Ionizing radiation responses appear incidental to desiccation responses in the bdelloid rotifer Adineta vaga.

BACKGROUND: The remarkable resistance to ionizing radiation found in anhydrobiotic organisms, such as some bacteria, tardigrades, and bdelloid rotifers has been hypothesized to be incidental to their desiccation resistance. Both stresses produce reactive oxygen species and cause damage to DNA and other macromolecules. However, this hypothesis has only been investigated in a few species. RESULTS: In this study, we analyzed the transcriptomic response of the bdelloid rotifer Adineta vaga to desiccation and to low- (X-rays) and high- (Fe) LET radiation to highlight the molecular and genetic mechanisms triggered by both stresses. We identified numerous genes encoding antioxidants, but also chaperones, that are constitutively highly expressed, which may contribute to the protection of proteins against oxidative stress during desiccation and ionizing radiation. We also detected a transcriptomic response common to desiccation and ionizing radiation with the over-expression of genes mainly involved in DNA repair and protein modifications but also genes with unknown functions that were bdelloid-specific. A distinct transcriptomic response specific to rehydration was also found, with the over-expression of genes mainly encoding Late Embryogenesis Abundant proteins, specific heat shock proteins, and glucose repressive proteins. CONCLUSIONS: These results suggest that the extreme resistance of bdelloid rotifers to radiation might indeed be a consequence of their capacity to resist complete desiccation. This study paves the way to functional genetic experiments on A. vaga targeting promising candidate proteins playing central roles in radiation and desiccation resistance.

Technical note: Vendor-agnostic water phantom for 3D dosimetry of complex fields in particle therapy.

PURPOSE: Three-dimensional (3D) dosimetry is a necessity to validate patient-specific treatment plans in particle therapy as well as to facilitate the development of novel treatment modalities. Therefore, a vendor-agnostic water phantom was developed and verified to measure high resolution 3D dose distributions. METHODS: The system was experimentally validated at the Marburger Ionenstrahl-Therapiezentrum using two ionization chamber array detectors (PTW Octavius 1500XDR and 1000P) with 150.68 MeV proton and 285.35 MeV/u 12 C beams. The dose distribution of several monoenergetic and complex scanned fields were measured with different step sizes to assess the reproducibility, absolute positioning accuracy, and general performance of the system. RESULTS: The developed system was successfully validated and used to automatically measure high resolution 3D dose distributions. The reproducibility in depth was better than ±25 micron. The roll and tilt uncertainty of the detector was estimated to be smaller than ±3 mrad. CONCLUSIONS: The presented system performed fully automated, high resolution 3D dosimetry, suitable for the validation of complex radiation fields in particle therapy. The measurement quality is comparable to commercially available systems.

Monte Carlo simulations of new 2D ripple filters for particle therapy facilities.

UNLABELLED: At particle therapy facilities with pencil beam scanning, the implementation of a ripple filter (RiFi) broadens the Bragg peak (BP), which leads to fewer energy steps from the accelerator required to obtain an homogeneous dose coverage of the planned target volume (PTV). At the Universitätsklinikum Gießen und Marburg, Germany, a new second generation RiFi has been developed with two-dimensional groove structures. In this work we evaluate this new RiFi design. METHODS: The Monte Carlo (MC) code SHIELD-HIT12A is used to determine the RiFi-induced inhomogeneities in the dose distribution for various ion types, initial particle energies and distances from the RiFi to the phantom surface as well as in the depth of the phantom. The beam delivery and monitor system (BAMS) used at Marburg, the Heidelberg Ionentherapiezentrum (HIT), Universitätsklinikum Heidelberg, Germany and the GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt, Germany is modeled and simulated. To evaluate the PTV dose coverage performance of the new RiFi design, the heavy ion treatment planning system TRiP98 is used for dose optimization. SHIELD-HIT12A is used to prepare the facility-specific physical dose kernels needed by TRiP, and for recalculating the physical dose distribution after TRiP optimization. RESULTS: At short distances from the RiFi to the phantom surface fine structures in the dose distribution are observed. For various RiFis, ion types and initial particle energies the distance dmax at which maximum dose inhomogeneity occurs is found and an expression for dmax is deduced. The distance d0.01 at which the dose inhomogeneity is less than 1% is estimated and used as a threshold distance at which dose distributions are considered homogeneous. The MC data are found to agree with analytical expressions for dmax and d0.01; both are inversely related to the angular distribution. Increasing scatter from the beam delivery and monitoring system results in reduced dmax and d0.01. Furthermore, dmax and d0.01 are found to be proportional to the RiFi period λ. CONCLUSION: Our findings clearly indicate that the dose inhomogeneity induced by RiFis does not add uncertainties to the dose distribution in the clinical setting. The new RiFi design can be used in treatments to obtain homogeneous PTV dose coverage with fewer energy steps while improving lateral penumbra, thereby reducing the required treatment time.

