47 year-old female patient headheachs since 3 months tired too heavy word, end of the year…? late...
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![Page 1: 47 year-old female patient Headheachs since 3 months Tired Too heavy word, end of the year…? Late July 2008 Consultations Family doctor Neurologist](https://reader035.vdocuments.mx/reader035/viewer/2022062516/56649d425503460f94a1d45a/html5/thumbnails/1.jpg)
47 year-old female patient
Headheachs since 3 monthsTired
Too heavy word, end of the year…?
Late July 2008
Consultations
• Family doctor
• Neurologist
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CT scanner followed by IRM
Primary brain tumor
Metastases
Abcess ???
• •
•
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Post-operative MRI
Large tumor resection
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Histopathological diagnose
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50 year-old male patientFirst epilepsia in 2004
Periventricular fronto-basal lesion
Biopsy: grade II astrocytoma
Complication: hematoma
Clinical evolution: uncontrolled epilepsia
Radiotherapy in 2005
June 2008Clinical evolution: Frontal syndrom
Agressivity
Some confusion
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• •
•
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Oriented frontal lobectomy
2d tumoral
pieces
Per operative analysis
• •
•
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Histopathological diagnose
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Post-operative CTscan
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WHO histopathological grading:
IPilocytic astrocytoma
Pleiomorphic xantoastrocytoma
well-circumscribed
II
Astrocytoma
IIIAnaplastic
astrocytoma
IV
Glioblastoma
diffusely infiltrative into normal brain parenchyma
Astrocytic Tumors
60-70 % of all gliomas about 5% of all solid tumors in adults 20% in children
Expected
survival
benign
Cure is expected by
surgery
malignant
10 – 20 years
highly malignant
3 – 5 years 0.5 - 3 years
WHO histopathological gradingII III IV
Angiogenesis
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Current Treatment Against High-grade Malignant Gliomas
Surgery
Anaplastic Astrocytoma
(WHO Grade III)
Anaplastic Oligodendroglioma(WHO Grade III)
Glioblastoma(WHO Grade IV)
+
Chemotherapy(PCV)
Cytogenetic Analyses 1p19q Status
Radiotherapy at Recurrence+ Temodal
Radiotherapy
Followed byChemotherapy
(PCV, Temodal)
Radiotherapy+
Chemotherapy(Temodal)
Histopathological Grading
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A B C
D E F
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Cancer cell migration: A coordinated process between adhesion, motility and invasion
Cell movement
adhesion complexes
new adhesion complex
ADHESION
INVASION
cancercells
secreteproteases
proteasesmake holes
in tissuethat cancer
cells can cross
actincytoskeleton
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Glioblastomas (GBM) are associated with dismal prognoses because:
New types of compounds are needed to efficiently combat
devastating cancers
PI3-K Akt/PKB (PTEN) mTOR,
NFkappaB and Ras/Raf/MEK/ERK
Lefranc et al., J Clin Oncol, April 2005
McCubrey et al., Advan Enzym Regul 2006
under press
Ras
Raf
SOS
PI3KPIP2 PI3P
Akt
Transcription factors
Grb2
MAPK/ERK
mTOR inhibitors(rapamycin) mTOR
nFkB
IkBIKK
P P
PTEN
Src
Resistance to cytotoxic insultsApoptosis
Invasion / Migration
Growth Factors
Akt inhibitorsPI3K inhibitors
they are resistant to apoptosis, and so to pro-apoptotic cytotoxic drugs,
because constitutive activation of distinct anti-apoptotic signaling
pathways including:
Lefranc and Kiss, Neurosurgical Focus 2006
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Stupp and Colleagues (N Engl J Med, 2005): Long-Term Treatment with TMZ
TMZ offers greater therapeutic benefits to GBM patients when administered during radiotherapy
60Gy
TMZ 75 mg/m²
2GyN= 286, radiotherapy alone
N= 287, combined therapy
TMZ 200 mg/m²TMZ 150 mg/m²0-7 cycles, median 3 cycles
2-year survival rate
10.4%
26.5%
Ran
dom
izat
ion
Hegi and Colleagues (N Engl J Med, 2005): MGMT Gene Silencing and Benefit
from Temozolomide in Glioblastoma
Benefit from Temozolomide
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Why Temozolomide Is It Active
In Glioblastomas, which Are Resistant
to Apoptosis?
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TMZ 100µM induces autophagy in
apoptosis-resistant glioblastoma cells
(Kanzawa T et al., Cell Death Differ,
2004)
TMZ 100µM induces late apoptosis in
p53Wt glioblastoma cells (Roos WP et al.,
Oncogene, 2007)P P
mTOR inactivation
Anticancer therapies
DR
Caspase-8
Cas
pa s
e-8
Cas
pa s
e-8
FA
DD
FA
DD
Effector caspases
DISC
Lysosome
Autophagolysosome
Type II PCDAutophagy
Type I PCDApoptosis
LC3-I
LC3-II
Mitochondria
Growth FactorReceptor
Autophagosome
Caspase-9
Lefranc et al., The Oncologist, 2007
TMZ 100µM activates stress mechanisms that
include the angiogenesis-inducing
proteins HIF-1 and VEGF in glioblastoma cells (Fisher T et al.,
Cancer J, 2007)
Metronomic treatment of TMZ reduces angiogenesis in
orthotopic models of gliomas
(Kim JT et al., Oncology Reports,
2006)
Combining Avastin with Temozolomide Increases the Anti-Tumor Efficacy of Temozolomide in Human Glioblastomas Orthotopic Xenografts
(Mathieu et al., accepted for publication )
Angiogenesis
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0.5 mm
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GL5 human GBM
0 10 20 30 40 50 60 70 80 90 100 110 120 130
Days post tumor graf
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
Cu
mu
lati
ve P
rop
orti
on S
urv
ivin
g
Ctrl PCV Avastin/Irinotecan Temodal
J0 J52.106GL5 GBM cells
PCV (4x1); 10/10/0.63 mg/Kg IV
Ava/IRI (5x1); 10/10 mg/Kg IV
TMZ (5x1); 40 mg/Kg PO
p 0.0007p 0.0006
p 0.002
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From Yamanaka R, Trends in Mol Med 2008
Dentritic Cell Vaccinotherapy
From Parney et al., Neurosurgery 2000
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Dentritic Cell Vaccinotherapy
From Yamanaka R, Trends in Mol Med 2008
Dr Steven de Vleeschouwer, « Clinical experience with DC vaccinotherapy at KUL hospital », May 25th 2009
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