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Purpose: Atrial fibrillation (AFib) is the most common cardiac arrhythmia that affects millions of patients world-wide. AFib is usually treated with minimally invasive, time consuming catheter ablation techniques. While recently noninvasive radiosurgery to the pulmonary vein antrum (PVA) in the left atrium has been proposed for AFib treatment, precise target location during treatment is challenging due to complex respiratory and cardiac motion. A MRI linear accelerator (MRI-Linac) could solve the problems of motion tracking and compensation using real-time image guidance. In this study, the authors quantified target motion ranges on cardiac magnetic resonance imaging (MRI) and analyzed the dosimetric benefits of margin reduction assuming real-time motion compensation was applied Methods: For the imaging study, six human subjects underwent real-time cardiac MRI under free breathing. The target motion was analyzed retrospectively using a template matching algorithm. The planning study was conducted on a CT of an AFib patient with a centrally located esophagus undergoing catheter ablation, representing an ideal case for cardiac radiosurgery. The target definition was similar to the ablation lesions at the PVA created during catheter treatment. Safety margins of 0 mm (perfect tracking) to 8 mm (untracked respiratory motion) were added to the target, defining the planning target volume (PTV). For each margin, a 30 Gy single fraction IMRT plan was generated. Additionally, the influence of 1 and 3 T magnetic fields on the treatment beam delivery was simulated using Monte Carlo calculations to determine the dosimetric impact of MRI guidance for two different Linac positions Results: Real-time cardiac MRI showed mean respiratory target motion of 10.2 mm (superior-inferior), 2.4 mm (anterior-posterior), and 2 mm (left-right). The planning study showed that increasing safety margins to encompass untracked respiratory motion leads to overlapping structures even in the ideal scenario, compromising either normal tissue dose constraints or PTV coverage. The magnetic field caused a slight increase in the PTV dose with the in-line MRI-Linac configuration. Conclusions: The authors' results indicate that real-time tracking and motion compensation are mandatory for cardiac radiosurgery and MRI-guidance is feasible, opening the possibility of treating cardiac arrhythmia patients completely noninvasively [ABSTRACT FROM AUTHOR]

Poster Highlights: Poster highlights 15: Particles and microbeams OC-0474: Feasibility of prostate SBRT with DIL boost in various platforms: A Crowd Knowledge based study A. Savini, E. Villaggi, O. Blanck, C. Moustakis, V. Hernandez, S. Russo, M. Esposito, R. De Blas Piñol, N. Hardcastle, J. Saez, R. Doro, M.D. Falco, V. Silvestri, B. Nardiello, S. Broggi, L. Strigari, S. Cilla, S. Strolin, M. Stasi, P. Mancosu. [Extracted from the article]

To develop expert recommendations for multiparametric dose prescriptions of SBRT according to ICRU report 91 to harmonize current SBRT practice and clinical trial design. Based on results of a working group literature summary a 2-tier Delphi-consensus process of 24 physician and physics experts from 3 European countries was conducted. Degree of consensus was predefined for overarching (OA) and organ specific (OS) statements (≥80%, 60-79%, <60% for high, intermediate and poor consensus). Post first round, statements were refined in a live discussion with 125 participants for the second round of the Delphi process. Experts consented on a total of 14 OA and 17 OS statements of SBRT of primary and secondary lung as well as liver, pancreas, adrenal and kidney tumors. Degree of consent was ≥80% in 79% and 41% of OA and OS statements, respectively, with higher consensus for lung compared to upper abdomen. In round 2, degree of consent ≥80% increased to 100% for OA and 88% in OS statements. No consensus was reached for dose escalation of liver metastases after chemotherapy (47%) and single fraction SBRT for kidney primaries (13%). In round 2, no statements had 60-79% consensus. In 29 of 31 statements a high consensus was achieved after a 2-tier Delphi process, and 1 statement (kidney) was clearly refused. The Delphi process was able to achieve a high degree of consensus for dose prescription of SBRT. In summary, clear recommendations for both OA and OS could be defined. This contributes significantly to harmonization and for the design of clinical trials in SBRT. Specific exemplary cases will be deducted from the statements in the next step. [ABSTRACT FROM AUTHOR]

