Validation of a High-Throughput Dicentric Chromosome Assay Using Complex Radiation Exposures.

Validation of biodosimetry assays is routinely performed using primarily orthovoltage irradiators at a conventional dose rate of approximately 1 Gy/min. However, incidental/ accidental exposures caused by nuclear weapons can be more complex. The aim of this work was to simulate the DNA damage effects mimicking those caused by the detonation of a several kilotons improvised nuclear device (IND). For this, we modeled complex exposures to: 1. a mixed (photons + IND-neutrons) field and 2. different dose rates that may come from the blast, nuclear fallout, or ground deposition of radionuclides (ground shine). Additionally, we assessed whether myeloid cytokines affect the precision of radiation dose estimation by modulating the frequency of dicentric chromosomes. To mimic different exposure scenarios, several irradiation systems were used. In a mixed field study, human blood samples were exposed to a photon field enriched with neutrons (ranging from 10% to 37%) from a source that mimics Hiroshima's A-bomb's energy spectrum (0.2-9 MeV). Using statistical analysis, we assessed whether photons and neutrons act in an additive or synergistic way to form dicentrics. For the dose rates study, human blood was exposed to photons or electrons at dose rates ranging from low (where the dose was spread over 32 h) to extremely high (where the dose was delivered in a fraction of a microsecond). Potential effects of cytokine treatment on biodosimetry dose predictions were analyzed in irradiated blood subjected to Neupogen or Neulasta for 24 or 48 h at the concentration recommended to forestall manifestation of an acute radiation syndrome in bomb survivors. All measurements were performed using a robotic station, the Rapid Automated Biodosimetry Tool II, programmed to culture lymphocytes and score dicentrics in multiwell plates (the RABiT-II DCA). In agreement with classical concepts of radiation biology, the RABiT-II DCA calibration curves suggested that the frequency of dicentrics depends on the type of radiation and is modulated by changes in the dose rate. The resulting dose-response curves suggested an intermediate dicentric yields and additive effects of photons and IND-neutrons in the mixed field. At ultra-high dose rate (600 Gy/s), affected lymphocytes exhibited significantly fewer dicentrics (P < 0.004, t test). In contrast, we did not find the dose-response modification effects of radiomitigators on the yields of dicentrics (Bonferroni corrected P > 0.006, ANOVA test). This result suggests no bias in the dose predictions should be expected after emergency cytokine treatment initiated up to 48 h prior to blood collection for dicentric analysis.

Dosimetric assessment of patient dose calculation on a deep learning-based synthesized computed tomography image for adaptive radiotherapy.

PURPOSE: Dose computation using cone beam computed tomography (CBCT) images is inaccurate for the purpose of adaptive treatment planning. The main goal of this study is to assess the dosimetric accuracy of synthetic computed tomography (CT)-based calculation for adaptive planning in the upper abdominal region. We hypothesized that deep learning-based synthetically generated CT images will produce comparable results to a deformed CT (CTdef) in terms of dose calculation, while displaying a more accurate representation of the daily anatomy and therefore superior dosimetric accuracy. METHODS: We have implemented a cycle-consistent generative adversarial networks (CycleGANs) architecture to synthesize CT images from the daily acquired CBCT image with minimal error. CBCT and CT images from 17 liver stereotactic body radiation therapy (SBRT) patients were used to train, test, and validate the algorithm. RESULTS: The synthetically generated images showed increased signal-to-noise ratio, contrast resolution, and reduced root mean square error, mean absolute error, noise, and artifact severity. Superior edge matching, sharpness, and preservation of anatomical structures from the CBCT images were observed for the synthetic images when compared to the CTdef registration method. Three verification plans (CBCT, CTdef, and synthetic) were created from the original treatment plan and dose volume histogram (DVH) statistics were calculated. The synthetic-based calculation shows comparatively similar results to the CTdef-based calculation with a maximum mean deviation of 1.5%. CONCLUSIONS: Our findings show that CycleGANs can produce reliable synthetic images for the adaptive delivery framework. Dose calculations can be performed on synthetic images with minimal error. Additionally, enhanced image quality should translate into better daily alignment, increasing treatment delivery accuracy.

Fiducial detection and registration for 3D IMRT QA with organ-specific dose information.

