Conventional cancer treatment based on radiotherapy or chemotherapy affects all dividing cells. By directing the therapy specifically to the tumor cells, normal cells can be spared. Tumor targeting molecules carrying a cytotoxic moiety is then an attractive approach. In this thesis, an affibody molecule with high affinity for the protein HER-2, that is strongly associated with aggressive forms of breast cancer, was selected. After radiolabeling with 125I, the affibody molecule, in monovalent and bivalent form, was tested in vitro in HER-2 overexpressing tumor cells and in transplanted tumors in mice. It was shown that the HER-2 targeting affibody molecule bound its target in a specific manner, both in vitro and in vivo. The small size of the affibody molecule resulted in fast clearance through the kidneys. An impressive tumor-to-blood ratio of 10 eight hours post injection was achieved and the tumors could easily be visualized in a gamma camera. The biologic effects of the bivalent affibody molecule and a monovalent affinity maturated version was measured and compared with the effects of the monoclonal antibody trastuzumab. It was found that although all molecules target the same protein, the effects differed greatly. The affibody molecule was also labeled with the alpha-emitting radionuclide 211At. Specific decrease in survival was seen in HER-2 overexpressing cells receiving the 211At labeled affibody molecule. The sensitivity to the treatment differed between cell lines, probably as a result of differences between the cell lines in internalization and nuclear size. The 211At labeled affibody molecules were also tested in vivo, where stability of the 211At label was a problem. To circumvent this problem, more stable conjugation chemistry was tested, as well as strategies to prevent uptake of released 211At by normal organs. This thesis describes the selection and optimization of affibody molecules for medical use for the first time.

Aim: The overall aim of this thesis was to acquire knowledge about daily life with focus on eating problems during the trajectory of care for patients with head and neck cancer treated with radiotherapy. Method: The data in study I were gained from medical and nursing records of 50 patients. Documented parameters of eating problems, their causes and consequences, and undertaken interventions were collected before treatment, during radiotherapy, and one, six, and twelve months after completion of treatment, using a study-specific audit instrument. Data were analysed with descriptive and inferential non-parametric statistics. In study II eight patients were interviewed during the radiotherapy treatment period with focus on experiences of eating problems. In study III nine patients were interviewed six to twelve weeks after treatment with the focus on experiences of daily life during the trajectory of care having eating problems. In study IV twelve patients were interviewed about their conceptions of the significance of a supportive nursing care clinic during the whole trajectory of care. Data were analysed with interpretative phenomenology (II, III) and phenomenography (IV). Findings: The four studies showed that being a patient in the trajectory of care often meant that life was disturbed and threatened. This was partly due to the eating problems and their consequences, which could occur during the whole trajectory of care (I, III, IV) but was experienced as most intense and severe during radiotherapy (II) and the nearest weeks after completion of radiotherapy (III, IV). The disturbances and threats experienced due to eating problems could affect the whole person as they were physical (I-IV), psychological, social and existential (II, III). The experiences of eating problems due to the tumour and its treatment and the experience of having cancer per se were strongly connected as one phenomenon, which disturbed and threatened the informants’ daily life. The other part that disturbed the patients’ life was the waiting in suspense. A long and trying waiting in uncertainty was experienced due to lack of knowledge and support, practical as well as emotional. This was most pronounced during pauses in radiotherapy (III) and after completion of the treatment when the lack of support from the health care was obvious (I, II, III). The patients were then most often left to their own devices. In order to endure, they needed both inner strength, described as own coping strategies, and strength from outside, described as support from family, friends and health care professionals (II, III). The nurse clinic was found to give a hand to hold during the whole trajectory of care (IV). It could meet these patients’ needs of knowledge, care and support, both concerning practical measures related to the eating problems and other side-effects of the treatment, and concerning their emotional needs. In addition the nurse clinic could support the relatives in their worries and anxiety (IV). Conclusion: This thesis showed the necessity of continuous assessment, treatment and evaluation of patients’ problems, and the patients’ needs of information and support throughout the trajectory of care.

At the University Hospital of Umeå, NUS, a new radiation treatment department is being built. The purpose of this master thesis is to evaluate the actual radiation protection outside three out of five treatment rooms in the building, including two Varian and one Siemens accelerator, and to verify that the radiation limits for the staff and the general public, stated by the Swedish Radiation Safety Authority, are obeyed. The evaluation of the radiation protection shielding is made through measurements. The nominal photon beam energies 6 and 15 MV (dose rates up to 500 MU/min) can be used, which means that both photons and neutrons will contribute to the effective dose. For the photon measurements, two different GM counters have been used and for the neutron measurements a Neutron detector with a polyethylene moderator and a 3He recoil proton counter tube was applied. The thesis also includes a literature study of the photon and neutron energy spectra outside the treatment rooms in order to check that the measurement equipments are suitable to use. The measured doses of the radiation shielding are below the radiation limits per week and year but the measurements indicate too high values per hour, i.e. momentary dose rate, at the height of isocenter of the primary walls and at the gap under the door for all three accelerators. The rooms with the Varian accelerators also show too high values per hour at the secondary wall where the door is attached. However, the limiting value per hour is only a recommendation and no extra reinforcement in therefore required. Nevertheless, one should avoid placing a workplace, for example a writing desk, close to the secondary and primary walls.

