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__NOTOC__
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{{Glioblastoma multiforme}}
{{Glioblastoma multiforme}}
{{CMG}}{{AE}}{{SR}}
{{CMG}}{{AE}}{{Marjan}}


==Overview==
==Overview==
Glioblastoma multiforme may be classified according to the molecular alterations into four subtypes.<ref name="pmid20129251">{{cite journal| author=Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD et al.| title=Integrated genomic analysis identifies clinically relevant subtypes of Glioblastoma multiforme characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. | journal=Cancer Cell | year= 2010 | volume= 17 | issue= 1 | pages= 98-110 | pmid=20129251 | doi=10.1016/j.ccr.2009.12.020 | pmc=PMC2818769 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20129251  }} </ref> Genes involved in the pathogenesis of glioblastoma multiforme include ''[[Mdm2]]'', ''[[PTEN]]'', ''IDH1'', ''[[p53]]'', ''[[EGFR]]'', ''PDGFRA'', and chromosomes 10p, 10q, 17p, and 19q. On gross pathology, the characteristic findings of glioblastoma multiforme include a poorly-marginated, diffusely infiltrating, firm or gelatinous mass with a central [[necrosis|necrotic]] core. On microscopic histopathological analysis, the characteristic findings of glioblastoma multiforme include [[pleomorphic]] [[astrocytes]] with marked [[atypia]], [[mitosis]], [[necrosis]], and microvascular proliferation.<ref name=ddd>Pathology of Glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/Glioblastoma</ref>
Genes involved in the pathogenesis of glioblastoma multiforme include [[Mdm2]], [[PTEN]], IDH1, [[p53]], [[EGFR]], PDGFRA, and chromosomes 10p, 10q, 17p, and 19q. On [[gross pathology]], the characteristic findings of glioblastoma multiforme include a poorly-marginated, diffusely infiltrating, firm or gelatinous mass with a central [[necrosis|necrotic]] core. On microscopic histopathological analysis, the characteristic findings of glioblastoma multiforme include [[pleomorphic]] [[astrocytes]] with marked [[atypia]], [[mitosis]], [[necrosis]], and microvascular proliferation. Another important alteration is methylation of MGMT, a suicide DNA repair enzyme. Methylation is described to impair DNA transcription and therefore, expression of the MGMT enzyme. MGMT methylation is associated with an improved response to treatment with DNA-damaging chemotherapeutics, such as temozolomide. Glioblastoma multiforme exhibits numerous alterations in genes that encode for ion channels, including upregulation of gBK potassium channels and ClC-3 chloride channels. Upregulating these ion channels, the tumor cells can facilitate increased ion movement over the cell membrane, thereby increasing H2O movement through osmosis, which aids the tumor cells in changing cellular volume very rapidly.