PURPOSE: Two-dimensional (2D) IMRT QA has been widely performed in Radiation Oncology clinic. However, concerns regarding its sensitivity in detecting delivery errors and its clinical meaning have been raised in publications. In this study, a robust methodology of three-dimensional (3D) IMRT QA using fiducial registration and structure-mapping was proposed to acquire organ-specific dose information. METHODS: Computed tomography (CT) markers were placed on the PRESAGE dosimeter as fiducials before CT simulation. Subsequently, the images were transferred to the treatment planning system to create a verification plan for the examined treatment plan. Patient's CT images were registered to the CT images of the dosimeter for structure mapping according to the positions of the fiducials. After irradiation, the 3D dose distribution was read-out by an optical-CT (OCT) scanner with fiducials shown on the OCT dose images. An automatic localization algorithm was developed in MATLAB to register the markers in the OCT images to those in the CT images of the dosimeter. SlicerRT was used to show and analyze the results. Fiducial registration error was acquired by measuring the discrepancies in 20 fiducial registrations, and thus the fiducial localization error and target registration error (TRE) was estimated. RESULTS: Dosimetry comparison between the calculated and measured dose distribution in various forms were presented, including 2D isodose lines comparison, 3D isodose surfaces with patient's anatomical structures, 2D and 3D gamma index, dose volume histogram and 3D view of gamma failing points. From the analysis of 20 fiducial registrations, fiducial registration error was measured to be 0.62 mm and fiducial localization error was calculated to be 0.44 mm. Target registration uncertainty of the proposed methodology was estimated to be within 0.3 mm in the area of dose measurement. CONCLUSIONS: This study proposed a robust methodology of 3D measurement-based IMRT QA for organ-specific dose comparison and demonstrated its clinical feasibility.

Temperature dependence and temporal stability of stacked radiochromic sheets for three-dimensional dose verification.

PURPOSE: Recently a novel radiochromic sheet dosimeter, termed as PRESAGE sheets, consisting of leuco crystal violet dye and radical initiator had been developed and characterized. This study examines the dosimeter's temporal stability and storage temperature dependence postirradiation, and its applicability for dose verification in three dimensions (3D) as a stack dosimeter. METHODS: PRESAGE sheets were irradiated using 6 MV photons at a dose range of 0-20 Gy with the change in optical density measured using a flatbed scanner. Following their irradiation, PRESAGE sheets were stored in different temperature environments (-18 °C, 4 °C, and 22 °C) and scanned at different time points, ranging from 1 to 168 h postirradiation, to track changes in measured signal and linearity of dose response. Multiple PRESAGE sheets were bound together to create a 12 × 13 × 8.7 cm3 film stack, with EBT3 film inserted between the sheets in the central region of the stack, that was treated using a clinical VMAT plan. Based on the results from the time and storage temperature study, two-dimensional (2D) relative dose distribution measurements in PRESAGE were acquired promptly following irradiation at selected planes in the coronal, sagittal, and axial orientation of the film stack and compared to the treatment planning system calculations in their respective axes. Dose distribution measurements on the coronal axis of the stack dosimeter were also independently verified using EBT3 film. RESULTS: The dose response was observed to be linear (R2 > 0.995) with sheets stored in colder temperatures retaining their signal and dose response sensitivity for extended periods postirradiation. Sheets stored in 22 °C environment should be measured within an hour postirradiation. Sheets stored in a 4 °C and -18 °C environment can be scanned up to 20- and 72 h postirradiation, respectively, while preserving the integrity of their dose response sensitivity and linearity of dose response within a mean absolute percent error of 2.0%. For instance, at 20 h postirradiation the dose response sensitivity for sheets stored in a -18 °C, 4 °C, and 22 °C temperature environment was measured to be 97%, 91%, and 77% of their original values measured within an hour postirradiation, respectively. The 2D gamma pass rate for central slices exceed 95% for PRESAGE film stack compared with treatment planning system on selected planes in the axial, coronal, and sagittal orientation and EBT3 film in the coronal orientation using a 2D gamma index of 2%/2mm. The gamma pass rate in comparing the calculated dose distribution with the measured dose distribution from PRESAGE-LCV was observed to decrease in sheets scanned at later elapsed times postirradiation. In one example, the gamma pass rate for 2%/2mm criteria in the coronal plane was observed to decrease from 97.7% pass rate when scanned within an hour postirradiation to 92.1% pass rate when scanned at 20 h postirradiation under room temperature conditions. CONCLUSIONS: This is the first study to demonstrate that the temporal stability of PRESAGE sheets can be enhanced through its storage in colder temperature environments postirradiation and that sheets as a film stack dosimeter hold promise for precise relative dose distribution measurements in 3D where advanced optical CT is unavailable.

Dosimetric characterization of a body-conforming radiochromic sheet.

