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Supplemental Methods. Description of additional methods and procedures used in the study.

Supplemental Tables S1-S2. Hirsch Score was calculated from tumors and their respective stroma from Figure 5 (S1); All potential flank implanted stromal:tumor and tumor:tumor combinations were measured bi-weekly to chart growth kinetics (S2).

Supplemental Figures S1-S6. Comparison of HN11 and TU167 by RNA-Seq Expression (S1); Suppression of Radiation-induced GLI1 using shRNA Model (S2); Cyst Formation Following Radiation Treatment in Orthotopic TU167-implanted Tumors (S3); Radiation-induced Gli1 Expression and the Effect of Rapamycin Inhibition in HN11 Cells (S4); Effect of siRNA inhibition on Head Neck Cancer Cells and Gli1 Nuclear Translocation (S5); Schema and Histology Detailing Radiation-induced Tumor Repopulation (S6).

Supplemental Table and Figure Legends. Legends for Supplemental Figures S1-S6 and Supplemental Tables S1-S2.

Three-dimensional in-vivo dose verification is one of the standing challenges in radiation therapy. X-ray-induced acoustic tomography has recently been proposed as an imaging method for use in in-vivo dosimetry. The aim of this study was to investigate the accuracy of reconstructing three-dimensional (3D) absolute dose using x-ray-induced acoustic tomography. We performed this investigation using two different tomographic dose reconstruction techniques.Two examples of 3D dose reconstruction techniques for x-ray acoustic imaging are investigated. Dose distributions are calculated for varying field sizes using a clinical treatment planning system. The induced acoustic pressure waves which are generated by the increase in temperature due to the absorption of pulsed MV x-rays are simulated using an advanced numerical modeling package for acoustic wave propagation in the time domain. Two imaging techniques, back projection and iterative time reversal, are used to reconstruct the 3D dose distribution in a water phantom with open fields. Image analysis is performed and reconstructed depth dose curves from x-ray acoustic imaging are compared to the depth dose curves calculated from the treatment planning system. Calculated field sizes from the reconstructed dose profiles by back projection and time reversal are compared to the planned field size to determine their accuracy. The iterative time reversal imaging technique is also used to reconstruct dose in an example clinical dose distribution. Image analysis of this clinical test case is performed using the gamma passing rate. In addition, gamma passing rates are used to validate the stopping criteria in the iterative time reversal method.Water phantom simulations showed that back projection does not adequately reconstruct the shape and intensity of the depth dose. When compared to the depth of maximum dose calculated by a treatment planning system, the maximum dose depth by back projection is shifted deeper by 55 and 75 mm for 4 × 4 cm and 10 × 10 cm field sizes, respectively. The reconstructed depth dose by iterative time reversal accurately agrees with the planned depth dose for a 4 × 4 cm field size and is shifted deeper by 12 mm for the 10 × 10 cm field size. When reconstructing field sizes, the back projection method leads to 18% and 35% larger sizes for the 4 × 4 cm and 10 × 10 cm fields, respectively, whereas the iterative time reversal method reconstructs both field sizes with 2% error. For the clinical dose distribution, we were able to reconstruct the dose delivered by a 1 degree sub-arc with a good accuracy. The reconstructed and planned doses were compared using gamma analysis, with 96% gamma passing rate at 3%/2 mm.Our results show that the 3D x-ray acoustic reconstructed dose by iterative time reversal is considerably more accurate than the dose reconstructed by back projection. Iterative time reversal imaging has a potential for use in 3D absolute dosimetry.

Objective. The concept of using kilovoltage (kV) and megavoltage (MV) beams concurrently has potential applications in cone beam computed tomography (CBCT) guided radiation therapy, such as single breath hold scans, metal artifact reduction, and simultaneous imaging during MV treatment delivery. However, MV cross-scatter generated during MV beam delivery degrades CBCT image quality. To address this, a 2D antiscatter grid and a cross-scatter correction method were investigated in the context of high dose MV treatment delivery. Approach. A 3D printed, tungsten 2D antiscatter grid prototype was utilized in kV CBCT scans to reduce MV cross-scatter fluence during concurrent MV beam delivery. Remaining cross-scatter in projections was corrected by using the 2D grid itself as a cross-scatter intensity sampling device, referred to as grid-based scatter sampling (GSS). To test this approach, kV CBCT acquisitions were performed while delivering 6 and 10 MV beams, mimicking high dose rate treatment delivery scenarios. kV and MV beam deliveries were not synchronized to eliminate MV beam delivery interruption. MV cross-scatter suppression performance of the proposed approach was evaluated in projections and CBCT images of phantoms. Main results. 2D grid reduced the intensity of MV cross-scatter in kV projections by a factor of 3 on the average, when compared to conventional antiscatter grid. Remaining cross scatter as measured by the GSS method was within 7% of measured reference intensity values, and subsequently corrected. CBCT image quality was improved substantially during concurrent kV–MV beam delivery. Median Hounsfield Unit (HU) inaccuracy was up to 182 HU without our methods, and it was reduced to a median 6.5 HU with our 2D grid and scatter correction approach. Our methods provided a factor of 2–6 improvement in contrast-to-noise ratio. Significance. This investigation demonstrates the utility of 2D antiscatter grids and grid-based scatter sampling in suppressing MV cross-scatter. Our approach successfully minimized the effects of MV cross-scatter in concurrent kV CBCT imaging and high dose MV treatment delivery scenarios. Hence, robust MV cross-scatter suppression is potentially feasible without MV beam delivery interruption or compromising kV image acquisition rate.

