Evaluation of specific RBE in different cells of hippocampus under high-dose proton irradiation in rats.

The study aimed to determine the specific relative biological effectiveness (RBE) of various cells in the hippocampus following proton irradiation. Sixty Sprague-Dawley rats were randomly allocated to 5 groups receiving 20 or 30 Gy of proton or photon irradiation. Pathomorphological neuronal damage in the hippocampus was assessed using Hematoxylin-eosin (HE) staining. The expression level of NeuN, Nestin, Caspase-3, Olig2, CD68 and CD45 were determined by immunohistochemistry (IHC). The RBE range established by comparing the effects of proton and photon irradiation at equivalent biological outcomes. Proton20Gy induced more severe damage to neurons than photon20Gy, but showed no difference compared to photon30Gy. The RBE of neuron was determined to be 1.65. Similarly, both proton20Gy and proton30Gy resulted in more inhibition of oligodendrocytes and activation of microglia in the hippocampal regions than photon20Gy and photon30Gy. However, the expression of Olig2 was higher and CD68 was lower in the proton20Gy group than in the photon30Gy group. The RBE of oligodendrocyte and microglia was estimated to be between 1.1 to 1.65. For neural stem cells (NSCs) and immune cells, there were no significant difference in the expression of Nestin and CD45 between proton and photon irradiation (both 20 and 30 Gy). Therefore, the RBE for NSCs and immune cell was determined to be 1.1. These findings highlight the varying RBE values of different cells in the hippocampus in vivo. Moreover, the actual RBE of the hippocampus may be higher than 1.1, suggesting that using as RBE value of 1.1 in clinical practice may underestimate the toxicities induced by proton radiation.

Dosimetric feasibility study ("proof of concept") of refractory ventricular tachycardia radioablation using proton minibeams.

PURPOSE: Preclinical data demonstrated that the use of proton minibeam radiotherapy reduces the risk of toxicity in healthy tissue. Ventricular tachycardia radioablation is an area under clinical investigation in proton beam therapy. We sought to simulate a ventricular tachycardia radioablation with proton minibeams and to demonstrate that it was possible to obtain a homogeneous coverage of an arrhythmogenic cardiac zone with this technique. MATERIAL AND METHODS: An arrhythmogenic target volume was defined on the simulation CT scan of a patient, localized in the lateral wall of the left ventricle. A dose of 25Gy was planned to be delivered by proton minibeam radiotherapy, simulated using a Monte Carlo code (TOPAS v.3.7) with a collimator of 19 0.4 mm-wide slits spaced 3mm apart. The main objective of the study was to obtain a plan ensuring at least 93% of the prescription dose in 93% of the planning target volume without exceeding 110% of the prescribed dose in the planning target volume. RESULTS: The average dose in the planning treatment volume in proton minibeam radiotherapy was 25.12Gy. The percentage of the planning target volume receiving 93% (V93%), 110% (V110%), and 95% (V95%) of the prescribed dose was 94.25%, 0%, and 92.6% respectively. The lateral penumbra was 6.6mm. The mean value of the peak-to-valley-dose ratio in the planning target volume was 1.06. The mean heart dose was 2.54Gy versus 5.95Gy with stereotactic photon beam irradiation. CONCLUSION: This proof-of-concept study shows that proton minibeam radiotherapy can achieve a homogeneous coverage of an arrhythmogenic cardiac zone, reducing the dose at the normal tissues. This technique, ensuring could theoretically reduce the risk of late pulmonary and breast fibrosis, as well as cardiac toxicity as seen in previous biological studies in proton minibeam radiotherapy.

An artificial neural network based approach for predicting the proton beam spot dosimetric characteristics of a pencil beam scanning technique.

