When astronauts travel in space, they are exposed to high energy cosmic radiations. The cosmic ray spectrum contains very high energy particles, generally up to several GeV per nucleon. Currently NASA is funding research on the effects, such as acute radiation sickness, of cosmic radiation. Animal models are used to conduct the studies of radiation effects of particles in the range of several MeV/nucleon to about 1000 MeV/nucleon. In order to compare different radiations, the biological effectiveness relative to a specific radiation is usually used. For low energy heavy ions and neutrons 250 keV photons are usually used for the reference radiation but their depth dose distribution is very different from that for cosmic rays. In this research, the advantages of using high energy electrons as the reference radiation for research on cosmic radiation were demonstrated. The conclusion is based on the evaluation of the dose distributions and microdosimetric spectra of the electrons and high energy protons as a function of depth in a tissue equivalent absorber as determined by Geant4 simulation.

In radiotherapy with protons, a constant relative biological effectiveness (RBE) of 1.1 is traditionally applied, i.e. protons are assumed to be 10\% more effective than photons in killing cells. This constant RBE is however being questioned, as an abundance of in vitro studies indicate a variable RBE with particle energy, and as in vivo studies also show unexpected toxities near proton track ends, thereby indicating that a variable RBE might also be present clinically. Variable RBE is in turn typically described by a model. For protons, the vast majority of suggested models are based on the linear quadratic (LQ) model, where an expression for RBE is derived by comparing the dose from protons and a reference radiation (typically photons) to achieve a desired survival fraction. The parameters for the model are subsequently obtained by fitting parameters of the derived expression to in vitro data, where the survival fraction of cells has been determined as a function of dose and an averaging over the fluence spectrum of linear energy transfer (LET). While the beam quality parameter typically is the averaged LET, how the averaged LET value has been calculated or determined has often not been fully provided, possibly introducing a source of error in the estimated RBE value. This can vary with respect to the averaging method (typical dose- or track averaging), included particles (only primary, or also including secondaries) and other aspects. Furthermore, while LET is the most commonly used beam quality descriptor, other quantities exist such as Q and z*2/β2 , here renamed as Qeff. These alternative metrics have been shown to better correlate with RBE across different particle species compared to LET, and can possibly also perform better for a single particle species. However, this has so far not been systematically tested or verified. Paper I investigates which kind of averaged LET is provided in the scientific literature for the purpose of RBE determination, for both protons and other hadronic particles. It also attempts to quantify the corresponding impact to the calculated RBE values. Paper II investigates which beam quality descriptor is most suitable for predicting RBE by simulating the experimental setup of recently published high throughput in vitro cell survival studies for RBE determination by a Monte Carlo particle transport code, and fitting parameters to a phenomenological LQ-based model based on the cell survival data. Different variations of LET, Q and Qeff are included, to generate both linear and non linear variable RBE models. In paper I, it is shown that averaged LET for the purpose of RBE determination is, typically, not entirely well defined with a significant minority not mentioning which averaging method is used, and a majority not mentioning what particles are included when averaging. The corresponding impact to the RBE for protons is, in most cases, small, unless heavier secondary particles are included. In paper II it is shown that Q and especially Qeff are expected to better predict RBE compared to LET by a statistically significant margin, for both linear and non-linear models, suggesting they are likely to be more suitable beam quality descriptors to use in a LQ based phenomenological variable RBE model.

Background: Current studies in radiotherapy aim to develop better methods for curing patients fromcancer. Since different types of radiation interact with biological matter in various ways, the resultsof their interaction and their effectiveness with respect to the biological damage to cells have ageneral investigation interest. Aim: The work in this project aims to use a mathematical model to fit a pre-existing data onclonogenic survival of cells irradiated by different types of radiation and report the fittingparameters. Various radiobiological concepts were investigated and compared between differentradiation qualities used in this work. Materials and Methods: The repairable-conditionally repairable (RCR) damage model parametrisedwith respect to the linear energy transfer (LET) of the cell oxygenation was used for fittingexperimental cell survival data for human salivary gland cells irradiated in oxic and hypoxicconditions with protons, 12C-, 20Ne- and 3He-ions. Results: Good consistency with the entire cell survival data was achieved. RCR-model was robustenough to achieve agreement with cell survival data for LET values excluded from fitting procedure.Slope of cell survival curves for the three ions increased up to optimal LET value reaching maximumthere and it decreased at higher LETs. RBE of 3He-ions showed the most rapid increase in low-LETregion and reached a higher maximum as compared with other ions. RBE of the three ions increasedapproximately in the same LET region as a and c parameters of RCR-model, but no underlyingradiobiological mechanism could explain any of curve shape similarities. The RBE of 12C-ions reachedmaximum approximately at 126 keV/μm, which is the optimal LET that could possibly correspond tothe steepest cell survival curve. It was observed how the cell oxygenation became less important forcell irradiation with very high LET values. Conclusion: The results showed that it is feasible to use the RCR model to fit the broad range of cellsurvival curves corresponding to different radiation qualities and the assessment of their relativebiological effectiveness in oxic and hypoxic irradiation conditions. RCR-model may have a possible application in cell irradiation with other ion beams than those used in this work.