Purpose Two-dimensional antiscatter grids (2DASG) for cone beam computed tomography (CBCT) is a new area of research to reduce scatter intensity, and consequently improve CBCT image quality. One of the challenges in implementation of 2DASGs is their septa shadows that are impinged on the projections. If these artifacts are not corrected, they may lead to ring artifacts in CBCT images. In this work, we present a novel method to suppress ring artifacts in FPD-based CBCT images. Methods Briefly, our method first detects the locations of 2DASG's septa shadows in projections and then, reduces projection pixel values in septa shadows iteratively until a residual-based convergence criterion is met. To suppress the 2DASG's septa shadows, we developed a total variation minimization (TVM) formulation, referred to as adaptive-diffusive total variation minimization (adTVM), where the diffusivity regularization parameter was adaptively adjusted during each iteration based on the magnitude of the local pixel gradients. To test our method, we have acquired CBCT scans of phantoms using three 2DASG prototypes with different grid geometries. Projections were acquired with a linac mounted CBCT system, operated in offset detector geometry. These projections were then corrected in the following steps: first, projections were corrected using a gantry angle-specific gain correction map; next, projections were corrected by applying our adTVM method. CBCT images were reconstructed using FDK filtered backprojection algorithm. To evaluate adTVM's performance, pixel value statistics and contrast-to-noise ratio (CNR) were compared in CBCT images corrected with and without our adTVM method. Results Without our adTVM method, all three 2DASG prototypes introduced ring artifacts with varying intensities in CBCT images. With our method, significant reduction in ring artifacts was observed in all test cases. Standard deviation of CT numbers was reduced by 7-74% in uniform density phantom CBCT images, CNR was increased by 8-67%, and CT number accuracy of contrast objects embedded in the phantom was preserved. Conclusion We propose a new method to suppress ring artifacts caused by the 2DASG's septa shadows in CBCT images. Our initial investigations indicated that adTVM method could substantially reduce such ring artifacts while preserving CT number accuracy and maintaining good spatial resolution. Therefore, our method may potentially play an important role in enabling the implementation of 2DASGs in flat panel detector based CBCT systems.

PURPOSE We have been investigating two-dimensional (2D) antiscatter grids (2D ASGs) to reduce scatter fluence and improve image quality in cone beam computed tomography (CBCT). In this work, two different aspects of 2D ASGs, their scatter rejection and correction capability, were investigated in CBCT experiments. To correct residual scatter transmitted through the 2D ASG, it was used as a scatter measurement device with a novel method: grid-based scatter sampling. METHODS Three focused 2D ASG prototypes with grid ratios of 8, 12, and 16 were developed for linac-mounted offset detector CBCT geometry. In the first phase, 2D ASGs were used as a scatter rejection device, and the effect of grid ratio on CT number accuracy and contrast-to-noise ratio (CNR) evaluated in CBCT images. In the second phase, a grid-based scatter sampling method which exploits the signal modulation characteristics of the 2D ASG's septal shadows to measure and correct residual scatter transmitted through the grid was implemented. To evaluate CT number accuracy, the percent change in CT numbers was measured by changing the phantom from head to pelvis size and configuration. RESULTS When 2D ASG was used as a scatter rejection device, CT number accuracy increased and the CT number variation due to change in phantom dimensions was reduced from 23% to 2-6%. A grid ratio of 16 yielded the lowest CT number variation. All three 2D ASGs yielded improvement in CNR, up to a factor of two in pelvis-sized phantoms. When 2D ASG prototypes were used for both scatter rejection and correction, CT number variations were reduced further, to 1.3-2.6%. In comparisons with a clinical CBCT system and a high-performance radiographic ASG, 2D ASG provided higher CT number accuracy under the same imaging conditions. CONCLUSIONS When 2D ASG is used solely as a scatter rejection device, substantial improvement in CT number accuracy can be achieved by increasing the grid ratio. Two-dimensional ASGs also provided significant CNR improvement even at lower grid ratios. Two-dimensional ASGs used in conjunction with the grid-based scatter sampling method provided further improvement in CT number accuracy, irrespective of the grid ratio, while preserving 2D ASGs' capacity to improve CNR. The combined effect of scatter rejection and residual scatter correction by 2D ASG may accelerate implementation of new techniques in CBCT that require high quantitative accuracy, such as radiotherapy dose calculation and dual energy CBCT.

While two-dimensional antiscatter grids (2D grid) reduce scatter intensity substantially in Cone Beam Computed Tomography (CBCT), a small fraction of scattered radiation is transmitted through the 2D grid to the detector. Residual scatter limits the accuracy of CT numbers and interferes with the correction of grid’s septal shadows, or footprint, in projections. If grid’s septal shadows are not adequately suppressed in projections, it will lead to ring artifacts in CBCT images. In this work, we present a new method to correct residual scatter transmitted through the grid by employing the 2D grid itself as a residual scatter measurement device. Our method, referred as grid-based scatter sampling (GSS), exploits the spatial modulation of primary x-ray fluence by 2D grid’s septal shadows. The shape of the signal modulation pattern varies as a function of residual scatter intensity registered by detector pixels. Such a variation in signal pattern was employed to measure residual scatter intensity in each projection, and subsequently, residual scatter was subtracted from each projection. To validate the GSS method, CBCT imaging experiments were conducted using a 2D antiscatter grid prototype in a linac mounted CBCT system. The effect of GSS method on the ring artifact reduction was quantified by measuring noise in CBCT images. In addition, the nonuniformity of Hounsfield Units (HU) and HU accuracy was measured in both head and pelvis-sized phantoms. In qualitative evaluations, GSS method successfully reduced ring artifacts caused by 2D grid’s footprint. Image noise reduced by 23% due to reduction of ring artifacts. HU nonuniformity in water-equivalent sections was reduced from 20 HU to 10 HU, and streak artifacts between high density inserts were reduced. The phantom size dependent variations in HU was also reduced after application of GSS method. Without GSS method, HU of density inserts reduced by 9% on the average when phantom size was increased from head to pelvis. With GSS method, HU values reduced only by 5% under the same conditions. In summary, GSS method complements the 2D grid’s scatter suppression performance, by correcting the scatter transmitted through the grid. This approach does not require additional scatter-measurement hardware, such as beam-stop arrays, since the grid itself is employed as the scatter measurement device. By suppressing residual scatter in projections, our proposed method successfully reduced artifacts caused by 2D grid’s footprint, and further improved CT number accuracy.