Utilising Machine Learning (ML) models to predict dosimetric parameters in pencil beam scanning proton therapy presents a promising and practical approach. The study developed Artificial Neural Network (ANN) models to predict proton beam spot size and relative positional errors using 9000 proton spot data. The irradiation log files as input variables and corresponding scintillation detector measurements as the label values. The ANN models were developed to predict six variables: spot size in thex-axis,y-axis, major axis, minor axis, and relative positional errors in thex-axis andy-axis. All ANN models used a Multi-layer perception (MLP) network using one input layer, three hidden layers, and one output layer. Model performance was validated using various statistical tools. The log file recorded spot size and relative positional errors, which were compared with scintillator-measured data. The Root Mean Squared Error (RMSE) values for the x-spot and y-spot sizes were 0.356 mm and 0.362 mm, respectively. Additionally, the maximum variation for the x-spot relative positional error was 0.910 mm, while for the y-spot, it was 1.610 mm. The ANN models exhibit lower prediction errors. Specifically, the RMSE values for spot size prediction in the x, y, major, and minor axes are 0.053 mm, 0.049 mm, 0.053 mm, and 0.052 mm, respectively. Additionally, the relative spot positional error prediction model for the x and y axes yielded maximum errors of 0.160 mm and 0.170 mm, respectively. The normality of models was validated using the residual histogram and Q-Q plot. The data over fit, and bias were tested using K (k = 5) fold cross-validation, and the maximum RMSE value of the K fold cross-validation among all the six ML models was less than 0.150 mm (R-Square 0.960). All the models showed excellent prediction accuracy. Accurately predicting beam spot size and positional errors enhances efficiency in routine dosimetric checks.

Tuning spatially fractionated radiotherapy dose profiles using the moiré effect.

Spatially Fractionated Radiotherapy (SFRT) has demonstrated promising potential in cancer treatment, combining the advantages of reduced post-radiation effects and enhanced local control rates. Within this paradigm, proton minibeam radiotherapy (pMBRT) was suggested as a new treatment modality, possibly producing superior normal tissue sparing to conventional proton therapy, leading to improvements in patient outcomes. However, an effective and convenient beam generation method for pMBRT, capable of implementing various optimum dose profiles, is essential for its real-world application. Our study investigates the potential of utilizing the moiré effect in a dual collimator system (DCS) to generate pMBRT dose profiles with the flexibility to modify the center-to-center distance (CTC) of the dose distribution in a technically simple way.We employ the Geant4 Monte Carlo simulations tool to demonstrate that the angle between the two collimators of a DCS can significantly impact the dose profile. Varying the DCS angle from 10 ∘ to 50 ∘ we could cover CTC ranging from 11.8 mm to 2.4 mm, respectively. Further investigations reveal the substantial influence of the multi-slit collimator's (MSC) physical parameters on the spatially fractionated dose profile, such as period (CTC), throughput, and spacing between MSCs. These findings highlight opportunities for precision dose profile adjustments tailored to specific clinical scenarios.The DCS capacity for rapid angle adjustments during the energy transition stages of a spot scanning system can facilitate dynamic alterations in the irradiation profile, enhancing dose contrast in normal tissues. Furthermore, its unique attribute of spatially fractionated doses in both lateral directions could potentially improve normal tissue sparing by minimizing irradiated volume. Beyond the realm of pMBRT, the dual MSC system exhibits remarkable versatility, showing compatibility with different types of beams (X-rays and electrons) and applicability across various SFRT modalities.Our study illuminates the dual MSC system's potential as an efficient and adaptable tool in the refinement of pMBRT techniques. By enabling meticulous control over irradiation profiles, this system may expedite advancements in clinical and experimental applications, thereby contributing to the evolution of SFRT strategies.

Benchmarking proton RBE models.

Objective.To biologically optimise proton therapy, models which can accurately predict variations in proton relative biological effectiveness (RBE) are essential. Current phenomenological models show large disagreements in RBE predictions, due to different model assumptions and differences in the data to which they were fit. In this work, thirteen RBE models were benchmarked against a comprehensive proton RBE dataset to evaluate predictions when all models are fit using the same data and fitting techniques, and to assess the statistical robustness of the models.Approach.Model performance was initially evaluated by fitting to the full dataset, and then a cross-validation approach was applied to assess model generalisability and robustness. The impact of weighting the fit and the choice of biological endpoint (either single or multiple survival levels) was also evaluated.Main results.Fitting the models to a common dataset reduced differences between their predictions, however significant disagreements remained due to different underlying assumptions. All models performed poorly under cross-validation in the weighted fits, suggesting that some uncertainties on the experimental data were significantly underestimated, resulting in over-fitting and poor performance on unseen data. The simplest model, which depends linearly on the LET but has no tissue or dose dependence, performed best for a single survival level. However, when fitting to multiple survival levels simultaneously, more complex models with tissue dependence performed better. All models had significant residual uncertainty in their predictions compared to experimental data.Significance.This analysis highlights that poor quality of error estimation on the dose response parameters introduces substantial uncertainty in model fitting. The significant residual error present in all approaches illustrates the challenges inherent in fitting to large, heterogeneous datasets and the importance of robust statistical validation of RBE models.

