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Tu Esmo Imaging Of Glioma Ppt
1. MPI/Uni Cologne
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Imaging of glioma
2. Human Imaging Methods
mm proton spin, density, diffusion
MRI
X-ray attenuation
CT blood flow
blood/tissue oxgenation
Spatial resolution
glucose metabolism
PET amino/nucleic acid metabolism
transmitter metabolism
SPECT receptor density
cell labeling
tissue pH
cm MRS/CSI
metabolite/drug concentration
3. Glioma Grades and Prognosis
WHO grade Median survival Histological types
1 Cure possible Pilocytic astrocytoma (children)
2 10-16 years Oligodendroglioma
2 6-8 years Astrocytoma
Anaplastic Astrocytoma
3 3 years
Anaplastic Oligodendroglioma
4 3-24 months Glioblastoma
6. Tractography
Non-isotropic diffusion-weighted MRI
Diffusion-Tensor Imaging (DTI)
Displacement and distorsion of
Normal fibre tracts by glioblastoma
Image-derived parameters: Mean diffusivity and fractional anisotropy
7. Magnetic resonance spectroscopy (MRS)
Resonance shifts induced by (mostly endogeneous)
millimolar substrate concentrations
• H-1 (protons):
– Choline (increased in most gliomas),
– NAA (intermediary metabolite of normal brain)
– Lactate (in some gliomas, below detection in bormal
brain)
– Creatine, Lipids, (Alanine, Acetate, Succinate)
• P-31: ATP, PCr, inorganic Phosphate, Phosphoesters, pH
• C-13 (exogeneous): Glycolysis
• F-19 (exogeneous): Fluorinated drugs
8. Indicators of malignant degeneration
Vascular changes Cellular changes
• Increase of vascularity • Increase of glycolysis
– Endothelial activation: – FDG PET
Amino-Acid PET/SPECT – MRS: lactate
– Blood volume and blood • Change of lipid metabolism
flow: – PET: C11/F18 choline,
• Dynamic CT, acetate
perfusion/diffusion- – MRS: increase of choline,
weighted MRI altered phospholipid signal
• SPECT, PET • Increase of cellular proliferation
• BBB breakdown rate
– MRI/CT contrast – Nucleoside PET (requires
enhancement BBB damage for uptake)
9. Imaging blood volume and flow
Technique Contrast Agent/ Tracer Biomarkers
Dynamic contrast enhanced CT Nonionic iodine containing
(DCE-CT) contrast Blood flow
Blood volume
Dynamic relaxivity enhanced MRI Contrast transfer coefficient (Ktrans)
(DRCE-MRI) Standard small molecular Capillary endothelial permeability surface area
weight Gd based contrast product (PS)
Dynamic susceptibility enhanced agent Volume of the Extravascular Extracellular space (ve)
MRI (DSCE-MRI)
Xenon-CT Inhaled Xenon Blood flow
Arterial Spin Labeled MRI (ASL) Endogenous water Blood flow
Bulk blood flow in large vessels
Quantitative phase contrast
Endogenous water CSF flow
imaging (MRI)
Intra-cranial pressure (ICP)
99mTc-HMPAO
Single photon emission
133Xenon Blood flow
tomography (SPECT)
123I-IMP
15O-water Blood flow
Positron emission tomography 11C-butanol Distribution coefficient
(PET) 15O/11C-CO
Blood volume
11C/62Cu-albumine
10. Metabolic Tracers for PET & SPECT
• Glucose metabolism
– FDG PET: Grading, localization of malignant parts, tumor vs.
necrosis
• Ion transport
– Tl-211 SPECT, Rb-82 PET
• Amino acids: Activated transport even in 70% of low-grade tumors;
monitoring of therapy and progression; detection of recurrent tumor
(vs. necrosis)
– PET: C-11-methionine, F-18-fluoro-ethyltyrosine (FET), FDOPA,
F-18-fluorotyrosine (F-TYR)
– SPECT: I-123-Iodo-methyltyrosine (IMT)
• Proliferation markers: C-11-thymidine, F-18-fluorothymidine (FLT)
• Intermediary metabolism: C-11 or F-18-labeled choline and acetate
• Hypoxia: F-18-fluoro-misonidazole (FMISO) and related compounds
12. FDG uptake and prognosis in glioblastoma
Hölzer et al.
JCAT, 1992
13. 0. 0
0. 0 2 µ
0. 0 4
0. 0 6
0. 0 8
0.00 1
mol glucose/100g/min
0.02 1
Very high FDG uptake in lymphoma
14. Differentiation of
necrosis versus recurrent tumor
Large necrosis
without significant
glucose metabolism
Small, metabolically
active recurrent
tumor
MPI
MRI fusion FDG PET Cologne
16. FDG PET for brain tumours
• Diagnosis of lymphoma (very high uptake)
• Detection and localisation of malignant gliomas
– Selection of target point for biopsy to maximise
diagnostic yield
– Recurrent high-grade tumour (vs. necrosis)
– Malignant degeneration of low-grade glioma
17. Limitations for using increased FDG
uptake as indicator of malignancy
• High glucose metabolism in normal grey matter
– Dependent on neuronal function
– Further increase in focal epilepsy
• Glycolytic activity of macrophages
– Wide range of glucose metabolism in inflammatory
lesions
• Tumor uptake not strictly related to malignancy
– Higher uptake in oligodendroglioma than in astrocytoma
– High uptake in some benign tumours: Schwannomas,
rapidly growing meningiomas
– Low uptake in some malignant lesions: Micronecrosis in
GBM, metastasis
18. Amino acid tracers
• Transport only
– by large neutral amino acid carrier (L-type)
• F-18-fluoro-ethyltyrosine (FET)
• SPECT: I-123-Iodo-methyltyrosine (IMT)
– by asymmetric carrier (A-type)
• aminoisobutyric acid, ACPC
• Transport and complex metabolism
– C-11-methionine
– F-18-Fluoro-DOPA
• Transport and protein incorporation
– C-11 tyrosine, leucine
– F-18-fluorotyrosine (F-TYR)
19. C-11-Methionine Uptake is related to
Histological Grade and Tumor Type
Results in 83 untreated and histologically
verified gliomas
Herholz, K., et al.: 11C-Methionine PET for differential diagnosis of low-grade gliomas.
