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Purpose: The oxygen depletion hypothesis has been proposed as a rationale to explain the observed phenomenon of FLASH-radiotherapy (FLASH-RT) sparing normal tissues while simultaneously maintaining tumor control. In this study we examined the distribution of DNA Damage Response (DDR) markers in irradiated 3D multicellular spheroids to explore the relationship between FLASH-RT protection and radiolytic-oxygen-consumption (ROC) in tissues., Methods: Studies were performed using a Varian Truebeam linear accelerator delivering 10 MeV electrons with an average dose rate above 50 Gy/s. Irradiations were carried out on 3D spheroids maintained under a range of O 2 and temperature conditions to control O 2 consumption and create gradients representative of in vivo tissues., Results: Staining for pDNA-PK (Ser2056) produced a linear radiation dose response whereas γH2AX (Ser139) showed saturation with increasing dose. Using the pDNA-PK staining, radiation response was then characterised for FLASH compared to standard-dose-rates as a function of depth into the spheroids. At 4 °C, chosen to minimize the development of metabolic oxygen gradients within the tissues, FLASH protection could be observed at all distances under oxygen conditions of 0.3-1 % O 2 . Whereas at 37 °C a FLASH-protective effect was limited to the outer cell layers of tissues, an effect only observed at 3 % O 2 . Modelling of changes in the pDNA-PK-based oxygen enhancement ratio (OER) yielded a tissue ROC g 0 -value estimate of 0.73 ± 0.25 µM/Gy with a k m of 5.4 µM at FLASH dose rates., Conclusions: DNA damage response markers are sensitive to the effects of transient oxygen depletion during FLASH radiotherapy. Findings support the rationale that well-oxygenated tissues would benefit more from FLASH-dose-rate protection relative to poorly-oxygenated tissues., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved.)

Introduction: Dynamic tumor tracking (DTT) is a motion management technique where the radiation beam follows a moving tumor in real time. Not modelling DTT beam motion in the treatment planning system leaves an organ at risk (OAR) vulnerable to exceeding its dose limit. This work investigates two planning strategies for DTT plans, the "Boolean OAR Method" and the "Aperture Sorting Method," to determine if they can successfully spare an OAR while maintaining sufficient target coverage., Materials and Methods: A step-and-shoot intensity modulated radiation therapy (sIMRT) treatment plan was re-optimized for 10 previously treated liver stereotactic ablative radiotherapy patients who each had one OAR very close to the target. Two planning strategies were investigated to determine which is more effective at sparing an OAR while maintaining target coverage: (1) the "Boolean OAR Method" created a union of an OAR's contours from two breathing phases (exhale and inhale) on the exhale phase (the planning CT) and protected this combined OAR during plan optimization, (2) the "Aperture Sorting Method" assigned apertures to the breathing phase where they contributed the least to an OAR's maximum dose., Results: All 10 OARs exceeded their dose constraints on the original plan four-dimensional (4D) dose distributions and average target coverage was V 100%  = 91.3% ± 2.9% (ranging from 85.1% to 94.8%). The "Boolean OAR Method" spared 7/10 OARs, and mean target coverage decreased to V 100%  = 87.1% ± 3.8% (ranging from 80.7% to 93.7%). The "Aperture Sorting Method" spared 9/10 OARs and the mean target coverage remained high at V 100%  = 91.7% ± 2.8% (ranging from 84.9% to 94.5%)., Conclusions: 4D planning strategies are simple to implement and can improve OAR sparing during DTT treatments. The "Boolean OAR Method" improved sparing of OARs but target coverage was reduced. The "Aperture Sorting Method" further improved sparing of OARs and maintained target coverage., (© 2024 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Purpose: To assess the feasibility of using the diaphragm as a surrogate for liver targets during MDTT., Methods: Diaphragm as surrogate for markers: a dome-shaped phantom with implanted markers was fabricated and underwent dual-orthogonal fluoroscopy sequences on the Vero4DRT linac. Ten patients participated in an IRB-approved, feasibility study to assess the MDTT workflow. All images were analyzed using an in-house program to back-project the diaphragm/markers position to the isocenter plane. ExacTrac imager log files were analyzed. Diaphragm as tracking structure for MDTT: The phantom "diaphragm" was contoured as a markerless tracking structure (MTS) and exported to Vero4DRT/ExacTrac. A single field plan was delivered to the phantom film plane under static and MDTT conditions. In the patient study, the diaphragm tracking structure was contoured on CT breath-hold-exhale datasets. The MDTT workflow was applied until just prior to MV beam-on., Results: Diaphragm as surrogate for markers: phantom data confirmed the in-house 3D back-projection program was functioning as intended. In patients, the diaphragm/marker relative positions had a mean ± RMS difference of 0.70 ± 0.89, 1.08 ± 1.26, and 0.96 ± 1.06 mm in ML, SI, and AP directions. Diaphragm as tracking structure for MDTT: Building a respiratory-correlation model using the diaphragm as surrogate for the implanted markers was successful in phantom/patients. During the tracking verification imaging step, the phantom mean ± SD difference between the image-detected and predicted "diaphragm" position was 0.52 ± 0.18 mm. The 2D film gamma (2%/2 mm) comparison (static to MDTT deliveries) was 98.2%. In patients, the mean difference between the image-detected and predicted diaphragm position was 2.02 ± 0.92 mm. The planning target margin contribution from MDTT diaphragm tracking is 2.2, 5.0, and 4.7 mm in the ML, SI, and AP directions., Conclusion: In phantom/patients, the diaphragm motion correlated well with markers' motion and could be used as a surrogate. MDTT workflows using the diaphragm as the MTS is feasible using the Vero4DRT linac and could replace the need for implanted markers for liver radiotherapy., (© 2023 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)