Variegated Colors of Pediatric Glioblastoma Multiforme: What to Expect?

Malignant gliomas account for 35-45% of primary brain tumors; among these glioblastoma multiforme (GBM) is the most common adult brain tumor constituting approximately 85%. Its incidence is quite less in the pediatric population and treatment of these patients is particularly challenging. Exposure to ionizing radiation is the only environmental factor found to have any significant association with GBM. Several genetic alterations associated with GBM in adults have been well documented such as epidermal growth factor receptor amplification, overexpression of mouse double minute 2 homolog also known as E3 ubiquitin-protein ligase, Phosphatase and tensin homolog gene mutation, loss of heterozygosity of chromosome 10p and isocitrate dehydrogenase-1 mutation. However, data on genetic mutations in pediatric GBM is still lacking. Exophytic brain stem gliomas are rare tumors and are usually associated with a poor prognosis. The most effective treatment in achieving long-term survival in such patients, is surgical excision of the tumor and then chemoradiotherapy followed by adjuvant chemotherapy by temozolomide. This schedule is the standard treatment for GBM patients. In view of the rarity of pediatric GBM, we report here a case of pontine GBM in a 5-year-old girl.

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BRCAness as a Biomarker of Susceptibility to PARP Inhibitors in Glioblastoma Multiforme

Biomolecules ◽

10.3390/biom11081188 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1188

Author(s):

Mary-Ann Xavier ◽

Fernando Rezende ◽

Ricardo Titze-de-Almeida ◽

Bart Cornelissen

Keyword(s):

Glioblastoma Multiforme ◽

Growth Factor Receptor ◽

Standard Of Care ◽

Parp Inhibitors ◽

Genetic Alterations ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog ◽

Damage Repair ◽

Cancer Types ◽

Epidermal Growth

Glioblastoma multiforme (GBM) is the most common primary brain cancer. GBMs commonly acquire resistance to standard-of-care therapies. Among the novel means to sensitize GBM to DNA-damaging therapies, a promising strategy is to combine them with inhibitors of the DNA damage repair (DDR) machinery, such as inhibitors for poly(ADP-ribose) polymerase (PARP). PARP inhibitors (PARPis) have already shown efficacy and have received regulatory approval for breast, ovarian, prostate, and pancreatic cancer treatment. In these cancer types, after PARPi administration, patients carrying specific mutations in the breast cancer 1 (BRCA1) and 2 (BRCA2) suppressor genes have shown better response when compared to wild-type carriers. Mutated BRCA genes are infrequent in GBM tumors, but their cells can carry other genetic alterations that lead to the same phenotype collectively referred to as ‘BRCAness’. The most promising biomarkers of BRCAness in GBM are related to isocitrate dehydrogenases 1 and 2 (IDH1/2), epidermal growth factor receptor (EGFR), phosphatase and tensin homolog (PTEN), MYC proto-oncogene, and estrogen receptors beta (ERβ). BRCAness status identified by accurate biomarkers can ultimately predict responsiveness to PARPi therapy, thereby allowing patient selection for personalized treatment. This review discusses potential biomarkers of BRCAness for a ‘precision medicine’ of GBM patients.

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A comprehensive analysis of the angiogenesis-related genes in glioblastoma multiforme vs. brain lower grade glioma

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x20190131 ◽

2020 ◽

Vol 78 (1) ◽

pp. 34-38

Author(s):

Burcu BITERGE-SUT

Keyword(s):

Glioblastoma Multiforme ◽

Malignant Gliomas ◽

Genetic Alterations ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Lower Grade ◽

Nonsense Mutations ◽

Lower Grade Glioma ◽

Cancer Genome Atlas ◽

Genome Atlas

Abstract Brain tumors are one of the most common causes of cancer-related deaths around the world. Angiogenesis is critical in high-grade malignant gliomas, such as glioblastoma multiforme. Objective: The aim of this study is to comparatively analyze the angiogenesis-related genes, namely VEGFA, VEGFB, KDR, CXCL8, CXCR1 and CXCR2 in LGG vs. GBM to identify molecular distinctions using datasets available on The Cancer Genome Atlas (TCGA). Methods: DNA sequencing and mRNA expression data for 514 brain lower grade glioma (LGG) and 592 glioblastoma multiforme (GBM) patients were acquired from The Cancer Genome Atlas (TCGA), and the genetic alterations and expression levels of the selected genes were analyzed. Results: We identified six distinct KDR mutations in the LGG patients and 18 distinct KDR mutations in the GBM patients, including missense and nonsense mutations, frame shift deletion and altered splice region. Furthermore, VEGFA and CXCL8 were significantly overexpressed within GBM patients. Conclusions: VEGFA and CXCL8 are important factors for angiogenesis, which are suggested to have significant roles during tumorigenesis. Our results provide further evidence that VEGFA and CXCL8 could induce angiogenesis and promote LGG to progress into GBM. These findings could be useful in developing novel targeted therapeutics approaches in the future.

