PET Primena
Transcript of PET Primena
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Production, Use and
Applications of124I
Jason S. Lewis, PhDChief, Radiochemistry Service
Director, Cyclotron-Radiochemistry Core
Memorial-Sloan Kettering Cancer Center
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Memorial Sloan-Kettering Cancer Center
No Financial Disclosures
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Memorial Sloan-Kettering Cancer Center
Presentation
Decay Schemes, Cross Sections
Solid Targetry, Production, Separation
Methods
Clinical Applications
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124I Decay Scheme
T = 4.176 d
at least 25 electron capture transitions,6 positron transitions and 97
gamma-ray transitions. ~23% of disintegrations result in positron
emission while the gamma ray abundance >90% per disintegration.
Number of
distintegrations
Maximum
energy (MeV)
Average
energy (Mev)
+
0.002 0.820 0.3660.113 1.543 0.686
0.113 2.146 0.974
0.605 0.603
0.100 0.723
0.014 1.3250.017 1.376
0.030 1.509
0.104 1.691
MIRD Radionuclide Data and Decay Schemes
124I53
124Te (stable)52
+
+
+
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Image Quality
A mini Derenzo phantom filled with radionuclides imaged on a microPET- Focus scanner(Siemens Medical Systems). It is important to note that although this degradation is noted with
small animal PET scanners with high resolution (1- 2 mm), this degradation is often not seen with
clinical scanners with 4-5 mm resolution. New reconstruction algorithms can also be used to
enhance image quality.
Images are courtesy of Dr. Richard Laforest, Washington University School of Medicine
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Routes for Production of124I(values calculated from excitation functions measured at Jlich, Courtesy of Dr. Syed Qaim)
Impurity [%]Nuclear
reaction
Energy range
[MeV]
Thick targetyield of 124I
[MBq/Ah](mCi/Ah)
124Te(d,2n) 14 10 17.5 (0.47) - 1.7 -
126Te(p,3n) 38 28 222 (6) 148 1.0 1.0
natSb(,xn) 22 13 1.02 (0.03) 890 13 16
121Sb(,n) 22 13 2.1(0.06) 895
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Targetry - MSKCC
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Washington University
Dry distillation under Argon atmosphere
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Memorial Sloan-Kettering Cancer Center
Washington University 76Br
Can remove up to 90% of the radioactivity
from the 63Cu276Se target. Activity is trapped on quartz tube.
Removal of radioactivity by washing withNH4OH.
Recovery of radioactivity up to 76%.
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Memorial Sloan-Kettering Cancer Center
Washington University 76Br
Quartz tube changed
every two or three
productions0.000
0.200
0.400
0.600
0.800
1.000
1.200
1.400
1.600
1.800
2.000
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45
Run
ProductionRate
(mCi/uA*h)
0.0%
20.0%
40.0%
60.0%
80.0%
100.0%
120.0%
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45
Run
PercentRecovered
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Memorial Sloan-Kettering Cancer Center
University of Wisconsin: Vertical Target Station
Courtesy of R. Jerry Nickles, PhD J. A. Nye UW PhD Thesis
CTI RDS 112 11MeV
Vertical Solid Target w/KF Mounting
Passive Armco Singlet
(L.R. Carroll et al., Int Symp Radiopharm Chem, Sydney,
Australia, 2003)
Quad Slit Set
Chilled He Cooling Rig at 3 Liter/sec
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Irradiation Conditions 20-degree incline
20 mil Platinum foil crucible
200 mg Al2Te3 11 2.5 MeV
3L/sec circulating chilled helium
30% Power in helium stream
dryice
University of Wisconsin: Sloping Solid Target
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Thermal distillation of iodide from Al2124Te3 glassy melt
900o C, sublimation of iodide in air stream
Trapped on chilled capillary quartz tube loaded w/Pt wire on a
film of weak base
Carbolite Furnace24/40grindings
Dry iceCharcoal trap15 SCCM
Air
Exhaust
University of Wisconsin: Harvesting Iodine
Courtesy of R. Jerry Nickles, PhD J. A. Nye UW PhD Thesis
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Targetry - Hammersmith Imanet
Courtesy of Mathias Glaser, PhD
O2
Al2O
3 Charcoal
NaOH (20 mM)
"Spoon"
Furnace tubeFurnace
Protons12.5 MeV
Helium Water
Cover foilTarget holder
Target
0 10 20 30 40
2
4
6
8
10
12
Relative Target yield
Batch yield
Run No.Re
lativetargetyield,
decay-corrected(MBq/Ah)
0
50
100
150
200
250
300
350
400
Batchyield(MBq)
0 5 10 15 20 25 30 350
100
200
300
400
500
600
700
800
Furnace temperature
Detector response
Time (min)
Furnacetemperature
(oC)
0
1000
2000
3000
4000
5000
