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Glioblastoma
 multiforme
4	
 week	
 history	
 of	
 
67	
 years-old	
 caucasian	
                       headache	
 “especially	
 
male	
 patient,	
 no	
                               when	
 I	
 wake	
 up”,	
 
significant	
 PMH                                    memory	
 loss;	
 right-
                                                       sided	
 mild	
 motor	
 
                                                                  weakness




         T1-weighted	
 axial	
 MRI	
 with	
 
                                               T2-weighted	
 axial	
 MRI
            intravenous	
 contrast
The	
 most	
 common	
 primary	
 brain	
 tumors	
 are	
 the	
 
           gliomas	
 (approximately	
 60%)


Among	
 all	
 gliomas,	
 Glioblastoma	
 is	
 the	
 most	
 
     common	
 and	
 most	
 aggressive	
 tumor



“Glioblastomas are densely cellular,
   pleomorphic tumors with mitotic
  activity and either microvascular
      proliferation or necrosis”
                                                (UpToDate	
 2012)
Classification


        Pilocytic	
 astrocytoma	
 (WHO	
 I)

                Diffuse	
 astrocytoma	
 (WHO	
 II)


                Anaplastic	
 astrocytoma	
 (WHO	
 III)


                Glioblastoma	
 (WHO	
 IV)
Epidemiology

Most	
 common	
 primary	
 brain	
 tumor	
 (15%)
        2-3	
 new	
 cases	
 per	
 100.000	
 people/y



                   It	
 affects	
 >45	
 adults	
 preferentially

                                                       Men	
 to	
 female	
 ratio	
 3:2
                                                         slightly	
 more	
 common	
 in	
 whites




               Overall	
 median	
 survival	
 after	
 optimal	
 
              therapy	
 is	
 less then 12 months
Rarely,	
 glioblastomas	
 presents	
 with	
 meningeal	
 dissemination,	
 
causing	
 meningeal	
 gliomatosis	
 symptoms
Prognostic
  factors
Prognostic
  factors
 Tumor grade
Prognostic
  factors
 Tumor grade


    Age
Prognostic
  factors
 Tumor grade


    Age


  Extent of
   surgery
Prognostic
  factors
 Tumor grade


     Age


  Extent of
   surgery



 Karnofsky PS
Prognostic	
 factors	
 for	
 survival	
 of	
 patients	
 with	
 glioblastoma:	
 
Recursive	
 partitioning	
 analysis.	
 Neuro-	
 oncology	
 2004;	
 6:231.	
 
Copyright	
 ©	
 2004	
 Duke	
 University	
 Press.
CT scan
 results	
 provide	
 a	
 
   high	
 degree	
 of	
 
confidence	
 for	
 this	
 
type	
 of	
 tumor	
 but	
 
  it	
 is	
 not	
 usually	
 
          adopted
MRI is	
 the	
 most	
 useful	
 technique
MRI is	
 the	
 most	
 useful	
 technique
                       low signal
                          area
MRI is	
 the	
 most	
 useful	
 technique
                       low signal
                          area

    cystic areas
MRI is	
 the	
 most	
 useful	
 technique
                       low signal
                          area

    cystic areas


 internal high
  signal areas
MRI is	
 the	
 most	
 useful	
 technique
                       low signal
                          area

    cystic areas


 internal high
  signal areas




                    irregular
                    enhanced
                      border
high signal
   area
high signal
   area


      hemorrhagic
        and flow
          voids
high signal
        area


           hemorrhagic
             and flow
               voids



midline shift
  and mass
   effect
high signal
        area


           hemorrhagic
             and flow
               voids



midline shift
  and mass
   effect



                diffuse
                 edema
PET scanning is	
 a	
 useful	
 adjunct	
 in	
 GBM	
 cases,	
 especially	
 
                    in	
 the	
 follow-up	
 after	
 resection



                                Differential	
 diagnosis	
 between	
 

        recurrent	
 or	
 residual	
 masses	
 and	
 scars	
 or	
 radiation	
 necrosis

                                   is	
 difficult	
 with	
 MRI	
 -	
 TC




                 PET	
 scans	
 is	
 helpful	
 in	
 these	
 cases
Treatment
   is	
 consistent	
 with   3typical	
 procedures:

                                  SURGERY

               RADIATION

CHEMOTHERAPY
The	
 initial	
 treatment	
 for	
 GBM	
 is	
 total	
 resection	
 
             with	
 preservation	
 of	
 neurologic	
 function



    preoperative	
 imaging                            MRI	
 -	
 PET




     frameless	
 stereotaxis	
 with	
 
       cortical	
 stimulation	
 and	
 
        language	
 assessments
                                                  intraoperative	
 
                                                    techniques
 operating	
 rooms	
 equipped	
 with	
 
CT	
 -	
 MRI	
 scanners	
 can	
 guide	
 the	
 
     resection	
 in	
 “real	
 time”
Biopsy



 Subtotal	
 resection




Gross	
 total	
 resection
Biopsy



 Subtotal	
 resection
   cutout at
      78%
Gross	
 total	
 resection
Radiation	
 dose	
 of	
 6000	
 cGy	
 administered	
 in	
 5	
 
    days	
 showed	
 a	
 median	
 survival	
 of	
 42	
 weeks




    Temozolomide	
 has	
 been	
 shown	
 to	
 improve:
median	
 progression-free	
 survival	
 (+2	
 months)
overall	
 survival	
 (+2	
 months)
likelihood	
 of	
 being	
 alive	
 in	
 2	
 years	
 (26%	
 vs	
 10%)
Genetic background
and new treatments
Alterations	
 of	
 receptor	
 tyrosine	
 kinases	
 (such	
 as	
 
EGFR)	
 that	
 activate	
 PI3K	
 signaling,	
 leading	
 
to	
 hyperproliferation	
 and	
 increased	
 cell	
 survival


   Dysregulation	
 of	
 the	
 p53	
 pathway	
 that	
 
   lead	
 to	
 effects	
 such	
 as	
 reduced	
 apoptosis


      L o s s	
  o f	
  c e l l - c y c l e	
  c o n t r o l	
  v i a	
 
      disruption	
 of	
 Rb	
 signaling	
 pathway
VEGF:	
 bevacizumab,	
 cediranib,	
 XL184,	
 
enzastaurin
EGFR:	
 nimotuzumab
PDGF:	
 imatinib                                     Vaccines
Integrin inbitor:	
 cilengitide
                                                    Gene therapy
Histone deactylase hinibitors:	
 
cilengitide,	
 thalidomide




     Intratumoral
          drug                                       Radio-
    administration:	
                           immunoconjugates
    carmustine	
 polymer	
 
        wafer,	
 CED
VEGF:	
 bevacizumab,	
 cediranib,	
 XL184,	
 
enzastaurin
EGFR:	
 nimotuzumab
PDGF:	
 imatinib     Patients should Vaccines
                                     be
Integrin inbitor:	
 cilengitide
                                                Gene therapy
                           encouraged to
Histone deactylase hinibitors:	
 
cilengitide,	
 thalidomide

                  participate in clinical
     Intratumoralstudies whenever
          drug                    Radio-
    administration:	
        immunoconjugates
                       possible
    carmustine	
 polymer	
 
