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Aim: To test 3D-printed immobilization devices for future use in magnetic resonance-guided focused ultrasound hyperthermia. Material & methods: Using a surface scanner, patient-specific pelvic immobilization devices were 3D printed. The setup reproducibility was measured both on linear accelerator (LINAC) and magnetic resonance. An ultrasound imaging probe was used to acquire reference images and later to acquire images once attached into the embedded holder. Results: Prepositioning accuracy was tested at LINAC using an optical surface monitoring and MRI and showed submillimeter accuracy and small angular rotations. Agreement was high between the ultrasound reference images versus the immobilized probe. Conclusion: Reported results are considered as a promising step toward a fast and precise positioning of patients and an easier integration of radiotherapy and magnetic resonance-guided focused ultrasound hyperthermia.

Figure S1B- Higher magnification showing the skin of the mini-pig 15 and 32 weeks post radiotherapy (RT). At 15 weeks, skin area irradiated with 31Gy-FLASH-RT shows hair regrowth but not with 31Gy-Conv-RT. At 32 weeks, skin area irradiated with 34Gy-FLASH-RT is healthy whereas contractile skin fibrosis is observed with 34 Gy-Conv-RT.

Supplementary Data Table S1: WHO staging system (TNM Classification of Tumors in Domestic Animals. Geneva: World Health Organization; 1980) Table S2: Cat patient and treatment characteristics

Purpose:Previous studies using FLASH radiotherapy (RT) in mice showed a marked increase of the differential effect between normal tissue and tumors. To stimulate clinical transfer, we evaluated whether this effect could also occur in higher mammals.Experimental Design:Pig skin was used to investigate a potential difference in toxicity between irradiation delivered at an ultrahigh dose rate called “FLASH-RT” and irradiation delivered at a conventional dose rate called “Conv-RT.” A clinical, phase I, single-dose escalation trial (25–41 Gy) was performed in 6 cat patients with locally advanced T2/T3N0M0 squamous cell carcinoma of the nasal planum to determine the maximal tolerated dose and progression-free survival (PFS) of single-dose FLASH-RT.Results:Using, respectively, depilation and fibronecrosis as acute and late endpoints, a protective effect of FLASH-RT was observed (≥20% dose-equivalent difference vs. Conv-RT). Three cats experienced no acute toxicity, whereas 3 exhibited moderate/mild transient mucositis, and all cats had depilation. With a median follow-up of 13.5 months, the PFS at 16 months was 84%.Conclusions:Our results confirmed the potential advantage of FLASH-RT and provide a strong rationale for further evaluating FLASH-RT in human patients.See related commentary by Harrington, p. 3

Purpose: To reconstruct the dose delivered during single-fraction urethra-sparing prostate stereotactic body radiotherapy (SBRT) accounting for intrafraction motion monitored by intraprostatic electromagnetic transponders (EMT). Methods: We analyzed data of 15 patients included in the phase I/II "ONE SHOT" trial and treated with a single fraction of 19 Gy to the planning target volume (PTV) and 17 Gy to the urethra planning risk volume. During delivery, prostate motion was tracked with implanted EMT. SBRT was interrupted when a 3-mm threshold was trespassed and corrected unless the offset was transient. Motion-encoded reconstructed (MER) plans were obtained by splitting the original plans into multiple sub-beams with isocenter shifts based on recorded EMT positions, mimicking prostate motion during treatment. We analyzed intrafraction motion and compared MER to planned doses. Results: The median EMT motion range (±SD) during delivery was 0.26 ± 0.09, 0.22 ± 0.14 and 0.18 ± 0.10 cm in the antero-posterior, supero-inferior, and left-right axes, respectively. Treatment interruptions were needed for 8 patients because of target motion beyond limits in the antero-posterior (n = 6) and/or supero-inferior directions (n = 4). Comparing MER vs. original plan there was a median relative dose difference of -1.9% (range, -7.9 to -1.0%) and of +0.5% (-0.3-1.7%) for PTV D98% and D2%, respectively. The clinical target volume remained sufficiently covered with a median D98% difference of -0.3% (-1.6-0.5%). Bladder and rectum dosimetric parameters showed significant differences between original and MER plans, but mostly remained within acceptable limits. Conclusions: The dosimetric impact of intrafraction prostate motion was minimal for target coverage for single-fraction prostate SBRT with real-time electromagnetic tracking combined with beam gating. Keywords: Dose reconstruction; Electromagnetic transponder; Intrafraction motion; Prostate cancer; Single-fraction; Stereotactic body radiotherapy.

New therapeutic options in radiotherapy (RT) are often explored in preclinical in-vivo studies using small animals. We report here on the feasibility of modern megavoltage (MV) linear accelerator (LINAC)-based RT for small animals using easy-to-use consumer 3D printing technology for dosimetric optimization and quality assurance (QA).In this study we aimed to deliver 5×2Gy to the half-brain of a rat using a 4MV direct hemi-field X-ray beam. To avoid the beam's build-up in the target and optimize dosimetry, a 1cm thick, customized, 3D-printed bolus was used. A 1:1 scale copy of the rat was 3D printed based on the CT dataset as an end-to-end QA tool. The plan robustness to HU changes was verified. Thermoluminescent dosimeters (TLDs), for both MV irradiations and for kV imaging doses, and a gafchromic film were placed within the phantom for dose delivery verifications. The phantom was designed using a standard treatment planning software, and was irradiated at the LINAC with the target aligned using kV on-board imaging.The plan was robust (dose difference1% for HU modification from 0 to 250). Film dosimetry showed a good concordance between planned and measured dose, with the steep dose gradient at the edge of the hemi-field properly aligned to spare the contralateral half-brain. In the treated region, the mean TLDs percentage dose differences (±2 SD) were 1.3% (±3.8%) and 0.9% (±1.7%) beneath the bolus. The mean (±2 SD) out-of-field dose measurements was 0.05Gy (±0.02Gy) for an expected dose of 0.04Gy. Imaging doses (2mGy) still spared the contralateral-brain.Use of consumer 3D-printers enables dosimetry optimization and QA assessment for small animals MV RT in preclinical studies using standard LINACS.