Ground-based passive generation of Solar Particle Event spectra: Planning and manufacturing of a 3D-printed modulator.

The generation of space radiation on Earth is essential to study and predict the effects of radiation on space travelers, electronics, or materials during future long-term space missions. Next to the heavy ions of the galactic cosmic rays, solar particle events play a major role concerning the radiation risk in space, which consist of intermediate-energy protons with broad spectra and energies up to a few hundred MeV. This work describes an approach for the ground-based generation of solar particle events. As a proof of principle, a passive beam modulator with a specific funnel-shaped periodic structure was designed and is used to convert a monoenergetic proton beam into a spectral proton energy distribution, mimicking a solar particle event from August 1972, which is known as one of the strongest recorded SPE events. The required proton beam of 220 MeV can be generated at many existing particle accelerators at research or particle therapy facilities. The planning, manufacturing and testing of the modulator is described step by step. Its correct manufacturing and the characteristics of the solar particle event simulator are tested experimentally and by means of Monte Carlo simulations. Future modulators will follow the same concept with minor adjustments such as a larger lateral extension. As of now, the presented beam modulator is available to the research community to conduct experiments at GSI for exposure under solar particle event conditions. In addition, researchers can use and apply the described concept to design and print their individualized modulator to reproduce any desired solar particle event spectrum or request the presented modulator geometry from the authors.

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.

Spread-out Bragg peak FLASH: quantifying normal tissue toxicity in a murine model.

Objective: A favorable effect of ultra-high dose rate (FLASH) radiation on normal tissue-sparing has been indicated in several preclinical studies. In these studies, the adverse effects of radiation damage were reduced without compromising tumor control. Most studies of proton FLASH investigate these effects within the entrance of a proton beam. However, the real advantage of proton therapy lies in the Spread-out Bragg Peak (SOBP), which allows for giving a high dose to a target with a limited dose to healthy tissue at the entrance of the beam. Therefore, a clinically relevant investigation of the FLASH effect would be of healthy tissues within a SOBP. Our study quantified the tissue-sparing effect of FLASH radiation on acute and late toxicity within an SOBP in a murine model. Material/Methods: Radiation-induced damage was assessed for acute and late toxicity in the same mice following irradiation with FLASH (Field dose rate of 60 Gy/s) or conventional (CONV, 0.34 Gy/s) dose rates. The right hindleg of unanesthetized female CDF1 mice was irradiated with single-fraction doses between 19.9-49.7 Gy for CONV and 30.4-65.9 Gy for FLASH with 5-8 mice per dose. The leg was placed in the middle of a 5 cm SOBP generated from a mono-energetic beam using a 2D range modulator. Acute skin toxicity quantified by hair loss, moist desquamation and toe separation was monitored daily within 29 days post-treatment. Late toxicity of fibrotic development measured by leg extendibility was monitored biweekly until 30 weeks post-treatment. Results: Comparison of acute skin toxicity following radiation indicated a tissue-sparing effect of FLASH compared to conventional single-fraction radiation with a mean protection ratio of 1.40 (1.35-1.46). Fibrotic development similarly indicated normal tissue sparing with a 1.18 (1.17-1.18) protection ratio. The acute skin toxicity tissue sparing was similar to data from entrance-beam irradiations of Sørensen et al. (4). Conclusion: Full dose-response curves for acute and late toxicity after CONV and FLASH radiation were obtained. Radiation within the SOBP retains the normal-tissue-sparing effect of FLASH with a dose-modifying factor of 40% for acute skin damage and 18% for fibrotic development.

