Radiation-induced lung toxicity in mice irradiated in a strong magnetic field.

Strong magnetic fields affect radiation dose deposition in MRI-guided radiation therapy systems, particularly at interfaces between tissues of differing densities such as those in the thorax. In this study, we evaluated the impact of a 1.5 T magnetic field on radiation-induced lung damage in C57L/J mice. We irradiated 140 mice to the whole thorax with parallel-opposed Co-60 beams to doses of 0, 9.0, 10.0, 10.5, 11.0, 12.0, or 13.0 Gy (20 mice per dose group). Ten mice per dose group were irradiated while a 1.5 T magnetic field was applied transverse to the radiation beam and ten mice were irradiated with the magnetic field set to 0 T. We compared survival and noninvasive assays of radiation-induced lung damage, namely respiratory rate and metrics derived from thoracic cone-beam CTs, between the two sets of mice. We report two main results. First, the presence of a transverse 1.5 T field during irradiation had no impact on survival of C57L/J mice. Second, there was a small but statistically significant effect on noninvasive assays of radiation-induced lung damage. These results provide critical safety data for the clinical introduction of MRI-guided radiation therapy systems.

Cost-effective immobilization for whole brain radiation therapy.

To investigate the inter- and intra-fraction motion associated with the use of a low-cost tape immobilization technique as an alternative to thermoplastic immobilization masks for whole-brain treatments. The results of this study may be of interest to clinical staff with severely limited resources (e.g., in low-income countries) and also when treating patients who cannot tolerate standard immobilization masks. Setup reproducibility of eight healthy volunteers was assessed for two different immobilization techniques. (a) One strip of tape was placed across the volunteer's forehead and attached to the sides of the treatment table. (b) A second strip was added to the first, under the chin, and secured to the table above the volunteer's head. After initial positioning, anterior and lateral photographs were acquired. Volunteers were positioned five times with each technique to allow calculation of inter-fraction reproducibility measurements. To estimate intra-fraction reproducibility, 5-minute anterior and lateral videos were taken for each technique per volunteer. An in-house software was used to analyze the photos and videos to assess setup reproducibility. The maximum intra-fraction displacement for all volunteers was 2.8 mm. Intra-fraction motion increased with time on table. The maximum inter-fraction range of positions for all volunteers was 5.4 mm. The magnitude of inter-fraction and intra-fraction motion found using the "1-strip" and "2-strip" tape immobilization techniques was comparable to motion restrictions provided by a thermoplastic mask for whole-brain radiotherapy. The results suggest that tape-based immobilization techniques represent an economical and useful alternative to the thermoplastic mask.

Multi-institutional MicroCT image comparison of image-guided small animal irradiators.

To recommend imaging protocols and establish tolerance levels for microCT image quality assurance (QA) performed on conformal image-guided small animal irradiators. A fully automated QA software SAPA (small animal phantom analyzer) for image analysis of the commercial Shelley micro-CT MCTP 610 phantom was developed, in which quantitative analyses of CT number linearity, signal-to-noise ratio (SNR), uniformity and noise, geometric accuracy, spatial resolution by means of modulation transfer function (MTF), and CT contrast were performed. Phantom microCT scans from eleven institutions acquired with four image-guided small animal irradiator units (including the commercial PXi X-RAD SmART and Xstrahl SARRP systems) with varying parameters used for routine small animal imaging were analyzed. Multi-institutional data sets were compared using SAPA, based on which tolerance levels for each QA test were established and imaging protocols for QA were recommended. By analyzing microCT data from 11 institutions, we established image QA tolerance levels for all image quality tests. CT number linearity set to R 2 > 0.990 was acceptable in microCT data acquired at all but three institutions. Acceptable SNR > 36 and noise levels <55 HU were obtained at five of the eleven institutions, where failing scans were acquired with current-exposure time of less than 120 mAs. Acceptable spatial resolution (>1.5 lp mm-1 for MTF = 0.2) was obtained at all but four institutions due to their large image voxel size used (>0.275 mm). Ten of the eleven institutions passed the set QA tolerance for geometric accuracy (<1.5%) and nine of the eleven institutions passed the QA tolerance for contrast (>2000 HU for 30 mgI ml-1). We recommend performing imaging QA with 70 kVp, 1.5 mA, 120 s imaging time, 0.20 mm voxel size, and a frame rate of 5 fps for the PXi X-RAD SmART. For the Xstrahl SARRP, we recommend using 60 kVp, 1.0 mA, 240 s imaging time, 0.20 mm voxel size, and 6 fps. These imaging protocols should result in high quality images that pass the set tolerance levels on all systems. Average SAPA computation time for complete QA analysis for a 0.20 mm voxel, 400 slice Shelley phantom microCT data set was less than 20 s. We present image quality assurance recommendations for image-guided small animal radiotherapy systems that can aid researchers in maintaining high image quality, allowing for spatially precise conformal dose delivery to small animals.

