Medical Physics Letter Proton-induced x-ray fluorescence CT imaging Magdalena Bazalova-Cartera) Department of Radiation Oncology, Stanford University, Stanford, California 94305-5847 and Global Station for Quantum Medical Science and Engineering, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo 060-8648, Japan
Moiz Ahmad Department of Radiation Oncology, Stanford University, Stanford, California 94305-5847
Taeko Matsuura and Seishin Takao Department of Medical Physics, Proton Beam Therapy Center, Hokkaido University Hospital, Sapporo 060-8648, Japan and Global Station for Quantum Medical Science and Engineering, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo 060-8648, Japan
Yuto Matsuo Department of Medical Physics, Proton Beam Therapy Center, Hokkaido University Hospital, Sapporo 060-8648, Japan
Rebecca Fahrig Department of Radiology, Stanford University, Stanford, California 94305
Hiroki Shirato and Kikuo Umegaki Department of Medical Physics, Proton Beam Therapy Center, Hokkaido University Hospital, Sapporo 060-8648, Japan and Global Station for Quantum Medical Science and Engineering, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo 060-8648, Japan
Lei Xing Department of Radiation Oncology, Stanford University, Stanford, California 94305-5847 and Global Station for Quantum Medical Science and Engineering, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo 060-8648, Japan
(Received 21 November 2014; revised 19 December 2014; accepted for publication 25 December 2014; published 26 January 2015) Purpose: To demonstrate the feasibility of proton-induced x-ray fluorescence CT (pXFCT) imaging of gold in a small animal sized object by means of experiments and Monte Carlo (MC) simulations. Methods: First, proton-induced gold x-ray fluorescence (pXRF) was measured as a function of gold concentration. Vials of 2.2 cm in diameter filled with 0%–5% Au solutions were irradiated with a 220 MeV proton beam and x-ray fluorescence induced by the interaction of protons, and Au was detected with a 3 × 3 mm2 CdTe detector placed at 90◦ with respect to the incident proton beam at a distance of 45 cm from the vials. Second, a 7-cm diameter water phantom containing three 2.2-diameter vials with 3%–5% Au solutions was imaged with a 7-mm FWHM 220 MeV proton beam in a first generation CT scanning geometry. X-rays scattered perpendicular to the incident proton beam were acquired with the CdTe detector placed at 45 cm from the phantom positioned on a translation/rotation stage. Twenty one translational steps spaced by 3 mm at each of 36 projection angles spaced by 10◦ were acquired, and pXFCT images of the phantom were reconstructed with filtered back projection. A simplified geometry of the experimental data acquisition setup was modeled with the MC TOPAS code, and simulation results were compared to the experimental data. Results: A linear relationship between gold pXRF and gold concentration was observed in both experimental and MC simulation data (R2 > 0.99). All Au vials were apparent in the experimental and simulated pXFCT images. Specifically, the 3% Au vial was detectable in the experimental [contrast-to-noise ratio (CNR) = 5.8] and simulated (CNR = 11.5) pXFCT image. Due to fluorescence x-ray attenuation in the higher concentration vials, the 4% and 5% Au contrast were underestimated by 10% and 15%, respectively, in both the experimental and simulated pXFCT images. Conclusions: Proton-induced x-ray fluorescence CT imaging of 3%–5% gold solutions in a small animal sized water phantom has been demonstrated for the first time by means of experiments and MC simulations. C 2015 American Association of Physicists in Medicine. [http://dx.doi.org/10.1118/1.4906169]
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Key words: x-ray fluorescence, protons, CT, Monte Carlo, gold contrast, molecular imaging 1. INTRODUCTION X-ray fluorescence computed tomography (XFCT) is an emerging modality for molecular imaging of probes containing high atomic number elements (Z), such as gold and platinum nanoparticles.1–3 This technique is based on x-ray excitation of imaging probes containing high-Z elements followed by fluorescence x-ray emission. The energy of the fluorescence x-ray is characteristic to the high-Z element, and it is measured with an energy-resolving photon-counting detector. 