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Context Children with brain tumors may have pubertal onset at an inappropriately young chronologic age. Hypothalamic-pituitary irradiation ≥18Gy has been found to be a risk factor; age at irradiation is associated with pubertal timing. However, the underlying mechanisms are unknown. Objective To determine the impact of body mass index (BMI) and catch-up growth on pubertal timing in females treated for medulloblastoma and other embryonal tumors. Design, Setting, and Patients Retrospective cohort analysis of 90 female patients treated for medulloblastoma and other embryonal tumors at Dana-Farber Cancer Institute/Boston Children’s Hospital from 1996 to 2016. Eighteen individuals met inclusion criteria, with a mean ± SD follow-up period of 11.9 ± 3.4 years. Main Outcome Measures Multiple linear regression models for age at pubertal onset and bone age discrepancy from chronologic age at pubertal onset assessed the joint influences of age at irradiation, hypothalamic irradiation dose, undernutrition duration, BMI standard deviation score (SDS) at pubertal onset, and catch-up BMI SDS. Results The mean ± SD age of pubertal onset was 9.2 ± 1.3 years and hypothalamic radiation dose was 31.9 ± 9.9 Gy. There was a direct relationship between age at irradiation and age at pubertal onset (β = 0.323 ± 0.144 [standard error] year per year; P = 0.04) that was significantly attenuated after adjusting for BMI SDS at pubertal onset (P = 0.5) and catch-up BMI SDS (P = 0.08), suggesting that BMI is a mediator. Conclusions Both absolute and catch-up BMI SDS at pubertal onset are significant mediators of pubertal timing and bone age discrepancy in pediatric medulloblastoma and other embryonal tumors, and thus, are targetable risk factors to optimize pubertal timing.

Background Medulloblastoma is an aggressive central nervous system (CNS) tumor that occurs mostly in the pediatric population. Treatment often includes a combination of surgical resection, craniospinal irradiation (CSI), and chemotherapy. Children who receive standard photon CSI are at risk for cardiac toxicities including coronary artery disease, left ventricular scarring and dysfunction, valvular damage, and atherosclerosis. Current survivorship guidelines recommend routine echocardiogram (ECHO) surveillance. In this multi-institutional study, we describe markers of cardiac dysfunction in medulloblastoma survivors. Methods A retrospective chart review of medulloblastoma patients who had photon beam CSI was followed by ECHO between 1980 and 2010 at Lurie Children’s Hospital and Dana-Farber/Boston Children’s Hospital. Results During the 30-year study period, 168 medulloblastoma patient records were identified. Included in this study were the 75 patients who received CSI or spinal radiation and ECHO follow-up. The mean age at CSI was 8.6 years (range, 2.9-20), and the mean number of years between radiation therapy (RT) completion and first ECHO was 7.4 (range, 2-16). Mean ejection fraction (EF) was 60.0% and shortening fraction (SF) was 33.8%. Five patients (7%) had abnormal ECHO results: three with EF Conclusion The majority of medulloblastoma patients who received CSI have relatively normal ECHOs post-treatment; however, 7% of patients had abnormal ECHOs. The implication of our study for medulloblastoma survivors is that further investigations are needed in this population with a more systematic, longitudinal assessment to determine predictors and screenings.

Objectives Damage to the posterior cerebellum can cause affective deficits in patients. In adults, cerebellar infarcts result in thermal hyperalgesia and affect descending modulation of pain. This study evaluated the effect of resection of low‐grade cerebellar tumors on pain processing in human children. Methods Twelve pediatric patients treated with surgery only for low‐grade gliomas (8 females, 4 males; mean age = 13.8 ± 5.6) and twelve matched controls (8 females, 4 males; mean age = 13.8 ± 5.7) were evaluated using quantitative sensory testing and fMRI. Five patients had tumors localized to posterior cerebellar hemispheres, henceforth identified as Crus Patients. Results Crus Patients had significantly lower pain tolerance to a cold pressor test than controls. No significant differences were detected between subject groups for heat and cold detection thresholds (HDT, CDT), and heat and cold pain thresholds (HPT, CPT). Crus Patients also showed significantly decreased fMRI responses to painful heat in anterior insula, which has been associated with pain affect. Interpretation Damage to posterior cerebellar hemispheres disrupted affective pain processing and endogenous pain modulation, resulting in decreased pain tolerance to suprathreshold noxious stimuli. This suggests that surgical resection of this region in children may increase the risk of developing pain disorders.

