DEVELOPMENT OFA MICRO-COMPUTED TOMOGRAPHY–BASED IMAGE-GUIDED
CONFORMAL RADIOTHERAPY SYSTEM FOR SMALL ANIMALS
HU ZHOU, PH.D.,* MANUEL RODRIGUEZ, PH.D.,* FRED VAN DEN HAAK, A.A.,* GEOFFREY NELSON, B.S.,*
RAHIL JOGANI, M.S.,* JIALI XU, B.S.,yXINZHI ZHU, PH.D.,yYONGJIANG XIAN, B.S.,x
PHUOC T. TRAN, M.D., PH.D.,* DEAN W. FELSHER, M.D., PH.D.,zPAUL J. KEALL, PH.D.,*
AND EDWARD E. GRAVES, PH.D.*
Departments of *Radiation Oncology andzMedicine, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA;
yPheniCo, Inc., Fremont, CA; andxBright Star Machine, Fremont, CA
Purpose: To report on the physical aspects of a system in which radiotherapy functionality was added to a micro-
application of this technology for irradiating tumors growing within the lungs of mice.
subject translation stage and a variable aperture collimator. Quality assurance protocols for these devices, includ-
ing measurement of translation stage positioning accuracy, collimator aperture accuracy, and collimator
alignment with the X-ray beam, were devised. Use of this system for image-guided radiotherapy was assessed
by irradiation of a solid water phantom as well as of two mice bearing spontaneous MYC-induced lung tumors.
Radiation damage was assessed ex vivo by immunohistochemical detection of gH2AX foci.
Results: The positioning error of the translation stage was found to be <0.05 mm, whereas after alignment of the
collimator with the X-ray axis through adjustment of its displacement and rotation, the collimator aperture error
was <0.1 mm measured at isocenter. Computed tomography image-guided treatment of a solid water phantom
demonstrated target localization accuracy to within 0.1 mm. Gamma-H2AX foci were detected within irradiated
lung tumors in mice, with contralateral lung tissue displaying background staining.
Conclusions: Addition of radiotherapy functionality to a microCT scanner is an effective means of introducing
image-guided radiation treatments into the preclinical setting. This approach has been shown to facilitate
small-animal conformal radiotherapy while leveraging existing technology.
? 2010 Elsevier Inc.
Mouse models, Radiotherapy, Image guidance, MicroCT.
Clinical radiotherapy (RT) technology has advanced tremen-
dously since the introduction of the linear accelerator.
Advances such as rotating radiation sources, conformal
collimators, and image guidance and verification are now
ogous systems for the treatment of laboratory animals lack
many of these now-standard clinical features. Delivery of
radiation treatments to experimental animal models of dis-
applying a single radiation field. Sparing of normal tissues is
accomplished with radiation shields, commonly sheets of
lead or custom-manufactured jigs, bearing openings through
which the desired radiation target within the animal is
exposed (1–5). The spatial and dosimetric accuracies achiev-
able with these systems are clearly limited and lag signifi-
cantly behind their clinical counterparts. Except in the case
of superficial targets, precise localization of the radiation
target as well as sparing of normal tissues are usually not
possible with this simple approach.
Recently severalthree-dimensional (3D) conformal
the gap between preclinical and clinical RT technology.
Stojadinovic et al. (6) have constructed a RT system around
a clinical192Ir high-dose-rate brachytherapy source, deliver-
ing beams restricted by fixed collimators from multiple
angles to irradiate animals similar to what is achieved with
conformal RT. Other groups have built systems from scratch,
using X-ray tubes for application of diagnostic and therapeu-
tic radiation. Wong et al. (7) have built a stand-alone system
encompassing a 225-kVp industrial X-ray tube and individu-
ally rotating X-ray, detector, and subject enclosures that can
Reprint requests to: Edward E. Graves, Ph.D., Department of
Radiation Oncology, Stanford University, 875 Blake Wilbur Drive,
Room G-202, Stanford, CA 94305-5847. Tel: (650) 723-5591; Fax:
(650) 498-4015; E-mail: email@example.com
Conflict of interest: none.
Received April 29, 2009, and in revised form Sept 23, 2009.