Detectorresponse(cpm)
0 5 10 15 20 25 30 35 40
0
50
100
150
200
Relativetargetyield,
decay-corr
ected(MBq/Ah)
Integrated beam current (Ah)
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State University of New York, Buffalo
Courtesy of Erol Bars, PhD
M i l Sl K tt i C C t
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State University of New York, Buffalo
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2006
I-124 Production Overview
Nuclear reaction: 124Te (p,n) 124I
Route selected for both high yield and high purity
124Te enriched Tellurium Oxide (TeO2) is the target materialmaterial
Thermo-distillation selected as recovery process
Recovery method associated with high recovery yields (90%)
(90%)
High Specific Activity (No Carrier Added) is desired
High radioactive concentration
[124I]NaI in NaOH solution (pH of 8.5) prevents volatilizationvolatilization
Flexibility to trap 124I in other solutions, and perform direct
direct
radio-labeling of precursors
Data prepared by
Bob Ylimaki, Bernard Lambert, Jean-Michel Geets
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2006
I-124 Production
IBA nirta solid target
Optimized for
124
TeO2
Low thermal conductivity
He cooling protects
target matrix
Remotely unloaded
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2006
IBA Nirta Solid target
Target disk 24mm
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2006
I-124 Production Process
Target Disk Irradiation
Optimal energy range for124I production
production while minimizing co-produced 123I:produced 123I: 14 - 9 MeV
Niobium degrader foil installed in targettarget
Thick target (0.9mm) fully stops beam
25A at 13Mev
Typical irradiation: 10-12 hours
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2006
I-124 Production Target Yield
Agreement with predicted 20MBq (0.54mCi)/uAh
124I Production YieldTypical Production Y ields
0
10
20
30
40
50
60
70
80
90
100
0 50 100 150 200 250
uA-h
mCi
124Te enrichment of 99.86%
Optimal 9-13 MeV makes less
less (< 3% vs. 30%) 123I
impurity, conserving 124Te;
As built: 100 mCi per 8 hour
hour production @ 25 A
(single)
Dual beam possible
I 124 P d ti P
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2006
I-124 Production Process
124I Radioiodine Recovery
Thermo-chromatographic recovery associated with high yieldyield
Diffusion/transport/trapping regimes optimized for iodide oxidation
oxidation species and target regeneration
Minimal maintenance
Nominal 90-95% trapping yield in 0.02M NaOH (less than 500 l)
500 l)
I 124 P d ti Q lit C t l
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2006
I-124 Production Quality Control
124I Radionuclidic Purity
Hyper-pure Germanium (HPGe) gamma spectrometry Conformance with American National Standards Institute (ANSI)
Institute (ANSI) Standard N42.14 assures universal acceptance
acceptance
Traceable 152Eu standard used for daily calibration
123I impurity minimized at End of Separation (EOS)
125I, 126I, 130I, 131I impurity levels below detection threshold of 0.1%threshold of 0.1%
Te content : less than 1g/ml
I 124 R di l b l d d
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2006
I-124 Radiolabeled compounds
I-124, NaI solution, activity level up to 20 mCi
I-124 MIBG
Collaboration : Wilex compound I-124 Radiolabeled cG250 antibody
Renal cell carcinoma imaging
Estimated worldwide 480,000 uncharacterizeduncharacterized renal masses are annually
identified
Prevents unnecessary nephrectomies I-124 ??
Other compounds
124I IBA d ti t
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2006
124I IBA production centers
IBAVCU, Richmond
VU, Amsterdam
IBA Radioisotopes Belgium
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2006
IBA Radioisotopes - Belgium
Fleurus facility: (14MeV- 1mA)
R&D center and radioisotopes production center
Memorial Sloan-Kettering Cancer Center
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GEMS NIH and Tubingen
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ACOM (Italy)
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ACOM (Italy)
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ACOM (Italy)
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124I Production Summary
Center Energy(MeV)
Experimental Yield(mCi/Ah)
Typicalrun
Actual activity(mCi)
ACOM 15.4 0.49 - 0.52 (n=10)
60 - 64% theor.
12 A/8h 50.9 - 56.8
Hammersmith 12.5 0.26 0.02 (n = 47) 10 A/2h 5.48
Wisconsin 11.0 0.23 18 A/4h 12.0
Jlich 16.0 0.16 10 A/8h 12.7
100.0
15 - 25
WUSTL 12.5 0.26 0.02 ~30
Essen 14.0 15 A/2h
~110.0
IBA 13.0 0.5 (93% theor.) 25 A/8h
NIH 12.5 0.018 0.005 (n = 4)
Tbingen 15.0 0.15 0.02 (n = 24)MSKCC 14.7 0.54 25 A/68h
Buffalo 14.1 0.53 0.64
(90% theor.)