Purpose: Aim of this study is to report the results of the radiotherapy quality assurance program of the PEACE V-STORM randomized phase II trial for pelvic nodal oligorecurrent prostate cancer (PCa). Material and methods: A benchmark case (BC) consisting of a postoperative case with 2 nodal recurrences was used for both stereotactic body radiotherapy (SBRT, 30 Gy/3 fx) and whole pelvic radiotherapy (WPRT, 45 Gy/25 fx + SIB boost to 65 Gy). Results: BC of 24 centers were analyzed. The overall grading for delineation variation of the 1st BC was rated as 'UV' (Unacceptable Variation) or 'AV' (Acceptable Variation) for 1 and 7 centers for SBRT (33%), and 3 and 8 centers for WPRT (46%), respectively. An inadequate upper limit of the WPRT CTV (n = 2), a missing delineation of the prostate bed (n = 1), and a missing nodal target volume (n = 1 for SBRT and WPRT) constituted the observed 'UV'. With the 2nd BC (n = 11), the overall delineation review showed 2 and 8 'AV' for SBRT and WPRT, respectively, with no 'UV'. For the plan review of the 2nd BC, all treatment plans were per protocol for WPRT. SBRT plans showed variability in dose normalization (Median D90% = 30.1 Gy, range 22.9-33.2 Gy and 30.6 Gy, range 26.8-34.2 Gy for nodes 1 and 2 respectively). Conclusions: Up to 46% of protocol deviations were observed in delineation of WPRT for nodal oligorecurrent PCa, while dosimetric results of SBRT showed the greatest disparities between centers. Repeated BC resulted in an improved adherence to the protocol, translating in an overall acceptable contouring and planning compliance rate among participating centers. Swiss Prostate Cancer Award grant from the Movember Foundation Belgian 'Kom Op Tegen Kanker' Scientific Association of Swiss Radiation Oncologists (SASRO) 6.901 JCR (2021) Q1, 56/245 Oncology 1.946 SJR (2021) Q1, 13/133 Hematology No data IDR 2021 UEM

Highlights • 7 patients were implanted with lung-specific electromagnetic transponders (EMT). • We report no complications from implantation and no migration of the EMT. • 7 non-small cell lung cancer patients underwent SBRT using EMT real-time tracking. • SBRT was delivered in free-breathing (FB) or in deep inspiration breath-hold (DIBH)., Background and purposes Motion management is crucial for optimal stereotactic body radiotherapy (SBRT) of moving targets. We aimed to describe our clinical experience with real-time tracking of lung-specific electromagnetic transponders (EMTs) for SBRT of early stage non-small cell lung cancer in free-breathing (FB) or deep inspiration breath-hold (DIBH). Material and methods Seven patients were implanted with EMTs. Simulation for SBRT was performed in FB and in DIBH. We prescribed 60 Gy in 3, 5 or 8 fractions to the tumor and delivered SBRT with volumetric modulated arcs and a 6 MV flattening filter free photon beam. Patients’ setup at the linac was performed using EMT positions and cone-beam CT (CBCT) verification. Four patients were treated in DIBH because of a dosimetric benefit. We analysed patient alignment and treatment delivery parameters using DIBH or FB and EMT real-time tracking. Results There were no complications from the EMT implantation. Visual inspection of CBCT before and/or after SBRT revealed good alignment of structures and EMTs. The median setup time was 9.8 min (range: 4.6–34.1 min) and the median session time was 14.7 min (range: 7.3–36.5 min). EMT positions in lungs remained stable during overall treatment and allowed real-time tracking both in FB and in DIBH SBRT. The treatment beam was gated when EMT centroid position exceeded tolerance thresholds ensuring correct delivery of radiation to the tumor. Conclusion Using EMTs for real-time tracking of tumor motion during lung SBRT proved to be safe, accurate and easy to integrate clinically for treatments in FB or DIBH.

The authors have requested that this preprint be removed from Research Square.

Optimal local treatment for nodal oligorecurrent prostate cancer is unknown. The randomized phase 2 PEACE V-STORM trial will explore the best treatment approach in this setting. Early results on the acute toxicity profile are projected to be published in quarter 3, 2021. ispartof: EUROPEAN UROLOGY FOCUS vol:7 issue:2 pages:241-244 ispartof: location:Netherlands status: published

Purpose Metallic hip implants (MHI) are common in elderly patients. For pelvic cancers radiotherapy , conventional approaches consist of MHI avoidance during treatment planning, which leads, especially in case of bilateral MHI, to a decreased quality or increased complexity of the treatment plan. The aim of this study is to investigate the necessity of using avoidance sectors (AvSe) using a 2-arcs coplanar pelvic volumetric modulated arc-therapy (VMAT) planning. Methods We evaluated: (1) The dose calculation error of a static 6 MV open beam traversing a MHI; (2) The magnitude of an error's decrease within the planning target volume (PTV) for a 360° VMAT treatment without AvSe as compared to the static open beam; (3) The dosimetric influence of MHI misalignment generated by patient's repositioning rolls during image-guided radiotherapy (IGRT). Results (1) In the static 6 MV beam configuration, for distances between 0.5 cm and 6 cm from the MHI, the median (maximum, number of points) dose calculation error was −1.55% (−2.5%, 11); (2) Compared to the static open beam, in the 360° VMAT treatment without AvSe a simulated error was decreased by a factor of 4.4/2.4 (median/minimum); (3) MHI anterior-posterior misalignment exceeding 0.6 cm, resulted in error at PTV surface of >2%. Conclusions A standard 2 coplanar arcs 360° VMAT treatment, with dedicated artifact reduction algorithms applied, decreased the error of static beam traversing MHI, in patients presenting a bilateral MHI and might be used to treat the pelvic region without MHI avoidance.

