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.

MRI magnitude signal-based proton beam visualisation in water phantoms reflects composite effects of beam-induced buoyant convection and radiation chemistry.

Objective. Local magnetic resonance (MR) signal loss was previously observed during proton beam irradiation of free-floating water phantoms at ambient temperature using a research prototype in-beam magnetic resonance imaging (MRI) scanner. The emergence of this MR signal loss was hypothesised to be dependent on beam-induced convection. The aim of this study was therefore to unravel whether physical conditions allowing the development of convection must prevail for the beam-induced MRI signatures to emerge.Approach. The convection dependence of MRI magnitude signal-based proton beam visualisation was investigated in combined irradiation and imaging experiments using a gradient echo (GE)-based time-of-flight (ToF) angiography pulse sequence, which was first tested for its suitability for proton beam visualisation in free-floating water phantoms at ambient temperature. Subsequently, buoyant convection was selectively suppressed in water phantoms using either mechanical barriers or temperature control of water expansivity. The underlying contrast mechanism was further assessed using sagittal imaging and variation of T1 relaxation time-weighting.Main results. In the absence of convection-driven water flow, weak beam-induced MR signal changes occurred, whereas strong changes did occur when convection was not mechanically or thermally inhibited. Moreover, the degree of signal loss was found to change with the variation of T1-weighting. Consequently, beam-induced MR signal loss in free-floating water phantoms at ambient temperature does not exclusively originate from buoyant convection, but is caused by local composite effects of beam-induced motion and radiation chemistry resulting in a local change in the water T1 relaxation time.Significance. The identification of ToF angiography sequence-based proton beam visualisation in water phantoms to result from composite effects of beam-induced motion and radiation chemistry represents the starting point for the future elucidation of the currently unexplained motion-based MRI contrast mechanism and the identification of the proton beam-induced material change causing T1 relaxation time lengthening.

Investigation of contrast mechanisms for MRI phase signal-based proton beam visualization in water phantoms.

PURPOSE: The low sensitivity and limitation to water phantoms of convection-dependent MRI magnitude signal-based proton beam visualization hinder its in vivo applicability in MR-integrated proton beam therapy. The purpose of the present study was, therefore, to assess possible contrast mechanisms for MRI phase signal-based proton beam visualization that can potentially be exploited to enhance the sensitivity of the method and extend its applicability to tissue materials. METHODS: To assess whether proton beam-induced magnetic field perturbations, changes in material susceptibility or convection result in detectable changes in the MRI phase signal, water phantom characteristics, experiment timing, and imaging parameters were varied in combined irradiation and imaging experiments using a time-of-flight angiography pulse sequence on a prototype in-beam MRI scanner. Velocity encoding was used to further probe and quantify beam-induced convection. RESULTS: MRI phase signal-based proton beam visualization proved feasible. The observed phase difference contrast was evoked by beam-induced buoyant convection with flow velocities in the mm/s range. Proton beam-induced magnetic field perturbations or changes in magnetic susceptibility did not influence the MRI phase signal. Velocity encoding was identified as a means to enhance the detection sensitivity. CONCLUSION: Because the MRI phase difference contrast observed during proton beam irradiation of water phantoms is caused by beam-induced convection, this method will unlikely be transferable to tightly compartmentalized tissue wherein flow effects are restricted. However, strong velocity encoded pulse sequences were identified as promising candidates for the future development of MRI-based methods for water phantom-based geometric quality assurance in MR-integrated proton beam therapy.

Direct visualization of proton beam irradiation effects in liquids by MRI.

The main advantage proton beams offer over photon beams in radiation therapy of cancer patients is the dose maximum at their finite range, yielding a reduction in the dose deposited in healthy tissues surrounding the tumor. Since no direct method exists to measure the beam's range during dose delivery, safety margins around the tumor are applied, compromising the dose conformality and reducing the targeting accuracy. Here, we demonstrate that online MRI can visualize the proton beam and reveal its range during irradiation of liquid-filled phantoms. A clear dependence on beam energy and current was found. These results stimulate research into novel MRI-detectable beam signatures and already find application in the geometric quality assurance for magnetic resonance-integrated proton therapy systems currently under development.

Out-of-field measurements and simulations of a proton pencil beam in a wide range of dose rates using a Timepix3 detector: Dose rate, flux and LET.

