Search

Background Pediatric brain tumor survivors (PBTS) are at risk of worse quality of life (QOL) due to the impact of neurotoxic treatments on the developing nervous system. Parenting factors such as protectiveness have been linked to worse QOL in childhood cancer survivors generally, but have yet to be explored for PBTS. We examined whether parenting behaviors moderated the association between neurotoxic treatment and QOL for PBTS. Methods PBTS (n = 40; ages 10–25) and their caregivers (n = 47) completed measures of parenting behaviors including warmth (support/connectedness) and psychological control (protectiveness) and QOL. We divided the sample into moderate/high and low neurotoxicity groups based on chart review using the Pediatric Neuro-Oncology Rating of Treatment Intensity and examined moderator effects. Results Survivor-reported primary caregiver warmth moderated the relationship between neurotoxicity and caregiver-reported QOL. Moderate/high neurotoxicity was associated with lower caregiver-reported QOL only when survivor-reported primary caregiver warmth was low, P = .02. Similar results were found for survivor-reported QOL. Caregiver-reported psychological control moderated the association between neurotoxicity and caregiver-reported QOL such that neurotoxicity only affected QOL at high levels of psychological control, P = .01. Conclusions Heightened associations between parenting and QOL in the context of neurotoxic treatments underscore the need to better support PBTS. Findings are consistent with research suggesting that family factors may be particularly important for children with other neurological insults. Limitations include cross-sectional design and a small/heterogeneous clinical sample with low ethnic/racial diversity. Prospective studies are needed to refine evidence-based screening and develop psychosocial intervention strategies to optimize QOL for PBTS and their families.

PURPOSE Infant and young childhood medulloblastoma (iMB) is usually treated without craniospinal irradiation (CSI) to avoid neurocognitive late effects. Unfortunately, many children relapse. The purpose of this study was to assess salvage strategies and prognostic features of patients with iMB who relapse after CSI-sparing therapy. METHODS We assembled a large international cohort of 380 patients with relapsed iMB, age younger than 6 years, and initially treated without CSI. Univariable and multivariable Cox models of postrelapse survival (PRS) were conducted for those treated with curative intent using propensity score analyses to account for confounding factors. RESULTS The 3-year PRS, for 294 patients treated with curative intent, was 52.4% (95% CI, 46.4 to 58.3) with a median time to relapse from diagnosis of 11 months. Molecular subgrouping was available for 150 patients treated with curative intent, and 3-year PRS for sonic hedgehog (SHH), group 4, and group 3 were 60%, 84%, and 18% ( P = .0187), respectively. In multivariable analysis, localized relapse ( P = .0073), SHH molecular subgroup ( P = .0103), CSI use after relapse ( P = .0161), and age ≥ 36 months at initial diagnosis ( P = .0494) were associated with improved survival. Most patients (73%) received salvage CSI, and although salvage chemotherapy was not significant in multivariable analysis, its use might be beneficial for a subset of children receiving salvage CSI < 35 Gy ( P = .007). CONCLUSION A substantial proportion of patients with relapsed iMB are salvaged after initial CSI-sparing approaches. Patients with SHH subgroup, localized relapse, older age at initial diagnosis, and those receiving salvage CSI show improved PRS. Future prospective studies should investigate optimal CSI doses and the role of salvage chemotherapy in this population.

There is a critical need to engage adolescents and young adults (AYAs) with cancer in conversations regarding “safer” sexual activity during treatment. Many providers, however, report lacking the knowledge and/or tools to engage in these discussions. This article describes the experience of one pediatric institution in assessing and addressing provider barriers to safer sexual activity discussions among AYAs with cancer. Feedback from patients and providers resulted in an educational handout detailing recommendations regarding safer sex practices for AYAs with cancer. Handout adoption, acceptability, appropriateness, and feasibility are described alongside barriers to assist other institutions seeking to develop similar interventions.

Background Cushing disease (CD) is uncommon in the pediatric population and is usually caused by benign pituitary corticotroph microadenomas. In some adults with CD, Crooke cell adenoma (CCA), a more aggressive histologic variant of corticotroph adenomas, has been described. CCA has rarely been reported in children as the etiology of CD and its course is not well described. Objectives To report a pediatric case of CCA, the youngest to our knowledge Case An 11-year-old African American female presented to the endocrinology clinic with concerns for diabetes, excessive weight gain and linear growth arrest. Workup for possible etiology showed: midnight salivary cortisol 0.924 (normal < 0.112 µg/dL), ACTH 119(6-48 pg/mL), morning cortisol 8.5 (normal < 1.8 µg/dL) post 1 mg dexamethasone mg/dL, consistent with the diagnosis of CD. Magnetic resonance imaging (MRI) showed a 4 mm pituitary microadenoma in the left anterior side of the adenohypophysis for which she underwent endoscopic endonasal transsphenoidal resection. Histopathologic examination revealed pituitary adenomatous tissue consisting of a uniform population of basophilic cells with granular cytoplasm, arranged in trabeculae and small nests with bundles encircling the nuclei, findings pathognomonic of CCA. Given persistence of hypercortisolemia, another transsphenoidal gross total resection of residual adenomatous tissue was performed 4 months later. This led to resolution of CD as evidenced by weight loss and linear growth. Twelve months following the second surgery, the patient experienced rapid weight gain and a decelerated linear growth accompanied by pubertal arrest. Another pituitary MRI showed a recurrent left sided adenoma (8×8×7 mm). Biochemical investigation this time again showed elevated midnight salivary cortisol and 24- hour urine free cortisol (UFC). In addition, AM cortisol was unsuppressed following 1 mg overnight dexamethasone administration. In response, repeat transsphenoidal gross total resection was performed, however residual microscopic disease in the cavernous sinus wall was highly suspected intraoperatively. A spine MRI did not show disseminated disease. Despite this, hypercortisolemia persisted both clinically and biochemically. The patient subsequently underwent proton beam radiation therapy in combination with adjuvant adrenolytic therapy with mitotane. The patient responded to these interventions with normalization of 24-hour UFC, resumption of linear growth, and pubertal progression. The treatment course was complicated by the development of isolated TSH deficiency requiring thyroid hormone replacement. Conclusion CCA is an aggressive entity described in the adult literature as a cause of CD. The current report adds to the limited pediatric cases of this disease. CCA can be equally aggressive in children and refractory to surgical treatment. Here, we show that it may respond to proton beam radiation and adrenolytic therapy. Pediatric endocrinologists should be aware of the rare occurrence of CCA in children and tailor treatment accordingly using a multi-disciplinary approach. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

PURPOSE Superior outcomes for medulloblastoma (MB) requires precise surgical resection which can be guided by tumor segmentation. We present the first attempt at automatic segmentation of MB tumors via a hierarchical transfer-learning model that (1) segments the entire tumor habitat (enhancing tumor (ET), necrosis/non-enhancing tumor (NET), edema), followed by (2) training separate models for each of the sub-compartments. Transfer learning from adult brain tumors is used to optimize segmentation of tumor sub-compartments for pediatric MB. METHODS We evaluated 300 adult glioma studies (BRATS) and 49 pediatric MB studies (2-18 years old), both consisting of Gd-T1w, T2w, FLAIR sequences. The MB cohort was collected from Children's Hospital of Los Angeles (Nf19) and Cincinnati Children’s Hospital Medical Center (Nf30). Scans were registered to age-specific pediatric atlases, followed by bias correction and skull-stripping. Ground truth for the tumor sub-compartments was generated via consensus across two experts. We employed a 3D nn-Unet segmentation model on BRATS dataset using initial learning rate of 0.01, stochastic gradient descent as optimizer, and an average of dice loss and cross-entropy loss as the loss function. A hierarchical transfer learning model with Models Genesis was then applied, which allowed for fine tuning every layer on the pediatric MB dataset, across 5-fold cross validation. Dice score was used as performance metric, such that a perfect overlap between ground truth and prediction would yield a Dice score of 1. RESULTS Our 3D hierarchical segmentation model yielded mean dice scores of 0.85±0.03 for the entire tumor habitat; 0.77±0.048 for ET, 0.73±0.09 for edema, and 0.56±0.09 for NET + necrosis segmentation, across cross-validation runs. Overall, tumor outline and segmentation matched well with the ground truth, especially for the entire tumor, ET and enhancing tumor sub-compartments. CONCLUSIONS Our segmentation approach holds promise for accurate automated delineation of the tumor sub-compartments in pediatric Medulloblastoma.