PURPOSE: A novel radiochromic PRESAGE sheet (Heuris Inc.) with 3 mm thickness has been developed as a measurement tool for 2D dosimetry. Its inherent ability to conform to irregular surfaces makes this dosimeter advantageous for patient surface dosimetry. This study is a comprehensive investigation into the PRESAGE sheet's dosimetric characteristic, accuracy and its potential use as a dosimeter for clinical applications. METHODS: The characterization of the dosimeter included evaluation of the temporal stability of the dose linearity, reproducibility, measurement uncertainties, dose rate, energy, temperature and angular dependence, lateral response artifacts, percent depth dose curve, and 2D dose measurement. Dose distribution measurements were acquired for regular square fields on a flat and irregular surface and an irregular modulated field on the smooth surface. All measurements were performed using an Epson 11000XL high-resolution scanner. RESULTS: The examined dosimeters exhibit stable linear response, standard error of repeated measurements within 2%, negligible dose rate, energy, and angular dependence. The same linear dose response was measured while the dosimeter was in contact with a heated water surface. Gamma test and histogram analysis of the dose difference between PRESAGE and EBT3 film, PRESAGE and the treatment planning system (TPS) were used to evaluate the measured dose distributions. The PRESAGE sheet dose distributions showed good agreement with EBT3 film and TPS. A discrepancy smaller than the statistical error of the two dosimeters was reported. CONCLUSIONS: This study established a full dosimetric characterization of the PRESAGE sheets with the purpose of laying the foundation for future clinical uses. The results presented here for the comparison of this novel dosimeter with those currently in use reinforce the possibility of using this dosimeter as an alternative for irregular surface dose measurements.

Focused ultrasound induced-blood-brain barrier opening in mouse brain receiving radiosurgery dose of radiation enhances local delivery of systemic therapy.

OBJECTIVE: Investigate the temporal effects of focused ultrasound (FUS)-induced blood-brain barrier (BBB) opening in post-radiotherapy mouse brains. METHODS AND MATERIALS: C57B6 mice without tumors were used to simulate the scenario after gross total resection (GTR) of brain tumor. Radiation dose of 6 Gy x 5 was delivered to one-hemisphere of the mouse brain. FUS-induced BBB-opening was delivered to the irradiated and non-irradiated brain and was confirmed with MRI. Dynamic MRI was performed to evaluate blood vessel permeability. Two time points were selected: acute (2 days after radiation) and chronic (31 days after radiation). RESULTS: BBB opening was achieved after FUS in the irradiated field as compared to the contralateral non-irradiated brain without any decrease in permeability. In the acute group, a trend for higher gadolinium concentration was observed in radiated field. CONCLUSION: Localized BBB-opening can be successfully achieved without loss of efficacy by FUS as early as 2 days after radiotherapy. ADVANCES IN KNOWLEDGE: Adjuvant radiation after GTR is commonly used for brain tumors. Focused ultrasound facilitated BBB-opening can be achieved without loss of efficacy in the post-irradiated brain as early as 2 days after radiation therapy. This allows for further studies on early application of FUS-mediated BBB-opening.

3D isocentricity analysis for clinical linear accelerators.

PURPOSE: To perform a three-dimensional (3D) concurrent isocentricity measurement of a clinical linear accelerator's (linac) using a single 3D dosimeter, PRESAGE. METHODS: A 3D dosimeter, PRESAGE, set up on the treatment couch of a Varian TrueBeam LINAC using the setup lasers, was irradiated under gantry angles of 0 ∘ , 50 ∘ , 160 ∘ , and 270 ∘ with the couch fixed at 0 ∘ and subsequently, under couch angles of 10 ∘ , 330 ∘ , 300 ∘ , and 265 ∘ with the gantry fixed at 270 ∘ . The 1 cm 2 (at 100 cm SAD) square fields were delivered at 6 MV with 800 MU/field. After irradiation, the dosimeter was scanned using a single-beam optical scanner and images were reconstructed with submillimeter resolution using filtered back-projection. Postprocessing was used to extract views parallel to the star-shot planes from which beam trajectories and the smallest circles enclosing these were drawn and extracted. These circles and information from the view orthogonal to both star-shots were used to represent the rotational centers as spheroids. The linac isocenter was defined by the distribution of midpoints between any, randomly selected, points lying inside the center spheroids defined by the table and gantry rotations; isocenter location and size were defined by the average midpoint and the distribution's semi-axes. Collimator rotations were not included in this study. RESULTS: Relative to the setup center defined by lasers, the table and gantry rotation center coordinates (lat., long., vert.) were measured in units of millimeters, to be (-0.24, 0.18, -0.52) and (0.10, 0.53, -0.52), respectively. Displacements from the setup center were 0.60 and 0.75 mm for the table and gantry centers, while the distance between them measured 0.49 mm. The linac's radiation isocenter was calculated to be at (-0.07, -0.17, 0.51) relative to the setup lasers and its size was found to be most easily described by a spheroid prolate in vertical direction with semi-axis lengths of 0.13 and 0.23 mm for the lateral-longitudinal and vertical directions, respectively. CONCLUSIONS: This study demonstrates how to measure the location and sizes of rotational centers in 3D with one setup. The proposed method provides a more comprehensive view on the isocentricity of LINAC than the conventional two-dimensional film measurements. Additionally, a new definition of isocenter and its size was proposed.

Impact of CMV Reactivation, Treatment Approaches, and Immune Reconstitution in a Nonmyeloablative Tolerance Induction Protocol in Cynomolgus Macaques.

