma, medulloblastoma and CNS germ cell tumor. Increased doses of temozolomide are feasible with AHCR. A phase II study using temozolomide, carboplatin and thiotepa with AHCR for children with recurrent malignant brain tumors is being conducted through the Pediatric Blood and Marrow Transplant Consortium.

Optic nerve sheath meningioma is most often discovered in adults and is relatively rare in children. We report a 12-year-old girl with an atypical primary optic nerve meningioma, which demonstrated restricted diffusion on magnetic resonance imaging and high Ki67 labeling index. The patient developed recurrence, despite aggressive surgical resection of primary tumor and local radiation. We are unaware of previous reports documenting this constellation of imaging and histopathologic findings.

RO-10. PROSPECTIVE SLOPES OVER EIGHT YEARS IN COGNITIVE MARKERS OF PHOTON RADIOTHERAPY FOR PEDIATRIC BRAIN TUMORS Carol L. Armstrong1,2, Julie Petersen1,3, Michael J. Fisher1,2, Robert A. Lustig1,2, Jane E. Minturn1,2, Jean B. Belasco1,2, Sarah Amedoro1, Cathy Bolton3, Peter C. Phillips1,2, and Christine E. Hill-Kayser1,2; The Children’s Hospital of Philadelphia, Philadelphia, PA, USA; The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Drexel University, Philadelphia, PA, USA PURPOSE: This prospective longitudinal study examined late-delayed effects (pre-treatment to 8y) of IMRT/conformal photon radiotherapy (RT) on cognition in children with brain tumors. We previously demonstrated that memory systems are affected differentially by RT, and investigated the pattern over eight years of these RT-specific cognitive markers. At the latedelayed phase, clinical information suggests a generalized decline in cognition, but no prospective studies report the late phase cognitive toxicity (.5 yr post treatment). METHODS: Participants were 28 patients with mixed primary brain tumors (18 males; age range: 4-17, M 1⁄4 9.04, SD 1⁄4 3.32; 61% had grosstotal resection)whocompletedbaseline andat leastone follow-upassessment frombaseline-8years (115 visits). Verbal-semantic memory wasassessed using a supraspan test of word memory (Rey Auditory Verbal Learning (RAVL, 4-forms)) for encoding, retrieval after interference, and retrieval after a delay. Complex Figure (CF, 2-forms) measured visuoperceptual memory immediately and after delay. Picture Recognition (PR) measured visual-semantic memory (accuracy, speed to recognize). Analyses used age-referenced Z scores in a mixed effects model; whole brain versus focal RT was a covariate. RESULTS: Verbal retrieval indices, but not encoding, were sensitive to the late-effects with progressive decline, and greater detriment in hippocampus-sensitive delayed retrieval. CF recall demonstrated continuous improvement to eight years. Bi-hemispherically processed PR demonstrated no decline over eight years. Dose burden significantly predicted retrieval but not encoding or recognition. CONCLUSIONS: Results evidence significant change over time, with differential changes in cognition, and no general decline. The sensitivity of retrieval infers multi-substrate injury not limited to hippocampus. Neuro-Oncology 18:iii159–iii164, 2016. doi:10.1093/neuonc/now082.10 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

To determine the relationship of high-contrast visual acuity (VA) and low-contrast letter acuity with retinal nerve fiber layer (RNFL) thickness in children with optic pathway gliomas.Cross-sectional convenience sample, with prospective data collection, from a tertiary care children's hospital of patients with optic pathway gliomas associated with neurofibromatosis type 1, sporadic optic pathway gliomas, and neurofibromatosis type 1 without optic pathway gliomas.Patients underwent best-corrected VA testing using surrounded H, O, T, V optotypes and low-contrast letter acuity (5%, 2.5%, and 1.25% low-contrast Sloan letter charts). Mean RNFL thickness (micrometers) was measured by a Stratus optical coherence tomography device (Carl Zeiss Meditec) using the fast RNFL thickness protocol. Eyes were classified as having abnormal vision if they had high-contrast VA of more than 0.1 logarithm of the minimal angle of resolution units or visual field loss. The association of subject age, glioma location, and RNFL thickness with both VA and low-contrast letter acuity scores was evaluated by 1-way analysis of variance and linear regression, using the generalized estimating equation approach to account for within-patient intereye correlations.Eighty-nine eyes of patients with optic pathway gliomas were included, and 41 were classified as having abnormal VA or visual field loss. Reduced RNFL thickness was associated significantly with higher logarithm of the minimal angle of resolution scores for both VA (P.001) and all low-contrast letter acuity charts (P.001) when accounting for age and glioma location.Eyes of most children with optic pathway gliomas and decreased RNFL thickness had abnormal VA or visual field loss.

Objectives To identify presenting symptoms, growth patterns, and outcomes of head and neck plexiform neurofibromas (PNs) in children with neurofibromatosis type 1 (NF-1); to determine which patients may benefit most from operative intervention in terms of duration of disease-free progression, perioperative morbidity, identification of malignancy, and symptom relief. Design A retrospective review of 39 pediatric patients with NF-1 who had PNs of the head and neck managed at a single tertiary referral center. Results Thirty-nine patients had 49 head and neck PNs, 11 small (≤5 cm) and 38 massive (>5 cm and/or involving multiple deep neck sites). Thirty-nine surgical procedures were performed on 18 of 35 patients with massive disease, and 4 procedures were performed on 4 of 11 patients with small tumors. Tumors recurred in 1 (25%) of 4 patients with small tumors and in 18 (100%) of 18 patients with massive tumors ( P = .001; mean time to regrowth, 3.1 years.) Conclusions Size and location of PN tumors most influenced presentation of clinical symptoms. Complete tumor resection was possible only in patients with small PNs. Patients with PNs of the head and neck were more likely to benefit from surgery if the indications were to (1) exclude malignancy in a rapidly enlarging mass; (2) provide relief from neurogenic pain or motor weakness; (3) improve symptoms caused by airway compression; or (4) enhance cosmesis in those with disfiguring disease.

A large proportion of children with Wilms' tumor will become long-term disease-free survivors. A small number of these children are at risk of developing second malignant neoplasms. There have been no previous reports of osteogenic sarcoma of the chest wall following treatment of Wilms' tumor. Our patient was age seven years when he received surgery, radiation therapy and chemotherapy for Wilms' tumor, eight years when he received radiation and chemotherapy for pulmonary metastases of Wilms' tumor, and 13 years when he developed osteogenic sarcoma of the chest wall.