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Background The prognosis for patients with pediatric high-grade glioma (pHGG) is poor despite aggressive multimodal therapy. Objective responses to targeted therapy with BRAF inhibitors have been reported in some patients with recurrent BRAF-mutant pHGG but are rarely sustained. Methods We performed a retrospective, multi-institutional review of patients with BRAF-mutant pHGG treated with off-label BRAF +/– MEK inhibitors as part of their initial therapy. Results Nineteen patients were identified, with a median age of 11.7 years (range, 2.3–21.4). Histologic diagnoses included HGG (n = 6), glioblastoma (n = 3), anaplastic ganglioglioma (n = 4), diffuse midline glioma (n = 3), high-grade neuroepithelial tumor (n = 1), anaplastic astrocytoma (n = 1), and anaplastic astroblastoma (n = 1). Recurrent concomitant oncogenic alterations included CDKN2A/B loss, H3 K27M, as well as mutations in ATRX, EGFR, and TERT. Eight patients received BRAF inhibitor monotherapy. Eleven patients received combination therapy with BRAF and MEK inhibitors. Most patients tolerated long-term treatment well with no grade 4–5 toxicities. Objective and durable imaging responses were seen in the majority of patients with measurable disease. At a median follow-up of 2.3 years (range, 0.3–6.5), three-year progression-free and overall survival for the cohort were 65% and 82%, respectively, and superior to a historical control cohort of BRAF-mutant pHGG patients treated with conventional therapies. Conclusions Upfront targeted therapy for patients with BRAF-mutant pHGG is feasible and effective, with superior clinical outcomes compared to historical data. This promising treatment paradigm is currently being evaluated prospectively in the Children’s Oncology Group ACNS1723 clinical trial.

Purpose: Medulloblastoma in children can be categorized into at least four molecular subgroups, offering the potential for targeted therapeutic approaches to reduce treatment-related morbidities. Little is known about the role of tumor microenvironment in medulloblastoma or its contribution to these molecular subgroups. Tumor microenvironment has been shown to be an important source for therapeutic targets in both adult and pediatric neoplasms. In this study, we investigated the hypothesis that expression of genes related to tumor-associated macrophages (TAM) correlates with the medulloblastoma molecular subgroups and contributes to a diagnostic signature.Methods: Gene-expression profiling using human exon array (n = 168) was analyzed to identify medulloblastoma molecular subgroups and expression of inflammation-related genes. Expression of 45 tumor-related and inflammation-related genes was analyzed in 83 medulloblastoma samples to build a gene signature predictive of molecular subgroups. TAMs in medulloblastomas (n = 54) comprising the four molecular subgroups were assessed by immunohistochemistry (IHC).Results: A 31-gene medulloblastoma subgroup classification score inclusive of TAM-related genes (CD163 and CSF1R) was developed with a misclassification rate of 2%. Tumors in the Sonic Hedgehog (SHH) subgroup had increased expression of inflammation-related genes and significantly higher infiltration of TAMs than tumors in the Group 3 or Group 4 subgroups (P < 0.0001 and P < 0.0001, respectively). IHC data revealed a strong association between location of TAMs and proliferating tumor cells.Conclusions: These data show that SHH tumors have a unique tumor microenvironment among medulloblastoma subgroups. The interactions of TAMs and SHH medulloblastoma cells may contribute to tumor growth revealing TAMs as a potential therapeutic target. Clin Cancer Res; 21(6); 1457–65. ©2014 AACR.

PDF file 92K, Supplemental Fig 5: Expression of PID1 protein in human brain tumors and cell lines

PDF file - 190K, Supplemental Fig 2: Proneural and Neural GBMs have higher PID1 mRNA; higher PID1 mRNA correlates with higher OS in patients with gliomas.