Purpose: To present the radiation therapy quality assurance results from a prospective multicenter phase 2 randomized trial of short versus protracted urethra-sparing stereotactic body radiation therapy (SBRT) for localized prostate cancer. Methods and Materials: Between 2012 and 2015, 165 patients with prostate cancer from 9 centers were randomized and treated with SBRT delivered either every other day (arm A, n = 82) or once a week (arm B, n = 83); 36.25 Gy in 5 fractions were prescribed to the prostate with (n = 92) or without (n = 73) inclusion of the seminal vesicles (SV), and the urethra planning-risk volume received 32.5 Gy. Patients were treated either with volumetric modulated arc therapy (VMAT; n = 112) or with intensity modulated radiation therapy (IMRT; n = 53). Deviations from protocol dose constraints, planning target volume (PTV) homogeneity index, PTV Dice similarity coefficient, and number of monitor units for each treatment plan were retrospectively analyzed. Dosimetric results of VMAT versus IMRT and treatment plans with versus without inclusion of SV were compared. Results: At least 1 major protocol deviation occurred in 51 patients (31%), whereas none was observed in 41. Protocol violations were more frequent in the IMRT group (P 98% (31.1 vs 30.8 Gy, P 2% (37.9 vs 38.7 Gy, P 50% (24.5% vs 33.5%, P =.0001). To achieve its goals volumetric modulated arc therapy required fewer monitor units than IMRT (2275 vs 3378, P 90% (9.1% vs 10.4%, P =.0003) and V80% (13.2% vs 15.7%, P =.0003). Conclusions: Protocol deviations with potential impact on tumor control or toxicity occurred in 31% of patients in this prospective clinical trial. Protocol deviations were more frequent with IMRT. Prospective radiation therapy quality assurance protocols should be strongly recommended for SBRT trials to minimize potential protocol deviations.

Purpose Ultra-high-dose-rate FLASH radiation therapy has been shown to minimize side effects of irradiation in various organs while keeping antitumor efficacy. This property, called the FLASH effect, has caused enthusiasm in the radiation oncology community because it opens opportunities for safe dose escalation and improved radiation therapy outcome. Here, we investigated the impact of ultra-high-dose-rate FLASH versus conventional-dose-rate (CONV) total body irradiation (TBI) on humanized models of T-cell acute lymphoblastic leukemia (T-ALL) and normal human hematopoiesis. Methods and Materials We optimized the geometry of irradiation to ensure reproducible and homogeneous procedures using eRT6/Oriatron. Three T-ALL patient–derived xenografts and hematopoietic stem/progenitor cells (HSPCs) and CD34+ cells isolated from umbilical cord blood were transplanted into immunocompromised mice, together or separately. After reconstitution, mice received 4 Gy FLASH and CONV-TBI, and tumor growth and normal hematopoiesis were studied. A retrospective study of clinical and gene-profiling data previously obtained on the 3 T-ALL patient-derived xenografts was performed. Results FLASH-TBI was more efficient than CONV-TBI in controlling the propagation of 2 cases of T-ALL, whereas the third case of T-ALL was more responsive to CONV-TBI. The 2 FLASH-sensitive cases of T-ALL had similar genetic abnormalities, and a putative susceptibility imprint to FLASH-RT was found. In addition, FLASH-TBI was able to preserve some HSPC/CD34+ cell potential. Interestingly, when HSPC and T-ALL were present in the same animals, FLASH-TBI could control tumor development in most (3 of 4) of the secondary grafted animals, whereas among the mice receiving CONV-TBI, treated cells died with high leukemia infiltration. Conclusions Compared with CONV-TBI, FLASH-TBI reduced functional damage to human blood stem cells and had a therapeutic effect on human T-ALL with a common genetic and genomic profile. The validity of the defined susceptibility imprint needs to be investigated further; however, to our knowledge, the present findings are the first to show benefits of FLASH-TBI on human hematopoiesis and leukemia treatment.

Purpose Our purpose was to assess the ability of electromagnetic transponders (EMTs) to localize and track movements in patients with prostate cancer (PCa) with metallic hip prostheses (MHPs) treated with curative radiation therapy (RT). Methods and Materials Data sets of 8 PCa patients with MHPs (3 bilateral and 5 unilateral) treated between 2016 and 2018 with RT and EMT tracking were retrospectively assessed. The distances between the 3 EMTs (apex to left, left to right, right to apex) and the isocenter were calculated both on planning computed tomography (CT) and cone beam CT (CBCT) at the first treatment fraction and compared with data reported by Calypso. EMT position and treatment interruptions triggered by Calypso were analyzed for all evaluable treatment fractions (n = 120). Localization accuracy was quantified by recording the geometric residual value (expected limit ≤0.2 cm) at the RT setup. Results The Calypso system was able to localize and track prostate position without any detectable interference from MHP. For every treatment fraction, the agreement between the CBCT images and Calypso guidance was optimal, with EMTs always within the defined tolerance (ie, CT-Calypso or CBCT-Calypso measured differences in inter-EMT distances within 0.3 cm). EMT to isocenter distances measured by Calypso reproduced CT data and were confirmed on CBCT scans. During RT, the EMT centroid exceeded the threshold 24 times (20% of all fractions): 5 times in the left-right, 15 times in the anteroposterior, and 4 times in the superoinferior directions. The largest motions recorded were in the anteroposterior axis: 0.6 cm anteriorly and 0.5 cm posteriorly in patients with unilateral and bilateral MHP, respectively. Conclusions Our study represents the first clinical experience assessing the localization and tracking accuracy of Calypso EMTs during curative RT of patients with PCa with unilateral or bilateral MHP.

