scholarly journals RADI-21. IMAGING CHARACTERISTICS OF BRAF V600E MUTATED PEDIATRIC BRAIN TUMORS

2018 ◽  
Vol 20 (suppl_2) ◽  
pp. i174-i174
Author(s):  
Nicholas Stence ◽  
Jean Mulcahy-Levy ◽  
Lindsey Hoffman ◽  
Adam Green ◽  
David Mirsky ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Pediatric Brain Tumors ◽  
Braf V600e ◽  
Imaging Characteristics ◽  
Pediatric Brain

scholarly journals EXTH-16. TREATMENT OF THREE DIFFERENT BRAF-V600E POSITIVE BRAIN TUMORS WITH VEMURAFENIB AND DABRAFENIB/TRAMETINIB: A CASE SERIES

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii90-ii90
Author(s):  
Nikita Dhir ◽  
Sheila Chandrahas ◽  
Chibuzo O’Suoji ◽  
Mohamad Al-Rahawan
Keyword(s):  
Targeted Therapy ◽  
Brain Tumors ◽  
Tumor Regression ◽  
Case Series ◽  
Pediatric Brain Tumors ◽  
Braf V600e ◽  
Cns Tumors ◽  
Braf Inhibitors ◽  
Pediatric Brain ◽  
Pediatric Cns Tumors

Abstract BACKGROUND The BRAF-V600E gene is a protein kinase involved in regulation of the mitogen activated protein kinase pathway (MAPK/MEK) and downstream extracellular receptor kinase (ERK). The BRAF-V600E mutation has a significant role in the progression of pediatric brain tumors. 85% of pediatric CNS tumors express the BRAF mutation. Thus, BRAF targeted therapy in pediatric CNS malignancies has potential to become the standard of care for tumors expressing this mutation. OBJECTIVE Current pediatric CNS brain tumor treatment focuses on chemotherapy and radiation, causing significant toxic side effects for patients. The significance of this case series lies in relaying our experience using targeted therapy in BRAF-V600E positive CNS pediatric brain tumors. METHODS We followed the disease course, progression, and treatment of three pediatric patients with three different CNS tumors. Each of these individuals was treated with surgical resection, chemotherapy, and/or radiation as per standard protocol. When that modality failed to reduce tumor progression, we found that each of their different tumors was BRAF-V600E positive and they were all started on targeted therapy. DISCUSSION Vemurafenib, Dabrafenib, and Trametinib are BRAF-V600E/MEK inhibitors that were initially used to treat melanomas. However, more research has shown that various pediatric CNS tumors are BRAF-V600 positive. Therapy with these BRAF inhibitors has been shown to slow tumor progression, but toxicity can be severe. This case series shows one patient with successful tumor regression, one patient with prolonged disease stabilization, and one patient with initial response but subsequent progression and ultimate death. It has been shown that using BRAF inhibitors in lower grade CNS tumors are more effective than higher grade CNS tumors. CONCLUSION The success of Vemurafenib and Dabrafenib/Trametinib in causing pediatric CNS tumor regression is promising, but further studies are needed to solidify their role in pediatric CNS cancers.

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.

Tumor molecular profiling in advanced pediatric brain tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e21516-e21516
Author(s):  
Gargi D. Basu ◽  
Thanemozhi G Natarajan ◽  
Szabolcs Szelinger ◽  
Candyce M Bair ◽  
Tracey White ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Brain Tumors ◽  
Pediatric Brain Tumors ◽  
Molecular Profiling ◽  
Small Sample ◽  
Braf V600e ◽  
Low Grade ◽  
High Grade ◽  
Clinical Sequencing ◽  
Pediatric Brain

e21516 Background: With the advent of high-throughput molecular profiling, clinical outcome in pediatric cancers has greatly improved due to our greater understanding of genetic origin of pediatric cancer, and availability of biomarker specific treatment options. However, pediatric brain tumors continue to be challenging in terms of therapy. The goal of this study was to evaluate the utility of integrative clinical sequencing in pediatric patients with brain tumors. Methods: Targeted exome sequencing of 562 genes in paired tumor-normal DNA was performed on 14 patients and tumor DNA and RNA was sequenced on additional 4 patients. Sequence analysis identified SNVs, indels, copy number events, fusions, alternate transcripts, breakpoints, TMB and MSI status. Clinically, actionable alterations were identified which could be targeted by FDA approved agents or clinical trials. Results: A total of 18 patients (1-17 y.o.) with low grade (n = 5) and high grade (n = 13) brain tumors were profiled. The cohort consisted of a spectrum of GBMs (45%), medulloblastomas (10%) astrocytomas (22%), and other brain tumors (23%). At least one targetable, driver alteration was identified in 83% of all patients, and 92% of high-grade patients had at least one targetable driver event. Targetable mutations were identified in histone and chromatin modifier genes like H3F3A in 3/18 cases (17%), SETD2, ARID1A, PBRM1 in 2/18 cases (11%), activation of PI3K/AKT/mTOR pathway genes in 6/18 cases (33%), DNA repair genes NBN, ATRX and BRCA2 in 3/18 cases (17%); BRAF V600E in 3 high-grade and a KIAA1549/BRAF fusion in a low-grade tumor, activation of cell cycle in 2/18 cases (11%), activation of FGFR pathway with FGFR1/TACC1 fusion and activating mutation in 2/18 cases (11%), activation of PDGFRA in 2/18 samples (11%), TP53 mutations in 4/18 cases (22%). A breakpoint translocation concurrent with LOH of PTCH1 locus was noted in a medulloblastoma patient. High TMB or MSI instability was not observed. Conclusions: Our results underline the importance of clinical sequencing in identifying targetable markers in high- risk brain tumors. Although limited by small sample size, our study highlights the need for ongoing clinical trials to integrate the genomic discoveries leading to better clinical outcomes.

