Development and characterization of modular mouse phantoms for end-to-end testing and training in radiobiology experiments.

Objective. In radiation oncology, experiments are often carried out using mice as a model forin vivoresearch studies. Due to recent technological advances in the development of high-precision small-animal irradiation facilities, the importance of quality assurance for both dosimetry and imaging is increasing. Additive manufacturing (AM) offers the possibility to produce complex models from a three-dimensional data set and to build cost-effective phantoms that can easily be adapted to different purposes. The aim of this work was therefore to develop detailed anatomical mouse models for quality assurance and end-to-end testing of small-animal irradiation and imaging by means of AM.Approach. Two mouse phantom concepts were designed, constructed, and examined for this purpose. The first model includes cavities corresponding to the most important organs. The final solid model was constructed using AM in two separate parts that can be attached with a plug connection after filling these cavities with tissue-equivalent mixtures. Moreover, different radiation dosimeters can be placed in the lower part of the model. For the second concept, AM was used for building modules like the phantom outer shell and bones, so that different mixtures can be used as a filling, without modifying the phantom structure.Main results.CT as well as Micro-CT scans of both concepts showed an excellent quality and adequate image contrast, with material attenuation properties close to those of mouse tissues, apart from the current bone surrogates. Radiation dose measurements with radiochromic films were, with some exceptions in areas with larges bone volumes, in agreement with calculations within less than ±4%.Significance. AM shows great potential for the development of mouse models that are inexpensive, easy to adapt, and accurate, thus enabling their use for quality assurance in small-animal radiotherapy and imaging. The introduction of such 3D-printable mouse phantoms in the workflow could also significantly reduce the use of living animals for optimization and testing of new imaging and irradiation protocols.

The Microbeam Insert at the White Beam Beamline P61A at the Synchrotron PETRA III/DESY: A New Tool for High Dose Rate Irradiation Research.

High dose rate radiotherapies such as FLASH and microbeam radiotherapy (MRT) both have developed to the stage of first veterinary studies within the last decade. With the development of a new research tool for high dose rate radiotherapy at the end station P61A of the synchrotron beamline P61 on the DESY campus in Hamburg, we increased the research capacity in this field to speed up the translation of the radiotherapy techniques which are still experimental, from bench to bedside. At P61, dose rates of several hundred Gy/s can be delivered. Compared to dedicated biomedical beamlines, the beam width available for MRT experiments is a very restrictive factor. We developed two model systems specifically to suit these specific technical parameters and tested them in a first set of experiments.

Nutritional Status Impacts Quality of Life in Head and Neck Cancer Patients Undergoing (Chemo)Radiotherapy: Results from the Prospective HEADNUT Trial.

Malnutrition negatively impacts quality of life (QoL) in patients with head and neck cancer (HNC). This is the first prospective study to assess the impact of malnutrition (defined by the bioelectrical impedance analysis (BIA)-derived fat-free mass index) on QoL in patients with HNC undergoing (chemo)radiotherapy. Between October 2018 and October 2020, 58 HNC patients prospectively completed the QoL-questionnaires EORTC-QLQ-C30 and EORTC-QLQ-H&N35 at the beginning (tb) and at the end of (chemo)radiotherapy (te) as well as during follow-up (tf). At these time points, nutritional risk assessment (MUST, NRS-2002, Nutriscore), BIA measurement and laboratory testing was performed by a permanent study team. Differences between malnourished (n = 14) and well-nourished patients (n = 44) were observed in UICC classification (P < 0.001) and HPV status (P = 0.03). Well-nourished patients showed higher baseline hemoglobin (P = 0.025) and albumin (P = 0.005), but lower c-reactive protein levels (P < 0.001). At tb, mostly malnourished patients presented with worse QoL. Multivariable analysis showed that MUST, NRS-2002, HPV status, and UICC classification were related to QoL. Nutritional status has a crucial impact on QoL. The nutritional screening protocols MUST and NRS-2002 are suitable for identifying patients at risk and predicting QoL in patients with HNC undergoing (chemo)radiotherapy.

In-situ x-ray fluorescence imaging of the endogenous iodine distribution in murine thyroids.

X-ray fluorescence imaging (XFI) is a non-invasive detection method of small quantities of elements, which can be excited to emit fluorescence x-ray photons upon irradiation with an incident x-ray beam. In particular, it can be used to measure nanoparticle uptake in cells and tissue, thus making it a versatile medical imaging modality. However, due to substantially increased multiple Compton scattering background in the measured x-ray spectra, its sensitivity severely decreases for thicker objects, so far limiting its applicability for tracking very small quantities under in-vivo conditions. Reducing the detection limit would enable the ability to track labeled cells, promising new insights into immune response and pharmacokinetics. We present a synchrotron-based approach for reducing the minimal detectable marker concentration by demonstrating the feasibility of XFI for measuring the yet inaccessible distribution of the endogenous iodine in murine thyroids under in-vivo conform conditions. This result can be used as a reference case for the design of future preclinical XFI applications as mentioned above.

