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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.

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: 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.

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.

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.

BACKGROUND: The prognosis for pediatric high-grade glioma (pHGG) is poor despite aggressive multi-modal 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 10.7 years (range: 1.8–20.3). 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 (PFS) and overall survival (OS) for the cohort were 65% and 82%, respectively, and superior to a historical control cohort treated with conventional therapies. CONCLUSIONS: Upfront targeted therapy for patients with BRAF-mutant pHGG is feasible and effective, with superior clinical outcomes observed compared to historical data. This promising treatment paradigm is currently being evaluated prospectively in the Children’s Oncology Group ACNS1723 clinical trial.

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.

Introduction: For many forms of cancers, survival improvement in the AYA population has lagged behind that of younger patients. One contributing factor could be differences in drug metabolism and tolerance of cancer treatment. Although previous studies have documented greater vincristine-related neurotoxicity (VRNT) in AYA vs. younger patients, comparative vincristine PK studies have yielded mixed results with no clear difference in PK related to age. One limitation of these studies is that age, rather than a more physiological assessment of developmental maturity, was used for the comparison. The primary aim of this study was to determine whether developmental differences in vincristine PK related to Tanner Stage could be detected in a sample of children and AYAs undergoing treatment for ALL. Our hypothesis was that vincristine PK would be related to Tanner Stage. Methods: From September 2014-March 2015, a purposeful sample of 30 patients with a diagnosis of ALL treated at Children's Hospital of Los Angeles were recruited to this IRB-approved study either prior to starting Induction phase or during Maintenance phase. Tanner Stage was classified as ≤2 or ≥4, excluding Tanner Stage 3. Vincristine blood levels were obtained around the first dose during Induction or any single monthly dose during Maintenance at pre-specified time points: 0 min, 10 min, 30 min, 1 hour, 12 hour (Induction only), and 24 hours. For all patients, the vincristine dose was 1.5 mg/m2 (max 2 mg). Vincristine levels were determined by high performance liquid chromatography. Mean vincristine clearance was compared using the independent T-test. Univariate and multivariate linear regression analysis via backward selection was performed using Tanner Stage, age, sex, BMI, fluconazole exposure, and treatment phase as predictors. P-values were two-sided with significance set at < 0.05. Results: The age range was 1-24 yrs (< 10 yrs, n=12; 10+ yrs, n=18). 15 (50.0%) patients were female; and 26 (86.7%) were Hispanic. BMI was underweight/normal for 20 (66.7%). Fluconazole was being administered to 19 (63.3%). Tanner Stage was ≤ 2 for 14 patients (46.7%) and ≥ 4 for 16 (53.3%). Mean vincristine clearance (standard error) for the Tanner ≤ 2 and ≥ 4 groups was 61.14 (18.42) and 68.75 (10.05) L/h*m2, respectively (p=0.71). As summarized in Tables 1 and 2, in both univariate and multivariate analyses no predictors, including Tanner Stage, were associated with vincristine clearance. Conclusions: In this pilot study, we were unable to detect an association between vincristine clearance and Tanner Stage. These data suggest that even when using a measure more reflective of physiological maturity than age, substantial developmental differences in vincristine clearance appear to be lacking. This calls into question the potential explanation of altered clearance for the increased VRNT observed in AYAs, and suggests that future investigations should be directed toward potential developmental differences in vincristine pharmacodynamics. Our data may have implications for understanding other differences in chemotherapy toxicity observed in AYAs. Table 1. Univariate Analysis of Vincristine Clearance Predictor Clearance Unit: L/h*m2 Diff (SE) F-test P-value Tanner stage ≥4 vs. ≤2 7.615 (20.279) 0.71012 Age 10+ vs. Table 2. Multivariate analysis of Vincristine Clearance Model #1 Model # 2 Endpoint Predictor Diff (SE) LRT P-value Predictor Diff (SE) LRT P-value Clearance Unit: L/h*m2 Age 10+ vs Disclosures No relevant conflicts of interest to declare.