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Biology guided radiotherapy (BgRT) uses real-time PET data from the tumor to guide the planned dose to the tumor. The aim of this study is to test the effect of tumor growth on the accuracy of BgRT delivery. A custom-built fillable patient-specific quality assurance (PSQA) insert containing a ball target and a C-shape OAR was used. The ball shaped target is divided into 4 quadrants. Three of the 4 quadrants were filled with FDG using a target-to-background ratio of 8:1. PET avid area was contoured as GTV and a 5 mm margin was added to generate the PTV. An additional 5 mm margin was added to create Biology Tracking Zone (BTZ), where the PET emissions will be used to plan and treat using BgRT. The same PET biodistribution of three compartments filled (3/4) is used during the first set of BgRT deliveries to test the accuracy of this non-uniform biodistribution. In the second set of BgRT deliveries, all 4 quadrants of the ball target were filled with FDG to demonstrate the growth of tumor in the 4th compartment. Both BgRT deliveries were repeated multiple times as PET activity decayed down to 5 kBq/ml activity concentration (AC) or Normalized Target Signal (NTS) down to 2. Resulting BgRT delivery doses were captured with the patient-specific quality assurance (PSQA) and evaluated with 3%/2mm gamma criteria. For the 3/4th filled target BgRT experiment, the AC during PET modeling was 12.3, and during PreScan PET was AC was 19.7, 13.6, 10.9, 7.2, 6.1 and 5.1 kBq/ml. The Normalized Target Signal (NTS) during modeling was 12.3 while after PreScan PET NTS was 10.7, 8.6, 9.6, 6.2, 6.5 and 5.9. In tumor growth case where all quadrants were filled, the AC was 13.7, 12.1, 9.8, 9.5, and 5.5 while the NTS was 8.3, 7.2, 7.2, 7.9 and 7.0. The patient-specific quality assurance (PSQA) gamma pass rates were 93.2%, 97.4%, 96%, 100% and 92.9% for the 3/4 deliveries and 96.3%, 93.5%, 99.1%, 96.9% and 95.7% for the 4/4 delivery. The plan designed for the 3/4 biodistribution was successfully treated for both 3/4 filled case and 4/4 filled case. The accuracy of delivery was maintained as the FDG decayed as well as the shape of the tumor changed, suggesting that the BgRT delivery is robust even though the AC decreases to the half of the values that BgRT planned was based on. [ABSTRACT FROM AUTHOR]

Biology guided radiotherapy (BgRT) on a medical technology platform promise to fulfill a unique need for treating multiple metastatic tumors guided by the PET signal emitted from each target using a single injection. We investigate the feasibility of sequentially treating five small targets of varying diameters, in the same session, using one FDG fill. A custom patient-specific quality assurance (PSQA) insert containing five spherical targets of diameters 8, 9, 11, 13, 16 mm were each filled with FDG at a target-to-background (T:B) ratio of 20:1. The Modeling PET used to optimize the BgRT plan was acquired on medical technology within 25 minutes of filling the phantom. For treatment planning, the PTV was a 5 mm expansion of the PET-avid GTV, while the biology tracking zone (BTZ) was a 5 mm expansion of the PTV. Plan optimization and delivery to all five targets were completed on the same day. For each target, a 50 Gy in 5 fractions BgRT plan was optimized and were treated sequentially from small to large targets. During delivery, to test the effect of FDG decay on BgRT delivery, an injection to treatment time of 80 minutes is used for the 8 mm target while 230 minutes was used for the last target (16 mm). Activity concentration (AC, kBq/ml) and Normalized Target Signal (NTS) is measured for each target during modeling PET session and right before the BgRT delivery (PreScan PET). Margin loss and gain are defined as the maximum distance in mm between the planned and delivered BgRT 97% isodose lines. The absolute-dose gamma passing rates using 3%/2mm and 3%/3 mm criteria were used to evaluate the BgRT delivered doses captured using the patient-specific quality assurance (PSQA). All BgRT plans were successfully planned and delivered. For the five targets (in small to large order), the AC was 13.0, 20.0, 30.6, 42.4 and 56.8 during the PET modeling, and 10.4, 10.0, 12.4, 15.1 and 14.8 during PreScan PET preceding each BgRT plan delivery. The NTS for the five targets during PET modeling was 15.4, 25.9, 30.3, 26.2 and 31.4 while during PreScan PET was 10.6, 10.4, 14.0, 20.0 and 17.8. The patient-specific quality assurance (PSQA) pass rates at 3%/2mm were 88.3%, 98.0%, 95.5%, 99.2%, and 99.7% respectively, while 3%/3mm yielded 90.9%, 99.7%, 99.8%, 100% and 100%. The margin loss was 0, 1.0, 1.7, 1.6 and 1.5 mm, while the margin gain was 3.3, 0.5, 1.7, 0.5 and 1.3 mm. As expected, despite the same T:B fill concentration of 20:1, the detected PET AC was inversely proportional to target diameter in the PET modeling, where all targets were imaged at once. The lower PET AC during treatment compared to modeling PET was due to the FDG radioactive decay (half-life: 109 minutes) but was greater than 5kBq/ml AC limit for each target. Despite the lower PET counts during delivery, dosimetric results of these static BgRT deliveries were in good agreement for targets larger than 9 mm in this experiment. More tests will be performed to establish BgRT delivery accuracy for small targets both in static and motion deliveries, using varying T:B ratios. [ABSTRACT FROM AUTHOR]

In this study, we aimed to detect paroxysmal atrial fibrillation episodes before they occur so that patients can take precautions before putting their and others' lives in potentially life-threatening danger. We used the atrial fibrillation prediction database, open data from PhysioNet, and assembled our process based on convolutional neural networks. Conventional heart rate variability features are calculated from time-domain measures, frequency-domain measures using power spectral density estimations, time-frequency-domain measures using wavelet transform, and nonlinear Poincaré plot measures. In addition, we also applied an alternative heart rate normalization, which gave promising results only in a few studies, before calculating these heart rate variability features. We used these features directly and their normalized versions using min–max normalization and z-score normalization methods. Thus, heart rate variability features extracted from six different combinations of these normalizations, in addition to no normalization cases, were applied to the convolutional neural network classifier. We tuned the classifiers' hyperparameters using 90% of feature sets and tested the classifiers' performances using 10% of feature sets. The proposed approach resulted in 87.76% accuracy, 91.30% precision, 80.04% recall, and 87.50% f1-score in heart rate variability with z-score feature normalization. When the heart rate normalization was also utilized, the suggested method gave 100% accuracy, 100% precision, 100% recall, and 100% f1-score in heart rate variability with z-score feature normalization. The proposed method with heart rate normalization and z-score normalization methods resulted in better classification performance than similar studies in the literature. By comparing the existing studies, we conclude that our approach provides a much better tool to determine a near-future paroxysmal atrial fibrillation episode. However, although the achieved benchmarks are impressive, we note that the approach needs to be supported by other studies and on other datasets before clinical trials. [ABSTRACT FROM AUTHOR]