The Effects of Combined Exposure to Simulated Microgravity, Ionizing Radiation, and Cortisol on the In Vitro Wound Healing Process.

Human spaceflight is associated with several health-related issues as a result of long-term exposure to microgravity, ionizing radiation, and higher levels of psychological stress. Frequent reported skin problems in space include rashes, itches, and a delayed wound healing. Access to space is restricted by financial and logistical issues; as a consequence, experimental sample sizes are often small, which limits the generalization of the results. Earth-based simulation models can be used to investigate cellular responses as a result of exposure to certain spaceflight stressors. Here, we describe the development of an in vitro model of the simulated spaceflight environment, which we used to investigate the combined effect of simulated microgravity using the random positioning machine (RPM), ionizing radiation, and stress hormones on the wound-healing capacity of human dermal fibroblasts. Fibroblasts were exposed to cortisol, after which they were irradiated with different radiation qualities (including X-rays, protons, carbon ions, and iron ions) followed by exposure to simulated microgravity using a random positioning machine (RPM). Data related to the inflammatory, proliferation, and remodeling phase of wound healing has been collected. Results show that spaceflight stressors can interfere with the wound healing process at any phase. Moreover, several interactions between the different spaceflight stressors were found. This highlights the complexity that needs to be taken into account when studying the effect of spaceflight stressors on certain biological processes and for the aim of countermeasures development.

FLASH radiotherapy with carbon ion beams.

FLASH radiotherapy is considered a new potential breakthrough in cancer treatment. Ultra-high dose rates (>40 Gy/s) have been shown to reduce toxicity in the normal tissue without compromising tumor control, resulting in a widened therapeutic window. These high dose rates are more easily achievable in the clinic with charged particles, and clinical trials are, indeed, ongoing using electrons or protons. FLASH could be an attractive solution also for heavier ions such as carbon and could even enhance the therapeutic window. However, it is not yet known whether the FLASH effect will be the same as for sparsely ionizing radiation when densely ionizing carbons ions are used. Here we discuss the technical challenges in beam delivery and present a promising solution using 3D range-modulators in order to apply ultra-high dose rates (UHDR) compatible with FLASH with carbon ions. Furthermore, we will discuss the possible outcome of C-ion therapy at UHDR on the level of the radiobiological and radiation chemical effects.

Thick shielding against galactic cosmic radiation: A Monte Carlo study with focus on the role of secondary neutrons.

The exposure to galactic cosmic radiation (GCR) is a major health concern for astronauts. Crewed missions with durations of several years are foreseen in future space exploration projects such as permanent habitats on the Moon and flights to Mars. This aim requires elaborate space radiation shielding concepts and a proper understanding of the underlying radiation physics and radiobiology as well as their interplay. In the present work, Monte Carlo simulations to assess the performance of different materials (polyethylene, aluminum, Moon regolith) as thick shields (up to 400 g/cm2) against GCR were conducted using the FLUKA code. Absorbed dose, dose equivalent and the mean quality factor at 1 cm depth in the ICRU sphere as a function of shielding thickness were calculated in a spherical shell configuration for both solar minimum and solar maximum GCR conditions. Large differences were observed in the performance of the studied materials as thick GCR shields. Special attention was paid to the build-up and moderation of secondary neutrons. A method to reduce the neutron contributions to ambient dose equivalent by means of a two-layer shielding combination is proposed. The present study can be useful for considerations on thick shielding of Moon or Mars habitats built from local regolith.

Development, Monte Carlo simulations and experimental evaluation of a 3D range-modulator for a complex target in scanned proton therapy.