PURPOSE Scattered radiation remains to be a major cause of image quality degradation in Flat Panel Detector (FPD)-based Cone-beam computed tomography (CBCT). We have been investigating a novel two-dimensional antiscatter grid (2D-ASG) concept to reduce scatter intensity, and hence improve CBCT image quality. We present the first CBCT imaging experiments performed with the 2D-ASG prototype, and demonstrate its efficacy in improving CBCT image quality. METHODS A 2D-ASG prototype with septa focused to x-ray source was additively manufactured from tungsten and mounted on a Varian TrueBeam CBCT system. CBCT projections of phantoms were acquired with an offset detector geometry using TrueBeam's "developer" mode. To minimize the effect of gantry flex, projections were gain corrected on angle-specific bases. CBCT images were reconstructed using a filtered backprojection algorithm and image quality improvement was quantified by measuring contrast-to-noise ratio (CNR) and CT number accuracy in images acquired with no antiscatter grid (NO-ASG), conventional one dimensional antiscatter grid (1D-ASG), and the 2D-ASG prototype. RESULTS A significant improvement in contrast resolution was achieved using our 2D-ASG prototype compared to results of 1D-ASG and NO-ASG acquisitions. Compared to NO-ASG and 1D-ASG experiments, the CNR of material inserts improved by as much as 86% and 54% respectively. Using 2D-ASG, CT number underestimation in water equivalent material section of the phantom was reduced by up to 325 HU when compared to NO-ASG and up to 179 HU when compared to 1D-ASG. CONCLUSION We successfully performed the first CBCT imaging experiments with a 2D-ASG prototype. 2D-ASG provided significantly higher CT number accuracy, higher CNR, and diminished scatter-induced image artifacts in qualitative evaluations. We strongly believe that utilization of a 2D-ASG may potentially lead to better soft tissue visualization in CBCT and may enable novel clinical applications that require high CT number accuracy.

Aim High fraction of scattered radiation in cone-beam CT (CBCT) imaging degrades CT number accuracy and visualization of low contrast objects. To suppress scatter in CBCT projections, we developed a focused, two-dimensional antiscatter grid (2DASG) prototype. In this work, we report on the primary and scatter transmission characteristics of the 2DASG prototype aimed for linac mounted, offset detector geometry CBCT systems in radiation therapy, and compared its performance to a conventional one-dimensional ASG (1DASG). Methods The 2DASG is an array through-holes separated by 0.1 mm septa that was fabricated from tungsten using additive manufacturing techniques. Through-holes’ focusing geometry was designed for offset detector CBCT in Varian TrueBeam system. Two types of ASGs were evaluated: a) a conventional 1DASG with a grid ratio of 10, b) the 2DASG prototype with a grid ratio of 8.2. To assess the scatter suppression performance of both ASGs, Scatter-to-primary ratio (SPR) and scatter transmission fraction (Ts) were measured using the beam stop method. Scatter and primary intensities were modulated by varying the phantom thickness between 10 and 40 cm. Additionally, the effect of air gap and bow tie (BT) filter on SPR and Ts were evaluated. Average primary transmission fraction (TP) and pixel specific primary transmission were also measured for both ASGs. To assess the effect of transmission characteristics on projection image signal-to-noise ratio (SNR) improvement factor was calculated. Improvement in contrast to noise ratio (CNR) was demonstrated using a low contrast object. Results In comparison to 1DASG, 2DASG reduced SPRs by a factor of 3 to 6 across the range of phantom setups investigated. Ts values for 1D and 2DASGs were in the range of 21 to 29%, and 5 to 14%, respectively. 2DASG continued to provide lower SPR and Ts at increased air gap and with BT filter. Tp of 1D and 2DASGs were 70.6% and 84.7%, respectively. Due to the septal shadow of the 2DASG, its pixel specific primary transmission values varied between 32.5% and 99.1%. With respect to 1DASG, 2DASG provided up to factor of 1.7 more improvement in SNR across the SPR range investigated. Moreover, 2DASG provided improved visualization of low contrast objects with respect to 1DASG and NOASG setups. Conclusions When compared to a conventional 1DASG, 2DASG prototype provided noticeably lower SPR and Ts values, indicating its superior scatter suppression performance. 2DASG also provided 19% higher average primary transmission that was attributed to the absence of interseptal spacers and optimized grid geometry. Our results indicate that the combined effect of lower scatter and higher primary transmission provided by 2DASG may potentially translate into more accurate CT numbers and improved contrast resolution in CBCT images. This article is protected by copyright. All rights reserved.

Aim A single-institution review assessing patient characteristics contributing to daily organ motion in postoperative endometrial and cervical cancer patients treated with intensity-modulated radiotherapy (IMRT). Background The Radiation Therapy Oncology Group has established consensus guidelines for postoperative pelvic IMRT, recommending a 7 mm margin on all three axes of the target volume. Materials and methods Daily shifts on 457 radiation setups for 18 patients were recorded in the x axis (lateral), y axis (superior–inferior) and z axis (anterior–posterior); daily positions of the planning tumor volume were referenced with the initial planning scan to quantify variations. Results Of the 457 sessions, 85 (18.6%) had plan shifts of at least 7 mm in one of the three dimensions. For obese patients (body mass index [BMI] ≥ 30), 75/306 (24.5%) sessions had plan shifts ≥7 mm. Odds of having a shift ≥7 mm in any direction was greater for obese patients under both univariate (OR 4.227, 95% CI 1.235–14.466, p = 0.021) and multivariate (OR 5.000, 95% CI 1.341–18.646, p = 0.016) analyses (MVA). Under MVA, having a BMI ≥ 30 was associated with increased odds of shifts in the anterior–posterior (1.173 mm, 95% CI 0.281–2.065, p = 0.001) and lateral (2.074 mm, 95% CI 1.284–2.864, p 0.000) directions but not in the superior–inferior axis (0.298 mm, 95% CI −0.880 to 1.475, p = 0.619) exceeding 7 mm. Conclusions Based on these findings, the standard planned tumor volume expansion of 7 mm is less likely to account for daily treatment changes in obese patients.

Purpose: To study the imageeffects of the time‐wise dynamic aspect of intravenous contrast agents to enable contrast‐enhanced cone‐beam CT (CE‐ CBCT) localization of liver lesions for stereotactic body radiation therapy(SBRT).Methods: A model was developed to study dynamic IV contrast agents using static phantoms and to derive optimum parameters for CE‐ CBCTimaging. Ten samples containing iodine at 0–5 mg/mL were prepared in cylindrical tubes, corresponding roughly to 0–100 HU as measured by 120 kV helical CTimaging. Each sample was imaged separately in a tissue‐ equivalent phantom, yielding ten datasets (roughly 650 projections each) corresponding to these static CBCTimages. To reconstructimages of dynamic contrast concentrations, the CBCT 2D projections were re‐ assembled to match the expected amount of contrast at different points in time. This model was applied to published hepatic contrast enhancement curves, and optimum imaging and contrast injection parameters were derived. Results: A signal‐to‐noise ratio (SNR) decrease of 25%–75% in dynamic CE‐CBCT images from ideal CT of samples with a 20–100 HU difference from water was observed in the un‐optimized scans. This demonstrates the difficulty of CE‐CBCT, and was noticed even in geometries that minimize or eliminate x‐ray scatter, detector glare, and motion. Using our model, we found parameters for iodine injection, CBCT scanning, and injection/scanning timing which optimize contrast enhancement, and a 100% SNR increase with respect to the un‐optimized scans was achieved. Conclusions: The effect of IV contrast is severely degraded in CBCT, and optimization of image and timing parameters is crucial for improved CE‐CBCT imaging for target localization. CBCT has very low temporal resolution, and the pharmacokinetics of IV contrast must be carefully considered in order to apply this technique to localize liver lesions for SBRT. This model will be used to establish the feasibility of CE‐ CBCT for routine localization of liver lesions.