Biology-guided radiotherapy (BgRT) is a novel platform that combines real-time PET imaging with a 6MV Linac to target tumors. The performance and safety of BgRT was assessed in the BIOGUIDE-X clinical trial. This study aims to report on the BgRT workflow steps and assess the time required for each step of the BgRT process during this trial. A total of nine patients were enrolled in the second Cohort of the BIOGUIDE-X study which included patients treated with stereotactic body radiotherapy (SBRT) for lung tumors (5) and bone tumors (4). The pre-treatment BgRT workflow includes CT simulation, contouring, imaging-only (BgRT Modeling) PET acquisition, BgRT planning, patient specific QA and plan approval. The imaging-only PET acquisition on the X1 collects a representative PET volumetric 3D image and is an input to develop the BgRT treatment plan. The steps during the BgRT delivery session are kVCT localization, PET pre-scan, PET evaluation and BgRT delivery. The PET PreScan is a 1-pass short-duration PET acquisition that is used to confirm that the PET biodistribution on the day of treatment is consistent with that of the imaging-only PET. During BIOGUIDE-X, the BgRT delivery step was replaced by a 4-pass long-PET acquisition that was used to emulate the expected BgRT dose distribution without turning the beam on. To assess BgRT workflow, times from 18F-FDG injection to image-only PET acquisition, 18F-FDG injection to PET pre-scan, Pre-scan to PET evaluation, and PET evaluation to BgRT delivery (long PET acquisition) were recorded. Time between the 18F-FDG injection and the X1 imaging-only PET scan was 84 ± 19 minutes which includes time for 18F-FDG update. Average time to perform imaging-only PET scan was 26 ± 4 minutes. During the BgRT 'delivery' session, the mean time between the kVCT acquisition and PET pre-scan acquisition was 7 ± 3 minutes. The mean time to acquire a 1-pass PET pre-scan was 6 ± 1 then followed by 6 ± 1 minutes for the PET pre-scan dose calculation to estimate the BgRT doses that it would have delivered for this fraction. On average, the PET reconstruction, the PET signal localization verification and the evaluation of safety metrics took 11 ± 4 minutes. The mean time for BgRT 'delivery' was 27 ± 5 minutes based on the 4-pass long PET acquisition. Time from the start of the BgRT session to the end of the BgRT 'delivery' with this version of the investigative product release was 65 ± 9 minutes. The new processes introduced by the BgRT technology were evaluated and found clinically feasible. Improvements are being undertaken to shorten the time required for each step and to increase patient comfort ahead of BgRT clinical implementation. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): The X1 system ("X1") integrates a fully functional Positron Emission Tomography (PET) combined with a fan-beam kVCT system into the architecture of a ring-gantry linear accelerator (LINAC) for biology-guided radiotherapy (BgRT) delivery. The integration of PET into a LINAC framework required design features that deviate from the diagnostic setting. For instance, the X1 houses two opposed 90° PET arcs that rotate at 60 RPM to generate sinogram reconstructed images rather than a static, circumferential array of detectors. To better understand X1 PET performance, we conducted a side-by-side comparison of images of a PET phantom obtained sequentially on the X1 PET subsystem and a traditional PET/CT scanner.Materials/methods: An independent quality assurance phantom utilized a custom insert with two-insert targets filled with 18F-fluorodeoxyglucose (FDG) diluted water. Spherical target had a diameter of 22 mm and C-shape geometry consisted of an active volume of 26mm axial length and 255-degree partial annulus with major and minor radii of 27 mm x 12 mm, respectively. The targets were filled with an activity concentration of 9.3 kBq/ml to achieve a target to background ratio of 8:1 simulating the target uptake with hot background in a patient. The phantom was imaged within 30 minutes of preparation on the X1 PET and then immediately transferred to a PET/CT Biograph scanner for a second image. This experiment was repeated three times in separate days to assess reproducibility of PET acquisition. The PET images were visually assessed by the radiation oncologists to ensure the PET signal is within PTV. The PET signals of the targets were also evaluated using the full-width-half-max (FWHM) calculated on left-right (RL), anterior-posterior (AP) and superior-inferior (SI) directions for both targets and compared to the physical dimensions of the cavities.Results: The imaging acquisition tests were successfully completed on all three days for both systems, as per the prescribed workflow. In all experiments, radiation oncologists verified that the PET avid area were within the PTV in both systems. Average FWHM results of the 22 mm spherical target on X1 PET were 24.5, 21.7 and 17.0 mm as compared to 20.0, 20.0 and 18.2 mm for PET/CT in LR, AP and SI directions, respectively. For the C-shape object X1 PET resulted in 18.8, 19.5, 21.8 and 25.0 mm whereas the PET/CT resulted in 12.7, 13.2, 13.2 and 24.7 mm FWHMs for the two RL C-shape legs, AP and SI directions, respectively as compared to 15-, 15-, 15- and 26-mm physical dimensions.Conclusion: The X1 PET subsystem - which utilizes dual PET arcs and a sinogram image reconstruction algorithm in order to integrate into a LINAC architecture - generates images that are qualitatively comparable to a traditional PET scanner. In general, X1 FWHM results were slightly larger and PET/CT ones were smaller than the physical dimensions in axial plane. Both systems slightly underestimated the target size in SI direction. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): To evaluate Biology-guided Radiotherapy (BgRT) plans generated using PET data acquired on the first installation of the Reflexion™ X1 system. BgRT treatment planning optimizes for fluence indirectly by calculating firing filters that best translate the X1 acquired PET image to the fluences that deliver the prescribed radiation dose. During a treatment session, the firing filters are applied to limited time sampled (LTS) PET images to calculate delivery fluences.Materials/methods: An FDG fillable phantom insert that consists of a 22 mm diameter spherical target (PTV1, ball) and a C-shape object (PTV2 with 26mm axial length, 255° partial annulus with major and minor radii of 27 mm and 12 mm) was imaged using a CT Simulator to create planning contours. The water filled insert surrounding these objects was filled with FDG to simulate a warm background. Both targets were filled with FDG, simulating a target to background ratio of 8:1. Two different BgRT treatment plans were generated for PTV1 simulating homogenous uptake, and PTV2 with an inhomogeneous FDG uptake due to necrosis (a cylinder encompassing the C shape PET avid object). A structure that is 12.5 mm away from these targets was used to simulate OAR. Two PET/CT imaging acquisitions were performed on the RefleXion X1 masking the signal outside of each target plus 10 mm margin. Two different BgRT plans were generated prescribing 50 Gy delivered in 5 fractions to each target, separately. The quality of each treatment plan was evaluated based on PTV coverage, Conformity Index at 50% and 80% isodose lines (CI50, CI80) and OAR sparing. Both BgRT plans then delivered to the independent quality assurance tool for patient specific QA verification where the 3%/3 mm gamma criteria was used.Results: BgRT plans for both homogenous and heterogenous FDG uptake targets were created successfully. Prescription dose coverages were 94.2% and 96.3% for PTV1 and PTV2, respectively. The maximum OAR doses were 30.9 and 33.0 Gy and average OAR doses were 14.4 and 20.1 Gy for PTV1 and PTV2 plans, respectively. CI50 were 7.7 and 6.8 where CI80 were 2.5 and 2.6 for PTV1 and PTV2 plans. The patient specific QA passed with 100 % for both plans.Conclusion: This is the first report of the BgRT plan creation and QA delivery using a clinical installation of the Reflexion X1 system, opening the potential towards BgRT dose delivery using the real time FDG uptake measurements to biologically guide active radiation beam delivery. The X1 system was able to optimize and deliver the BgRT plans for both homogenous and heterogenous FDG uptake scenarios. BgRT is a new paradigm of dose optimization, where a new set of optimization and evaluation approaches will be needed. [ABSTRACT FROM AUTHOR]