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Phase I/II Trial of Erlotinib and Temozolomide With Radiation Therapy in the Treatment of Newly Diagnosed Glioblastoma Multiforme: North Central Cancer Treatment Group Study N0177

Journal of Clinical Oncology ◽

10.1200/jco.2008.18.0612 ◽

2008 ◽

Vol 26 (34) ◽

pp. 5603-5609 ◽

Cited By ~ 182

Author(s):

Paul D. Brown ◽

Sunil Krishnan ◽

Jann N. Sarkaria ◽

Wenting Wu ◽

Kurt A. Jaeckle ◽

...

Keyword(s):

Glioblastoma Multiforme ◽

Phase I ◽

Recursive Partitioning ◽

Growth Factor Receptor ◽

Treatment Resistance ◽

Class Iii ◽

Egfr Amplification ◽

Phosphatase And Tensin Homolog ◽

End Point ◽

Tensin Homolog

Purpose Epidermal growth factor receptor (EGFR) amplification in glioblastoma multiforme (GBM) is a common occurrence and is associated with treatment resistance. Erlotinib, a selective EGFR inhibitor, was combined with temozolomide (TMZ) and radiotherapy (RT) in a phase I/II trial. Patients and Methods Adults not taking enzyme-inducing anticonvulsants after resection or biopsy of GBM were treated with erlotinib (150 mg daily) until progression. Erlotinib was delivered alone for 1 week, then concurrently with TMZ (75 mg mg/m2 daily) and RT (60 Gy), and finally, concurrently with up to six cycles of adjuvant TMZ (200 mg/m2 daily for 5 days every 28 days). The primary end point was survival at 1 year. Results Ninety-seven eligible patients were accrued with a median follow-up time of 22.2 months. By definition, the primary end point was successfully met with a median survival time of 15.3 months. However, there was no sign of benefit in overall survival when comparing N0177 with the RT/TMZ arm of the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial 26981/22981 (recursive partitioning analysis [RPA] class III, 19 v 21 months; RPA class IV, 16 v 16 months; RPA class V, 8 v 10 months, respectively). Presence of diarrhea, rash, and EGFRvIII, p53, phosphatase and tensin homolog (PTEN), combination EGFR and PTEN, and EGFR amplification status were not predictive (P > .05) of survival. Conclusion Although the primary end point was successfully met using nitrosourea-based (pre-TMZ) chemotherapy era historic controls, there was no sign of benefit compared with TMZ era controls. Analyses of molecular subsets did not reveal cohorts of patients sensitive to erlotinib. TMZ chemotherapy combined with RT resulted in improved outcomes compared with historical controls who received nitrosourea-based chemotherapies.

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Comprehensive Genomic Profiling of Recurrent Classic Glioblastoma in a Patient Surviving Eleven Years Following Antineoplaston Therapy

Cancer and Clinical Oncology ◽

10.5539/cco.v4n2p41 ◽

2015 ◽

Vol 4 (2) ◽

pp. 41 ◽

Cited By ~ 1

Author(s):

Stanislaw R. Burzynski ◽

Tomasz J. Janicki ◽

Gregory S. Burzynski

Keyword(s):

Kinase Inhibitor ◽

Growth Factor Receptor ◽

Recurrent Glioblastoma ◽

Genomic Profiling ◽

Term Survival ◽

Long Term Survival ◽

Tensin Homolog ◽

Phase Ii Studies ◽

Comprehensive Genomic Profiling

Most patients with recurrent glioblastoma (RGBM) die within 6 months regardless of treatment. In phase II studies of Antineoplaston A10 and AS2-1 injections (ANP), our investigators have reported objective responses and long-term survival in RGBM. Using a next-generation sequencing (NGS) based assay of 343 cancer-related genes and introns, comprehensive genomic profiling of tumor tissue obtained from a RGBM patient (who remains alive and well) was performed 11 years after diagnosis and permitted assignment of the patient’s RGBM to the classical subgroup. The most important genomic alterations included amplification of epidermal growth factor receptor (EGFR), cyclin-dependent kinase inhibitor 2A and 2B (CDKN2A/B), loss of phosphatase and tensin homolog (PTEN) and telomerase reverse transcriptase (TERT) mutation. An analysis of the signaling networks and other targets of ANP therapy was recently performed and presented in this publication. Based on our findings, patients with classical RGBM have a reasonable possibility of responding to ANP therapy and experiencing long-term survival. It is proposed that this subgroup of RGBM patients be enrolled in a genomics-driven clinical trial of ANP therapy.