The impact of motion on onboard MRI-guided pencil beam scanned proton therapy treatments.

Objective.Online magnetic resonance imaging (MRI) guidance could be especially beneficial for pencil beam scanned (PBS) proton therapy of tumours affected by respiratory motion. For the first time to our knowledge, we investigate the dosimetric impact of respiratory motion on MRI-guided proton therapy compared to the scenario without magnetic field.Approach.A previously developed analytical proton dose calculation algorithm accounting for perpendicular magnetic fields was extended to enable 4D dose calculations. For two geometrical phantoms and three liver and two lung patient cases, static treatment plans were optimised with and without magnetic field (0, 0.5 and 1.5 T). Furthermore, plans were optimised using gantry angle corrections (0.5 T +5° and 1.5 T +15°) to reproduce similar beam trajectories compared to the 0 T reference plans. The effect of motion was then considered using 4D dose calculations without any motion mitigation and simulating 8-times volumetric rescanning, with motion for the patient cases provided by 4DCT(MRI) data sets. Each 4D dose calculation was performed for different starting phases and the CTV dose coverageV95%and homogeneityD5%-D95%were analysed.Main results.For the geometrical phantoms with rigid motion perpendicular to the beam and parallel to the magnetic field, a comparable dosimetric effect was observed independent of the magnetic field. Also for the five 4DCT(MRI) cases, the influence of motion was comparable for all magnetic field strengths with and without gantry angle correction. On average, the motion-induced decrease in CTVV95%from the static plan was 17.0% and 18.9% for 1.5 T and 0.5 T, respectively, and 19.9% without magnetic field.Significance.For the first time, this study investigates the combined impact of magnetic fields and respiratory motion on MR-guided proton therapy. The comparable dosimetric effects irrespective of magnetic field strength indicate that the effects of motion for future MR-guided proton therapy may not be worse than for conventional PBS proton therapy.

Study on induced radioactivity and individual dose evaluation in Gantry room for Varian ProBeam Proton Therapy System.

Proton therapy has emerged as an advantageous modality for tumor radiotherapy due to its favorable physical and biological properties. However, this therapy generates induced radioactivity through nuclear reactions between the primary beam, secondary particles, and surrounding materials. This study focuses on systematically investigating the induced radioactivity in the gantry room during pencil beam scanning, utilizing both experimental measurements and Monte Carlo simulations. Results indicate that patients are the primary source of induced radioactivity, predominantly producing radionuclides such as 11C, 13N, and 15O. Long-term irradiation primarily generates radionuclides like 22Na, 24Na, and 54Mn etc. Additionally, this study estimates the individual doses received by medical workers in the gantry room, the irradiation dose for patient escorts, and the additional dose to patients from residual radiation. Finally, the study offers recommendations to minimize unnecessary irradiation doses to medical workers, patient escorts, and patients.

Comparing interplay effects in scanned proton therapy of lung cancer: Free breathing with various layer and volume rescanning versus respiratory gating with different gate widths.