Accepted for publication Nov 11, 2009.
Int. J. Radiation Oncology Biol. Phys., Vol. -, No. -, pp. 1–9, 2010
Copyright ? 2010 Elsevier Inc.
Printed in the USA. All rights reserved
0360-3016/10/$–see front matter
ARTICLE IN PRESS
be used to deliver noncoplanar radiation beams to animals.
Our group has addressed this technical challenge by
adding RT functionality to a micro-computed tomography
(microCT) scanner, to leverage existing technology to
produce a preclinical system for image-guided RT (8). In
this article we report on the physical aspects of this system
as well as evaluation of the accuracy of this instrument. In
addition, we demonstrate the application of this technology
for irradiating tumors growing within the lungs of mice.
METHODS AND MATERIALS
GE RS120 MicroCT. An eXplore RS120 microCT scanner
(GE Medical Systems, London, ON, Canada) served as the platform
for the development of a radiation delivery system. This system can
operate at tube currents of 70–120 kVp and has been previously
demonstrated to be capable of dose rates of up to 2 Gy per minute
beam time at depths relevant to small-animal treatments (9).
Figure 1a shows the scanner gantry. The CT isocenter is located
at the center of a plexiglass tube (the CT bore). The X-ray tube
and detector are fixed on the gantry on opposite sides of the bore.
The RS120 microCT system has a stage housing, inside which an
animal couch stage moves along the CT axial direction (the z-axis
in the CT coordinate system) to carry the animal into and out of
the bore for imaging. A nose cone on this bed allows continuous
delivery of isoflurane anesthesia to a subject while it is on the
To serve as a RT device, this system requires several additional
functionalities that are not necessary for microCT imaging. These
added capabilities include the ability to restrict the width of the
beam to target a specific volume of tissue and the ability to shift
an arbitrary 3D point within a subject to the system isocenter for
treatment. To meet these needs, we integrated a two-dimensional
(2D) translation stage with the existing z-stage inside the shield to
accomplish 3Dmovement andmounted avariable-aperture collima-
Animal couch. The microCT includes an animal couch clamped
on a motor-driven stage that moves the animal in and out of the
scanner along the z-direction, installed inside the X-ray shielded
stage housing. We added a 2D stage that moves in the two other
directions (x or left/right, and y or up/down) inside the housing,
as shown in Fig. 1b. To move the stage within the 10.2-cm bore,
Fig. 1. The GE RS120 microCT and the additional components necessary for small-animal radiotherapy. (a) View of the
scanner gantry after removing the X-ray shield and animal stage housing. The large silver disk is the rotating gantry, with
theX-raytube,H-shaped collimatormountingbar,subjectbore,anddetector arrangedbottom totop, respectively.(b) Cus-
tomtwo-dimensional translation stage for subject positioning, mounted on top of the existing z-axis translation stage of the
scanner. (c) Schematic representation of a single stage of the variable-aperture collimator, formed by six sliding blocks
mounted on linear tracks. (d) Final two-stage collimator apparatus after installation on the H mounting bar of the scanner
2I. J. Radiation Oncology d Biology d Physics Volume -, Number -, 2010
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the maximum travel distance in x and y were designed to be 50.8
mm and 20 mm, respectively. The 2D stage is installed on the exist-
either manually through a control box or through software controls
installed on the microCT control PC.
Collimator. Avariable-aperturecollimator permanentlyinstalled
on the scanner gantry between the X-ray source and the subject bore
allows shaping of the X-ray beam for RT, or alternately passage of
the full beam to facilitate imaging without removing the device. The
design goal of the collimator was to vary the X-ray beam diameter
from 0 (fully closed) to 102 mm (fully open) at the CT isocenter.
The attenuation in the shielded area was designed to be more than
95%. The complete collimator assembly and its placement on the
scanner gantry are shown in Fig. 1d.