BgRT was approved for clinical use and a medical technology company was commissioned for SCINTIX BgRT at our institution. These abstract aims to evaluate the congruence of the measured PET signal during BgRT and the delivered doses for the first two patients treated with BgRT to their lung tumors. Biology-guided Radiotherapy (BgRT) uses PET emissions from the patient to guide the radiotherapy beam to tumor. During delivery of BgRT, while the PET emissions are collected, they are converted into beamlets and delivered to the patient. At the end of this process, a PET image is reconstructed and the delivered dose is calculated for that fraction. Two patients were treated with SCINTIX™ BgRT at our institution, each receiving 50 Gy/4 fractions to their lung tumors. The GTV is contoured in end-expiration phase of the simulation 4DCT and a 5 mm margin was added to generate PTV. The tumor motion extent was captured using the ITV and a 10 mm margin was added to ITV to generate Biological Tracking Zone (BTZ). For each fraction, the mean PET intensity in GTV was measured and used to threshold the signal to find the centroid of PET biodistribution. The 80% isodose line, corresponding to 10 Gy, was converted to a volume and used to estimate the centroid of the delivered doses. The distance between the PET and 80% dose centroids were used to estimate the congruence of the PET signal and delivered BgRT doses for each fraction. For comparison, the BgRT plans were calculated with a grid size of 2.1 mm, and the PET image acquired had a grid size of 4 mm. Both patients were able to complete their course of treatment successfully. For Patient 1, the PET modeling mean PET signal in GTV was 19.5 kBq/ml and it was 22.0, 21.1 18.7 and 18.6 for the 4 fractions. Patient 2 had a PET modeling mean intensity of 18.8 kBq/ml and during the treatments it was 21.0, 14.3, 17.9 and 12.4. A total of eight post-treatment delivered dose volumes were calculated using the fluence patterns delivered by the X1. The mean congruence of the PET and delivered doses for patient 1 was 0.5, 2.0, 0.6 and 1.8 mm whereas the Patient 2 had the delivered doses agree with 1.3, 0.8, 2.7 and 1.4 mm for 4 fractions. From 8 fractions analyzed, the maximum disagreement was 1.0, 2.4 and 1.7 mm in the L/R, A/P and S/I directions. The BgRT doses agreed well with the isocenter of the PET, confirming that the medical technology company system delivered doses for both patients where the PET signal was emanating from. Given the pixel size of the dose calculation (2.1 mm) and the PET pixel size (4.0 mm), the measured agreement provide assurance for the geometric accuracy of BgRT delivery in patients. [ABSTRACT FROM AUTHOR]

Histological images play a critical role in both clinical pathology and preclinical research. For instance, one way to study normal tissue radiation response is to assess the intestinal crypts in histological images. However, discrepancies in staining protocols can introduce visual inconsistencies among images, which not only challenge human interpretation but also impede the effectiveness and reliability of automated analytical systems, including deep learning (DL) models. Here, we explored an unsupervised attention-guided DL method for stain normalization in H&E-stained histological images to enhance subsequent analysis and automation process. Our dataset consists of 350 H&E-stained mouse intestinal cross-section images from a prior study on abdominal normal tissue response to radiation. Experts categorized these images into two sets: (1) 200 target images (187/13 for train/test) representing the desired target stain style, and (2) 150 source images (136/14 for train/test) with suboptimal stain styles to normalize. Within each group, stain variations are also present. CycleGAN serves as the backbone model. Additionally, to obtain a realistic stain translation preserving all content details, attention network was implemented in each generator to highlight the discriminative regions between the source and target domains, thereby focusing the generator's efforts on these relevant areas. The network was trained without the need for paired images or additional supervision, aiming to translate source images into the target stain style accurately. Furthermore, to assess the effectiveness of our stain normalization technique, we compared the performance of an in-house DL model for auto-detection of intestinal crypts on both original and normalized images. This model, specifically trained on images with the target stain style, allowed us to quantitatively evaluate the improvement in downstream histological analysis post-normalization. Qualitatively, our approach generates images that not only match the desired stain characteristics but also retain all structural details. Quantitatively, we achieved a structural similarity index (SSIM) of 0.89 between source and normalized images. Notably, applying our stain normalization method markedly enhanced the performance of the subsequent crypt auto-detection. The sensitivity of detecting intestinal crypts increased dramatically from 0 to 0.72 when utilizing the normalized images compared to the original ones with stain variations. Our approach demonstrates a robust capability to normalize stain color distributions across histological images without compromising their structural content. This method is adaptable to a wide range of histological image types, holding significant potential to enhance the accuracy, reliability, and resource utilization of subsequent image analysis processes, particularly in deep learning-based downstream tasks. [ABSTRACT FROM AUTHOR]

A Biology-guided Radiotherapy (BgRT) based device is designed to use Positron Emission Tomography (PET) signals to achieve tracked dose delivery. The goal of this study is to investigate the dose delivery accuracy in case of interruption during BgRT treatment, and resumption in a separate treatment session for a multi-target delivery, as the PET activity continues to decay. A custom-built large anthropomorphic phantom (LAP) including a 26 mm spherical target with 3D independent motion and two 22 mm spherical targets with 1D sinusoidal motion embedded in water was used. All three targets were filled with FGD in an 8:1 target to background uptake ratio (41.52 kBq/ml in target and 5.19 kBq/ml in background). During BgRT delivery, the treatment was intentionally paused during delivery to the second target and the current treatment session was ended to generate a partial fraction. Then the partial fraction was continued in a new session, where the CT scan localization and PET pre-scan were repeated using the existing PET activity present in the phantom. The newly acquired PET pre-scan, was then used to determine if sufficient PET counts were present to resume treatment delivery. The interruption and recovery algorithm is designed to calculate the fluence that needs to be delivered to the remaining targets as well as the residual fluence to be given to the targets that have already received partial dose prior to the interruption. Once the new fluence is recomputed, the treatment is resumed. The delivered doses were captured using radiochromic film (EBT-XD) inserted in the target as well as post-treatment dose calculations based on the delivered beamlet sequence to evaluate the results in terms of dosimetric coverage and margin loss. The margin loss is calculated as the maximum difference between the distance from the Clinical Target Volume (CTV) contour to the 97% isodose contour in the treatment plan and the on the film. The dosimetric coverage is defined as the percentage of voxels within the CTV that lies within 97% and 130% of the prescribed dose. As shown in the table below, a margin loss of less than 3 mm for all targets and 100% CTV coverage was achieved. After treatment interruptions, the PET safety evaluation based on the PET pre-scan helped to determine whether the treatment could be continued on the same day using the same injected PET activity (an NTS value ≧ 2 and AC value ≧ 5 kBq/ml). This study demonstrated that the BgRT system is able to deliver the prescribed dose to all targets with independent motion, even when an interruption and resumption occurs during treatment. In case such an interruption if the remaining PET activity satisfies the BgRT safety evaluation, the treatment can continue to deliver the remainder of the BgRT doses. [ABSTRACT FROM AUTHOR]