24 A/8h
ACOM, IBA 18 MeV IBA cyclotron using COSTIS; Buffalo 30 MeV IBA cyclotron; NIH,
Tbingen GE PETtrace; MSKCC EBCO TR19; WUSTL CS15; Wisconsin CTI 11 MeV;
Essen CS28; Hammersmith Scanditronix MC40
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Target Substrates and Yields
Center Target(mg)
Substrate Enrichment Al2O3 w/w(%)
99.50 5
6
6.7
5
6
5
5.2
99.3
99.86
99.8
99.8
99.7
96.0
99.5
99.8
99.86
IsolationYield
90%
90%
70 5%
31%
80%
65%
95%
89 5%
TeO2
TeO2
TeO2
Cu2Te
TeO2
TeO2
Al2Te3
TeO2
TeO2
SpecificActivity
(Ci/mol)
ACOM 260
Hammersmith 1100 0.746
Wisconsin 200
Jlich 200
IBA
Tbingen 600
MSKCC 200 >30
WUSTL
Essen
Buffalo 600
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Clinical Applications
Na124I has been used for the diagnosis of thyroid
disease and for evaluating the spread of
metastatic thyroid carcinoma. (Eschmann et al., Eur JNucl Med Mol Imaging. 2002;29:760-67; Freudenberg et al., EurRadiology 2003;13:L19-L23)
One study reported the distribution of124
I in 64patients with a variety of thyroid conditions (Frey P,et l., J Clin Endocrin Metab. 1986;63:918-27)
A number of small molecules have been labeledwith 124I as analogs of131I compounds; e.g.,131/124I-mIBG. (Ott RJ, et al.,Br J Radiol. 1992;65:787-91)
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Clinical Applications
124I-FIAU is a specific marker substrate for gene
expression of HSV-1-tk. Used to identify the
location, magnitude, and extent of vector-mediated HSV-1-tk gene expression in a phase
I/II clinical trial of gene therapy for recurrent
glioblastoma in five patients. (Jacobs A, et al., LancetOncology. 2001;358:729-29)
124I-IUdR has been used to measure the
proliferative activity of tumors in 20 patients withbrain tumors, including meningiomas and
gliomas. (Blasberg RG, et al. Cancer Research. 2000;60:624-35)
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[124I]FIAU signal in established infections as imaged by PET/CT: Fused
PET and CT images, taken at 2 hours after radiotracer administration.
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124I-Dosimetry in Metastases
PK, 53 yo white male with numerous
pulmonary nodules discovered on routine
CXR, while being W/U for prostate Ca 4/28/00 Papillary thyroid Ca, moderately
differentiated, locally invasive, 2.0 cm indiameter, with 13/23 lymph nodes
Refered for Dosimetry 7/2000
Memorial Sloan-Kettering Cancer Center
124I Th id I i
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124I Thyroid Imaging
4/25/2000
CXR PA . LT.
Memorial Sloan-Kettering Cancer Center
124I I di i Th id C
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124I-Iodine in Thyroid Cancer
277269
229 cGy/mCi203 cGy/mCi
125 cGy/mCi
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Clinical Applications
Differentiation and Oncofetal Antigens
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G250 C b i h d IX h i
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G250- Carbonic anhydrase IX, a chronic
hypoxia response protein
PET provides excellent imaging with 124I-cG250 in clear cell cancer
Determination of carbonic anhydrase IX expressing phenotype,
identifies clear cell and determines surgical approach
Divgi et al: Lancet Oncol. 2007 Apr;8(4):304-10.
Memorial Sloan-Kettering Cancer Center
124I G250 (5 Ci 10 )
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124I-cG250 (5 mCi, 10 mg)
6D
Non Contrast (PET/ CT
Fusion
Contrast CT
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A33 ti ti ht j ti t i
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A33 antigen: a tight junction protein
Not constitutively
internalized Accumulation in
junctional complex
components Possibly suitable for
multistep targeting
methodsA33-occludin
Courtesy I Mellman, PhD
Memorial Sloan-Kettering Cancer Center
015 LD
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015:LD
70 YO Female
Presented with anemia. Splenic flexure lesions,hepatic metastasis.