Fluopyram, a broad spectrum fungicide, caused an increased incidence of thyroid follicular cell (TFC) adenomas in males at the highest dose evaluated (750 ppm equating to 105 mg/kg/day) in the mouse oncogenicity study. A series of short-term mechanistic studies were conducted in the male mouse to characterize the mode of action (MOA) for the thyroid tumor formation and to determine if No Observed Effect Levels (NOELs) exist for each key event identified. The proposed MOA consists of an initial effect on the liver by activating the constitutive androstane (Car) and pregnane X (Pxr) nuclear receptors causing increased elimination of thyroid hormones followed by an increased secretion of thyroid stimulating hormone (TSH). This change in TSH secretion results in an increase of TFC proliferation which leads to hyperplasia and eventually adenomas after chronic exposure. Car/Pxr nuclear receptors were shown to be activated as indicated by increased activity of specific Phase I enzymes (PROD and BROD, respectively). Furthermore, evidence of increased T4 metabolism was provided by the induction of phase II enzymes known to preferentially use T4 as a substrate. Additional support for the proposed MOA was provided by demonstrating increased Tsh β transcripts in the pituitary gland. Finally, increased TFC proliferation was observed after 28 days of treatment. In these dose–response studies, clear NOELs were established for phase 2 liver enzyme activities, TSH changes and TFC proliferation. Furthermore, compelling evidence for Car/Pxr activation being the molecular initiating event for these thyroid tumors was provided by the absence of the sequential key events responsible for the TCF tumors in Car/Pxr KO mice when exposed to fluopyram. In conclusion, fluopyram thyroid toxicity is mediated by activation of hepatic Car/Pxr receptors and shows a threshold dependent MOA. [ABSTRACT FROM AUTHOR]

Highlights: [•] Ten structurally diverse chemicals were screened for endocrine activity. [•] The chemicals were judged intrinsic to modern life with unknown endocrine activity. [•] All were inactive in the hERTa assay but four affected steroidogenesis in H295R cells. [•] One chemical, caffeine, also affected pubertal parameters in male and female rats. [•] Hazard assessment and exposure considerations have to be considered for ED regulation. [ABSTRACT FROM AUTHOR]

While the results of prospective studies support the use of postoperative stereotactic radiotherapy (RT) to the resection cavity (RC) as the standard of care after surgery, there are several issues that need to be investigated such as factors for improving local control, risk of leptomeningeal disease and radiation necrosis. Further, the optimal dose and fractionation is still under debate. The working group "Stereotactic Radiotherapy" of the German Society of Radiation Oncology (DEGRO) analyzed its multi-institutional database with 661 patients who received postoperative stereotactic RT to the RC. Treatment was performed at 13 centers between 2008 and 2021. Patient characteristics, treatment details, and follow-up data including overall survival (OS), local control (LC) were evaluated. Cox Regression and Kaplan-Meier curves with Log-rank Tests were calculated for selected variables. In this retrospective study, overall survival was 61.5% at 1 year, 47.6% at 2 years, and 35.5% at 3 years, and local control was 84.6% at 1 year, 74.8% at 2 years, and 72.8% at 3 years. 96% of patients were treated with hypofractionated stereotactic radiotherapy (HSRT), only 26 patients received single fraction radiosurgery (4%). Prognostic factors associated with overall survival were Karnofsky Performance Status, RPA and GPA class, controlled primary tumor and absence of extracranial metastases, whereas prognostic factor associated with local control was planning target volume (23 mL or less). HSRT is the most common fractionation form in the treatment of RCs in this multicenter analysis. This approach results in excellent OS and LC outcomes. OS in patients with resected brain metastases is mainly influenced by performance status. In regard to local control, RT of large cavities remain a challenge with significantly worse outcome. [ABSTRACT FROM AUTHOR]