The energy dependent response of silicon diodes in photon beams is a known problem. A new approach to solve this problem is by correcting the response, a response model was suggested by Yin et al. (2002, 2004), and later refined by Eklund and Ahnesjö (2009). In this work a prototype software was developed to calculate correction factors for arbitrary measurement points in MLC shaped fields using fluence pencil beam kernels to calculate the spectra used by the model of Eklund and Ahnesjö (2009). This work investigate this approach for large field sizes. It was found that the relative dose measurements of the corrected unshielded diode agreed with ionization chamber measurements within 1% at the central axis. Measurements made off axis (square and irregular fields) agreed within 2%, better results were achieved within the fields when the off axis beam softening were taken into consideration. This work has also shown that this new approach is an alternitive to shielded diodes and that corrected diodes will in some cases provide more reliable results.

In this project several tests were performed to evaluate the performance of an On-Board Imager® (OBI) mounted on a clinical linear accelerator. The measurements were divided into three parts; geometric accuracy, image registration and couch shift accuracy, and image quality. A cube phantom containing a radiation opaque marker was used to study the agreement with treatment isocenter for both kV-images and cone-beam CT (CBCT) images. The long term stability was investigated by acquiring frontal and lateral kV images twice a week over a 3 month period. Stability in vertical and longitudinal robotic arm motion as well as the stability of the center-of-rotation was evaluated. Further, the agreement of kV image and CBCT center with MV image center was examined. A marker seed phantom was used to evaluate and compare the three applications in image registration; 2D/2D, 2D/3D and 3D/3D. Image registration using kV-kV image sets were compared with MV MV and MV-kV image sets. Further, the accuracy in 2D/2D matches with images acquired at non-orthogonal gantry angles was evaluated. The image quality in CBCT images was evaluated using a Catphan® phantom. Hounsfield unit (HU) uniformity and linearity was compared with planning CT. HU accuracy is crucial for dose verification using CBCT data. The geometric measurements showed good long term stability and accurate position reproducibility after robotic arm motions. A systematic error of about 1 mm in lateral direction of the kV-image center was detected. A small difference between kV and CBCT center was observed and related to a lateral kV detector offset. The vector disagreement between kV- and MV-image centers was  2 mm at some gantry angles. Image registration with the different match applications worked sufficiently. 2D/3D match was seen to correct more accurately than 2D/2D match for large translational and rotational shifts. CBCT images acquired with full-fan mode showed good HU uniformity but half fan images were less uniform. In the soft tissue region the HU agreement with planning CT was reasonable while a larger disagreement was observed at higher densities. This work shows that the OBI is robust and stable in its performance. With regular QC and calibrations the geometric precision of the OBI can be maintained within 1 mm of treatment isocenter.

X-ray fluorescence is a well-understood phenomenon in which irradiation of certain materials, such as gold, with x-rays causes the emission of secondary x-rays with characteristic energies. By performing computed tomography using these fluorescence x-rays, the material of interest can be imaged inside an object. Our research group has already demonstrated that x-ray fluorescence computed tomography (XFCT) imaging using a typical 110 kVp microfocus x-ray tube is feasible for a small animal-sized object containing a distribution of a solution of low concentration gold nanoparticles. The primary goal of this thesis work was to study the effect of source x-ray energy spectra on gold fluorescence detection using the XFCT system. A computational approach using the Monte Carlo method was used. First, a computational model was created using the Monte Carlo N-Particle (MCNP) transport code based on the experimental setup of the pre-existing XFCT system. Simulations were run to verify the validity of the MCNP model as an accurate representation of the actual system by means of comparison with experimentally-obtained data. Finally, the model was used for further purely computational work. In the MCNP model, the source spectrum was changed to reflect several theoretical and experimentally obtained options. The effect of these changes on gold fluorescence production was documented and quantified using the signal-to-background ratio and other qualitative measures. The results from this work provided clues on how to improve the detection of fluorescence photons from gold nanoparticle-loaded objects using the XFCT system. This will benefit future research on the development of the XFCT system in the context of making it more feasible for gold nanoparticle-based preclinical molecular imaging applications.