This study is the first proof of concept that the FLASH effect can be triggered by X-rays. Our results show that a 10 Gy whole-brain irradiation delivered at ultra-high dose-rate with synchrotron generated X-rays does not induce memory deficit; it reduces hippocampal cell-division impairment and induces less reactive astrogliosis.

The Oriatron eRT6 is an experimental high dose-per-pulse linear accelerator (linac) which was designed to deliver an electron beam with variable dose-rates, ranging from a few Gy/min up to hundreds of Gy/s. It was built to study the radiobiological effects of high dose-per-pulse/dose-rate electron beam irradiation, in the context of preclinical and cognitive studies. In this work, we report on the commissioning and beam monitoring of the Oriatron eRT6 prototype linac. The beam was characterized in different steps. The output stability was studied by performing repeated measurements over a period of 20 months. The relative output variations caused by changing beam parameters, such as the temporal electron pulse width, the pulse repetition frequency and the pulse amplitude were also analyzed. Finally, depth dose curves and field sizes were measured for two different beam settings, resulting in one beam with a conventional radiotherapy dose-rate and one with a much higher dose-rate. Measurements were performed with Gafchromic EBT3 films and with a PTW Advanced Markus ionization chamber. In addition, we developed a beam current monitoring system based on the signals from an induction torus positioned at the beam exit of the waveguide and from a graphite beam collimator. The stability of the output over repeated measurements was found to be good, with a standard deviation smaller than 1%. However, non-negligible day-to-day variations of the beam output were observed. Those output variations showed different trends depending on the dose-rate. The analysis of the relative output variation as a function of various beam parameters showed that in a given configuration, the dose-rate could be reliably varied over three orders of magnitude. Interdependence effects on the output variation between the parameters were also observed. The beam energy and field size were found to be slightly dose-rate-dependent and suitable mainly for small animal irradiation. The beam monitoring system was able to measure in a reproducible way the total charge of electrons that exit the machine, as long as the electron pulse amplitude remains above a given threshold. Furthermore, we were able to relate the charge measured with the monitoring system to the absorbed dose in a solid water phantom. The Oriatron eRT6 was successfully commissioned for preclinical use and is currently in full operation, with studies being performed on the radiobiological effects of high dose-per-pulse irradiation.

This study shows for the first time that normal brain tissue toxicities after WBI can be reduced with increased dose rate. Spatial memory is preserved after WBI with mean dose rates above 100Gy/s, whereas 10Gy WBI at a conventional radiotherapy dose rate (0.1Gy/s) totally impairs spatial memory.

The purpose of this work was to establish an empirical model of the ion recombination in the Advanced Markus ionization chamber for measurements in high dose rate/dose-per-pulse electron beams. In addition, we compared the observed ion recombination to calculations using the standard Boag two-voltage-analysis method, the more general theoretical Boag models, and the semiempirical general equation presented by Burns and McEwen. Two independent methods were used to investigate the ion recombination: (a) Varying the grid tension of the linear accelerator (linac) gun (controls the linac output) and measuring the relative effect the grid tension has on the chamber response at different source-to-surface distances (SSD). (b) Performing simultaneous dose measurements and comparing the dose-response, in beams with varying dose rate/dose-per-pulse, with the chamber together with dose rate/dose-per-pulse independent Gafchromic™ EBT3 film. Three individual Advanced Markus chambers were used for the measurements with both methods. All measurements were performed in electron beams with varying mean dose rate, dose rate within pulse, and dose-per-pulse (10(-2) ≤ mean dose rate ≤ 10(3) Gy/s, 10(2) ≤ mean dose rate within pulse ≤ 10(7) Gy/s, 10(-4) ≤ dose-per-pulse ≤ 10(1) Gy), which was achieved by independently varying the linac gun grid tension, and the SSD. The results demonstrate how the ion collection efficiency of the chamber decreased as the dose-per-pulse increased, and that the ion recombination was dependent on the dose-per-pulse rather than the dose rate, a behavior predicted by Boag theory. The general theoretical Boag models agreed well with the data over the entire investigated dose-per-pulse range, but only for a low polarizing chamber voltage (50 V). However, the two-voltage-analysis method and the Burns & McEwen equation only agreed with the data at low dose-per-pulse values (≤ 10(-2) and ≤ 10(-1) Gy, respectively). An empirical model of the ion recombination in the chamber was found by fitting a logistic function to the data. The ion collection efficiency of the Advanced Markus ionization chamber decreases for measurements in electron beams with increasingly higher dose-per-pulse. However, this chamber is still functional for dose measurements in beams with dose-per-pulse values up toward and above 10 Gy, if the ion recombination is taken into account. Our results show that existing models give a less-than-accurate description of the observed ion recombination. This motivates the use of the presented empirical model for measurements with the Advanced Markus chamber in high dose-per-pulse electron beams, as it enables accurate absorbed dose measurements (uncertainty estimation: 2.8-4.0%, k = 1). The model depends on the dose-per-pulse in the beam, and it is also influenced by the polarizing chamber voltage, with increasing ion recombination with a lowering of the voltage.