3D XFCT images of the distribution of the molecular probe are then reconstructed from multiple projections acquired while rotating the x-ray source.4 XFCT imaging is commonly performed with x-ray beams generated by synchrotrons or polychromatic x-ray tubes. Synchrotron x-ray beams have a narrow energy spectrum, resulting in higher XFCT imaging sensitivity due to the decreased Compton scatter background in the detected x-ray spectrum. Polychromatic x-ray tubes are more readily available and thus more convenient for widespread applications of XFCT imaging technology. Development of Compton scatter removal technique has dramatically improved the sensitivity of the imaging approach, which may make it practical for in vivo imaging with a desktop XFCT system.5,6 An alternative approach to decrease the Compton scatter background is to image with a proton beam. In this work, we present the first simulation and experimental study of XFCT imaging of a small animal sized object induced by a proton beam. Particle-induced x-ray emission (PIXE) spectrometry is a known method for elemental analysis of thin samples.7 Most commonly, a narrow low-energy (2–3 MeV) proton beam excites the atoms of the sample, and the fluorescence x-rays are detected by a high energy resolution of ∼150 eV Si(Li) detector placed at 90◦ with respect to the incident proton beam. The detection efficiency of Si(Li) detectors is the highest in the 5–25 keV energy range, which makes it suitable for detection of K-shell fluorescence x-ray of elements with 20 < Z < 50 and of L-shell fluorescence x-rays of elements with Z > 50. X-rays at these energies have a high attenuation coefficient and should be emitted from depths of less than 1 mm within the sample. Thus, the previously described PIXE method is limited to imaging of thin samples, such as mineral sections8 and tissue slides.9 Similarly, PIXE tomography has been limited to imaging of millimeter sized objects, such as small worms10 and hair.11 PIXE tomography of a hair was also simulated with a fast CUDA based algorithm.12 Here, we advance PIXE in two aspects. First, we use a higher energy proton beam that penetrates to larger depths and produces higher energy fluorescence x-rays, which enables proton beam x-ray fluorescence imaging at larger depths. Second, we introduce proton-induced XFCT (pXFCT) technique for imaging of small animal sized objects, in which 3D images of contrast agents can be reconstructed. We present the first experimental and simulation study of XFCT Medical Physics, Vol. 42, No. 2, February 2015
imaging of a small animal sized object induced by a proton beam. Specifically, we show pXFCT images of a water phantom containing vials with 3%–5% concentrations of gold.
2. MATERIALS AND METHODS Experiments and simulations of proton-induced gold x-ray fluorescence (pXRF) and proton-induced XFCT imaging are presented in this paper. The data acquisition and processing techniques for both methods are described in Secs. 2.A–2.D. 2.A. Proton-induced x-ray fluorescence experiments
Proton x-ray fluorescence experiments were performed with a proton beam therapy system (Hitachi, Ltd., Tokyo, Japan) located at the Hokkaido University Hospital (Sapporo, Japan). The 70–220 MeV clinical proton beam can be delivered over 360◦ using spot scanning technology. A 220 MeV proton beam of 7 mm in FWHM with particle rate of 2.5 × 109 protons/s was used for all experiments presented in this work. 2.A.1. Data acquisition
Two sets of experiments were performed. First, we evaluated the linearity of pXRF signal as a function of gold concentration. Second, we acquired a 2D pXFCT image of a phantom containing vials with varying concentrations of gold solutions. First, pXRF signal as a function of gold concentration was quantified in an experiment in which a single vial was irradiated at a time. We sequentially irradiated 2.2 cm diameter vials containing water solutions of gold chloride (AuCl3, Salt Lake Metals, Salt Lake City, UT) with gold concentrations ranging from 0% to 5% Au in 1% intervals (i.e., 0–50 mgAu/ml in 10 mgAu/ml intervals) with 3 × 1011 220 MeV protons. The phantom was placed 40 cm from the beam gantry, and scattered x-rays were detected with a 3 × 3 mm2 XR-123 CdTe detector (Amptek, Bedford, MA) placed 45 cm away from the vial at 90◦ with respect to the incident proton beam. Fluorescence as a function of gold concentration was evaluated by analyzing the acquired x-ray spectra. A solid water block was placed behind the vials and served as a proton beam dump. Brass and lead shielding were placed in the path between the beam dump and the CdTe detector in order to decrease the detector background (see Fig. 1 for configuration; note that, the sample was not rotated for these measurements). Second, we used pXFCT to image a 70-mm diameter water phantom containing 22-mm diameter vials with water solution of gold chloride with gold concentrations of 3%, 4%, and 5% (i.e., 30, 40, and 50 mgAu/ml) (Fig. 1). XFCT image acquisition was performed with a proton pencil beam in a first generation CT scanning geometry with stationary source
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F. 1. Schematics (a) and a photograph (b) of the experimental setup for pXFCT data acquisition.