Stray radiation produced by ultra-high dose-rates (UHDR) proton pencil beams is characterized using ASIC-chip semiconductor pixel detectors. A proton pencil beam with an energy of 220 MeV was utilized to deliver dose rates (DR) ranging from conventional radiotherapy DRs up to 270 Gy/s. A MiniPIX Timepix3 detector equipped with a silicon sensor and integrated readout electronics was used. The chip-sensor assembly and chipboard on water-equivalent backing were detached and immersed in the water-phantom. The deposited energy, particle flux, DR, and the linear energy transfer (LET(Si)) spectra were measured in the silicon sensor at different positions both laterally, at different depths, and behind the Bragg peak. At low-intensity beams, the detector is operated in the event-by-event data-driven mode for high-resolution spectral tracking of individual particles. This technique provides precise energy loss response and LET(Si) spectra with radiation field composition resolving power. At higher beam intensities a rescaling of LET(Si) can be performed as the distribution of the LET(Si) spectra exhibits the same characteristics regardless of the delivered DR. The integrated deposited energy and the absorbed dose can be thus measured in a wide range. A linear response of measured absorbed dose was obtained by gradually increasing the delivered DR to reach UHDR beams. Particle tracking of scattered radiation in data-driven mode could be performed at DRs up to 0.27 Gy/s. In integrated mode, the saturation limits were not reached at the measured out-of-field locations up to the delivered DR of over 270 Gy/s. A good agreement was found between measured and simulated absorbed doses.

Combined proton radiography and irradiation for high-precision preclinical studies in small animals.

Background and purpose: Proton therapy has become a popular treatment modality in the field of radiooncology due to higher spatial dose conformity compared to conventional radiotherapy, which holds the potential to spare normal tissue. Nevertheless, unresolved research questions, such as the much debated relative biological effectiveness (RBE) of protons, call for preclinical research, especially regarding in vivo studies. To mimic clinical workflows, high-precision small animal irradiation setups with image-guidance are needed. Material and methods: A preclinical experimental setup for small animal brain irradiation using proton radiographies was established to perform planning, repositioning, and irradiation of mice. The image quality of proton radiographies was optimized regarding the resolution, contrast-to-noise ratio (CNR), and minimal dose deposition in the animal. Subsequently, proof-of-concept histological analysis was conducted by staining for DNA double-strand breaks that were then correlated to the delivered dose. Results: The developed setup and workflow allow precise brain irradiation with a lateral target positioning accuracy of<0.26mm for in vivo experiments at minimal imaging dose of<23mGy per mouse. The custom-made software for image registration enables the fast and precise animal positioning at the beam with low observer-variability. DNA damage staining validated the successful positioning and irradiation of the mouse hippocampus. Conclusion: Proton radiography enables fast and effective high-precision lateral alignment of proton beam and target volume in mouse irradiation experiments with limited dose exposure. In the future, this will enable irradiation of larger animal cohorts as well as fractionated proton irradiation.

Characterization of magnetic interference and image artefacts during simultaneous in-beam MR imaging and proton pencil beam scanning.

For the first time, a low-field open magnetic resonance (MR) scanner was combined with a proton pencil beam scanning (PBS) research beamline. The aim of this study was to characterize the magnetic fringe fields produced by the PBS system and measure their effects on MR image quality during simultaneous PBS irradiation and image acquisition. A magnetic field camera measured the change in central resonance frequency (Δf res) and magnetic field homogeneity (ΔMFH) of the B0 field of the MR scanner during operation of the beam transport and scanning magnets. The beam energy was varied between 70 - 220 MeV and beam scanning was performed along the central horizontal and vertical axis of a 48 × 24 cm2 radiation field. The time structure of the scanning magnets' fringe fields was simultaneously recorded by a tri-axial Hall probe. MR imaging experiments were conducted using the ACR (American College of Radiology) Small MRI Phantom and a spoiled gradient echo pulse sequence during simultaneous volumetric irradiation. Computer simulations were performed to predict the effects of B 0 field perturbations due to PBS irradiation on MR image formation in k-space. Setting the beam transport magnets, horizontal and vertical scanning magnets resulted in a maximum Δf res of 50, 235 and 4 Hz, respectively. The ΔMFH was less than 3 parts per million for all measurements. MR images acquired during beam energy variation and vertical beam scanning showed no visual loss in image quality. However, MR images acquired during horizontal beam scanning showed severe coherent ghosting artefacts in phase encoding direction. Both simulated and measured k-space phase maps prove that these artefacts are caused by phase-offsets. This study shows first experimental evidence that simultaneous in-beam MR imaging during proton PBS irradiation is subject to severe loss of image quality in the absence of magnetic decoupling between the PBS and MR system.

First application of a high-resolution silicon detector for proton beam Bragg peak detection in a 0.95 T magnetic field.