3D-Printed Small-Animal Immobilizer for Use in Preclinical Radiotherapy.

We have designed a method for immobilizing the subjects of small-animal studies using a study group-specific 3D-printed immobilizer that significantly reduces interfraction rotational variation. A cone-beam CT scan acquired from a single specimen in a study group was used to create a 3D-printed immobilizer that can be used for all specimens in the same study group. 3D printing allows for the incorporation of study-specific features into the immobilizer design, including geometries suitable for use in MR and CT scanners, holders for fiducial markers, and anesthesia nose cones of various sizes. Using metrics of rotational setup variations, we compared the current setup in our small-animal irradiation system, a half-pipe bed, with the 3D-printed device. We also assessed translational displacement within the immobilizer. The printed design significantly reduced setup variation, with average reductions in rotational displacement of 76% ± 3% (1.57 to 0.37°) in pitch, 78% ± 3% (1.85 to 0.41°) in yaw, and 87% ± 3% (5.39 to 0.70°) in roll. Translational displacement within the printed immobilizer was less than 1.5 ± 0.3 mm. This method of immobilization allows for repeatable setup when using MR or CT scans for the purpose of radiotherapy, streamlines the workflow, and places little burden on the study subjects.

Technical Note: A Monte Carlo study of magnetic-field-induced radiation dose effects in mice.

PURPOSE: Magnetic fields are known to alter radiation dose deposition. Before patients receive treatment using an MRI-linear accelerator (MRI-Linac), preclinical studies are needed to understand the biological consequences of magnetic-field-induced dose effects. In the present study, the authors sought to identify a beam energy and magnetic field strength combination suitable for preclinical murine experiments. METHODS: Magnetic field dose effects were simulated in a mouse lung phantom using various beam energies (225 kVp, 350 kVp, 662 keV [Cs-137], 2 MV, and 1.25 MeV [Co-60]) and magnetic field strengths (0.75, 1.5, and 3 T). The resulting dose distributions were compared with those in a simulated human lung phantom irradiated with a 6 or 8 MV beam and orthogonal 1.5 T magnetic field. RESULTS: In the human lung phantom, the authors observed a dose increase of 45% and 54% at the soft-tissue-to-lung interface and a dose decrease of 41% and 48% at the lung-to-soft-tissue interface for the 6 and 8 MV beams, respectively. In the mouse simulations, the magnetic fields had no measurable effect on the 225 or 350 kVp dose distribution. The dose increases with the Cs-137 beam for the 0.75, 1.5, and 3 T magnetic fields were 9%, 29%, and 42%, respectively. The dose decreases were 9%, 21%, and 37%. For the 2 MV beam, the dose increases were 16%, 33%, and 31% and the dose decreases were 9%, 19%, and 30%. For the Co-60 beam, the dose increases were 19%, 54%, and 44%, and the dose decreases were 19%, 42%, and 40%. CONCLUSIONS: The magnetic field dose effects in the mouse phantom using a Cs-137, 3 T combination or a Co-60, 1.5 or 3 T combination most closely resemble those in simulated human treatments with a 6 MV, 1.5 T MRI-Linac. The effects with a Co-60, 1.5 T combination most closely resemble those in simulated human treatments with an 8 MV, 1.5 T MRI-Linac.

