Methods for High Resolution PET - Stanford University · Methods for High Resolution PET Neal...
Transcript of Methods for High Resolution PET - Stanford University · Methods for High Resolution PET Neal...
Methods for High Resolution PET
Neal ClinthorneRadiology / Nuclear Medicine
University of MichiganAnn Arbor
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Ring of PhotonDetectors
• Inject positron emitting radiotracer intopatient
• Tracer localizes according to its metabolicproperties
• Radionuclide decays, emitting β+.
• β+ annihilates with e– from tissue, formingback-to-back 511 keV photon pair
• Photon pairs detected via timecoincidence (<5ns) indicate line alongwhich positron annihilated
• By collecting many (>106) events, activitydistribution can be reconstructed
PET Basics
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PET Brain Images
PET tracers use “elements of life” (N, C, O, F) and can be designed to follow specific metabolic pathways
Temporal change in distribution is used to estimate parameters in kinetic models
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• Many tumors have higher than normal uptake.
• Image the whole body to find metastases.
MetastasesShown withRed Arrows
Brain Heart
Bladder
Normal Uptake inOther OrgansShown in Blue
FDG PET for Cancer / Oncology
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PET
CTFused PET + CT
*Data courtesy of David Townsend, U. Tenn.
PET / CT for Anatomic Correlation
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479
50 Gy
417
[18F]FLT
[18F]FAZA
Tumor control
Pre-RT 1 week 2 weeks
[18F]FLT
Pre-RT 1 week 2 weeks
35 Gy
[18F]FAZA
No tumor control Small AnimalPET35 Gy total (no tumor control)Mean tumor volume increase (+60%)Decrease in [18F]FLT uptakeIncrease in [18F]FAZA uptake
50 Gy total (tumor control)Mean tumor volume decrease (-20%)Decrease in [18F]FLT uptakeDecrease in [18F]FAZA uptake
Inhomogeneity of intratumoral uptake
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• Patient port ~60 cm diameter.• 15 cm axial coverage (patient bed moved for larger span).• 4–5 mm fwhm intrinsic spatial resolution.• ~2% solid angle coverage.• ~ $2 million dollars or more with CT
Images courtesy of GE Medical Systems and Siemens / CTI PET Systems
PET Cameras
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+ “Parallel” Operation– Expensive– Low spatial resolution
Early PET DetectorsThe Cyclotron Corporation PCT 4600
BGO
¾” PMT
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05001000150020002500300035004000
Counts
X-Ratio
Y-Ratio
Uniformly illuminate block.For each event, compute
X-Ratio and Y-Ratio,then plot 2-D position.
Individual crystals show upas dark regions.
Profile shows overlap (i.e.identification not perfect).
ProfilethroughRow 2
Early BGO Block Detectors
Many individual crystals multiplexed among a few (4) photomultipliersLSO or LYSO scintillators generally used now
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Position SensitivePhotomultiplier Tube
Fiber OpticBundle
LSO ScintillatorCrystals
(2x2x10 mm)
*Image courtesy of Simon Cherry, UC Davis
17 cmDetector Ring
Diameter
Small Animal PET Cameras
Miniature Version of “Standard” PET CameraMany crystals coupled to PSPMT
Distortions
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Photon Counting Noise
1M Events 10 M Events
Higher efficiency is better!
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2-D (w/ Septa)+ Septa Reduce Scatter
+ Simple image reconstruction– Smaller Solid Angle for Trues
3-D (w/o Septa)– No Scatter Suppression
– More difficult reconstruction+ Larger Solid Angle for Trues
Inter-PlaneSepta
NoSepta
Volume (“3D”) Acquisition Increases Efficiency
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Event detection probability isproduct of individual photondetection probabilities.
Attenuation depends on entirepath length through object
d1
d2
P1 = e!µ"d1
P2 = e!µ"d2
P = e!µ"(d1+d2)
Annihilation Photon Attenuation
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Distortion Caused by Attenuation
EmissionDistribution
Linear AttenuationDistribution
Measured Sinogram
Reconstruction
Distorted Image
True Emission Sinogram and Image
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• Simultaneous decays can causeerroneous coincident events(“randoms”)
• For 3-D PET, randoms can be ashigh as 50% of image.
• Random Rate isRate1 x Rate2 x 2 Δt
• Randoms reduced by narrowcoincidence window Δt.