and detector and rotating imaging object. The phantom was placed on a rotation/translation stage built from components by Velmex (Bloomfield, NY) and controlled by in-house LabView software (National Instruments, Austin, TX). The phantom was first carefully centered at the center of the beam and then moved by −35 mm to the start scanning position. Subsequently, pXFCT data acquisition was initiated by starting the proton beam and simultaneous continuous translation of the phantom across the 70 mm extent of the phantom. The CdTe detector was programmed to acquire 21 readings in 20 s intervals during the 70 mm translation lasting 420 s. During each projection, the translation stage moved by 3.3 mm, which caused minor motion blurring in the reconstructed pXFCT images. For each of the translations, approximately 5 × 1010 protons were delivered and x-ray spectra with 22 eV energy bins acquired with the CdTe detector. After each 70 mm translation, the phantom was rotated by 10◦, translated by −70 mm to the original scan position, and a new translation and data acquisition were initiated. The phantom was rotated over 360◦ resulting in 756 x-ray spectra with 21 translation steps and 36 rotations steps.
2.A.2. Fluorescence peak analysis
The x-ray spectra were analyzed in (The Mathworks, Nattick, MA). Both Kα 1 and Kα 2 peaks of gold at 68.80 and 66.99 keV (Table I) were used to quantify gold xray fluorescence. Due to the x-ray scatter in the phantom and in the surrounding objects and the detector energy resolution of 1.5 keV, the peaks broadened and appeared as a single peak in the experimentally acquired x-ray spectra [Fig. 2(a)]. As a result, the peaks were analyzed together using the 64–71 keV window set around the combined fluorescence peak. For calculation of the net number of gold fluorescence x-rays, background x-rays were subtracted from the fluorescence peak by second order interpolation using the neighboring 10 keV bins on either side of the combined peak widow. The estimated background for spectra acquired with the 2% and 5% Au vials is plotted in Fig. 2(a). Medical Physics, Vol. 42, No. 2, February 2015
In the pXRF linearity experiment, the number of fluorescence counts in each 0%–5% Au vial was calculated and plotted against the true Au concentration. In the pXFCT experiment, each of the 756 acquired x-ray spectra was analyzed, and the calculated Au pXRF signal reordered into a sinogram with 21 pencil beam steps and 36 rotation steps. 2.B. Proton-induced x-ray fluorescence Monte Carlo (MC) simulations
The experimental pXRF and pXFCT acquisition setup was also modeled using simplified geometries with the Monte Carlo method. 2.B.1. Simulation geometry
The experimental setup was simulated in the TOPAS code (version 1.0-b12)14 based on the 4 Monte Carlo package (version 10.0).15 The pXFCT data acquisition geometry was simplified by only modeling the beam and the phantom, no surrounding objects, such as the rotation stage, the treatment couch, x-ray shielding, or the solid water beam dump were considered. Additionally, in order to significantly reduce the calculation time, a 4π spherical detector with 45 cm in radius instead of a 9 mm2 detector placed at 45 cm was modeled. As a result, the number of simulated protons could be reduced by a factor of 2.83 × 105 (the ratio of the detector surface areas). First, the XFR signal linearity experiment was modeled, in which a single borosilicate vial with varying concentrations of AuCl3 was irradiated. A 7 mm FWHM monoenergetic
T I. K -shell x-ray transition energies and intensities for gold normalized to Kα 1 (Ref. 13).
Energy (keV) Intensity w (%)
K α1
K α2
K β1
K β2
K β3
68.80 100
66.99 59
77.98 23
80.15 8
77.58 12
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F. 2. Experimental (a) and simulated x-ray spectra with simplified (b) and actual (c) geometry for 0%, 2%, and 5% Au solutions. In (a), the vertical lines designate the fluorescence peak window between 64 and 71 keV and the interpolated background is shown with dashed lines. Simulated spectra with simplified geometry and ideal detector energy response with 0.5 keV energy bins is shown in (b). A comparison of the experimental and simulated spectrum using a more realistic geometry for the 5% Au solution is presented in (c).
220 MeV proton beam impinged on the center of the vials, and scattered x-rays were scored at the detector plane. X-rays with energies 0.99) between Au pXRF signal and the true Au concentration. The error bars are evaluated as standard deviation from three consecutive measurements. The simulated data presented in Fig. 4(b) show about 1.7 times higher pXRF signal compared to the experimental data. The linear fit with R2 > 0.99 also demonstrates a linear relationship between the simulated gold XFR signal and the true Au concentration. The error bars are not visible in Fig. 4(b), thanks to the 4), and the detection limit for the studied experimental setup was 1.7% Au. CNR calculated based on the simulated pXFCT image is approximately two times higher than CNR calculated from the experimental pXFCT image, which is in agreement with the pXRF signal presented in Fig. 4.