==Pathophysiology==
==Pathophysiology==
Line 12: Line 12:
====Molecular alterations====
====Molecular alterations====
*There are four subtypes of glioblastoma multiforme.<ref name="pmid20129251">{{cite journal| author=Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD et al.| title=Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma multiforme characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. | journal=Cancer Cell | year= 2010 | volume= 17 | issue= 1 | pages= 98-110 | pmid=20129251 | doi=10.1016/j.ccr.2009.12.020 | pmc=PMC2818769 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20129251  }} </ref>  
*There are four subtypes of glioblastoma multiforme.<ref name="pmid20129251">{{cite journal| author=Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD et al.| title=Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma multiforme characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. | journal=Cancer Cell | year= 2010 | volume= 17 | issue= 1 | pages= 98-110 | pmid=20129251 | doi=10.1016/j.ccr.2009.12.020 | pmc=PMC2818769 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20129251  }} </ref>  
*Tumors in the "''classical''" subtype is characterized by mutations in ''[[EGFR]]''.  
*Tumors in the "classical" subtype is characterized by mutations in [[EGFR]].  
*The "''proneural''" subtype often has high rates of alterations in ''[[TP53]]'', ''PDGFRA'', and ''IDH1''.
*The "proneural" subtype often has high rates of alterations in [[TP53]], PDGFRA, and IDH1.
*The "''mesenchymal''" subtype is characterized by mutations in ''[[NF1]]'', and ''[[EGFR]]''.  
*The "mesenchymal" subtype is characterized by mutations in [[NF1]], and [[EGFR]].  
*The "''neural''" subtype has several mutations in many of the same genes as the other groups.
*The "''neural''" subtype has several mutations in many of the same genes as the other groups.
*Majority of the genetic alterations in glioblastoma multiforme are clustered in three pathways: ''[[p53]]'', ''[[Rb]]'', and PI3K/AKT.  
*Majority of the [[genetic]] alterations in glioblastoma multiforme are clustered in three pathways: ''[[p53]]'', ''[[Rb]]'', and PI3K/AKT.  
*Another important alteration is [[methylation]] of MGMT, a suicide [[DNA]] repair enzyme. Methylation is described to impair DNA [[transcription]] and therefore, expression of the MGMT enzyme. Since MGMT can only repair one DNA alkylation due its suicide repair mechanism, reverse capacity is low and methylation of the MGMT gene promoter greatly affects DNA repair capacity. Hence, MGMT methylation is associated with an improved response to treatment with DNA-damaging chemotherapeutics, such as [[temozolomide]].
*Another important alteration is [[methylation]] of MGMT, a suicide [[DNA]] repair enzyme. [[Methylation]] is described to impair DNA [[transcription]] and therefore, expression of the MGMT enzyme. Since MGMT can only repair one [[DNA]] [[alkylation]] due its suicide repair mechanism, reverse capacity is low and methylation of the MGMT gene promoter greatly affects DNA repair capacity. Hence, MGMT [[methylation]] is associated with an improved response to treatment with DNA-damaging chemotherapeutics, such as [[temozolomide]].


====Glioblastoma multiforme stem-like cells====
====Glioblastoma multiforme stem-like cells====
Line 24: Line 24:


====Metabolism====
====Metabolism====
*The ''IDH1'' gene is frequently [[mutated]] in glioblastoma multiforme (primary: 5%, secondary: 80%). By producing very high concentrations of the oncometabolite D-2-hydroxyglutarate and dysregulating the function of the wild-type IDH1-enzyme, it induces profound changes to the metabolism of ''IDH1''-mutated glioblastoma multiforme compared with ''IDH1'' wild-type glioblastoma multiforme or healthy [[astrocytes]].
*The IDH1 gene is frequently [[mutated]] in glioblastoma multiforme (primary: 5%, secondary: 80%). By producing very high concentrations of the oncometabolite D-2-hydroxyglutarate and dysregulating the function of the wild-type IDH1-enzyme, it induces profound changes to the [[metabolism]] of IDH1-mutated glioblastoma multiforme compared with IDH1 wild-type glioblastoma multiforme or healthy [[astrocytes]].
*The ''IDH1'' mutation increases the dependence of glioblastoma multiforme on [[glutamine]] or [[glutamate]] as an energy source. Since healthy [[astrocyte]]s excrete glutamate, ''IDH1''-mutated glioblastoma multiforme cells do not favor dense tumor structures but instead migrate, invade and disperse into healthy parts of the brain where [[glutamate]] concentrations are higher. This may explain the invasive behaviour of these ''IDH1''-mutated glioblastoma multiforme.
*The ''IDH1'' mutation increases the dependence of glioblastoma multiforme on [[glutamine]] or [[glutamate]] as an energy source. Since healthy [[astrocyte]]s excrete [[glutamate]], ''IDH1''-mutated glioblastoma multiforme cells do not favor dense tumor structures but instead migrate, invade and disperse into healthy parts of the brain where [[glutamate]] concentrations are higher. This may explain the [[invasive]] behavior of these IDH1-mutated glioblastoma multiforme.


====Ion channels====
====Ion channels====
*Glioblastoma multiforme exhibits numerous alterations in [[genes]] that encode for [[ion channels]], including upregulation of gBK potassium channels and ClC-3 chloride channels.
*Glioblastoma multiforme exhibits numerous alterations in [[genes]] that encode for [[ion channels]], including upregulation of gBK [[potassium channels]] and ClC-3 [[chloride channels]].
*Upregulating these ion channels, the tumor cells can facilitate increased ion movement over the cell membrane, thereby increasing H<sub>2</sub>O movement through [[osmosis]], which aids the tumor cells in changing cellular volume very rapidly. This is helpful in their extremely aggressive invasive behavior, because quick adaptations in cellular volume can facilitate movement through the extracellular matrix of the brain.
*Upregulating these ion channels, the [[tumor]] [[cells]] can facilitate increased ion movement over the [[cell membrane]], thereby increasing H<sub>2</sub>O movement through [[osmosis]], which aids the tumor cells in changing [[cellular]] volume very rapidly. This is helpful in their extremely aggressive invasive [[behavior]], because quick adaptations in cellular volume can facilitate movement through the [[extracellular]] [[matrix]] of the brain.


