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Multimodality small animal imaging: registration of functional EPR images with
MRI anatomy
Supported by grants DAMD17-02-1-0034 (DoD) and P41EB002034(NIBIB)
Chad R. Haney, Adrian Parasca, Charles A. Pelizzari, Greg S. Karczmar*, Howard J. Halpern
Department of Radiation and Cellular Oncology and *Department of RadiologyThe University of Chicago
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In Vivo EPR Imaging – Topic of NIBIB Research Resource
(PI: Howard Halpern, MD, PhD)
• Long term goal - develop EPR imaging techniques which provide functional information that can be of use in designing, delivering, and assessing cancer therapy.
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Biological imaging to enhance targeting of radiation therapy: oxygen imaging
• Intensity modulated radiation therapy allows sophisticated control over spatial distribution of radiation dose
• Areas of hypoxia could be given extra dose if we could identify them
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Why EPR Imaging?• Spectroscopic Imaging: Specific quantitative
sensitivity to Oxygen, Temperature, Viscosity, pH, Thiol
• No water background obscures spectrum of interest (vs MRI)
• ~600 times stronger coupling to magnetic field, environment (vs MRI)
• Deep sensitivity at lower frequency (vs optical)• Noninvasive (vs probes)
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EPR in vivo oximetry techniques• Localized spectroscopy with implanted
particulate probes (Dartmouth)
• Spectroscopic imaging with stepped fixed gradients, water soluble probes– CW (Chicago, OSU, Aberdeen, L’Aquila)– pulsed (NCI, Chicago)
• OMRI (NCI, Aberdeen)– dynamic nuclear polarization using EPR spin
probes
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EPR is analogous to NMR:
Fix RF frequency, sweep field or fix field, sweep frequency:
figure 2.7 field modulation and phase sensitive detection
Zeeman splitting of electron spin energy states in magnetic field
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EPRI is not identical to MRI:
• Relaxation times ~10-6 as long
• pulsed gradient techniques not applicable
• FID correspondingly short → demanding of pulsed measurement techniques π/2 pulse ~50 ns long, FID lasts few μs
• have to introduce spin probe – no endogenous signal
• frequency ~660 times higher for given field (or, field 660 times lower for given frequency)
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RF penetration favors lower frequency
250 MHz ~6 T MRI,90 G EPR
S/N
N~ 1.2
IN LOSSY,CONDUCTIVETISSUE
proton Larmor frequency = 4258 Hz/gauss42.6 MHz at 1 Tesla
electron Larmor frequency = 2.80 MHz/gauss28 GHz at 1 Tesla
ratio meas/calc
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Continuous wavespectral spatial imaging:
each voxel yields a spectrum whose linewidth increases linearly with local oxygen concentration
fixed stepped field gradients, sweptmagnetic field
EPR line broadening for current narrow line spin probes: approximately 0.5 mG/torr O2
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Line width pO2 calibration
Oxygen dependence of lorentzian line width obtained in a series of homogenous solutions of OX31spin probe
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Spectral-spatial projection(a) With no gradient, a field sweep integrates over all spatial locations. This is a pure spectral projection.
(b) A gradient along the x direction couples the spatial and spectral coordinates (the spectrum is shifted linearly with position).
(c) A field sweep now corresponds to a projection along a direction rotated in the spectral-spatial plane. Larger gradients correspond to larger rotation angles. Pure spatial projection would require infinite gradient.
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250 MHz Spectrometer Magnetsvarying diameter homogeneous field regions (90 G)
Small8 cmdiam.
Intermediate 15 cm diam.
Large30 cm diam.
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Mouse Image using OX063 spin probe
PC3 human prostate cancer xenograft on nude mouse hind limb
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Registration of EPR with MRI for anatomically aided analysis
Registration based on
- Fiducials
- Surfaces
- Intensity distribution
Note high intensity due to poor clearance of spin probe from tumor, and low oxygen tension in same region
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Early fiducial markers filled with dilute spin probe solution.Problem: need to remove during 4D image to avoid artifacts
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Immobilization cast, fiducial markers for serial and intermodality registration
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Alignment of MRI and EPRI (red)
fiducial surfaces
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Manual refinement of initial registration estimatebased on fiducials
19Application: radiation inducible antivascular gene therapy
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PC3 tumor treated with Ad.CMV.null virus (control)
Pre treatment: mean pO2 in tumor 44.6 torr, std 35.1, SEM 1.62.
tumor volume from MRI: 0.160 mL
4 days post treatment (right): mean pO2 in tumor 28.7 torr, std 29.1, SEM 1.065.
tumor volume from MRI: 0.422 mL
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4 days post treatment: mean pO2 in tumor 31.7 torr, std 17.1, SEM 0.472.
tumor volume from MRI: 0.417 mL
PC3 tumor treated with Ad.EGR-TNFα virus + 10 Gy
Pre treatment: mean pO2 in tumor 27.3, std 36.1, SEM 1.122 tumor volume from MRI: 0.524 mL
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Conclusions• 4D EPR Images can be obtained with ~1 mm spatial
resolution and ~1.5mG (~3 torr pO2) spectral resolution
• Preliminary images of increased and decreased regional oxygenation levels following radiation + adeno-EGR-TNF anti-vascular therapy have been seen.
• These images may have potential for biologically-based planning and assessment of radiation therapy
• Registration of these functional images with anatomic images such as MRI is key to accurate interpretation and to eventual clinical applications
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Chicago EPRI Lab:
Howard HalpernMartyna ElasColin MailerChad HaneyCharles PelizzariKazuhiro IchikawaGene BarthBen WilliamsKang-Hyun AhnAdrian ParascaVS Subramanian
Chicago MRI Lab:
Greg KarczmarJonathan RiverXiaobing FanMarta Zamora
EGRF-TNF radiation therapy:
Ralph WeichselbaumHelena MauceriMichael Beckett
Denver EPR Lab: Gareth Eaton Sandra Eaton Richard Quine George Rinard