Supplemental Methods and Supplemental Figures 1-9 Supplemental Figure 1. Overview of samples studies and 31-gene signature development Supplemental Figure. 2. Non-negative matrix factorization (NMF) analysis of the combined cohort of medulloblastoma samples (n=168) (A) Cophenetic correlation coefficient based on 2000 clustering runs for 2-10 clusters utilizing genes obtained at varying coefficients of variation; the data demonstrate that the highest cophenetic correlation coefficient was obtained at 4 clusters with 369 genes. (B) NMF consensus heatmap of 4 subgroups using the dataset containing 369 genes with high coefficient of variation. (C) Silhouette plot for identification of outliers. Outliers (n=31) were defined as samples with a silhouette width

PDF file - 159K, Supplemental Fig 1: PID1 mRNA is lower in less favorable medulloblastomas in two additional independent datasets; PID1 mRNA correlates with rf-PFS when analyzing CHLA medulloblastomas by tertiles.

PDF file - 17K, Supplemental Fig 4: PID1 increases the proportion of cells in Sub G0/G1 in CHLA-259 medulloblastoma cells.

Purpose: We present here the first report of PID1 (Phosphotyrosine Interaction Domain containing 1; NYGGF4) in cancer. PID1 was identified in 2006 as a gene that modulates insulin signaling and mitochondrial function in adipocytes and muscle cells.Experimental Design and Results: Using four independent medulloblastoma datasets, we show that mean PID1 mRNA levels were lower in unfavorable medulloblastomas (groups 3 and 4, and anaplastic histology) compared with favorable medulloblastomas (SHH and WNT groups, and desmoplastic/nodular histology) and with fetal cerebellum. In two large independent glioma datasets, PID1 mRNA was lower in glioblastomas (GBM), the most malignant gliomas, compared with other astrocytomas, oligodendrogliomas and nontumor brains. Neural and proneural GBM subtypes had higher PID1 mRNA compared with classical and mesenchymal GBM. Importantly, overall survival and radiation-free progression-free survival were longer in medulloblastoma patients whose tumors had higher PID1 mRNA (univariate and multivariate analyses). Higher PID1 mRNA also correlated with longer overall survival in patients with glioma and GBM. In cell culture, overexpression of PID1 inhibited colony formation in medulloblastoma, atypical teratoid rhabdoid tumor (ATRT), and GBM cell lines. Increasing PID1 also increased cell death and apoptosis, inhibited proliferation, induced mitochondrial depolaization, and decreased serum-mediated phosphorylation of AKT and ERK in medulloblastoma, ATRT, and/or GBM cell lines, whereas siRNA to PID1 diminished mitochondrial depolarization.Conclusions: These data are the first to link PID1 to cancer and suggest that PID1 may have a tumor inhibitory function in these pediatric and adult brain tumors. Clin Cancer Res; 20(4); 827–36. ©2013 AACR.

PDF file - 440K, Supplemental Table 1: Characteristics of the CHLA Medulloblastoma Patients. Supplemental Table 2: Neural and Proneural GBM subgroups have higher PID1 mRNA compared to Classical and Mesenchymal.

Supplemental Tables 1-6 Supplemental Table 1. Patient and tumor characteristics Supplemental Table 2. TLDA design (45 genes) Supplemental Table 3. Information for samples evaluated using HuE Supplemental Table 4. TLDA 31-gene molecular classification of core samples Supplemental Table 5. TLDA 31-gene classification for samples without HuEx data Supplemental Table 6. TLDA 31-gene Confusion Matrix

PDF file - 42K, Supplemental Fig 3: PID1 also inhibits colony formation using two other plasmid expression vectors.