The purpose of this work was to develop and manufacture a 3D range-modulator (3D RM) for a complex target contour for scanned proton therapy. The 3D RM is considered to be a viable technique for the very fast dose application in patient-specific tumors with only one fixed energy. The RM was developed based on a tumor from a patient CT and manufactured with high-quality 3D printing techniques with both polymer resin and aluminum. Monte Carlo simulations were utilized to investigate its modulating properties and the resulting dose distribution. Additionally, the simulation results were validated with measurements at the Marburg Ion-Beam Therapy Centre. For this purpose, a previously developed water phantom was used to conduct fast, automated high-resolution dose measurements. The results show a very good agreement between simulations and measurements and indicate that highly homogeneous dose distributions are possible. The delivered dose is conformed to the distal as well as to the proximal edge of the target. The 3D range-modulator concept combines a high degree of dose homogeneity and conformity, comparable to standard IMPT with very short irradiation times, promising clinically applicable dose distributions for lung and/or FLASH treatment, comparable and competitive to those from conventional irradiation techniques.

FLASH with carbon ions: Tumor control, normal tissue sparing, and distal metastasis in a mouse osteosarcoma model.

BACKGROUND AND PURPOSE: The FLASH effect is a potential breakthrough in radiotherapy because ultra-high dose-rate irradiation can substantially widen the therapeutic window. While the normal tissue sparing at high doses and short irradiation times has been demonstrated with electrons, photons, and protons, so far evidence with heavy ions is limited to in vitro cell experiments. Here we present the first in vivo results with high-energy 12C-ions delivered at an ultra-high dose rate. MATERIALS AND METHODS: LM8 osteosarcoma cells were subcutaneously injected in the posterior limb of female C3H/He mice 7 days before radiation exposure. Both hind limbs of the animals were irradiated with 240 MeV/n 12C-ions at ultra-high (18 Gy in 150 ms) or conventional dose rate (∼18 Gy/min). Tumor size was measured until 28 days post-exposure, when animals were sacrificed and lungs, limb muscles, and tumors were collected for further histological analysis. RESULTS: Irradiation with carbon ions was able to control the tumour both at conventional and ultra-high dose rate. FLASH decreases normal tissue toxicity as demonstrated by the reduced structural changes in muscle compared to conventional dose-rate irradiation. Carbon ion irradiation in FLASH conditions significantly reduced lung metastasis compared to conventional dose-rate irradiation and sham-irradiated animals. CONCLUSIONS: We demonstrated the FLASH effect in vivo with high-energy carbon ions. In addition to normal tissue sparing, we observed tumor control and a substantial reduction of lung metastasis in an osteosarcoma mouse model.

Experimental Comparison of Fiducial Markers Used in Proton Therapy: Study of Different Imaging Modalities and Proton Fluence Perturbations Measured With CMOS Pixel Sensors.

Fiducial markers are used for image guidance to verify the correct positioning of the target for the case of tumors that can suffer interfractional motion during proton therapy. The markers should be visible on daily imaging, but at the same time, they should produce minimal streak artifacts in the CT scans for treatment planning and induce only slight dose perturbations during particle therapy. In this work, these three criteria were experimentally investigated at the Heidelberg Ion Beam Therapy Center. Several small fiducial markers with different geometries and materials (gold, platinum, and carbon-coated ZrO2) were evaluated. The streak artifacts on treatment planning CT were measured with and without iMAR correction, showing significantly smaller artifacts from markers lighter than 6 mg and a clear improvement with iMAR correction. Daily imaging as X-ray projections and in-room mobile CT were also performed. Markers heavier than 6 mg showed a better contrast in the X-ray projections, whereas on the images from the in-room mobile CT, all markers were clearly visible. In the other part of this work, fluence perturbations of proton beams were measured for the same markers by using a tracker system of several high spatial resolution CMOS pixel sensors. The measurements were performed for single-energy beams, as well as for a spread-out Bragg peak. Three-dimensional fluence distributions were computed after reconstructing all particle trajectories. These measurements clearly showed that the ZrO2 markers and the low-mass gold/platinum markers (0.35mm diameter) induce perturbations being 2-3 times lower than the heavier gold or platinum markers of 0.5mm diameter. Monte Carlo simulations, using the FLUKA code, were used to compute dose distributions and showed good agreement with the experimental data after adjusting the phase space of the simulated proton beam compared to the experimental beam.