PURPOSE: We investigated interplay effects and treatment time (TT) in scanned proton therapy for lung cancer patients. We compared free-breathing (FB) approaches with multiple rescanning strategies and respiratory-gating (RG) methods with various gating widths to identify the superior irradiation technique. METHODS: Plans were created with 4/1, 2/2, and 1/4 layered/volume rescans of FB (L4V1, L2V2, and L1V4), and 50%, 30%, and 10% gating widths of the total respiratory curves (G50, G30, and G10) of the RG plans with L4V1. We calculated 4-dimensional dynamic doses assuming a constant sinusoidal curve for six irradiation methods. The reconstructed doses per fraction were compared with planned doses in terms of dose differences in 99% clinical-target-volume (CTV) (ΔD99%), near-maximum dose differences (ΔD2%) at organs-at-risk (OARs), and TT. RESULTS: The mean/minimum CTV ΔD99% values for FB were -1.0%/-4.9%, -0.8%/-4.3%, and -0.1%/-1.0% for L4V1, L2V2, and L1V4, respectively. Those for RG were -0.3%/-1.7%, -0.1%/-1.0%, and 0.0%/-0.5% for G50, G30, and G10, respectively. The CTV ΔD99% of the RGs with less than 50% gate width and the FBs of L1V4 were within the desired tolerance (±3.0%), and the OARs ΔD2% for RG were lower than those for FB. The mean TTs were 90, 326, 824, 158, 203, and 422 s for L4V1, L2V2, L1V4, G50, G30, and G10, respectively. CONCLUSIONS: FB (L4V1) is the most efficient treatment, but not necessarily the optimal choice due to interplay effects. To satisfy both TT extensions and interplay, RG with a gate width as large as possible within safety limits is desirable.

Using the gamma-index analysis for inter-fractional comparison of in-beam PET images for head-and-neck treatment monitoring in proton therapy: A Monte Carlo simulation study.

GOAL: In-beam Positron Emission Tomography (PET) is a technique for in-vivo non-invasive treatment monitoring for proton therapy. To detect anatomical changes in patients with PET, various analysis methods exist, but their clinical interpretation is problematic. The goal of this work is to investigate whether the gamma-index analysis, widely used for dose comparisons, is an appropriate tool for comparing in-beam PET distributions. Focusing on a head-and-neck patient, we investigate whether the gamma-index map and the passing rate are sensitive to progressive anatomical changes. METHODS/MATERIALS: We simulated a treatment course of a proton therapy patient using FLUKA Monte Carlo simulations. Gradual emptying of the sinonasal cavity was modeled through a series of artificially modified CT scans. The in-beam PET activity distributions from three fields were evaluated, simulating a planar dual head geometry. We applied the 3D-gamma evaluation method to compare the PET images with a reference image without changes. Various tolerance criteria and parameters were tested, and results were compared to the CT-scans. RESULTS: Based on 210 MC simulations we identified appropriate parameters for the gamma-index analysis. Tolerance values of 3 mm/3% and 2 mm/2% were suited for comparison of simulated in-beam PET distributions. The gamma passing rate decreased with increasing volume change for all fields. CONCLUSION: The gamma-index analysis was found to be a useful tool for comparing simulated in-beam PET images, sensitive to sinonasal cavity emptying. Monitoring the gamma passing rate behavior over the treatment course is useful to detect anatomical changes occurring during the treatment course.

Development of porous structure for broadening Bragg-peak in scanning carbon-ion radiotherapy: Monte Carlo simulation and experimental validation.

PURPOSE: The present study aimed to develop a porous structure with plug-ins (PSP) to broaden the Bragg peak width (BPW, defined as the distance in water between the proximal and distal 80% dose) of the carbon ion beam while maintaining a sharp distal falloff width (DFW, defined as the distance along the beam axis where the dose in water reduces from 80% to 20%). METHODS: The binary voxel models of porous structure (PS) and PSP were established in the Monte Carlo code FLUKA and the corresponding physical models were manufactured by 3D printing. Both experiment and simulation were performed for evaluating the modulation capacity of PS and PSP. BPWs and DFWs derived from each integral depth dose curves were compared. Fluence homogeneity of 430 MeV/u carbon-ion beam passing through the PSP was recorded by analyzing radiochromic films at six different locations downstream the PSP in the experiment. Additionally, by changing the beam spot size and incident position on the PSP, totally 48 different carbon-ion beams were simulated and corresponding deviations of beam metrics were evaluated to test the modulating stability of PSP. RESULTS: According to the measurement data, the use of PSP resulted in an average increase of 0.63 mm in BPW and a decrease of 0.74 mm in DFW compared to PS. The 2D radiation field inhomogeneities were lower than 3 % when the beam passing through a ≥ 10 cm PMMA medium. Furthermore, employing a spot size of ≥ 6 mm ensures that beam metric deviations, including BPW, DFW, and range, remain within a deviation of 0.1 mm across various incident positions. CONCLUSION: The developed PSP demonstrated its capability to effectively broaden the BPW of carbon ion beams while maintaining a sharp DFW comparing to PS. The superior performance of PSP, indicates its potential for clinical use in the future.