Background The incidence and biology of IDH1/2 mutations in pediatric gliomas are unclear. Notably, current treatment approaches by pediatric and adult providers vary significantly. We describe the frequency and clinical outcomes of IDH1/2-mutant gliomas in pediatrics. Methods We performed a multi-institutional analysis of the frequency of pediatric IDH1/2-mutant gliomas, identified by next-generation sequencing (NGS). In parallel, we retrospectively reviewed pediatric IDH1/2-mutant gliomas, analyzing clinico-genomic features, treatment approaches, and outcomes. Results Incidence: Among 851 patients with pediatric glioma who underwent NGS, we identified 78 with IDH1/2 mutations. Among patients 0–9 and 10–21 years old, 2/378 (0.5%) and 76/473 (16.1%) had IDH1/2-mutant tumors, respectively. Frequency of IDH mutations was similar between low-grade glioma (52/570, 9.1%) and high-grade glioma (25/277, 9.0%). Four tumors were graded as intermediate histologically, with one IDH1 mutation. Outcome: Seventy-six patients with IDH1/2-mutant glioma had outcome data available. Eighty-four percent of patients with low-grade glioma (LGG) were managed observantly without additional therapy. For low-grade astrocytoma, 5-year progression-free survival (PFS) was 42.9% (95%CI:20.3–63.8) and, despite excellent short-term overall survival (OS), numerous disease-related deaths after year 10 were reported. Patients with high-grade astrocytoma had a 5-year PFS/OS of 36.8% (95%CI:8.8–66.4) and 84% (95%CI:50.1–95.6), respectively. Patients with oligodendroglioma had excellent OS. Conclusions A subset of pediatric gliomas is driven by IDH1/2 mutations, with a higher rate among adolescents. The majority of patients underwent upfront observant management without adjuvant therapy. Findings suggest that the natural history of pediatric IDH1/2-mutant glioma may be similar to that of adults, though additional studies are needed.

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.

To develop an MR multitasking-based dynamic imaging for cerebrovascular evaluation (MT-DICE) technique for simultaneous quantification of permeability and leakage-insensitive perfusion with a single-dose contrast injection.MT-DICE builds on a saturation-recovery prepared multi-echo fast low-angle shot sequence. The k-space is randomly sampled for 7.6 min, with single-dose contrast agent injected 1.5 min into the scan. MR multitasking is used to model the data into six dimensions, including three spatial dimensions for whole-brain coverage, a saturation-recovery time dimension, and a TE dimension for dynamicmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:mrowmml:msubmml:miT/mml:mimml:mn1/mml:mn/mml:msub/mml:mrowmml:annotation$$ {\mathrm{T}}_1 $$/mml:annotation/mml:semantics/mml:mathandmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:mrowmml:msubsupmml:miT/mml:mimml:mn2/mml:mnmml:mo*/mml:mo/mml:msubsup/mml:mrowmml:annotation$$ {\mathrm{T}}_2^{\ast } $$/mml:annotation/mml:semantics/mml:mathquantification, respectively, and a contrast dynamics dimension for capturing contrast kinetics. The derived pixel-wisemml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:mrowmml:msubmml:miT/mml:mimml:mn1/mml:mn/mml:msubmml:mo//mml:momml:msubsupmml:miT/mml:mimml:mn2/mml:mnmml:mo*/mml:mo/mml:msubsup/mml:mrowmml:annotation$$ {\mathrm{T}}_1/{\mathrm{T}}_2^{\ast } $$/mml:annotation/mml:semantics/mml:mathtime series are converted into contrast concentration-time curves for calculation of kinetic metrics. The technique was assessed for its agreement with reference methods inmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:mrowmml:msubmml:miT/mml:mimml:mn1/mml:mn/mml:msub/mml:mrowmml:annotation$$ {\mathrm{T}}_1 $$/mml:annotation/mml:semantics/mml:mathandmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:mrowmml:msubsupmml:miT/mml:mimml:mn2/mml:mnmml:mo*/mml:mo/mml:msubsup/mml:mrowmml:annotation$$ {\mathrm{T}}_2^{\ast } $$/mml:annotation/mml:semantics/mml:mathmeasurements in eight healthy subjects and, in three of them, inter-session repeatability of permeability and leakage-insensitive perfusion parameters. Its feasibility was also demonstrated in four patients with brain tumors.MT-DICEmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:mrowmml:msubmml:miT/mml:mimml:mn1/mml:mn/mml:msubmml:mo//mml:momml:msubsupmml:miT/mml:mimml:mn2/mml:mnmml:mo*/mml:mo/mml:msubsup/mml:mrowmml:annotation$$ {\mathrm{T}}_1/{\mathrm{T}}_2^{\ast } $$/mml:annotation/mml:semantics/mml:mathvalues of normal gray matter and white matter were in excellent agreement with reference values (intraclass correlation coefficients = 0.860/0.962 for gray matter and 0.925/0.975 for white matter ). Both permeability and perfusion parameters demonstrated good to excellent intersession agreement with the lowest intraclass correlation coefficients at 0.694. Contrast kinetic parameters in all healthy subjects and patients were within the literature range.Based on dynamicmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:mrowmml:msubmml:miT/mml:mimml:mn1/mml:mn/mml:msubmml:mo//mml:momml:msubsupmml:miT/mml:mimml:mn2/mml:mnmml:mo*/mml:mo/mml:msubsup/mml:mrowmml:annotation$$ {\mathrm{T}}_1/{\mathrm{T}}_2^{\ast } $$/mml:annotation/mml:semantics/mml:mathmapping, MT-DICE allows for simultaneous quantification of permeability and leakage-insensitive perfusion metrics with a single-dose contrast injection.