4. DISCUSSION We have presented a proton-induced XFCT imaging study through experimental investigations and Monte Carlo simulations. We have demonstrated that pXFCT of animal sized objects might become a feasible imaging modality. The limitations of the approach and future areas of investigation are described. One of the main disadvantages of pXFCT imaging with a small-area detector is the long imaging time and the associated
F. 6. Reconstructed Au concentration (a) and CNR (b) calculated from experimental and Monte Carlo simulated pXFCT images. Medical Physics, Vol. 42, No. 2, February 2015
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high imaging dose. In our experimental setup, the total imaging time was 252 min resulting in estimated mean imaging dose to the phantom of 580 Gy. However, if a 2-cm wide detector ring is used, the imaging dose will decrease to 92 mGy, which is lower than the imaging doses typically delivered during microCT procedures.17 Additionally, for imaging during proton radiotherapy, doses in the order of units of Gy will be high enough to result in high XRF signal. Only Kα peaks were analyzed in the presented studies. It can be seen in Fig. 2 that K β peaks (energies are listed in Table I) are visible in the 5% Au spectra not only in the simulated data but also in the experimental data. We predict that CNR of pXFCT imaging could be further increased if an x-ray detector with higher energy resolution is used and K β peaks included in the XRF analysis. As mentioned above, the MC simulation geometry was simplified. X-ray scattered off the rotation/translation stage, the treatment couch, or the solid water beam dump was not accounted for. Figure 2 demonstrates that the experimental x-ray background around the gold fluorescence peaks was about three times higher than the background in the MC simulations. X-ray background can be reduced by placing a collimator in front of the detector to limit its detection area to the imaging field of view. Additionally, only x-rays were scored in the phase-space file, but in practice, other particles such as protons, neutrons, but mainly electrons, reach the detector and interact with it. Interactions of the other particles with the detector further increase the detector background. Moreover, the CdTe detector response was not taken into account in our simulations. The detector response results in broadening of x-ray fluorescence peaks and apparent higher counts of low-energy x-rays.18 Here, we briefly compare imaging sensitivities of XFCT conventionally performed with x-ray excitation beams to the presented pXFCT. By means of MC simulations, we calculated the sensitivity of gold XFCT imaging induced with photon, electron, and proton beams,19 and we showed that XFCT images of a 2-cm water phantom induced by a monoenergetic 81 keV photon beam had 400 times higher CNR compared to pXFCT images induced with a 250 MeV beam. We therefore expect that XFCT images of the studied phantom acquired with an idealized 81 keV beam would have an approximately 400 times higher CNR than the presented pXFCT images. In other words, concentrations of 0.004% Au would be visible in 81 keV XFCT images acquired with a similar experimental setup and equal imaging dose. We anticipate two main advantages of pXFCT over XFCT. First, pXFCT can likely be used for imaging of larger objects, as protons, unlike x-rays, do not exponentially attenuate in tissue. For example, an 81 keV photon beam attenuates to 1% of its initial fluence at 25 cm depth, which directly translates into generation of 100 times less XRF. Note that, a 220 MeV proton beam does not attenuate up to approximately 30 cm depth, at which the depth of 220 MeV Bragg peak occurs. Second, pXFCT can be conveniently acquired with a scanning pencil beam on proton therapy machines offering this technology. Our future work will consist of exploring pXFCT applications, such as gold marker tracking with proton beam x-ray Medical Physics, Vol. 42, No. 2, February 2015
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fluorescence during proton beam radiotherapy. We will study the feasibility of detection and quantification of pXRF emitted from gold markers implanted in the tumor site by means of experiments and Monte Carlo simulations. Gold marker tracking should be feasible considering the bulk gold at close to 100% concentrations compared to the 3%–5% concentrations in this study. This increased fluorescence will be offset by the small volume of the Au markers compared to the system resolution, and the increased attenuation path length of the fluorescence as it exits the body. Additionally, pXFCT could be used to guide nanoparticle enhanced proton radiotherapy, in which high gold nanoparticle concentrations in the order of 0.1%–1% have been used.20–22
5. CONCLUSIONS We have presented the first experimental and Monte Carlo simulation results of proton-induced x-ray fluorescence CT imaging of a small animal sized object. We were able to detect 3%–5% gold concentrations in 2.2 cm vials placed in a 7-cm diameter water phantom. pXFCT may be used in future applications such as small animal imaging with gold contrast agents or in guiding proton radiation therapy using gold markers.