Fano cavity test and investigation of the response of the Roos chamber irradiated by proton beams in perpendicular magnetic fields up to 1 T.

Objective. The aim of this work is to investigate the response of the Roos chamber (type 34001) irradiated by clinical proton beams in magnetic fields.Approach. At first, a Fano test was implemented in Monte Carlo software package GATE version 9.2 (based on Geant4 version 11.0.2) using a cylindrical slab geometry in a magnetic field up to 1 T. In accordance to an experimental setup (Fuchset al2021), the magnetic field correction factorskQB⃗of the Roos chamber were determined at different energies up to 252 MeV and magnetic field strengths up to 1 T, by separately simulating the ratios of chamber signalsMQ/MQB⃗,without and with magnetic field, and the dose-conversion factorsDw,QB⃗/Dw,Qin a small cylinder of water, with and without magnetic field. Additionally, detailed simulations were carried out to understand the observed magnetic field dependence.Main results. The Fano test was passed with deviations smaller than 0.25% between 0 and 1 T. The ratios of the chamber signals show both energy and magnetic field dependence. The maximum deviation of the dose-conversion factors from unity of 0.22% was observed at the lowest investigated proton energy of 97.4 MeV andB⃗= 1 T. The resultingkQB⃗factors increase initially with the applied magnetic field and decrease again after reaching a maximum at around 0.5 T; except for the lowest 97.4 MeV beam that show no observable magnetic field dependence. The deviation from unity of the factors is also larger for higher proton energies, where the maximum lies at 1.0035(5), 1.0054(7) and 1.0069(7) for initial energies ofE0= 152, 223.4 and 252 MeV, respectively.Significance. Detailed Monte Carlo studies showed that the observed effect can be mainly attributed to the differences in the transport of electrons produced both outside and inside of the air cavity in the presence of a magnetic field.

SAPPHIRE -establishment of small animal proton and photon image-guided radiation experiments.

Thein vivoevolution of radiotherapy necessitates innovative platforms for preclinical investigation, bridging the gap between bench research and clinical applications. Understanding the nuances of radiation response, specifically tailored to proton and photon therapies, is critical for optimizing treatment outcomes. Within this context, preclinicalin vivoexperimental setups incorporating image guidance for both photon and proton therapies are pivotal, enabling the translation of findings from small animal models to clinical settings. TheSAPPHIREproject represents a milestone in this pursuit, presenting the installation of the small animal radiation therapy integrated beamline (SmART+ IB, Precision X-Ray Inc., Madison, Connecticut, USA) designed for preclinical image-guided proton and photon therapy experiments at University Proton Therapy Dresden. Through Monte Carlo simulations, low-dose on-site cone beam computed tomography imaging and quality assurance alignment protocols, the project ensures the safe and precise application of radiation, crucial for replicating clinical scenarios in small animal models. The creation of Hounsfield lookup tables and comprehensive proton and photon beam characterizations within this system enable accurate dose calculations, allowing for targeted and controlled comparison experiments. By integrating these capabilities,SAPPHIREbridges preclinical investigations and potential clinical applications, offering a platform for translational radiobiology research and cancer therapy advancements.

Dose and dose rate dependence of the tissue sparing effect at ultra-high dose rate studied for proton and electron beams using the zebrafish embryo model.

PURPOSE: A better characterization of the dependence of the tissue sparing effect at ultra-high dose rate (UHDR) on physical beam parameters (dose, dose rate, radiation quality) would be helpful towards a mechanistic understanding of the FLASH effect and for its broader clinical translation. To address this, a comprehensive study on the normal tissue sparing at UHDR using the zebrafish embryo (ZFE) model was conducted. METHODS: One-day-old ZFE were irradiated over a wide dose range (15-95 Gy) in three different beams (proton entrance channel, proton spread out Bragg peak and 30 MeV electrons) at UHDR and reference dose rate. After irradiation the ZFE were incubated for 4 days and then analyzed for four different biological endpoints (pericardial edema, curved spine, embryo length and eye diameter). RESULTS: Dose-effect curves were obtained and a sparing effect at UHDR was observed for all three beams. It was demonstrated that proton relative biological effectiveness and UHDR sparing are both relevant to predict the resulting dose response. Dose dependent FLASH modifying factors (FMF) for ZFE were found to be compatible with rodent data from the literature. It was found that the UHDR sparing effect saturates at doses above âˆ¼ 50 Gy with an FMF of âˆ¼ 0.7-0.8. A strong dose rate dependence of the tissue sparing effect in ZFE was observed. The magnitude of the maximum sparing effect was comparable for all studied biological endpoints. CONCLUSION: The ZFE model was shown to be a suitable pre-clinical high-throughput model for radiobiological studies on FLASH radiotherapy, providing results comparable to rodent models. This underlines the relevance of ZFE studies for FLASH radiotherapy research.