PURPOSE: To report on experimental results of a high spatial resolution silicon-based detector exposed to therapeutic quality proton beams in a 0.95 T transverse magnetic field. These experimental results are important for the development of accurate and novel dosimetry methods in future potential real-time MRI-guided proton therapy systems. METHODS: A permanent magnet device was utilized to generate a 0.95 T magnetic field over a 4 × 20 × 15 cm3 volume. Within this volume, a high-resolution silicon diode array detector was positioned inside a PMMA phantom of 4 × 15 × 12 cm3 . This detector contains two orthogonal strips containing 505 sensitive volumes spaced at 0.2 mm apart. Proton beams collimated to a circle of 10 mm diameter with nominal energies of 90 MeV, 110 MeV, and 125 MeV were incident on the detector from an edge-on orientation. This allows for a measurement of the Bragg peak at 0.2 mm spatial resolution in both the depth and lateral profile directions. The impact of the magnetic field on the proton beams, that is, a small deflection was also investigated. A Geant4 Monte Carlo simulation was performed of the experimental setup to aid in interpretation of the results. RESULTS: The nominal Bragg peak for each proton energy was successfully observed with a 0.2 mm spatial resolution in the 0.95 T transverse magnetic field in both a depth and lateral profiles. The proton beam deflection (at 0.95 T) was a consistent 2 ±0.5 mm at the center of the magnetic volume for each beam energy. However, a pristine Bragg peak was not observed for each energy. This was caused by the detector packaging having small air gaps between layers of the phantom material surrounding the diode array. These air gaps act to degrade the shape of the Bragg peak, and further to this, the nonwater equivalent silicon chip acts to separate the Bragg peak into multiple peaks depending on the proton path taken. Overall, a promising performance of the silicon detector array was observed, however, with a qualitative assessment rather than a robust quantitative dosimetric evaluation at this stage of development. CONCLUSIONS: For the first time, a high-resolution silicon-based radiation detector has been used to measure proton beam Bragg peak deflections in a phantom due to a strong magnetic field. Future efforts are required to optimize the detector packaging to strengthen the robustness of the dosimetric quantities obtained from the detector. Such high-resolution silicon diode arrays may be useful in future efforts in MRI-guided proton therapy research.

Integrating a low-field open MR scanner with a static proton research beam line: proof of concept.

On-line image guidance using magnetic resonance (MR) imaging is expected to improve the targeting accuracy of proton therapy. However, to date no combined system exists. In this study, for the first time a low-field open MR scanner was integrated with a static proton research beam line to test the feasibility of simultaneous irradiation and imaging. The field-of-view of the MR scanner was aligned with the beam by taking into account the Lorentz force induced beam deflection. Various imaging sequences for extremities were performed on a healthy volunteer and on a patient with a soft-tissue sarcoma of the upper arm, both with the proton beam line switched off. T 1-weighted spin echo images of a tissue-mimicking phantom were acquired without beam, with energised beam line magnets and during proton irradiation. Beam profiles were acquired for the MR scanner's static magnetic field alone and in combination with the dynamic gradient fields during the acquisition of different imaging sequences. It was shown that MR imaging is feasible in the electromagnetically contaminated environment of a proton therapy facility. The observed quality of the anatomical MR images was rated to be sufficient for target volume definition and positioning. The tissue-mimicking phantom showed no visible beam-induced image degradation. The beam profiles depicted no influence due to the dynamic gradient fields of the imaging sequences. This study proves that simultaneous irradiation and in-beam MR imaging is technically feasible with a low-field MR scanner integrated with a static proton research beam line.

Technical Note: Experimental verification of magnetic field-induced beam deflection and Bragg peak displacement for MR-integrated proton therapy.

PURPOSE: Given its sensitivity to anatomical variations, proton therapy is expected to benefit greatly from integration with magnetic resonance imaging for online anatomy monitoring during irradiation. Such an integration raises several challenges, as both systems mutually interact. The proton beam will experience quasi-continuous energy loss and energy-dependent electromagnetic deflection at the same time, giving rise to a deflected beam trajectory and an altered dose distribution with a displaced Bragg peak. So far, these effects have only been predicted using Monte Carlo and analytical models, but no clear consensus has been reached and experimental benchmark data are lacking. We measured proton beam trajectories and Bragg peak displacement in a homogeneous phantom placed inside a magnetic field and compared them to simulations. METHODS: Planar dose distributions of proton pencil beams (80-180 MeV) traversing the field of a 0.95 T NdFeB permanent magnet while depositing energy in a PMMA slab phantom were measured using EBT3 radiochromic films and simulated using the Geant4 toolkit. Deflected beam trajectories and the Bragg peak displacement were extracted from the measured planar dose distributions and compared against the simulations. RESULTS: The lateral beam deflection was clearly visible on the EBT3 films and ranged from 1 to 10 mm for 80 to 180 MeV, respectively. Simulated and measured beam trajectories and Bragg peak displacement agreed within 0.8 mm for all studied proton energies. CONCLUSIONS: These results prove that the magnetic field-induced Bragg peak displacement is both measurable and accurately predictable in a homogeneous phantom at 0.95 T, and allows Monte Carlo simulations to be used as gold standard for proton beam trajectory prediction in similar frameworks for MR-integrated proton therapy.