Post-lumpectomy radiotherapy (RT) reduces in-breast tumor recurrence by eradicating residual, occult breast cancer (BC) that may be in the mm size scale. The ability of FLASH-RT to eradicate BC relative to conventional dose rate (CONV) RT is unknown. ∼ 20Gy RT is currently used clinically for single-fraction breast IORT. Determine the effectiveness of FLASH compared to CONV in eradicating small tumors in an orthotopic, syngeneic model of BC using single-fraction 20 or 30Gy RT. Radiation sensitive, mammary tumor cell line Py117 from the transgenic model of the mouse mammary tumor virus promoter driving the polyoma middle T antigen (MMTV- PyMT) efficiently forms non-metastatic, orthotopic tumors in C57BL/6 mice. 106 Py117 cells were injected orthotopically into the left 4th mammary fat pad of C57Bl/6J mice. Radiotherapy was performed with a custom jig that allows for fixed positioning of the target volume (2x2cm radiation field) with 5mm of margin into surrounding tissue. Tumors were irradiated at ∼30mm3 volume or, for comparison, at a range of greater volumes (200-800mm3) with 20 or 30Gy FLASH or CONV with 16-17 MeV electrons. Small 30mm3 tumors regressed until ∼ day 15 after 20Gy single fraction RT then regrew for both FLASH and CONV. 30mm3 tumors were eradicated with both FLASH and CONV at 30Gy with no regrowth up to day 35 post-RT. Larger tumors irradiated with 30Gy regressed until ∼ day 12 post-RT then regrew for both FLASH and CONV. There was no significant difference in growth delay or tumor eradication between FLASH and CONV in any cohort. FLASH was as effective as CONV in controlling growth and eradicating murine BC. Based on other preclinical studies, single-fraction doses between 20 and 30Gy, as well as hypofractioned RT schedules, may identify FLASH doses that achieve comparable tumor control with less toxicity than CONV. Such findings would encourage clinical trials of FLASH in human BC. [ABSTRACT FROM AUTHOR]

A classical approach for evaluating normal tissue radiation response is to count the number of intestinal regenerating crypts in mouse histological images acquired after abdominal radiation. However, manual counting is time-consuming and subject to inter-observer variations. The goal of this study is to build a deep learning-based pipeline for automatically identifying intestinal regenerating crypts to facilitate high-throughput studies. Sixty-six healthy C57BL/6 female mice underwent 16 MeV whole abdominal electron irradiation. The small bowel was collected from each mouse 4 days post-irradiation, and 9 jejunal cross-sections from each were processed together in a single slide. The slides were stained with hematoxylin and eosin (H&E) and subsequently scanned (x20), providing one electronic histological image per mouse. Regenerating crypts, consisting of more than 10 basophilic crypt epithelial cells, were manually identified using point annotations in histological images. The pipeline was built to take the input of the image containing 9 cross sections and automatically identify the regenerating crypts on each cross section. It mainly consists of two components, cross section segmentation using intensity thresholding and morphological operations and crypt identification using a UNet. The dataset was randomly split into 46, 10, and 10 slide images for UNet training, validation, and testing. Each slide image was split into grid tiles with a voxel size of 200 × 200, and 40 × 40 square masks were placed with centers at manual point annotations on tiles with regenerating crypts. 5203/5198 tiles (w/wo crypt mask) were extracted to train UNet by minimizing dice loss. The mask probability map generated by the UNet was post-processed to identify the crypt position. Postprocessing hyperparameters were tuned using the validation dataset. The model accuracy was evaluated using the testing dataset by computing the mean absolute error (MAE) of the crypt number averaged across all cross sections. The number of regenerating crypts on testing cross sections ranges from 1 to 63. The testing cross-section-wise MAE achieved by the platform is 3.5±4.8 crypts. 81.25% of testing cross sections have absolute number differences less than or equal to 5 crypts. Our established deep learning-based pipeline can accurately count the number of regenerating crypts in mouse intestinal histological images. We have integrated it into an online platform that enables automatic crypt identification and allows users to interactively modify auto-identified crypt annotations. The acquired annotations from the platform will be used to finetune the deep learning model to achieve better identification performance. [ABSTRACT FROM AUTHOR]

We present the first dosimetric measurements of single session, multi-target BgRT deliveries using a clinically realistic motion phantom on a research-only version of the RefleXion X1 system. A custom-made anthropomorphic phantom of a human torso with embedded fillable targets mimicking 18F-FDG-avid lesions was used. From the three embedded spherical targets, Target 1 was 26 mm in diameter coupled with a 3D independent respiratory motion with 22 mm range, whereas Target 2 and 3 were 22 mm in diameter and moved with a 1D 5 mm maximum sinusoidal motion. The 18F-FDG concentration in the background cavity of the phantom was 5 kBq/ml, and the targets were loaded with 10:1, 8:1 and 6:1 contrast relative to the background for Targets 1, 2, 3, respectively. Spherical structures were contoured as GTVs (CTV = GTV) and a 5 mm margin was added to create PTVs. Motion extent of the tumors were captured to create biological tracking zones for each target. Treatment plans were generated using a research version of the Reflexion treatment planning software to deliver 8 Gy/fx to the PTVs. The treatment delivery was repeated 2 times, and each time the phantom was refilled according to the plan. PET image evaluation metrics for each of the three targets were also recorded. Target dosimetry was measured using a combination of radiographic film and ion chamber. The maximum distance between the 97% prescription isodose line from the plan and the film measurements was used to characterize the dosimetric accuracy of the tracked deliveries. CTV and PTV min, max, and mean doses measured on film were also recorded for each target. Treatment plans were successfully created with 100% prescription dose coverage to each target loaded with different FDG ratios. Total treatment times for the single-plan, three-target deliveries were less than 80 minutes. PET evaluation metrics at imaging-only and pre-scan, and planning and film dosimetry to the GTV and PTV for each of the three targets is shown in table below (mean ± standard deviation of both deliveries). The CTV dose coverage was maintained for all targets. The shrinkage distance of the 97% prescription dose isodose line on the film plane for all three targets was less than 3 mm for both tests, and ranged from -0.4 to -2.34 mm. These results demonstrate that high tracking accuracy and dosimetric accuracy can be achieved in single session, multi-target deliveries over a range of target-to-background 18F-FDG concentrations and target motion patterns. [ABSTRACT FROM AUTHOR]

