scholarly journals In Vivo and Ex Vivo Pediatric Brain Tumor Models: An Overview

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhiqin Li ◽  
Sigrid A. Langhans
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Drug Development ◽  
Pediatric Brain Tumor ◽  
Genetic Alterations ◽  
Benign Tumors ◽  
Tumor Type ◽  
Tumor Models ◽  
Pediatric Brain

After leukemia, tumors of the brain and spine are the second most common form of cancer in children. Despite advances in treatment, brain tumors remain a leading cause of death in pediatric cancer patients and survivors often suffer from life-long consequences of side effects of therapy. The 5-year survival rates, however, vary widely by tumor type, ranging from over 90% in more benign tumors to as low as 20% in the most aggressive forms such as glioblastoma. Even within historically defined tumor types such as medulloblastoma, molecular analysis identified biologically heterogeneous subgroups each with different genetic alterations, age of onset and prognosis. Besides molecularly driven patient stratification to tailor disease risk to therapy intensity, such a diversity demonstrates the need for more precise and disease-relevant pediatric brain cancer models for research and drug development. Here we give an overview of currently available in vitro and in vivo pediatric brain tumor models and discuss the opportunities that new technologies such as 3D cultures and organoids that can bridge limitations posed by the simplicity of monolayer cultures and the complexity of in vivo models, bring to accommodate better precision in drug development for pediatric brain tumors.

scholarly journals Preclinical Models of Pediatric Brain Tumors—Forging Ahead

2018 ◽  
Vol 5 (4) ◽  
pp. 81 ◽  
Author(s):  
Tara Dobson ◽  
Vidya Gopalakrishnan
Keyword(s):  
Brain Tumor ◽  
Cognitive Abilities ◽  
Pediatric Brain Tumor ◽  
Economic Incentives ◽  
Molecular Heterogeneity ◽  
Tumor Models ◽  
Preclinical Research ◽  
Pediatric Brain

Approximately five out of 100,000 children from 0 to 19 years old are diagnosed with a brain tumor. These children are treated with medication designed for adults that are highly toxic to a developing brain. Those that survive are at high risk for a lifetime of limited physical, psychological, and cognitive abilities. Despite much effort, not one drug exists that was designed specifically for pediatric patients. Stagnant government funding and the lack of economic incentives for the pharmaceutical industry greatly limits preclinical research and the development of clinically applicable pediatric brain tumor models. As more data are collected, the recognition of disease sub-groups based on molecular heterogeneity increases the need for designing specific models suitable for predictive drug screening. To overcome these challenges, preclinical approaches will need continual enhancement. In this review, we examine the advantages and shortcomings of in vitro and in vivo preclinical pediatric brain tumor models and explore potential solutions based on past, present, and future strategies for improving their clinical relevancy.

scholarly journals RARE-25. DISSECTING THE CONTEMPORARY EPIDEMIOLOGY OF PRIMARY AND SECONDARY BRAIN TUMORS IN INFANCY THROUGH CHILDHOOD

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i46-i46
Author(s):  
Nayan Lamba ◽  
Bryan Iorgulescu
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Brain Metastases ◽  
Pediatric Brain Tumor ◽  
Pediatric Brain Tumors ◽  
National Registry ◽  
Late Childhood ◽  
Tumor Type ◽  
Sellar Region ◽  
Pediatric Brain