BACKGROUND Medulloblastoma is an aggressive central nervous system (CNS) tumor that occurs mostly in the pediatric population. Treatment includes surgical resection, craniospinal radiation (CSI) and chemotherapy. Children who receive standard photon radiation (RT) are at risk for cardiac toxicities. Potential late effects include coronary artery disease, left ventricular scarring and dysfunction, valvular damage and atherosclerosis. Current survivorship guidelines recommend routine ECHO surveillance for these patients but this comes at significant health care costs over a lifetime. We describe the experience of cardiac dysfunction in medulloblastoma survivors in a multi-institution study. METHODS A retrospective chart review of medulloblastoma patients treated between 1980 and 2010 with radiation at Lurie Children’s Hospital and Dana-Farber/ Boston Children’s Hospital who had an echocardiogram done following completion of therapy. RESULTS 168 patients were treated for medulloblastoma during the study time. Of whom, 80 patients had echocardiogram follow up and 76 received photon irradiation. The latter were included in the study. The mean age at CSI was 8.6 years (range 2.9- 20), and mean number of years post RT at echocardiogram 7.4 years (range 2–16). Mean ejection fraction (EF) was 60.03% and shortening fraction (SF) 33.8%. Four patients (5%) had abnormal results, all of which had EF CONCLUSION Patients who received craniospinal irradiation for medulloblastoma therapy have relatively normal echocardiograms post treatment. Although RT may result in cardiac risks, echocardiograms may not be the most cost effective or efficacious mode to evaluate the risk in these survivors long term.

INTRODUCTION The incidence of IDH mutations in pediatric glioma is unclear. Recent publications suggest rates ranging between 0–20%. Therapy poses challenges as it is unclear if the biology and prognosis of pediatric IDH-mutant gliomas are identical to adults. METHODS We performed an IRB approved, systematic retrospective search for IDH-mutant gliomas in the Dana-Farber Cancer Institute/Boston Children’s Hospital database between 2009–2018, analyzing incidence, demographics, histology, co-occurring genetic alterations and outcome. RESULTS We identified 575 patients with glioma, ages 0–21 years. Of these, 394 underwent biopsy/resection (0–9 years:n=204; 10–21 years:n=190), with 294 genetic testing. Fifteen of 294 tumors (5%) were IDH1-mutant. Among patients 0–9 years and 10–21 years, 1/156 (0.6%) and 14/138 (10%) had IDH1-mutant tumors, respectively. Among patients 10–21 year old, 13/115 low-grade gliomas were IDH1-mutant (11%). High-grade gliomas accounted for the remaining 23, with one IDH1-mutant glioma (4%). Most common co-occurring genetic alterations for diffuse astrocytoma (n=12) were TP53 (n=9) and ATRX (n=2). Three patients with IDH1-mutant oligodendrogliomas had 1p/19q deletion. Eleven IDH1-mutant patients were evaluable for outcomes with median follow-up of five years. Five-year radiation-free, progression-free and overall survival for patients with low-grade histology were 76% and 100%, respectively. One patient with high-grade glioma recurred 1.2 years after upfront chemo-radiation and died soon after recurrence. CONCLUSION IDH-mutant gliomas comprise a small proportion of pediatric gliomas. Incidence rate is higher in the second decade of life. Comparative analyses between pediatric IDH-mutant gliomas and adult historical cohorts are currently underway, evaluating outcomes, radiation therapy and frequency of malignant transformation.