To suppress scatter in cone beam computed tomography (CBCT), two-dimensional antiscatter grids (2D grid) have been recently proposed. In this work, we developed several grid prototypes with higher grid ratios and smaller grid pitches than previous designs, and quantified their primary and scatter transmission properties in the context of CBCT for radiation therapy. Three focused 2D grid prototypes were developed with grid ratios at 12 and 16, and grid pitches at 2 and 3 mm. Their scatter transmission properties were measured between 80-140 kVp, and benchmarked against a high performance radiographic grid (1D grid) using a Varian TrueBeam CBCT system. The effect of source-grid misalignment on the primary transmission and the improvement in contrast-to-noise ratio (CNR) were also evaluated. Changing the grid pitch from two to three mm increased the average primary transmission from 84% to 89%. Maximum scatter-to-primary ratio (SPR) with grid ratio of 12 was 0.3, and increasing the grid ratio to 16 reduced SPR by 30%. A 10 mm misalignment in 2D grid position led to a 6%-8% reduction in average primary transmission, and reduction was more pronounced for the higher grid ratio. 2D grids provided up to factor of seven lower SPR and 21% better primary transmission than the 1D grid, and their scatter transmission exhibited lower energy dependence. While 2D grids provided up to factor of 2.3 higher CNR improvement, a significant variation in CNR improvement was not observed among different grid pitch and ratios. In summary, grid ratio of 16 and grid pitch of 2 mm can keep SPRs below 0.2 even in high scatter conditions, while keeping primary transmission fractions above 80%, key benefits of the investigated 2D grids in improving image quality of CBCT. However, such grids require precise alignment in source-grid geometry during CBCT acquisitions. This study also implies that 2D grids can provide substantially better scatter suppression and primary transmission than high-performance 1D grids currently available.

Stereotactic radiation therapy (SRT) is an increasingly commonly used technique in children. The use of image guidance increases the ability to accurately position patients. With our robotic couch, rotational errors that can be corrected are limited to approximately 3 degrees. Given this limitation, we reviewed the rotational setup errors in our pediatric brain tumor population.We reviewed the rotational corrections for all pediatric (age ≤21 years old) patients treated at our facility from 2009 to 2011. We compared children5 years old treated to children between 5 and 21 years old (≥5 years old). Also, we analyzed the effect of steroid use and trends in rotational errors over the treatment period in each age group.The mean pitch, roll, and yaw rotational setup errors for younger children are -0.70 ± 2.60 degrees, -0.06 ± 1.89 degrees, and 0.69 ± 2.42 degrees, respectively; for children ≥5 years old, they are 0.46 ± 2.09 degrees, -0.06 ± 1.89 degrees, and 0.69 ± 2.42 degrees, respectively. The mean pitch corrections are larger for children5 years old (P.001) and the variance of the pitch, roll, and yaw corrections are all larger for children5 years old (P.001). The frequency of rotational errors above 3 degrees for pitch, roll, and yaw is 21.7%, 10.6%, and 20.9% for children5 years old, and 15.6%, 2.1%, and 13.8% for children ≥5 years old. In both age groups, pitch and roll corrections were larger for children treated with steroids.Rotational errors in our pediatric population occur more frequently than previously reported, and are more common in younger children and in children treated with steroids. These rotational set up errors may not be fully correctable due to mechanical and safety limitations. We have altered our planning and treatment process to better account for rotational errors in children receiving SRT.

In animal irradiation models, reported dose can vary significantly from the actual doses delivered. We describe an effective method for in vivo dose verification.Mice bearing commercially-available cell line or patient-derived tumor cell orthotopic or flank xenografts were irradiated using a 160 kVp, 25 mA X-ray source. Entrance dose was evaluated using optically-stimulated luminescence dosimeters (OSLD) and exit dose was assessed using radiochromic film dosimetry.Tumor position within the irradiation field was validated using external fiducial markers. The average entrance dose in orthotopic tumors from 10 OSLDs placed on two different animal irradiation days was 514 ± 37 cGy (range: 437-545). Exit dose measurements taken from seven radiochromic films on two separate days were 341 ± 21 cGy (a 34% attenuation). Flank tumor irradiation doses measured by OSLD were 368 ± 9 cGy compared to exit doses of 330 cGy measured by radiochromic film.Variations related to the irradiation model can lead to significant under or overdosing in vivo which can affect tumor control and/or biologic endpoints that are dose-dependent. We recommend that dose measurements be determined empirically based on the mouse model and irradiator used and dose compensation adjustments performed to ensure correct and appropriate doses.

Purpose: Scattered radiation remains to be a major contributor to image quality degradation in CBCT. To address the scatter problem, a focused, 2D antiscatter grid (2DASG) prototype was designed, and fabricated using additive manufacturing processes. Its scatter and primary transmission properties were characterized using a linac mounted CBCT system. Methods: The prototype 2DASG was composed of rectangular grid holes separated by tungsten septa, and has a grid pitch of 2.91 mm, grid ratio of 8, and a septal thickness of 0.1 mm. Each grid hole was aligned or focused towards the x-ray source in half-fan (i.e. offset detector) geometry of the Varian TrueBeam CBCT system. Scatter and primary transmission experiments were performed by using acrylic blocks and the beam-stop method. Transmission properties of a radiographic ASG (1DASG) (grid ratio of 10) was also performed by using the identical setup. Results: At 30 cm phantom thickness, scatter to primary ratio (SPR) was 4.51 without any ASG device. SPR was reduced to 1.28 with 1DASG, and it was further reduced to 0.28 with 2DASG. Scatter transmission fraction (Ts) of 1DASG was 21%, and Ts was reduced to 5.8% with 2DASG. The average primary transmission fraction (Tp) of 1DASG was 70.6%, whereas Tp increased to 85.1% with 2DASG. Variation of Tp across 40 cm length (the long axis of flat panel detector) was 2.6%. Conclusion: When compared to conventional ASGs, the focused 2DASG can vastly improve scatter suppression and primary transmission performance. Due to precise alignment of 2DASG's grid holes with respect to beam divergence, high degree of primary transmission through the 2DASG was maintained across the full length of the prototype. We strongly believe that robust scatter rejection and primary transmission characteristics of our 2DASG can translate into both improved quantitative accuracy and soft tissue resolution in linac mounted CBCT systems.