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.

Purpose: Primary germ cell tumors (GCTs) are the most common central nervous system (CNS) neoplasm in patients with Down syndrome (DS). However, a standard-of-care has not been established due to a paucity of data. Methods: A retrospective multi-institutional analysis was conducted, in addition to a comprehensive review of the literature. Results: Ten patients from six institutions (five USA, one Brazil) were identified, in addition to 31 patients in the literature from 1975 to 2021. Of the 41 total patients (mean age 9.9 years; 61% male), 16 (39%) had non-germinomatous germ cell tumors (NGGCTs), 16 (39%) had pure germinomas and eight (19.5%) had teratomas. Basal ganglia was the most common tumor location (n=13; 31.7%), followed by posterior fossa (n=7; 17%). Nine patients (22%) experienced disease relapse or progression, of which four died from tumor progression (one germinoma, three teratomas). Sixteen patients (39%) experienced treatment-related complications, of which eight (50%) died (five germinomas, three NGGCTs). Of the germinoma patients, two died from chemotherapy-related sepsis, one from post-surgery cardiopulmonary failure, one from pneumonia and one from Moyamoya following radiation-therapy (RT). Of the NGGCT patients, one died from chemotherapy-related sepsis, one from post-surgical infection and one from pneumonia following surgery/chemotherapy/RT. Three-year overall survival was 66% for all histological types – 62% germinomas, 79% for NGGCTs, and 53% for teratomas. Conclusion: Patients with DS treated for CNS GCTs are at an increased risk of treatment-related adverse events. A different therapeutic approach may need to be considered to mitigate treatment-related complications and long-term neurocognitive sequelae.

The study of respiratory plasticity in animal models spans decades. At the bench, researchers use an array of techniques aimed at harnessing the power of plasticity within the central nervous system to restore respiration following spinal cord injury. This field of research is highly clinically relevant. People living with cervical spinal cord injury at or above the level of the phrenic motoneuron pool at spinal levels C3-C5 typically have significant impairments in breathing which may require assisted ventilation. Those who are ventilator dependent are at an increased risk of ventilator-associated co-morbidities and have a drastically reduced life expectancy. Pre-clinical research examining respiratory plasticity in animal models has laid the groundwork for clinical trials. Despite how widely researched this injury is in animal models, relatively few treatments have broken through the preclinical barrier. The three goals of this present review are to define plasticity as it pertains to respiratory function post-spinal cord injury, discuss plasticity models of spinal cord injury used in research, and explore the shift from preclinical to clinical research. By investigating current targets of respiratory plasticity research, we hope to illuminate preclinical work that can influence future clinical investigations and the advancement of treatments for spinal cord injury.

Atypical teratoid rhabdoid tumor (ATRT) is a rare, highly malignant central nervous system cancer arising in infants and younger children, historically considered to be homogeneous, monogenic, and incurable. Recent use of intensified therapies has modestly improved survival for ATRT; however, a majority of patients will still succumb to their disease. While ATRTs almost universally exhibit loss of SMARCB1 (BAF47/INI1/SNF5), recent whole genome, transcriptome, and epigenomic analyses of large cohorts reveal previously underappreciated molecular heterogeneity. These discoveries provide novel insights into how SMARCB1 loss drives oncogenesis and confer specific therapeutic vulnerabilities, raising exciting prospects for molecularly stratified treatment for patients with ATRT.

