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The Occurrence, Evolution and Treatment of Glioblastoma

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 12853

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Dr. Antonella Mangraviti

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Department of Neuroscience, Mental Health and Sense Organs (NESMOS), Sapienza University of Rome, 00189 Rome, Italy
Interests: brain tumors; glioblastoma; drug delivery; nanobased delivery systems; neuroimaging; stem cells; antiangiogenetic drugs; preclinical animal models; cerebral blood flow imaging
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Of the 100,000 new cases of diffuse gliomas diagnosed every year worldwide, approximately 75% are glioblastoma. Novel therapeutics over the past couple of decades have only met with limited success, and median survival remains at 14 to 17 months. However, recent advances in gene profiling and proteomics have led to significant breakthroughs in the taxonomy, classification, and grading of both adults and pediatric brain gliomas. The aim of this Special Issue is to shed light on the molecular heterogeneity of this tumor in both adults and children, as well as to evaluate the benefits of multimodal treatment strategies involving surgery, radiotherapy, and chemotherapy. With new drug candidates now at different stages of clinical development, this approach takes full advantage of research on molecular and gene profiling to ensure ever more precise diagnoses as well as new promising treatments.

We welcome submissions, including original papers and reviews. Our Special Issue will focus on, but is not restricted to, the following:

Tumor signatures in primary vs. secondary gliomas;
The role of recently identified biomarkers in both the prognosis and treatment of pediatric gliomas;
Role of checkpoints inhibitors in low- and high-grade gliomas;
Mechanisms of recurrence of high-grade gliomas;
Molecular and radiological features in low-grade gliomas shifting into high-grade gliomas;
Role of re-surgery and re-radiation in recurrent GBMs;
New developments in the armamentarium of pre-, intra-, and post-operative tools for the treatment of newly diagnosed/recurrent GBMs;
Role of radiomics and neuroimaging in deep-seeded and multifocal gliomas for improved patient treament and information;
Midbrain gliomas: managment and prognosis.

Dr. Antonella Mangraviti
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

GBM
low grand and high grade
pediatric diffuse gliomas
signaling pathways in GBMs
recurrent gliomas
midbrain gliomas
radiomics in brain tumors
re-surgery and re-radiation in GBMs
immunotherapy
targeted therapies for GBMs

Published Papers (9 papers)

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Research

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17 pages, 3184 KiB

Open AccessArticle

Furanocoumarins as Enhancers of Antitumor Potential of Sorafenib and LY294002 toward Human Glioma Cells In Vitro

by Joanna Sumorek-Wiadro, Adrian Zając, Krystyna Skalicka-Woźniak, Wojciech Rzeski and Joanna Jakubowicz-Gil

Int. J. Mol. Sci. 2024, 25(2), 759; https://doi.org/10.3390/ijms25020759 - 7 Jan 2024

Viewed by 821

Abstract

Furanocoumarins are naturally occurring compounds in the plant world, characterized by low molecular weight, simple chemical structure, and high solubility in most organic solvents. Additionally, they have a broad spectrum of activity, and their properties depend on the location and type of attached substituents. Therefore, the aim of our study was to investigate the anticancer activity of furanocoumarins (imperatorin, isoimperatorin, bergapten, and xanthotoxin) in relation to human glioblastoma multiforme (T98G) and anaplastic astrocytoma (MOGGCCM) cell lines. The tested compounds were used for the first time in combination with LY294002 (PI3K inhibitor) and sorafenib (Raf inhibitor). Apoptosis, autophagy, and necrosis were identified microscopically after straining with Hoechst 33342, acridine orange, and propidium iodide, respectively. The levels of caspase 3 and Beclin 1 were estimated by immunoblotting and for the blocking of Raf and PI3K kinases, the transfection with specific siRNA was used. The scratch test was used to assess the migration potential of glioma cells. Our studies showed that the anticancer activity of furanocoumarins strictly depended on the presence, type, and location of substituents. The obtained results suggest that achieving higher pro-apoptotic activity is determined by the presence of an isoprenyl moiety at the C8 position of the coumarin skeleton. In both anaplastic astrocytoma and glioblastoma, imperatorin was the most effective in induction apoptosis. Furthermore, the usage of imperatorin, alone and in combination with sorafenib or LY294002, decreased the migratory potential of MOGGCCM and T98G cells. Full article

(This article belongs to the Special Issue The Occurrence, Evolution and Treatment of Glioblastoma)

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15 pages, 2325 KiB

Open AccessArticle

Intracranial Assessment of Androgen Receptor Antagonists in Mice Bearing Human Glioblastoma Implants

by Nomi Zalcman, Liraz Larush, Haim Ovadia, Hanna Charbit, Shlomo Magdassi and Iris Lavon