The Small Area Tracking system of the COMPASS experiment at CERN includes a set of 20 large area, fast position-sensitive Gas Electron Multiplier (GEM) detectors, designed to reliably operate in the harsh radiation environment of the experiment. We describe in detail the design, choice of materials, assembly procedures and quality controls used to manufacture the devices. The test procedure in the laboratory, the performance in test beams and in the initial commissioning phase in the experiment are presented and discussed.

Local control and overall survival in patients with advanced head and neck squamous cell cancer (HNSCC) remains dismal. Signaling through the Hedgehog (Hh) pathway is associated with epithelial-to-mesenchymal transition, and activation of the Hh effector transcription factor Gli1 is a poor prognostic factor in this disease setting. Here, we report that increased GLI1 expression in the leading edge of HNSCC tumors is further increased by irradiation, where it contributes to therapeutic inhibition. Hh pathway blockade with cyclopamine suppressed GLI1 activation and enhanced tumor sensitivity to radiotherapy. Furthermore, radiotherapy-induced GLI1 expression was mediated in part by the mTOR/S6K1 pathway. Stroma exposed to radiotherapy promoted rapid tumor repopulation, and this effect was suppressed by Hh inhibition. Our results demonstrate that Gli1 that is upregulated at the tumor–stroma intersection in HNSCC is elevated by radiotherapy, where it contributes to stromal-mediated resistance, and that Hh inhibitors offer a rational strategy to reverse this process to sensitize HNSCC to radiotherapy. Cancer Res; 74(23); 7024–36. ©2014 AACR.

In using flat panel detectors (FPD) for cone beam computed tomography (CBCT), pixel gain variations may lead to structured nonuniformities in projections and ring artifacts in CBCT images. Such gain variations can be caused by change in detector entrance exposure levels or beam hardening, and they are not accounted by conventional flat field correction methods. In this work, the authors presented a method to identify isolated pixel clusters that exhibit gain variations and proposed a pixel gain correction (PGC) method to suppress both beam hardening and exposure level dependent gain variations.To modulate both beam spectrum and entrance exposure, flood field FPD projections were acquired using beam filters with varying thicknesses. "Ideal" pixel values were estimated by performing polynomial fits in both raw and flat field corrected projections. Residuals were calculated by taking the difference between measured and ideal pixel values to identify clustered image and FPD artifacts in flat field corrected and raw images, respectively. To correct clustered image artifacts, the ratio of ideal to measured pixel values in filtered images were utilized as pixel-specific gain correction factors, referred as PGC method, and they were tabulated as a function of pixel value in a look-up table.0.035% of detector pixels lead to clustered image artifacts in flat field corrected projections, where 80% of these pixels were traced back and linked to artifacts in the FPD. The performance of PGC method was tested in variety of imaging conditions and phantoms. The PGC method reduced clustered image artifacts and fixed pattern noise in projections, and ring artifacts in CBCT images.Clustered projection image artifacts that lead to ring artifacts in CBCT can be better identified with our artifact detection approach. When compared to the conventional flat field correction method, the proposed PGC method enables characterization of nonlinear pixel gain variations as a function of change in x-ray spectrum and intensity. Hence, it can better suppress image artifacts due to beam hardening as well as artifacts that arise from detector entrance exposure variation.

Purpose: Simultaneous utilization of kV and MV projections is a promising approach to correct metal artifacts in CBCT. However, due to inherent differences in attenuation, beam hardening, and scattering properties of kV and MV beams, it is challenging to employ kV and MV projections in the same CBCT set. To address these limitations, a novel method was developed to generate hybrid kV/MV projections, and to correct metal artifacts in CBCT images. Methods: First, a calibration dataset-based method was developed to correct beam hardening and scatter in kV and MV projections, and to convert MV projections to kV-equivalent attenuation maps. In the next stage, hybrid kV/MV projections were synthesized by weighted summation of corrected kV and MV projections; a user-controlled, generalized logistic curve was utilized as the weighting function, and its shape determined the relative weight of kV and MV projections with respect to relative attenuation differences on a pixel-by-pixel basis. Results: Phantoms with integrated metal hardware were imaged using 125 kVp and 6 MV beams from a linac with on-board KV imaging. CBCT images were reconstructed from KV-only projections and from hybrid kV/MV projections. In kV-only CBCT sets, metal hardware lead to severe artifacts and HU variations. HU values were underestimated by — 400±117 in a Catphan phantom with femoral implants. On the other hand, CBCT reconstructed from hybrid kV/MV projections exhibited significantly less metal artifacts, and the underestimation in HU values was reduced to — 100±73. Similar results were observed in all imaging experiments. Conclusion: Our method was successful in reducing metal artifacts, and improving CT number accuracy in CBCT images. Consistency of corrections appeared to be robust under diverse imaging conditions. The user-controlled weighting function allowed fine tuning the balance between the level of desired metal artifact suppression and the preservation of soft tissue contrast in CBCT images.

In this work, we investigated the effects of scattered radiation and beam quality on the low contrast performance relevant to cone beam breast CT imaging. For experiments, we used our benchtop conebeam CT system and constructed a phantom consisting of simulated fat and soft tissues. We varied the field of view (FOV) along the z direction to observe its effect on scattered radiation. The beam quality was altered by varying the tube voltage from 50 to 100 kV. We computed the contrast-to-noise ratio (CNR) from reconstructed images and normalized it to the square root of dose measured at the center of the phantom. The results were used as the figure of merit (FOM). The effect of the beam quality on the scatter to primary ratio (SPR) had minimal impact and the SPR was primarily dominated by the FOV. In the central section of the phantom, increasing the FOV from 4 to 16 cm resulted in drop of CNR in the order of 15-20% at any given kVp setting. For a given FOV, the beam quality had insignificant effect on the FOM in the central section of the phantom. In the peripheral section, a 10 % drop in FOM was observed when the kVp setting was increased from 50 to 100. At lower kVp values, the primary x-ray transmission through the thicker parts of the phantom was severely reduced. Under such circumstances, ring artifacts were observed due to imperfect flat field correction at very low signal intensities. Higher kVp settings and higher SPRs helped to increase the signal intensity in highly attenuating regions and suppressed the ring artifacts.

