Towards a novel small animal proton irradiation platform: the SIRMIO project.

Background: Precision small animal radiotherapy research is a young emerging field aiming to provide new experimental insights into tumor and normal tissue models in different microenvironments, to unravel complex mechanisms of radiation damage in target and non-target tissues and assess efficacy of novel therapeutic strategies. For photon therapy, modern small animal radiotherapy research platforms have been developed over the last years and are meanwhile commercially available. Conversely, for proton therapy, which holds potential for an even superior outcome than photon therapy, no commercial system exists yet. Material and methods: The project SIRMIO (Small Animal Proton Irradiator for Research in Molecular Image-guided Radiation-Oncology) aims at realizing and demonstrating an innovative portable prototype system for precision image-guided small animal proton irradiation, suitable for installation at existing clinical treatment facilities. The proposed design combines precise dose application with in situ multi-modal anatomical image guidance and in vivo verification of the actual treatment delivery. Results and conclusions: This manuscript describes the status of the different components under development, featuring a dedicated beamline for degradation and focusing of clinical proton beams, along with novel detector systems for in situimaging and range verification. The foreseen workflow includes pre-treatment proton transmission imaging, complemented by ultrasonic tumor localization, for treatment planning and position verification, followed by image-guided delivery with on site range verification by means of ionoacoustics (for pulsed beams) and positron-emission-tomography (PET, for continuous beams). The proposed compact and cost-effective system promises to open a new era in small animal proton therapy research, contributing to the basic understanding of in vivo radiation action to identify areas of potential breakthroughs for future translation into innovative clinical strategies.

On the robustness of multilateration of ionoacoustic signals for localization of the Bragg peak at pre-clinical proton beam energies in water.

Objectives.The energy deposited in a medium by a pulsed proton beam results in the emission of thermoacoustic waves, also called ionoacoustics (IA). The proton beam stopping position (Bragg peak) can be retrieved from a time-of-flight analysis (ToF) of IA signals acquired at different sensor locations (multilateration). This work aimed to assess the robustness of multilateration methods in proton beams at pre-clinical energies for the development of a small animal irradiator.Approach.The accuracy of multilateration performed using different algorithms; namely, time of arrival and time difference of arrival, was investigatedin-silicofor ideal point sources in the presence of realistic uncertainties on the ToF estimation and ionoacoustic signals generated by a 20 MeV pulsed proton beam stopped in a homogeneous water phantom. The localisation accuracy was further investigated experimentally based on two different measurements with pulsed monoenergetic proton beams at energies of 20 and 22 MeV.Main results.It was found that the localisation accuracy mainly depends on the position of the acoustic detectors relative to the proton beam due to spatial variation of the error on the ToF estimation. By optimally positioning the sensors to reduce the ToF error, the Bragg peak could be locatedin-silicowith an accuracy better than 90µm (2% error). Localisation errors going up to 1 mm were observed experimentally due to inaccurate knowledge of the sensor positions and noisy ionoacoustic signals.Significance.This study gives a first overview of the implementation of different multilateration methods for ionoacoustics-based Bragg peak localisation in two- and three-dimensions at pre-clinical energies. Different sources of uncertainty were investigated, and their impact on the localisation accuracy was quantifiedin-silicoand experimentally.

Development and pre-clinical test of a phosphorous-32 containing polyetheretherketone foil aiming at urethral stricture prevention by low-dose-rate brachytherapy.