Purpose The aim of this study was to assess the suitability of Gafchromic EBT3 films for reference dose measurements in the beam of a prototype high dose-per-pulse linear accelerator (linac), capable of delivering electron beams with a mean dose-rate (Ḋm) ranging from 0.07 to 3000 Gy/s and a dose-rate in pulse (Ḋp) of up to 8·106 Gy/s. To do this, we evaluated the overall uncertainties in EBT3 film dosimetry as well as the energy and dose-rate dependence of their response. Material and Methods Our dosimetric system was composed of EBT3 Gafchromic films in combination with a flatbed scanner and was calibrated against an ionization chamber traceable to primary standard. All sources of uncertainties in EBT3 dosimetry were carefully analyzed using irradiations at a clinical radiotherapy linac. Energy dependence was investigated with the same machine by acquiring and comparing calibration curves for three different beam energies (4, 8 and 12 MeV), for doses between 0.25 and 30 Gy. Ḋm dependence was studied at the clinical linac by changing the pulse repetition frequency (f) of the beam in order to vary Ḋm between 0.55 and 4.40 Gy/min, while Ḋp dependence was probed at the prototype machine for Ḋp ranging from 7·103 to 8·106 Gy/s. Ḋp dependence was first determined by studying the correlation between the dose measured by films and the charge of electrons measured at the exit of the machine by an induction torus. Furthermore, we compared doses from the films to independently calibrated thermo-luminescent dosimeters (TLD) that have been reported as being dose-rate independent up to such high dose-rates. Results We report that uncertainty below 4% (k=2) can be achieved in the dose range between 3 and 17 Gy. Results also demonstrated that EBT3 films did not display any detectable energy dependence for electron beam energies between 4 and 12 MeV. No Ḋm dependence was found either. In addition, we obtained excellent consistency between films and TLDs over the entire Ḋp range attainable at the prototype linac confirming the absence of any dose-rate dependence within the investigated range (7·103 to 8·106 Gy/s). This aspect was further corroborated by the linear relationship between the dose per pulse (Dp) measured by films and the charge per pulse (Cp) measured at the prototype linac exit. Conclusion Our study shows that the use of EBT3 Gafchromic films can be extended to reference dosimetry in pulsed electron beams with a very high dose-rate. The measurement results are associated with an overall uncertainty below 4% (k=2) and are dose-rate and energy independent. This article is protected by copyright. All rights reserved.

Purpose The Leksell Gamma Knife (LGK) Icon has been recently introduced to provide Gamma Knife technology with frameless stereotactic treatments which use an additional cone-beam CT (CBCT) imaging system and a motion tracking system (IFMM, Intra-Fraction Motion Management). The system was commissioned for the treatment unit itself as well as the imaging system. Methods The LGK Icon was calibrated using an A1SL ionization chamber. EBT3 radiochromic films were employed to independently check the machine calibration, to measure the relative output factors (ROFs) and to collect dose distributions. Coincidence between CBCT isocenter and radiological focus was evaluated by means of EBT3 films. CBCT image quality was investigated in terms of spatial resolution, contrast-to-noise ratio (CNR), and uniformity for the two presets available (low dose and high dose). Computed Tomography Dose Index (CTDI) was also measured for both presets. Results The absolute dose rate of the LGK Icon was 3.86 ± 0.09 Gy/min. This result was confirmed by EBT3 readings. ROF were found to be 0.887 ± 0.035 and 0.797 ± 0.032 for the 8 mm and 4 mm collimators, respectively, which are within 2% of the Monte Carlo-derived ROF values. Excellent agreement was found between calculated and measured dose distribution with the gamma pass rate >95% of points for the nine dose distributions analyzed with 3%/1 mm criteria. CBCT isocenter was found to be within 0.2 mm with respect to radiological focus. Image quality parameters were found to be well within the manufacturer's specifications with the high-dose preset being superior in terms of CNR and uniformity. CTDI values were 2.41 mGy and 6.32 mGy, i.e. −3.6% and 0.3% different from the nominal values for the low-dose and high-dose presets, respectively. Conclusions The LGK Icon was successfully commissioned for clinical use. The use of the EBT3 to characterize the treatment unit was demonstrated to be feasible. The CBCT imaging system operates well within the manufacturer's specifications and provides good geometrical accuracy.

PURPOSE To evaluate the planning feasibility of dose-escalated total marrow irradiation (TMI) with simultaneous integrated boost (SIB) to the active bone marrow (ABM) using volumetric modulated arc therapy (VMAT), and to assess the impact of using planning organs at risk (OAR) volumes (PRV) accounting for breathing motion in the optimization. METHODS Five patients underwent whole-body CT and thoraco-abdominal 4DCT. A planning target volume (PTV) including all bones and ABM was contoured on each whole-body CT. PRV of selected OAR (liver, heart, kidneys, lungs, spleen, stomach) were determined with 4DCT. Planning consisted of 9-10 full 6 MV photon VMAT arcs. Four plans were created for each patient with 12 Gy prescribed to the PTV, with or without an additional 4 Gy SIB to the ABM. Planning dose constraints were set on the OAR or on the PRV. Planning objective was a PTV Dmean

The interaction of trace metals with naturally occurring organic matter (NOM) is a key process of the speciation of trace elements in aquatic environments. The rate of dissociation of metal-NOM complexes will impact the amount of free metal available for biouptake. Assessing the bioavailability of plutonium (Pu) helps to predict its toxic effects on aquatic biota. However, the rate of dissociation of Pu-NOM complexes in natural freshwaters is currently unknown. Here, we used the technique of diffusive gradients in thin films (DGT) with several diffusive layer thicknesses to provide new insights into the dissociation kinetics of Pu-NOM complexes. Results show that Pu complexes with NOM (mainly fulvic acid) are somewhat labile (0.2 ≤ ξ ≤ 0.4), with kd = 7.5 × 10(-3) s(-1). DGT measurements of environmental Pu in organic-rich natural water confirm these findings. In addition, we determined the effective diffusion coefficients of Pu(V) in polyacrylamide (PAM) gel in the presence of humic acid using a diffusion cell (D = 1.70 ± 0.25 × 10(-6) cm(2) s(-1)). These results show that Pu(V) is a more mobile species than Pu(IV).

