Post on 29-Apr-2018
Image Guidance
• Frame-based (stereotactic)
• Frame less (neuronavigation) – No indication for DIPG yet…..
Stereotaxy
• Stereo " tridimensional " and taxis "arrangement »
• Reach any part of the brain with pinpoint accuracy (less than one thousandth of a degree)
• Use of cartesian coordinates
• 2 elements:
– Stereotactic atlas / image-guided
– Stereotactic apparatus
Stereotactic Frame
• Form of a cube or a sphere
• Attached to the patient’s skull
• Coordinates in the 3 axes of space
Stereotactic Procedure
• Local or general anesthesia
• The device is fixed to the skull
• Stereotactic coordinates (entry point & targets)
• Needle placed according the coordinates to reach the target
• Allows to: – Tissue sample
– Remove fluid
– Inject fluid
– Radiosurgery
– Functional Neurosurgery
CED= Convection Enhanced Delivery
• Positive pressure gradient and bulk flow
• Distribution along white matter tracts
• 10 000 fold greater concentration
• Feasability in preclinical models
(Sandberg, Guarnieri, Souweidane..)
• Feasability in a child with DIPG
Lonser 2007
Biopsy Autopsy
• Diagnosis on MRI
• Risk of neurological deterioration
• Small & few samples
• Molecular Profiling AT DIAGNOSIS
• Understand the biology to find target genes
• ……..personalized treatment
• RT and CT can modify biology
• High amount of tissue
• Molecular Profiling
CONS
PRO
Brainstem biopsy
• High degree of accuracy with low operative morbidity
• As safe as stereotactic biopsy of the supratentorial space
Routes
Transfrontal
• Precoronal entry
• Long
• All the segments of the brainstem
• Important to avoid ventricles, vessels, tentorium
Transcerebellar
• Through the middle cerebellar peduncle
• Short • Pontine and upper
medullary • Cross less eloquent
structures • Important to avoid the 4th
ventricle and CN nuclei
Right or left side?
• Depends on the tumor extension & clinical signs
• Choose the most disabled size
• Avoid to add controlateral deficits
• Chernov Clin Neurol Neurosurg 2009 Jul – 30 MRI-spectro and 39 MRI. – No significant difference for diagnostic yield
• Not helpful to choose a target
MRI Spectro
JNeurosurg Pediatrics 1:270–276, 2008 Diffusion tensor imaging of brainstem tumors: axonal degeneration of motor and sensory tracts KATHLEENJ. HELTON, M.D.,1JAMESK. WEEKS, M.D.,1NICHOLASS. PHILLIPS, B.A.,1 PINGZOU, PH.D.,1LARRYE. KUN, M.D.,1RAJAB. KHAN, M.D.,1AMARGAJJAR, M.D.,2 MARYAMFOULADI, M.D.,2ALBERTOBRONISCER, M.D.,2FREDERICKBOOP, M.D.,3 CHIN-SHANGLI, PH.D.,4ANDROBERTJ. OGG, PH.D.1
Diffusion Tensor MRI
• 7 children with DIPG / 8 healthy adults • It may help in Planning Biopsies….
PET
• 8 children had both planning • 2 of them had non diag samples in areas of MRI+ / FIDG – • It may help in Planning Biopsies….
1- the frame is fixed on the skull
General anesthesia, referent point post-right, as low as possible
4- calculation of the coordinates
Software
Entry point, target point and path
Hands made
Target point
Background
• Dismal Pronostic
• No effective treatment
Biopsies in a part of a trial
Biopsies to find new markers
DIPG biopsy Necker Series
• 90 (2002-2012)
• 4 parents refused
• Number of samples (up to 8)
• No Mortality
• 4 Transient worsening (VII + hemiparesis)
• 2 disseminations along the trajectory at relapse
Serie Necker (at time of analysis)
32 aCGH 23 GE 5 stem cells culture
60 biopsies- 38 frozen
3.3 microg of DNA (range 0.805- 21.5) 2.3 microg of RNA (range 0.048-15.84)
Contrôles Smears
Groupe Proneural / Oligodendroglial
Oligo Olig2
10% mutation PDGFRA (domaine extra cellulaire)
Facteur transcription SOX10
Groupe Mesenchymateux / ProAngiogenique
MT network, Carro et al, Nature 2010
Upregulation of Transcription Factors regulating mesenchymal genes: STAT3, BHLHE40, CEBPA, RUNX1, FOSL2, ZNF238
SNAI1 et SNAI2/Slug
Mes Phenotype: TNC, OSMR, VIM, YKL40/CHI3L1
Vim
Proangiogenic genes: VEGFA, VWF, PECAM1, TREM1, OSMR, PLAU
Stem cells markers
Neurospheres culture and xenograft from DIPG Thiriant et al, PloS One 2011
• Overexpression of stem cell markers
• Overexpression of Mesenchymal markers
« the tumor is heterogeneous, so the biopsy does not reflect the biology of the whole tumor »
Not so sure!!!
DIPG Molecular Biology
• Puget/Grill – Mutations
• 7 patients (Ped blood cancer)
– Genomic • 61 patients (Plos One)
• Louis (JNEN 1993) – 7 patients
• Paugh (JCO 2010) – 7 patients
• Zarghooni (JCO 2010) – 11 patients
• Warren (Neurooncol 2011) – 13 patients
Biopsy Autopsy
• Chromosomal Aberrations
– Gain 1q, 7
– Loss 10q
• Potential targeted therapy
– Gains/Amplifications
• PDGFRA (1/3), MET, PARP1, MYCN, MDM4, AKT3/pI3K, EGFR
– Loss/Deletions
• PTEN, CDKN2A
Séries Autopsies Biologie Moléculaire
• Chromosomal Aberrations
– Gain 1q, 2p, 7p
– Loss 10q, 14q,17p
• Potential targeted therapy
– Gains/Amplifications
• PDGFRA (1/3), MET, PARP1, MYCN, MDM4, AKT3/pI3K, EGFR
– Loss/Deletions
• PTEN, P53, CDKN2A
– Mutations TP53 (40%), PI3KCA (15%), PDGFRA (8.8%)
Série Biopsies Biologie Moléculaire
95
Trial accepted by the French NCI (INCa-PHRC 2011)
If more than one biomarker, dasatinib arm is favored, then mTOR inhibitor If no biomarker identified or blank biopsy, treatment allocated randomly 109 patients (phase I/II for dasatinib and mTOR inhibitor)
Thanks to parents and children who participated in this research, especially to Liv.
CNRS UMR 8203 (IGR): L. Mir, G. Vassal, B. Geoerger, S. Puget, J. Grill, C. Barbosa, V. Scott, E. Daudigos, E. DeCarli, F. Andreiuolo, L. Guerrini-Rousseau, C. Jubert, P. Opolon.
Functional Genomics and Bioinformatics (IGR): C. Philippe, B. Job, C. Richon, P. Dessen, V. Lazar.
Neuropathology (Sainte-Anne Hospital) P. Varlet, C. Miquel
INSERM U752 (Sainte-Anne) H. Chneiweiss, M.P Junier, B. Bessette
CRB Necker S. Dubleumortier, N. Brousse
Neurochirurgie pédiatrique (Necker) S. Puget, C. Sainte-Rose, M.Zerah, T.Roujeau, T. Blauwblomme
Royal Marsden (Sutton) C. Jones, R. Reis, D. Bax, D. Carvalho
Financial Support LEEM recherche, Etoile de Martin, ARNP, INCA-Cancéropole