Figure 1c shows the principle of the collimator, in which 12
pentagonal lead-brass blocks were arranged in two planes, forming
two stages of collimation. The two stages consist of arrays of sliding
described previously (8). The two hexagonal apertures are arranged
coaxially, offset by 30?, and each is driven by a linear stepper motor
through a lead screw, a more robust driving mechanism than the
rotational scheme described previously. The two stages will hereaf-
ter be referred to as the ‘‘near’’ (closest to the X-ray source)
and ‘‘far’’ collimators. By setting the size of the two apertures to
a constant ratio, equal to the distance ratio of the two hexagons
from the X-ray source spot, a regular dodecagon beam profile is
formed. A position sensor attached to each stage reports the aperture
size of the stage. A brass plate with a circular opening, attached to
near side of the collimator, shields the control electronics within
the device from irradiation. A graphical user interface (GUI) on
the microCT control personal computer allows the user to specify
collimator apertures, either independently or synchronized, to fit
the divergence of the X-ray beam.
Treatmentplanningsystem. A treatmentplanning system isunder
development. This system includes a GUI based on the RT_Image
software package (10) and is linked to a Monte Carlo dose computa-
tion system based on the EGSnrc code. The GUI allows the user to
manuallyspecifya sequence ofbeams, settingtheisocenters,widths,
angular directions, and exposure times for each.
Translation stage. The geometric calibration of the translation
stage determined the relationship between the physical positions
and the machine units of the stages. In the calibration each stage
was set with a series of machine units, and the physical positions
were measured after each movement. The stages were repeatedly
moved back and forth to determine the effects of any potential
Geometriccalibration of the
calibration of the collimator included two major measurements:
the physical aperture vs. machine unit calibration, and the collima-
tor–beam axis alignment. The physical aperture/machine control
unit calibration was performed to determine the relationship
between the physical aperture size and the machine readings.
To find the parameters of this relationship, several cylinders with
diameters ranging from 6 mm to 36 mm with precisions of 0.025
mm were prepared. For each measurement, one of these cylinders
was inserted in the aperture of one fully open collimator stage,
and the aperture was then reduced until the cylinder was tightly
held. Calipers were used to verify the collimator aperture size after
removal of the cylinder, and the position sensor reading at this
location was recorded. These readings were then fit to a linear
function of the cylinder diameter to obtain the calibration parame-
ters. The measurement was repeated several times with the aperture
setting from fully closed to fully open, and vice versa.
Alignment of collimator axis with X-ray beam. The X-ray beam
axis is defined as a straight line passing the source spot center and
perpendicular to the CT axis. Alignment of the collimator axis
with this line was necessary to ensure that the collimator focuses
the radiation beam on the isocenter regardless of aperture size.
Misalignment may result from displacement and/or tilting of the
collimator axis with respect to the beam axis. Displacement was
measured through several methods, including a split-field test
(11), imaging of a fixed object through a collimator at angles of
0?and 180?, and by evaluation of the hexagonal profiles produced
plane creates an effect similar to displacement in the appearance of
assumed to be zero, the angle of tilting can be derived from the law
of sines. A composite alignment procedure therefore consisted of
iterative measurement and correction of the displacement and tilting
of the collimator until the error fell within a tolerance of 0.1 mm.
Several sets of positioning screws were set to allow reproducible
translation and angular positioning of the collimator.
Collimator performance. When
aperture, the control software compares the current sensor reading
with the user-specified new aperture size to calculate the
required shift. After performing this shift, the software makes this
comparison again and iterates this process until the discrepancy
between the desired and actual aperture sizes is below a tolerance.
The error tolerance of the collimator aperture measured at the CT
isocenter was set to 0.1 mm when the aperture is >20 mm, and
0.05 mm for smaller apertures. These error tolerances were chosen
in an effort to balance device accuracy with collimator adjustment
time. The performance of the collimator was measured by repeat-
edly setting the collimator with different apertures and recording
the aperture size error and the setting time, to evaluate the reliability
of the mechanism and the control algorithm.