Abstract Introduction Herein we utilize national registry data to evaluate the epidemiology of primary and secondary pediatric brain tumors according to the WHO2016 classification. Methods Pediatric patients (age≤14) presenting between 2004–2017 with a brain tumor were identified by ICD-O-3 and brain metastasis (2010–2017) coding from the National Cancer Database (comprising >70% of newly-diagnosed cancers in the U.S.), and categorized by NICHD age stages: infant (<1yr; n=1,686), toddler (1-2yrs; n=1,732), early- (2-5yrs; n=6,712), middle- (6-11yrs; n=9,175), and late- (12-14yrs; n=5,042) childhood. Patients’ age, sex, race/ethnicity, and overall survival, and tumor location and size were evaluated by WHO2016 tumor type. Results 24,347 pediatric brain tumor patients were identified. Overall, other astrocytic tumors (24% of females, 20% of males), diffuse astrocytic/oligodendroglial gliomas (23% of females, 21% of males – 64% of which were midline), embryonal (13% of females, 19% of males), and sellar region tumors (12% of females, 8% of males) predominated. Embryonal tumors prevailed in infancy (24%) and toddlerhood (24%), declining to 9% in late childhood; only 40% were female. Ependymal tumors peaked at 15% in toddlerhood (6% overall), whereas choroid plexus tumors peaked at 11% in infancy (1.9% overall). A minority of brain tumors were of neuronal & mixed neuronal-glial (6.1%), germ cell (3.8%), cranial nerve (3.2%), mesenchymal non-meningothelial (2.4%), meningioma (1.6%), pineal (1.1%), hematological/histiocytic (0.5%), and other glioma (0.2%) types. Brain metastases were rare (1.5% overall; from 4.0% in infancy to 0.8% in late childhood; and only 41% were female) – 61% came from adrenal neuroblastoma, 16% from sarcomas, and 6% from malignant rhabdoid tumors/extracranial AT/RT. Conclusions Pediatric brain metastases overwhelmingly originate from adrenal neuroblastoma. Although, overall, diffuse astrocytic/oligodendroglial, other astrocytic, embryonal, and sellar region tumors predominate among pediatric brain tumors, together they only comprise 70% of cases and their distribution varies substantially by patients’ age and sex.

scholarly journals A pediatric brain tumor atlas of genes deregulated by somatic genomic rearrangement

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yiqun Zhang ◽  
Fengju Chen ◽  
Lawrence A. Donehower ◽  
Michael E. Scheurer ◽  
Chad J. Creighton
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Tyrosine Kinases ◽  
Pediatric Brain Tumor ◽  
Pediatric Brain Tumors ◽  
Altered Expression ◽  
Critical Pathways ◽  
Cis Regulation ◽  
Or Gene ◽  
Pediatric Brain

AbstractThe global impact of somatic structural variants (SSVs) on gene expression in pediatric brain tumors has not been thoroughly characterised. Here, using whole-genome and RNA sequencing from 854 tumors of more than 30 different types from the Children’s Brain Tumor Tissue Consortium, we report the altered expression of hundreds of genes in association with the presence of nearby SSV breakpoints. SSV-mediated expression changes involve gene fusions, altered cis-regulation, or gene disruption. SSVs considerably extend the numbers of patients with tumors somatically altered for critical pathways, including receptor tyrosine kinases (KRAS, MET, EGFR, NF1), Rb pathway (CDK4), TERT, MYC family (MYC, MYCN, MYB), and HIPPO (NF2). Compared to initial tumors, progressive or recurrent tumors involve a distinct set of SSV-gene associations. High overall SSV burden associates with TP53 mutations, histone H3.3 gene H3F3C mutations, and the transcription of DNA damage response genes. Compared to adult cancers, pediatric brain tumors would involve a different set of genes with SSV-altered cis-regulation. Our comprehensive and pan-histology genomic analyses reveal SSVs to play a major role in shaping the transcriptome of pediatric brain tumors.

scholarly journals DIPG-60. PILOT STUDY OF CIRCULATING TUMOR CELLS IN PEDIATRIC HIGH GRADE BRAIN TUMORS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii299-iii299
Author(s):  
Wafik Zaky ◽  
Long Dao ◽  
Dristhi Ragoonanan ◽  
Izhar Bath ◽  
Sofia Yi ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Pediatric Brain Tumor ◽  
Pediatric Brain Tumors ◽  
Disease Assessment ◽  
Liquid Biopsies ◽  
Capture Method ◽  
Pediatric Brain