Critical discoveries over the past two decades have transformed our understanding of medulloblastoma from a single entity into a clinically and biologically heterogeneous disease composed of at least four molecularly distinct subgroups with prognostically and therapeutically relevant genomic signatures. Contemporary clinical trials also have provided valuable insight guiding appropriate treatment strategies. Despite therapeutic and biological advances, medulloblastoma patients across the age spectrum experience tumor- and treatment-related morbidity and mortality. Using an updated risk stratification approach integrating both clinical and molecular features, ongoing research seeks to (1) cautiously reduce therapy and mitigate toxicity in low-average risk patients, and (2) thoughtfully intensify treatment with incorporation of novel, biologically guided agents for patients with high-risk disease. Herein, we review important historical and contemporary studies, discuss management updates, and summarize current knowledge of the biological landscape across unique pediatric, infant, young adult, and relapsed medulloblastoma populations.

While autopsy-repository programs with a variety of pediatric central nervous system (CNS) tumor types are a critical resource for preclinical neuro-oncology research, few exist and there is no published guidance on how to develop one. The goal of this prospective Pediatric Brain Tumor Repository (PBTR) study was to develop such a program at Cincinnati Children’s Hospital Medical Center (CCHMC) and then publish the quantitative and experiential data as a guide to support the development of similar programs. Protocols and infrastructure were established—to educate oncologists and families, establish eligibility, obtain consent, address pre- and post-autopsy logistics (e.g., patient and tissue transportation), process and authenticate tissue samples, and collect and analyze data. Of the 129 pediatric CNS tumor patients at CCHMC who died between 2013 and 2018, 109 were eligible for our study. Of these, 74% (81 of 109) were approached for PBTR donation, and 68% (55 of 81) consented. In the final year of the study, approach and consent rates were 93% and 85%, respectively. Median time from death to autopsy (postmortem interval, PMI) was 10 h (range, 1.5–30). In the outpatient setting, PMI increased with distance (from the hospice/home where the patient died to CCHMC). In all patients, PMI appeared to be lower, when consent was obtained more than 24 h before death. Procurement of autopsy specimens need not be a barrier in neuro-oncology research. Regional centers, strict timing-of-consent, patient education, and dedicated staff are all needed to minimize PMI and, thereby, increase the value of the procured tissue for an array of basic and translational research applications.

Cyclin-dependent kinase-retinoblastoma (CDK-RB) pathway is dysregulated in some diffuse intrinsic pontine gliomas (DIPG). We evaluated safety, feasibility, and early efficacy of the CDK4/6-inhibitor ribociclib, administered following radiotherapy in newly-diagnosed DIPG patients. Following radiotherapy, eligible patients received ribociclib in 28-day cycles (350 mg/m2; 21 days on/7 days off). Feasibility endpoints included tolerability for at least 6 courses, and a less than 2-week delay in restarting therapy after 1 dose reduction. Early efficacy was measured by 1-year and median overall survival (OS). Patient/parent-by-proxy reported outcomes measurement information system (PROMIS) assessments were completed prospectively. The study included 10 evaluable patients, 9 DIPG and 1 diffuse midline glioma (DMG)—all 3.7 to 19.8 years of age. The median number of courses was 8 (range 3–14). Three patients required dose reduction for grade-4 neutropenia, and 1 discontinued therapy for hematological toxicity following course 4. The most common grade-3/4 toxicity was myelosuppression. After 2 courses, MRI evaluations in 4 patients revealed increased necrotic volume, associated with new neurological symptoms in 3 patients. The 1-year and median OS for DIPG was 89% and 16.1 months (range 10–30), respectively; the DMG patient died at 6 months post-diagnosis. Five patients donated brain tissue and tumor; 3 were RB+ . Ribociclib administered following radiotherapy is feasible in DIPG and DMG. Increased tumor necrosis may represent a treatment effect. These data warrant further prospective volumetric analyses of tumors with necrosis. Feasibility and stabilization findings support further investigation of ribociclib in combination therapies. NCT02607124.

Molecularly targeted therapy with MEK inhibitors has been increasingly incorporated into the treatment of pediatric low-grade gliomas, but this promising therapy is associated with distinctive and specific toxicities. Understanding life-threatening MEK inhibitor toxicities and their management is critical to MEK inhibitor safety, especially among young children. This report describes severe hyponatremia associated with trametinib in an infant with progressive low-grade glioma without underlying endocrine dysfunction, which recurred despite significant dose reduction. Therapy with an alternative MEK inhibitor, binimetinib, provided excellent tumor response without hyponatremia, suggesting that some toxicities may be avoided by changing MEK inhibitor agents within the same class.

Background Genomic aberrations in the cell cycle and PI3K/Akt/mTOR pathways have been reported in diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG). Dual inhibition of CDK4/6 and mTOR has biologic rationale and minimal overlapping toxicities. This study determined the recommended phase 2 dose (RP2D) of ribociclib and everolimus following radiotherapy in children with DIPG and HGG. Methods Patients were enrolled according to a Rolling-6 design and received ribociclib and everolimus once daily for 21 and 28 days, respectively. All patients with HGG and biopsied DIPG were screened for retinoblastoma protein presence by immunohistochemistry. Pharmacokinetics were analyzed. Results Nineteen patients enrolled (median age: 8 years [range: 2-18]). Three patients enrolled at each dose level 1 and 2 without dose-limiting toxicities (DLT). Thirteen patients were enrolled at dose level 3, with one patient experiencing a DLT (grade 3 infection). One patient came off therapy before cycle 9 due to cardiac toxicity. The most common grade 3/4 toxicities were neutropenia (33%), leucopenia (17%), and lymphopenia (11%). Steady-state everolimus exposures in combination were 1.9 ± 0.9-fold higher than single-agent administration. Median overall survival for 15 patients with DIPG was 13.9 months; median event-free survival for four patients with HGG was 10.5 months. Two longer survivors had tumor molecular profiling identifying CDKN2A/B deletion and CDK4 overexpression. Conclusion The combination of ribociclib and everolimus following radiotherapy in children with newly diagnosed DIPG and HGG was well tolerated, with a RP2D of ribociclib 170 mg/m2 and everolimus 1.5 mg/m2. Results will inform a molecularly guided phase II study underway to evaluate efficacy.