X-ray Fluorescence Uptake Measurement of Functionalized Gold Nanoparticles in Tumor Cell Microsamples.

Quantitative cellular in vitro nanoparticle uptake measurements are possible with a large number of different techniques, however, all have their respective restrictions. Here, we demonstrate the application of synchrotron-based X-ray fluorescence imaging (XFI) on prostate tumor cells, which have internalized differently functionalized gold nanoparticles. Total nanoparticle uptake on the order of a few hundred picograms could be conveniently observed with microsamples consisting of only a few hundreds of cells. A comparison with mass spectroscopy quantification is provided, experimental results are both supported and sensitivity limits of this XFI approach extrapolated by Monte-Carlo simulations, yielding a minimum detectable nanoparticle mass of just 5 pg. This study demonstrates the high sensitivity level of XFI, allowing non-destructive uptake measurements with very small microsamples within just seconds of irradiation time.

X-ray-Based Techniques to Study the Nano-Bio Interface.

X-ray-based analytics are routinely applied in many fields, including physics, chemistry, materials science, and engineering. The full potential of such techniques in the life sciences and medicine, however, has not yet been fully exploited. We highlight current and upcoming advances in this direction. We describe different X-ray-based methodologies (including those performed at synchrotron light sources and X-ray free-electron lasers) and their potentials for application to investigate the nano-bio interface. The discussion is predominantly guided by asking how such methods could better help to understand and to improve nanoparticle-based drug delivery, though the concepts also apply to nano-bio interactions in general. We discuss current limitations and how they might be overcome, particularly for future use in vivo.

Roadmap for metal nanoparticles in radiation therapy: current status, translational challenges, and future directions.

This roadmap outlines the potential roles of metallic nanoparticles (MNPs) in the field of radiation therapy. MNPs made up of a wide range of materials (from Titanium, Z = 22, to Bismuth, Z = 83) and a similarly wide spectrum of potential clinical applications, including diagnostic, therapeutic (radiation dose enhancers, hyperthermia inducers, drug delivery vehicles, vaccine adjuvants, photosensitizers, enhancers of immunotherapy) and theranostic (combining both diagnostic and therapeutic), are being fabricated and evaluated. This roadmap covers contributions from experts in these topics summarizing their view of the current status and challenges, as well as expected advancements in technology to address these challenges.

Feasibility of clinical electron beam formation using polymer materials produced by fused deposition modeling.

The main challenge in electron external beam radiation therapy with clinical accelerators is the absence of integrated systems to form irregular fields. The current approach to provide conformal irradiation is to use additional metallic shaping blocks, with inefficient and expensive workflows. This work presents a simple method to form therapeutic electron fields using 3D printed samples. These samples are manufactured by fused deposition modeling, which can affect crucial properties, such as material homogeneity, due to the presence of residual air-filled cavities. The applicability of this method was therefore investigated with a set of experiments and Monte Carlo simulations aimed at determining the electron depth dose distribution in polymer materials. The results show that therapeutic electron beams with energies 6-20 MeV can be effectively absorbed using these polymeric samples. The model developed in this study provides a way to assess the dose distribution in such materials and to calculate the appropriate thickness of polymer samples for therapeutic electron beam formation. It is shown that for total absorption of 6 MeV electron beams the material thickness should be at least 4 cm, while this value should be at least 8 cm for 12 MeV and 11 cm for 20 MeV, respectively. The results can be used to further develop 3D printing procedures for medical electron beam profile formation, allowing the creation of a collimator or absorber with patient-specific configuration using rapid prototyping systems, thus contributing to improve the accuracy of dose delivery in electron radiotherapy within a short manufacturing time.

Determining dose enhancement factors of high-Z nanoparticles from simulations where lateral secondary particle disequilibrium exists.

Nanoparticles (NPs) containing high atomic number (high-Z) materials have been shown to enhance the radiobiological effectiveness of ionizing radiation. This effect is often attributed to an enhancement of the absorbed dose in the vicinity of the NPs, based on Monte Carlo simulations that show a significant local enhancement of the energy deposition on the microscopic scale. The results of such simulations may be significantly biased and lead to a severe overestimation of the dose enhancement if the condition of secondary particle equilibrium is not met in the simulation setup. This current work shows an approach to estimate a 'realistic' dose enhancement from the results of such biased simulations which is based on published photon interaction data and provides a way for correcting biased results.

Targeted nanoparticles for tumour radiotherapy enhancement-the long dawn of a golden era?