===Genetics===
===Genetics===
*Development of glioblastoma multiforme is the result from multiple genetic [[mutations]].
*Development of glioblastoma multiforme is the result from multiple genetic [[mutations]].
*Genes involved in the pathogenesis of glioblastoma multiforme include the following:<ref name=ddd>Pathology of Glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/Glioblastoma</ref>
*Genes involved in the [[pathogenesis]] of glioblastoma multiforme include the following:<ref name="ddd">Pathology of Glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/Glioblastoma</ref>


{| style="border: 0px; font-size: 90%; margin: 3px; width: 600px" align=center
{| style="border: 0px; font-size: 90%; margin: 3px; width: 600px" align="center"
|valign=top|
| valign="top" |
|+
|+
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Types of glioblastoma multiforme}}
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Types of glioblastoma multiforme}}
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:Primary​
:Primary​
| style="padding: 5px 5px; background: #F5F5F5;" |
| style="padding: 5px 5px; background: #F5F5F5;" |
*''[[Mdm2]]''
*[[Mdm2]]
*''[[PTEN]]''
*[[PTEN]]  
*Chromosome 10p
*Gene on chromosome 10p
|-
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
:Secondary
:Secondary
| style="padding: 5px 5px; background: #F5F5F5;" |
| style="padding: 5px 5px; background: #F5F5F5;" |
*''IDH1''
*IDH1
*''[[p53]]''
*[[p53]]
*Chromosome 10q
*Gene on chromosome 10q
*Chromosome 17p
*Gene on chromosome 17p
*Chromosome 19q
*Gene on chromosome 19q
|-
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
:Classic
:Classic
| style="padding: 5px 5px; background: #F5F5F5;" |
| style="padding: 5px 5px; background: #F5F5F5;" |
*''[[EGFR]]''
*[[EGFR]]
|-
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
:Proneural
:Proneural
| style="padding: 5px 5px; background: #F5F5F5;" |
| style="padding: 5px 5px; background: #F5F5F5;" |
*''[[TP53]]''
*[[TP53]]
*''PDGFRA''
*PDGFRA
*''IDH1''
*IDH1
|-
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
:Mesenchymal
:Mesenchymal
| style="padding: 5px 5px; background: #F5F5F5;" |
| style="padding: 5px 5px; background: #F5F5F5;" |
*''[[NF-1]]''
*[[NF-1]]
|}
|}


===Associated Conditions===
===Associated Conditions===
Glioblastoma multiforme may be associated with:<ref name=ddd>Pathology of Glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/Glioblastoma</ref>
Glioblastoma multiforme may be associated with:<ref name="ddd">Pathology of Glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/Glioblastoma</ref>
*[[Neurofibromatosis type 1]]
*[[Neurofibromatosis type 1]]
*[[Li-Fraumeni syndrome]]
*[[Li-Fraumeni syndrome]]
*[[Turcot syndrome]]
*[[Turcot syndrome]]
*Ollier disease
*[[Enchondroma|Ollier disease]]
*[[Maffucci syndrome]]
*[[Maffucci syndrome]]
*[[Tuberous sclerosis]]
*[[Tuberous sclerosis]]
Line 87: Line 87:
==Pathology==
==Pathology==
===Gross Pathology===
===Gross Pathology===
On gross pathology, the characteristic findings of glioblastoma multiformes include:<ref name=ddd>Pathology of Glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/Glioblastoma multiforme</ref><ref name=ccc>Pathology of Glioblastoma multiforme. Libre Pathology. http://librepathology.org/wiki/index.php/Glioblastoma</ref>
 
|[[File:Glioblastoma multiformeGross.jpg|thumb|none|300px|Gross pathology of glioblastoma multiforme.[https://upload.wikimedia.org/wikipedia/commons/6/60/Glioblastoma_multiforme.jpg Source:Wikimedia Commons] ]]
 