BACKGROUND: Dual inhibition of CDK4/6 and mTOR in DIPG and pediatric HGG has strong biologic rationale, given prevalent genetic alterations resulting in upregulated cell cycle and PI3K/mTOR pathways in these diseases, as well as non-overlapping agent toxicities. This study sought to evaluate safety/tolerability and determine the recommended phase 2 dose (RP2D) of ribociclib and everolimus among children with newly diagnosed DIPG and HGG post-radiotherapy. METHODS: Patients were enrolled according to a Rolling-6 design and received oral ribociclib and everolimus once daily for 21 and 28 days, respectively, starting 2-4 weeks post-completion of radiotherapy. All HGG and biopsied DIPG patients were screened for RB protein presence by immunohistochemistry. Pharmacokinetics and survival data were analyzed. RESULTS: Nineteen patients enrolled (median age: 8 years [range: 2-18]). Three patients enrolled at each of dose levels 1 and 2 without dose-limiting toxicities (DLTs). Thirteen patients enrolled at dose level 3, with one patient experiencing a DLT (grade 3 infection). One patient came off therapy prior to cycle 9 due to cardiac toxicity. The most common grade 3/4 toxicities were neutropenia (33%), leucopenia (17%), and lymphopenia (11%). Steady-state everolimus exposures in combination were 1.9±0.9-fold higher than single-agent administration. Median overall survival (OS) for 15 patients with DIPG was 13.9 months, with 12-, 24-, and 36-month OS of 53.3%, 38.9%, and 38.9%. Median event-free survival for four patients with HGG was 10.5 months. Among patients with tumor molecular profiling, two longer survivors (OS: 20, >37 months) had evidence of cell cycle upregulation with CDKN2A/B deletion and CDK4 overexpression identified. CONCLUSIONS: The combination of ribociclib and everolimus was well-tolerated post-radiotherapy in children with newly diagnosed DIPG and HGG, with a RP2D of ribociclib 170 mg/m2 days 1-21 and everolimus 1.5 mg/m2 days 1-28. Results will inform a molecularly-guided phase II study currently underway to evaluate efficacy.

BACKGROUND: Oncogenic fusions involving neurotrophic tyrosine receptor kinase (NTRK) have been identified across cancer types and represent potential therapeutic targets given availability of TRK inhibitors. Gliomas harboring NTRK fusions have been described most commonly in infants with high-grade histology and hemispheric tumor location, though there is emerging evidence suggesting clinical, histopathologic, and molecular heterogeneity. Herein, we present two cases of NTRK-rearranged suprasellar/ optic pathway gliomas. CASE DESCRIPTIONS: The first patient was diagnosed at 6 months old with an extensive suprasellar/ optic pathway tumor, treated with carboplatin/ vincristine, which initially responded but subsequently progressed. A biopsy was then performed, with pathology consistent with infiltrating piloid astrocytoma with anaplastic features (elevated mitoses and Ki-67 index); a BCAN-NTRK1 fusion was identified by RT-PCR and confirmed by Sanger sequencing. After further disease progression on vinblastine monotherapy, this patient began treatment with entrectinib (NCT02650401), with favorable clinical and radiographic responses thus far. The second patient was diagnosed with a large suprasellar/ optic pathway tumor at 3 years old, and underwent upfront partial resection, revealing similar infiltrating piloid/pilocytic astrocytoma with anaplastic features (elevated mitoses and Ki-67 index). A diagnosis of “midline” infantile high-grade glioma (HGG) was also considered, as with the former case. Sequencing demonstrated a SOX10-NTRK3 rearrangement, resulting in an integrated diagnosis of NTRK-fused infantile HGG, for which the patient recently started treatment with larotrectinib (NCT04655404). Both patients’ fusions retain the entire kinase domain of respective NTRK partners, supporting oncogenicity, and neither tumor harbored additional somatic pathogenic variants (both lacked BRAF alterations). Methylation profiling did not confidently classify either tumor. CONCLUSIONS: NTRK-rearranged gliomas may present with primary suprasellar/ optic pathway involvement in infants. Given the potential to offer targeted therapy, testing for the presence of NTRK fusions should be strongly considered for infantile gliomas in any location, including midline, and across the histologic spectrum.

Background The COVID‐19 pandemic has prompted unprecedented challenges, contributing to greater difficulties among families of children with special health care needs, such as pediatric brain tumor survivors. We examined the impact of the pandemic on psychosocial functioning of adolescent and emerging adult survivors and their parents. We hypothesized that COVID‐19 disruptions and survivor social connectedness would be associated with survivor‐reported posttraumatic stress and family outcomes, including family functioning, parenting, and parent mental health. Procedure Fifty‐five families (44 survivors, 48 parents) were recruited via phone and email to participate in the study. Survivors were ages 13–25 (M = 19.62, SD = 3.47) and at least 5 years post diagnosis. Parents completed the COVID‐19 Exposure and Family Impact Survey (CEFIS), and survivors completed the Environmental influences on Child Health Outcomes (ECHO) COVID‐19 child self‐report form, which assessed pandemic impacts on their psychosocial functioning. Results Parents reported a mean of 7.52 (SD = 2.83) disruptions to their families’ lives. The pandemic negatively affected survivors’ life satisfaction (M diff = 0.46, t(44) = 3.96, p

Objective Neuropsychological testing is often recommended for pediatric brain tumor survivors, yet little is known about perceptions of testing and resources. The purpose of this study is to examine survivor and caregiver perceptions about neuropsychology and resources and identify factors associated with receipt of neuropsychological testing. Method Survivors and their families (N = 55) completed questionnaires on demographics and family functioning. The Neurological Predictive Scale was used to rate treatment intensity and expected impact on neuropsychological functioning. Chi squares and logistic regression were used to examine the associations between demographic, disease, and treatment factors and receipt of neuropsychological testing. Qualitative interviews (N = 25) were completed with a subset of families and coded with thematic content analysis and a multicoder consensus process with high inter-rater reliability (kappas .91–.93). Results The majority of survivors received neuropsychological testing. Survivors were more likely to receive neuropsychological testing if they were younger and if their caregivers had less than a college education and lower income. Qualitatively, families identified neurocognitive concerns. Some families reported that neuropsychological testing was helpful in clarifying deficits or gaining accommodations, while other families had difficulty recalling results or identified barriers to services. To mitigate the impact of deficits, families implemented metacognitive strategies and advocated for their survivor at school. Families desired more resources around the transition to adulthood and more opportunities for connection with other survivors. Conclusions Many families valued insights from neuropsychological services yet identified room for further improvement to address barriers and ensure accessibility and comprehensibility of neuropsychological findings.

Background Craniospinal irradiation (CSI) is part of the treatment of central nervous system (CNS) tumors and is associated with cardiovascular disease in adults. Global myocardial strain analysis including longitudinal peak systolic strain (GLS), circumferential peak systolic strain (GCS), and radial peak systolic strain (GRS) can reveal subclinical cardiac dysfunction. Methods Retrospective, single-center study in patients managed with CSI vs. age-matched controls. Clinical data and echocardiography, including myocardial strain analysis, were collected at early ( Results Echocardiograms were available at 20 early and 34 late time points. Patients at the late time point were older (21.7 ± 10.4 vs. 13.3 ± 9.6 years) and further out from CSI (13.1 ± 8.8 vs. 0.2 ± 0.3 years). Standard echocardiographic parameters were normal for both groups. For early, CSI vs. control: GLS was − 16.8 ± 3.6% vs. -21.3 ± 4.0% (p = 0.0002), GCS was − 22.5 ± 5.2% vs. -21.3 ± 3.4% (p = 0.28), and GRS was 21.8 ± 11.0% vs. 26.9 ± 7.7% (p = 0.07). For late, CSI vs. control: GLS was − 16.2 ± 5.4% vs. -21.6 ± 3.7% (p p = 0.42), and GRS was 22.5 ± 10.0% vs. 27.3 ± 8.3% (p = 0.03). Radiation type (proton vs. photon), and radiation dose ( Conclusions Subclinical cardiac systolic dysfunction by GLS is present both early and late after CSI. These results argue for future studies to determine baseline cardiovascular status and the need for early initiation of longitudinal follow-up post CSI.