Purpose Preclinical studies using a new treatment modality called FLASH Radiotherapy (FLASH-RT) need a two-phase procedure to ensure minimal uncertainties in the delivered dose. The first phase requires a new investigation of the reference dosimetry lying outside the conventional metrology framework from national metrology institutes but necessary to obtain traceability, repeatability, and stability of irradiations. The second consists of performing special quality assurance procedure prior to irradiation. Materials and Methods The Oriatron eRT6 (PMB-Alcen, France) is an experimental high dose-per-pulse linear accelerator, delivering a 6 MeV pulsed electron beam with mean dose-rates, ranging from a few Gy/min up to thousands of Gy/s. Absolute dosimetry is investigated with alanine, thermo-luminescent dosimeters (TLD) and radiochromic films as well as an ionization chamber for relative stability. The beam characteristic and dosimetry are prepared for three different setups. Results A cross-check between alanine, films and TLD revealed a dose agreement within 3% for dose-rates between 0.078 Gy/s and 1050 Gy/s, showing that these dosimeters are suitable for absolute dosimetry for FLASH-RT. In absence of appropriate setup dependent corrections, active dosimetry can reveal dose deviations up to 15% of the prescribed dose. These differences reduce to less than 3% when our dosimetric procedure is applied. Conclusion We developed procedures to accurately irradiate biological models. Our method is based on validated absolute dosimeters and extends their use to routine FLASH irradiations. We reached an agreement of 3% between the delivered and prescribed dose and developed the requirements needed for workflows of preclinical and clinical studies.

Purpose: Previous studies using FLASH radiotherapy (RT) in mice showed a marked increase of the differential effect between normal tissue and tumors. To stimulate clinical transfer, we evaluated whether this effect could also occur in higher mammals. Experimental Design: Pig skin was used to investigate a potential difference in toxicity between irradiation delivered at an ultrahigh dose rate called “FLASH-RT” and irradiation delivered at a conventional dose rate called “Conv-RT.” A clinical, phase I, single-dose escalation trial (25–41 Gy) was performed in 6 cat patients with locally advanced T2/T3N0M0 squamous cell carcinoma of the nasal planum to determine the maximal tolerated dose and progression-free survival (PFS) of single-dose FLASH-RT. Results: Using, respectively, depilation and fibronecrosis as acute and late endpoints, a protective effect of FLASH-RT was observed (≥20% dose-equivalent difference vs. Conv-RT). Three cats experienced no acute toxicity, whereas 3 exhibited moderate/mild transient mucositis, and all cats had depilation. With a median follow-up of 13.5 months, the PFS at 16 months was 84%. Conclusions: Our results confirmed the potential advantage of FLASH-RT and provide a strong rationale for further evaluating FLASH-RT in human patients. See related commentary by Harrington, p. 3

Introduction We report on the treatment management and the dosimetric results of deep inspiration breath hold (DIBH) volumetric modulated arc therapy (VMAT) treatments for breast cancer patients. Methods A total of sixty-four patients with breast cancer beneficiated from DIBH VMAT treatments since the implementation of this technique in our department in October 2016. The simulation CT (CTsim) room is equipped with the Real-time Position Management™ (RPM 1.7) Respiratory Gating (Varian) and the treatments are delivered on either a TrueBeam with Respiratory Gating or a Varian Linac with RPM. DIBH coaching is performed by the RTTs the day of CTsim. CTsim is acquired when the patient is able to maintain a reproducible and stable DIBH for at least 20 s. The “reference” breathing curve acquired at CTsim is saved, and personalized gating thresholds are defined for treatment delivery. The treatment is delivered using a 6 MV beam with 2 partial arcs (200°) and 2 “tangential-like” arcs (50°). For dosimetric analysis, patients were divided into 9 groups depending on the anatomical regions (breast and lymph nodes) included in the planning target volume (PTV), the breast laterality (50 left, 10 right and 4 double-sided irradiations) and the presence of a simultaneous integrated boost (SIB). The total dose was renormalized at the same value (50 Gy) for each group (4 different dose prescriptions and fractionations are used in Geneva). Results Patient setup is controlled with DIBH kV/kV and CBCT images. The RTTs need to continuously coach the patient as he cannot visualize its DIBH level during the session. Using DIBH technique requires additional time compared to a free breathing treatment (35 vs. 20 min per fraction). As for dosimetry, in all groups, more than 95% of the PTV received at least 95% of the prescribed dose. The dose received by 2% of the PTV did not exceed 107.3% for groups without SIB, and 111.4% for groups with SIB. Mean dose ( D mean ) to the heart was 5 Gy for groups without internal mammary chain (IMC) irradiation, 6 Gy with IMC, and reached 8 Gy for double-sided breast and whole left breast with SIB irradiations. D mean of the contralateral breast did not exceed 2.8 Gy for groups without IMC, and 3.8 Gy for groups with IMC. As for the contralateral lung: D mean was 3 Gy and 5 Gy, V 5 Gy was 20% and 40%, for groups without and with IMC respectively. For the homolateral lung, D mean was below 9.5 Gy for breast alone groups (+/-SIB) and 13.9 Gy for IMC + SIB groups, V 5 Gy was below 50% for breast alone groups, below 56.1 % for SIB groups, and below 78.7% for IMC + SIB groups. Conclusions Radiotherapy treatment of breast cancer using DIBH and a VMAT technique is more and more used in our center because of the excellent achievable OAR dose sparing and the good reproducibility of patient positioning. The additional time resource needed for this treatment modality is compensated by the gain in treatment quality.

