<p>Medical X-ray imaging is an important tool in diagnostic radiology. The ionising-radiation dose to the patient is justified by the clinical benefit of the examination. Nonetheless, detectors that operate at even lower doses and provide more information to the radiologist are desired. A hybrid pixel detector has the potential to provide a leap in detector technology as it incorporates a more advanced signal-processing capability than currently used detectors.</p><p>The DIXI digital detector is a hybrid pixel detector developed for X-ray imaging. It consists of a readout chip and a semiconductor sensor. The division in two parts makes it possible to optimise each part individually. The detector is divided into square pixels with a size of 270 x 270 μm2. DIXI has the ability to count single photons and every readout pixel has two embedded counters to allow the acquisition of two images close in time. A discriminator enables the selection of photons with energies above a preset threshold level.</p><p>The readout chip Angie has been developed and its performance has been evaluated in terms of noise, threshold variation and capability to perform energy weighted counting. Silicon sensors have been fabricated, and a control system for DIXI has been designed and built. An electroless process for deposition of Ni/Au bumps on the chip and sensor has been optimised as a preparation for the assembly of a complete detector, which is being assembled by flip-chip bonding using anisotropic conductive film.</p><p>A simulation library for the DIXI detector has been set up and results on the image quality are reported for different exposures and working conditions. A theoretical model for hybrid pixel detectors based on the cascaded linear system theory has been developed. The model can be used to investigate and optimise the detector for different detector configurations and operating conditions.</p>

<p> Two-pion production reactions in proton-proton collisions have been studied using the PROMICE/WASA detector and an internal cluster gas-jet target at the CELSIUS storage ring in Uppsala. Three out of the four isospin-independent reaction channels have been measured at several energies in the intermediate and near threshold energy region. Important parts of the analysis include the identification of neutral pions from the invariant mass of the decay gammas, the identification of positive pions with the delayed pulse technique and the use of Monte Carlo simulations to understand the detector response. The total cross sections for the pp®ppπ⁺π^-, the pp®ppπ⁰π⁰ and the pp®pnπ⁺π⁰ reactions are presented at beam energies ranging from 650 to 775 MeV. </p><p>The production mechanism for two-pion production near threshold seems to be dominated by resonance production. The contribution from the non-resonant terms alone can not reproduce the total cross sections. In most models, two-pion production is governed by the δ and the <i>N</i>^* resonances in either one or both of the participating nucleons. </p><p>The <i>N</i>^*(1440)®N(πp)^T=0_S−<i>wave</i> transition has been suggested as the dominating production mechanism for two-pion production in proton-proton collisions. However, the total cross sections presented in this thesis show that other production mechanisms also must give large contributions. </p>

The increasing demand for characterization of nuclear fuel, both from an operator and authority point of view, motivates the development of new experimental and, preferable, non-destructive methods. In this thesis, some methods based on nuclear spectroscopic techniques are presented. Various parameters of irradiated fuel are shown to be determined with high accuracy and confidence by utilizing gamma-ray scanning, tomography and passive neutron assay. Specifically, fuel parameters relevant for a secure storage of spent nuclear fuel in a long-term repository, such as e.g. burnup and decay heat, are shown to be determined with adequate accuracy. The techniques developed are expected to be implemented in the planned encapsulation facility in Sweden. Also, a device for tomographic measurements of the spatial distribution of thermal power in nuclear fuel assemblies has been built, tested and evaluated. The device utilizes single photon emission computed tomography (SPECT) in order to reconstruct the gamma-ray source distribution within a fuel assembly. The device is expected to be an important tool for validating reactor core simulators regarding new fuel designs. For safeguards purposes, two experimental methods for verifying the integrity, i.e. the possible loss of fissile material from a nuclear fuel assembly, are presented. Verification of integrity is shown to be possible on an individual fuel rod level.

Two-pion production reactions in proton-proton collisions have been studied using the PROMICE/WASA detector and an internal cluster gas-jet target at the CELSIUS storage ring in Uppsala. Three out of the four isospin-independent reaction channels have been measured at several energies in the intermediate and near threshold energy region. Important parts of the analysis include the identification of neutral pions from the invariant mass of the decay gammas, the identification of positive pions with the delayed pulse technique and the use of Monte Carlo simulations to understand the detector response. The total cross sections for the pp®ppπ+π-, the pp®ppπ0π0 and the pp®pnπ+π0 reactions are presented at beam energies ranging from 650 to 775 MeV. The production mechanism for two-pion production near threshold seems to be dominated by resonance production. The contribution from the non-resonant terms alone can not reproduce the total cross sections. In most models, two-pion production is governed by the δ and the N* resonances in either one or both of the participating nucleons. The N*(1440)®N(πp)T=0S−wave transition has been suggested as the dominating production mechanism for two-pion production in proton-proton collisions. However, the total cross sections presented in this thesis show that other production mechanisms also must give large contributions.