BACKGROUND: Cytomegalovirus (CMV) infection is a serious complication in immunosuppressed patients, specifically transplant recipients. Here, we describe the development and use of an assay to monitor the incidence and treatment of CMV viremia in a Cynomolgus macaque model of bone marrow transplantation (BMT) for tolerance induction. We address the correlation between the course of viremia and immune reconstitution. METHODS: Twenty-one animals received a nonmyeloablative conditioning regimen. Seven received cyclosporine A for 28 days and 14 received rapamycin. A CMV polymerase chain reaction assay was developed and run twice per week to monitor viremia. Nineteen recipients were CMV seropositive before BMT. Immune reconstitution was monitored through flow cytometry and CMV viremia was tracked via quantitative polymerase chain reaction. RESULTS: Recipients developed CMV viremia during the first month post-BMT. Two animals developed uncontrollable CMV disease. CMV reactivation occurred earlier in cyclosporine A-treated animals compared with those receiving rapamycin. Post-BMT, T-cell counts remained significantly lower compared with pretransplant levels until CMV reactivation, at which point they increased during the viremic phase and approached pretransplant levels 3 months post-BMT. Management of CMV required treatment before viremia reached 10 000 copies/mL; otherwise clinical symptoms were observed. High doses of ganciclovir resolved the viremia, which could subsequently be controlled with valganciclovir. CONCLUSIONS: We developed an assay to monitor CMV in Cynomolgus macaques. CMV reactivation occurred in 100% of seropositive animals in this model. Rapamycin delayed CMV reactivation and ganciclovir treatment was effective at high doses. As in humans, CD8 T cells proliferated during CMV viremia.

Performance of the cone beam computed tomography-based patient positioning system on the Gamma Knife Icon™.

PURPOSE: Cone beam computed tomography (CBCT) imaging has been implemented on the Leksell Gamma Knife® Icon™ for assessing patient positioning in mask-based Gamma Knife radiosurgery. The purpose of this study was to evaluate the performance of the CBCT-based patient positioning system as a tool for frameless Gamma Knife radiosurgery. METHODS: Daily quality assurance (QA) CBCT precision test results from a 12-month period were analyzed for the geometric accuracy and the stability of the imager. The performance of the image acquisition module and the image registration algorithm was evaluated using an anthropomorphic head phantom (CIRS Inc., Norfolk, VA) and a XYZR axis manual positioning stage (TOAUTO Inc., Guangdong, China). The head phantom was fixed on a mask adaptor and manually translated in the X, Y, Z directions or rotated around the X, Y, Z axes in the range of ±10 mm or ±10º. A CBCT scan was performed after each manual position setup followed by an image registration to the reference scan. To assess the overall setup uncertainties in fractionated treatment, two cylindrical Presage phantoms (Heuris Inc., Skillman, NJ) of 15 cm diameter and 10 cm height were irradiated with identical prescription dose and shot placement following standard mask-based treatment workflow according to two different fraction schedules: a single fraction treatment of 7.5 Gy and a 5-fraction treatment with 1.5 Gy per fraction. RESULTS: The averaged vector deviations of the four marks from their preset values are 0.087, 0.085, 0.095, and 0.079 mm from the 212 daily QA tests. The averaged displacements in the X, Y, Z coordinates and the pitch, yaw, roll angles from the image registration tests are 0.23, 0.27, 0.14, 0.32º, 0.19º, 0.31º from the manual setup. The corresponding maximum differences are 0.41, 0.33, 0.29 mm, 0.45º, 0.31º, and 0.43º, respectively. Compared to the treatment plan using the 2% & 1 mm criteria, the averaged 2D Gamma passing rate is 98.25% for the measured dose distribution from the Presage phantom with 1-fraction irradiation and 95.12% for the 5-fraction irradiation. The averaged Gamma passing rates are 99.53% and 98.16% for the 1-fraction and 5-fraction irradiations using the 2% & 2 mm criteria. CONCLUSIONS: The CBCT imager and the image registration algorithm can reproduce phantom position with <0.5 mm/0.5º uncertainty. A systematic contribution from the interfraction phantom repositioning procedure was observed in the Gamma analysis over the irradiated volumes of two end-to-end test phantoms.

An investigation of clinical treatment field delivery verification using cherenkov imaging: IMRT positioning shifts and field matching.