Background Rhabdoid tumors (RTs) arise within (atypical teratoid/rhabdoid tumor [AT/RT]) or outside the brain (extra [e]CNS-RT) and are driven mainly by inactivation of the SWItch/sucrose nonfermentable (SWI/SNF) complex subunit SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1). A pathognomonic hallmark of RTs is heterogeneous multilineage differentiation, including anomalous neuronal differentiation in some eCNS-RTs. Because remodeling of the SWI/SNF complex regulates differentiation, we hypothesized that SWI/SNF Brahma-associated factors (BAF) and polybromo-associated BAF (PBAF) complex heterogeneity are related to both multilineage differentiation and clinical outcome. Methods We performed an integrated analysis of SWI/SNF complex alterations in the developing kidney and cerebellum (most common regions of RT origin) in comparison to eCNS-RT (n = 14) and AT/RT (n = 25) tumors. RT samples were interrogated using immunohistochemistry, DNA methylation, and gene expression analyses. Results The SWI/SNF BAF paralogs actin-like protein (ACTL)6A and ACTL6B were expressed in a mutually exclusive manner in the developing cerebellum and kidney. In contrast, a subset of eCNS-RTs lost mutual exclusivity and coexpressed both subunits. These tumors showed aberrant DNA methylation of genes that regulate neuronal and renal development and demonstrated immunohistochemical evidence of neuronal differentiation. In addition, low expression of the PBAF subunit polybromo-1 (PBRM1) identified a group of AT/RTs in younger children with better overall prognosis. PBRM1-low AT/RT and eCNS-RTs showed altered DNA methylation and gene expression in immune-related genes. PBRM1 knockdown resulted in lowering immunosuppressive cytokines, and PBRM1 levels in tumor samples showed an inverse relationship with cluster of differentiation (CD)8 cytotoxic T-cell infiltration. Conclusions Heterogeneity in SWI/SNF BAF (ACTL6A/ACTL6B) and PBAF (PBRM1) subunits is related to histogenesis, contributes to the immune microenvironment and prognosis in RTs, and may inform opportunities to develop immunotherapies.

Medulloblastoma is the most common malignant brain tumor of childhood. Despite multi-modal therapies, ~30% of patients experience disease recurrence, which portends a poor prognosis. At initial recurrence, intensive chemotherapy may be effective prior to various consolidation therapies including high dose chemotherapy with autologous stem cell rescue or irradiation. We report outcomes for nine children treated at two institutions with the following regimen: cyclophosphamide 1500mg/m2/dose days 1,2; irinotecan 125mg/m2/dose days 1,8; temozolomide 150mg/m2/dose days 1-5, and oral etoposide 50mg/m2/dose days 1-7. Patients received 2-4 cycles based upon disease response and physician preference. The mean time from initial diagnosis to first recurrence was 19 months. After receiving two cycles of therapy, two patients had complete response (CR) and proceeded to consolidation. Of the remaining seven patients, five had partial response (PR) and two had stable disease (SD). Overall response rate was 78% after 2 cycles. Two patients with PR proceeded directly to consolidation with irradiation. Five patients (3 PR, 2 SD) received 2 additional cycles. After four cycles there was one CR, two with minimal residual disease, one SD and one progressive disease (PD). Four patients (44%) are alive with no evidence of disease (NED). One patient died of consolidation-related toxicity but had NED at time of death 28 months from initial recurrence. Five patients developed PD. Two patients died of disease, two are alive with disease, and one is alive with NED after PD and additional therapy. There were no treatment-related deaths. Infection was the most common complication. Five patients had febrile neutropenia and two developed sepsis. One patient required dose reduction for prolonged thrombocytopenia. Peripheral blood stem cell collection was achieved in all patients for whom it was attempted. This re-induction regimen is generally well-tolerated and effective in inducing responses for children with recurrent medulloblastoma.

