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METHODS Through the Advancing Treatment for Pediatric Craniopharyngioma (ATPC) consortium we accumulated preoperative MRIs and tumor RNA for 50 unique ACP patients. MRIs were assessed quantitatively for 28 different features and analyzed using Multiple Factor Analysis (MFA) and optimal clustering was determined via maximization of Bayesian Information Criterion (BIC). Following bulk RNAseq, differential expression and pathway enrichment were performed using standard methodologies (i.e., DESeq2 and GSEA). RESULTS MRI features were well represented in the first 3 dimensions of MFA (variance explained=67.32%); specifically tumor/cyst size, ventricular size, and cyst fluid diffusivity. Using this three-way axis, we identified 3 patient subgroups. Transcriptional differences between these subgroups indicated one group was enriched for DNA damage response and MYC related pathways, one group enriched for SHH, and one group enriched for WNT/β-catenin and EMT-related pathways. CONCLUSION This preliminary work suggests that there may be unique gene expression variants within ACP, which may be identified preoperatively using easily quantifiable MRI parameters. These radiogenomic signatures could provide prognostic information and/or guidance in the selection of antitumor therapies for children with ACP.

Pediatric brain tumor survivors experience significant cognitive sequelae from their diagnosis and treatment. The exact mechanisms of cognitive injury are poorly understood, and validated predictors of long-term cognitive outcome are lacking. Large-scale, distributed brain systems provide a window into brain organization and function that may yield insight into these mechanisms and outcomes. We evaluated functional network architecture, cognitive performance, and brain-behavior relationships in pediatric brain tumor patients. Patients ages 8–18 years old with diagnosis of a brain tumor underwent awake resting state functional Magnetic Resonance Imaging during regularly scheduled clinical visits and were tested with the National Institutes of Health Toolbox Cognition Battery. Age- and sex-matched typically developing children were used as controls. We observed that functional network organization was significantly altered in patients compared to controls (p < 0.001), with the integrity of the dorsal attention network particularly affected (p < 0.0001). Moreover, patients demonstrated significant impairments in multiple domains of cognitive performance, including attention (p < 0.0001). Finally, a significant amount of variance (R squared = 0.52, F = 3.2, p < 0.05) of age-adjusted total composite scores from the Toolbox was explained by changes in segregation between the dorsal attention and default mode networks. Our results suggest that changes in functional network organization may provide insight into long-term changes in cognitive function in pediatric brain tumor patients.

Background Leptomeningeal disease and hydrocephalus are present in up to 30% of patients with diffuse intrinsic pontine glioma (DIPG), however there are no animal models of cerebrospinal fluid (CSF) dissemination. As the tumor-CSF-ependymal microenvironment may play an important role in tumor pathogenesis, we identified characteristics of the Nestin-tumor virus A (Nestin-Tva) genetically engineered mouse model (GEMM) that make it ideal to study the interaction of tumor cells with the CSF and its associated pathways with implications for the development of treatment approaches to address CSF dissemination in DIPG. Methods A Nestin-TVa model of DIPG utilizing the three most common DIPG genetic alterations (H3.3K27M, PDGF-B, p53) was used for this study. All animals underwent MR imaging and a subset underwent histopathologic analysis with H&E and beta-IV tubulin. Results Tumor dissemination within the CSF pathways (ventricles, leptomeninges) was present in 76% (25/33) of animals, with invasion of the choroid plexus, disruption of the ciliated ependyma and regional subependymal fluid accumulation. Ventricular enlargement consistent with hydrocephalus was present in 94% (31/33). Ventricle volume correlated with region specific transependymal CSF flow (periventricular T2 signal), localized anterior to the lateral ventricles. Subependymal tumor cells were also present subjacent to the 4th ventricle in a post-mortem human specimen. Conclusions This is the first study to report CSF pathway tumor dissemination an animal model of DIPG and is representative of CSF dissemination seen clinically. Understanding the CSF-tumor-ependymal microenvironment has significant implications for treatment of DIPG through targeting mechanisms of tumor spread within the CSF pathways.