2/6/07 2 foci Adenocarcinoma with mucinousfeature
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I-A33 in Colorectal Ca: uptake in occult
aorto-caval node
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CT
FDGI-124 A33
Fused A33-CT
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124I A33 in Primary Colorectal Cancer
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124I-A33 in Primary Colorectal Cancer
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010:RK
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010:RK
65 yo presented with rectal cancer stage IV to
the liver at presentation 9/5/02
Initial surgery 5/29/03 rectum and liver Recurrent liver metastasis
11/22/2005 Liver Metastatic adenocarcinoma
consistent with colorectal 4.1 cm. and
concurrent : Metastatic disease to lymph node
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010:RK
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010:RK
FDG FUSIONI-124 A33 7 D
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Correlation of antigen sites with antibody
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Correlation of antigen sites with antibody
uptake
0 2 4 6
0.000
0.002
0.004
0.006
0.008
0.010
0.012
0.014
0.016
0.018
Ileum
Mid Colon
LN Colon
Tumor
Correlation Between124
I-A33 In VivoUptake
and In VitroDetermination of A33 sites
Data: Data33_B
Model: linear
C hi^2 = 2.7 48 1E -6
R^2 = 0.88546
a 0.00244 0.00088
b 0.00202 0.00027
124I-A33(%I
D/g)
Sites (pmoles/mg)
Memorial Sloan-Kettering Cancer Center
Images of 124I-A33 (IVIG) in Patient No 13
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Images of I A33 (IVIG) in Patient No.13
ARG(72h expo)
H&E
Section T1S2-10, 6x12mm
Tumor tissue-1 Tumor tissue-2 Tumor tissue-3(Aorta lymph node) (Anterior aortic node) (Vena lymph node)
Section T2S10, 8x11mm
Section T3S8, 7x18mm
Section T1S2-10, 6x12mm Section T2S10, 8x11mm Section T3S8, 7x18mm
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MSKCC Novel Antibodies
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A33: Colorectal Cancer
G250: Renal Cancer
F-19: Colorectal; Breast; Pancreatic
3F8: Neuroblastoma; SCLC; Glioma;Melanoma; Sarcoma
M195: AML, PML, CML
MSKCC Novel Antibodies
Memorial Sloan-Kettering Cancer Center
3F8*
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3F8
Anti-GD2
Neuroblastoma
SCLC
Brain tumors
Osteosarcoma
Drs. NKV Cheung, B. Kushner, K. Kramer, Shakeel Modak
Memorial Sloan-Kettering Cancer Center
CNS Neuroblastoma Dosimetry and
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y
Treatment with radiolabeled 3F8 antibody
Ludwig Center for CancerImmunotherapy
Pediatric PO1 Cheung and Kramer
Memorial Sloan-Kettering Cancer Center
Sagittal section from serial 124I-3F8 PET
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images of pediatric patient with neuroblastoma
Quantitative PET images used to estimate the radiation dose
from 50 mCi of131I-3F8.
CSF in 4th ventricle = 2,176 cGy thoracic CSF = 1,004 cGy
4 hours 24 hours 48 hours
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Patient #1: Patient #2:
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PFS at 5 yrs PFS at 4 yrs
Salvage Regimen Salvage Regimen
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Long standing CR after clearance of CSF and
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MR
1 monthpost 30mCi 131I-8H9
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New Directions Small Molecules
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Radiolabeled Small Molecule Inhibitor of
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N
N
N
N
O
O
F
NH
H2N
124I
HSP 90 - [124
I]PU-DZ8
2-fluoro-9-[3-2-propylamino)propyl]-8-
(4-iodo-1,3-benzodioxol-5-yl)methyl
adenine
PI: Gabriela Chiosis, PhD with Kishore Pillarsetty, Ph.D.
Memorial Sloan-Kettering Cancer Center
Ansamycins bind to the ADP\ATP switch site
i H 90
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in Hsp90
O
NH
Me OMeMe
OMe
O
Me
MeO
OHO
O
NH2
H3CO
Geldanamycin (GM)
NH
Me OMeMe
OMe
O
Me
O
MeO
OHO
O
NH2
HN
17-AAG
Memorial Sloan-Kettering Cancer Center
124I-PU-DZ8 in Breast Cancer
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3 hours 17 hours
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Acknowledgements
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g
Howard Sheh and the Cyclotron Team - MSKCC Drs. Steven Larson and Jorge Carrasquillo MSKCC
Dr. Gabriela Chiosis - SKI
Drs. Peter Smith-Jones and Kishore Pillarsetty - MSKCC Dr. Syed Qaim Forschungszentrum Jlich
Dr. Paola Panichelli ACOM Spa, Italy
Dr. Jerry Nickels University of Wisconsin
Dr. Mathias Glaser Hammersmith Imanet Ltd
Drs. Bob Ylimaki, Bernard Lambert, Jean-Michel Geets IBA
Dr. Erol Bars State University of New York, Buffalo
Lucie Tang Washington University
Drs. Uno Zetterbery, Erik Stromqvist, Armando Sera - GEMS