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A practical review of prognostic correlations of molecular biomarkers in glioblastoma

Neurosurgical FOCUS ◽

10.3171/2015.1.focus14755 ◽

2015 ◽

Vol 38 (3) ◽

pp. E4 ◽

Cited By ~ 50

Author(s):

Michael Karsy ◽

Jayson A. Neil ◽

Jian Guan ◽

Mark A. Mahan ◽

Howard Colman ◽

...

Keyword(s):

Clinical Trials ◽

Molecular Markers ◽

Growth Factor ◽

Dna Methyltransferase ◽

Growth Factor Receptor ◽

Predictive Biomarker ◽

Isocitrate Dehydrogenase 1 ◽

Tensin Homolog ◽

Formidable Challenge ◽

Phosphoinositide 3 Kinase

Despite extensive efforts in research and therapeutics, achieving longer survival for patients with glioblastoma (GBM) remains a formidable challenge. Furthermore, because of rapid advances in the scientific understanding of GBM, communication with patients regarding the explanations and implications of genetic and molecular markers can be difficult. Understanding the important biomarkers that play a role in GBM pathogenesis may also help clinicians in educating patients about prognosis, potential clinical trials, and monitoring response to treatments. This article aims to provide an up-to-date review that can be discussed with patients regarding common molecular markers, namely O-6-methylgua-nine-DNA methyltransferase (MGMT), isocitrate dehydrogenase 1 and 2 (IDH1/2), p53, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), Phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), and 1p/19q. The importance of the distinction between a prognostic and a predictive biomarker as well as clinical trials regarding these markers and their relevance to clinical practice are discussed.

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PD-L1 Expression Correlated with p53 Expression in Pediatric Glioblastoma Multiforme

Brain Sciences ◽

10.3390/brainsci11020262 ◽

2021 ◽

Vol 11 (2) ◽

pp. 262

Author(s):

Jakub Litak ◽

Wiesława Grajkowska ◽

Justyna Szumiło ◽

Paweł Krukow ◽

Ryszard Maciejewski ◽

...

Keyword(s):

Glioblastoma Multiforme ◽

Pediatric Population ◽

Malignant Gliomas ◽

Immune Checkpoints ◽

Histopathological Diagnosis ◽

High Grade ◽

P53 Expression ◽

Mortality And Morbidity ◽

Glioblastoma Multiform ◽

Pediatric Glioblastoma

High-grade gliomas are infrequent in the pediatric population compared to adults, nevertheless, mortality and morbidity caused by malignant gliomas in this group of patients remain significant. PD-L1 and PD-1 Immune checkpoints (IC) molecules maintain immunological balance between activation and suppression. Eighteen patients with a histopathological diagnosis of pediatric glioblastoma multiforme (GBM, WHO IV) were studied. In total, PD-L1 expression was detected in 8 patients (44%). The molecular aspect of IC and immunotherapy targeted on PD-1/PD-L1 axis in pediatric population may be a promising adjuvant therapy in pediatric glioblastoma multiform treatment, however, this subject requires further investigation.

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Glioblastoma Multiforme and Genetic Mutations: The Issue Is Not Over Yet. An Overview of the Current Literature

Journal of Neurological Surgery Part A Central European Neurosurgery ◽

10.1055/s-0039-1688911 ◽

2019 ◽

Vol 81 (01) ◽

pp. 064-070 ◽

Cited By ~ 9

Author(s):

Nicola Montemurro

Keyword(s):