BACKGROUND/RATIONAL: Following initial irradiation sparing therapy, many young children with relapsed medulloblastoma can be salvaged with craniospinal irradiation (CSI). However, the interval to relapse is short and neurocognitive sequelae remain a major concern. The contribution of molecular subgrouping may help refine indications and modalities of salvage strategies in this population. METHOD: From a cohort of 151 young children with molecularly characterized relapsed medulloblastoma, subset analysis of the SHH medulloblastoma was conducted to describe the practice of salvage radiotherapy and associated post-relapse survival (PRS). RESULTS: Sixty-seven SHH medulloblastoma patients (46 M0; 54 GTR; 11 non-ND/MBEN) received salvage therapy with curative intent. Before relapse, 54 (80.6%) received conventional chemotherapy (CC), 13 (19.4%) high-dose chemotherapy (HDC), while seven had additional focal radiotherapy (fRT). Median time to relapse was 11.1 months (range 3.8-41.0) and 43.3% were localized. Thirty patients (16 localized relapse) underwent surgery. Forty-seven (71.2%) received salvage radiotherapy (20 with CC; 10 with HDC; 15 alone, two unknown). CSI and fRT accounted for 82% and 18% respectively. CSI median dose was 36Gy (range 18-39Gy). Ten patients (eight with localized relapse) received CSI doses ≤23.4Gy. Nineteen patients (28.8%) did not receive any radiotherapy (nine HDC; 10 CC only). Radiotherapy was associated with better 3-year PRS (73.0% versus 36.1%; p=0.001). All patients treated with CSI ≤ 23.4Gy were alive at median follow-up of 69 months(24-142). Six of nine patients treated with HDC without irradiation were alive at last follow-up. Sixty-three percent of patients received reduced dose CSI(≤23.4Gy), fRT, or no radiotherapy, and their PRS did not significantly differ from those who received CSI ≥ 30.6Gy (p = 0.54). CONCLUSION: While salvage CSI provided PRS benefit in this SHH medulloblastoma cohort, we report the use of reduced salvage radiotherapy and irradiation avoidance in 63% of the patients, with 60% alive at last follow-up.

BACKGROUND: The B-cell-specific Moloney murine leukemia virus integration site-1 (BMI-1) protein, implicated in self-renewal and DNA-damage signaling, is highly expressed in DIPG and HGG. Preclinically, BMI-1 modulation by unesbulin (PTC596 [which mediates hyperphosphorylation and subsequent degradation of BMI-1]) leads to DIPG/HGG cell proliferation blockade, mitotic abnormalities, and tumor cell sensitization to radiation-induced DNA damage. METHODS: This phase Ib study sought to determine the maximally tolerated dose/ recommended phase 2 dose (RP2D) of unesbulin administered concurrently with radiotherapy and adjuvantly in children with newly diagnosed DIPG or HGG. Patients were enrolled according to a Rolling-6 design and received oral unesbulin twice weekly during radiotherapy and as maintenance therapy. RESULTS: Twenty-seven patients enrolled (median age: 8.5 years [range: 2-18]), including 18 patients with DIPG and nine patients with HGG. Unesbulin was administered in capsule formulation in the first nine patients, then tablet formulation for subsequent patients. Within the capsule formulation group, three dose-limiting toxicities (DLTs) were observed in two patients on dose level 2 (grade 4 neutropenia). Within the tablet formulation group, four DLTs were experienced by three patients on dose level 2 (grade 3 ALT elevation, grade 3 dehydration/vomiting, grade 3 decreased ejection fraction, grade 4 neutropenia). Dose level 1 was declared the RP2D, and six additional patients enrolled in the expansion cohort at this dose without DLTs. Most common drug-related grade 3/4 toxicities were neutropenia (48%), leucopenia (35%), and elevated ALT (26%). Similar pharmacokinetic profiles were observed for capsule and tablet formulations, consistent with adult data. Survival outcomes and genomics results will be shared at time of presentation. CONCLUSIONS: The RP2D of unesbulin in children newly diagnosed with DIPG or HGG is 200mg/m2 twice weekly, concurrent with and following radiotherapy. The recently opened surgical cohort will assess intratumoral pharmacokinetics and inhibition of tumor BMI-1 signaling, with results forthcoming.

PURPOSE: Survivors of pediatric glioma are at risk of developing physical and neurocognitive sequelae secondary to their tumor and its treatment. The contribution of these conditions to attainment of functional independence has not previously been examined. METHODS: 1,284 adult survivors of pediatric glioma (48% male, median [range] 30 [18-51] years at assessment, 22 [15-34] years since diagnosis) completed the CCSS Neurocognitive Questionnaire with impairment defined as scores > 90th %ile of sibling norms. Treatment exposures were categorized as surgery only, chemotherapy (± surgery), or cranial radiation (± chemotherapy/surgery). Self-reported chronic health conditions (CHCs) were graded by organ system using NCI’s CTCAE v4.3. Latent class analysis utilized six factors (employment, marital status, independent living, driver’s license, assistance with routine needs, assistance with personal care needs) to identify classes of functional independence. Multivariable modified Poisson regression evaluated relative risk (RR) of neurocognitive impairment between the classes, adjusting for sex, race, age at assessment, and age at diagnosis. Path analysis explored the impact of treatment exposures on functional independence, mediated by Grade 2-4 CHCs and neurocognitive impairment. RESULTS: Three latent classes of functional independence were identified: independent (58%), moderately independent (20%), and non-independent (22%). Compared to the independent class, non-independent survivors were at elevated risk for impaired task efficiency (RR=3.86, 95% CI, 2.97-5.01), memory (RR=2.39, 95% CI, 1.91-2.98), organization (RR=2.04, 95% CI, 1.64-2.54), and emotional regulation (RR=1.67, 95% CI, 1.30-2.15). Path analysis revealed significant direct paths from cranial radiation (β=0.14), impaired task efficiency (β=0.42), and sensorimotor (β=0.22) and endocrine conditions (β=0.24) to non-independence. Cranial radiation also was indirectly associated with non-independence through impaired task efficiency (β=0.06), and sensorimotor (β=0.06) and endocrine conditions (β=0.10). CONCLUSIONS: Neurocognitive impairment and chronic health conditions partially mediate the association between treatment exposures and attainment of independence in adulthood, identifying potential intervention targets to promote independence in long-term survivors.

While autopsy-repository programs with a variety of pediatric central nervous system (CNS) tumor types are a critical resource for preclinical neuro-oncology research, few exist and there is no published guidance on how to develop one. The goal of this prospective Pediatric Brain Tumor Repository (PBTR) study was to develop such a program at Cincinnati Children's Hospital Medical Center (CCHMC) and then publish the quantitative and experiential data as a guide to support the development of similar programs.Protocols and infrastructure were established-to educate oncologists and families, establish eligibility, obtain consent, address pre- and post-autopsy logistics (e.g., patient and tissue transportation), process and authenticate tissue samples, and collect and analyze data.Of the 129 pediatric CNS tumor patients at CCHMC who died between 2013 and 2018, 109 were eligible for our study. Of these, 74% (81 of 109) were approached for PBTR donation, and 68% (55 of 81) consented. In the final year of the study, approach and consent rates were 93% and 85%, respectively. Median time from death to autopsy (postmortem interval, PMI) was 10 h (range, 1.5-30). In the outpatient setting, PMI increased with distance (from the hospice/home where the patient died to CCHMC). In all patients, PMI appeared to be lower, when consent was obtained more than 24 h before death.Procurement of autopsy specimens need not be a barrier in neuro-oncology research. Regional centers, strict timing-of-consent, patient education, and dedicated staff are all needed to minimize PMI and, thereby, increase the value of the procured tissue for an array of basic and translational research applications.