The Leksell Gamma Knife (LGK) Icon has been recently introduced to provide Gamma Knife technology with frameless stereotactic treatments which use an additional cone-beam CT (CBCT) imaging system and a motion tracking system (IFMM, Intra-Fraction Motion Management). The system was commissioned for the treatment unit itself as well as the imaging system.The LGK Icon was calibrated using an A1SL ionization chamber. EBT3 radiochromic films were employed to independently check the machine calibration, to measure the relative output factors (ROFs) and to collect dose distributions. Coincidence between CBCT isocenter and radiological focus was evaluated by means of EBT3 films. CBCT image quality was investigated in terms of spatial resolution, contrast-to-noise ratio (CNR), and uniformity for the two presets available (low dose and high dose). Computed Tomography Dose Index (CTDI) was also measured for both presets.The absolute dose rate of the LGK Icon was 3.86 ± 0.09 Gy/min. This result was confirmed by EBT3 readings. ROF were found to be 0.887 ± 0.035 and 0.797 ± 0.032 for the 8 mm and 4 mm collimators, respectively, which are within 2% of the Monte Carlo-derived ROF values. Excellent agreement was found between calculated and measured dose distribution with the gamma pass rate95% of points for the nine dose distributions analyzed with 3%/1 mm criteria. CBCT isocenter was found to be within 0.2 mm with respect to radiological focus. Image quality parameters were found to be well within the manufacturer's specifications with the high-dose preset being superior in terms of CNR and uniformity. CTDI values were 2.41 mGy and 6.32 mGy, i.e. -3.6% and 0.3% different from the nominal values for the low-dose and high-dose presets, respectively.The LGK Icon was successfully commissioned for clinical use. The use of the EBT3 to characterize the treatment unit was demonstrated to be feasible. The CBCT imaging system operates well within the manufacturer's specifications and provides good geometrical accuracy.

We examine a cosmological model with a dark energy density of the form $\rho_{DE}(t)=\rho_X(t)+\rho_Z(t)$, where $\rho_X$ is the component that accelerates the Hubble expansion at late times and $\rho_Z(t)$ is an extra contribution proportional to $H^2(t)$. This form of $\rho_Z(t)$ follows from the recent proposal that the contribution of zero-point fluctuations of quantum fields to the total energy density should be computed by subtracting the Minkowski-space result from that computed in the FRW space-time. We discuss theoretical arguments that support this subtraction. By definition, this eliminates the quartic divergence in the vacuum energy density responsible for the cosmological constant problem. We show that the remaining quadratic divergence can be reabsorbed into a redefinition of Newton's constant only under the assumption that the energy-momentum tensor of vacuum fluctuations is conserved in isolation. However, in the presence of an ultra-light scalar field $X$ with $m_X, Comment: 7 pages, 3 figures; v3: improved discussion, references added

Introduction We report on the quality assurance (QA) and treatment management of the first patient included in the ONE SHOT trial. ONE SHOT, single shot stereotactic body radiotherapy (SBRT) for localized prostate cancer, is a multicenter single arm phase I/II trial which will enrolled 45 patients in total. Its main objective is to determine the safety and efficacy of a single SBRT fraction at a dose of 19 Gy in patients with localized prostate cancer. Indeed, recent data showed good tolerance and biochemical control after single interstitial application of 19/20 Gy to the prostate or after SBRT in five fractions, so that ultra-hypofractionated single-dose SBRT employing imaged-guided radiotherapy and real-time tumour tracking with implanted electromagnetic transponders (Calypso® with DynamicEdge™ gating) may be feasible with a safe toxicity profile and an optimal long-term tumor control. Methods Three Calypso beacons were implanted in the patient prostate 4 days before the planning CT scan. The patient was imaged with empty rectum and full bladder with 1 mm slices thickness. For urethra contouring and visualization during treatment, a non-radiopaque catheter was inserted during CT simulation and before the treatment delivery. The prescription dose was 19 Gy in a single fraction to the whole prostate gland ±proximal seminal vesicles and 17 Gy to the urethra planning-risk volume (PRV). The plan consisted into 2 full VMAT arcs using 10MV FFF beam from the TrueBeam linac with 6 degrees of freedom couch. It was optimized on Eclipse TPS (Varian) with Rapidplan™, a knowledge-based planning software, and the dose was calculated with AAA v13026 algorithm. QA controls included portal dosimetry (PD) (Varian, PDIP v13026), absolute dose measurements with Diamond detector (PTW) inserted in Lucy 3D QA phantom (Standard Imaging) and Gafchromic film measurements (EBT-XD films). Results The treatment plan of the first ONE SHOT patient satisfied the dose-volume constraints for all OARs and the coverage requirement for the PTV and PRV. The total number of monitor units for the two arcs was 7125. The results of the PD QA were within the tolerance, with Gamma index 1%/1 mm = 98.7%. For absolute dose measurement, the difference between expected and measured dose was 1.7% inside PRV and 3% in the PTV region. Film gamma index with 4%/1 mm criteria was 97.4%. Patient positioning before treatment required two cone-beam CT (CBCT) before the first arc, because Calypso detected a 2 mm shift in the longitudinal direction after the couch adjustment made after the 1st CBCT. The first arc was treated without interruption and a third CBCT was acquired between the arcs. However, no shift was observed and the second arc was treated without patient realignment. Conclusions QA results were all within the tolerance for SBRT treatment and the first ONE SHOT patient was treated successfully as planned.