• Time of flight across tomograph ringrequires Δt > 4 ns.
Random Rate ∝ (Activity Density)2
Random Coincidences
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• Compton scatter in patientproduces erroneous coincidenceevents
• ~15% of events are scattered in2-D PET(i.e. if tungsten septa used)
• ~50% of events are scatteredin 3-D Whole Body PET
• ~30% of events are scatteredin 3-D Brain PET
• Correspondingly small in smallanimal PET
Compton Scatter
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• Penetration of 511 keVphotons into crystal ringblurs measured position
• Blurring worsens asattenuation lengthincreases
• Can be eliminated bymeasuring depth ofinteraction
RadialProjection
TangentialProjection
Depth-of-Interaction Uncertainty
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1 cm
Resolution significantly worse at edge of FOVNear Tomograph Center 14 cm from Tomograph Center
Point Source Images in 60 cm Ring Diameter Camera
Resolution Across FOV
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Positron RangeDistribution
F-18 C-11 N-13 O-15Max energy (MeV) 0.64 0.97 1.19 1.72Mean energy (MeV) 0.25 0.39 0.49 0.74FWHM (mm) 0.10 0.19 0.28 0.50FWTM (mm) 1.03 1.86 2.53 4.14
[by Levin and Hoffman]
Positron Annihilation Point Distribution
Positron Range Before Annihilation
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Combined Resolution Effects
• Detector resolution (3D)• Acolinearity (0.5° FWHM – 2.2mm / 1000mm)• Positron range (<1mm for F-18, ~5mm for Rb-82)• Subject motion during scan• Additional blurring in reconstruction
22222
det recmotacoltotrrrrrr ++++= !
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Goals: Submillimeter PET forMice and Rats
1-2 mm PET for humans inspecific regions of interest
Detour
What makes one imaging systembetter than another?
(Especially in light of “resolution recovery”)
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Example – Coded AperturesWhich aperture is best?
• 3 different apertures – same overall counting efficiency– 1 Pinhole, 10 pixel FWHM resolution– 10 Pinholes, √10 pixel FWHM– 100 Pinholes, 1 pixel FWHM
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Expected MeasurementsProjection: 1 pinhole
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Expected MeasurementsProjection: 10 pinholes
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Expected MeasurementsProjection: 100 pinholes
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Reconstructions
OK, which is best??
1 10
100 Original
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It Depends!
• Images were reconstructed at different resolutions
• Need to decide on desired image resolution toaccomplish task as well as tolerable noise
• Need to compare noise at desired resolution (or vice-versa)
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Noise vs. Resolution Results
0 2 4 6 8 10 12 14 16 18 200
500
1000
1500
2000
2500
3000
3500
4000
Operating Resolution (mm FWHM)
Limiting Standard Deviation
100 Pinholes
10 Pinholes
1 Pinhole
0.5 1 1.5 2 2.5 3 3.5 4 4.50
200
400
600
800
1000
Operating Resolution (mm FWHM)
Limiting Standard Deviation
6 8 10 12 14 16 18 200
5
10
15
20
Operating Resolution (mm FWHM)
Limiting Standard Deviation
Single pinholeperforms better ifPSF width > itsnatural resolutionis desired
10 pinholes performbetter if PSF widith >their naturalresolution is desired
Each system has a different noise-resolution tradeoff!
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Desirable PET Detector Characteristics
• Circumferential resolution 1mm or less
• Sufficient depth-of-interaction (DOI) resolution
• Timing resolution < 5ns FWHM (even less is better)
• Low deadtime (system singles countrates >107)
• Good energy resolution (<15% FWHM)
• High detection efficiency
• Ability to resolve multiple hits due to Compton scatter
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Interactions at 511 keV
• The most desirable coincidence interactions are photoelectric-photoelectric
• Photo-Photo coincidence efficiency less than 17%, 10%, and 4% forBGO, LSO, and NaI, respectively
0.20<<1%>99%<1%Si
0.3418%77%5%NaI
0.8833%61%6%LSO
0.9741%53%6%BGO
Attenuation/cmPhotoelectricCompton CoherentMaterial
Compton scatter is most prevalent interaction of 511 keV photons in PET Detectors!
