Multimodality small animal imaging: registration of functional EPR images with MRI anatomy

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Multimodality small animal imaging registration
of functional EPR images with MRI anatomy
Chad R. Haney, Adrian Parasca, Charles A.
Pelizzari, Greg S. Karczmar, Howard J.
Halpern Department of Radiation and Cellular
Oncology and Department of Radiology The
University of Chicago
Supported by grants DAMD17-02-1-0034 (DoD) and
P41EB002034(NIBIB)
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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, LAquila)
• pulsed (NCI, Chicago)
• OMRI (NCI, Aberdeen)
• dynamic nuclear polarization using EPR spin
  probes

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EPR is analogous to NMR
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
• p/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
proton Larmor frequency 4258 Hz/gauss 42.6 MHz
at 1 Tesla electron Larmor frequency 2.80
MHz/gauss 28 GHz at 1 Tesla
250 MHz 6 T MRI, 90 G EPR S/N w0.8
ratio meas/calc
Nw 1.2 IN LOSSY, CONDUCTIVE TISSUE
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Continuous wave spectral spatial imaging each
voxel yields a spectrum whose linewidth increases
linearly with local oxygen concentration fixed
stepped field gradients, swept magnetic 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
(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)
Intermediate 15 cm diam.
Large 30 cm diam.
Small 8 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
estimate based on fiducials
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Application 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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PC3 tumor treated with Ad.EGR-TNFa virus 10 Gy
Pre treatment mean pO2 in tumor 27.3, std 36.1,
SEM 1.122 tumor volume from MRI 0.524 mL
4 days post treatment mean pO2 in tumor 31.7
torr, std 17.1, SEM 0.472. tumor volume from
MRI 0.417 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 Halpern Martyna
Elas Colin Mailer Chad Haney Charles
Pelizzari Kazuhiro Ichikawa Gene Barth Ben
Williams Kang-Hyun Ahn Adrian Parasca VS
Subramanian
Chicago MRI Lab Greg Karczmar Jonathan
River Xiaobing Fan Marta Zamora
Denver EPR Lab Gareth Eaton Sandra
Eaton Richard Quine George Rinard
EGRF-TNF? radiation therapy Ralph
Weichselbaum Helena Mauceri Michael Beckett