INTRODUCTION Immune checkpoint inhibition through PD-1 and CTLA-4 blockade has shown efficacy in some adult malignancies and is being investigated in pediatrics. We describe our institutional experience with immune checkpoint inhibition in pediatric CNS tumors. METHODS We performed a retrospective chart review of patients with recurrent, progressive, or refractory pediatric CNS tumors treated with immunotherapy at Dana-Farber/Boston Children’s Hospital between 2018–2019. RESULTS Eleven patients were identified, with median age of 11 years (range:3–9). Diagnoses included DIPG (n=3), HGG (n=4), ependymoma (n=1), craniopharyngioma (n=1), HGNET (n=1) and NGGCT (n=1). Eight patients had recurrent disease (5 local; 3 disseminated); three had refractory disease (non-recurrent). Nine patients were treated with combination therapy (ipilimumab/nivolumab); two patients received monotherapy with either nivolumab or pembrolizumab. Median time from initial diagnosis-to-treatment was 8 months (range 0.8–156). Ten patients received radiation therapy (RT) prior to immunotherapy, with one receiving concurrent RT. Median duration of treatment was 6.1 months (range:1–19). Therapy was discontinued in nine patients: seven due to disease progression and two due to adverse events (colitis, transaminitis). Other pertinent toxicities included type 1 diabetes, hypothyroidism and skin toxicity. Based on iRANO criteria, best responses included partial (n=4), stable (n=6) and progressive disease (n=1). Durable response (>12months) was noted in two patients (HGG and progressive NGGCT). CONCLUSION Immune checkpoint inhibition appears to have clinical benefit and is relatively well tolerated in this cohort of patients. Results from recently completed prospective clinical trials will be critical to inform clinical decisions.

INTRODUCTION: Pediatric low-grade gliomas (pLGGs) are the most common CNS tumor of childhood and comprise a heterogenous group of tumors. Children with progressive pLGG typically require numerous regimens of therapy including surgical resection, chemotherapy and rarely, radiation therapy. The presence of frequent genetic alterations activating the mitogen-activated-protein-kinase (MAPK) signaling pathway has recently led to a more targeted therapeutic approach. We describe our institutional experience using trametinib, an FDA-approved MEK inhibitor for recurrent/progressive pLGGs. METHODS: We performed a retrospective, IRB approved, chart review of all patients with recurrent/progressive pLGGs treated with trametinib off-study at Dana-Farber / Boston’s Children’s Cancer and Blood Disorder Center between 2016–2018. RESULTS: Eleven patients were identified, with ten evaluable for response. Median age at commencement of trametinib treatment was 14.7 years old (range 7.3–25.9 years; 6 male: 5 female). Molecular status included KIAA 1549-BRAF fusion (n=3), NF1 (n=4), FGFR mutation and heterozygous CDKN2A loss (n=1 each), unknown mutational status (n=2). Median number of prior treatment regimens was 5 (range 1–7). Median duration on treatment with trametinib was 13.4 months (range 1.5–24.8 months). Based on RANO criteria, responses included partial (n=1), minor response (n=1) and stable disease (n=5) as best response. Four patients remain on therapy with trametinib (range 1.5–24.8 months) with two patients having discontinued therapy secondary to disease progression. The most common toxicities were skin rash, fatigue and gastrointestinal disturbance. Five patients required dose reduction for toxicities. Two patients experienced intracranial hemorrhage (ICH) while on trametinib (at 5 and 498 days). While it is unclear whether ICH was directly attributable to trametinib, therapy was discontinued. CONCLUSION: Trametinib appears to be an effective treatment for patients with recurrent/progressive pLGG. The toxicities of this therapy warrant further investigation, particularly the potential risk for intracranial hemorrhage. Early phase clinical trials are underway.