Int. J. Mol. Sci. 2024, 25(1), 332; https://doi.org/10.3390/ijms25010332 - 26 Dec 2023

Viewed by 708

Abstract

The median survival time of patients with an aggressive brain tumor, glioblastoma, is still poor due to ineffective treatment. The discovery of androgen receptor (AR) expression in 56% of cases offers a potential breakthrough. AR antagonists, including bicalutamide and enzalutamide, induce dose-dependent cell death in glioblastoma and glioblastoma-initiating cell lines (GIC). Oral enzalutamide at 20 mg/kg reduces subcutaneous human glioblastoma xenografts by 72% (p = 0.0027). We aimed to further investigate the efficacy of AR antagonists in intracranial models of human glioblastoma. In U87MG intracranial models, nude mice administered Xtandi (enzalutamide) at 20 mg/kg and 50 mg/kg demonstrated a significant improvement in survival compared to the control group (p = 0.24 and p < 0.001, respectively), confirming a dose–response relationship. Additionally, we developed a newly reformulated version of bicalutamide, named “soluble bicalutamide (Bic-sol)”, with a remarkable 1000-fold increase in solubility. This reformulation significantly enhanced bicalutamide levels within brain tissue, reaching 176% of the control formulation’s area under the curve. In the U87MG intracranial model, both 2 mg/kg and 4 mg/kg of Bic-sol exhibited significant efficacy compared to the vehicle-treated group (p = 0.0177 and p = 0.00364, respectively). Furthermore, combination therapy with 8 mg/kg Bic-sol and Temozolomide (TMZ) demonstrated superior efficacy compared to either Bic-sol or TMZ as monotherapies (p = 0.00706 and p = 0.0184, respectively). In the ZH-161 GIC mouse model, the group treated with 8 mg/kg Bic-sol as monotherapy had a significantly longer lifespan than the groups treated with TMZ or the vehicle (p < 0.001). Our study demonstrated the efficacy of androgen receptor antagonists in extending the lifespan of mice with intracranial human glioblastoma, suggesting a promising approach to enhance patient outcomes in the fight against this challenging disease. Full article

(This article belongs to the Special Issue The Occurrence, Evolution and Treatment of Glioblastoma)

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15 pages, 3523 KiB

Open AccessArticle

Development of A Radiomic Model for MGMT Promoter Methylation Detection in Glioblastoma Using Conventional MRI

by Fabio M. Doniselli, Riccardo Pascuzzo, Massimiliano Agrò, Domenico Aquino, Elena Anghileri, Mariangela Farinotti, Bianca Pollo, Rosina Paterra, Valeria Cuccarini, Marco Moscatelli, Francesco DiMeco and Luca Maria Sconfienza

Int. J. Mol. Sci. 2024, 25(1), 138; https://doi.org/10.3390/ijms25010138 - 21 Dec 2023

Cited by 1 | Viewed by 879

Abstract

The methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter is a molecular marker associated with a better response to chemotherapy in patients with glioblastoma (GB). Standard pre-operative magnetic resonance imaging (MRI) analysis is not adequate to detect MGMT promoter methylation. This study aims to evaluate whether the radiomic features extracted from multiple tumor subregions using multiparametric MRI can predict MGMT promoter methylation status in GB patients. This retrospective single-institution study included a cohort of 277 GB patients whose 3D post-contrast T1-weighted images and 3D fluid-attenuated inversion recovery (FLAIR) images were acquired using two MRI scanners. Three separate regions of interest (ROIs) showing tumor enhancement, necrosis, and FLAIR hyperintensities were manually segmented for each patient. Two machine learning algorithms (support vector machine (SVM) and random forest) were built for MGMT promoter methylation prediction from a training cohort (196 patients) and tested on a separate validation cohort (81 patients), based on a set of automatically selected radiomic features, with and without demographic variables (i.e., patients’ age and sex). In the training set, SVM based on the selected radiomic features of the three separate ROIs achieved the best performances, with an average of 83.0% (standard deviation: 5.7%) for accuracy and 0.894 (0.056) for the area under the curve (AUC) computed through cross-validation. In the test set, all classification performances dropped: the best was obtained by SVM based on the selected features extracted from the whole tumor lesion constructed by merging the three ROIs, with 64.2% (95% confidence interval: 52.8–74.6%) accuracy and 0.572 (0.439–0.705) for AUC. The performances did not change when the patients’ age and sex were included with the radiomic features into the models. Our study confirms the presence of a subtle association between imaging characteristics and MGMT promoter methylation status. However, further verification of the strength of this association is needed, as the low diagnostic performance obtained in this validation cohort is not sufficiently robust to allow clinically meaningful predictions. Full article