Background: The aim of this analysis was to model the effect of local control (LC) on overall survival (OS) in patients treated with stereotactic body radiotherapy (SBRT) for liver or lung metastases from colorectal cancer.Methods: The analysis is based on pooled data from two retrospective SBRT databases for pulmonary and hepatic metastases from 27 centers from Germany and Switzerland. Only patients with metastases from colorectal cancer were considered to avoid histology as a confounding factor. An illness-death model was employed to model the relationship between LC and OS.Results: Three hundred eighty-eight patients with 500 metastatic lesions (lung n = 209, liver n = 291) were included and analyzed. Median follow-up time for local recurrence assessment was 12.1 months. Ninety-nine patients with 112 lesions experienced local failure. Seventy-one of these patients died after local failure. Median survival time was 27.9 months in all patients and 25.4 months versus 30.6 months in patients with and without local failure after SBRT. The baseline risk of death after local failure exceeds the baseline risk of death without local failure at 10 months indicating better survival with LC.Conclusion: In CRC patients with lung or liver metastases, our findings suggest improved long-term OS by achieving metastatic disease control using SBRT in patients with a projected OS estimate of > 12 months. [ABSTRACT FROM AUTHOR]

Background Stereotactic body radiotherapy (SBRT) for oligometastatic disease is characterized by an excellent safety profile; however, experiences are mostly based on treatment of one single metastasis. It was the aim of this study to evaluate safety and efficacy of SBRT for multiple pulmonary metastases. Patients and methods This study is based on a retrospective database of the DEGRO stereotactic working group, consisting of 637 patients with 858 treatments. Cox regression and logistic regression were used to analyze the association between the number of SBRT treatments or the number and the timing of repeat SBRT courses with overall survival (OS) and the risk of early death. Results Out of 637 patients, 145 patients were treated for multiple pulmonary metastases; 88 patients received all SBRT treatments within one month whereas 57 patients were treated with repeat SBRT separated by at least one month. Median OS for the total patient population was 23.5 months and OS was not significantly influenced by the overall number of SBRT treatments or the number and timing of repeat SBRT courses. The risk of early death within 3 and 6 months was not increased in patients treated with multiple SBRT treatments, and no grade 4 or grade 5 toxicity was observed in these patients. Conclusions In appropriately selected patients, synchronous SBRT for multiple pulmonary oligometastases and repeat SBRT may have a comparable safety and efficacy profile compared to SBRT for one single oligometastasis. [ABSTRACT FROM AUTHOR]

In patients with refractory ventricular tachycardia (VT), STereotactic Arrhythmia Radioablation (STAR) showed promising results for otherwise untreatable patients. The STOPSTORM.eu project coordinates European efforts to validate STAR. The primary goal of this critical structures benchmark study was to harmonize contouring of organs at risk (OARs) for STAR within the STOPSTORM.eu consortium. The results enable to refine protocols and guidelines to ensure treatment harmonization. Three STAR cases were selected for this benchmark study and sent to all radiation oncology centers within the consortium. Every case had a contrast-enhanced cardiac CT which was already deformed to the primary planning-CT to contour the OARs in detail. Every center was asked to contour 31 OARs according to literature-based guidelines. The resulting structure sets were qualitatively evaluated in an oncology imaging informatics system (technology company). For all structures and specific subset of structures the Dice coefficient (DICE) was calculated in a treatment planning system for all possible combinations of two centers. Twenty centers participated in the critical structure contouring benchmark. Contouring of the structures was performed with high accuracy according to the provided guidelines. The contours of common OARs, such as the heart, stomach, esophagus, bronchus, aorta and spinal canal in had a high conformity (median DICE resp. 0.92, 0.78, 0.71, 0.57, 0.87 and 0.71). In the substructures of the heart (chambers, valves, arteries, and nodes), deviations in the contours occurred more frequently. While the cardiac chambers had a high conformity value (median DICE of 0.84), the valves, arteries and nodes had lower values (median DICE of resp. 0.16, 0.31 and 0.26). However, these structures do not yet have a consensus for treatment planning purposes and late toxicity but need to be contoured correctly for future analysis within the STOPSTORM.eu project. This large and unique STOPSTORM.eu multi-center critical structures benchmark study showed a high accuracy regarding standard critical structures. For cardiac substructures some deviations occurred resulting in the development of new definitions for contouring these structures within the consortium. In addition, a close collaboration between radiation oncologist and cardiac electrophysiologist is warranted to reach optimal and effective STAR treatment. [ABSTRACT FROM AUTHOR]