PURPOSE: Cherenkov light emission has been shown to correlate with ionizing radiation dose delivery in solid tissue. An important clinical application of Cherenkov light is the real-time verification of radiation treatment delivery in vivo. To test the feasibility of treatment field verification, Cherenkov light images were acquired concurrent with radiation beam delivery to standard and anthropomorphic phantoms. Specifically, we tested two clinical treatment scenarios: (a) Observation of field overlaps or gaps in matched 3D fields and (b) Patient positioning shifts during intensity modulated radiation therapy (IMRT) field delivery. Further development of this technique would allow real-time detection of treatment delivery errors on the order of millimeters so that patient safety and treatment quality can be improved. METHODS: Cherenkov light emission was captured using a PI-MAX4 intensified charge coupled device (ICCD) system (Princeton Instruments). All radiation delivery was performed using a Varian Trilogy linear accelerator (linac) operated at 6 MV or 18 MV for photon and 6 MeV or 16 MeV for electron studies. Field matching studies were conducted with photon and electron beams at gantry angles of 0°, 15°, and 45°. For each modality and gantry angle, a total of three data sets were acquired. Overlap and gap distances of 0, 2, 5, and 10 mm were tested and delivered to solid phantom material of 30 × 30 × 5 cm3 . Phantom materials used were white plastic water and brown solid water. Tests were additionally performed on an anthropomorphic phantom with an irregular surface. Positioning shift studies were performed using IMRT fields delivered to a thoracic anthropomorphic phantom. For thoracic phantom measurements, the camera was placed laterally to observe the entire right side of the phantom. Fields were delivered with known translational patient positioning shifts in four directions. Changes in the Cherenkov fluence were evaluated through the generation of difference maps from unshifted Cherenkov images. All images were evaluated using ImageJ, Python, and MATLAB software packages. RESULTS: For matched fields, Cherenkov images were able to quantitate matched field separations with discrepancies between 2 and 4 mm, depending on gantry angle and beam energy or modality. For all photon and electron beams delivered at a gantry angle of 0°, image analysis indicated average discrepancies of less than 2 mm for all field gaps and overlaps, with 83% of matched fields exhibiting discrepancies less than 1 mm. Beams delivered obliquely to the phantom surface exhibited average discrepancies as high as 4 mm for electron beams delivered at large oblique angles. Finally, for IMRT field delivery, vertical and lateral patient positioning shifts of 2 mm were detected in some cases, indicating the potential detectability threshold of using this technique alone. CONCLUSIONS: Our study indicates that Cherenkov imaging can be used to support and bolster current treatment delivery verification techniques, improving our ability to recognize and rectify millimeter-scale delivery and positioning errors.

Dosimetric verification and commissioning for a small animal image-guided irradiator.

In recent years, small animal image-guided irradiators have been widely utilized in preclinical studies involving rodent models. However, the dosimetry commissioning of such equipment involving kilovoltage small-field dosimetry has not received as much interest as the megavoltage small-field dosimetry used clinically. To date, a paucity of measured kilovoltage beam data, especially for field sizes less than 3 mm, can be found in the literature. For improvement of rodent treatments in the future, this work aims to provide comprehensive and accurate beam data for the small animal radiation research platform (SARRP, Xstrahl) using EBT3 Gafchromic films and Monte Carlo calculation, with submillimeter resolution and accuracy. This work includes three primary tasks: (1) establish an optimized film measurement protocol for small field dosimetry of kilovoltage photon beam. (2) Acquire dosimetric data including (a) depth dose curves from the surface to 6 cm depth (b) beam profiles, (c) penumbra, (d) cone factors and (e) 2D dose distribution. These tasks were undertaken for a 220 kVp photon beam with five different small field widths and 33 cm source to surface distance (0.5 mm and 1 mm circular fields, 3 × 3 mm2, 5 × 5 mm2, 10 × 10 mm2 square fields). Beam data was measured with EBT3 films. (3) Provide comparative dosimetry for film measurements, Monte Carlo calculations, and the dose calculations performed with the SARRP treatment planning system, Muriplan. For the majority of parameters, film measurement agreed with Monte Carlo simulation within 1%. There were, however, discrepancies between measured beam data and Muriplan treatment planning data. Specifically, for PDD, Muriplan underestimates the dose for field sizes of 0.5 mm and 1 mm. For beam profiles comparisons, the calculation from Muriplan predicts a smaller lateral distance between the 50% isodose lines compared to film measurement. There is a difference of 0.18, 0.72, 0.6 mm between Muriplan and film for field sizes of 3, 5, 10 mm, respectively. This work demonstrates that accurate and precise kilovoltage small-field dosimetry can be conducted using EBT3 Gafchromic film with an optimized protocol. In addition, discrepancies between measured beam data and Muriplan were identified.

Velocity-based Adaptive Registration and Fusion for Fractionated Stereotactic Radiosurgery Using the Small Animal Radiation Research Platform.