We have clinically observed that larger rotational setup errors are more prominent in pediatric patients who received radiation therapy for brain tumors. In this work, we quantitatively evaluated the daily setup corrections in pitch, roll, and yaw axes for children who received intracranial radiation therapy under x-ray image guidance.Daily localization data of 43 patients between the ages of 10 months and 21.9 years were analyzed in this study. Patients were immobilized with thermoplastic mask during treatments, and 2D orthogonal x-ray images wereacquired for setup corrections before each treatment. Rotational setup corrections in pitch, roll, and yaw axes were extracted from 873 treatment fractions, and were analyzed for the whole group of patients and for two age groups:5 and = 5 years old.The mean values for the pitch corrections were 1.91° and 1.65° (p:0.02), roll corrections were 1.37° and 1° (p0.001), and yaw corrections were 1.93° and 1.47° (p0.001), respectively. For patients5 years, 21.7% of treatments had pitch corrections more than 3°, versus 15.6% of treatments required pitch corrections more than 3° for patients= 5 years. Similarly, 10.6% of roll corrections and 20.9% of yaw corrections were more than 3° for patients5 years. On the other hand, 2.1% of roll and 13.8% of yaw corrections were more than 3° for patients = 5 years old.Data indicate that children less than 5 years old are more prone to rotational setup errors during intracranial radiation therapy. This can be attributed to reduced efficacy of immobilization devices due to smaller and rounder anatomicalfeatures of pediatric patients, and challenges in setup while the patient is under anesthesia. The role of daily image guidance and rotational setup corrections becomes important to ensure target coverage, especially for children5 years old.

Purpose: In using flat panel detectors (FPD) for cone beam computed tomography (CBCT), pixel gain variations may lead to structured nonuniformities in projections and ring artifacts in CBCT images. Such gain variations can be caused by change in detector entrance exposure levels or beam hardening, and they are not accounted by conventional flat field correction methods. In this work, the authors presented a method to identify isolated pixel clusters that exhibit gain variations and proposed a pixel gain correction (PGC) method to suppress both beam hardening and exposure level dependent gain variations. Methods: To modulate both beam spectrum and entrance exposure, flood field FPD projections were acquired using beam filters with varying thicknesses. “Ideal” pixel values were estimated by performing polynomial fits in both raw and flat field corrected projections. Residuals were calculated by taking the difference between measured and ideal pixel values to identify clustered image and FPD artifacts in flat field corrected and raw images, respectively. To correct clustered image artifacts, the ratio of ideal to measured pixel values in filtered images were utilized as pixel-specific gain correction factors, referred as PGC method, and they were tabulated as a function of pixel value in a look-up table. Results: 0.035% of detector pixels lead to clustered image artifacts in flat field corrected projections, where 80% of these pixels were traced back and linked to artifacts in the FPD. The performance of PGC method was tested in variety of imaging conditions and phantoms. The PGC method reduced clustered image artifacts and fixed pattern noise in projections, and ring artifacts in CBCT images. Conclusions: Clustered projection image artifacts that lead to ring artifacts in CBCT can be better identified with our artifact detection approach. When compared to the conventional flat field correction method, the proposed PGC method enables characterization of nonlinear pixel gain variations as a function of change in x-ray spectrum and intensity. Hence, it can better suppress image artifacts due to beam hardening as well as artifacts that arise from detector entrance exposure variation.

Purpose: To improve CT number accuracy and contrast sensitivity, a novel 2D antiscatter grid (ASG) for flat panel detector (FPD) based CBCT imaging was evaluated. Experiments were performed to characterize the scatter rejection and contrast sensitivity performance of ASG. The reduction in primary transmission for various ASG geometries was also evaluated by a computational model. Methods: The 2D ASG design was based on multi-hole collimators used in Nuclear Medicine. It consisted of abutted hexagon shaped apertures with 2.5 mm pitch and 32 mm height, and separated by 0.25 mm thick lead septa. Scatter-to-primary ratio (SPR), contrast-to-noise ratio (CNR), and mean primary transmission were measured using a benchtop FPD/x-ray source system. Acrylic slabs of varying thicknesses were imaged with a contrast-detail phantom to measure CNR and SPR under different scatter conditions. Primary transmission was also measured by averaging pixel values in flood field images without the phantom. We additionally explored variation of primary transmission with pitch and septum thickness using a computational model of our ASG. Results: Our 2D ASG reduced the SPR from 3.3 to 0.12, and improved CNR by 50% in 20 cm thick slab phantom projections acquired at 120 kVp. While the measured primary transmission was 72.8%, our simulations show that primary transmission can be increased to 86% by reducing the septum thickness to 0.1 mm. Primary transmission further increases to 93% if septum thickness of 0.1 mm is used in conjunction with an increased pitch of 4 mm. Conclusion: The 2D ASG appears to be a promising scatter rejection device, offering both superior scatter rejection and improved contrast sensitivity. Though its lead footprint reduced primary transmission, our work shows that optimization of aperture pitch and septum thickness can significantly improve the primary transmission.

The pharmacokinetic behavior of iodine contrast agents makes it difficult to achieve significant enhancement during contrast-enhanced cone-beam CT (CE-CBCT). This study modeled this dynamic behavior to optimize CE-CBCT and improve the localization of liver lesions for SBRT. We developed a model that allows for controlled study of changing iodine concentrations using static phantoms. A projection database consisting of multiple phantom images of differing iodine/scan conditions was built. To reconstruct images of dynamic hepatic concentrations, hepatic contrast enhancement data from conventional CT scans were used to re-assemble the projections to match the expected amount of contrast. In this way the effect of various parameters on image quality was isolated, and using our dynamic model we found parameters for iodine injection, CBCT scanning, and injection/scanning timing which optimize contrast enhancement. Increasing the iodine dose, iodine injection rate, and imaging dose led to significant increases in signal-to-noise ratio (SNR). Reducing the CBCT imaging time also increased SNR, as the image can be completed before the iodine exits the liver. Proper timing of image acquisition played a significant role, as a 30 second error in start time resulted in a 40% SNR decrease. The effect of IV contrast is severely degraded in CBCT, but there is promise that, with optimization of the injection and scan parameters to account for iodine pharmacokinetics, CE-CBCT which models venous-phase blood flow kinetics will be feasible for accurate localization of liver lesions.