Diplomová práce je zaměřena na optimální modelování nýtového spoje pro tři různé konfigurace pomocí metody konečných prvků v programu MSC. Nastran/Patran. Na základě prezentovaných výsledků je možné virtuálně simulovat chování nýtových spojů při zatížení, za účelem správného návrhu před provedením statických pevnostních zkoušek. Použitím těchto MKP simulací v procesu certifikace výrobku lze významně redukovat časovou i finanční náročnost pevnostních zkoušek. Při lepším porozumění chování konstrukce lze také lépe predikovat reálnou únosnost nýtových spojů.

Research in radiotherapy for cancer treatment focuses on finding methods that can improve the compromise between tumour cell inactivation versus damage to the surrounding healthy tissue. As new radiation modalities such as proton therapy become accessible for everyday clinical practice, a better understanding of the variation in biological response of the tumour and healthy tissues would improve treatment planning to achieve optimal outcome. The development of radiobiological models capable of accurate predictions of biological effectiveness is needed. Existing radiation quality descriptors such as absorbed dose and LET are insufficient to explain variation in biological effectiveness for different treatment modalities. The stochastic nature of ionizing radiation creates discrete patterns of energy deposition (ED) sites which can now be analysed through sophisticated computer simulations (e.g. Monte Carlo track structure codes). This opens the possibility to develop a nanometre characterization of radiation quality based on the spatial cluster patterns of ED. The aim of this thesis is to investigate the track structure (ED spatial pattern) properties of several radiation qualities at a micro- and nanometric scale while exploring their influence in biological response through correlations with published experimental data. This work uses track structure data simulated for a set of 15 different radiation qualities: 4 commonly used brachytherapy sources, 6 different proton energies, 4 different carbon ion energies, and 60Co photons used as reference radiation for quantification of biological effectiveness. At a micrometre level, the behaviour of the microdosimetric spread in energy deposition for target sizes of the order of cell nuclei was analysed. The degree of the influence it had in the biological response was found to be negligible for photon sources but for protons and carbon ions the impact increased with decreasing particle energy suggesting it may be a confounding factor in biological response. Finally, this thesis outlines a framework for modelling the relative biological effectiveness based on the frequency distribution of cluster order as a surrogate for the nanometre classification for the physical properties of radiation quality. The results indicate that this frequency is a valuable descriptor of ionizing radiation. The positive correlation across the different types of ionizing radiation encourages further development of the framework by incorporating the behavior of the microdosimetric spread and expanding tests to other experimental datasets.

<p>The development of new irradiation techniques is presently a very active field of research with increased availability of more sophisticated modalities such as intensity modulated photons (IMRT), protons and light ions. The primary aim of this work is to evaluate if the dose-distributions using IMRT and protons contribute to clinical advantages. A secondary aim is to investigate the potential clinical implication of the increased relative biological effect (RBE) for protons at the end of the Bragg peak. </p><p>The potential benefits are evaluated using physical dose measures and dose-response models for normal tissue complication probability (NTCP) and tumour control probability (TCP). Comparative treatment planning was performed using three locally advanced tumour types, left-sided node positive breast cancer, hypopharyngeal cancer, and rectal cancer. All studies showed that both IMRT and protons could improve the dose distributions compared to 3D-CRT, and significantly improve treatment results with lower NTCPs and, concerning hypopharyngeal cancer, higher TCP. Protons always resulted in smaller volumes receiving intermediate and low radiation doses.</p><p>Using protons or IMRT for left-sided node-positive breast cancer, the advantage is a significantly decreased risk for cardiac mortality (from 6.7% to 1%) and radiation induced pneumonitis (from 28.2% to less than 3%) compared to 3D-CRT. For hypopharyngeal cancer, protons and IMRT provide more selective treatment plans, higher TCP since a simultaneous boost technique is feasible, and better parotid gland sparing for several patients. For locally advanced rectal cancer, the NTCP for small bowel is potentially reduced by approximately 50% using IMRT or protons; protons have an even greater potential if the structure of the small bowel is parallel.</p><p>A variable RBE correction is developed and applied to a clinical proton treatment plan. A significant difference is obtained compared to the commonly accepted RBE correction of 1.1. This indicates that a variable RBE may be of importance in future proton treatment planning.</p><p>This thesis provides support for increased use both IMRT and proton radiotherapy, although stronger for protons. Therefore, investments in proton facilities with capacity for large clinical trials can be supported.</p>