Reduction of recombination effects in large plane parallel beam monitors for FLASH radiotherapy with scanned ion beams.

PURPOSE: Radiotherapy escalating dose rates above 50Gys-1, might offer a great potential in treating tumours while further sparing healthy tissue. However, these ultra-high intensities of FLASH-RT lead to new challenges with regard to dosimetry and beam monitoring. FLASH experiments at HIT (Heidelberg Ion Beam Therapy Center) and at GSI (GSI Helmholtz Centre for Heavy Ion Research) have shown a significant loss of signal in the beam monitoring system due to recombination effects. To enable accurate beam monitoring, this work investigates the recombination loss of different fill gases in the plane parallel ionisation chambers (ICs). METHODS: Therefore, saturation curves at high intensities were measured for the currently used fill gases Ar/CO2 (80/20) and pure He and also for He/CO2 mixtures as alternative fill gases. Furthermore, breakdown voltages and ion mobilities were measured in ICs filled with He/CO2 mixtures. A numerical model for volume recombination in plane parallel ionisation chambers was developed and implemented in Python. This includes a novel simulation method of the space charge effect from the charge carriers in the detector volume and predicts a significant effect on the electric field for high intensity beams. RESULTS: Even at high intensities the He/CO2 mixtures allow operation of the ICs at an electric field strength of 2 kVcm-1 or more which reduces recombination to negligible levels at intensities larger than 3 × 101012C-ions per second. Our measurements show that added fractions of CO2 to He decrease the ion mobility in the fill gas but significantly increase the breakdown voltage in the ICs compared to pure He.

Dose Attenuation in Innovative Shielding Materials for Radiation Protection in Space: Measurements and Simulations.

Galactic cosmic rays (GCR) are among the main deterrents to manned space exploration. Currently, the most realistic way to reduce the dangers caused by GCR to acceptable levels is passive shielding. Light materials guarantee the strongest dose attenuation per unit mass. High-density polyethylene is considered the gold standard for radiation protection in space. Nevertheless, accelerator-based experimental campaigns already showed the advantages of more hydrogen-rich innovative shielding materials such as lithium hydride. The experimental campaigns of this work focused on the absorbed dose attenuation properties of lithium-based hydrides chemically stabilized with a paraffin matrix. Such materials were compared to pure lithium-based hydrides, polyethylene, structural materials such as spacecraft aluminum alloys and lithium batteries, and in situ shielding materials such as Moon regolith and its main components silicon and silicon dioxide. The experimental results were compared to simulations performed with PHITS, FLUKA, and Geant4, which are among the most used Monte Carlo codes for radiation protection in space. The simulations showed systematic differences and highlighted the pressing need for reliable nuclear cross-section models.

Depth dose measurements in water for 11C and 10C beams with therapy relevant energies.

Owing to the favorable depth-dose distribution and the radiobiological properties of heavy ion radiation, ion beam therapy shows an improved success/toxicity ratio compared to conventional radiotherapy. The sharp dose gradients and very high doses in the Bragg peak region, which represent the larger physical advantage of ion beam therapy, make it also extremely sensitive to range uncertainties. The use of ß +-radioactive ion beams would be ideal for simultaneous treatment and accurate online range monitoring through PET imaging. Since all the unfragmented primary ions are potentially contributing to the PET signal, these beams offer an improved image quality while preserving the physical and radiobiological advantages of the stable counterparts. The challenging production of radioactive ion beams and the difficulties in reaching high intensities, have discouraged their clinical application. In this context, the project Biomedical Applications of Radioactive ion Beams (BARB) started at GSI (Helmholtzzentrum für Schwerionenforschung GmbH) with the main goal to assess the technical feasibility and investigate possible advantages of radioactive ion beams on the pre-clinical level. During the first experimental campaign 11C and 10C beams were produced and isotopically separated with the FRagment Separator (FRS) at GSI. The ß +-radioactive ion beams were produced with a beam purity of 99% for all the beam investigated (except one case where it was 94%) and intensities potentially sufficient to treat a small animal tumors within few minutes of irradiation time, ∼ 106 particle per spill for the 10C and ∼ 107 particle per spill for the 11C beam, respectively. The impact of different ion optical parameters on the depth dose distribution was studied with a precision water column system. In this work, the measured depth dose distributions are presented together with results from Monte Carlo simulations using the FLUKA software.