Cyclin-dependent kinase-retinoblastoma (CDK-RB) pathway is dysregulated in some diffuse intrinsic pontine gliomas (DIPG). We evaluated safety, feasibility, and early efficacy of the CDK4/6-inhibitor ribociclib, administered following radiotherapy in newly-diagnosed DIPG patients.Following radiotherapy, eligible patients received ribociclib in 28-day cycles (350 mg/mThe study included 10 evaluable patients, 9 DIPG and 1 diffuse midline glioma (DMG)-all 3.7 to 19.8 years of age. The median number of courses was 8 (range 3-14). Three patients required dose reduction for grade-4 neutropenia, and 1 discontinued therapy for hematological toxicity following course 4. The most common grade-3/4 toxicity was myelosuppression. After 2 courses, MRI evaluations in 4 patients revealed increased necrotic volume, associated with new neurological symptoms in 3 patients. The 1-year and median OS for DIPG was 89% and 16.1 months (range 10-30), respectively; the DMG patient died at 6 months post-diagnosis. Five patients donated brain tissue and tumor; 3 were RB+ .Ribociclib administered following radiotherapy is feasible in DIPG and DMG. Increased tumor necrosis may represent a treatment effect. These data warrant further prospective volumetric analyses of tumors with necrosis. Feasibility and stabilization findings support further investigation of ribociclib in combination therapies.NCT02607124.

Pediatric cancer patients have a high prevalence of vitamin D deficiency. Children and young adults with acute lymphoblastic leukemia are at high risk for associated poor bone outcomes due to contributing effects of chemotherapy and supportive care. Evidence-based vitamin D guidelines are lacking in this population.This is a retrospective study following the implementation of an institutional guideline for standardized monitoring and supplementing vitamin D based on 25-hydroxyvitamin D levels and patient age. Goal 25-hydroxyvitamin D level was defined as ≥30 ng/mL and levels were checked every 3 months.Over a period of 22 months, 69 patients (median age, 6.7 y) were included. At diagnosis, 42 patients (60.8%) were insufficient. Among insufficient patients at diagnosis, 83.3% became sufficient at first repeat level following supplementation. At completion of the study 95.6% of patients were sufficient. Insufficiency was more common in winter than summer at baseline (74.3% vs. 47.1%, P=0.03), though the impact of seasonality was overcome following the algorithm. Throughout the study 4 patients had supratherapeutic but nontoxic levels.Vitamin D replacement guidelines implemented in the pediatric and young adult acute lymphoblastic leukemia population markedly increased the percentage of vitamin D sufficient patients in a short period of time.

To develop A Survivor's Journey, a web-based psychosocial intervention for adolescent and young adult (AYA) survivors of pediatric brain tumors (PBTs).Stages of development included focus groups with five AYA survivors (ages 16-23 years) and six parents to identify needs and challenges, as well as surveys and interviews with clinical care providers at a survivorship clinic.Concerns reported by AYA survivors, parents, and providers were similar to those reported in the literature, including fatigue, memory deficits, poor mood, health concerns, and challenging peer relationships. However, concerns varied across survivors, underscoring the need for customizable interventions. Survivors and parents were interested in an intervention targeting psychosocial functioning and late effects, and reported a strong preference for web-based interventions that would reduce cost and travel burden on the family.Based on review of the literature, survivor and parent feedback, as well as provider input, a customizable intervention, A Survivor's Journey, was developed consisting of five core sessions (addressing concerns common to AYA survivors such as memory, staying positive, and problem solving) and up to seven supplemental sessions (addressing variable needs of survivors such as managing fatigue, inattention, planning/organization, communication/relationships, and self-care).Despite growing recognition of long-term challenges and late effects, there are few interventions targeting psychosocial well-being of AYA survivors. If efficacious, A Survivor's Journey will be an accessible and cost-effective intervention to improve psychosocial functioning of AYA survivors of PBT.

INTRODUCTION 77Lu-DOTATATE, a radionuclide therapy which binds SST2A, has demonstrated efficacy in neuroendocrine tumors and evidence of CNS penetration, supporting potential expansion within pediatric neuro-oncology. Understanding the prevalence of SST2A expression across pediatric CNS tumors is essential to identify patients who may benefit from somatostatin receptor-targeted therapy and to further elucidate the oncogenic role of SST2A. METHODS SST2A immunohistochemistry (IHC) was performed on tumor specimens and interpreted by two experienced pathologists (blinded), utilizing semi-quantitative scoring of membranous expression within viable tumor. Immunoreactive cell percentage was visually scored as 0 (none), 1 (< 10%), 2 (10-50%), 3 (51-80%), or 4 (>80%). Staining intensity was scored as 0 (none), 1 (weak), 2 (moderate), or 3 (strong). Combined scores for each specimen were calculated by multiplying percent immunoreactivity and staining intensity values (range=0-12). RESULTS A total of 117 tumor samples from 113 patients were analyzed. Significant differences in SST2A IHC scores were observed across histopathologic diagnoses, with consistently high scores in medulloblastoma (mean±SD=7.6±3.6 [n=36]) and meningioma (5.7±3.4 [n=15]), compared to minimal or absent expression in ATRT (0.3±0.6 [n=3]), ETMR (1.0±0 [n=3]), ependymoma (grades I-III; 0.2±0.7 [n=26]), and high-grade glioma (grades III-IV; 0.4±0.7 [n=22]). Pineoblastoma (3.8±1.5 [n=4]) and other embryonal tumors (2.3±3.8 [n=8]) exhibited intermediate, variable expression. Among expressors, there was no association between SST2A IHC score and patient age, sex, presence of metastases, likelihood of relapse, or prior treatment. In a subset of paired primary and recurrent specimens from 3 patients, SST2A IHC scores remained largely unchanged. Among medulloblastomas, SST2A IHC scores were higher in non-SHH (8.6±3.2) than SHH (5.0±3.3) molecular subgroups (p=0.033). CONCLUSIONS High membranous SST2A expression was demonstrated in medulloblastoma, meningioma, and some rarer embryonal tumors with potential diagnostic, biologic, and therapeutic implications. Somatostatin receptor-targeted therapy such as 177Lu-DOTATATE deserves further investigation in these highly SST2A-expressing pediatric CNS tumors.

CSI is part of the treatment of CNS tumors and is associated with cardiovascular disease; data in pediatric/young-adult patients are limited. Myocardial-strain-analysis can reveal subclinical dysfunction. Retrospective, single-center study in CNS tumor patients managed with CSI from 1986–2018. Clinical details, and echocardiography including myocardial-strain-analysis were collected at T1=first echocardiogram after CSI, and T2=most recent echocardiogram. Data are mean±standard deviation. Echocardiograms were available in 44 patients (36%female, 14±8.0years) at T1 and 39 patients (38%female, 21.0±11.3years) at T2. Standard echocardiography was normal for all subjects. At T1, global longitudinal peak systolic strain (GLS) was -16.3%±3.7% in CSI vs. -21.6%±3.5% in controls (p0.95); GRS was 5.5±9.5% (p

BACKGROUND Recent discoveries have provided valuable insight into the genomic landscape of pediatric low-grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs’ genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence. METHODS Fluorescence in situ hybridization, mutation-specific immunohistochemistry, exome analyses, and/or targeted sequencing were performed on paired tumor samples from diagnostic and subsequent surgeries. RESULTS Ninety-four tumor samples from 45 patients (41 with two specimens, four with three specimens) from three institutions underwent testing. Conservation of BRAF fusion, BRAFV600E mutation, and FGFR1 rearrangement status was observed in 100%, 98%, and 96% of paired specimens, respectively. No loss or gain of IDH1 mutations or NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. Changes in CDKN2A deletion status occurred in 10 patients (40%), with acquisition of CDKN2A deletion in seven (including three who received chemotherapy [two with temozolomide] and one who received radiation) and loss in three (including one who received targeted therapy and radiation). A trend toward shorter time to progression was observed among patients with acquired CDKN2A deletions compared to patients without acquisition of this alteration (median: 5.5 versus 14.0 months [p=0.078]). CONCLUSIONS Most targetable genetic aberrations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or radiation. However, changes in CDKN2A deletion status over time were demonstrated. Acquisition of CDKN2A deletion may define a higher risk subgroup of pediatric LGGs with a poorer prognosis. Given the potential for targeted therapies for tumors harboring CDKN2A deletions, biopsy at recurrence may be indicated in certain patients, especially those with rapid progression.