First clinical experience following the consensus guide for calibrating a proton stopping power ratio curve in a new proton centre.

BACKGROUND AND PURPOSE: This work introduces the first assessment of CT calibration following the ESTRO's consensus guidelines and validating the HLUT through the irradiation of biological material. METHODS: Two electron density phantoms were scanned with two CT scanners using two CT scan energies. The stopping power ratio (SPR) and mass density (MD) HLUTs for different CT scan energies were derived using Schneider's and ESTRO's methods. The comparison metric in this work is based on the Water-Equivalent Thickness (WET) difference between the treatment planning system and biological irradiation measurement. The SPR HLUTs were compared between the two calibration methods. To assess the accuracy of using MD HLUT for dose calculation in the treatment planning system, MD vs SPR HLUT was compared. Lastly, the feasibility of using a single SPR HLUT to replace two different energy CT scans was explored. RESULTS: The results show a WET difference of less than 3.5% except for the result in the Bone region between Schneider's and ESTRO's methods. Comparing MD and SPR HLUT, the results from MD HLUT show less than a 3.5% difference except for the Bone region. However, the SPR HLUT shows a lower mean absolute percentage difference as compared to MD HLUT between the measured and calculated WET difference. Lastly, it is possible to use a single SPR HLUT for two different CT scan energies since both WET differences are within 3.5%. CONCLUSION: This is the first report on calibrating an HLUT following the ESTRO's guidelines. While our result shows incremental improvement in range uncertainty using the ESTRO's guideline, the prescriptional approach of the guideline does promote harmonization of CT calibration protocols between different centres.

Impact of iodinated oil in proton therapy on relative stopping power of liver post-cTACE.

Objective. Conventional transarterial chemoembolization (cTACE) is a common treatment for hepatocellular carcinoma (HCC), often with unsatisfactory local controls. Combining cTACE with radiotherapy shows a promise for unresectable large HCC, with proton therapy preserving healthy liver tissue. However, the proton therapy benefits are subject to the accuracy of tissue relative stopping power (RSP) prediction. The RSP values are typically derived from computed tomography (CT) images using stoichiometric calibration. Lipiodol deposition significantly increases CT numbers in liver regions of post-cTACE. Hence, it is necessary to evaluate the accuracy of RSP in liver regions of post-cTACE.Approach. Liver, water, and iodinated oil samples were prepared. Some liver samples contained iodinated oil. The water equivalent path length (WEPL) of sample was measured through the pullbacks of spread-out Bragg peak (SOBP) depth-dose profiles scanned in a water tank with and without sample in the beam path. Measured RSP values were compared to estimated RSP values derived from the CT number based on the stoichiometric calibration method.Main results. The measured RSP of water was 0.991, confirming measurement system calibration. After removing the RSP contribution from container walls, the pure iodinated oil and liver samples had RSP values of 1.12 and 1.06, while the liver samples mixed with varying oil volumes (5 ml, 10 ml, 15 ml) showed RSP values of 1.05, 1.05 and 1.06. Using the stoichiometric calibration method, pure iodinated oil and liver samples had RSP values of 2.79 and 1.06. Liver samples mixed with iodinated oil (5 ml, 10 ml, 15 ml) had calculated RSP values of 1.21, 1.34, and 1.46. The RSP discrepancy reached 149.1% for pure iodinated oil.Significance.Iodinated oil notably raises CT numbers in liver tissue. However, there is almost no effect on its RSP value. Proton treatment of post-cTACE HCC patients can therefore be overshooting if no proper measures are taken against this specific effect.