Purpose: Primary or recurrent urethral stenoses are common clinical problems. The aim of this feasibility study was development and application test of a novel radioactive catheter for potential use in low-dose-rate (LDR) brachytherapy to prevent urethral stenosis. Material and methods: A beta radiation emitting phosphorous-32 (32P)-foil was developed and integrated in indwelling catheter, which is usually inserted after surgical intervention in the urethra. Activity and dose distribution were measured after neutron activation of the phosphorus-31 (31P)-foil component with scintillation techniques as well as radiochromic films, and compared to MC simulations. Practicability and radiation safety of this new applicator were tested on male rabbits, which, before catheter application, had undergone a new method of stricture induction by radial laser light irradiation. Results: Measured dose distributions of catheters with 32P-foils were found to be in good agreement with MC simulations. Wash-out tests confirmed the radioactive catheter setup to be inside permitted limits of a sealed source. Strictures could be induced by laser light in all animals, surgically treated by slitting and irradiation with a 7-day dose of 15 Gy or 30 Gy, without adverse effects of radiation during a 4-week observation time. Conclusions: This proof-of-concept study presents a safe and technically simple approach to LDR brachytherapy intending to prevent urethral stenosis. The prescribed irradiation dose can be administered in a reproducible and precise manner using a urethral catheter as a carrier of beta radiating foil. The study duration of 63 days was too short to make statistically significant stricture-related conclusions. This approach may be considered for similar problems in other hollow organs and in cases regarding superficial hyper-proliferation.

Proton beam range verification by means of ionoacoustic measurements at clinically relevant doses using a correlation-based evaluation.

Purpose: The Bragg peak located at the end of the ion beam range is one of the main advantages of ion beam therapy compared to X-Ray radiotherapy. However, verifying the exact position of the Bragg peak within the patient online is a major challenge. The goal of this work was to achieve submillimeter proton beam range verification for pulsed proton beams of an energy of up to 220 MeV using ionoacoustics for a clinically relevant dose deposition of typically 2 Gy per fraction by i) using optimal proton beam characteristics for ionoacoustic signal generation and ii) improved signal detection by correlating the signal with simulated filter templates. Methods: A water tank was irradiated with a preclinical 20 MeV proton beam using different pulse durations ranging from 50 ns up to 1 µs in order to maximise the signal-to-noise ratio (SNR) of ionoacoustic signals. The ionoacoustic signals were measured using a piezo-electric ultrasound transducer in the MHz frequency range. The signals were filtered using a cross correlation-based signal processing algorithm utilizing simulated templates, which enhances the SNR of the recorded signals. The range of the protons is evaluated by extracting the time of flight (ToF) of the ionoacoustic signals and compared to simulations from a Monte Carlo dose engine (FLUKA). Results: Optimised SNR of 28.0 ± 10.6 is obtained at a beam current of 4.5 µA and a pulse duration of 130 ns at a total peak dose deposition of 0.5 Gy. Evaluated ranges coincide with Monte Carlo simulations better than 0.1 mm at an absolute range of 4.21 mm. Higher beam energies require longer proton pulse durations for optimised signal generation. Using the correlation-based post-processing filter a SNR of 17.8 ± 5.5 is obtained for 220 MeV protons at a total peak dose deposition of 1.3 Gy. For this clinically relevant dose deposition and proton beam energy, submillimeter range verification was achieved at an absolute range of 303 mm in water. Conclusion: Optimal proton pulse durations ensure an ideal trade-off between maximising the ionoacoustic amplitude and minimising dose deposition. In combination with a correlation-based post-processing evaluation algorithm, a reasonable SNR can be achieved at low dose levels putting clinical applications for online proton or ion beam range verification into reach.

Scanning irradiation device for mice in vivo with pulsed and continuous proton beams.

A technical set-up for irradiation of subcutaneous tumours in mice with nanosecond-pulsed proton beams or continuous proton beams is described and was successfully used in a first experiment to explore future potential of laser-driven particle beams, which are pulsed due to the acceleration process, for radiation therapy. The chosen concept uses a microbeam approach. By focusing the beam to approximately 100 × 100 µm(2), the necessary fluence of 10(9) protons per cm(2) to deliver a dose of 20 Gy with one-nanosecond shot in the Bragg peak of 23 MeV protons is achieved. Electrical and mechanical beam scanning combines rapid dose delivery with large scan ranges. Aluminium sheets one millimetre in front of the target are used as beam energy degrader, necessary for adjusting the depth-dose profile. The required procedures for treatment planning and dose verification are presented. In a first experiment, 24 tumours in mice were successfully irradiated with 23 MeV protons and a single dose of 20 Gy in pulsed or continuous mode with dose differences between both modes of 10%. So far, no significant difference in tumour growth delay was observed.