Functionalized fullerenes in self-assembled monolayers.

Anisotropy of intermolecular and molecule-substrate interactions holds the key to controlling the arrangement of fullerenes into 2D self-assembled monolayers (SAMs). The chemical reactivity of fullerenes allows functionalization of the carbon cages with sulfur-containing groups, thiols and thioethers, which facilitates the reliable adsorption of these molecules on gold substrates. A series of structurally related molecules, eight of which are new fullerene compounds, allows systematic investigation of the structural and functional parameters defining the geometry of fullerene SAMs. Scanning tunnelling microscopy (STM) measurements reveal that the chemical nature of the anchoring group appears to be crucial for the long-range order in fullerenes: the assembly of thiol-functionalized fullerenes is governed by strong molecule-surface interactions, which prohibit formation of ordered molecular arrays, while thioether-functionalized fullerenes, which have a weaker interaction with the surface than the thiols, form a variety of ordered 2D molecular arrays owing to noncovalent intermolecular interactions. A linear row of fullerene molecules is a recurring structural feature of the ordered SAMs, but the relative alignment and the spacing between the fullerene rows is strongly dependent on the size and shape of the spacer group linking the fullerene cage and the anchoring group. Careful control of the chemical functionality on the carbon cages enables positioning of fullerenes into at least four different packing arrangements, none of which have been observed before. Our new strategy for the controlled arrangement of fullerenes on surfaces at the molecular level will advance the development of practical applications for these nanomaterials.

Physical characterization of3He ion beams for radiotherapy and comparison with4He.

There is increasing interest in using helium ions for radiotherapy, complementary to protons and carbon ions. A large number of patients were treated with4He ions in the US heavy ion therapy project and novel4He ion treatment programs are under preparation, for instance in Germany and Japan.3He ions have been proposed as an alternative to4He ions because the acceleration of3He is technically less difficult than4He. In particular, beam contaminations have been pointed out as a potential safety issue for4He ion beams. This motivated a series of experiments with3He ion beams at Gesellschaft für Schwerionenforschung (GSI), Darmstadt. Measured3He Bragg curves and fragmentation data in water are presented in this work. Those experimental data are compared with FLUKA Monte Carlo simulations. The physical characteristics of3He ion beams are compared to those of4He, for which a large set of data became available in recent years from the preparation work at the Heidelberger Ionenstrahl-Therapiezentrum (HIT). The dose distributions (spread out Bragg peaks, lateral profiles) that can be achieved with3He ions are found to be competitive to4He dose distributions. The effect of beam contaminations on4He depth dose distribution is also addressed. It is concluded that3He ions can be a viable alternative to4He, especially for future compact therapy accelerator designs and upgrades of existing ion therapy facilities.

Monte Carlo simulations and dose measurements of 2D range-modulators for scanned particle therapy.