Methodology for small animals targeted irradiations at conventional and ultra-high dose rates 65 MeV proton beam.

As part of translational research projects, mice may be irradiated on radiobiology platforms such as the one at the ARRONAX cyclotron. Generally, these platforms do not feature an integrated imaging system. Moreover, in the context of ultra-high dose-rate radiotherapy (FLASH-RT), treatment planning should consider potential changes in the beam characteristics and internal movements in the animal. A patient-like set-up and methodology has been implemented to ensure target coverage during conformal irradiations of the brain, lungs and intestines. In addition, respiratory cycle amplitudes were quantified by fluoroscopic acquisitions on a mouse, to ensure organ coverage and to assess the impact of respiration during FLASH-RT using the 4D digital phantom MOBY. Furthermore, beam incidence direction was studied from mice µCBCT and Monte Carlo simulations. Finally,in vivodosimetry with dose-rate independent radiochromic films (OC-1) and their LET dependency were investigated. The immobilization system ensures that the animal is held in a safe and suitable position. The geometrical evaluation of organ coverage, after the addition of the margins around the organs, was satisfactory. Moreover, no measured differences were found between CONV and FLASH beams enabling a single model of the beamline for all planning studies. Finally, the LET-dependency of the OC-1 film was determined and experimentally verified with phantoms, as well as the feasibility of using these filmsin vivoto validate the targeting. The methodology developed ensures accurate and reproducible preclinical irradiations in CONV and FLASH-RT without in-room image guidance in terms of positioning, dose calculation andin vivodosimetry.

The implementation of an image-guided system at a proton therapy center facility.

PURPOSE: Pencil Beam Scanning (PBS) proton therapy has similar requirements on patient alignment to within 1 mm and 1-degree accuracy as photon radiosurgery. This study describes general workflow, acceptance, and commissioning test procedures and their respective results for an independent robotic arm used for Image Guided Radiotherapy (IGRT) for a Proton Therapy System. METHODS: The system is equipped with kV-imaging techniques capable of orthogonal and Cone-Beam Computed Tomography (CBCT) imaging modalities mounted on an independent robotic arm gantry attached to the ceiling. The imaging system is capable of 360-degree rotation around patients to produce CBCT and kilovoltage orthogonal images. The imaging hardware is controlled by Ehmet Health XIS software, and MIM Software handles the image fusion and registration to an acceptable accuracy of ≤1-mm shifts for patients' alignment. The system was tested according to the requirements outlined in the American Association of Physicists in Medicine (AAPM) Task Group (TG) 142 and TG 179. The system tests included (1) safety, functionality, and connectivity, (2) mechanical testing, (3) image quality, (4) image registration, and (5) imaging dose. Additional tests included imaging gantry isocentricity with a laser tracker and collision-avoiding system checks. RESULTS: The orthogonal and volumetric imaging are comparable in quality to other commercially available On-Board Imagers (OBI) systems. The resulting spatial resolution values were 1.8-, 0.8-, and 0.5-Line Pairs per Millimeter (lp/mm) for orthogonal, full-fan CBCT, and half-fan CBCT, respectively. The image registration is accurate to within 1 mm and 1 degree. The data shows consistent imaging-guided system performance with standard deviations in x, y, and z of 0.7, 0.8, and 0.7 mm, respectively. CONCLUSIONS: The system provides excellent image quality and performance, which can be used for IGRT. The proven accuracy of the x-ray imaging and positioning system at McLaren Proton Therapy Center (MPTC) is 1 mm, making it suitable for proton therapy.

Phantosmia during proton radiation and differences in frequency of phantosmia rates based on proton craniospinal irradiation technique for pediatric brain tumor patients.