BACKGROUND Due to disease and/or treatment-related injury, such as hypothalamic, visual, and endocrine damage, quality of life (QoL) scores after childhood-onset Adamantinomatous Craniopharyngioma (ACP) are among the lowest of all pediatric brain tumors. Decision-making regarding management would be aided by more complete understanding of a patients likely QoL trajectory following intervention. METHODS We retrospectively analyzed caregiver and patient-reported QoL-instruments from the first 50 patients (ages 1–17 years at diagnosis) enrolled in the international Advancing Treatment for Pediatric Craniopharyngioma (ATPC) consortium. Surveys included 205 pediatric-relevant questions and were completed at diagnosis, and 1- and 12-months following diagnosis. Using Multiple Correspondence Analysis (MCA), these categorical QoL surveys were interrogated to identify time-dependent patient subgroups. Additionally, custom deep learning classifiers were developed using Google’s TensorFlow framework. RESULTS By representing QoL data in the reduced dimensionality of MCA-space, we identified QoL subgroups that either improved or declined over time. We assessed differential trends in QoL responses to identify variables that were subgroup specific (Kolmogorov-Smirnov p-value < 0.1; n=20). Additionally, our optimized deep learning classifier achieved a mean 5-fold cross-validation area under precision-recall curve score > 0.99 when classifying QoL subgroups at 12 month follow-up, using only baseline data. CONCLUSIONs This work demonstrates the existence of time-dependent QoL-based ACP subgroups that can be inferred at time-of-diagnosis via machine learning analyses of baseline survey responses. The ability to predict an ACP patient’s QoL trajectory affords caregivers valuable information that can be leveraged to maximize that patient’s psychosocial state and therefore improve overall therapy.

While most pediatric brain tumor patients become long-term survivors, there are known long-term effects in processing speed, executive function and other cognitive domains secondary to surgery, radiation therapy, chemotherapy, and the tumor itself. However, the effects of these factors on the functional neuroanatomy underlying cognition is poorly understood.

BACKGROUND: Adamantinomatous Craniopharyngioma (ACP) is associated with considerable short and long-term morbidity. There are currently no well-established directed therapies. Recent studies demonstrated pro-inflammatory characteristics in both the solid and cyst compartments, but no data have examined whether immunosuppressive mechanisms are active in these tumors. METHODS: This study utilized a variety of platforms to examine immunosuppressive markers in cyst fluid and associated solid tumor components of ACP. Analyte levels in ACP were compared with other common pediatric brain tumors and normal tissue in order to identify immunosuppressive factors that were overexpressed in ACP. Cyst fluid and cells contained therein were analyzed using multiplex cytokine analysis and flow cytometry, respectively. A large transcriptomic database of ACP and other pediatric tumors and normal brain was queried for immunosuppressive gene expression. Immunohistochemistry was used to further validate gene expression data. RESULTS: ACP demonstrated highly elevated levels of IDO-1 (FC 9.43 versus all other tumor/tissue types, p=1.4x10-28), confirmed by IHC staining for IDO-1 in the epithelial tumor compartment. Elevated levels of IL-10 were demonstrated in cyst fluid and solid tumor compartments. Myeloid cells from the ACP cyst compartment demonstrated low levels of CD64 and HLA-DR expression, combined with high levels of CD163 expression. This pattern is most consistent with an immunosuppressive, pro-tumor milieu. Both CD4 and CD8(+) T-cells demonstrated positive staining for PD-1, most consistent with an exhausted phenotype. Consistent with this, PD-L1 mRNA was elevated in ACP tumor samples versus many other tumor types. CONCLUSIONS: Pediatric ACP is characterized by immunosuppressive factors in both the solid and cyst fluid compartments. This finding must be further considered within the context of the pro-inflammatory characteristics that have been previously described. It further raises the prospect of clinical translation through the application of available immune-directed therapies, in particular those that elicit therapeutic benefit through reversal of immunosuppression.