INTRODUCTION Irradiation-sparing approaches are used in young children with medulloblastoma (MB) given the vulnerability of the developing brain to neurocognitive impairment. Limited data are available following relapse for these patients. We aimed to describe the management and outcomes of young children with MB who relapsed after initial treatment without craniospinal irradiation (CSI). METHODS International retrospective study including patients with MB diagnosed between 1995-2017, ≤ 72 months old, initially treated without CSI, who subsequently relapsed. RESULTS Data are available for 66 patients. The median age at initial diagnosis was 27 months (range, 6-72). At diagnosis, 27 patients had metastatic disease. Initial therapy included conventional chemotherapy or with high-dose chemotherapy (HDC) in 30 and 36 patients, respectively. Eight (12.1%) received upfront focal irradiation. Molecular subgrouping was available for 27 (41%) patients. Ten were SHH, five group 3, six group 4 and six others were non-WNT/non-SHH. The median time from initial diagnosis to relapse was 13 months (range, 3-63). Relapse was local, disseminated, or combined in 39%, 32%, and 29%, respectively. The median time to death from relapse was 18 months. Curative intent therapy was given in 53 patients with irradiation (81%), conventional chemotherapy without HDC (40%), and HDC (25%). For patients who received irradiation, 85% received CSI (median dose 33 Gy, 18-41.4) and 15% focal irradiation. Ten patients received chemotherapy without salvage irradiation. The median follow-up time was 44 months (range, 4-255), 33 (62%) patients who underwent curative-intent therapy were alive, including 8/10 SHH, 2/3 group 3, 2/6 group 4, and 4/5 non-WNT/non-SHH. Three of four patients with SHH and treated without salvage radiotherapy are survivors. The 5-year OS for curative intent was 70%. CONCLUSION A substantial proportion of young children who relapse following irradiation-sparing strategies can be salvaged. A proportion of children with SHH MB can be salvaged without salvage radiotherapy.

BACKGROUND Although pediatric brain tumor survivors are at high risk for a variety of psychosocial and neurocognitive late effects, there are few evidence-based interventions to address their needs. The purpose of this study was to test the efficacy of an online problem-solving intervention on improving the quality of life and executive dysfunction among adolescent and young adult brain tumor survivors. PROCEDURE A Survivor's Journey was adapted from a similar intervention for survivors of traumatic brain injuries, and involved self-guided web modules providing training in problem-solving as a tool for coping with everyday challenges, as well as weekly teleconferences with a trained therapist. Survivors (n = 19) between the ages of 13 and 25, and their caregivers, completed standardized measures of their emotional and behavioral functioning, executive functioning, and quality of life before and after the 12- to 16-week intervention. RESULTS Participation in the intervention led to significant improvements in self-reported overall (Mpre = 62.03, SDpre = 17.67, Mpost = 71.97, SDpost = 16.75; d = 0.58, P = 0.01) and physical quality of life (Mpre = 63.13, SDpre = 21.88, Mpost = 75.00, SDpost = 21.33; d = 0.55, P

BACKGROUND: Molecular profiling is commonly performed in pediatric CNS tumors, however the clinical utilization of genomic data in pediatric neuro-oncology is not fully characterized. We describe a single institution experience adopting a personalized therapeutic approach based on tumor genetic alterations. METHODS: We retrospectively analyzed genomic data, generated using fluorescent in situ hybridization, single gene, or panel sequencing, of pediatric CNS tumors in patients diagnosed between 2010 and 2018 at Cincinnati Children’s Hospital Medical Center. We aimed to identify common genetic aberrations, characterize targeted therapies used, and disease response. RESULTS: One hundred and sixty patients (median age: 7 years, range: 0–27 years) had tumor sequencing performed yielding 147 evaluable results. Low-grade lesions (LGL) (N=94, 63.9%), were mostly low-grade gliomas and glioneuronal tumors; high-grade lesions (HGL) (N=53, 36.0%) included high-grade gliomas (N=35), embryonal neoplasms (N=12), and choroid plexus carcinomas (N=3). Specific BRAF aberrations were more interrogated in LGL while larger panel sequencing was performed in HGL. Targetable aberrations were found in 99 patients (67.3%), most commonly BRAF alterations in LGL as expected, and aberrations in the RTK-PI3K pathway in HGL. Among 99 patients, 56.5% received therapy informed by sequencing data. Thirty three patients with LGL (35.1%) received targeted therapy after a median of 3 prior therapies and remained on treatment for a median of 7 months (range: 1–24 months). Twenty three patients with HGL (43.4%) received targeted therapy after a median of 2 therapies and remained on treatment for a median of 3 months (range: 1–23 months). Targeted therapy was most frequently stopped due to disease progression, only 5 patients developed toxicity that led to cessation of targeted agents. CONCLUSION: Targetable alterations are frequent in pediatric CNS tumors; when identified they guided therapy in a majority of patients commonly at progression and were used earlier and more often in HGL. GERM CELL TUMORS

PURPOSE Treatment of medulloblastoma has evolved from surgery and radiotherapy to contemporary multimodal regimens. However, the impact on long-term health outcomes remains unknown. METHODS Cumulative incidence of late mortality (5 or more years from diagnosis), subsequent neoplasms (SNs), and chronic health conditions were evaluated in the Childhood Cancer Survivor Study among 5-year survivors of medulloblastoma diagnosed between 1970 and 1999. Outcomes were evaluated by treatment exposure, including historical therapy (craniospinal irradiation [CSI] ≥ 30 Gy, no chemotherapy), high risk (CSI ≥ 30 Gy + chemotherapy), standard risk (CSI < 30 Gy + chemotherapy), and by treatment decade (1970s, 1980s, 1990s). Rate ratios (RRs) and 95% CIs estimated long-term outcomes using multivariable piecewise exponential models. RESULTS Among 1,311 eligible survivors (median age, 29 years [range, 6 to 60 years]; median time from diagnosis, 21 years [range, 5 to 44 years]), the 15-year cumulative incidence rate of all-cause late mortality was 23.2% (diagnosed 1970s) versus 12.8% (1990s; P = .002), with a recurrence-related mortality rate of 17.7% versus 9.6% ( P = .008). Lower late mortality rates as a result of other health-related causes were not observed. Among 997 survivors who completed a baseline survey, the 15-year cumulative incidence of SNs was higher among survivors with multimodal therapy (standard risk, 9.5%; historical, 2.8%; P = .03). Survivors treated in the 1990s had a higher cumulative incidence of severe, disabling, life-threatening, and fatal chronic health conditions (56.5% in 1990s v 39.9% in 1970s; P < .001) and were more likely to develop multiple conditions (RR, 2.89; 95% CI, 1.31 to 6.38). However, survivors of standard-risk therapy were less likely to use special education services than high-risk therapy survivors (RR, 0.84; 95% CI, 0.75 to 0.93). CONCLUSION Historical changes in medulloblastoma therapy that improved 5-year survival have increased the risk for SNs and debilitating health conditions for survivors yet reduced the need for special education services.

