Exploiting Laboratory Insights to Improve Outcomes of Pediatric Central Nervous System Tumors

2016 ◽  
pp. e540-e546 ◽  
Author(s):  
Giles W. Robinson ◽  
Hendrik Witt ◽  
Adam Resnick
Keyword(s):  
Brain Tumor ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Pediatric Brain Tumor ◽  
Pediatric Brain Tumors ◽  
Low Grade ◽  
Short Period ◽  
Tumor Management ◽  
The Impact ◽  
Pediatric Brain

Over a relatively short period of time, owing to improvements in biotechnology, our ability to identify the molecular mechanisms within pediatric brain tumors has dramatically increased. These findings have reshaped the way that we describe these diseases and have provided insights into how to better treat these often devastating diseases. Although still far from reaching the full therapeutic potential these advancements hold, the impact of these findings is steadily taking hold of pediatric brain tumor management. In this article, we summarize the major discoveries within three common pediatric brain tumor categories; medulloblastoma, ependymoma, and low-grade glioma. We discuss the current impact of these findings on treatment and the direction these findings may take the field of pediatric neuro-oncology.

scholarly journals PATH-21. TELOMERE LENGTH ANALYSIS OF CNS TUMORS IN THE PEDIATRIC BRAIN TUMOR ATLAS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii428-iii428
Author(s):  
Jo Lynn Rokita ◽  
Krutika Gaonkar ◽  
Heba Ijaz ◽  
Daniel Miller ◽  
Tasso Karras ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Gene Mutations ◽  
Pediatric Brain Tumor ◽  
High Grade Glioma ◽  
Pediatric Brain Tumors ◽  
Low Grade ◽  
Alternative Lengthening ◽  
Length Analysis ◽  
Telomere Lengthening ◽  
Pediatric Brain

Abstract Subsets of pediatric cancers, including high grade glioma (pHGG), have high rates of uniquely long telomeres, associated with ATRX gene mutations and alternative lengthening of telomeres (ALT). Ultimately, these cancers may benefit from a therapy stratification approach. In order to identify and further characterize pediatric brain tumors with telomere lengthening (TL), we determined the intratelomeric content in silico from paired WGS of 918 tumors from CBTTC Pediatric Brain Tumor Atlas (PBTA). The results were highly concordant with experimental assays to determine ALT in a subset of 45 pHGG tumors from the set. Overall, 13% of the PBTA cohort had telomere lengthening. We confirmed the highest rate of TL (37%) in the pHGG cohort (37/100 tumors; 30/82 patients). There was no statistical difference in age, gender or survival in subset analysis. As expected, the patient pHGG tumors with telomere lengthening were enriched for ATRX mutations (60%, q= 1.76e-3). However, 6 tumors without ATRX mutation also had normal protein expression, suggesting a different mechanism of inactivation or TL. The pHGG tumors with telomere lengthening had increased mutational burden (q=8.98e-3) and included all known pHGG cases (n=6) in the cohort with replication repair deficiencies. Of interest, the second highest rate of telomere lengthening was 9 subjects (24%) in the craniopharyngioma cohort. None of the craniopharyngioma tumors had ATRX mutations or low ATRX expression, and 55% of those with TL had CTNNB1 mutations. Finally, lower rates of telomere lengthening were found in medulloblastoma (10%), ependymoma (10%), low grade astrocytoma (8%) and ganglioglioma (7/47, 15%).

scholarly journals IMMU-21. INVESTIGATION OF WHITE BLOOD CELL CHARACTERISTICS IN CSF SAMPLES AT PEDIATRIC BRAIN TUMOR DIAGNOSIS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii364-iii364
Author(s):  
Hunter Greer ◽  
Kristen Campbell ◽  
Sadaf Samay ◽  
Adam Green
Keyword(s):  
Brain Tumor ◽  
Tumor Cell ◽  
Pediatric Brain Tumor ◽  
High Grade Glioma ◽  
Pediatric Brain Tumors ◽  
Tumor Diagnosis ◽  
Low Grade ◽  
Brain Tumor Diagnosis ◽  
Pediatric Brain ◽  
Insight Into