PURPOSE: To implement Velocity-based image fusion and adaptive deformable registration to enable treatment planning for preclinical murine models of fractionated stereotactic radiosurgery (fSRS) using the small animal radiation research platform (SARRP). METHODS AND MATERIALS: C57BL6 mice underwent 3 unique cone beam computed tomography (CBCT) scans: 2 in the prone position and a third supine. A single T1-weighted post-contrast magnetic resonance imaging (MRI) series of a murine metastatic brain tumor model was selected for MRI-to-CBCT registration and gross tumor volume (GTV) identification. Two arms were compared: Arm 1, where we performed 3 individual MRI-to-CBCT fusions using rigid registration, contouring GTVs on each, and Arm 2, where the authors performed MRI-to-CBCT fusion and contoured GTV on the first CBCT followed by Velocity-based adaptive registration. The first CBCT and associated GTV were exported from MuriPlan (Xstrahl Life Sciences) into Velocity (Varian Medical Systems, Inc, Palo Alto, CA). In Arm 1, the second and third CBCTs were exported similarly along with associated GTVs (Arm 1), while in Arm 2, the first (prone) CBCT was fused separately to the second (prone) and third (supine) CBCTs, performing deformable registrations on initial CBCTs and applying resulting matrices to the contoured GTV. Resulting GTVs were compared between Arms 1 and 2. RESULTS: Comparing GTV overlays using repeated MRI fusion and GTV delineation (Arm 1) versus those of Velocity-based CBCT and GTV adaptive fusion (Arm 2), mean deviations ± standard deviation in the axial, sagittal, and coronal planes were 0.46 ± 0.16, 0.46 ± 0.22, and 0.37 ± 0.22 mm for prone-to-prone and 0.52 ± 0.27, 0.52 ± 0.36, and 0.68 ± 0.31 mm for prone-to-supine adaptive fusions, respectively. CONCLUSIONS: Velocity-based adaptive fusion of CBCTs and contoured volumes allows for efficient fSRS planning using a single MRI-to-CBCT fusion. This technique is immediately implementable on current SARRP systems, facilitating advanced preclinical treatment paradigms using existing clinical treatment planning software.

Dosimetric and geometric characteristics of a small animal image-guided irradiator using 3D dosimetry/optical CT scanner.

PURPOSE: The precise dosimetric and geometric characteristics of small animal irradiators are essential to achieving reproducible dose delivery, especially in cases where image-guidance is utilized. Currently, radiochromic film is the established measurement tool used to evaluate beam characteristics for these systems. However, only 2D information can be acquired with film. This study characterized both the dosimetric and geometric properties of the small animal research radiation platform (SARRP, Xstrahl) for commissioning purposes using a 3D radiochromic dosimetry system with a submillimeter resolution optical computed tomography (OCT) scanner. METHODS: Like a modern clinical linear accelerator, the SARRP features both a beam delivery system and a cone beam computed tomography (CBCT) imaging system. Dosimetric and geometric characteristics of the SARRP were studied using EBT3 radiochromic film and 3D PRESAGE dosimeters. Dosimetric measurements included percent depth dose (PDD) curves and beam profiles. For geometric evaluation, the isocenter sizes of the treatment stage and gantry rotations as well as their coincidence were measured using star shot patterns. A commercial Epson Expression 11000XL flatbed scanner was used for readout of irradiated EBT3 films at 300 dpi resolution. Each irradiated PRESAGE dosimeter was scanned using a submillimeter resolution single laser beam OCT scanner. Acquired data were reconstructed with a resolution of 0.3 mm/pixel. RESULTS: PDD data measured from films and 3D dosimeters agree to within ±3% for depths up to 5 cm, for both 3 × 3 and 10 × 10 mm2 fixed collimation. Profiles were analyzed at 10, 20, and 30 mm depth for 3 × 3 mm2 and 10 × 10 mm2 fields. The FWHM measurements for both dosimeters agreed to within 0.01 mm, and the penumbras agreed to within 0.1 mm for 3 × 3 mm2 and 0.5 mm for 10 × 10 mm2 . Gantry and treatment stage isocenter sizes were determined to be 0.21 and 0.43 mm using EBT3 film, and 1.72 and 0.75 mm using PRESAGE dosimeters. Absolute isocenter shifts, evaluated with 3D phantoms, were 0.80 mm for the gantry rotation isocenter (treatment isocenter) with respect to the laser-defined setup isocenter, and 0.71 mm for the gantry rotation isocenter relative to treatment stage rotation isocenter (CBCT isocenter). The difference between CBCT isocenter and laser-defined setup isocenter was 0.68 mm. CONCLUSIONS: This study demonstrated that 3D PRESAGE dosimeters can be used for verification of precise targeting for the SARRP. This 3D dosimetry system can be utilized to obtain information on both geometric and dosimetric properties, as well as acquire beam data parameters for the purpose of commissioning image-guided small animal irradiator systems.

Quality Assessment of Stereotactic Radiosurgery of a Melanoma Brain Metastases Model Using a Mouselike Phantom and the Small Animal Radiation Research Platform.