The development of new irradiation techniques is presently a very active field of research with increased availability of more sophisticated modalities such as intensity modulated photons (IMRT), protons and light ions. The primary aim of this work is to evaluate if the dose-distributions using IMRT and protons contribute to clinical advantages. A secondary aim is to investigate the potential clinical implication of the increased relative biological effect (RBE) for protons at the end of the Bragg peak. The potential benefits are evaluated using physical dose measures and dose-response models for normal tissue complication probability (NTCP) and tumour control probability (TCP). Comparative treatment planning was performed using three locally advanced tumour types, left-sided node positive breast cancer, hypopharyngeal cancer, and rectal cancer. All studies showed that both IMRT and protons could improve the dose distributions compared to 3D-CRT, and significantly improve treatment results with lower NTCPs and, concerning hypopharyngeal cancer, higher TCP. Protons always resulted in smaller volumes receiving intermediate and low radiation doses. Using protons or IMRT for left-sided node-positive breast cancer, the advantage is a significantly decreased risk for cardiac mortality (from 6.7% to 1%) and radiation induced pneumonitis (from 28.2% to less than 3%) compared to 3D-CRT. For hypopharyngeal cancer, protons and IMRT provide more selective treatment plans, higher TCP since a simultaneous boost technique is feasible, and better parotid gland sparing for several patients. For locally advanced rectal cancer, the NTCP for small bowel is potentially reduced by approximately 50% using IMRT or protons; protons have an even greater potential if the structure of the small bowel is parallel. A variable RBE correction is developed and applied to a clinical proton treatment plan. A significant difference is obtained compared to the commonly accepted RBE correction of 1.1. This indicates that a variable RBE may be of importance in future proton treatment planning. This thesis provides support for increased use both IMRT and proton radiotherapy, although stronger for protons. Therefore, investments in proton facilities with capacity for large clinical trials can be supported.

The dosimetric properties of fast-neutron beams with energies ≤80 MeV were explored using Monte Carlo techniques. Taking into account transport of all relevant types of released charged particles (electrons, protons, deuterons, tritons, 3He and α particles) pencil-beam dose distributions were derived and used to calculate absorbed dose distributions. Broad-beam depth doses in phantoms of different materials were calculated and compared and the scaling factors required for converting absorbed dose in one material to absorbed dose in another derived. The scaling factors were in good agreement with available published data and show that water is a good substitute for soft tissue even at neutron energies as high as 80 MeV. The inherent penumbra and the fraction of absorbed dose due to photon interactions were also studied, and found to be consistent with measured values reported in the literature. Treatment planning in fast-neutron therapy is commonly performed using dose calculation algorithms designed for photon beam therapy. When applied to neutron beams, these algorithms have limitations arising from the physical models used. Monte Carlo derived neutron pencil-beam kernels were parameterized and implemented in the photon dose calculation algorithms of the TMS (MDS Nordion) treatment planning system. It was shown that these algorithms yield good results in homogeneous water media. However, the method used to calculate heterogeneity corrections in the photon dose calculation algorithm did not yield correct results for neutron beams in heterogeneous media. To achieve results with adequate accuracy using Monte Carlo simulations, fundamental cross-section data are needed. Neutron cross-sections are still not sufficiently well known. At the The Svedberg Laboratory in Uppsala, Sweden, an experimental facility has been designed to measure neutron-induced charged-particle production cross-sections for (n,xp), (n,xd), (n,xt), (n,x3He) and (n,xα) reactions at neutron energies up to 100 MeV. Depending on neutron energy, these generated particles account for up to 90% of the absorbed dose. In experimental determination of the cross-sections, measured data have to be corrected for the energies lost by the charged particles before leaving the target in which they were generated. To correct for the energy-losses, a computational code (CRAWL) was developed. It uses a stripping method. With the limitation of reduced energy resolution, spectra derived using CRAWL compares well with those derived using other methods. In fast-neutron therapy, the relative biological effectiveness (RBE) varies from 1.5 to 5, depending on neutron energy, dose level and biological end-point. LET and other physical quantities, developed within the field of microdosimetry over the past couple of decades, have been used to describe RBE variations between different fast-neutron beams as well as within a neutron irradiated body. In this work, a Monte Carlo code (SHIELD-HIT) capable of transporting all charged particles contributing to absorbed dose, was used to calculate energy-differential charged particle spectra. Using these spectra, values of the RBE related quantities LD, γD, γ* and R were derived and studied as function of neutron energy, phantom material and position in a phantom. Reasonable agreement with measured data in the literature was found and indicates that the quantities may be used to predict RBE variations in an arbitrary fast-neutron beam.