Introduction Stereotactic body radiation therapy (SBRT) is applied in the oligometastatic setting to treat liver metastases. However, factors influencing tumor control probability (TCP) other than radiation dose have not been thoroughly investigated. Here we set out to investigate such factors with a focus on the influence of histology and chemotherapy prior to SBRT using a large multi-center database from the German Society of Radiation Oncology. Methods 452 SBRT treatments in 363 patients were analyzed after collection of patient, tumor and treatment data in a multi-center database. Histology was considered through random effects in semi-parametric and parametric frailty models. Dose prescriptions were parametrized by conversion to the maximum biologically effective dose using alpha/beta of 10 Gy (BED max ). Results After adjusting for histology, BED max was the strongest predictor of TCP. Larger PTV volumes, chemotherapy prior to SBRT and simple motion management techniques predicted significantly lower TCP. The model predicted a BED of 209 ± 67 Gy 10 necessary for 90% TCP at 2 years with no prior chemotherapy, but 286 ± 78 Gy 10 when chemotherapy had been given. Breast cancer metastases were significantly more responsive to SBRT compared to other histologies with 90% TCP at 2 years achievable with BED max of 157 ± 80 Gy 10 or 80 ± 62 Gy 10 with and without prior chemotherapy, respectively. Conclusions Besides dose, histology and pretreatment chemotherapy were important factors influencing local TCP in this large cohort of liver metastases. After adjusting for prior chemotherapy, our data add to the emerging evidence that breast cancer metastases do respond better to hypofractionated SBRT compared to other histologies. [ABSTRACT FROM AUTHOR]

Background Radical local treatment of pulmonary metastases is practiced with increasing frequency due to acknowledgment and better understanding of oligo-metastatic disease. This study aimed to develop a nomogram predicting overall survival (OS) after stereotactic body radiotherapy (SBRT) for pulmonary metastases. Patients and methods A multi-institutional database of 670 patients treated with SBRT for pulmonary metastases was used as training cohort. Cox regression analysis with bidirectional variable elimination was performed to identify factors to be included into the nomogram model to predict 2-year OS. The calibration rate of the nomogram was assessed by plotting the actual Kaplan–Meier 2-year OS against the nomogram predicted survival. The nomogram was externally validated using two separate monocentric databases of 145 and 92 patients treated with SBRT for pulmonary metastases. Results The median follow up of the trainings cohort was 14.3 months, the 2-year and 5-year OS was 52.6% and 23.7%, respectively. Karnofsky performance index, type of the primary tumor, control of the primary tumor, maximum diameter of the largest treated metastasis and number of metastases (1 versus >1) were significant prognostic factors in the Cox model (all p < 0.05). The calculated concordance-index for the nomogram was 0.73 (concordance indexes of all prognostic factors between 0.54 and 0.6). Based on the nomogram the training cohort was divided into 4 groups and 2-year OS ranged between 24.2% and 76.1% (predicted OS between 30.2% and 78.4%). The nomogram discriminated between risk groups in the two validation cohorts (concordance index 0.68 and 0.67). Conclusions A nomogram for prediction of OS after SBRT for pulmonary metastases was generated and externally validated. This tool might be helpful for interdisciplinary discussion and evaluation of local and systemic treatment options in the oligo-metastatic setting. Key message A nomogram for prediction of overall survival after stereotactic body radiotherapy (SBRT) for pulmonary metastases was developed and externally validated. This tool might be helpful for interdisciplinary discussion and evaluation of local and systemic treatment options in the oligo-metastatic setting. [ABSTRACT FROM AUTHOR]