Despite considerable progress in (I) our understanding of the aetiopathology of head and neck cancer and (II) the precise delivery of radiotherapy, long-term survival rates for many patients with head and neck cancer remain disappointingly low. Over the past years, gold nanoparticles (NP) have emerged as promising radiation dose enhancers. In a recent study published in Nanoscale, Popovtzer et al. have used gold NP coated with an antibody against the epidermal growth factor receptor (EGFR) in an attempt to enhance radiation-induced tumour cell killing in a head and neck cancer xenograft model. They report a significant impact of the combined treatment with radiation and gold NP on tumour growth and suggest an involvement of apoptosis, inhibition of angiogenesis and diminished tissue repair. In this perspective, we illustrate the underlying radiobiophysical concepts and discuss some of the challenges associated with this and related nanoparticle-radiotherapy studies from a physics, chemistry, biology and therapy angle. We conclude that strong interdisciplinary collaborations spanning all these areas are crucially important to proceed towards effective cancer treatment with gold NP "from bench to bedside".

Ionization cross section data of nitrogen, methane, and propane for light ions and electrons and their suitability for use in track structure simulations.

Track structure Monte Carlo simulations are frequently applied in micro- and nanodosimetry to calculate the radiation transport in detail. The use of a well-validated set of cross section data in such simulation codes ensures accurate calculations of transport parameters, such as ionization yields. These cross section data are, however, scarce and often discrepant when measured by different groups. This work surveys literature data on ionization and charge-transfer cross sections of nitrogen, methane, and propane for electrons, protons, and helium particles, focusing on the energy range between 100 keV and 20 MeV. Based on the evaluated data, different models for the parametrization of the cross section data are implemented in the code ptra, developed for simulating proton and alpha particle transport in an ion-counting nanodosimeter. The suitability of the cross section data is investigated by comparing the calculated mean ionization cluster size and energy loss with experimental results in either nitrogen or propane. For protons, generally good agreement between measured and simulated data is found when the Rudd model is used in ptra. For alpha particles, however, a considerable influence of different parametrizations of cross sections for ionization and charge transfer is observed. The ptra code using the charge-transfer data is, nevertheless, successfully benchmarked by the experimental data for the calculation of nanodosimetric quantities, but remaining discrepancies still have to be further investigated (up to 13% lower energy loss and 19% lower mean ionization cluster size than in the experiment). A continuation of this work should investigate data for the energy loss per interaction as well as differential cross section data of nitrogen and propane. Interpolation models for ionization and charge-transfer data are proposed. The Barkas model, frequently used for a determination of the effective charge in the ionization cross section, significantly underestimates both the energy loss (by up to 19%) and the mean ionization cluster size (up to 65%) for alpha particles. It is, therefore, not recommended for particle-track simulations.

Effect of a static magnetic field on nanodosimetric quantities in a DNA volume.

PURPOSE: With the advent of magnetic resonance imaging (MRI)-guided radiation therapy it is becoming increasingly important to consider the potential influence of a magnetic field on ionising radiation. This paper aims to study the effect of a magnetic field on the track structure of radiation to determine if the biological effectiveness may be altered. METHODS: Using the Geant4-DNA (GEometry ANd Tracking 4) Monte Carlo simulation toolkit, nanodosimetric track structure parameters were calculated for electrons, protons and alpha particles moving in transverse magnetic fields up to 10 Tesla. Applying the model proposed by Garty et al., the track structure parameters were used to derive the probability of producing a double-strand break (DSB). RESULTS: For simulated primary particles of electrons (200 eV-10 keV), protons (300 keV-30 MeV) and alpha particles (1-9 MeV) the application of a magnetic field was shown to have no significant effect (within statistical uncertainty limits) on the parameters characterizing radiation track structure or the probability of producing a DSB. CONCLUSIONS: The null result found here implies that if the presence of a magnetic field were to induce a change in the biological effectiveness of radiation, the effect would likely not be due to a change in the track structure of the radiation.

Nanodosimetry-based quality factors for radiation protection in space.

Evaluation and monitoring of the cancer risk from space radiation exposure is a crucial requirement for the success of long-term space missions. One important task in the risk calculation is to properly weigh the various components of space radiation dose according to their assumed contribution to the cancer risk relative to the risk associated with radiation of low ionization density. Currently, quality factors of radiation both on the ground and in space are defined by national and international commissions based on existing radiobiological data and presumed knowledge of the ionization density distribution of the radiation field at a given point of interest. This approach makes the determination of the average quality factor ofa given radiation field a rather complex task. In this contribution, we investigate the possibility to define quality factors of space radiation exposure based on nanodosimetric data. The underlying formalism of the determination of quality factors on the basis of nanodosimetric data is described, and quality factors for protons and ions (helium and carbon) of different energies based on simulated nanodosimetric data are presented. The value and limitations of this approach are discussed.