ACKNOWLEDGMENTS The authors would like to thank Cesare Jenkins for his help with assembling the rotation/translation stage and to Joseph Perl and Jan Schuman for their help with TOPAS physics settings. The authors wish to acknowledge the support from NIBIB (1K99EB016059 and 1R01 EB016777) and NCI (1R01 CA176553). a)Author
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Moiz Ahmad Department of Radiation Oncology, Stanford University, Stanford, California 94305-5847
Taeko Matsuura and Seishin Takao Department of Medical Physics, Proton Beam Therapy Center, Hokkaido University Hospital, Sapporo 060-8648, Japan and Global Station for Quantum Medical Science and Engineering, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo 060-8648, Japan
Yuto Matsuo Department of Medical Physics, Proton Beam Therapy Center, Hokkaido University Hospital, Sapporo 060-8648, Japan
Rebecca Fahrig Department of Radiology, Stanford University, Stanford, California 94305
Hiroki Shirato and Kikuo Umegaki Department of Medical Physics, Proton Beam Therapy Center, Hokkaido University Hospital, Sapporo 060-8648, Japan and Global Station for Quantum Medical Science and Engineering, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo 060-8648, Japan
Lei Xing Department of Radiation Oncology, Stanford University, Stanford, California 94305-5847 and Global Station for Quantum Medical Science and Engineering, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo 060-8648, Japan
(Received 21 November 2014; revised 19 December 2014; accepted for publication 25 December 2014; published 26 January 2015) Purpose: To demonstrate the feasibility of proton-induced x-ray fluorescence CT (pXFCT) imaging of gold in a small animal sized object by means of experiments and Monte Carlo (MC) simulations. Methods: First, proton-induced gold x-ray fluorescence (pXRF) was measured as a function of gold concentration. Vials of 2.2 cm in diameter filled with 0%–5% Au solutions were irradiated with a 220 MeV proton beam and x-ray fluorescence induced by the interaction of protons, and Au was detected with a 3 × 3 mm2 CdTe detector placed at 90◦ with respect to the incident proton beam at a distance of 45 cm from the vials. Second, a 7-cm diameter water phantom containing three 2.2-diameter vials with 3%–5% Au solutions was imaged with a 7-mm FWHM 220 MeV proton beam in a first generation CT scanning geometry. X-rays scattered perpendicular to the incident proton beam were acquired with the CdTe detector placed at 45 cm from the phantom positioned on a translation/rotation stage. Twenty one translational steps spaced by 3 mm at each of 36 projection angles spaced by 10◦ were acquired, and pXFCT images of the phantom were reconstructed with filtered back projection. A simplified geometry of the experimental data acquisition setup was modeled with the MC TOPAS code, and simulation results were compared to the experimental data. Results: A linear relationship between gold pXRF and gold concentration was observed in both experimental and MC simulation data (R2 > 0.99). All Au vials were apparent in the experimental and simulated pXFCT images. Specifically, the 3% Au vial was detectable in the experimental [contrast-to-noise ratio (CNR) = 5.8] and simulated (CNR = 11.5) pXFCT image. Due to fluorescence x-ray attenuation in the higher concentration vials, the 4% and 5% Au contrast were underestimated by 10% and 15%, respectively, in both the experimental and simulated pXFCT images. Conclusions: Proton-induced x-ray fluorescence CT imaging of 3%–5% gold solutions in a small animal sized water phantom has been demonstrated for the first time by means of experiments and MC simulations. C 2015 American Association of Physicists in Medicine. [http://dx.doi.org/10.1118/1.4906169]
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Key words: x-ray fluorescence, protons, CT, Monte Carlo, gold contrast, molecular imaging 1. INTRODUCTION X-ray fluorescence computed tomography (XFCT) is an emerging modality for molecular imaging of probes containing high atomic number elements (Z), such as gold and platinum nanoparticles.1–3 This technique is based on x-ray excitation of imaging probes containing high-Z elements followed by fluorescence x-ray emission. The energy of the fluorescence x-ray is characteristic to the high-Z element, and it is measured with an energy-resolving photon-counting detector. 3D XFCT images of the distribution of the molecular probe are then reconstructed from multiple projections acquired while rotating the x-ray source.4 XFCT imaging is commonly performed with x-ray beams generated by synchrotrons or polychromatic x-ray tubes. Synchrotron x-ray beams have a narrow energy spectrum, resulting in higher XFCT imaging sensitivity due to the decreased Compton scatter background in the detected x-ray spectrum. Polychromatic x-ray tubes are more readily available and thus more convenient for widespread applications of XFCT imaging technology. Development of Compton scatter removal technique has dramatically improved the sensitivity of the imaging approach, which may make it practical for in vivo imaging with a desktop XFCT system.5,6 An alternative approach to decrease the Compton scatter background is to image with a proton beam. In this work, we present the first simulation and experimental study of XFCT imaging of a small animal sized object induced by a proton beam. Particle-induced x-ray emission (PIXE) spectrometry is a known method for elemental analysis of thin samples.7 Most commonly, a narrow low-energy (2–3 MeV) proton beam excites the atoms of the sample, and the fluorescence x-rays are detected by a high energy resolution of ∼150 eV Si(Li) detector placed at 90◦ with respect to the incident proton beam. The detection efficiency of Si(Li) detectors is the highest in the 5–25 keV energy range, which makes it suitable for detection of K-shell fluorescence x-ray of elements with 20 < Z < 50 and of L-shell fluorescence x-rays of elements with Z > 50. X-rays at these energies have a high attenuation coefficient and should be emitted from depths of less than 1 mm within the sample. Thus, the previously described PIXE method is limited to imaging of thin samples, such as mineral sections8 and tissue slides.9 Similarly, PIXE tomography has been limited to imaging of millimeter sized objects, such as small worms10 and hair.11 PIXE tomography of a hair was also simulated with a fast CUDA based algorithm.12 Here, we advance PIXE in two aspects. First, we use a higher energy proton beam that penetrates to larger depths and produces higher energy fluorescence x-rays, which enables proton beam x-ray fluorescence imaging at larger depths. Second, we introduce proton-induced XFCT (pXFCT) technique for imaging of small animal sized objects, in which 3D images of contrast agents can be reconstructed. We present the first experimental and simulation study of XFCT Medical Physics, Vol. 42, No. 2, February 2015
imaging of a small animal sized object induced by a proton beam. Specifically, we show pXFCT images of a water phantom containing vials with 3%–5% concentrations of gold.
2. MATERIALS AND METHODS Experiments and simulations of proton-induced gold x-ray fluorescence (pXRF) and proton-induced XFCT imaging are presented in this paper. The data acquisition and processing techniques for both methods are described in Secs. 2.A–2.D. 2.A. Proton-induced x-ray fluorescence experiments
Proton x-ray fluorescence experiments were performed with a proton beam therapy system (Hitachi, Ltd., Tokyo, Japan) located at the Hokkaido University Hospital (Sapporo, Japan). The 70–220 MeV clinical proton beam can be delivered over 360◦ using spot scanning technology. A 220 MeV proton beam of 7 mm in FWHM with particle rate of 2.5 × 109 protons/s was used for all experiments presented in this work. 2.A.1. Data acquisition
Two sets of experiments were performed. First, we evaluated the linearity of pXRF signal as a function of gold concentration. Second, we acquired a 2D pXFCT image of a phantom containing vials with varying concentrations of gold solutions. First, pXRF signal as a function of gold concentration was quantified in an experiment in which a single vial was irradiated at a time. We sequentially irradiated 2.2 cm diameter vials containing water solutions of gold chloride (AuCl3, Salt Lake Metals, Salt Lake City, UT) with gold concentrations ranging from 0% to 5% Au in 1% intervals (i.e., 0–50 mgAu/ml in 10 mgAu/ml intervals) with 3 × 1011 220 MeV protons. The phantom was placed 40 cm from the beam gantry, and scattered x-rays were detected with a 3 × 3 mm2 XR-123 CdTe detector (Amptek, Bedford, MA) placed 45 cm away from the vial at 90◦ with respect to the incident proton beam. Fluorescence as a function of gold concentration was evaluated by analyzing the acquired x-ray spectra. A solid water block was placed behind the vials and served as a proton beam dump. Brass and lead shielding were placed in the path between the beam dump and the CdTe detector in order to decrease the detector background (see Fig. 1 for configuration; note that, the sample was not rotated for these measurements). Second, we used pXFCT to image a 70-mm diameter water phantom containing 22-mm diameter vials with water solution of gold chloride with gold concentrations of 3%, 4%, and 5% (i.e., 30, 40, and 50 mgAu/ml) (Fig. 1). XFCT image acquisition was performed with a proton pencil beam in a first generation CT scanning geometry with stationary source
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F. 1. Schematics (a) and a photograph (b) of the experimental setup for pXFCT data acquisition.
and detector and rotating imaging object. The phantom was placed on a rotation/translation stage built from components by Velmex (Bloomfield, NY) and controlled by in-house LabView software (National Instruments, Austin, TX). The phantom was first carefully centered at the center of the beam and then moved by −35 mm to the start scanning position. Subsequently, pXFCT data acquisition was initiated by starting the proton beam and simultaneous continuous translation of the phantom across the 70 mm extent of the phantom. The CdTe detector was programmed to acquire 21 readings in 20 s intervals during the 70 mm translation lasting 420 s. During each projection, the translation stage moved by 3.3 mm, which caused minor motion blurring in the reconstructed pXFCT images. For each of the translations, approximately 5 × 1010 protons were delivered and x-ray spectra with 22 eV energy bins acquired with the CdTe detector. After each 70 mm translation, the phantom was rotated by 10◦, translated by −70 mm to the original scan position, and a new translation and data acquisition were initiated. The phantom was rotated over 360◦ resulting in 756 x-ray spectra with 21 translation steps and 36 rotations steps.