Neurology 50(5), 1316-1322. 1998.
20. Astrocytoma Grade II:
Relation between C-11-methionine and tumor cell density
High cellular
Low cellularity in
and vascular
area with low
density in area
methionine
with increased
uptake
uptake of
methionine
25. Growth of Glioblastoma
C-11-methionine
after tu resection
C-11-methionine
Follow-up day 141
"hot spot" in FDG corresponds to new tumor
FDG
day 140
26. Prognostic value of residual C-11-
methionine uptake after resection
Patients without areas of elevated
MET uptake after initial treatment
(3 GBMs, 4 anaplastic
astrocytomas, 1 anaplastic
oligodendroglioma)
Nariai et al., 2005
27. Evaluation of glioma chemotherapy
by C-11-methionine
• Case report: Continuous decline with PCV in
oligoastrocytoma (Herholz et al., 2003)
• Responses to 6 cycles of PCV in oligodendroglioma (n=7,
Tang et al., 2005)
• Response after 3 cycles of temozolomide in malignant
glioma predicts outcome (n=15, Galldiks et al., 2006)
• Work in progress: use of PET as outcome parameter in
clinical trials
28. Decline of Methionine Uptake during
Successful Chemotherapy of Anaplastic Oligoastrocytoma
MPI/Uni
Cologne
Herholz K et al. (2003) Journal of Neuroimaging 13, 269-271
29. Amino acid tracers for gliomas
Strengths Limitations
• Increased uptake even in • Not strictly tumor-specific
most low-grade gliomas (but still better than FDG)
• Clinically useful for • Less informative for
– Planning and grading and prognosis than
monitoring of therapy FDG
– Location of most active • Often little uptake in
tumor parts metastases and lymphoma
– Study of infiltration
30. Thymidine (TdR) and Fluorthymidine (FLT)
While in normal cells TK1 activity is
about 10-fold increased only during
the DNA synthetic phase, in
malignant cells there is a higher and
permanent increase of TK1activity
In cell culture experiments,
FLT uptake correlated well
with percentage of cells in S-
Phase and TK1 activity in
most cell lines, although
some cell lines appear to
use a TK1-independent
pathway for DNA synthesis
Krohn et al., 2005
31. Glioblastoma
FLT uptake in contrast
enhancing area
Uptake of C-11-
methionine extends
into infiltration zone
Jacobs et al., JNM, 2006
32. Correlation between FLT uptake and
proliferation index in high-grade glioma
Ullrich et al., Clinical Cancer Research, 2008
33. Thymidine tracers for brain tumors
Strengths Limitations
• Probably most closely • Not for low-grade gliomas
linked to proliferation (uptake dependent on BBB
• Potential for therapy breakdown)
monitoring • Kinetic data analysis
• Good target to background required to differentiate
signal in malignant gliomas TK1 activity from
unspecific uptake in areas
with BBB damage
35. Imaging of gene transfer
• Use of substrates for transferred genes, e.g. 2′-
fluoro-2′-deoxy-1-β-D-arabinofuranosyl-5-124I-
iodo-uracil (124I-FIAU) and related compounds for
imaging HSV-TK
Jacobs et al., Lancet, 2001
36. Contribution of PET to Development of
Chemotherapy
• Measurement of tumor blood flow and BBB
permeability for chemotherapy
• Labeling chemotherapeutics (BCNU,
temozolomide, gefinitib): Local pharmacokinetics
• Assessment of pharmacodynamics in new drugs
• Assessing multiple drug resistance (C-11-verapamil,
Vaalburg et al., 2002)
37. Radiotherapy
• Improved target delineation in radiotherapy for
operated gliomas with C-11-methionine (Grosu et
al., 2005)
• Tumors with higher pre-treatment uptake may have
a better response to radiation therapy (Ribom et al.,
2002) and chemotherapy (Brock et al., 2000)
• Uptake of F-18-misonidazole may indicate presence
of radioresistant hypoxic tissue
• F-18-labeled borono phenylalanine for planning of
neutron capture therapy (Imahori et al. 1998)
38. Summary & Perspectives
• Advanced imaging techniques
– Demonstrate metabolic heterogeneity within most
gliomas
– Provide localised and specific information that is useful
for planning and monitoring of treatment
• Targeting of biopsies
• Early detection of recurrence
• Imaging needs integration with multidisciplinary glioma
management, including systematic longitudinal and
intervention studies
• Imaging has the potential to increase the efficiency of
therapeutic trials, especially in phase I/II