Biology-guided radiotherapy (BgRT) is a novel tracked dose delivery modality using real-time positron emission tomography (PET) to guide radiotherapy beamlets. The present study was performed with sequential cohorts of participants to evaluate the performance and safety of BgRT. Primary endpoints were previously reported. We hereby report on one of the secondary endpoints assessing a novel treatment planning machine with integrated dual kVCT/PET imaging ("novel device") performance in comparison to a third-party diagnostic PET/CT scan. This single-arm, open-label, prospective study included participants with at least 1 FDG-avid targetable primary or metastatic tumor (≥2cm and ≤5cm) in the lung or bone. PET imaging data were collected on the novel device and on a third-party diagnostic PET/CT performed in sequence once at the planning timepoint in Cohort I, and immediately before the last fraction among patients undergoing stereotactic radiotherapy in Cohort II. Three central read radiation oncologists (CRRO) provided an interpretation of the novel device PET scans which were compared to an agreement standard based on 3 central radiologists' review of the paired diagnostic PET/CT scan. Positive percent agreement for localization of the target tumor within the biology-tracking zone (BTZ) was the key metric because it reflects whether advancing patients to subsequent steps in the BgRT workflow based on the novel device's imaging was ultimately appropriate. In Cohort 1, 6 image comparisons were performed. The positive (%) agreement for the aggregate radiation oncologist review was 100% (5/5), reflecting that in all 5 cases where the aggregate radiation oncologists deemed the tumor to fall within the BTZ based upon the novel device PET images, the central radiologists came to the same conclusion upon review of the paired diagnostic PET/CT images. The overall (%) agreement for the aggregate radiation oncologist review was 83.3% (5/6): localization was not established on the novel device in 1 case, even though it was established on the diagnostic PET/CT. This would not pose risk in real world practice as BgRT candidacy would be aborted for tumors not visible on the novel device. In Cohort II, among the 7 image comparisons, there was 100% positive percent agreement between the aggregate CRRO and the agreement standard as the localization criteria was met in both scans for all 7 patients. This was concordant with a 100% overall percent agreement. This investigation demonstrated a 100% positive percent agreement between central review of this novel device images by radiation oncologists and central review of the accompanying third-party PET/CT images by radiologists. There were no cases where a positive localization by the aggregate CRRO was not confirmed by the third-party PET/CT standard, providing evidence against the likelihood of falsely positive localizations on the novel device that would inappropriately advance patients in the workflow. [ABSTRACT FROM AUTHOR]

For safe clinical translation of electron FLASH, hardware tools for real-time beam control and software tools for treatment planning are necessary. The purpose of this study is to prototype high-throughput hardware for real-time beam control, along with accurate beam modeling of a modern clinical Linac configured to deliver FLASH dose-rates. For real-time beam current monitoring, a beam current transformer (BCT) was initially coupled to a fast digitizer and its linearity was established by varying dose per pulse. The radiation pulse width was modified, and this change was measured using the BCT. The BCT was then used to measure the variability of dose per pulse and pulse width due to a mistuned linear accelerator system. Next, the BCT was interfaced with a field programmable gate array (FPGA) which provides the ability for high-throughput and deterministic control of the Linac based on dose accumulation. For beam modeling, the program, TOol for PArticle Simulation (TOPAS), was used to obtain beam parameters by using Bayesian optimization of the beam energy, source size, angular, and energy spread via comparison of simulated and representative dose profiles. The beam model would then be employed to calculate 3D dose distribution in a CT scan of a 3D-printed anatomically realistic mouse phantom. The area under the current-time curve from the BCT exhibited excellent linearity (response = 12.80 nC/Gy) up to 2.5 Gy/Pulse (R2 = 0.99). The peak beam current for the electron FLASH beam was measured to be ∼10 mA for an instantaneous dose-rate of ∼5×105 Gy/s. The measured radiation pulse width agreed with the expected value (3.7 μs). The pulse width was then shortened and the measurement by the BCT indicated pulse widths of 1.8 μs and 0.5 μs corresponding to 0.7 Gy/pulse and 0.3 Gy/pulse, respectively. The beamline exhibited a ramp-up in dose per pulse and pulse width when using the automatic frequency controller (AFC). For the first pulse, the dose delivered was ∼0.1-0.3 Gy and the pulse width was 0.6 μs. The output stabilized to nominal values of dose and pulse width after 3-4 pulses. This ramp-up was mitigated by manually tuning the RF resonance with the AFC disabled, after which the BCT exhibited constant output and pulse width. The beam modeling work is in progress. We demonstrated that a BCT can provide real-time measurement of per-pulse output suitable as input for FLASH beam control based on dose accumulation. The next steps are to quantify the accuracy of the dose control mechanism with the FPGA-based hardware. Potential failure modes will be identified and mitigated in parallel with the development of the hardware. A 3D-printed mouse phantom has been constructed to facilitate beam modeling work for treatment planning (in progress). On completion of this work, it is expected that we will have key infrastructure elements needed to move towards an eventual FDA investigational device exemption for clinical trials. [ABSTRACT FROM AUTHOR]

Biology-guided radiotherapy (BgRT) uses outgoing emissions after administration of an injected radiotracer to dynamically guide the delivery of radiation treatment to PET-avid targets. In this study, we evaluated the tracking performance of FDG-guided BGRT for two potential types of motion management (respiratory and non-respiratory (gastrointestinal)) while exploring different target shapes: spherical and non-spherical. BgRT is designed to ensure target coverage while keeping organ-at-risk (OAR) doses low. A large custom anthropomorphic phantom with 2 robotic articulating arms was used to place a target and organ-at-risk inside a 27-liter water filled cavity. The targets consisted of an integrated ion chamber inside a 3D printed 22 mm sphere or a small non-spherical ovoid shape filled with FDG. The hot FDG-filled OAR consisted of either a 3D printed large C-shape annulus (mimicking a heart), large ovoid (mimicking a kidney), or a 30 mm sphere, all with integrated ion chambers. Both the 3D printed target and the OAR were filled with an 8:1 concentration ratio versus the water background. Three different 10 Gy/fraction treatment plans with two different target shapes and realistic nearby OARs were created with a 5 mm margin added to the CTV to generate the PTV. 3D printed targets and OARs were loaded with EBT-XD radiographic film. A 3D elliptical motion trajectory with breathing induced hysteresis with a maximum amplitude of +/- 12 mm was used for the respiratory motion model. An asymmetric slow-moving drift waveform with long-step shifts of +13/-5mm mm was used for the non-respiratory (gastrointestinal) motion model. Dosimetric results were evaluated based on 2-dimensional comparisons between measured film and planned dose distributions for the target and OAR. BgRT must maintain a prescription dose margin greater than 2 mm on the CTV for the three different motion experiments. Also, ion-chamber point dose and maximum film dose on the OAR must be within bounds predicted by the treatment planning system. BgRT was able to meet minimum margin requirements (a margin loss < 3mm) and meet prescription dose coverage in both motion management scenarios while maintaining OAR dose limits within the plan predicted bounds (see Table 1). BgRT is able to provide motion management in complex cases that is agnostic to the type of motion. BgRT is able to maintain the PTV coverage with less than 3 mm reduction from the original 5mm margin. [ABSTRACT FROM AUTHOR]