To establish that this hybrid microCT/RT system could accurately
localize an arbitrary target within a subject for irradiation, a phantom
was constructed. The phantom consisted of 10 sheets of solid water
measuring 6 ? 6 ? 0.3 cm stacked to form a cube. Within one of the
central sheets, a hole of diameter 0.3 cm was drilled at a location of
(10 mm, 10 mm) from the upper left corner. A 3-mm-diameter metal
sphere was secured in the center of this hole, and sheets of
radiochromic film were sandwiched within the solid water stack
above and below the sheet bearing the sphere. This phantom was
then placed on the microCT subject bed and secured so that the films
and solid water sheets were coplanar with the plane of rotation of the
scanner gantry. The phantom was imaged using a standard microCT
protocol (400 views, 0.9?view increment, 70 kVp, 40 mA, 25 ms
exposure per view). The image data were reconstructed at an
isotropic resolution of 0.1mm per pixel and viewedwith RT_Image.
The location of the metal sphere was identified in the microCT
images, and the translation stage offsets needed to shift the sphere
to the scanner isocenter were calculated. These offsets were applied,
and subsequently the phantom was irradiated with eight 120-kVp,
50-mA beams spaced at 45?increments, using exposure times
calculated from beam commissioning data to deliver a total dose of
on it wasused to assess theaccuracy of targeting of the metal sphere.
Small animal image-guided radiotherapy d H. ZHOU et al.3
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Toassess whetherthis unitcould beused todeliver conformal RT
to a murine subject, we irradiated tumors in the lungs of two mice to
a doseof 2 Gyatisocenter. Transgenicmice werecreated that, when
treated with tetracycline, express the MYC oncogene in the cells of
the lung. These mice develop spontaneous lung carcinomas within
a median of 52 weeks of MYC induction (12). Two such mice
bearing late-stage disease were selected for treatment with RT.
A subject mouse was placed on the microCT bed and anesthetized
with isoflurane. MicroCT data were acquired as 400 projections
equally spaced over 360?(70 kVp, 40 mA, 25 ms exposure per
view), which were then reconstructed into volumetric CT images
using a cone-beam algorithm. The whole-body dose of the microCT
scan was estimated using RT commissioning data to be 6 cGy,
images from 0?(darker) and 180?(lighter) gantry angles is used to compute the offset of the collimator from the beam axis.
(b) Measurement of collimator offset by imaging a fixed object. The average of the object location seen at 0?and at 180?
gives the scanner isocenter, whereas the collimator center can be measured according to the hexagonal profile. (c) Mea-
surement of collimator offset by fitting the hexagonal profiles produced by each collimator stage, with both stages set at
isocenter apertures of 20 mm. Asymmetry in the dodecagon is apparent, produced by offset between the centers of the
two hexagons. The white scale bar is 2.5 mm at isocenter. (d) Two-hexagon analysis after iterative alignment of the col-
limator with the X-ray beam axis. The collimator apertures are set to 10 mm at isocenter to improve visual detection of any
misalignment. The white scale bar is 2.5 mm at isocenter.
4 I. J. Radiation Oncology d Biology d PhysicsVolume -, Number -, 2010
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comparable to that reported previously for microCT scanners (13).
Thereconstructed 3Dvolume was loaded intoRT_Image tolocalize
the tumor and calculate the appropriate position settings for the 3D
translation stage and the collimator. After adjusting the stages and
collimator, RT was delivered as a series of eight 120-kVp, 50-mA
beams equally spaced over 360?to a dose of 2 Gy at isocenter. A
Monte Carlo model was used to simulate the dose distribution
produced by this treatment (14).
Immediately after irradiation, the mice were killed and tissues
harvested. The lungs of the mice including the target tumor were
excised, fixed in formalin, and cut into 20-mm sections. They
were then stained with antibodies against gH2AX, a histone protein
that is recruited to the site of double-strand breaks (15), as well as
4’,6-diamidino-2-phenylindole (DAPI) to visualize cell nuclei.
These immunohistochemical sections were then visualized with
on the microCT gantry. The weight of the collimator assem-
bly was 17 lb, which was counterweighted on the gantry by
the addition of lead disk weights to the outer cylindrical
counterweights. MicroCT images acquired before and after
installation of the collimator demonstrated no measurable
degradation in image quality after addition of the collimator.
Translation stage. The motors driving the translation
stage in x and y have resolutions of 787.6 and 1400.9
steps/mm, respectively. The reproducibility, determined by
comparing the physical position of the device and the motor
readings, is better than 0.05 mm in both directions.