 
On gross pathology, the characteristic findings of glioblastoma multiforme include:<ref name="ddd">Pathology of Glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/Glioblastoma multiforme</ref><ref name="ccc">Pathology of Glioblastoma multiforme. Libre Pathology. http://librepathology.org/wiki/index.php/Glioblastoma</ref>
*[[Supratentorial]] [[white matter]] is the most common location
*[[Supratentorial]] [[white matter]] is the most common location
*Poorly-marginated, diffusely infiltrating mass with a central [[necrosis|necrotic]] core
*Poorly-marginated, diffusely infiltrating mass with a central [[necrosis|necrotic]] core
Line 97: Line 101:


===Microscopic Pathology===
===Microscopic Pathology===
On microscopic histopathological analysis, the characteristic findings of glioblastoma multiformes include:<ref name=ddd>Pathology of Glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/Glioblastoma</ref><ref name=ccc>Pathology of Glioblastoma multiforme. Libre Pathology. http://librepathology.org/wiki/index.php/Glioblastoma</ref>
On microscopic histopathological analysis, the characteristic findings of glioblastoma multiformes include:<ref name="ddd">Pathology of Glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/Glioblastoma</ref><ref name="ccc">Pathology of Glioblastoma multiforme. Libre Pathology. http://librepathology.org/wiki/index.php/Glioblastoma</ref>
*[[Pleomorphic]] [[astrocytes]] with marked [[atypia]] and [[mitosis]]
*[[Pleomorphic]] [[astrocytes]] with marked [[atypia]] and [[mitosis]]
*[[Necrosis]] and microvascular proliferation
*[[Necrosis]] and microvascular proliferation
*(+/-) Pseudopalisading necrosis
*(+/-) Pseudopalisading necrosis
**[[Tumor]] cells lined-up like a picket fence around necrotic areas
**[[Tumor]] cells lined-up like a picket fence around [[necrotic]] areas
 
According to WHO classification of [[brain tumors]], glioblastoma multiforme is termed as grade IV tumor.<ref name=ddd>Pathology of Glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/Glioblastoma</ref>


|[[File:Glioblastoma - intermed mag.jpg|thumb|none|200px|Microscopic image of Glioblastoma multiforme.[https://commons.wikimedia.org/w/index.php?search=Glioblastoma+multiforme&title=Special:Search&fulltext=1&searchToken=4ff0iez2xvah0wraspjgr6z31#%2Fmedia%2FFile%3AGlioblastoma_-_intermed_mag.jpg Source:Wikimedia Commons] ]]


<div align="left">
According to WHO [[classification]] of [[brain tumors]], glioblastoma multiforme is termed as grade IV tumor.<ref name="ddd">Pathology of Glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/Glioblastoma</ref>
<gallery heights="175" widths="175">
Image:Glioblastoma (1).jpg|Glioblastoma multiforme (histology slide)
</gallery>
</div>


===Markers===
===Immunohistochemistry===
Glioblastoma multiforme is demonstrated by positivity to [[tumor markers]] such as [[GFAP]].<ref name=ddd>Pathology of glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/Glioblastoma</ref>
Glioblastoma multiforme is demonstrated by positivity to [[tumor markers]] such as [[GFAP]].<ref name="ddd">Pathology of glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/Glioblastoma</ref>


==References==
==References==

Latest revision as of 14:02, 29 July 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2]

Overview

Genes involved in the pathogenesis of glioblastoma multiforme include Mdm2, PTEN, IDH1, p53, EGFR, PDGFRA, and chromosomes 10p, 10q, 17p, and 19q. On gross pathology, the characteristic findings of glioblastoma multiforme include a poorly-marginated, diffusely infiltrating, firm or gelatinous mass with a central necrotic core. On microscopic histopathological analysis, the characteristic findings of glioblastoma multiforme include pleomorphic astrocytes with marked atypia, mitosis, necrosis, and microvascular proliferation. Another important alteration is methylation of MGMT, a suicide DNA repair enzyme. Methylation is described to impair DNA transcription and therefore, expression of the MGMT enzyme. MGMT methylation is associated with an improved response to treatment with DNA-damaging chemotherapeutics, such as temozolomide. Glioblastoma multiforme exhibits numerous alterations in genes that encode for ion channels, including upregulation of gBK potassium channels and ClC-3 chloride channels. Upregulating these ion channels, the tumor cells can facilitate increased ion movement over the cell membrane, thereby increasing H2O movement through osmosis, which aids the tumor cells in changing cellular volume very rapidly.