BACKGROUND RAS/RAF/MEK/ERK pathway activation is the primary driver for most pediatric low-grade gliomas (pLGG). MEK162 (binimetinib) is an orally bioavailable MEK1/2 inhibitor with superior brain penetration in a preclinical model. The primary objective of this multi-institutional phase II and target validation study was to assess stratum-specific efficacy of binimetinib in progressive pLGG. METHODS Eligible children aged 1-18 years with previously treated radiographically progressive pLGG were enrolled and treated with binimetinib, starting dose 32mg/m2/dose twice daily. Stratum 1 included patients with pLGG with documented BRAF fusion; stratum 2, neurofibromatosis 1 (NF1)-associated pLGG; stratum 3, sporadic pLGG without documented BRAF fusion; and stratum 4, patients undergoing planned tumor biopsy who began binimetinib preoperatively. Partial and minor responses (PR and MR) were defined as ≥50% and ≥25% decrease in maximal two-dimensional measurements. RESULTS Of 86 patients enrolled, 85 were evaluable for response. Of these, 48 (56%) showed a radiographic response (30 PR and 18 MR) in the first year of treatment. Response rate for stratum 1 (n=28) was 50% (12 PR and 2 MR); 12 (43%) had stable disease (SD) and 2 (7%) progressive disease (PD). Stratum 2 (n=21) response rate was 43% (5 PR, 4 MR), with 12 (57%) SD and no PD. Stratum 3 (n=29) response rate was 69% (10 PR, 10 MR), 4 (14%) SD and 5 (17%) PD. Stratum 4 (n=7) include 3 PR, 2 MR, 2 SD. Nineteen (22%) discontinued treatment for toxicity (most commonly dermatologic), and an additional 42 (49%) required dose reduction. Median dose at the time of PR/MR was 28mg/m2; responses were seen at doses as low 16mg/m2. CONCLUSION Binimetinib is highly effective in the treatment of both NF1-associated and sporadic pLGG, with or without documented BRAF fusion. Modified dosing strategies to improve tolerability may be considered in future trials.

BACKGROUND: A standard-of-care has not been established for the management of patients with Down syndrome (DS) who develop primary central nervous system (CNS) germ cell tumors (GCTs) – the most common CNS neoplasm in DS – despite being more susceptible to treatment-related adverse events. METHODS: Data from large academic institutions were collected and a comprehensive review of the medical literature was conducted. RESULTS: Ten patients from six institutions (five USA, one Brazil) were reviewed. Additionally, thirty-one patients were identified in the literature from 1975-2021. Of the 41 total patients, mean age was ten years (range, birth to 35 years); males were predominant (61%). Basal ganglia were the most common tumor location (n=12; 29%), followed by posterior fossa (n=7; 17%). Sixteen patients had non-germinomatous germ cell tumors (NGGCTs) (39%), 14 had pure germinomas (34%), and eight had teratomas (20%); histology was unreported for two (5%). Nine patients (22%) experienced disease relapse, of which four died from tumor progression (one germinoma versus three teratoma). Fifteen patients (37%) experienced treatment-related complications - seven died (four germinoma versus three NGGCT). Of the germinoma patients, two died from chemotherapy-related sepsis, one from post-surgery cardiopulmonary failure, and one from Moyamoya following radiation-therapy (RT) only. Of the NGGCT patients, one died from chemotherapy-related sepsis, one from post-surgical infection, and one from pneumonia following surgery/chemotherapy/RT. Three-year overall survival (OS) was 66% for all histological types - 62% germinoma, 79% for NGGCT, and 53% for teratoma. Three-year OS for patients who received RT or chemotherapy was 71% and 75% respectively. Twenty-seven patients remain alive at latest follow-up (mean follow-up from diagnosis: 46.8 months). CONCLUSIONS: Patients with DS treated for CNS GCTs are at an increased risk of treatment-related adverse events. A different therapeutic approach may need to be considered for this patient population to mitigate treatment-related complications and long-term neurocognitive sequelae.