2.A.2. Fluorescence peak analysis
The x-ray spectra were analyzed in (The Mathworks, Nattick, MA). Both Kα 1 and Kα 2 peaks of gold at 68.80 and 66.99 keV (Table I) were used to quantify gold xray fluorescence. Due to the x-ray scatter in the phantom and in the surrounding objects and the detector energy resolution of 1.5 keV, the peaks broadened and appeared as a single peak in the experimentally acquired x-ray spectra [Fig. 2(a)]. As a result, the peaks were analyzed together using the 64–71 keV window set around the combined fluorescence peak. For calculation of the net number of gold fluorescence x-rays, background x-rays were subtracted from the fluorescence peak by second order interpolation using the neighboring 10 keV bins on either side of the combined peak widow. The estimated background for spectra acquired with the 2% and 5% Au vials is plotted in Fig. 2(a). Medical Physics, Vol. 42, No. 2, February 2015
In the pXRF linearity experiment, the number of fluorescence counts in each 0%–5% Au vial was calculated and plotted against the true Au concentration. In the pXFCT experiment, each of the 756 acquired x-ray spectra was analyzed, and the calculated Au pXRF signal reordered into a sinogram with 21 pencil beam steps and 36 rotation steps. 2.B. Proton-induced x-ray fluorescence Monte Carlo (MC) simulations
The experimental pXRF and pXFCT acquisition setup was also modeled using simplified geometries with the Monte Carlo method. 2.B.1. Simulation geometry
The experimental setup was simulated in the TOPAS code (version 1.0-b12)14 based on the 4 Monte Carlo package (version 10.0).15 The pXFCT data acquisition geometry was simplified by only modeling the beam and the phantom, no surrounding objects, such as the rotation stage, the treatment couch, x-ray shielding, or the solid water beam dump were considered. Additionally, in order to significantly reduce the calculation time, a 4π spherical detector with 45 cm in radius instead of a 9 mm2 detector placed at 45 cm was modeled. As a result, the number of simulated protons could be reduced by a factor of 2.83 × 105 (the ratio of the detector surface areas). First, the XFR signal linearity experiment was modeled, in which a single borosilicate vial with varying concentrations of AuCl3 was irradiated. A 7 mm FWHM monoenergetic
T I. K -shell x-ray transition energies and intensities for gold normalized to Kα 1 (Ref. 13).
Energy (keV) Intensity w (%)
K α1
K α2
K β1
K β2
K β3
68.80 100
66.99 59
77.98 23
80.15 8
77.58 12
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F. 2. Experimental (a) and simulated x-ray spectra with simplified (b) and actual (c) geometry for 0%, 2%, and 5% Au solutions. In (a), the vertical lines designate the fluorescence peak window between 64 and 71 keV and the interpolated background is shown with dashed lines. Simulated spectra with simplified geometry and ideal detector energy response with 0.5 keV energy bins is shown in (b). A comparison of the experimental and simulated spectrum using a more realistic geometry for the 5% Au solution is presented in (c).
220 MeV proton beam impinged on the center of the vials, and scattered x-rays were scored at the detector plane. X-rays with energies 0.99) between Au pXRF signal and the true Au concentration. The error bars are evaluated as standard deviation from three consecutive measurements. The simulated data presented in Fig. 4(b) show about 1.7 times higher pXRF signal compared to the experimental data. The linear fit with R2 > 0.99 also demonstrates a linear relationship between the simulated gold XFR signal and the true Au concentration. The error bars are not visible in Fig. 4(b), thanks to the 4), and the detection limit for the studied experimental setup was 1.7% Au. CNR calculated based on the simulated pXFCT image is approximately two times higher than CNR calculated from the experimental pXFCT image, which is in agreement with the pXRF signal presented in Fig. 4.