PURPOSE: To establish a novel preclinical model for stereotactic radiosurgery (SRS) with combined mouselike phantom quality assurance in the setting of brain metastases. METHODS AND MATERIALS: C57B6 mice underwent intracranial injection of B16-F10 melanoma cells. T1-weighted postcontrast magnetic resonance imaging (MRI) was performed on day 11 after injection. The MRI images were fused with cone beam computed tomography (CBCT) images using the Small Animal Radiation Research Platform (SARRP). The gross tumor volume (GTV) was contoured using the MRI. A single sagittal arc using the 3 × 3 mm2 collimator was used to deliver 18 Gy prescribed to the isocenter. MRI was performed 7 days after radiation treatment, and the dose delivered to the mice was confirmed using 2 mouselike anthropomorphic phantoms: 1 in the axial orientation and the other in the sagittal orientation. The SARRP output was measured using a PTW Farmer type ionization chamber as per the American Association of Physicists in Medicine Task Group report 61, and the H-D curve was generated up to a maximum dose of 30 Gy. Irradiated films were analyzed based on optical density distribution and H-D curve. RESULTS: The tumor volume on day 11, before intervention, was 2.48 ± 1.37 mm3 in the no-SRS arm versus 3.75 ± 1.19 mm3 in the SRS arm (NS). In the SRS arm, GTV maximum dose (Dmax) and mean dose were 2048 ± 207 and 1785 ± 14 cGy. Using the mouselike phantoms, the radiochromic film showed close precision in comparison with projected isodose lines, with a Dmax of 1903.4 and 1972.7 cGy, the axial and sagittal phantoms, respectively. Tumor volume 7 days after treatment was 7.34 ± 8.24 mm3 in the SRS arm and 60.20 ± 40.4 mm3 in the no-SRS arm (P=.009). No mice in the control group survived more than 22 days after implantation, with a median overall survival (mOS) of 19 days; mOS was not reached in the SRS group, with 1 death noted. CONCLUSIONS: Single-fraction SRS of 18 Gy delivered in a single arc can be delivered accurately with MRI T1-weighted postcontrast-based treatment planning. The mouse like phantom allows for verification of dose delivery and accuracy.

AAPM TG 158: Measurement and calculation of doses outside the treated volume from external-beam radiation therapy.

The introduction of advanced techniques and technology in radiotherapy has greatly improved our ability to deliver highly conformal tumor doses while minimizing the dose to adjacent organs at risk. Despite these tremendous improvements, there remains a general concern about doses to normal tissues that are not the target of the radiation treatment; any "nontarget" radiation should be minimized as it offers no therapeutic benefit. As patients live longer after treatment, there is increased opportunity for late effects including second cancers and cardiac toxicity to manifest. Complicating the management of these issues, there are unique challenges with measuring, calculating, reducing, and reporting nontarget doses that many medical physicists may have limited experience with. Treatment planning systems become dramatically inaccurate outside the treatment field, necessitating a measurement or some other means of assessing the dose. However, measurements are challenging because outside the treatment field, the radiation energy spectrum, dose rate, and general shape of the dose distribution (particularly the percent depth dose) are very different and often require special consideration. Neutron dosimetry is also particularly challenging, and common errors in methodology can easily manifest as errors of several orders of magnitude. Task Group 158 was, therefore, formed to provide guidance for physicists in terms of assessing and managing nontarget doses. In particular, the report: (a) highlights major concerns with nontarget radiation; (b) provides a rough estimate of doses associated with different treatment approaches in clinical practice; (c) discusses the uses of dosimeters for measuring photon, electron, and neutron doses; (d) discusses the use of calculation techniques for dosimetric evaluations; (e) highlights techniques that may be considered for reducing nontarget doses; (f) discusses dose reporting; and (g) makes recommendations for both clinical and research practice.

Effect of Ex Vivo-Expanded Recipient Regulatory T Cells on Hematopoietic Chimerism and Kidney Allograft Tolerance Across MHC Barriers in Cynomolgus Macaques.

BACKGROUND: Infusion of recipient regulatory T (Treg) cells promotes durable mixed hematopoietic chimerism and allograft tolerance in mice receiving allogeneic bone marrow transplant (BMT) with minimal conditioning. We applied this strategy in a Cynomolgus macaque model. METHODS: CD4 CD25 Treg cells that were polyclonally expanded in culture were highly suppressive in vitro and maintained high expression of FoxP3. Eight monkeys underwent nonmyeloablative conditioning and major histocompatibility complex mismatched BMT with or without Treg cell infusion. Renal transplantation (from the same BMT donor) was performed 4 months post-BMT without immunosuppression to assess for robust donor-specific tolerance. RESULTS: Transient mixed chimerism, without significant T cell chimerism, was achieved in the animals that received BMT without Treg cells (N = 3). In contrast, 2 of 5 recipients of Treg cell BMT that were evaluable displayed chimerism in all lineages, including T cells, for up to 335 days post-BMT. Importantly, in the animal that survived long-term, greater than 90% of donor T cells were CD45RA CD31, suggesting they were new thymic emigrants. In this animal, the delayed (to 4 months) donor kidney graft was accepted more than 294 days without immunosuppression, whereas non-Treg cell BMT recipients rejected delayed donor kidneys within 3 to 4 weeks. Early CMV reactivation and treatment was associated with early failure of chimerism, regardless of Treg cell administration. CONCLUSIONS: Our studies provide proof-of-principle that, in the absence of early CMV reactivation (and BM-toxic antiviral therapy), cotransplantation of host Treg cell can promote prolonged and high levels of multilineage allogeneic chimerism and robust tolerance to the donor.