INTRODUCTION: Ependymoma is the third commonest malignant CNS tumor in children. Despite multimodal therapy, prognosis of relapsed ependymoma remains poor with long-term progression-free survival (PFS) of approximately 30%. Approaches to treating relapsed ependymoma are extremely varied. Here, we describe our experience and clinical outcomes of children after first relapse of intracranial ependymoma. METHODS: We performed a retrospective, IRB approved, chart review of patients with recurrent intracranial ependymoma treated at Dana-Farber / Boston Children’s Cancer and Blood Disorder Center from 1990 to 2017. RESULTS: Thirty-four patients with relapsed intracranial ependymoma (12 ST, 21 PF, 1 metastatic) were identified. Median time-to-first-relapse was 13.7 months (range:2.0–53.8). Eight patients had metastatic disease at first relapse. Five-year PFS and overall survival (OS) after first relapse was 23.5% and 60.9%, respectively. Median PFS and OS were 12 months and 66 months. Treatments for first relapse included surgery, radiation and/or chemotherapy/biologic therapy. GTR and localized disease were associated with improved OS on univariate analysis, with GTR being an independent prognostic factor for PFS and OS on multivariate analysis (p=0.02 & 0.013, respectively). Median PFS and OS for patients with GTR was 1.5 and 13 years, respectively (versus 0.4 and 2.3 years for STR / no resection [p=0.023 & 0.001, respectively]). Eighteen patients received radiation at first relapse (14 focal radiation, 8 re-irradiation). Patients who were radiated/re-irradiated at relapse showed longer median PFS and OS, however, these did not meet statistical significance. Chemotherapeutic (n=16) and biologic agents (n=3) used in this cohort were heterogenous and did not significantly impact outcome. Median time-to-second-relapse was 10.2 months (range:2.0–124.8). CONCLUSION: Relapsed intracranial ependymoma has a poor prognosis and unrelenting chronic course despite multimodal therapy. GTR is associated with improved outcomes after first relapse and should be pursued when possible. Novel therapeutic strategies are needed for this disease.

BACKGROUND Pediatric low-grade gliomas are among the most common childhood neoplasms, yet their post-treatment surveillance remains nonstandardized, relying on arbitrarily chosen imaging intervals. OBJECTIVE To optimize postoperative magnetic resonance imaging (MRI) surveillance protocols for pediatric low-grade gliomas. METHODS Patients aged 0 to 21 yr with pediatric low-grade gliomas, treated between 1990 and 2016 were retrospectively analyzed. The timing of surveillance imaging and radiologic tumor outcomes were extracted, and the effect of patient age, tumor location, histology, and extent of resection as prognostic factors was studied. An algorithm was developed to analyze the detection efficacy and cost of all possible surveillance protocols. RESULTS A total of 517 patients were included with a median follow-up of 7.7 yr (range: 2-25.1 yr) who underwent 8061 MRI scans (mean 15.6 scans per patient). Tumor recurrence was detected radiologically in 292 patients (56.5%), of whom, 143 underwent reoperation. The hazards ratio (HR) of recurrence was higher in patients who underwent biopsy (HR = 3.60; 95% confidence interval (CI): 2.45-5.30; P

Background Preclinical models show that an antiangiogenic regimen at low-dose daily (metronomic) dosing may be effective against chemotherapy-resistant tumors. We undertook a prospective, open-label, single-arm, multi-institutional phase II study to evaluate the efficacy of a “5-drug” oral regimen in children with recurrent or progressive cancer. Procedure Patients ≤21 years old with recurrent or progressive tumors were eligible. Treatment consisted of continuous oral celecoxib, thalidomide, and fenofibrate, with alternating 21-day cycles of low-dose cyclophosphamide and etoposide. Primary endpoint was to assess, within eight disease strata, activity of the 5-drug regimen over 27 weeks. Blood and urine angiogenesis markers were assessed. Results One hundred one patients were enrolled; 97 began treatment. Median age was 10 years (range: 191 days–21 years); 47 (49%) were female. Disease strata included high-grade glioma (HGG, 21 patients), ependymoma (19), low-grade glioma (LGG, 12), bone tumors (12), medulloblastoma/primitive neuroectodermal tumor (PNET, 8), leukemia (4), neuroblastoma (3), and miscellaneous tumors (18). Treatment was generally well tolerated; most common toxicities were hematologic. Twenty-four (25%) patients completed 27 weeks therapy without progression, including HGG: 1 (5%), ependymoma: 7 (37%), LGG: 7 (58%), medulloblastoma/PNET: 1, neuroblastoma: 1, and miscellaneous tumors: 7 (39%). Best response was complete response (one patient with medulloblastoma), partial response (12), stable disease (36), progressive disease (47), and inevaluable (1). Baseline serum thrombospondin levels were significantly higher in patients successfully completing therapy than in those who progressed (P = 0.009). Conclusion The 5-drug regimen was well tolerated. Clinical activity was demonstrated in some but not all tumor strata. Pediatric Blood Cancer 2014;61:636–642. © 2013 The Authors Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.