4. DISCUSSION We have presented a proton-induced XFCT imaging study through experimental investigations and Monte Carlo simulations. We have demonstrated that pXFCT of animal sized objects might become a feasible imaging modality. The limitations of the approach and future areas of investigation are described. One of the main disadvantages of pXFCT imaging with a small-area detector is the long imaging time and the associated
F. 6. Reconstructed Au concentration (a) and CNR (b) calculated from experimental and Monte Carlo simulated pXFCT images. Medical Physics, Vol. 42, No. 2, February 2015
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high imaging dose. In our experimental setup, the total imaging time was 252 min resulting in estimated mean imaging dose to the phantom of 580 Gy. However, if a 2-cm wide detector ring is used, the imaging dose will decrease to 92 mGy, which is lower than the imaging doses typically delivered during microCT procedures.17 Additionally, for imaging during proton radiotherapy, doses in the order of units of Gy will be high enough to result in high XRF signal. Only Kα peaks were analyzed in the presented studies. It can be seen in Fig. 2 that K β peaks (energies are listed in Table I) are visible in the 5% Au spectra not only in the simulated data but also in the experimental data. We predict that CNR of pXFCT imaging could be further increased if an x-ray detector with higher energy resolution is used and K β peaks included in the XRF analysis. As mentioned above, the MC simulation geometry was simplified. X-ray scattered off the rotation/translation stage, the treatment couch, or the solid water beam dump was not accounted for. Figure 2 demonstrates that the experimental x-ray background around the gold fluorescence peaks was about three times higher than the background in the MC simulations. X-ray background can be reduced by placing a collimator in front of the detector to limit its detection area to the imaging field of view. Additionally, only x-rays were scored in the phase-space file, but in practice, other particles such as protons, neutrons, but mainly electrons, reach the detector and interact with it. Interactions of the other particles with the detector further increase the detector background. Moreover, the CdTe detector response was not taken into account in our simulations. The detector response results in broadening of x-ray fluorescence peaks and apparent higher counts of low-energy x-rays.18 Here, we briefly compare imaging sensitivities of XFCT conventionally performed with x-ray excitation beams to the presented pXFCT. By means of MC simulations, we calculated the sensitivity of gold XFCT imaging induced with photon, electron, and proton beams,19 and we showed that XFCT images of a 2-cm water phantom induced by a monoenergetic 81 keV photon beam had 400 times higher CNR compared to pXFCT images induced with a 250 MeV beam. We therefore expect that XFCT images of the studied phantom acquired with an idealized 81 keV beam would have an approximately 400 times higher CNR than the presented pXFCT images. In other words, concentrations of 0.004% Au would be visible in 81 keV XFCT images acquired with a similar experimental setup and equal imaging dose. We anticipate two main advantages of pXFCT over XFCT. First, pXFCT can likely be used for imaging of larger objects, as protons, unlike x-rays, do not exponentially attenuate in tissue. For example, an 81 keV photon beam attenuates to 1% of its initial fluence at 25 cm depth, which directly translates into generation of 100 times less XRF. Note that, a 220 MeV proton beam does not attenuate up to approximately 30 cm depth, at which the depth of 220 MeV Bragg peak occurs. Second, pXFCT can be conveniently acquired with a scanning pencil beam on proton therapy machines offering this technology. Our future work will consist of exploring pXFCT applications, such as gold marker tracking with proton beam x-ray Medical Physics, Vol. 42, No. 2, February 2015
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fluorescence during proton beam radiotherapy. We will study the feasibility of detection and quantification of pXRF emitted from gold markers implanted in the tumor site by means of experiments and Monte Carlo simulations. Gold marker tracking should be feasible considering the bulk gold at close to 100% concentrations compared to the 3%–5% concentrations in this study. This increased fluorescence will be offset by the small volume of the Au markers compared to the system resolution, and the increased attenuation path length of the fluorescence as it exits the body. Additionally, pXFCT could be used to guide nanoparticle enhanced proton radiotherapy, in which high gold nanoparticle concentrations in the order of 0.1%–1% have been used.20–22
5. CONCLUSIONS We have presented the first experimental and Monte Carlo simulation results of proton-induced x-ray fluorescence CT imaging of a small animal sized object. We were able to detect 3%–5% gold concentrations in 2.2 cm vials placed in a 7-cm diameter water phantom. pXFCT may be used in future applications such as small animal imaging with gold contrast agents or in guiding proton radiation therapy using gold markers.
ACKNOWLEDGMENTS The authors would like to thank Cesare Jenkins for his help with assembling the rotation/translation stage and to Joseph Perl and Jan Schuman for their help with TOPAS physics settings. The authors wish to acknowledge the support from NIBIB (1K99EB016059 and 1R01 EB016777) and NCI (1R01 CA176553). a)Author
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