Geometric calibration of the collimator. The machine
the cylinders of different standard diameters and reading the
position sensorsofthecollimator, fromwhichlinearrelations
were obtained for the near and far stages. The fitting uncer-
tainty was 0.15% on average (maximum 0.36%), obtained
from the variation of repeated measurements. The size of
these apertures at the isocenter was then measured using
both radiochromic film and the CT detector, allowing expres-
sion of the relationship between the collimator machine units
and the aperture sizes. These relationships were implemented
in the collimator control software. As observed previously by
Rodriguez et al. (9), the penumbras of the near and far colli-
mators were not significantly different, and they were there-
fore handled identically by the aperture control software.
tor alignment procedure required five iterations of the dis-
placement-tilting adjustment and measurement. Figure 2
demonstrates the split-field, imaged object, and two hexagon
measurement techniques used to assess displacement. In addi-
tion to the displacements required to align the collimator with
procedure were <0.1 mm.
Collimator performance. The results of the performance
measurements are listed in Table 1. Aperture sizes at isocen-
ter could be achieved by the control software with errors of
<1.0%. Adjustment of the collimator from a fully open
position to an aperture relevant for small-animal RT required
between 20 and 40 s to iterate to the desired tolerable error.
Figure 3shows theresultsof atest designed to evaluate the
ability of the system to locate and deliver radiation beams to
a target within a subject. A metal sphere served as a CT-vis-
ible target within a cubic solid water phantom. Streak and
ring artifacts are visible in the reconstructed CT image
because of high X-ray attenuation within the sphere. The
centroid of the received dose distribution colocalized with
the position of the target metal sphere to within ?0.1 mm
in the x and y scanner axes. This experiment was repeated
with the film positioned in the y and z scanner axes, and
similar results were obtained.
Results obtained from irradiation of a tumor-bearing
mouse are shown in Fig. 4. Simulation of the dose distribu-
tion achieved by a simple eight-field plan using 8-mm beams
2 Gy, whereas doses to surrounding lung were in the range of
0.3 Gy. A star pattern is visible, due to the small numbers of
beams used. The total treatment time required for this plan,
including setup and delivery, was 45 min. Sections collected
from the target tumor immediately after irradiation showed
the presence of gH2AX foci, indicating the formation of
DNA double-strand breaks. Sectionstaken from contralateral
Table 1. Performance assessment of the collimator apparatus
Near stageFar stage
aperture (mm)Error (%) Closing time (s) Opening time (s)Error (%) Closing time (s) Opening time (s)
Small animal image-guided radiotherapy d H. ZHOU et al.5
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MicroCT presents an intriguing platform for the engineer-
ingofsmall-animal RTdevicesbecause ofthe advanced state
of development of this technology. We have added hardware
and software to an existing scanner to produce a hybrid
imaging and RT system. The 2D translation stage and
variable aperture collimator needed to introduce RT capabil-
ity to this system can be manufactured at a cost of less than
$25,000, facilitating commercial development of this system
as a low-cost add-on option to existing microCT scanners.
Fig. 3. Evaluation of subject targeting accuracy using a solid water phantom. (a) Phantom containing a metal sphere and
radiochromic film was placed on the scanner bed and imaged with microCT. (b) MicroCT image of the phantom showing
the metal inclusion, and the radiation treatment plan that was constructed in RT_Image. (c) Superposition of a the solid
water/metal sphere phantom and the adjacent irradiated film. Crosshairs identify the positions of the center of the sphere
and the center of the delivered dose distribution, which agree to within 0.1 mm.
6 I. J. Radiation Oncology d Biology d PhysicsVolume -, Number -, 2010
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Fig. 4. Treatment of a murine spontaneous lung tumor with the microCT radiotherapy system. (a–c) MYC-induced tumor
growing in the base of the right lung of a mouse was imaged with microCT, shown in axial, coronal, and sagittal sections,
with the tumor volume outlined in red. (d) Treatment consisting of eight beams of diameter 8 mm at isocenter with angular
dosedeliveredby thisplan,withthe1-,1.4-,and 1.8-Gyisodosecontours showningreen, yellow,andred,respectively. (f)
Gamma-H2AX (green) and 4’,6-diamidino-2-phenylindole (DAPI, blue) immunohistochemical sections from the target
tumor. (g) Corresponding immunohistochemical sections from the left lung that received an average dose of 0.3 Gy.