Evaluation of intrinsic respiratory signal determination methods for 4D CBCT adapted for mice.

PURPOSE: 4D CT imaging in mice is important in a variety of areas including studies of lung function and tumor motion. A necessary step in 4D imaging is obtaining a respiratory signal, which can be done through an external system or intrinsically through the projection images. A number of methods have been developed that can successfully determine the respiratory signal from cone-beam projection images of humans, however only a few have been utilized in a preclinical setting and most of these rely on step-and-shoot style imaging. The purpose of this work is to assess and make adaptions of several successful methods developed for humans for an image-guided preclinical radiation therapy system. METHODS: Respiratory signals were determined from the projection images of free-breathing mice scanned on the X-RAD system using four methods: the so-called Amsterdam shroud method, a method based on the phase of the Fourier transform, a pixel intensity method, and a center of mass method. The Amsterdam shroud method was modified so the sharp inspiration peaks associated with anesthetized mouse breathing could be detected. Respiratory signals were used to sort projections into phase bins and 4D images were reconstructed. Error and standard deviation in the assignment of phase bins for the four methods compared to a manual method considered to be ground truth were calculated for a range of region of interest (ROI) sizes. Qualitative comparisons were additionally made between the 4D images obtained using each of the methods and the manual method. RESULTS: 4D images were successfully created for all mice with each of the respiratory signal extraction methods. Only minimal qualitative differences were noted between each of the methods and the manual method. The average error (and standard deviation) in phase bin assignment was 0.24 ± 0.08 (0.49 ± 0.11) phase bins for the Fourier transform method, 0.09 ± 0.03 (0.31 ± 0.08) phase bins for the modified Amsterdam shroud method, 0.09 ± 0.02 (0.33 ± 0.07) phase bins for the intensity method, and 0.37 ± 0.10 (0.57 ± 0.08) phase bins for the center of mass method. Little dependence on ROI size was noted for the modified Amsterdam shroud and intensity methods while the Fourier transform and center of mass methods showed a noticeable dependence on the ROI size. CONCLUSIONS: The modified Amsterdam shroud, Fourier transform, and intensity respiratory signal methods are sufficiently accurate to be used for 4D imaging on the X-RAD system and show improvement over the existing center of mass method. The intensity and modified Amsterdam shroud methods are recommended due to their high accuracy and low dependence on ROI size.

Evaluation of hyperpolarized [1-¹³C]-pyruvate by magnetic resonance to detect ionizing radiation effects in real time.

Ionizing radiation (IR) cytotoxicity is primarily mediated through reactive oxygen species (ROS). Since tumor cells neutralize ROS by utilizing reducing equivalents, we hypothesized that measurements of reducing potential using real-time hyperpolarized (HP) magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) can serve as a surrogate marker of IR induced ROS. This hypothesis was tested in a pre-clinical model of anaplastic thyroid carcinoma (ATC), an aggressive head and neck malignancy. Human ATC cell lines were utilized to test IR effects on ROS and reducing potential in vitro and [1-¹³C] pyruvate HP-MRS/MRSI imaging of ATC orthotopic xenografts was used to study in vivo effects of IR. IR increased ATC intra-cellular ROS levels resulting in a corresponding decrease in reducing equivalent levels. Exogenous manipulation of cellular ROS and reducing equivalent levels altered ATC radiosensitivity in a predictable manner. Irradiation of ATC xenografts resulted in an acute drop in reducing potential measured using HP-MRS, reflecting the shunting of reducing equivalents towards ROS neutralization. Residual tumor tissue post irradiation demonstrated heterogeneous viability. We have adapted HP-MRS/MRSI to non-invasively measure IR mediated changes in tumor reducing potential in real time. Continued development of this technology could facilitate the development of an adaptive clinical algorithm based on real-time adjustments in IR dose and dose mapping.