Telomerase activation is critical in many cancers including central nervous system (CNS) tumors. Imetelstat is an oligonucleotide that binds to the template region of the RNA component of telomerase, inhibiting its enzymatic activity. We conducted an investigator-sponsored molecular biology (MB) and phase II study to estimate inhibition of tumor telomerase activity and sustained responses by imetelstat in children with recurrent CNS malignancies. In the MB study, patients with recurrent medulloblastoma, high-grade glioma (HGG) or ependymoma undergoing resection received one dose of imetelstat as a 2-h intravenous infusion at 285 mg/m(2), 12-24 h before surgery. Telomerase activity was evaluated in fresh tumor from surgery. Post-surgery and in the phase II study, patients received imetelstat IV (days 1 and 8 q21-days) at 285 mg/m(2). Imetelstat pharmacokinetic and pharmacodynamic studies were performed. Of two evaluable patients on the MB trial, intratumoral telomerase activity was inhibited by 95 % compared to baseline archival tissue in one patient and was inevaluable in one patient. Forty-two patients (40 evaluable for toxicity) were enrolled: 9 medulloblastomas, 18 HGG, 4 ependymomas, 9 diffuse intrinsic pontine gliomas. Most common grade 3/4 toxicities included thrombocytopenia (32.5 %), lymphopenia (17.5 %), neutropenia (12.5 %), ALT (7.5 %) and AST (5 %) elevation. Two patients died of intratumoral hemorrhage secondary to thrombocytopenia leading to premature study closure. No objective responses were observed. Telomerase inhibition was observed in peripheral blood mononuclear cells (PBMCs) for at least 8 days. Imetelstat demonstrated intratumoral and PBMC target inhibition; the regimen proved too toxic in children with recurrent CNS tumors.

Background Blue rubber bleb nevus syndrome (BRBNS) is a rare multifocal venous malformation syndrome involving predominantly the skin and gastrointestinal tract. Traditional treatment modalities include corticosteroids, interferon-α, sclerotherapy, and aggressive surgical resection. Sirolimus has been used in several single case reports. Procedure We performed a single-institution retrospective review of four children with BRBNS, who received sirolimus as part of their treatment regimens. A diagnosis of BRBNS was based on clinical, radiologic, and pathologic criteria. Results Median age was 6.5 years (range: 2–16 years). Pathologic evaluations revealed a combined malformation with venous and lymphatic components. The novel finding of a lymphatic component was confirmed with PROX-1 immunostaining. Patients received oral sirolimus with target drug levels between 10 and 13 ng/ml. Responses to treatment were defined as stabilization/decrease in size of lesions; resolution of transfusion requirements; reduction in pain, and improvement in quality of life (QOL). Median time to response was 1.5 months (SD ± 0.96 month, range: 1–3 months). Median follow-up was 21 months (range: 18–26 months). Lesion size and characteristics improved in all patients. All patients reported decrease in pain and improvement in QOL. All three patients requiring transfusions became transfusion-independent. One patient had resolution of coagulopathy. Adverse effects of sirolimus consisted of mucositis in three patients and neutropenia in one patient. Conclusions Sirolimus is safe and efficient for the treatment of BRBNS. Further prospective studies are needed to evaluate the long-term effectiveness of this drug. This is the first report that identifies a lymphatic component as part of BRBNS.

INTRODUCTION Irradiation-sparing approaches are used in young children with medulloblastoma (MB) given the vulnerability of the developing brain to neurocognitive impairment. Limited data are available following relapse for these patients. We aimed to describe the management and outcomes of young children with MB who relapsed after initial treatment without craniospinal irradiation (CSI). METHODS International retrospective study including patients with MB diagnosed between 1995–2017, ≤ 72 months old, initially treated without CSI, who subsequently relapsed. RESULTS Data are available for 52 patients (32 male). Median age at initial diagnosis was 27 months (range, 6–72) with 24 being metastatic. Initial therapy included conventional chemotherapy alone or high-dose chemotherapy (HDC) in 21 and 31 subjects, respectively. Three received upfront focal irradiation. Molecular subgrouping, available for 24 tumors, included 9 SHH and 15 non-WNT/non-SHH. Median time to relapse was 13 months (range, 3–63). Relapse was local, disseminated or combined in 20, 15, and 16, respectively. Salvage therapy with curative intent was given in 42/52 patients, including CSI in 28 subjects (median dose 36Gy, 18–41.4) or focal irradiation in 5 others. Three received HDC only. At a median follow-up time of 46 months (range, 4–255), 25 (48%) were alive, including 7/9 SHH and 7/15 non-WNT/non-SHH. The 2- and 5-year OS was 67% and 56% (SE, 7%), respectively. Two of 3 patients with SHH who did not receive salvage radiotherapy are survivors. CONCLUSION A substantial proportion of young children who relapse following irradiation-sparing strategies can be salvaged. Neurocognitive and ototoxicity outcomes are being evaluated.

INTRODUCTION Recent discoveries have provided valuable insight into the genomic landscape of pediatric low grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs’ genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence. METHODS Fluorescence in situ hybridization, mutation-specific immunohistochemistry, and exome analyses were performed on paired tumor samples from primary diagnostic and subsequent surgeries. RESULTS 101 tumor samples from 48 patients (43 with 2 specimens, 5 with 3 specimens) from 3 institutions underwent testing. BRAF fusion and BRAFV600E status were conserved in 100% and 97% of paired specimens, respectively. No loss or gain of IDH1 mutations or FGFR1, NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. CDKN2A deletions were acquired in 7 patients (including 3 who received chemotherapy [2 with temozolomide] and 1 who received radiation), and were associated with a trend toward shorter time to progression (median: 5.5 vs. 13.0 months [p=0.08]). CONCLUSIONS Most targetable genetic alterations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or radiation. However, CDKN2A deletion acquisition was demonstrated and may define a higher risk group. Given potential for targeted therapies for tumors acquiring CDKN2A deletions, performing a biopsy at recurrence may be indicated in certain patients, especially those with rapid progression.

Molecularly targeted therapy with MEK inhibitors is increasingly being incorporated into the treatment of pediatric low-grade gliomas (LGGs). Trametinib is an orally available MEK1/2 inhibitor that has demonstrated tumor control in LGGs with BRAF alterations. Safe expansion of MEK inhibitor therapy within the pediatric patient population demands adequate understanding of and surveillance for potential MEK-inhibitor specific toxicities, especially among young children. Hyponatremia has been reported in adult patients receiving BRAF/MEK inhibitor combination treatment as well as in two pediatric patients with known diabetes insipidus treated with trametinib monotherapy. To our knowledge, single-agent trametinib has not previously been reported to be associated with hyponatremia in children in the absence of an underlying endocrinopathy. We present a case of hyponatremia associated with trametinib use in an infant with progressive LGG without known endocrine dysfunction, which recurred after significant dose reduction. Therapy with an alternative MEK1/2 inhibitor, binimetinib, provided excellent tumor response without hyponatremia. Hyponatremia is a rare but serious side effect of trametinib, even without underlying pituitary dysfunction. Infants and patients lacking the ability to quickly regulate fluid intake in response to osmolality changes are at particular risk of suffering severe consequences from hyponatremia and should be monitored closely with initiation of trametinib. Switching to a different drug within the same class may offer an alternative to significant dose reduction or discontinuation due to this toxicity.