(This article belongs to the Special Issue The Occurrence, Evolution and Treatment of Glioblastoma)

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15 pages, 3187 KiB

Open AccessArticle

Comparison between [⁶⁸Ga]Ga-PSMA-617 and [¹⁸F]FET PET as Imaging Biomarkers in Adult Recurrent Glioblastoma

by Caterina Brighi, Simon Puttick, Amanda Woods, Paul Keall, Paul A. Tooney, David E. J. Waddington, Vicki Sproule, Stephen Rose and Michael Fay

Int. J. Mol. Sci. 2023, 24(22), 16208; https://doi.org/10.3390/ijms242216208 - 11 Nov 2023

Cited by 2 | Viewed by 1550

Abstract

The aim of this prospective clinical study was to evaluate the potential of the prostate specific membrane antigen (PSMA) targeting ligand, [⁶⁸Ga]-PSMA–Glu–NH–CO–NH–Lys-2-naphthyl-L-Ala-cyclohexane-DOTA ([⁶⁸Ga]Ga-PSMA-617) as a positron emission tomography (PET) imaging biomarker in recurrent glioblastoma patients. Patients underwent [⁶⁸Ga]Ga-PSMA-617 and O-(2-[¹⁸F]-fluoroethyl)-L-tyrosine ([¹⁸F]FET) PET scans on two separate days. [⁶⁸Ga]Ga-PSMA-617 tumour selectivity was assessed by comparing tumour volume delineation and by assessing the intra-patient correlation between tumour uptake on [⁶⁸Ga]Ga-PSMA-617 and [¹⁸F]FET PET images. [⁶⁸Ga]Ga-PSMA-617 tumour specificity was evaluated by comparing its tumour-to-brain ratio (TBR) with [¹⁸F]FET TBR and its tumour volume with the magnetic resonance imaging (MRI) contrast-enhancing (CE) tumour volume. Ten patients were recruited in this study. [⁶⁸Ga]Ga-PSMA-617-avid tumour volume was larger than the [¹⁸F]FET tumour volume (p = 0.063). There was a positive intra-patient correlation (median Pearson r = 0.51; p < 0.0001) between [⁶⁸Ga]Ga-PSMA-617 and [¹⁸F]FET in the tumour volume. [⁶⁸Ga]Ga-PSMA-617 had significantly higher TBR (p = 0.002) than [¹⁸F]FET. The [⁶⁸Ga]Ga-PSMA-617-avid tumour volume was larger than the CE tumour volume (p = 0.0039). Overall, accumulation of [⁶⁸Ga]-Ga-PSMA-617 beyond [¹⁸F]FET-avid tumour regions suggests the presence of neoangiogenesis in tumour regions that are not overly metabolically active yet. Higher tumour specificity suggests that [⁶⁸Ga]-Ga-PSMA-617 could be a better imaging biomarker for recurrent tumour delineation and secondary treatment planning than [¹⁸F]FET and CE MRI. Full article

(This article belongs to the Special Issue The Occurrence, Evolution and Treatment of Glioblastoma)

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17 pages, 4698 KiB

Open AccessArticle

Exploring the Functional Roles of Telomere Maintenance 2 in the Tumorigenesis of Glioblastoma Multiforme and Drug Responsiveness to Temozolomide

by Shao-Wei Feng, Zih-Syuan Wu, Yi-Lin Chiu and Shih-Ming Huang

Int. J. Mol. Sci. 2023, 24(11), 9256; https://doi.org/10.3390/ijms24119256 - 25 May 2023