Abstract BACKGROUND Despite its increasing use, circulating tumor cells (CTCs) have not been studied in pediatric brain tumors. METHODS Cell surface vimentin (CSV) is a marker for CTC detection. We developed an automated CSV-based CTC capture method for pediatric brain tumor using the Abnova Cytoquest platform. PBMCs isolated from blood samples from 52 brain tumor patients were processed to isolate CSV+ CTCs. Captured cells were then stained for CSV and CD45 and scanned to determine the number of CTCs. DIPG samples were additionally examined for H3K27M expression on CSV+ cells. Long term cancer survivors were used as a control cohort. RESULTS 86.4% of all the samples exhibited between 1–13 CSV+ CTCs, with a median of 2 CSV+ CTCs per sample. Using a value of ≥ 1 CTC as a positive result, the sensitivity and specificity of this test was 83.05% and 60.0% respectively. 19 DIPG samples were analyzed and 70% (13 samples) were positive for 1–5 CTCs. Five of these 7 positive CSV+ CTCs DIPG samples were also positive for H3K27M mutations by immunohistochemistry (71%). Mean survival in days for the CTC positive and negative DIPG samples were 114 and 211 days, respectively (p= 0.13). CONCLUSION This is the first study of CTCs in pediatric CNS tumors using an automated approach. Patients with brain tumors can exhibit CSV+ CTCs within peripheral blood. The use of specific molecular markers such as H3K27M can improve the diagnostic capability of liquid biopsies and may enable future disease assessment for personalized therapy.

scholarly journals Intraoperative Detection of Pediatric Brain Tumor Margins Using Raman Spectroscopy.

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Rashad Jabarkheel ◽  
Jonathon J Parker ◽  
Chi-Sing Ho ◽  
Travis Shaffer ◽  
Sanjiv Gambhir ◽  
...  
Keyword(s):  
Machine Learning ◽  
Raman Spectroscopy ◽  
Brain Tumor ◽  
Brain Tumors ◽  
Brain Tissue ◽  
Pediatric Brain Tumor ◽  
Tissue Samples ◽  
Tumor Margins ◽  
Pediatric Brain ◽  
Tumor Debulking

Abstract INTRODUCTION Surgical resection is a mainstay of treatment in patients with brain tumors both for tissue diagnosis and for tumor debulking. While maximal resection of tumors is desired, neurosurgeons can be limited by the challenge of differentiating normal brain from tumor using only microscopic visualization and tactile feedback. Additionally, intraoperative decision-making regarding how aggressively to pursue a gross total resection frequently relies on pathologic preliminary diagnosis using frozen sections which are both time consuming and fallible. Here, we investigate the potential for Raman spectroscopy (RS) to rapidly detect pediatric brain tumor margins and classify brain tissue samples equivalent to histopathology. METHODS Using a first-of-its-kind rapid acquisition RS device we intraoperatively imaged fresh ex vivo pediatric brain tissue samples (2-3 mm × 2-3 mm × 2-3 mm) at the Lucille Packard Children's Hospital. All imaged samples received standard final histopathological analysis, as RS is a nondestructive imaging technique. We curated a labeled dataset of 575 + unique Raman spectra gathered from 160 + brain samples resulting from 23 pediatric patients who underwent brain tissue resection as part of tumor debulking or epilepsy surgery (normal controls). RESULTS To our knowledge we have created the largest labeled Raman spectra dataset of pediatric brain tumors. We are developing an end-to-end machine learning model that can predict final histopathology diagnosis within minutes from Raman spectral data. Our preliminary principle component analyses suggest that RS can be used to classify various brain tumors similar to “frozen” histopathology and can differentiate normal from malignant brain tissue in the context of low-grade glioma resections. CONCLUSION Our work suggests that machine learning approaches can be used to harness the material identification properties of RS for classifying brain tumors and detecting their margins.

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