The first clinical biology-guided radiation therapy (BgRT) system – RefleXionTM X1 - was installed and commissioned for clinical use at our institution. This study aimed at evaluating the treatment plan quality and delivery efficiency for IMRT/SBRT cases without PET-guidance. Forty-two patient plans across six cancer sites (conventionally-fractionated lung, head and neck, anus, prostate, brain, and lung SBRT) planned with the EclipseTM treatment planning system (TPS) and treated with either a TrueBeam® or Trilogy® were selected for this retrospective study. For each Eclipse VMAT plan, two corresponding plans were generated on the X1 TPS with 10 mm jaws (X1 10mm) and 20 mm jaws (X1 20mm) using our institutional planning constraints. All clinically relevant metrics in this study, including PTV D95%, PTV D2%, Conformity Index (CI), R50, organs- at-risk (OAR) constraints, and beam-on time were analyzed and compared between 126 VMAT and RefleXion plans using paired t-tests. All but three planning metrics were either equivalent or superior for the X1 10mm plans as compared to the Eclipse VMAT plans across all planning sites investigated. The Eclipse VMAT and X1 10mm plans generally achieved superior plan quality and sharper dose fall-off superior/inferior to targets as compared to the X1 20mm plans, however, the X1 20mm plans were still considered acceptable for treatment. Strong correlation was observed between the TPS-calculated beam-on time and PTV length in the superior-inferior direction for the X1 10mm (R 2 = 0. 87) and X1 20mm (R 2 = 0. 85) plans. On average, the required beam-on time increased by a factor of 1.6 across all sites for X1 10mm compared to X1 20mm plans. Clinically acceptable IMRT/SBRT treatment plans were generated with the X1 TPS for both the 10 mm and 20 mm jaw settings. The X1 10mm plans were equivalent or superior to the Eclipse VMAT plans, however the beam-on times were longer. [ABSTRACT FROM AUTHOR]

Biology-guided radiotherapy (BgRT) is a novel tracked dose delivery modality that uses positron emission tomography (PET) emissions to deliver hypofractionated planned fluence to the target. This study evaluated PET biodistribution changes within target during BgRT delivery. Two phantom experiments were designed to evaluate the FDG signal variations and dosimetric effects under stationary target and moving target on a non-clinical investigational radiotherapy system. For the stationary case, a custom built cylindrical 4-D detector phantom insert with a spherical target of 22 mm in diameter containing 4 quadrants that can be filled independently was used to mimic homogenous and non-homogenous FDG uptake conditions. A C-shape insert was used as a PET avid OAR. For simulating PET signal loss within tumor: BgRT plan was created for the spherical target with all quadrants filled and the plan was delivered when ¾ volume of the target was PET-avid. For the PET signal gain within tumor scenario: BgRT plan was created for the same spherical CTV structure where ¾ volume of the target was filled with FDG, mimicking non-homogeneous uptake, and delivered to a full volume PET-avid target. The dosimetric accuracy of BgRT delivery was evaluated using 3%/3 mm Gamma criterion using 4-D detector measurements. Target biodistribution changes under motion was evaluated by creating a BgRT plan with an FDG filled 26 mm diameter spherical target as a CTV and C-shape OAR moving independently (target:3D respiratory, OAR: sinusoidal motions) within a large water filled phantom. During BgRT delivery the PET avid target insert was switched to a smaller 22 mm spherical insert, simulating 40% uniform PET distribution reduction within 26mm CTV. For the moving target experiment, BgRT delivered dose was evaluated using the radiographic film under the condition of CTV coverage ≥97% and maximum dose ≤130%. For all the experiments, the target and the C-shaped OAR were filled with FDG at a ratio of 8:1 with respect to the water background mimicking normal tissue uptake, and a 5 mm CTV to PTV expansion to be targeted with a prescription of 50Gy in 5 fractions. For the stationary scenarios, BgRT delivery at remissive and progressive conditions achieved gamma pass-rate of 93.2 and 97.7%, respectively. The CTV coverage goals for the motion experiment were met where the minimum CTV dose was 103.3% and the maximum dose was 123.8%. This study evaluated the biodistribution changes within CTV from planning to delivery suggesting the BgRT delivery is robust with respect to daily variations of PET signal within the PTV under these experimental conditions. Clinical feasibility of BgRT needs further evaluation. [ABSTRACT FROM AUTHOR]

Studies show ultra-high dose rate (UHDR) radiotherapy (RT), at rates of ≥40 Gy per second, can produce the FLASH effect: reduced toxicity with equal tumor control when compared to conventional RT. Leveraging these benefits for clinical translation can profoundly impact RT. Early clinical trials exhibited safe delivery of UHDR-RT using specialized RT machines. Our prior study showed that a reversible configuration of a standard linear accelerator (LINAC) can be optimized for UHDR output. Here, we explored the components necessary for clinically practical delivery of LINAC-based electron FLASH RT. Using a standard, clinically operational system for image-guided radiation, we configured the program board for a decommissioned electron beam energy for UHDR delivery. No LINAC hardware manipulation or exchange was performed. Key changes included adjustment of the dose per pulse and pulse delivery control using the gating interface. Of note, the scattering foil remained in place within the beam so that field sizes and depth doses could approximate those of standard clinical operations. A commercial electron arc applicator was installed at the face of the gantry using the standard applicator mount to allow for short SSD electron collimation. Copper electron blocks were fabricated with apertures ranging from 3.0 to 20.0 cm. Dose rates were measured at dmax for 100 to 59 cm source-to-surface distances (SSD) (level of machine head) and beam profile measurements were captured at 80 cm SSD using an IC profiler and radiographic film. UHDR rates ranging from 36.8 to 112.8 Gy/s were measured at 100 to 59 cm SSD, respectively. An 80 cm SSD was selected for treatment arrangement measurements to maintain UHDR and clinical utility, allowing for 13.5 cm of clearance. UHDR ≥60 Gy/s was observed at 80 cm SSD with all field sizes, using a standard, scattered electron beam, with an R80 depth of 6.1 cm, approximating to a 16-18 MeV energy. Average dose per pulse was measured at 0.33 Gy/pulse. Circular block apertures of 3, 10, and 20 cm exhibited beam flatness <5.0 % variability and symmetry of 2.2 to 6.2%. Penumbra width between the 80 and 20% isodose lines (IDL) measured at 0.7, 1.1, and 1.4 cm, respectively. Optimizing a reversible setup for UHDR irradiation on a standard LINAC, electron delivery at dose rates expected to produce the FLASH effect was achieved. Flat, homogenous field sizes, ranging from 3 to 20 cm of coverage, were obtained at a clinically practical SSD of 80 cm with a treatment depth of 6.1 cm to the 80% IDL. This setup would enable UHDR irradiation at useful depths for a number of different clinical indications, bringing us a step closer to practical UHDR RT using a standard LINAC in future clinical trials. [ABSTRACT FROM AUTHOR]