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Centroid of Energy Distribution
Crystal array
PSPMT16 mm
511 keVphotons
16 mm
BGO LSO NaI
2mm x 2mm x 20mm thick crystals
EGS4 Monte Carlo Simulations
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Does It Affect Performance?
DOI uncertainty included in both images
True first interaction position Centroid of scattered E distribution
- EGS4 Monte Carlo simulations- BGO PET ( 17.6 cm I.D. 16 cm length segmented with 3 mm x 3mm x 20 mm crystals)- Point sources at 0, 3, 6, 9, 12, 15, and 18 mm from center of FOV- Filtered back projection reconstruction
High Resolution Small Animal PETArtist’s Conception
2nd detector(non position sensitive)
1st detector(high resolution)
First Concept
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“Compton” PET
BGOdetector
Sidetector
Si-Si
BGO-BGO
Si-BGO
Very high resolution achievable in small field-of-view
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High Resolution Imaging Probes
• Do not need complete inner detector – partial high resolutiondetector sufficient in many cases
• Can potentially be used in conjunction with existing PETinstruments
• Probes for head & neck cancer and prostate imaging currentlyunder development
511 keV photon Scattered photon
LOR (position uncertainty)
BGO - BGO
FOV
Si - BGO
PET Probe
detector
Position
tracker
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Effects of Detector Resolution
• Already large uncertainty along path of annihilation photons(undone by tomographic reconstruction)
• Resolution determined primarily by uncertainty transverse to thephoton paths
θ1 θ2
D1 D2
Detectors
( ) ( ) ( )( )2
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22
22
222
11
22
11
22cossincossin135.2
CDCDDR !"!"#!"!"# +++$%
α (1-α)
RDAnnihilationPhoton Path
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Spatial Resolution• Detectors of 1mm, 2mm, and 3mm FWHM in coincidence with
6mm FWHM detector
0 5 10 15 20 25 30 35 400
1
2
3
4
5
6
Distance from probe face (cm)
Resolution (mm FWHM)
Probe resolution = 1mm FWHM
2 mm
3 mm
Spatial resolution improves close to detector with good resolution
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Can It Have Enough Efficiency?
0
5
10
15
20
25
0 10 20 30 40 50 60
BGO diameter (cm)
Ab
so
lute
eff
icie
ncy (
%) BGO-BGO
Si-BGO
Si-Si
0
2
4
6
8
10
0 0.8 1.6 2.4 3.2 4 4.8 5.6 6.4 7.2
Silicon thickness (cm)
Ab
so
lute
eff
icie
ncy (
%) Si-BGO
Si-Si
Further evaluate a system having the following characteristics
• Silicon 4cm ID, 7.2cm OD (16 layers of 0.3 mm × 0.3 mm × 1 mm elements)
• BGO detector 17.6 cm diameter, 16 cm length, and 2 cm thicknesssegmented into 3 mm × 3 mm × 20 mm crystals
Simulated System and Results
3 x 3 x 20 mm3 BGO Crystals
0.3 x 0.3 x 1 mm3 Silicon Pixels, 16 layers
16 cm
4 cm
4 cm
1.6 cm
2 cm
17.6 cm
Lower E Threshold: 350 keV
Interaction Selection Method:BGO crystal with Maximum E
Si-Si Sensitivity: 1.0 % *FWHM = 230 µm
Si-BGO Sensitivity : 9.0% *FWHM = 790 µm
BGO-BGO Sensitivity: 21.0 % *FWHM = 1.45 mm
Image reconstruction: FBP
* Does not include acolinearity and positron range
Overall Spatial Resolution
Spatial Resolution (mm FWHM) Event Geometric Geometric Overall + Acolinearity F-18 C-11 N-13 O-15 Si-Si 0.234 0.241 0.393 0.443 0.492 0.553 Si-BGO 0.788 0.816 1.062 1.261 1.419 1.742 BGO-BGO 1.452 1.458 1.977 2.270 2.490 3.069
Si-Si Si-BGO BGO-BGO
Simulated Multiple Disk Sources Object
Diameters of Disks : 1, 2, 4, 6, 8, and 10 mm
Center of disks : 1 cm from center of FOV
-2 -1 0 1 2
x (cm)
-2
-1
y (cm) 0
1
2
2D Images of Simulated Multiple Disk Sources
Si-Si (100k) Si-BGO (800k) BGO-BGO(1.9M)
- Filtered back projection (FBP)- BGO crystal with Maximum Energy was used- Images were reconstructed with different system efficiencies
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Combined Reconstruction Using ML
- Maximum likelihood Expectation Maximization (ML-EM)- Iteration number = 200
Si-Si (160k) + Si-BGO (1.4M) + BGO-BGO (3.1M)
4 cm x 4 cm
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Can a Small Amount of Hi Res Data Havean Effect on Performance?