In patients with refractory ventricular tachycardia (VT), Stereotactic Arrhythmia Radioablation (STAR) showed promising results for otherwise untreatable patients. The STOPSTORM.eu project coordinates European efforts to clinically validate STAR and to refine protocols and guidelines. The aim of this work is to present the current clinical STAR practice in Europe based on three examples as baseline for further optimization. Target Volumes (TV) and Organs-at-Risk (OAR) were generated from previous consortium benchmarks and consensus definitions for three well-selected STAR cases. Planning Target Volumes (PTV) were generated based on three different compensation strategies for cardiac and respiratory motion and overlapped/close OARs like coronary arteries or stomach. The STOPSTORM.eu members were asked to generate single fraction treatment plans with 25 Gy dose prescription based on ICRU report 91 for each case based on their STAR clinical practice through multi-disciplinary discussion. Resulting dose distributions were analyzed independently using a customized platform for multi-center treatment planning studies. By November 2021, 20 centers submitted 22, 23 and 22 treatment plans for case 1, 2 and 3, respectively, mostly (75% of plans) using Intensity Modulated Arc Therapy (IMAT) with 6 MeV FFF beams (73% of the IMAT plans) among other commonly used techniques for stereotactic radiotherapy. Presently, used guidelines for STAR treatment planning and OAR dose limits vary greatly and are mostly based on the AAPM TG-101 report and RAVENTA trial publication. As a major finding, 73% of the submitted plans showed close OAR sparing overachieving high PTV coverage (Figure 1 and Table 1) arguing that lower doses may also result in clinical efficiency. Cases 1 and 3 dose distributions (referenced as A. and C. in Figure 2) highlighted how OARs sparing also resulted in heavy PTV under dosing for some participants. From this first STOPSTORM.eu multi-center/multi-platform treatment planning benchmark study we obtained important information concerning current clinical practice from major European centers performing Stereotactic Arrhythmia Radioablation for VT. With the strongly varying approaches of the centers as basis, the key task for the STOPSTORM.eu project is to find consensus, aiming to harmonize and optimize STAR practice in Europe. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study is the correction of the lateral scanner artifact, i.e., the effect that, on a large homogeneously exposed EBT3 film, a flatbed scanner measures different optical densities at different positions along the x axis, the axis parallel to the elongated light source. At constant dose, the measured optical densitiy profiles along this axis have a parabolic shape with significant dose dependent curvature. Therefore, the effect is shortly called the parabola effect. The objective of the algorithm developed in this study is to correct for the parabola effect. Any optical density measured at given position x is transformed into the equivalent optical density c at the apex of the parabola and then converted into the corresponding dose via the calibration of c versus dose. Methods: For the present study EBT3 films and an Epson 10000XL scanner including transparency unit were used for the analysis of the parabola effect. The films were irradiated with 6 MV photons from an Elekta Synergy accelerator in a RW3 slab phantom. In order to quantify the effect, ten film pieces with doses graded from 0 to 20.9 Gy were sequentially scanned at eight positions along the x axis and at six positions along the z axis (the movement direction of the light source) both for the portrait and landscape film orientations. In order to test the effectiveness of the new correction algorithm, the dose profiles of an open square field and an IMRT plan were measured by EBT3 films and compared with ionization chamber and ionization chamber array measurement. Results: The parabola effect has been numerically studied over the whole measuring field of the Epson 10000XL scanner for doses up to 20.9 Gy and for both film orientations. The presented algorithm transforms any optical density at position x into the equivalent optical density that would be measured at the same dose at the apex of the parabola. This correction method has been validated up to doses of 5.2 Gy all over the scanner bed with 2D dose distributions of an open square photon field and an IMRT distribution. Conclusions: The algorithm presented in this study quantifies and corrects the parabola effect of EBT3 films scanned in commonly used commercial flatbed scanners at doses up to 5.2 Gy. It is easy to implement, and no additional work steps are necessary in daily routine film dosimetry. [ABSTRACT FROM AUTHOR]