Investigating the accuracy of co-registered ionoacoustic and ultrasound images in pulsed proton beams.

The sharp spatial and temporal dose gradients of pulsed ion beams result in an acoustic emission (ionoacoustics), which can be used to reconstruct the dose distribution from measurements at different positions. The accuracy of range verification from ionoacoustic images measured with an ultrasound linear array configuration is investigated both theoretically and experimentally for monoenergetic proton beams at energies relevant for pre-clinical studies (20 and 22 MeV). The influence of the linear sensor array arrangement (length up to 4 cm and number of elements from 5 to 200) and medium properties on the range estimation accuracy are assessed using time-reversal reconstruction. We show that for an ideal homogeneous case, the ionoacoustic images enable a range verification with a relative error lower than 0.1%, however, with limited lateral dose accuracy. Similar results were obtained experimentally by irradiating a water phantom and taking into account the spatial impulse response (geometry) of the acoustic detector during the reconstruction of pressures obtained by moving laterally a single-element transducer to mimic a linear array configuration. Finally, co-registered ionoacoustic and ultrasound images were investigated using silicone inserts immersed in the water phantom across the proton beam axis. By accounting for the sensor response and speed of sound variations (deduced from co-registration with ultrasound images) the accuracy is improved to a few tens of micrometers (relative error less than to 0.5%), confirming the promise of ongoing developments for ionoacoustic range verification in pre-clinical and clinical proton therapy applications.

Enhancement of the ionoacoustic effect through ultrasound and photoacoustic contrast agents.

The characteristic depth dose deposition of ion beams, with a maximum at the end of their range (Bragg peak) allows for local treatment delivery, resulting in better sparing of the adjacent healthy tissues compared to other forms of external beam radiotherapy treatments. However, the optimal clinical exploitation of the favorable ion beam ballistic is hampered by uncertainties in the in vivo Bragg peak position. Ionoacoustics is based on the detection of thermoacoustic pressure waves induced by a properly pulsed ion beam (e.g., produced by modern compact accelerators) to image the irradiated volume. Co-registration between ionoacoustics and ultrasound imaging offers a promising opportunity to monitor the ion beam and patient anatomy during the treatment. Nevertheless, the detection of the ionoacoustic waves is challenging due to very low pressure amplitudes and frequencies (mPa/kHz) observed in clinical applications. We investigate contrast agents to enhance the acoustic emission. Ultrasound microbubbles are used to increase the ionoacoustic frequency around the microbubble resonance frequency. Moreover, India ink is investigated as a possible mean to enhance the signal amplitude by taking advantage of additional optical photon absorption along the ion beam and subsequent photoacoustic effect. We report amplitude increase of up to 200% of the ionoacoustic signal emission in the MHz frequency range by combining microbubbles and India ink contrast agents.

I-BEAT: Ultrasonic method for online measurement of the energy distribution of a single ion bunch.

The shape of a wave carries all information about the spatial and temporal structure of its source, given that the medium and its properties are known. Most modern imaging methods seek to utilize this nature of waves originating from Huygens' principle. We discuss the retrieval of the complete kinetic energy distribution from the acoustic trace that is recorded when a short ion bunch deposits its energy in water. This novel method, which we refer to as Ion-Bunch Energy Acoustic Tracing (I-BEAT), is a refinement of the ionoacoustic approach. With its capability of completely monitoring a single, focused proton bunch with prompt readout and high repetition rate, I-BEAT is a promising approach to meet future requirements of experiments and applications in the field of laser-based ion acceleration. We demonstrate its functionality at two laser-driven ion sources for quantitative online determination of the kinetic energy distribution in the focus of single proton bunches.