Purpose: To improve quantitative accuracy of CT numbers in kV‐CBCT, we developed a method to correct kV projections using MV images acquired during CBCT acquisition. This method exploits inherent characteristics of MV image signal, such as relatively lower scatter fraction and lower sensitivity to elemental composition, to both correct for scatter and suppress metal artifacts in kV‐CBCT. Methods: To correct for scatter in kV‐CBCT, two water‐based mapping functions were developed to correct beam hardening in MV projections, and to transform them to kV‐equivalent MV projections in Radon space. At a given gantry angle, the difference in log‐attenuation values between kV‐equivalent MV and raw kV projections served as the estimate of scatter distribution. Smoothed scatter distributions were subtracted from the raw kV projections to obtain corrected kV projections. In addition, the difference between kV‐equivalent MV and scatter‐corrected kV projections were used to identify image pixels that exhibited nonlinearities due to metal objects in raw KV projections. Such pixels were replaced by the corresponding pixel values in the kV‐equivalent MV projections. Standard filter‐backprojection algorithm was utilized to reconstruct the CBCT image from corrected KV projections. Results: Varian TrueBeam linac operated in research mode was utilized to acquire kV‐MV projections. In a torso phantom image, shading artifacts due to scatter was reduced from 300 HU to less than 100 HU after corrections. Two steel rods placed on the surface of the phantom lead to more than 600 HU image streaks in the uncorrected kV‐CBCT image. After metal artifact corrections, variation in CT numbers was reduced below 100 HU. Conclusion: Scatter and metal artifacts can be significantly reduced in kV‐CBCT using our approach. Improved quantitative accuracy of CT numbers may enable CBCT image based dose calculations in radiation therapy, and be particularly useful to reduce range uncertainties in particle therapy for patients with metallic implants.

Purpose: Latest generation linear accelerators (linacs), i.e., TrueBeam (Varian Medical Systems, Palo Alto, CA) and its stereotactic counterpart, TrueBeam STx, have several unique features, including high-dose-rate flattening-filter-free (FFF) photon modes, reengineered electron modes with new scattering foil geometries, updated imaging hardware/software, and a novel control system. An evaluation of five TrueBeam linacs at three different institutions has been performed and this work reports on the commissioning experience. Methods: Acceptance and commissioning data were analyzed for five TrueBeam linacs equipped with 120 leaf (5 mm width) MLCs at three different institutions. Dosimetric data and mechanical parameters were compared. These included measurements of photon beam profiles (6X, 6XFFF, 10X, 10XFFF, 15X), photon and electron percent depth dose (PDD) curves (6, 9, 12 MeV), relative photon output factors (Scp), electron cone factors, mechanical isocenter accuracy, MLC transmission, and dosimetric leaf gap (DLG). End-to-end testing and IMRT commissioning were also conducted. Results: Gantry/collimator isocentricity measurements were similar (0.27–0.28 mm), with overall couch/gantry/collimator values of 0.46–0.68 mm across the three institutions. Dosimetric data showed good agreement between machines. The average MLC DLGs for 6, 10, and 15 MV photons were 1.33 ± 0.23, 1.57 ± 0.24, and 1.61 ± 0.26 mm, respectively. 6XFFF and 10XFFF modes had average DLGs of 1.16 ± 0.22 and 1.44 ± 0.30 mm, respectively. MLC transmission showed minimal variation across the three institutions, with the standard deviation

81 Background: Preclinical studies have shown that nitric oxide (NO) is produced by upregulation of inducible nitric oxide synthase (iNOS) in activated macrophages recruited to the site of cytotoxic injury from radiation or chemotherapy. NO stabilizes hypoxia-inducible factor 1-alpha (HIF1α), leading to increased vascular endothelial growth factor, thus promoting tumor angiogenesis as a recovery mechanism from the initial cytotoxic insult. Because glycine (G) suppresses macrophage activation, we hypothesized that dietary supplementation with G would inhibit HIF1α expression and enhance tumor growth delay by preventing recovery angiogenesis. Methods: PC3 cells were transfected with a HIF1α-inducible luciferase reporter and grown as nude mice xenografts. As tumors grew to 100mm3, mice were continued in 1 of 4 conditions: 1) control (C) diet ; 2) a 5%G diet; 3) C diet with ad libitum drinking water treated with L-NAME (500mg/L), an iNOS inhibitor; or 4) C diet with a single injection of carrageenan (2mg/500uL), a selective macrophagicidal agent. After 3 days tumors were irradiated with 0 Gy (sham) or 6 Gy using a 160kV source. Tumor growth and quantitative bioluminescence data were then collected (n = 4 mice/group). Results: HIF1α expression as assessed by bioluminescence increased more than two fold 4-6 days after 6 Gy (p

Purpose: Latest generation linear accelerators(linacs), TrueBeam (Varian Medical Systems, Palo Alto, CA) and its stereotactic counterpart, TrueBeam STx, have several unique features, including high‐dose‐rate flattening‐filter‐free (FFF) photon modes, reengineered electron modes with new scattering foil geometries, updated imaging hardware/software, and a novel control system. We have performed a comprehensive evaluation of three TrueBeam linacs at three different institutions and report on our commissioning experience. Methods: Acceptance and commissioning data were analyzed for three TrueBeam linacs equipped with 120 leaf (5 mm width) MLCs at three different institutions. Dosimetric data and mechanical parameters were compared. These included measurements of photon beam profiles (6X, 6XFFF, 10X, 10XFFF, 15X), photon and electron percent depth dose (PDD)curves (6MeV, 9MeV, 12MeV), relative photon output factors (Scp),electron cone factors, mechanical isocenter accuracy, MLC transmission, and dosimetric leaf gap (DLG). Results: Gantry/collimator isocentricity measurements were similar (0.27–0.28mm), with overall couch/gantry/collimator values of 0.46–0.68mm across the three institutions. Dosimetric data showed good agreement between machines. The largestdiscrepancy was observed with measured MLC DLG (for 6, 10 and 15 MV photons, average DLGs were 1.95 ± 1.15mm, 2.22 ± 1.30 mm, and 2.20 ± 1.24mm, respectively). Photon and electron PDDs were comparable for all energies. 6, 15 and 10 MV photon beam quality, %dd(10)x varied less than 0.3% for all machines. Electron beam quality specifier (R50) showed less than 1.7% variation for all energies. Output factors (Scp) and electron cone factors agreed within 0.27%, on average; largest variations were observed for small field sizes (0.77% variation, 2×2cm2) and small cone sizes (0.39% variation, 6×6 cm2 cone), respectively. Conclusions: Overall, strong agreement was observed in TrueBeam commissioning data. This comprehensive set of multi‐institutional data may serve as a benchmark for other institutions embarking on TrueBeam commissioning, ultimately improving the safety/quality of beam commissioning