BACKGROUND: Unusual olfactory perception, often referred to as "phantosmia" or "cacosmia" has been reported during brain radiotherapy (RT), but is infrequent and does not typically interfere with the ability to deliver treatment. We seek to determine the rate of phantosmia for patients treated with proton craniospinal irradiation (CSI) and identify any potential clinical or treatment-related associations. METHODS: We performed a retrospective review of 127 pediatric patients treated with CSI, followed by a boost to the brain for primary brain tumors in a single institution between 2016 and 2021. Proton CSI was delivered with passive scattering (PS) proton technique (n = 53) or pencil beam scanning technique (PBS) (n = 74). Within the PBS group, treatment delivery to the CSI utilized a single posterior (PA) field (n = 24) or two posterior oblique fields (n = 50). We collected data on phantom smell, nausea/vomiting, and the use of medical intervention. RESULTS: Our cohort included 80 males and 47 females. The median age of patients was 10 years (range: 3-21). Seventy-one patients (56%) received concurrent chemotherapy. During RT, 104 patients (82%) developed worsening nausea, while 63 patients (50%) reported episodes of emesis. Of those patients who were awake during CSI (n = 59), 17 (29%) reported phantosmia. In the non-sedated group, we found a higher rate of phantosmia in patients treated with PBS (n = 16, 42%) than PS (n = 1, 4.7%) (p = .002). Seventy-eight patients (61%) required medical intervention after developing nausea/vomiting or phantosmia during RT. Two patients required sedation due to the malodorous smell during CSI. We did not find any significant difference in nausea/vomiting based on treatment technique. CONCLUSION: Proton technique significantly influenced olfactory perception with greater rates of phantosmia with PBS compared to PS. Prospective studies should be performed to determine the cause of these findings and determine techniques to minimize phantosmia during radiation therapy.

Proton Therapy in Breast Cancer: A Review of Potential Approaches for Patient Selection.

Proton radiotherapy may be a compelling technical option for the treatment of breast cancer due to its unique physical property known as the "Bragg peak." This feature offers distinct advantages, promising superior dose conformity within the tumor area and reduced radiation exposure to surrounding healthy tissues, enhancing the potential for better treatment outcomes. However, proton therapy is accompanied by inherent challenges, primarily higher costs and limited accessibility when compared to well-developed photon irradiation. Thus, in clinical practice, it is important for radiation oncologists to carefully select patients before recommendation of proton therapy to ensure the transformation of dosimetric benefits into tangible clinical benefits. Yet, the optimal indications for proton therapy in breast cancer patients remain uncertain. While there is no widely recognized methodology for patient selection, numerous attempts have been made in this direction. In this review, we intended to present an inspiring summarization and discussion about the current practices and exploration on the approaches of this treatment decision-making process in terms of treatment-related side-effects, tumor control, and cost-efficiency, including the normal tissue complication probability (NTCP) model, the tumor control probability (TCP) model, genomic biomarkers, cost-effectiveness analyses (CEAs), and so on. Additionally, we conducted an evaluation of the eligibility criteria in ongoing randomized controlled trials and analyzed their reference value in patient selection. We evaluated the pros and cons of various potential patient selection approaches and proposed possible directions for further optimization and exploration. In summary, while proton therapy holds significant promise in breast cancer treatment, its integration into clinical practice calls for a thoughtful, evidence-driven strategy. By continuously refining the patient selection criteria, we can harness the full potential of proton radiotherapy while ensuring maximum benefit for breast cancer patients.

Machine learning approach for proton range verification using real-time prompt gamma imaging with Compton cameras: addressing the total deposited energy information gap.

Objective.Compton camera imaging shows promise as a range verification technique in proton therapy. This work aims to assess the performance of a machine learning model in Compton camera imaging for proton beam range verification improvement.Approach.The presented approach was used to recognize Compton events and estimate more accurately the prompt gamma (PG) energy in the Compton camera to reconstruct the PGs emission profile during proton therapy. This work reports the results obtained from the Geant4 simulation for a proton beam impinging on a polymethyl methacrylate (PMMA) target. To validate the versatility of such an approach, the produced PG emissions interact with a scintillating fiber-based Compton camera.Main results.A trained multilayer perceptron (MLP) neural network shows that it was possible to achieve a notable three-fold increase in the signal-to-total ratio. Furthermore, after event selection by the trained MLP, the loss of full-energy PGs was compensated by means of fitting an MLP energy regression model to the available data from true Compton (signal) events, predicting more precisely the total deposited energy for Compton events with incomplete energy deposition.Significance.A considerable improvement in the Compton camera's performance was demonstrated in determining the distal falloff and identifying a few millimeters of target displacements. This approach has shown great potential for enhancing online proton range monitoring with Compton cameras in future clinical applications.