AB S TRACT purpose : To further investigate the effects of respiratory motions on CBCT imaging, as well as 4D-CT examinations, with a future goal of using obtained results to implement new methods for individual margins and daily matching procedures into routine clinical practice. background : Since the implementation of CBCT combined with modern accelerators, a higher degree of accuracy has been made possible in RT. However, due to the slow gantry speed of linear accelerators, the imaging procedure of CBCT is a slow process which is thereby degraded by internal motion such as respiration. material and methods : Attain patient specific respiratory motion patterns from CBCT projection data of previous examinations. Utilize this data to perform simulations for both CBCT and 4D-CT using a steering system which allows for arbitrary motion patterns in the longitudinal direction. results : Various imaging with CBCT showed that the resulting images during respiratory motion, can be described by the Probability Density Function of the motion for as long as it does not cause related distortions. This also meant that convolution could be implemented as a model to estimate the CBCT images during oscillation, knowing the object and motion pattern. The 4D-CT examinations using the steering system showed that irregular motion patterns were less accurately described than regular patterns, making the actual motion an important feature to combine together with the measured amplitude. conclusions : It was made clear that CBCT images can be described by the PDF, and thus can be seen as a Color Intensity Projection of the object position. Also it has been shown that the projection data of CBCT images contains valuable information about the respiratory motion of the patient. Another conclusion is that with the help of fiducials, the position of the target within the respiratory cycle can be determined relative to the 4D-CT examination, enabling further input data as to the daily matching procedure, proper applied margins as well as dose to the OAR.

In dieser Arbeit wird die Bildgebung durch eine Compton-Kamera zur Überwachung der Partikelstrahlentherapie erstmals an der Technischen Universität Dresden untersucht. Die inhärenten Beschränkungen der Methode wurden durch Berechnungen und Monte Carlo Simulationen studiert. Im Zuge dieser Untersuchungen erschien der Raumtemperatur-Halbleiter Cadmium Zink Tellurid als ein vielversprechendes Detektor-Material. Zur weiteren Untersuchung wurde eine einfache Compton-Kamera konstruiert bestehend aus einem Cadmium Zink Tellurid Detektor und einem ortsempfndlichen Szintillationsdetektor. Das System hat gezeigt, dass eine akkurate Bildgebung mit radioaktiven Punktquellen unter Laborbedingungen möglich ist. Weitere praktische Beschränkungen der Compton-Bildgebung unter Strahlbedingungen konnten durch Experimente an einem Protonen-Strahl hergeleitet werden. Durch die experimentellen Erfahrungen mit der in dieser Arbeit entwickelten Compton-Kamera konnten wertvolle Informationen gesammelt werden, die erlauben, die Bildrekonstruktion zu evaluieren und dazu beitragen, die weitere Forschung hin zu einer klinisch anwendbaren Compton-Kamera zu leiten. / This work presents the first efforts at the Dresden University of Technology to study the feasibility of Compton imaging as a modality to monitor ion beam radiation therapy. The inherent limitations of the method have been studied by means of calculation and Monte Carlo simulation. As a result, the room-temperature semiconductor cadmium zinc telluride appeared as a promising detector material for a clinical device. For more detailed investigation, a simple Compton camera has been constructed comprising a cadmium zinc telluride detector and a position sensitive scintillation detector. This system has proven that accurate imaging of radioactive point sources in the laboratory is feasible. More practical restrictions of Compton imaging in beam conditions have been derived through experiments at a proton facility. Through the experimental work with the Compton camera developed in this work, valuable information was gathered which allowed to test the image reconstruction and to direct the further research towards a clinical Compton camera system.

Glioblastoma multiforme (GBM) is the most aggressive and most common primary brain tumor in adults accounting for 50-60% of primary brain tumors. The prognosis for patients with GBM remains poor and treatment is mainly palliative with a mean survival time of less than one year. Radiotherapy is used extensively in the management of glioblastoma either alone or in combination with surgery and/or chemotherapy. However, this tumor is one of the most resistant tumors to radiotherapy thus limiting the benefit of this form of treatment. <p>Studies have shown that malignant tumors have a high content of glutathione an antioxidant responsible for protecting the cells against damage from free radicals (mainly superoxide, hydroxyl and hydrogen peroxide). It is well established that glutathione, by neutralizing these free radicals plays a major role in radioresistance. Glioblastoma has relatively high levels of glutathione. In this study, by reducing the glutathione content of glioblastoma in a rat model, we were able to investigate the effect of this reduction in enhancing the effect of radiotherapy as a form of treatment for glioblastoma multiforme in a rat model. <p>By injecting L-Buthionine-SR-Sulfoximine (BSO) in to the tumor tissue, the glutathione content of the tumor was reduced by about 70% of its initial value. When administered into the tumors 2 hours prior to radiotherapy the animals so treated had a significantly longer median survival time compared with animals that received radiotherapy alone.

Cervix cancer affects women of all ages and causes significant morbidity and mortality. Locally advanced disease is curable with radiotherapy (RT) in about 50% of patients, although often at the expense of serious side effects. In order to improve the therapeutic ratio of tumour control versus normal tissue toxicity, conformal intensity-modulated radiotherapy (IMRT) is being investigated. However, inter- and intra-fractional motion of cervix cancer can contribute to both geographical miss of the target and overdosing of surrounding normal tissues, particularly in the setting of conformal IMRT with steep dose gradients. Defining the target volume accurately and understanding the dose consequence of these complex intra-pelvic organ dynamics during external beam radiotherapy forms the essential foundations for future treatment optimization and adaptation. This in turn will lead to improvements in tumour control and disease-free survival while minimising treatment toxicity.