Microdosimetric characteristics of 50 kV X rays at different depths for breast intraoperative radiotherapy.

An intraoperative radiation therapy (IORT) device with 50 kV X rays was designed to deliver a single dose to the tumour bed after local excision of breast cancer. The quality of a radiation can be determined by the microscopic distribution of energy transfers along and across the charged particle tracks. The lineal energy, y, serves as an accurate measure of local energy concentration. The dose mean lineal energy, yD, is an indicator of radiation quality. For low linear energy transfer radiation, the ratio of its dose mean lineal energy to that of (60)Co gamma rays can serve as a good indicator of the relative biological effectiveness (RBE) at low doses. In this study, microdosimetric simulations are performed for soft tissue irradiated by 50 kV X rays generated from the IORT device, with a 4-cm breast applicator attached. All energy transfers are recorded with the location coordinates in the tissue. Microdosimetric single events in a sphere of 1 µm in diameter are scored as a function of radial distances from the applicator surface. Single-event spectra are then constructed. From those single-event spectra, dose mean lineal energy is calculated. Compared with dose mean lineal energy of (60)Co gamma rays, the estimated RBEs at low doses are given for the X rays at different depths in the tissue. The RBEs at clinically relevant doses, as a function of depth, are also presented.

Fetal radiation monitoring and dose minimization during intensity modulated radiation therapy for glioblastoma in pregnancy.

We examined the fetal dose from irradiation of glioblastoma during pregnancy using intensity modulated radiation therapy (IMRT), and describe fetal dose minimization using mobile shielding devices. A case report is described of a pregnant woman with glioblastoma who was treated during the third trimester of gestation with 60 Gy of radiation delivered via a 6 MV photon IMRT plan. Fetal dose without shielding was estimated using an anthropomorphic phantom with ion chamber and diode measurements. Clinical fetal dose with shielding was determined with optically stimulated luminescent dosimeters and ion chamber. Clinical target volume (CTV) and planning target volume (PTV) coverage was 100 and 98 % receiving 95 % of the prescription dose, respectively. Normal tissue tolerances were kept below quantitative analysis of normal tissue effects in the clinic (QUANTEC) recommendations. Without shielding, anthropomorphic phantom measurements showed a cumulative fetal dose of 0.024 Gy. In vivo measurements with shielding in place demonstrated a cumulative fetal dose of 0.016 Gy. The fetal dose estimated without shielding was 0.04 % and with shielding was 0.026 % of the target dose. In vivo estimation of dose equivalent received by the fetus was 24.21 mSv. Using modern techniques, brain irradiation can be delivered to pregnant patients in the third trimester with very low measured doses to the fetus, without compromising target coverage or normal tissue dose constraints. Fetal dose can further be reduced with the use of shielding devices, in keeping with the principle of as low as reasonably achievable.

Initial clinical experience performing patient treatment verification with an electronic portal imaging device transit dosimeter.

PURPOSE: To prospectively evaluate a 2-dimensional transit dosimetry algorithm's performance on a patient population and to analyze the issues that would arise in a widespread clinical adoption of transit electronic portal imaging device (EPID) dosimetry. METHODS AND MATERIALS: Eleven patients were enrolled on the protocol; 9 completed and were analyzed. Pretreatment intensity modulated radiation therapy (IMRT) patient-specific quality assurance was performed using a stringent local 3%, 3-mm γ criterion to verify that the planned fluence had been appropriately transferred to and delivered by the linear accelerator. Transit dosimetric EPID images were then acquired during treatment and compared offline with predicted transit images using a global 5%, 3-mm γ criterion. RESULTS: There were 288 transit images analyzed. The overall γ pass rate was 89.1%±9.8% (average±1 SD). For the subset of images for which the linear accelerator couch did not interfere with the measurement, the γ pass rate was 95.7%±2.4%. A case study is presented in which the transit dosimetry algorithm was able to identify that a lung patient's bilateral pleural effusion had resolved in the time between the planning CT scan and the treatment. CONCLUSIONS: The EPID transit dosimetry algorithm under consideration, previously described and verified in a phantom study, is feasible for use in treatment delivery verification for real patients. Two-dimensional EPID transit dosimetry can play an important role in indicating when a treatment delivery is inconsistent with the original plan.