Genomic aberrations in the cell cycle and mTOR pathways have been reported in diffuse pontine gliomas (DIPG) and high-grade gliomas (HGG). Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus administered during maintenance therapy following radiotherapy was determined in the phase I study as a rolling 6 design. Ribociclib and everolimus were administered once daily for 21 days and 28 days, respectively starting two-four weeks post completion of radiotherapy. All HGG patients and any DIPG patient who had undergone biopsy were screened for RB protein by immunohistochemistry. Eighteen eligible patients enrolled (median age 8 years; range: 2–18). Six patients enrolled at dose levels 1,2, and 3 without dose limiting toxicities (DLT). Currently, five patients are enrolled at dose level 3 expansion cohort. The median number of cycles are 4.5 (range: 1–20+). Among the expansion cohort, one dose limiting toxicity included a grade 3 infection and one patient required a dose reduction in course 3 due to grade 3 ALT and grade 4 hypokalemia. The most common grade 3/4 adverse events included neutropenia. Preliminary pharmacokinetic studies on 12 patients suggest an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus following radiotherapy in newly diagnosed DIPG and HGG is anticipated to be 170 mg/m2/day x 21 days and 1.5 mg/ m2/day every 28 days which is equivalent to the adult RP2D.

Purpose/objective Our goal was to examine the feasibility and preliminary efficacy of an app-based coaching intervention (Social Participation and Navigation; SPAN) to help survivors of acquired brain injury attain social participation goals. Research Method/Design: This is a nonrandomized pilot trial of SPAN, including 15 adolescents (9 with traumatic brain injury, 6 with brain tumor) between the ages of 14-22. The SPAN intervention consisted of a mobile app to support the development and implementation of social participation goals, weekly video-conference coaching sessions to identify goals and step-by-step action plans, and online didactic materials. Assessments were completed pre- and postintervention. Satisfaction with the intervention, confidence in the adolescents' ability to participate in and plan social activities and manage their emotions and behaviors, and frequency and satisfaction with social participation were assessed via self- and parent-report questionnaires developed for this project. Behavior problems, social competence, and social problems were measured by using the Child Behavior Checklist and the Youth Self-Report. Results High levels of participant and parent satisfaction were reported. Increases in parent-reported frequency of social participation and teen-reported confidence in their ability to participate and develop social participation goals and plans were observed. A decline in parent-reported total problems, internalizing problems, externalizing problems, and social problems was noted. Conclusion/implications Results support the feasibility of the program, because participants were able to successfully meet with their coaches and use the app to develop and accomplish social participation goals. Further research will be needed to refine the app and program, particularly when reaching out to populations beyond traumatic brain injury. (PsycINFO Database Record

High grade astrocytomas are brain tumors that currently have no cure. Understanding mechanisms that sustain and help them to resist therapy are urgently necessary. The capicua (CIC) transcriptional repressor is a target of receptor tyrosine kinase (RTK) signaling. Upon phosphorylation by RTK signaling, CIC loses its repressor activity. We hypothesize that loss of CIC activity and the subsequent activation of the genes it normally represses plays an important role in astrocytoma biology. In humans, CIC inactivating mutations are found in a subset of gliomas, specifically oligodendrogliomas associated with 1p/19q chromosomal losses. In astrocytoma and oligodendroglioma without 1p/19q loss, CIC mutations are rare. Given the genetic heterogeneity of gliomas, it is conceivable that subpopulations within astrocytomas may utilize different mechanisms to ablate CIC activity, for example through RTK signaling. Using a novel mouse model of astrocytoma with enhanced RTK signaling, we identified that CIC expression was decreased by 50–70% compared to normal cortex and correlated with significant increased RNA and protein levels of known oncogenic signals including E-twenty six transformation specific (ETS)-related transcription factor 4 (ETV4) and matrix metalloproteinase 2 (MMP2). Mouse astrocytoma tumor spheres also had lower CIC protein levels and higher protein levels of ETV4 and MMP2 compared to normal neurospheres. Low CIC-expressing human astrocytoma stem cells were also highly expressing ETV4 and MMP2. Functional effects of CIC knockdown in mouse astrocytoma tumor spheres included enhanced self-renewal and invasiveness which also correlated with increased ETV4 and MMP2. Intracranial tumors generated from injection of control or CIC knockdown glioma stem cells into mouse brain led to no difference in Kaplan-Meier survival curves however, histological analysis suggested that the CIC knockdown tumors displayed evidence of enhanced pleomorphism, spindle shaped cells and staghorn vasculature. These studies highlight that even when not mutated, CIC activity may be dynamically regulated to modulate astrocytoma biology.

Pediatric high-grade gliomas (pHGGs) are aggressive neoplasms representing approximately 20% of brain tumors in children. Current therapies offer limited disease control, and patients have a poor prognosis. Empiric use of targeted therapy, especially at progression, is increasingly practiced despite a paucity of data regarding temporal and therapy-driven genomic evolution in pHGGs. To study the genetic landscape of pHGGs at recurrence, we performed whole exome and methylation analyses on matched primary and recurrent pHGGs from 16 patients. Tumor mutational profiles identified three distinct subgroups. Group 1 (n = 7) harbored known hotspot mutations in Histone 3 (H3) (K27M or G34V) or IDH1 (H3/IDH1 mutants) and co-occurring TP53 or ACVR1 mutations in tumor pairs across the disease course. Group 2 (n = 7), H3/IDH1 wildtype tumor pairs, harbored novel mutations in chromatin modifiers (ZMYND11, EP300 n = 2), all associated with TP53 alterations, or had BRAF V600E mutations (n = 2) conserved across tumor pairs. Group 3 included 2 tumors with NF1 germline mutations. Pairs from primary and relapsed pHGG samples clustered within the same DNA methylation subgroup. ATRX mutations were clonal and retained in H3G34V and H3/IDH1 wildtype tumors, while different genetic alterations in this gene were observed at diagnosis and recurrence in IDH1 mutant tumors. Mutations in putative drug targets (EGFR, ERBB2, PDGFRA, PI3K) were not always shared between primary and recurrence samples, indicating evolution during progression. Our findings indicate that specific key driver mutations in pHGGs are conserved at recurrence and are prime targets for therapeutic development and clinical trials (e.g. H3 post-translational modifications, IDH1, BRAF V600E). Other actionable mutations are acquired or lost, indicating that re-biopsy at recurrence will provide better guidance for effective targeted therapy of pHGGs. Electronic supplementary material The online version of this article (10.1186/s40478-017-0479-8) contains supplementary material, which is available to authorized users.

Targeted chemotherapeutics provide a promising new treatment option in neuro-oncology. The ability of these compounds to penetrate the blood-brain barrier is crucial for their successful incorporation into patient care. “CNS Targeted Agent Prediction” (CNS-TAP) is a multi-institutional and multidisciplinary translational program established at the University of Michigan for evaluating the central nervous system (CNS) activity of targeted therapies in neuro-oncology. In this report, we present the methodology of CNS-TAP in a series of pediatric and adolescent patients with high-risk brain tumors, for which molecular profiling (academic and commercial) was sought and targeted agents were incorporated. Four of five of the patients had potential clinical benefit (partial response or stable disease greater than 6 months on therapy). We further describe the specific drug properties of each agent chosen and discuss characteristics relevant in their evaluation for therapeutic suitability. Finally, we summarize both tumor and drug characteristics that impact the ability to successfully incorporate targeted therapies into CNS malignancy management.