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 RONC-19. TWO CASES OF RE-IRRADIATION FOR LATE RECURRENT OR RADIATION-INDUCED TUMOR AFTER RADIATION THERAPY FOR PEDIATRIC BRAIN TUMORS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii459-iii459
Author(s):  
Takashi Mori ◽  
Shigeru Yamaguchi ◽  
Rikiya Onimaru ◽  
Takayuki Hashimoto ◽  
Hidefumi Aoyama
Keyword(s):  
Radiation Therapy ◽  
Brain Tumors ◽  
Tumor Resection ◽  
Intensity Modulated Radiation Therapy ◽  
Late Recurrence ◽  
Pediatric Brain Tumors ◽  
Suprasellar Region ◽  
Radiation Induced ◽  
Pediatric Brain

Abstract BACKGROUND As the outcome of pediatric brain tumors improves, late recurrence and radiation-induced tumor cases are more likely to occur, and the number of cases requiring re-irradiation is expected to increase. Here we report two cases performed intracranial re-irradiation after radiotherapy for pediatric brain tumors. CASE 1: 21-year-old male. He was diagnosed with craniopharyngioma at eight years old and underwent a tumor resection. At 10 years old, the local recurrence of suprasellar region was treated with 50.4 Gy/28 fr of stereotactic radiotherapy (SRT). After that, other recurrent lesions appeared in the left cerebellopontine angle, and he received surgery three times. The tumor was gross totally resected and re-irradiation with 40 Gy/20 fr of SRT was performed. We have found no recurrence or late effects during the one year follow-up. CASE 2: 15-year-old female. At three years old, she received 18 Gy/10 fr of craniospinal irradiation and 36 Gy/20 fr of boost to the posterior fossa as postoperative irradiation for anaplastic ependymoma and cured. However, a anaplastic meningioma appeared on the left side of the skull base at the age of 15, and 50 Gy/25 fr of postoperative intensity-modulated radiation therapy was performed. Two years later, another meningioma developed in the right cerebellar tent, and 54 Gy/27 fr of SRT was performed. Thirty-three months after re-irradiation, MRI showed a slight increase of the lesion, but no late toxicities are observed. CONCLUSION The follow-up periods are short, however intracranial re-irradiation after radiotherapy for pediatric brain tumors were feasible and effective.

scholarly journals Ras, TrkB, and ShcA Protein Expression Patterns in Pediatric Brain Tumors

2021 ◽  
Vol 10 (10) ◽  
pp. 2219
Author(s):  
Monika Prill ◽  
Agnieszka Karkucinska-Wieckowska ◽  
Magdalena Lebiedzinska-Arciszewska ◽  
Giampaolo Morciano ◽  
Agata Charzynska ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Expression Patterns ◽  
Pediatric Brain Tumors ◽  
Astrocytic Tumors ◽  
Embryonal Tumors ◽  
Altered Expression ◽  
Malignancy Grade ◽  
Oligodendroglial Tumors ◽  
Different Types ◽  
Pediatric Brain

Numerous papers have reported altered expression patterns of Ras and/or ShcA proteins in different types of cancers. Their level can be potentially associated with oncogenic processes. We analyzed samples of pediatric brain tumors reflecting different groups such as choroid plexus tumors, diffuse astrocytic and oligodendroglial tumors, embryonal tumors, ependymal tumors, and other astrocytic tumors as well as tumor malignancy grade, in order to characterize the expression profile of Ras, TrkB, and three isoforms of ShcA, namely, p66Shc, p52Shc, and p46Shc proteins. The main aim of our study was to evaluate the potential correlation between the type of pediatric brain tumors, tumor malignancy grade, and the expression patterns of the investigated proteins.

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