Abstract: The evaluation of the degree of percutaneous penetration of agrochemicals is a key part of risk assessment for operators. The availability of suitable and predictive experimental models is crucial, in particular in the case of lipophilic compounds which persist in the stratum corneum (SC). Regulatory models (rat in vivo, human and rat in vitro) and the innovative human skin grafted onto nude mice (HuSki) model were compared for their ability to predict the human skin absorption. Radiolabelled malathion, lindane and cypermethrin (4μg/cm2) were topically applied to each model. The % of applied dose absorbed and that present in skin and SC were evaluated at 24h. Additionally, the absorption profile of cypermethrin was evaluated in the in vivo rat and HuSki models for up to 11 days. We found that the human in vitro and HuSki models closely predicted the human skin absorption at 24h, while rat models overestimated the human skin absorption. Furthermore, our experiments with cypermethrin indicated that evaluation of % percutaneous absorption over extended periods of time was feasible with the HuSki model. In our studies the HuSki model overcame the limitations of the regulatory models and is promising to realistically refine the dermal absorption assessment of topically applied chemicals. [Copyright &y& Elsevier]

Poster discussion: PH: Quantitative functional and biological imaging PD-0298: Long-term characterization of MRImorphologic alterations after active motion-compensated liver SBRT G. Miebach, C. Dreher, P. Wojtal, H. Oppitz, A. Jahnke, G. Sarria, F.A. Giordano, O. Blanck, J. Boda-Heggemann. [Extracted from the article]

Background: The intent of this pooled analysis as part of the German society for radiation oncology (DEGRO) stereotactic body radiotherapy (SBRT) initiative was to analyze the patterns of care of SBRT for liver oligometastases and to derive factors influencing treated metastases control and overall survival in a large patient cohort.Methods: From 17 German and Swiss centers, data on all patients treated for liver oligometastases with SBRT since its introduction in 1997 has been collected and entered into a centralized database. In addition to patient and tumor characteristics, data on immobilization, image guidance and motion management as well as dose prescription and fractionation has been gathered. Besides dose response and survival statistics, time trends of the aforementioned variables have been investigated.Results: In total, 474 patients with 623 liver oligometastases (median 1 lesion/patient; range 1–4) have been collected from 1997 until 2015. Predominant histologies were colorectal cancer (n = 213 pts.; 300 lesions) and breast cancer (n = 57; 81 lesions). All centers employed an SBRT specific setup. Initially, stereotactic coordinates and CT simulation were used for treatment set-up (55%), but eventually were replaced by CBCT guidance (28%) or more recently robotic tracking (17%). High variance in fraction (fx) number (median 1 fx; range 1–13) and dose per fraction (median: 18.5 Gy; range 3–37.5 Gy) was observed, although median BED remained consistently high after an initial learning curve. Median follow-up time was 15 months; median overall survival after SBRT was 24 months. One- and 2-year treated metastases control rate of treated lesions was 77% and 64%; if maximum isocenter biological equivalent dose (BED) was greater than 150 Gy EQD2Gy, it increased to 83% and 70%, respectively. Besides radiation dose colorectal and breast histology and motion management methods were associated with improved treated metastases control.Conclusion: After an initial learning curve with regards to total cumulative doses, consistently high biologically effective doses have been employed translating into high local tumor control at 1 and 2 years. The true impact of histology and motion management method on treated metastases control deserve deeper analysis. Overall survival is mainly influenced by histology and metastatic tumor burden. [ABSTRACT FROM AUTHOR]