Glioblastoma Multiforme ◽

Dna Methyltransferase ◽

Expression Profiles ◽

Standard Of Care ◽

Genetic Alterations ◽

World Health ◽

Genetic Mutations ◽

Isocitrate Dehydrogenase 1 ◽

Medline Search ◽

Key Words Glioblastoma

Abstract Background and Objective Glioblastoma multiforme (GBM) is still a deadly disease with a poor prognosis and high mortality, despite the discovery of new biomarkers and new innovative targeted therapies. The role of genetic mutations in GBM is still not at all clear; however, molecular markers are an integral part of tumor assessment in modern neuro-oncology. Material and Methods We performed a Medline search for the key words “glioblastoma,” “glioblastoma multiforme,” and “genetic” or “genetics” from 1990 to the present, finding an exponential increase in the number of published articles, especially in the past 7 years. Results The understanding of molecular subtypes of gliomas recently led to a revision of the World Health Organization classification criteria for these tumors, introducing the concept of primary and secondary GBMs based on genetic alterations and gene or protein expression profiles. Some of these genetic alterations are currently believed to have clinical significance and are more related to secondary GBMs: TP53 mutations, detectable in the early stages of secondary GBM (found in 65%), isocitrate dehydrogenase 1/2 mutations (50% of secondary GBMs), and also O6-methylguanine-DNA methyltransferase promoter methylation (75% of secondary GBMs). Conclusion From the introduction of the first standard of care (SOC) established in 2005 in patients with a new diagnosis of GBM, a great number of trials have been conducted to improve the actual SOC, but the real turning point has never been achieved or is yet to come. Surgical gross total resection, with at least one more reoperation, radiation therapy plus concomitant and adjuvant temozolomide chemotherapy currently remains the current SOC for patients with GBM.

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Dual-isotope single-photon emission computerized tomography scanning in patients with glioblastoma multiforme: association with patient survival and histopathological characteristics of tumor after high-dose radiotherapy

Journal of Neurosurgery ◽

10.3171/jns.1998.89.1.0060 ◽

1998 ◽

Vol 89 (1) ◽

pp. 60-68 ◽

Cited By ~ 29

Author(s):

Richard B. Schwartz ◽

B. Leonard Holman ◽

Joseph F. Polak ◽

Basem M. Garada ◽

Marc S. Schwartz ◽

...

Keyword(s):

Survival Rate ◽

Glioblastoma Multiforme ◽

Single Photon ◽

Photon Emission ◽

High Dose ◽

Term Survival ◽

Content Type ◽

Dual Isotope ◽

Fine Print

Object. The study was conducted to determine the association between dual-isotope single-photon emission computerized tomography (SPECT) scanning and histopathological findings of tumor recurrence and survival in patients treated with high-dose radiotherapy for glioblastoma multiforme. Methods. Studies in which SPECT with 201Tl and 99mTc-hexamethypropyleneamine oxime (HMPAO) were used were performed 1 day before reoperation in 47 patients with glioblastoma multiforme who had previously been treated by surgery and high-dose radiotherapy. Maximum uptake of 201Tl in the lesion was expressed as a ratio to that in the contralateral scalp, and uptake of 99mTc-HMPAO was expressed as a ratio to that in the cerebellar cortex. Patients were stratified into groups based on the maximum radioisotope uptake values in their tumor beds. The significance of differences in patient gender, histological characteristics of tissue at reoperation, and SPECT uptake group with respect to 1-year survival was elucidated by using the chi-square statistic. Comparisons of patient ages and time to tumor recurrence as functions of 1-year survival were made using the t-test. Survival data at 1 year were presented according to the Kaplan—Meier method, and the significance of potential differences was evaluated using the log-rank method. The effects of different variables (tumor type, time to recurrence, and SPECT grouping) on long-term survival were evaluated using Cox proportional models that controlled for age and gender. All patients in Group I (201Tl ratio < 2 and 99mTc-HMPAO ratio < 0.5) showed radiation changes in their biopsy specimens: they had an 83.3% 1-year survival rate. Group II patients (201T1 ratio < 2 and 99mTc-HMPAO ratio of ≥ 0.5 or 201Tl ratio between 2 and 3.5 regardless of 99mTc-HMPAO ratio) had predominantly infiltrating tumor (66.6%); they had a 29.2% 1-year survival rate. Almost all of the patients in Group III (201Tl ratio > 3.5 and 99mTc-HMPAO ratio ≥ 0.5) had solid tumor (88.2%) and they had a 6.7% 1-year survival rate. Histological data were associated with 1-year survival (p < 0.01); however, SPECT grouping was more closely associated with 1-year survival (p < 0.001) and was the only variable significantly associated with long-term survival (p < 0.005). Conclusions. Dual-isotope SPECT data correlate with histopathological findings made at reoperation and with survival in patients with malignant gliomas after surgical and high-dose radiation therapy.

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