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47 year-old female patient

Late July 2008. 47 year-old female patient. Headheachs since 3 months Tired Too heavy word , end of the year …?. Consultations Family doctor Neurologist. CT scanner followed by IRM. Primary brain tumor Metastases Abcess ???. Post-operative MRI.

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47 year-old female patient

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  1. Late July 2008 47 year-old female patient Headheachssince 3 months Tired Tooheavyword, end of the year…? Consultations • Family doctor • Neurologist

  2. CT scanner followed by IRM Primary brain tumor Metastases Abcess ???

  3. Post-operative MRI Large tumor resection

  4. Histopathological diagnose

  5. 50 year-old male patient First epilepsia in 2004 Periventricular fronto-basal lesion Biopsy: grade II astrocytoma Complication: hematoma Clinical evolution: uncontrolled epilepsia Radiotherapy in 2005 June 2008 Clinical evolution: Frontal syndrom Agressivity Some confusion

  6. Per operative analysis Oriented frontal lobectomy 2d tumoral pieces

  7. Histopathological diagnose

  8. Post-operative CTscan

  9. Astrocytic Tumors benign malignant highly malignant I II III IV Pilocytic astrocytoma Pleiomorphic xantoastrocytoma Astrocytoma Anaplastic astrocytoma Glioblastoma well-circumscribed diffusely infiltrative into normal brain parenchyma Cure is expected by surgery 10 – 20 years 3 – 5 years 0.5 - 3 years Angiogenesis II III IV WHO histopathological grading  60-70 % of all gliomas  about 5% of all solid tumors in adults 20% in children WHO histopathological grading: Expected survival

  10. Histopathological Grading Anaplastic Oligodendroglioma (WHO Grade III) Anaplastic Astrocytoma (WHO Grade III) Glioblastoma (WHO Grade IV) Cytogenetic Analyses  1p19q Status Radiotherapy Radiotherapy + Chemotherapy (Temodal) + Chemotherapy (PCV) Followed by Chemotherapy (PCV, Temodal) Radiotherapy at Recurrence + Temodal Current Treatment Against High-grade Malignant Gliomas Surgery

  11. A C B F D E

  12. actin cytoskeleton secrete proteases adhesion complexes proteases make holes in tissue that cancer cells can cross new adhesion complex Cell movement Cancer cell migration: A coordinated process between adhesion, motility and invasion A DHESION I N VASION cancer cells

  13.  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 • Glioblastomas (GBM) are associated with dismal prognoses because: • they are resistant to apoptosis, and so to pro-apoptotic cytotoxic drugs, because constitutive activation of distinct anti-apoptotic signaling pathways including: New types of compounds are needed to efficiently combat devastating cancers Lefranc and Kiss, Neurosurgical Focus 2006

  14. 2-year survival rate N= 286, radiotherapy alone 2Gy 10.4% 26.5% TMZ 75 mg/m² TMZ 150 mg/m² TMZ 200 mg/m² 0-7 cycles, median 3 cycles N= 287, combined therapy Benefit from Temozolomide Stupp and Colleagues (N Engl J Med, 2005): Long-Term Treatment with TMZ 60Gy Randomization • TMZ offers greater therapeutic benefits to GBM patients when administered during radiotherapy Hegi and Colleagues (N Engl J Med, 2005): MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma

  15. Why Temozolomide Is It Active In Glioblastomas, which Are Resistant to Apoptosis?

  16. Lefranc et al., The Oncologist, 2007 TMZ 100µM induces late apoptosis in p53Wt glioblastoma cells (Roos WP et al., Oncogene, 2007) TMZ 100µM induces autophagy in apoptosis-resistant glioblastoma cells (Kanzawa T et al., Cell Death Differ, 2004) 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) Angiogenesis Combining Avastin with Temozolomide Increases the Anti-Tumor Efficacy of Temozolomide in Human Glioblastomas Orthotopic Xenografts (Mathieu et al., accepted for publication )

  17. 0.5 mm

  18. 2.106GL5 GBM cells J0 J5 PCV (4x1); 10/10/0.63 mg/Kg IV Ava/IRI (5x1); 10/10 mg/Kg IV TMZ (5x1); 40 mg/Kg PO p 0.002 p 0.0007 p 0.0006

  19. Dentritic Cell Vaccinotherapy From Parney et al., Neurosurgery 2000 From Yamanaka R, Trends in Mol Med 2008

  20. 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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