Cited by 3 | Viewed by 1516

Abstract

Glioblastoma multiforme (GBM) is a grade IV human glioma. It is the most malignant primary central nervous system tumor in adults, accounting for around 15% of intracranial neoplasms and 40–50% of all primary malignant brain tumors. However, the median survival time of GBM patients is still less than 15 months, even after treatment with surgical resection, concurrent chemoradiotherapy, and adjuvant chemotherapy with temozolomide (TMZ). Telomere maintenance 2 (TELO2) mRNA is highly expressed in high-grade glioma patients, and its expression correlates with shorter survival outcomes. Hence, it is urgent to address the functional role of TELO2 in the tumorigenesis and TMZ treatment of GBM. In this study, we knocked down TELO2 mRNA in GBM8401 cells, a grade IV GBM, compared with TELO2 mRNA overexpression in human embryonic glial SVG p12 cells and normal human astrocyte (NHA) cells. We first analyzed the effect of TELO2 on the Elsevier pathway and Hallmark gene sets in GBM8401, SVG p12, and NHA via an mRNA array analysis. Later, we further examined and analyzed the relationship between TELO2 and fibroblast growth factor receptor 3, cell cycle progression, epithelial–mesenchymal transient (EMT), reactive oxygen species (ROS), apoptosis, and telomerase activity. Our data showed that TELO2 is involved in several functions of GBM cells, including cell cycle progression, EMT, ROS, apoptosis, and telomerase activity. Finally, we examined the crosstalk between TELO2 and the responsiveness of TMZ or curcumin mediated through the TELO2–TTI1–TTI2 complex, the p53-dependent complex, the mitochondrial-related complex, and signaling pathways in GBM8401 cells. In summary, our work provides new insight that TELO2 might modulate target proteins mediated through the complex of phosphatidylinositol 3-kinase-related kinases in its involvement in cell cycle progression, EMT, and drug response in GBM patients. Full article

(This article belongs to the Special Issue The Occurrence, Evolution and Treatment of Glioblastoma)

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Review

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17 pages, 2001 KiB

Open AccessReview

Glioblastoma-Associated Mesenchymal Stem/Stromal Cells and Cancer-Associated Fibroblasts: Partners in Crime?

by Thibault Lootens, Bart I. Roman, Christian V. Stevens, Olivier De Wever and Robrecht Raedt

Int. J. Mol. Sci. 2024, 25(4), 2285; https://doi.org/10.3390/ijms25042285 - 14 Feb 2024

Viewed by 1216

Abstract

Tumor-associated mesenchymal stem/stromal cells (TA-MSCs) have been recognized as attractive therapeutic targets in several cancer types, due to their ability to enhance tumor growth and angiogenesis and their contribution to an immunosuppressive tumor microenvironment (TME). In glioblastoma (GB), mesenchymal stem cells (MSCs) seem to be recruited to the tumor site, where they differentiate into glioblastoma-associated mesenchymal stem/stromal cells (GA-MSCs) under the influence of tumor cells and the TME. GA-MSCs are reported to exert important protumoral functions, such as promoting tumor growth and invasion, increasing angiogenesis, stimulating glioblastoma stem cell (GSC) proliferation and stemness, mediating resistance to therapy and contributing to an immunosuppressive TME. Moreover, they could act as precursor cells for cancer-associated fibroblasts (CAFs), which have recently been identified in GB. In this review, we provide an overview of the different functions exerted by GA-MSCs and CAFs and the current knowledge on the relationship between these cell types. Increasing our understanding of the interactions and signaling pathways in relevant models might contribute to future regimens targeting GA-MSCs and GB-associated CAFs to inhibit tumor growth and render the TME less immunosuppressive. Full article

(This article belongs to the Special Issue The Occurrence, Evolution and Treatment of Glioblastoma)

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39 pages, 8589 KiB

Open AccessReview

Role of Glycolytic and Glutamine Metabolism Reprogramming on the Proliferation, Invasion, and Apoptosis Resistance through Modulation of Signaling Pathways in Glioblastoma

by Cristina Trejo-Solis, Daniela Silva-Adaya, Norma Serrano-García, Roxana Magaña-Maldonado, Dolores Jimenez-Farfan, Elizabeth Ferreira-Guerrero, Arturo Cruz-Salgado and Rosa Angelica Castillo-Rodriguez

Int. J. Mol. Sci. 2023, 24(24), 17633; https://doi.org/10.3390/ijms242417633 - 18 Dec 2023

Cited by 1 | Viewed by 1894

Abstract

Glioma cells exhibit genetic and metabolic alterations that affect the deregulation of several cellular signal transduction pathways, including those related to glucose metabolism. Moreover, oncogenic signaling pathways induce the expression of metabolic genes, increasing the metabolic enzyme activities and thus the critical biosynthetic pathways to generate nucleotides, amino acids, and fatty acids, which provide energy and metabolic intermediates that are essential to accomplish the biosynthetic needs of glioma cells. In this review, we aim to explore how dysregulated metabolic enzymes and their metabolites from primary metabolism pathways in glioblastoma (GBM) such as glycolysis and glutaminolysis modulate anabolic and catabolic metabolic pathways as well as pro-oncogenic signaling and contribute to the formation, survival, growth, and malignancy of glioma cells. Also, we discuss promising therapeutic strategies by targeting the key players in metabolic regulation. Therefore, the knowledge of metabolic reprogramming is necessary to fully understand the biology of malignant gliomas to improve patient survival significantly. Full article