Ionizing radiation-induced acoustics for radiotherapy and diagnostic radiology applications.

Acoustic waves are induced via the thermoacoustic effect in objects exposed to a pulsed beam of ionizing radiation. This phenomenon has interesting potential applications in both radiotherapy dosimetry and treatment guidance as well as low-dose radiological imaging. After initial work in the field in the 1980s and early 1990s, little research was done until 2013 when interest was rejuvenated, spurred on by technological advances in ultrasound transducers and the increasing complexity of radiotherapy delivery systems. Since then, many studies have been conducted and published applying ionizing radiation-induced acoustic principles into three primary research areas: Linear accelerator photon beam dosimetry, proton therapy range verification, and radiological imaging. This review article introduces the theoretical background behind ionizing radiation-induced acoustic waves, summarizes recent advances in the field, and provides an outlook on how the detection of ionizing radiation-induced acoustic waves can be used for relative and in vivo dosimetry in photon therapy, localization of the Bragg peak in proton therapy, and as a low-dose medical imaging modality. Future prospects and challenges for the clinical implementation of these techniques are discussed.

Time-of-flight spectrometry of ultra-short, polyenergetic proton bunches.

A common approach for spectrum determination of polyenergetic proton bunches from laser-ion acceleration experiments is based on the time-of-flight (TOF) method. However, spectra obtained using this method are typically given in relative units or are estimated based on some prior assumptions on the energy distribution of the accelerated ions. In this work, we present a new approach using the TOF method that allows for an absolute energy spectrum reconstruction from a current signal acquired with a sub-nanosecond fast and 10 µm thin silicon detector. The reconstruction is based on solving a linear least-squares problem, taking into account the response function of the detection system. The general principle of signal generation and spectrum reconstruction by setting up an appropriate system response matrix is presented. Proof-of-principle experiments at a 12 MV Tandem accelerator using different nanosecond-short (quasi-)monoenergetic and polyenergetic proton bunches at energies up to 20 MeV were successfully performed. Within the experimental uncertainties of 2.4% and 12.1% for energy and particle number, respectively, reconstructed energy distributions were found in excellent agreement with the spectra calculated using Monte Carlo simulations and measured by a magnetic spectrometer. This TOF method can hence be used for absolute online spectrometry of laser-accelerated particle bunches.

Submillimeter ionoacoustic range determination for protons in water at a clinical synchrocyclotron.

Proton ranges in water between 145 MeV to 227 MeV initial energy have been measured at a clinical superconducting synchrocyclotron using the acoustic signal induced by the ion dose deposition (ionoacoustic effect). Detection of ultrasound waves was performed by a very sensitive hydrophone and signals were stored in a digital oscilloscope triggered by secondary prompt gammas. The ionoacoustic range measurements were compared to existing range data from a calibrated range detector setup on-site and agreement of better than 1 mm was found at a Bragg peak dose of about 10 Gy for 220 MeV initial proton energy, compatible with the experimental errors. Ionoacoustics has thus the potential to measure the Bragg peak position with submillimeter accuracy during proton therapy, possibly correlated with ultrasound tissue imaging.

Preclinical study investigating the potential of low-dose-rate brachytherapy with 32P stents for the prevention of restenosis of paranasal neo-ostia.