Abstract BACKGROUND There has been a recent surge in investigation of immunity and immunotherapy, but their role in pediatric brain tumors is incompletely defined. We hypothesized that investigating an understudied dataset, WBC and differential results in CSF drawn at the time of pediatric brain tumor diagnosis to look for microscopic metastases, would provide insight into the role of immunology and potential for immunotherapy in these diseases and correlate with prognosis and/or metastasis. METHODS We conducted a retrospective comparison analysis of CSF values in 349 patients at our institution from samples drawn within 60 days of initial CNS tumor diagnosis from 1998–2018. We examined total nucleated cell count, absolute counts and percentages for WBC subtypes. We compared CSF values by tumor cell presence, patient vital status, and disease group: atypical teratoid rhabdoid tumor, ependymoma, germinoma, high-grade glioma (HGG), low-grade glioma (LGG), medulloblastoma, non-germinomatous germ cell tumor, and other embryonal tumors (OET). We used Wilcoxon and Kruskal-Wallis tests for comparisons. RESULTS Overall, higher lymphocyte percentage (p=0.002) and lower monocyte percentage (p=0.007) were associated with survival. WBC characteristics did not differ significantly based on tumor cell presence. Compared to medulloblastoma, ependymoma showed a more active CSF immune response, while LGG, HGG, and OET showed a less active response, based on total WBC and/or absolute neutrophil count (p=0.001–0.007). CONCLUSIONS Higher lymphocyte and lower monocyte percentages in CSF correlated with better prognosis overall; causality requires further investigation. Tumor subtypes varied in their immune stimulation, offering potential insight into which will be amenable to immunotherapy.

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.

A phase 1 study of AZD6244 in children with recurrent or refractory low-grade gliomas: A Pediatric Brain Tumor Consortium report.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 10065-10065 ◽  
Author(s):  
Anuradha Banerjee ◽  
Regina Jakacki ◽  
Arzu Onar-Thomas ◽  
Shengjie Wu ◽  
Theodore Nicolaides ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Phase 1 ◽  
Pediatric Brain Tumor ◽  
Low Grade ◽  
Phase 1 Study ◽  
Low Grade Gliomas ◽  
Pediatric Brain

scholarly journals SL1 GENETICS OF PEDIATRIC BRAIN TUMORS: RECENT ADVANCES AND FUTURE PERSPECTIVES

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii1-ii1
Author(s):  
David T W Jones
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Somatic Hypermutation ◽  
Tumor Biology ◽  
Pediatric Brain Tumor ◽  
Pediatric Brain Tumors ◽  
Braf V600e ◽  
Enhancer Element ◽  
Frequent Mutations ◽  
Pediatric Brain

Abstract The last decade has seen a true revolution in our understanding of the oncogenic mechanisms underlying human tumors, brought about by transformative advances in the technologies available to interrogate the (epi)genetic composition of cancer cells. The dynamic pediatric neuro-oncology community has proven to be very agile in adapting to these changes, and has arguably been at the forefront of some of the most exciting new discoveries in tumor biology in recent years. For example, high-throughput genomic sequencing has revealed highly frequent mutations in histone genes in pediatric glioblastoma; highlighted an ever-expanding role for oncogenic gene fusions in multiple pediatric brain tumor types, and also shed light on novel phenotypic patterns such as chromothripsis (dramatic chromosomal shattering) and somatic hypermutation - the latter being a possible marker for response to novel immunotherapeutic approaches. Epigenetic profiling has also identified a role for ‘enhancer hijacking’ (whereby genomic rearrangement brings an active enhancer element in close proximity to a proto-oncogene) in multiple pediatric brain tumors, and is even pointing towards a fundamentally new way in which tumors may be molecularly classified. In coming years, the major challenge will be to harness the power of these discoveries to more accurately diagnose patients and to identify potential therapeutic targets in a more personalized way, so that these major biological advances can also be translated into substantial clinical benefit. Examples such as the dramatic responses observed in childhood brain tumor sufferers to BRAF V600E and NTRK inhibitors demonstrate the promise that such an approach can hold, but it will require a fundamental shift in the way that clinical trials are planned and conducted in order to optimize patient care. This talk will highlight some of the most striking developments in the field, and look at the challenges that remain before these can lead to improved patient outcomes.

scholarly journals LGG-08. A PHASE II PROSPECTIVE STUDY OF SELUMETINIB IN CHILDREN WITH RECURRENT OR REFRACTORY LOW-GRADE GLIOMA (LGG): A PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC) STUDY

2017 ◽  
Vol 19 (suppl_4) ◽  
pp. iv34-iv35 ◽  
Author(s):  
Jason Fangusaro ◽  
Arzu Onar-Thomas ◽  
Tina Y Poussaint ◽  
Shengjie Wu ◽  
Azra H Ligon ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Prospective Study ◽  
Phase Ii ◽  
Pediatric Brain Tumor ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Pediatric Brain

scholarly journals Exploratory Evaluation of MR Permeability with 18F-FDG PET Mapping in Pediatric Brain Tumors: A Report from the Pediatric Brain Tumor Consortium

2013 ◽  
Vol 54 (8) ◽  
pp. 1237-1243 ◽  
Author(s):  
K. A. Zukotynski ◽  
F. H. Fahey ◽  
S. Vajapeyam ◽  
S. S. Ng ◽  
M. Kocak ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Fdg Pet ◽  
Pediatric Brain Tumor ◽  
Pediatric Brain Tumors ◽  
18F Fdg ◽  
Pediatric Brain
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