Small animal image-guided radiotherapy d H. ZHOU et al.7
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The collimator can be permanently installed on the microCT
gantry without compromising imaging ability, and can be
removed and reinstalledusing positioning markersto quickly
achieve alignment with the X-ray axis. Further development
of these mechanical components is ongoing, improving their
positioning accuracy and mechanical performance while
reducing their travel times so as to move toward potential
dynamic adjustment of this hardware during radiation
treatments. The conformal RT capabilities of this hybrid
device were demonstrated in phantoms as well as in vivo in
a spontaneous murine tumor model. Treatment of rats with
this unit is theoretically possible given the beam depth dose
profile reported previously (9); however, given the limited
travel distances of the motion stages, these larger animals
would have to be positioned on the bed such that the desired
target was close to the microCT isocenter.
On the basis of the Monte Carlo dosimetry simulation
generated for the lung tumor irradiation, it is apparent that
the kilovoltage beams of this system deliver significant
doses to bony structures. At present it is unknown whether
this dose will limit the application of this system. The mass
attenuation coefficient of human bone is an order of magni-
tude greater at the kilovoltage energies of this system rela-
tive to the megavoltage energies of clinical RT systems;
however, the elemental composition and density of mouse
bone have not been rigorously studied. Recent Monte Carlo
material modeling efforts have suggested that more rigorous
treatment of bony tissues in Monte Carlo simulations is re-
quired and suggest that the dose to mouse bones may be
overestimated when using material properties derived from
human bones (14). Ultimately the problem of bone dose
in RT is not unique to this system, because Monte Carlo
simulations have demonstrated elevated dose to bone using
X-ray energies from 120 to 300 kVp (data not shown). Eval-
uation of the biologic effects of bone dose in small-animal
models will be required to assess the significance of these
The increase in temperature in the X-ray generator and its
thermal limits provide constraints on the length of RT
treatments and correspondingly the doses that can be
delivered. We have measured the temperature rise in the
generator during several X-ray delivery sequences and
have found that a 6-min X-ray firing (corresponding to
a mouse dose of approximately 1 Gy) followed by
a 4-min cooling period results in a stable peak generator
temperature of 60?C over repeated firings. The addition
of cooling equipment to the generator could compensate
for temperature increases to reduce the duration of cooling
periods. It is also important to mention that conformal treat-
ment plans using large (more than 10) numbers of beams, in
which the dose per beam is <1 Gy, will cause smaller tem-
perature increases for each beam and thus require shorter
Heating of the X-ray tube is a second important consider-
ation. Replacement of the X-ray tube with a more robust
model, or alternately use of a larger focal spot at the cost of
increased beam penumbra, may be required for RT protocols
desiring radiosurgical doses (more than 20 Gy per fraction).
Rodriguez et al. (9) observed a 0.5-mm penumbra when
using the current 0.3-mm focal spot of the X-ray tube. The
tube has a second focal spot option of 0.9 mm, which would
be expected to increase the observed penumbra to 2 to 3 mm.
These two states could be selected on a per-application basis.
(<2 mm) tumors in sensitive sites such as brain or lung could
use the small focal spot at the cost of longer treatment times,
whereas irradiation of larger targets (large tumors, normal
tissues) could reduce treatment times through use of the large
focal spot, at the cost of spatial accuracy.
This work has shown that it is technically possible to
modify a microCT scanner to serve as a small-animal confor-
mal RT system, operating in a fashion analogous to current
clinical image-guided RT devices. Although the spontaneous
lung tumor model studied here was treated with only eight
beams, in principle this device can deliver large numbers of
beams from multiple angles, approaching current arc
treatment strategies. We anticipate that the applications of
radiationinmolecular biologystudies ofanimal tumorsusing
technology such as that demonstrated here will significantly
enhance our knowledge of radiobiology and provide a means
to study clinically relevant radiation treatment strategies in
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