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 10
10
20
30
40
50
60
norm(f-g)/norm(f)
sqrt(variance)
Desired resolution = 1mm FWHM Gaussian
Low Res data only
Low & Med Res
All data / Med & Hi Res data
0 0.2 0.4 0.6 0.8 10
0.05
0.1
0.15
0.2
0.25
norm(f - g) / norm(f)
sqrt(variance)
Low Res
Low + Med
Med + High
All
4mm FWHM Gaussian
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Experiments
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Silicon Pad Detectors for Compton Camera
• Double-metal Si paddetectors
• 1.4mm x 1.4mm pads, 16x 32 array
• 0.5mm and 1mmthicknesses
• Full depletion ~180V for1mm
• Readout via 4 x IdeasVATA GP-3 ASICs
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VATA Readout ASICs
GP-3: 2.5-3 µs shaping in slow channel200 ns peaking time in fast channel
Serial, sparse, sparse + adjacent channel readout
Energy Resolution
Tc-99m (140.5 keV)Am-241 (59.5 keV)
FWHM = 1.39 keV (0.99%)Pb Kα1 = 74.969 keV, Kα2 = 72.804 keV,Kβ1 = 84.936 keV, and Compton edge = 49.8 keV
FWHM = 1.49 keV (2.5 %)
Experimental Setup
Silicon detector
Source turntable
Lead shielding 1mm Tungsten Slit
Laser
Silicon detector
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Experimental System with BGO
BGO detectors flanksilicon for energy resolution
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Lines of Response for Point Source
Silicon detector 1LOR
Silicon detector 2
F-18 Source
Random Coincidences
Lots of randoms – coincidence window was ~2.5 µs
Point Source ComparisonMicroPET R4Compton PET
ML-EM Image reconstruction (no detectormodeling)Si-Si coincidence events only
0 1 2 3 4 5 cm
5
4
3
2
1
0
0 1 2 3 4 5 cm
5
4
3
2
1
0
Source
1.1~1.2 mm
0.4 mm
F-18
Glass wall0.2 mm
F-18 in glass capillary tubes
MAP Reconstruction
Intrinisic Resolution Measurment
Needle 25G (ID = 0.254 mm, OD = 0.5mm, SS_steel wall = 0.127 mm)
5
4
3
2
1
0
0 1 2 3 4 5 cm
0.254 mm
0.127 mm
Image Resolution= 700 µm FWHM
SS_steel wall
F-18
Resolution Uniformity
0 1 2 3 4 5 cm
5
4
3
2
1
0
Source pairs at 5, 10, 15, & 20mm off-axis
Sinogram
The sources in each pair are clearly separated at appropriate sinogram angles
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New Pad Detectors
1040 (26 x 40) 1mm x 1mm pads, 1mm thick Co-57 Spectrum
Should allow 0.5 – 0.6mm FWHM spatial resolution
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Challenges
• Number of electronics channels (1.25M for simulated system)
• Packaging
• Triggering threshold
• Time resolution
• Event classification
• Comparing performance with more conventional PET
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Packaging
Double-sided 14-layer hybrid (FR4) allows 4mm active detector in 5.6mm (~70%)Won’t work for 1mm x 1mm 1040 pad detectors!