Radiotherapy aims to sterilize cancer cells through ionization induced damages to their DNA whilst trying to reduce dose burdens to healthy tissues. This can be achieved to a certain extent by optimizing the choice of radiation to treat the patient, i.e. the types of particles and their energy based on their specific interaction patterns. In particular, the formation of complex clusters of energy deposits (EDs) increases with the linear energy transferred for a given particle. These differences cause variation in the relative biological effectiveness (RBE). The complexity of ED clusters might be related to complex forms of DNA damage, which are more difficult to repair and therefore prone to inactivate the cells. Hence, mapping of the number and complexity of ED clusters for different radiation qualities could aid to infer a surrogate measure substituting physical dose and LET as main predictors for the RBE .   In this work the spatial patterns of EDs at the nanometre scale were characterized for various energies of proton, helium, lithium and carbon ions. A track structure Monte Carlo code, LIonTrack, was developed to accurately simulate the light ion tracks in liquid water. The methods to emulate EDs at clinical dose levels in cell nucleus-sized targets for both 60Co photons and light ions were established, and applied to liquid water targets. All EDs enclosed in such targets were analyzed with a specifically developed cluster algorithm where clustering was defined by a single parameter, the maximum distance between nearest neighbour EDs. When comparing measured RBE for different radiation qualities, there are cases for which RBE do not  increase with LET but instead increase with the frequencies of high order ED clusters. A test surrogate-measure based on ED cluster frequencies correlated to parameters of experimentally determined cell survival. The tools developed in this thesis can facilitate future exploration of semi-mechanistic modelling of the RBE.

Tumours are characterised by unorganised vasculature, which often results in hypoxic regions. Hypoxia is a common cause for photon radiotherapy (RT) treatment failure, as hypoxic cells require up to 2-3 times higher doses compared to well-oxygenated cells for the same effect in terms of cell kill. The increase in dose that would be required to treat the tumours of cancer patients is limited by the radiation sensitivity of surrounding normal tissues. Using carbon ions instead of photons, the radiation dose can be conformed to the tumour to a much higher degree, resulting in an improved sparing of normal tissues. In addition, carbon ions have a much higher radiobiological effectiveness near the end of their range, which is positioned in the tumour. Also, the radiation modes of action leading to cell death when carbon ions interact with living tissues, are less sensitive to the oxygen status compared with the action modes of photons. The focus of this thesis lies in the development of models for the computation of the cell surviving fraction and tumour control probability (TCP) in hypoxic tumours after photon and carbon ion RT. The impact of fractionation was evaluated with regard to possible spatial changes in oxygenation, both for stereotactic body RT and for carbon ion RT. The feasibility of a method to determine and deliver the optimal photon dose for achieving a high TCP according to spatial variations in radiation sensitivity was evaluated in a treatment planning study. The radiobiological models were finally used for the theoretical quantification of the gain in using carbon ions instead of photons. The results show that there are great possibilities to increase the number of positive outcomes of radiation treatment of tumours if the key influential factors are taken into account, such as level and distribution of hypoxia, radiation quality and choice of fractionation schedule. / <p>At the time of the doctoral defence the following papers were unpublished and had a status as follows; Paper 3: Manuscript; Paper 4: Epubl ahead of print; Paper 5: Manuscript</p>