Tumour targeted radiotherapy is an appealing approach for treatment of disseminated tumour cells. A targeting agent that specifically binds to a structure on tumour cells is then used to transport therapeutically relevant radionuclides. The epidermal growth factor receptor, EGFR, is overexpressed on tumour cells in several malignancies, e.g. highly malignant gliomas. In this thesis, three types of radiolabelled EGF-conjugates, aimed for targeting to EGFR-expressing tumour cells, were developed and studied: EGF-dextran labelled with 125I, EGF labelled with 211At, and two EGF-chelates, DTPA-EGF and Bz-DTPA-EGF, labelled with the radioactive metals 111In and 177Lu. The targeting properties of radioiodinated EGF-dextran were first studied in cultured glioma cells. Radioiodine coupled to the dextran part of EGF-dextran was retained in cells appreciably longer than radioiodine coupled to EGF. This can give about 100 times increased radiation dose to tumour cells. Targeting with 211At-EGF was investigated in combination with the tyrosine kinase inhibitor gefitinib (Iressa™, ZD1839). The uptake of 211At-EGF in EGFR-expressing tumour cells increased with increasing gefitinib concentrations. This was the case for both gefitinib-resistant and gefitinib-sensitive cell lines. The effect of the combined treatment on cell survival, however, differed between the cell lines in an unexpected way. In gefitinib resistant cells, combined treatment decreased cell survival approximately 3.5 times relative to 211At-EGF treatment alone. In gefitinib sensitive cells, however, combined treatment increased the cell survival (i.e. a protective effect). The EGF-chelates studied ([111In]DTPA-EGF, [111In]Bz-DTPA-EGF and [177Lu]Bz-DTPA-EGF) all bound specifically with high affinity (Kd≈2 nM) to EGFR on cultured glioma cells. They were internalised after binding, and the cellular retention of radionuclides was high (60% remained after 45 h). A biodistribution study in mice showed that liver and kidneys accumulated a majority of the radioactivity. The EGF-chelates bound EGFR specifically also in vivo. A tumour-to-blood ratio of 25 was achieved in a preliminary study.

One of the main problems in curing cancer resides in the different microenvironment existing in tumours compared to the normal tissues. The mechanisms of failure are different for radiotherapy and chemotherapy, but they all relate to the poor blood supply known to exist in tumours. It is therefore very important to know the tumour microenvironmental conditions in order to devise techniques that will overcome the problems and will therefore improve the result of the treatment. The aims of the thesis were the modelling of tumour oxygenation and the simulation of polarographic oxygen measurements in order to assess and possibly to improve the accuracy of the electrode in measuring tumour oxygenation. It also aimed to evaluate the implications of tumour microenvironment for the radiotherapy outcome. The project used theoretical modelling as the main tool. The processes of oxygen diffusion and consumption were described mathematically for different conditions, the result being very accurate distributions of oxygen in tissues. A first simple model of tissue oxygenation was based on the oxygen diffusion around a single blood vessel. A more complex model built from the basic physical processes and measurable parameters allowed the simulation of realistical tissues with heterogeneous vasculature. This model also allowed the modelling of the two types of hypoxia known to appear in tumours and their influence on the tumour microenvironment. The computer simulation of tissues was also used for assessing the accuracy of the polarographic technique for measuring tumour oxygenation. The results of this study have shown that it is possible to model theoretically the tissue oxygenation starting from the basic physical processes. The particular application of our theoretical simulation to the polarographic oxygen electrode has shown that this experimental method does not give the oxygen values in individual cells. Because the electrode measures the average oxygenation in a relatively large tissue volume, the resulting oxygen distributions are different from the real ones and the extreme high and low values are not detected. It has further been found that the polarographic electrode cannot make distinction between various types of hypoxia existing in tumours, the geometrical distribution of the hypoxic cells influencing mostly the accuracy of the measurement. It was also shown that because of the averaging implied by the measurement process, electrode results should not be used directly to predict the response to radiation. Thus, the differences between the predictions in clinical tumour control obtained from the real or the measured oxygenations are of the order of tens of percents in absolute value. A method to improve the accuracy of the electrode, i.e. to improve the correlation between the results of the measurements and the actual tissue oxygenation, was proposed. In conclusion, theoretical modelling has been shown to be a very powerful tool for predicting the outcome of radiotherapy and it has the advantage of describing the tumour oxygenation in the least invasive manner. Furthermore it allows the investigation of the invasiveness and the accuracy of various experimental methods.