Pathophysiology

Pathogenesis

Molecular alterations

  • There are four subtypes of glioblastoma multiforme.[1]
  • Tumors in the "classical" subtype is characterized by mutations in EGFR.
  • The "proneural" subtype often has high rates of alterations in TP53, PDGFRA, and IDH1.
  • The "mesenchymal" subtype is characterized by mutations in NF1, and EGFR.
  • The "neural" subtype has several mutations in many of the same genes as the other groups.
  • Majority of the genetic alterations in glioblastoma multiforme are clustered in three pathways: p53, Rb, and PI3K/AKT.
  • Another important alteration is methylation of MGMT, a suicide DNA repair enzyme. Methylation is described to impair DNA transcription and therefore, expression of the MGMT enzyme. Since MGMT can only repair one DNA alkylation due its suicide repair mechanism, reverse capacity is low and methylation of the MGMT gene promoter greatly affects DNA repair capacity. Hence, MGMT methylation is associated with an improved response to treatment with DNA-damaging chemotherapeutics, such as temozolomide.

Glioblastoma multiforme stem-like cells

  • Cancer cells with stem cell-like properties have been found to be a cause of resistance to conventional treatment and high recurrence rate of glioblastoma multiforme.
  • A biomarker that exhibits cancer stem cell properties, Hes3, has been shown to regulate cells of glioblastoma multiforme when placed in culture.

Metabolism

  • The IDH1 gene is frequently mutated in glioblastoma multiforme (primary: 5%, secondary: 80%). By producing very high concentrations of the oncometabolite D-2-hydroxyglutarate and dysregulating the function of the wild-type IDH1-enzyme, it induces profound changes to the metabolism of IDH1-mutated glioblastoma multiforme compared with IDH1 wild-type glioblastoma multiforme or healthy astrocytes.
  • The IDH1 mutation increases the dependence of glioblastoma multiforme on glutamine or glutamate as an energy source. Since healthy astrocytes excrete glutamate, IDH1-mutated glioblastoma multiforme cells do not favor dense tumor structures but instead migrate, invade and disperse into healthy parts of the brain where glutamate concentrations are higher. This may explain the invasive behavior of these IDH1-mutated glioblastoma multiforme.

Ion channels

Genetics

  • Development of glioblastoma multiforme is the result from multiple genetic mutations.
  • Genes involved in the pathogenesis of glioblastoma multiforme include the following:[2]
Types of glioblastoma multiforme Genes
Primary​
Secondary
  • IDH1
  • p53
  • Gene on chromosome 10q
  • Gene on chromosome 17p
  • Gene on chromosome 19q
Classic
Proneural
Mesenchymal

Associated Conditions

Glioblastoma multiforme may be associated with:[2]

Pathology

Gross Pathology

|

Gross pathology of glioblastoma multiforme.Source:Wikimedia Commons


On gross pathology, the characteristic findings of glioblastoma multiforme include:[2][3]

Microscopic Pathology

On microscopic histopathological analysis, the characteristic findings of glioblastoma multiformes include:[2][3]

|

Microscopic image of Glioblastoma multiforme.Source:Wikimedia Commons

According to WHO classification of brain tumors, glioblastoma multiforme is termed as grade IV tumor.[2]

Immunohistochemistry

Glioblastoma multiforme is demonstrated by positivity to tumor markers such as GFAP.[2]

References

  1. ↑ Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD; et al. (2010). "Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma multiforme characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1". Cancer Cell. 17 (1): 98–110. doi:10.1016/j.ccr.2009.12.020. PMC 2818769. PMID 20129251.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Pathology of Glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/Glioblastoma
  3. ↑ 3.0 3.1 Pathology of Glioblastoma multiforme. Libre Pathology. http://librepathology.org/wiki/index.php/Glioblastoma


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