Purpose: Bowtie filters are known to reduce fraction of the scatter signals in CBCTimaging, particularly in cylindrically symmetric image acquisition geometries. However, patient anatomy and imaging geometry during daily CBCTimaging for radiation therapy often lack this symmetry. In this work, the performance of bowtie filters on reducing contaminant signals was investigated for clinically relevant CBCTimage acquisition setups. Methods: A torso phantom with elliptical cross section was imaged using a clinical CBCT system mounted on a linac gantry. A lead beam stopper array was placed around the phantom to sample contaminant signal distribution as a function of gantry angle. CBCT 2D projection images were acquired with and without bowtie filter at two different isocenter locations in the phantom: one at the center (prostate imaging geometry), and one at the periphery of the phantom (liver or lungimaging geometry). For each image set, contaminant‐to‐primary signal ratios (CPR) were calculated in 20 projection views with equiangular spacing. Also, bowtie filter's efficacy on reducing the dynamic range of total image signal (primary+contaminant) was evaluated. Results: For centrally located isocenter (prostate case), the median CPR was reduced from 1.1 (80th percentile range: 0.39–2.44) to 0.955 (0.49–1.89) with the use of bowtie filter. Relative total signal ranged from 0.21 to 18.4, and it was reduced from 0.25 to 10.72 with the bowtie filter. For peripherally located isocenter (lung/liver case), the median CPR decreased from 1.27(0.48–3.32) to 1.25(0.41–2.4) with bowtie filter. Relative total signal ranged from 0.17 to 13.57, and it increased from 0.24 to 31.6 with the bowtie filter. Conclusions: Although the use of bowtie filter may appear to be simple and effective in reducing contaminant signals and the dynamic range requirements, a single universal design may have suboptimal efficacy for the variety of patient imaging geometries typically observed in radiation therapy setting.

Purpose: The BrainLAB Novalis™ system allows for the delivery of image guided frameless stereotactic radiosurgery(SRS). At our institution, we use the Novalis Body ExacTrac™ to image the patient and make appropriate setup corrections prior to each treatment arc. Due to mechanical limitations, some arcs cannot be imaged — potentially decreasing treatment accuracy. The goal of this work is to assess the impact of our inability to image these arcs using setup correction data. Method and Materials: Thirty patients treated with intra‐cranial, frameless SRS at our institution were randomly selected for analysis. Patients' had 1–5 isocenters and were treated using 4–24 dynamic‐conformal arcs (DCAs). A total of 264 DCAs were delivered with 166 imaged. Setup correction data based on these images were acquired and differential corrections taken over intervals of either one or two DCAs (corresponding to time intervals of approximately 2.5 or 5 minutes) were obtained. Data were also separated based on treatment isocenter to gain a time series representation of the observed setup corrections. Results: Distributions of one and two arc interval corrections were compared using a two‐sample Kolmogorov‐Smirnov test and found to be similar (5% significance level) with mean values (± SD) for lateral, longitudinal, and vertical offsets of 0.2±1.1mm, −0.1±1.4mm, −0.1±1.2mm (one arc), and 0.1±0.9mm, 0.1±1.2mm, −0.2±1.2mm (two arc) respectively. The distribution of 3D vector displacements for all setup corrections indicated the mean 3D offset after a 2.5–5 minute interval to be 1.6±0.1mm (± SE). No clear trend in mean 3D vector displacements over the course of treatment was evident. Conclusion: Failure to image a DCA on the Novalis system is likely to have little impact on the overall setup accuracy when the time interval between corrections does not exceed 5 minutes. Our data suggests this fact is independent of the total treatment length.

Purpose: Increased dose to proximal bronchial tree (PBT) has been associated with higher incidence of toxicities in prior lungSBRT trials. In this study, the effect of pencil beam (PB) dose calculations on the PBT dose for targets within the PBT zone was evaluated using Monte Carlo (MC).Methods:LungSBRT plans with PTVs within the PBT zone were generated for 10 patients using a commercial treatment planningsoftware equipped with PB and MC algorithms. PBT within 2 cm of the PTV region was contoured on CT datasets for all patients. Treatment plans were generated using two different dose calculation methods: i) Pencil beam algorithm without inhomogeneity correction (PB‐IHC), and ii) PB with inhomogeneity correction (PB+IHC). Both plans for each patient had identical beam geometry, but different MLC shapes were used to achieve similar conformai dose coverage of PTV. All plans were normalized to have 98% of PTV receive 60Gy in 3 fx. Dose distribution for each plan was recalculated with MC by keeping the monitor units the same in respective plans. Dosimetric comparisons were performed between PB‐IHC, PB+IHC, and MC based dose distributions, where MC dose distributions were assumed to be the gold standard. Results: The MC mean values for PTVD95, PTVDmax, PBTDmean, and PBTDmax outside the PTV region were 67.7Gy, 83.1Gy, 38.5Gy, and 64.5Gy respectively. These values were higher than PB‐IHC by 9%±4.5%, 17%±9%, 19%±6%, and 16%±5.8%, and were lower than PB+IHC by 13%±4.7%, 9%±1.5%, 5%±1.8%, and 8%±2.4%, respectively. Conclusion: Compared to MC, PB+IHC overestimates the dose to both PTV and PBT, and PB‐IHC underestimates the dose to both PTV and PBT. Unrecognized dose hotspots in this region might influence the risk of toxicity to proximal airways. This issue should be considered when analyzing clinical toxicity data calculated using PB‐based algorithms without heterogeneity corrections.