This paper introduces the concept of a 2D range-modulator as a static device for generating spread-out Bragg peaks at very small distances to the target. The 2D range-modulator has some distinct advantages that can be highly useful for different research projects in particle therapy facilities. Most importantly, it creates an instantaneous, quasi-static irradiation field with only one energy, thus decreasing irradiation time tremendously. In addition, it can be manufactured fast and cost efficiently and its SOBP width and shape can be adjusted easily for the specific purpose/experiment. As the modulator is a static element, there is no need for rotation (e.g. like in a modulation wheel) or lateral oscillation and due to the small base structure period it can be positioned close to the target. Two different rapid prototyping manufacturing techniques were utilized. The modulation properties of one polymer and one steel modulator were investigated with both simulations and measurements. For this purpose, a sophisticated water phantom system (WERNER), that can perform fast, completely automated and high resolution dose measurements, was developed. Using WERNER, the dose distribution of a modulator can be verified quickly and reliably, both during experiments, as well as in a time constrained clinical environment. The maximum deviation between the Monte Carlo simulations and dose measurements in the spread-out Bragg peak region was 1.4% and 4% for the polymer and steel modulator respectively. They were able to create spread-out Bragg peaks with a high degree of dose homogeneity, thus validating the whole process chain, from the mathematical optimization and modulator development, to manufacturing, MC simulations and dose measurements. Combining the convenience, flexibility and cost-effectiveness of rapid prototyping with the advantages of highly customizable modulators, that can be adapted for different experiments, the 2D range-modulator is considered a very useful tool for a variety of research objectives. Moreover, we have successfully shown that the manufacturing of 2D modulators with high quality and high degree of homogeneity is possible, paving the way for the further development of the more complex 3D range-modulators, which are considered a viable option for the very fast treatment of moving targets and/or FLASH irradiation.

Compensating for beam modulation due to microscopic lung heterogeneities in carbon ion therapy treatment planning.

PURPOSE: To predict and mitigate for the degradation in physical and biologically effective dose distributions of particle beams caused by microscopic heterogeneities in lung tissue. MATERIALS AND METHODS: The TRiP98 treatment planning system was adapted to account for the beam-modulating effect of heterogeneous lung tissue in physical and biological inverse treatment planning. The implementation employs an analytical model that derives the degradation from the established "modulation power" parameter P mod and the total water-equivalent thickness of lung parenchyma traversed by the beam. Beam modulation was reproduced through an on-the-fly convolution of the reference Bragg curve with Gaussian kernels depending on the modulation power of lung tissue (upstream). For biological doses, the degradation was determined by modulating dose-averaged α , ß , and LET distributions. Carbon SOBP measurements behind lung substitute material were performed to validate the code. The implementation was then applied to a phantom and patient case. RESULTS: Experimental results show the passage through a 20-cm Gammex LN300 slab led to a decrease in target coverage and broadening of the SOBP distal fall-off. However, dose coverage was regained through optimization. A good agreement between calculated and measured SOBPs was also found. In addition, a patient case study revealed a 3.2% decrease in D 95 from degradation ( P mod = 450 µ m), which was reduced to a 0.4% difference after optimization. Furthermore, widening of the RBE distribution beyond the target distal edge was observed. This implies an increased degradation in the biological dose, which could be harmful to healthy tissues distal to the target. CONCLUSIONS: This is the first implementation capable of compensating for lung dose perturbations, which is more effective than margin extensions. A larger patient study is needed to examine the observed modulation in the RBE distribution and judge the clinical relevance also in IMPT, where margins might prove insufficient to recover target coverage.

Experimental determination of modulation power of lung tissue for particle therapy.

In particle therapy of lung tumors, modulating effects on the particle beam may occur due to the microscopic structure of the lung tissue. These effects are caused by the heterogeneous nature of the lung tissue and cannot be completely taken into account during treatment planning, because these micro structures are too small to be fully resolved in the planning CT. In several publications, a new material parameter called modulation power (Pmod) was introduced to characterize the effect. For various artificial lung surrogates, this parameter was measured and published by other groups and ranges up to approximately 1000µm. Studies investigating the influence of the modulation power on the dose distribution during irradiation are using this parameter in the rang of 100-800µm. More precise measurements forPmodon real lung tissue have not yet been published. In this work, the modulation power of real lung tissue was measured using porcine lungs in order to produce more reliable data ofPmodfor real lung tissue. For this purpose,ex-vivoporcine lungs were frozen in a ventilated state and measurements in a carbon ion-beam were performed. Due to the way the lungs were prepared and transferred to a solid state, the lung structures that modulate the beam could also be examined in detail using micro CT imaging. An optimization of the established methods of measuring the modulation power, which takes better account of the typical structures within lung tissue, was developed as well.