PURPOSE: Ostial restenosis is a common cause of failures in paranasal sinus surgery. The aim of the current study was to investigate the use of low-dose-rate brachytherapy to prevent neo-ostial restenosis in an animal model. METHODS AND MATERIALS: In 14 rabbits, maxillary neo-ostia were created and measured. One side each was stented with a regular silicone stent, the other side was either not stented (n = 7) or stented with a phosphorous-32 implanted stent depositing a low-dose radiation of 15 Gy (n = 7) within 1 week, after which all stents were removed. After a period of additional 12 weeks of recovery, the animals were sacrificed, the neo-ostia were again measured, and the areas and histopathologic changes compared in between the groups. RESULTS: After 15-Gy stenting, the mean ostial areas were even slightly enlarged by 5.1% compared to the area at stent removal, whereas a significant reduction in area, indicating a process of restenosis, by 56.1% or 54.0% was seen in the control groups with no stent and normal stent, respectively. Furthermore, no indication for adverse histopathologic radiation effects was seen in the 15-Gy group. CONCLUSIONS: Low-dose-rate brachytherapy with phosphorous-32 doped silicone stents showed promising results in the prevention of neo-ostium restenosis in this proof-of-concept study, indicating that further preclinical and clinical testing may be warranted.

Ionoacoustic tomography of the proton Bragg peak in combination with ultrasound and optoacoustic imaging.

Ions provide a more advantageous dose distribution than photons for external beam radiotherapy, due to their so-called inverse depth dose deposition and, in particular a characteristic dose maximum at their end-of-range (Bragg peak). The favorable physical interaction properties enable selective treatment of tumors while sparing surrounding healthy tissue, but optimal clinical use requires accurate monitoring of Bragg peak positioning inside tissue. We introduce ionoacoustic tomography based on detection of ion induced ultrasound waves as a technique to provide feedback on the ion beam profile. We demonstrate for 20 MeV protons that ion range imaging is possible with submillimeter accuracy and can be combined with clinical ultrasound and optoacoustic tomography of similar precision. Our results indicate a simple and direct possibility to correlate, in-vivo and in real-time, the conventional ultrasound echo of the tumor region with ionoacoustic tomography. Combined with optoacoustic tomography it offers a well suited pre-clinical imaging system.

[Implants with 32P-foils for LDR-brachytherapy of benign stenosis in urology and gastroenterology]. / (32)P-haltige Folien als Implantate für die LDR-Brachytherapie gutartiger Stenosen in der Urologie und Gastroenterologie.

For LDR-brachytherapy, a limited number of implant geometries and materials are available. To avoid wound healing related hyper-proliferation (stenosis, keloids) a novel radioactive foil system was developed based on beta emitting (32)P, which can be easily integrated in existing implants such as urethral catheters or bile duct stents. As substrate material for these foils PEEK (polyetherethercetone) was chosen because of its radiation hardness during neutron activation of (32)P. The activity was determined by liquid scintillation counting and gamma spectroscopy, dose distributions were measured with scintillation detectors and radiochromic films. The correlation between activity and dose was checked by Monte-Carlo-simulations (Geant4). Prototypes of the (32)P-implants have shown in wash-out tests the required tightness for sealed radioactive sources. In animal tests on urethra and bile duct, the uncomplicated and save application of (32)P-foils mounted on standard implants has been demonstrated, which is almost unchanged due to the simple radiation protection with plexiglass. This concept of radioactive implants with integrated (32)P-foils could extend essentially the application possibilities of LDR-brachytherapy.

Ion-beam-induced collective rotation of nanocrystals.

Vapor-deposited nanocrystalline titanium layers have been irradiated at room temperature with 350-MeV-Au ions up to 4x10;{15} Au/cm;{2}. Bombardment-induced texture changes were determined at the BESSY synchrotron light source. During off-normal irradiation, the nanocrystals undergo grain alignment and rotation up to approximately 90 degrees at the highest ion fluence. At the same time, the whole layer exhibits shear flow very similar to that observed previously in amorphous materials. Below 1x10;{15} Au/cm;{2}, a reversal of the ion incidence angle leads to a back rotation of the grains. These effects are absent or immeasurably small in coarse-grained titanium but have also been found in nanocrystalline TiN and NiO. The observations can be modeled by assuming that grain boundaries behave during ion bombardment like amorphous matter or by assuming a generation of disclination dipoles moving along grain boundaries.