Stacked hybrids, side viewNew stackable hybrid
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Packaging -- TAB Experiements
Al traces 8 µm thick x17 µm wide
40 µm dielectric inserts
Packing fraction >90%
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Triggering Threshold
• New hybrid routes analog anddigital signals to separatecables
• Trigger threshold can be set aslow as 3 keV
• 5.8 keV emission of Fe-55clearly seen (source <10 cps)
• But threshold spread too broadfor trimDAC alignment on VATAGP-3
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Timing• Desired time resolution <10ns
FWHM
• Marginal timing is evident
• Slower signal generation fromevents near backplane
• Large range of pulse-heightcoupled with leading-edge triggeris biggest issue
• Large time-walk is the resultBGO-Silicon timing spectrum for 511 keV source
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Simple Signal Generation Model
0 50 100 150 200 250 3000
0.5
1
1.5
2
2.5
x 10-9
Time (ns)
Signa;
200 V = Vdep
Threshold
0 50 100 150 200 250 3000
0.5
1
1.5
2
2.5
x 10-9
Threshold
500V = Vdep + 300V
Time (ns)
Signal
holes
electrons
p+ implant
n+ backplane + Alelectrode
n-bulk
1.4 mm
1 mm InteractionLocations
Simplified Pad Detector
• Depth dependence of signal evident
• Non-linear effect with depth
• Higher bias helps
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But…It gets worse!
• Pad size is nearly same asdetector thickness
• Weighting potential dependson x & y in addition to z
• Result is additional jitter due tounknown 3D interactionlocation
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T-CAD Simulation / Measurements
Energy deposited in Si detector vs. triggering time
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Solutions
• VATA GP-7 with 50 ns peaking time in fast channel• Low trigger threshold + secondary cut on energy
• Use 2 pad-to-pad 0.5mm thick detectors• Detector redesign – readout from both sides• Sum pad + 8 neighbors for more uniform triggering• Complete redesign of readout ASICs
Immediate
Longer Term
Reduction of scatter,
random,
and misclassified events
Event Classification -- Compton KinematicsCompton Kinematics
Angular Uncertainty Factors
Si
BGO
ESi
Doppler Broadening Detector Element Size Energy Resolution Photon Acolinearity
Si pad:
0.3 mm x .3 mm x 1 mm
BGO crystal:
3 mm x 3 mm x 20 mm
BGO
Si
EBGO
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Reducing Positron Range
Distance (mm)
0 Tesla
-4 -2 0 2
-4
-3
-2
-1
0
1
2
3
Distance (mm)
9 Tesla XZ-Plane
-4 -2 0 2
-4
-3
-2
-1
0
1
2
3
9 Tesla XY-Plane
-4 -2 0 2
-4
-3
-2
-1
0
1
2
3
• Embed PET FOV in strong magnetic field (Raylman, Hammer, etc.)• Positrons spiral and range is reduced transverse to B-field vector• Not very effective for F-18 positrons• Potentially useful for emitters with higher endpoint energies (I-124, Tc-94m,
etc.) increasingly being used in small animal imaging
Simulated PSF for I-124 at 0T and 9T
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MRI-Safe Silicon PET Imager
System rebuilt using no ferromagnetic materials…
…and inserted into boreof 7T MRI magnet at OSU
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Ga-68 Resolution Improvement at 7T
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Next Steps for Compton PET?
• Complete BGO / silicon PET test bench
• Test 1mm detectors with VATA GP-7s
• Attempt comparison in terms of noise-resolutiontradeoff with more conventional PET techniques
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Prostate Cancer
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C-11 Choline PETMay be correlated with prostate cancer aggressiveness
PET/CT Fusion Image PET / Histoloogy Fusion
Promising, however, difficult to detect small tumors even with high uptake
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Internal High Resolution Probe
Geant 4 Monte Carlo simulation of internal prostate probe
External PET ringInternal probe
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Noise Advantage vs. Resolution
1 2 3 4 5 6 7 8 9 100
2
4
6
8
10
12
14
Reconstructed Resolution (mm FWHM)
Hi-Res Noise Advantage
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Probe Construction and Performance
Courtesy of Stan Majewski and James Proffitt -- JLab
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Acknowledgments
UMichLes RogersScott WildermanLi HanSam HuhSang-June ParkBob KoeppeDave RaffelMorand Piert
OSUHarris KaganKlaus HonscheidDon BurdetteEric CochranShane Smith
CERNPeter WeilhammerEnrico ChesiAlan Rudge
IFIC/CSIC (Valencia)Carlos LacastaJuan FusterGabriela Llosa
IJS (Ljubljana)Marko MikuzGregor KrambergerAndrej StudenDejan Zontar
Gamma-Medica IdeasEinar NygardDirk MeierBjørn SundahlSindre Mikkelsenetc.
LEPSI (Strasbourg)Wojtek Dulinski
LBNLBill Moses
JLABStan MajewskiJames Proffitt