        wafer,	
 CED
Thank you

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Alberto fara Skullbase

  • 2. 4 week history of 67 years-old caucasian headache “especially male patient, no when I wake up”, significant PMH memory loss; right- sided mild motor weakness T1-weighted axial MRI with T2-weighted axial MRI intravenous contrast
  • 3. The most common primary brain tumors are the gliomas (approximately 60%) Among all gliomas, Glioblastoma is the most common and most aggressive tumor “Glioblastomas are densely cellular, pleomorphic tumors with mitotic activity and either microvascular proliferation or necrosis” (UpToDate 2012)
  • 4. Classification Pilocytic astrocytoma (WHO I) Diffuse astrocytoma (WHO II) Anaplastic astrocytoma (WHO III) Glioblastoma (WHO IV)
  • 5. Epidemiology Most common primary brain tumor (15%) 2-3 new cases per 100.000 people/y It affects >45 adults preferentially Men to female ratio 3:2 slightly more common in whites Overall median survival after optimal therapy is less then 12 months
  • 6. Rarely, glioblastomas presents with meningeal dissemination, causing meningeal gliomatosis symptoms
  • 8. Prognostic factors Tumor grade
  • 9. Prognostic factors Tumor grade Age
  • 10. Prognostic factors Tumor grade Age Extent of surgery
  • 11. Prognostic factors Tumor grade Age Extent of surgery Karnofsky PS
  • 12. Prognostic factors for survival of patients with glioblastoma: Recursive partitioning analysis. Neuro- oncology 2004; 6:231. Copyright © 2004 Duke University Press.
  • 13.
  • 14. CT scan results provide a high degree of confidence for this type of tumor but it is not usually adopted
  • 15. MRI is the most useful technique
  • 16. MRI is the most useful technique low signal area
  • 17. MRI is the most useful technique low signal area cystic areas
  • 18. MRI is the most useful technique low signal area cystic areas internal high signal areas
  • 19. MRI is the most useful technique low signal area cystic areas internal high signal areas irregular enhanced border
  • 20.
  • 21. high signal area
  • 22. high signal area hemorrhagic and flow voids
  • 23. high signal area hemorrhagic and flow voids midline shift and mass effect
  • 24. high signal area hemorrhagic and flow voids midline shift and mass effect diffuse edema
  • 25. PET scanning is a useful adjunct in GBM cases, especially in the follow-up after resection Differential diagnosis between recurrent or residual masses and scars or radiation necrosis is difficult with MRI - TC PET scans is helpful in these cases
  • 26.
  • 27. Treatment is consistent with 3typical procedures: SURGERY RADIATION CHEMOTHERAPY
  • 28. The initial treatment for GBM is total resection with preservation of neurologic function preoperative imaging MRI - PET frameless stereotaxis with cortical stimulation and language assessments intraoperative techniques operating rooms equipped with CT - MRI scanners can guide the resection in “real time”
  • 30. Biopsy Subtotal resection cutout at 78% Gross total resection
  • 31. Radiation dose of 6000 cGy administered in 5 days showed a median survival of 42 weeks Temozolomide has been shown to improve: median progression-free survival (+2 months) overall survival (+2 months) likelihood of being alive in 2 years (26% vs 10%)
  • 33. Alterations of receptor tyrosine kinases (such as EGFR) that activate PI3K signaling, leading to hyperproliferation and increased cell survival Dysregulation of the p53 pathway that lead to effects such as reduced apoptosis L o s s o f c e l l - c y c l e c o n t r o l v i a disruption of Rb signaling pathway
  • 34. VEGF: bevacizumab, cediranib, XL184, enzastaurin EGFR: nimotuzumab PDGF: imatinib Vaccines Integrin inbitor: cilengitide Gene therapy Histone deactylase hinibitors: cilengitide, thalidomide Intratumoral drug Radio- administration: immunoconjugates carmustine polymer wafer, CED
  • 35. VEGF: bevacizumab, cediranib, XL184, enzastaurin EGFR: nimotuzumab PDGF: imatinib Patients should Vaccines be Integrin inbitor: cilengitide Gene therapy encouraged to Histone deactylase hinibitors: cilengitide, thalidomide participate in clinical Intratumoralstudies whenever drug Radio- administration: immunoconjugates possible carmustine polymer wafer, CED

Editor's Notes

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  4. primary vs secondary GBM\n
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  14. they often miss small tumors (including lower-graded masses)\nmultifocal form is not clearly depicted\noverlapping images: diffuse multiple sclerosis, infarct with hemorrhagic transformation,\nbrain abscess, ecc\n
  15. hemorrhagic foci\ninternal flow voids, neovascularity\n
  16. hemorrhagic foci\ninternal flow voids, neovascularity\n
  17. hemorrhagic foci\ninternal flow voids, neovascularity\n
  18. hemorrhagic foci\ninternal flow voids, neovascularity\n
  19. hemorrhagic foci\ninternal flow voids, neovascularity\n
  20. hemorrhagic foci\ninternal flow voids, neovascularity\n
  21. hemorrhagic foci\ninternal flow voids, neovascularity\n
  22. hemorrhagic foci\ninternal flow voids, neovascularity\n
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  32. similar diagnostic image quality in both fusions and PET alone\n
  33. \n
  34. Malignant gliomas are characterized by poorly defined tumor margins with infiltration of neoplastic cells along white matter fibers and the perivascular spaces, which can extend well beyond the tumor margin as defined by the surgeon or by radiographic studies\n
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  36. \n
  37. \n
  38. \n
  39. progenitor cells vs adult cells\nSeveral gene mutations account for molecular and biologic background of GBM. In spite of the gene involved, all mutations lead to damaging one of these 3 key-regulatory pathways:\nPDGF, EGFR, IGF-1, IDH CDKN2A, CDKN2B, RB1, CDK4\n
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