Ultra-high dose rate (UHDR) radiotherapy (RT) at ≥40 Gy/s has been shown preclinically to reduce toxicity with similar tumor control compared to conventional RT, a phenomenon known as the FLASH effect. We previously described a configuration of a clinical-use LINAC that can output ∼17 MeV electron UHDR RT at 45-80 Gy/s with clinically feasible beam profiles, field sizes (3-20 cm), and SSDs (70-90 cm). Safe and effective clinical trials are needed to advance translation of FLASH treatment in humans, such as one proposed at our institution for cutaneous lymphomas. This study characterizes the beam output of our electron UHDR RT set-up under realistic clinical conditions for common anatomic sites using an anthropomorphic phantom, to assess its feasibility for clinical translation. Our electron UHDR RT set-up utilizes a treatment delivery system with a configured program board of a decommissioned electron energy to adjust the beam output and control, without hardware modification. The electron cone is replaced with a flat applicator with custom cut-outs that lies in the accessory mount. We tested this set-up under realistic clinical conditions on a RANDO phantom for treatment of the chest/breast, leg, and scalp. We used 3 cm and 10 cm circular field sizes at 80 cm SSD with the gantry angled en-face to the targets. Tissue-equivalent bolus and flexible tungsten-silicone skin collimators (made from silicone sheets with tungsten powder cut into donut shapes of varying diameters) were used to mimic clinical treatment standards. Measurements were done using radiographic film and we evaluated the beam width, percent depth dose, and penumbra width. All results reported include 1 cm bolus and skin collimators unless otherwise specified. The values for R80 (depth at 80% dose), beam width of 80% dose (at R95), and penumbra width (at R85) for the 10 cm chest/breast field are 5.2, 8.7, and 0.9 cm, respectively. Without skin collimators, the values are 5.4, 9.0, and 1.2 cm, respectively. The values for the 3 cm chest/breast field are 2.9, 1.9, and 0.6 cm, respectively. Without skin collimators, the values are 3.2, 1.9, and 0.7 cm, respectively. The values for the 10 cm leg field are 4.0, 6.6, and 0.9 cm, respectively. The values for the 3 cm scalp field (with 4 cm bolus to minimize dose penetration to the brain) are 1.1, 1.6, and 0.9 cm, respectively. The steep curvature of the leg and scalp sites led to expected decrease in beam flatness but retained a treatment area that allows for a reasonable range of tumor sizes and depths. Our configuration is able to deliver electron UHDR RT with clinically applicable beam profiles to various anatomic sites under realistic clinical conditions. Tungsten-silicone skin collimators are an easy-to-use tool to narrow the penumbra. Overall, these results show potential for treatment of superficial indications, including cutaneous lymphoma, extremity sarcoma, and partial breast irradiation, and place us one step closer toward the clinical translation of FLASH. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): The first clinical biology-guided radiation therapy (BgRT) system - RefleXion X1 - is installed and is being commissioned for clinical use at our institution. The system delivers 6MV-FFF beam via 50 firing positions at 850 cGy/min dose rate on 60 rpm rotating gantry with the couch advancing in 2.1 mm increments. Collimation is achieved through a binary multi-leaf collimator system composed of 64 (6.25 mm width at 850 cm SAD) leaves and 10mm or 20mm jaws. The purpose of this study was to compare the treatment plan quality and delivery efficiency for SBRT cases without PET-guidance.Materials/methods: Five lung cancer patients (50 Gy/4fx) with motion-inclusive PTV previously treated with VMAT SBRT were selected for this retrospective study. For each VMAT plan a corresponding plan was generated on the RefleXion treatment planning system (TPS) using our institutional planning constraints. VMAT SBRT plans used 1-2 partial arcs with 10MV-FFF energy and 2400 MU/min dose rate. RefleXion SBRT plans used all 50 firing positions and 1 cm jaw collimation. As plan normalization option does not yet exist in the RefleXion TPS, the plans were optimized to achieve PTV D95% coverage with 100% of prescription dose to the best of planner's ability. All clinically relevant metrics in this study, including plan PTV D95%, PTV D1%, 50% isodose volume (I50%), Conformity Index (CI), organs at risk constraints, and treatment time were analyzed and compared between VMAT and RefleXion plans using paired t-tests.Results: Clinically acceptable plans were obtained with both techniques. The average PTV volume was 14.1 ± 6.4cc. For VMAT and RefleXion plans, no statistically significant difference was observed in PTV D95%, PTV D1%, CI or I50%. Ipsilateral lung volume spared at 12.4 Gy (VS12.4) was slightly greater (31.6cc increase, P < 0.035) and skin Dmax was slightly lower (1.4 Gy decrease, P < 0.038) for RefleXion plans. Treatment beam-on time was significantly longer for RefleXion plans (23.4min increase, P < 0.0002).Conclusion: RefleXion TPS provided comparable plan quality to lung SBRT VMAT plans. Treatment beam-on time is significantly longer for the RefleXion system. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): A novel therapeutic machine that combines PET, fan beam kVCT and linear accelerator to support real-time PET-guided treatment, termed biology-guided radiotherapy (BgRT). This study reports the positioning accuracy, image quality, and dose commissioning of the kVCT imaging system of the first clinical BgRT machine at our institute.Materials/methods: The helical fan-beam kVCT subsystem consists of an X-ray tube with a voltage of 120kV and a 16-row GOS Ceramic Scintillator detector. The gantry rotation speed is 60 rpm. The tube currents are 45, 67, 133mA for 0.5 pitch; 100, 150, and 300mA for 0.5 pitch; 267 and 400mA for 1.333 pitch. The image slice thickness is 1.25mm with a field of view of 500mm and a resolution of 512 × 512. A ball-cube phantom was used to test the positioning accuracy of the kVCT subsystem with respect to the setup laser and MV beam. Catphan504 phantom was imaged with 0.5 pitch and 150mAs to test the kVCT image quality of the BgRT system, including the uniformity, noise, HU constancy, spatial resolution, geometric distortion, slice thickness, and low contrast visibility and detectability using the PIPSproTM software. The RTI MAS-2 and Piranha detectors were used to verify the accuracy of the mA and voltage. The CTDI dose was measured using a CTDI phantom and a Standard Imaging A101 pencil chamber.Results: The localization error of the ball cube phantom was -0.8, 0.9, and 0.3mm in IEC x, y, and z directions, respectively. For the Catphan504 tests, the vertical and horizontal uniformities were 0.926 and 0.857, respectively. The HU constancy tests of the air, water, polystyrene, acrylic, Delrin, Teflon were all within 40HU to the expected values. The modulation transfer function test results were 0.467, 0.528, and 0.595 lp/mm for F50, F40, and F30, respectively, which showed a comparable spatial resolution to regular CT simulators. The geometric distortion was 0.12mm and slice thickness inaccuracy was 0.13mm. The low contrast detectability was 0.734. The measured mA and voltage were within 5% of the nominal setting of 120 kV and 150 mA. The CTDIw was less than 1.4 cGy for body and 3 cGy for head with a protocol of 120 kVp, 150 mAs, and 1.25 mm slice thickness.Conclusion: This evaluation represents the kVCT characteristics of the novel BgRT system with architecture designed to accommodate CT, PET and a LINAC. The image quality and HU constancy are comparable to our CT simulators and is a useful tool for online adaptive radiotherapy. The commissioning data will serve as a standard for units installed at future clinical sites. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): A biologically guided radiotherapy (BgRT) system was developed and equipped with a novel O-ring gantry Linac, positron emission tomography (PET) and computed tomography technologies. This architectural design is to support real-time PET-guided treatment, termed biology-guided radiotherapy. To reduce latency between PET data acquisition and radiation delivery, the BgRT system incorporates a fast-transitioning binary multi-leaf collimator (MLC) leaves sandwiched between a split-jaw. This study reports the dosimetric commissioning of the first clinical BgRT machines at our institution, and compared with the reference data provided by the manufacturer.Materials/methods: The dosimetric commissioning of the 6 MV flattening filter-free (FFF) photon beam was characterized using a 3D water phantom and diode detectors at a source to surface distance of 85 cm. In-air profiles of 40cm x 2cm field, 40cm x 1cm field, and various leaf combinations plus in water PDD data of 12 field sizes (1.25, 2.5, 5, 10, 20 and 40 cm MLC opened leaves with 1 and 2cm jaw settings) were acquired first for beam modeling. Additional longitudinal and transverse profile scans were performed for these 12 field sizes at the depth of 1.5, 5, 10, 15 and 20 cm to verify the beam model accuracy. The relative outputs factors were measured with the W2 1mmx1mm scintillator at the depth of 10cm for the field sizes from the smallest 0.6cm x 1cm to the maximum 40cm x 2cm.Results: For the PDDs of reference field size of 10cm x 2cm measured at Stanford, the maximum doses (dmax) were 12.5mm within the manufacturer's reference range of 13 ± 0.75 mm. The percentage doses at 10cm depth (d10) at reference field size were 56.9% and 57.6% for Stanford and RefleXion measurements, respectively. The longitudinal field sizes for all tested fields were agreed within 0.5mm and the transverse off-axis ratio is within 1% in the beam core (80% of nominal field size). The output factors measured at our institute were ranging from 0.706 to 1.012 relative to the reference 10cm x 2cm field.Conclusion: This evaluation represents the first commissioning evaluation of the dosimetric characteristics of the BgRT system with architecture designed to accommodate both PET detector and LINAC subsystems. This data will serve as a clinical reference for the BgRT treatment planning system's beam model and can act as a standard for comparison and beam model improvement for units installed at future clinical sites. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Multiple preclinical in-vivo studies of ultra-high dose rate (FLASH) radiation therapy (RT) have shown reduced normal tissue toxicity with equivalent tumor control when compared to conventional dose rate RT, with benefits seen at dose rates ≥40 Gray (Gy) per second. Leveraging these benefits for clinical translation could profoundly impact RT. Extending an institutionally established reversible configuration of a linear accelerator (LINAC) for FLASH, we explored the feasibility of LINAC-based FLASH RT for potential clinical application.Materials/methods: A standard, clinical-use treatment delivery system was used. A single decommissioned beam's program circuit board was replaced with a dedicated experimental board, holding control parameters for RF power and gun current. Dose rates at an electron beam energy of ∼16 MeV were maximized at a gun current setting of 11.8V grid voltage. Notably, this setup kept the scattering foil in the beam, maintaining the advantages of the clinical utility of a standard scattered high-energy electron beam, and its inherent achievable field sizes and depth doses. For measurements, gantry and collimator rotations were set to 0° with open primary jaws. Dose rates were measured at central axis using radiographic film, with a 3 cm buildup of solid water and 20 cm downstream. FLASH treatments were delivered in 90 pulses, with 2 independent measurements at 4 source-to-surface distance (SSD) positions, including at the machine head (59 cm SSD). Percentage depth dose (PDD) was measured with a film strip placed between two vertical 5 cm thick solid water phantoms, obtained at 70, 80, and 100 cm SSD using FLASH, and 100 cm SSD with conventional dose rate 16 MeV electrons.Results: FLASH dose rates > 100 Gy/s were obtained using a standard, scattered electron beam at clinically relevant SSD's and depths with a clinical-use LINAC. Measured average dose rates at 100, 80, 70, and 59 cm SSD were 36.82, 59.52, 82.01, and 112.83 Gy/s, respectively. Average doses per pulse measured were 0.21, 0.33, 0.46, and 0.63 Gy/pulse, respectively. FLASH PDD's emulated 16-18 MeV energies, aligning closely with a conventional 16 MeV PDD. At 70, 80, and 100 cm SSD FLASH, and 100 cm SSD conventional 16 MeV, 90% fall-off measured at 5.2, 5.3, 5.5, and 5.2 cm depth, 80% at 5.9, 6.0, 6.1, and 5.7 cm and 50% at 7.0, 7.0, 7.1, and 6.8 cm depth, respectively.Conclusion: Using a readily reversible configuration of a standard LINAC, FLASH dose rates > 100 Gy/s was achievable at clinically applicable SSDs and depths. Balancing clinical feasibility with FLASH, further studies characterizing the FLASH beam at 70 to 90 cm SSD are underway, including development of a cone-less electron field shaping system and solutions for energy modulation. Advantages of our setup, using a standard scattering foil with high energy electrons, bring us a step closer to clinical practicality of FLASH RT delivery using a standard LINAC. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Biology-guided radiotherapy (BgRT) integrates PET detectors with a LINAC and delivers a real-time tracked dose of radiation to moving targets using a continuous stream of limited time-sampled (LTS) PET images as a biological fiducial. These LTS PET images are converted into fluences and delivered to the target that cumulatively sum to deliver the intended prescription dose to the planning target volume (PTV). Physical validation of BgRT directed at a moving target has not previously been reported.Materials/methods: An 18F-Fluorodeoxyglucose (FDG) fillable insert that fits inside the independent quality assurance tool cavity was used in these experiments. The insert included a 22mm diameter target enclosed within a Styrofoam mesh compartment, simulating a lung-like background. The insert was filled with FDG with a target-to-background ratio of 8:1, placed in the independent quality assurance tool cavity which was then mounted on a custom motion stage that could move in the axial direction (IEC-Y). Motion was simulated using a breathing waveform that had a large amplitude motion (from -14.3 mm to +14.4 mm with respect to the mean position), with random amplitude and period with a baseline shift over time, simulating breathing baseline shifts. A BgRT plan (prescription of 8Gy) was created using motion averaged PET images, acquired on a pre-commercial version of the RefleXion system using a 32 × 32 × 32mm (IEC-X, Y, Z) PTV - 5mm expansion over the clinical target volume (CTV). An internal tumor volume (ITV) based SBRT plan (prescription of 10Gy) with a 32 × 32 × 62mm PTV covering the motion extent was also created. Radiochromic EBT-XD film was inserted into a slot in the spherical target to measure the delivered dose. Using the same motion waveform, BgRT and SBRT plans were delivered to the moving target, with an additional 8Gy BgRT delivery (32 × 32 × 32mm PTV) to the stationary target serving as control. Dosimetric accuracy for moving targets was measured using the concept of coverage where 100% of the CTV receives at least 97% of the prescription dose and maximum dose in the CTV was = < 130% of the maximum planned dose.Results: Under motion, both SBRT (32 × 32 × 62mm PTV) and BgRT (32 × 32 × 32mm PTV) met CTV dose coverage. CTV dose ranges were a) Motion SBRT: measured = [10.4Gy,12.4Gy], plan = [9.7Gy, 17.2Gy], b) Motion BgRT: measured = [9.7Gy,11.2Gy], plan = [7.8Gy, 15.3Gy], c) Static BgRT: measured = [8.7Gy,10.1Gy], plan = [7.8Gy), 10.4Gy]. Motion coverage results indicate that BgRT with a PTV that is 48.4% smaller than the SBRT PTV, delivering a tracked dose to the moving target., indicating a more conformal delivery.Conclusion: This is the first report of BgRT delivery achieving a tracked dose distribution directed at a moving target. Because tracked distributions have better conformality and normal tissue sparing than free-breathing internal tumor volume approaches, BgRT may improve the toxic-therapeutic ratio for applications such as early-stage lung cancer. [ABSTRACT FROM AUTHOR]