Introduction One of the most common side effects from radiotherapy treatment of localized prostate cancer remains erectile dysfunction. Vessel-sparing radiotherapy has shown promising results on preserving erectile function when compared to historical series. In this dosimetric study, we aim to evaluate the influence of an endorectal balloon (ERB) on the dose sparing of internal pudendal arteries (IPA) in treatment planning of prostate stereotactic RT (SBRT). Methods Twelve localized prostate cancer patients, simulated with and without ERB, were planned to receive 36.25 Gy (7.25Gyx5) to the planning treatment volume (PTV). IPA were delineated on each scanners using registration with MRI. Plans with and without ERB were optimized using Rapidplan™ (Varian), a knowledge based software, with standard sparing of regionally involved organs at risk (rectal and bladder wall, and femoral heads) and no dose constraints on IPA. A total of 24 volumetric arc therapy plans were optimized using a 10MV FFF beam with 2 full arcs. SBRT doses to IPA ( D 2 % and D mean ) were compared between groups using non-parametric tests. Results The IPA volumes were similar in the two CT datasets, with a median volume of 4.75 cc (range, 3.8–7.2) vs. 4.95 cc (range, 3.8–7, p = 0.721) in patients with and without ERB, respectively. The median mean IPA dose was significantly lower using ERB (10.5 vs. 12.8 Gy, p = 0.023). Median IPA D 2 % was also lower with ERB (17.6 vs. 20.8 Gy without ERB), but the difference was not significant. No clinically significant differences in target coverage, rectal, and bladder walls doses were observed between the two groups. Conclusions The use of ERB for prostate SBRT showed a significant sparing of IPA compared to plans generated with an empty rectum. As no specific dose constraints are yet available for vessel-sparing SBRT, optimal reduction of IPA doses should be attempted for maximal EF preservation.

We construct a fully covariant theory of massive gravity which does not require the introduction of an external reference metric, and overcomes the usual problems of massive gravity theories (fatal ghosts instabilities, acausality and/or vDVZ discontinuity). The equations of motion of the theory are non-local, but respect causality. The starting point is the quadratic action proposed in the context of the degravitation idea. We show that it is possible to extended it to a fully non-linear covariant theory. This theory describes the five degrees of freedom of a massive graviton plus a scalar ghost. However, contrary to generic non-linear extensions of Fierz-Pauli massive gravity, the ghost has the same mass m as the massive graviton, independently of the background, and smoothly goes into a non-radiative degree of freedom for m-> 0. As a consequence, for $m\sim H_0$ the vacuum instability induced by the ghost is irrelevant even over cosmological time-scales. We finally show that an extension of the model degravitates a vacuum energy density of order $M_{Planck}^4$ down to a value of order $M_{Planck}^2 m^2$, which for $m \sim H_0$ is of order of the observed value of the vacuum energy density., 45 pages, 2 figs; v2: references and comments added. To appear in PRD

We give a detailed discussion of the use of the (3+1) decomposition and of Bardeen's variables in massive gravity linearized over a Minkowski as well as over a de Sitter background. In Minkowski space the Bardeen "potential" \Phi, that in the massless case is a non-radiative degree of freedom, becomes radiative and describes the helicity-0 component of the massive graviton. Its dynamics is governed by a simple Klein-Gordon action, supplemented by a term (\Box \Phi)^2 if we do not make the Fierz-Pauli tuning of the mass term. In de Sitter the identification of the variable that describes the radiative degree of freedom in the scalar sector is more subtle, and even involves expressions non-local in time. The use of this new variable provides a simple and transparent derivation of the Higuchi bound and of the disappearance of the scalar degree of freedom at a special value of $m_g^2/H^2$. The use of this formalism also allows us to uncover the existence of a hidden gauge symmetry of the massive theory, that becomes manifest only once the non-dynamical components of the metric are integrated out, and that is present both in Minkowski and in de Sitter., Comment: 22 pages, 1 figure. v2: added references. To appear in PRD

We re-examine the classic problem of the renormalization of zero-point quantum fluctuations in a Friedmann-Robertson-Walker background. We discuss a number of issues that arise when regularizing the theory with a momentum-space cutoff, and show explicitly how introducing non-covariant counter-terms allows to obtain covariant results for the renormalized vacuum energy-momentum tensor. We clarify some confusion in the literature concerning the equation of state of vacuum fluctuations. Further, we point out that the general structure of the effective action becomes richer if the theory contains a scalar field phi with mass m smaller than the Hubble parameter H(t). Such an ultra-light particle cannot be integrated out completely to get the effective action. Apart from the volume term and the Einstein-Hilbert term, that are reabsorbed into renormalizations of the cosmological constant and Newton's constant, the effective action in general also has a term proportional to F(phi)R, for some function F(phi). As a result, vacuum fluctuations of ultra-light scalar fields naturally lead to models where the dark energy density has the form rho_{DE}(t)=rho_X(t)+rho_Z(t), where rho_X is the component that accelerates the Hubble expansion at late times and rho_Z(t) is an extra contribution proportional to H^2(t). We perform a detailed comparison of such models with CMB, SNIa and BAO data., Comment: 23 pages, 9 figures. v3: refs added. To appear in Phys. Rev. D