(This article belongs to the Special Issue The Occurrence, Evolution and Treatment of Glioblastoma)

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45 pages, 1676 KiB

Open AccessReview

Preclinical Models and Technologies in Glioblastoma Research: Evolution, Current State, and Future Avenues

by Hasan Slika, Ziya Karimov, Paolo Alimonti, Tatiana Abou-Mrad, Emerson De Fazio, Safwan Alomari and Betty Tyler

Int. J. Mol. Sci. 2023, 24(22), 16316; https://doi.org/10.3390/ijms242216316 - 14 Nov 2023

Cited by 2 | Viewed by 2049

Abstract

Glioblastoma is the most common malignant primary central nervous system tumor and one of the most debilitating cancers. The prognosis of patients with glioblastoma remains poor, and the management of this tumor, both in its primary and recurrent forms, remains suboptimal. Despite the tremendous efforts that are being put forward by the research community to discover novel efficacious therapeutic agents and modalities, no major paradigm shifts have been established in the field in the last decade. However, this does not mirror the abundance of relevant findings and discoveries made in preclinical glioblastoma research. Hence, developing and utilizing appropriate preclinical models that faithfully recapitulate the characteristics and behavior of human glioblastoma is of utmost importance. Herein, we offer a holistic picture of the evolution of preclinical models of glioblastoma. We further elaborate on the commonly used in vitro and vivo models, delving into their development, favorable characteristics, shortcomings, and areas of potential improvement, which aids researchers in designing future experiments and utilizing the most suitable models. Additionally, this review explores progress in the fields of humanized and immunotolerant mouse models, genetically engineered animal models, 3D in vitro models, and microfluidics and highlights promising avenues for the future of preclinical glioblastoma research. Full article

(This article belongs to the Special Issue The Occurrence, Evolution and Treatment of Glioblastoma)

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13 pages, 965 KiB

Open AccessCase Report

Management and Molecular Characterization of Intraventricular Glioblastoma: A Single-Institution Case Series

by Megan Parker, Anita Kalluri, Joshua Materi, Sachin K. Gujar, Karisa Schreck, Debraj Mukherjee, Jon Weingart, Henry Brem, Kristin J. Redmond, Calixto-Hope G. Lucas, Chetan Bettegowda and Jordina Rincon-Torroella

Int. J. Mol. Sci. 2023, 24(17), 13285; https://doi.org/10.3390/ijms241713285 - 27 Aug 2023

Cited by 1 | Viewed by 1164

Abstract

While the central nervous system (CNS) tumor classification has increasingly incorporated molecular parameters, there is a paucity of literature reporting molecular alterations found in intraventricular glioblastoma (IVGBM), which are rare. We present a case series of nine IVGBMs, including molecular alterations found in standardized next-generation sequencing (NGS). We queried the clinical charts, operative notes, pathology reports, and radiographic images of nine patients with histologically confirmed IVGBM treated at our institution (1995–2021). Routine NGS was performed on resected tumor tissue of two patients. In this retrospective case series of nine patients (22% female, median (range) age: 64.3 (36–85) years), the most common tumor locations were the atrium of the right lateral ventricle (33%) and the septum pellucidum (33%). Five patients had preoperative hydrocephalus, which was managed with intraoperative external ventricular drains in three patients and ventriculoperitoneal shunts in one patient. Hydrocephalus was managed with subtotal resection of a fourth ventricular IVGBM in one patient. The most common surgical approach was transcortical intraventricular (56%). Gross total resection was achieved in two patients, subtotal resection was achieved in six patients, and one patient received a biopsy only. Immunohistochemistry for IDH1 R132H mutant protein was performed in four cases and was negative in all four. Genetic alterations common in glioblastoma, IDH-wildtype, were seen in two cases with available NGS data, including EGFR gene amplification, TERT promoter mutation, PTEN mutation, trisomy of chromosome 7, and monosomy of chromosome 10. Following surgical resection, four patients received adjuvant chemoradiation. Median survival among our cohort was 4.7 months (IQR: 0.9–5.8 months). Management of IVGBM is particularly challenging due to their anatomical location, presentation with obstructive hydrocephalus, and fast growth, necessitating prompt intervention. Additional studies are needed to better understand the genetic landscape of IVGBM compared to parenchymal glioblastoma and may further elucidate the unique pathophysiology of these rare tumors. Full article

(This article belongs to the Special Issue The Occurrence, Evolution and Treatment of Glioblastoma)

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