The development of digital detectors for X-ray imaging in medical diagnostics receives an increasing amount of attention. The detector under development at the Department of Radiation Sciences at Uppsala University is a hybrid pixel detector, which consists of a semiconductor sensor mounted onto a readout chip. The readout chip is capable of performing photon counting and has an externally adjustable threshold. A simulation tool for the detector and a model applying the linear-systems transfer theory to X-ray hybrid pixel detectors have been developed. Also a characterization of the readout chip has been done. In order to estimate the potential of the detector for diagnostic radiology, we investigate the image quality using the spatial frequency dependent detective quantum efficiency (DQE). By means of the detector simulations, the influence of threshold setting, noise sources, level of exposure and charge sharing on the DQE have been studied. By means of the linear-systems theory, a single analytical expression is provided to obtain the DQE of a hybrid pixel detector. The method developed in this thesis will make it possible to optimize a detector design according to a particular medical application. It will also permit modifications and new features to be included without having to construct a full detector system.

Biological treatment optimization aim at improving radiation therapy by accounting for the radiobiological tumour and normal tissues response properties when optimizing the dose delivery. Generally traditional methods, using only dosimetrical measures, disregard the nonlinear radiation response of different tumours and normal tissues. The accumulated knowledge on tissue response to radiation, in the form of more accurate dose response relations, cell survival models and their associated biological parameters, alongside with the tools for biological treatment plan optimization, has allowed the present investigation on the potential merits of biologically based treatment optimization in radiation therapy. With a more widespread implementation of intensity modulated radiation therapy in the clinic, there is an increasing demand for faster and safer treatment delivery techniques. In this thesis biological treatment plan optimization, using the probability to achieve complication free tumour control as the quantifier for treatment outcome, was applied to radiation therapy of early breast cancer and advanced cervix cancer. It is shown that very conformal dose distributions can generally be produced with 3 or 4 optimally orientated coplanar intensity modulated beams, without having clinically significant losses in treatment outcome from the optimal dose distribution. By using exhaustive search methods, the optimal coplanar beam directions for intensity modulated photon beams for early breast cancer and the optimal non-coplanar directions for an advanced cervix cancer were investigated. Although time consuming, exhaustive search methods have the advantage of revealing most features involving interactions between a small number of beams and how this may influence the treatment outcome. Thus phase spaces may serve as a general database for selecting an almost optimal treatment configuration for similar patients. Previous knowledge acquired with physically optimized uniform beam radiation therapy may not apply when intensity modulated biological optimization is used. Thus unconventional treatment directions were sometimes found.

Medical X-ray imaging is an important tool in diagnostic radiology. The ionising-radiation dose to the patient is justified by the clinical benefit of the examination. Nonetheless, detectors that operate at even lower doses and provide more information to the radiologist are desired. A hybrid pixel detector has the potential to provide a leap in detector technology as it incorporates a more advanced signal-processing capability than currently used detectors. The DIXI digital detector is a hybrid pixel detector developed for X-ray imaging. It consists of a readout chip and a semiconductor sensor. The division in two parts makes it possible to optimise each part individually. The detector is divided into square pixels with a size of 270 x 270 μm2. DIXI has the ability to count single photons and every readout pixel has two embedded counters to allow the acquisition of two images close in time. A discriminator enables the selection of photons with energies above a preset threshold level. The readout chip Angie has been developed and its performance has been evaluated in terms of noise, threshold variation and capability to perform energy weighted counting. Silicon sensors have been fabricated, and a control system for DIXI has been designed and built. An electroless process for deposition of Ni/Au bumps on the chip and sensor has been optimised as a preparation for the assembly of a complete detector, which is being assembled by flip-chip bonding using anisotropic conductive film. A simulation library for the DIXI detector has been set up and results on the image quality are reported for different exposures and working conditions. A theoretical model for hybrid pixel detectors based on the cascaded linear system theory has been developed. The model can be used to investigate and optimise the detector for different detector configurations and operating conditions.

<p>In this thesis, a model of tissue oxygenation is presented, that takes into account the heterogeneous nature of tumor vasculature. Even though the model is rather simple, the resulting oxygen distributions agree very well with clinically observed oxygen distributions for most tumors and healthy normal tissues. The model shows that the vascular density may not describe the oxygenation of a tissue sufficiently well, unless the heterogeneity of the vascular system is taken into account. Based on the oxygen distributions from the tissue model, the associated radiation response at low and high doses can be determined. </p><p>The radiation response of heterogeneous tumors should preferably be described by two clonogen compartments, one resistant and one sensitive, dominating the response at high and low radiation doses, respectively. Furthermore, each compartment should be characterized by the effective radiation resistance and the effective clonogen number. The resistant-sensitive model of radiation response has been analyzed in great detail. It accurately describes the response of severely heterogeneous tumors, both at low and high doses and LET values. The effective response parameters are given as integrals, averaged over the whole spectrum of radiation resistance. The parameters can also be determined from clinically established dose-response relations. </p><p>The main properties of the dose-response relation for a generally heterogeneous tumor is described in some detail. The normalized dose-response gradient has been generalized to take heterogeneities in both dose delivery and radiation response into account. This quantity is important for accurate treatment plan optimization using intensity modulated radiation therapy for individual patients. </p>