Hypoxia is one of the hallmarks of cancer. It was first postulated to occur in solid tumours by Thomlinson and Gray in 1955.1 The presence of hypoxia has been demonstrated in different types of solid tumours.2 Intratumoral hypoxia is caused by the lack of functional blood vessels in proliferating tumour tissue, resulting in low intratumoral oxygen concentrations. If hypoxia is severe or prolonged, cell death occurs.3 Malignant cells can undergo genetic and adaptive changes that allow them to escape from dying of oxygen deprivation. These changes are associated with a more aggressive malignant phenotype 4,5 conferring resistance to radiation 6,7 and chemotherapeutic agents.3,8,9 Hence hypoxia is known to be a key factor responsible for tumour resistance in humans. / Invasive polarographic oxygen sensor measurements have demonstrated hypoxia in solid tumours and it is generally defined to occur at an oxygen tension less than ten mmHg.10 Perhaps of more importance is that hypoxia has been demonstrated to be a prognostic indicator for local control after treatment with radiotherapy in glioma, head and neck and cervical cancers.11-13 It has also been able to predict for survival and the presence of distant metastases in soft tissue sarcomas.14 Finally, the significance of hypoxia in the activation and induction of functional molecules such as hypoxia inducible factors (HIFs) and VEGF, the modulation of gene expression (e.g. carbonic anhydrase IX), increased proto-oncogene levels, activation of nuclear factors and accumulation of other proteins (e.g. TP53) although progressing, is yet to be defined.15,16 / Thus, it is of clinical interest to understand the levels of hypoxia and numbers of hypoxic cell populations in tumours, particularly those resistant to radiation and chemotherapy. In doing so clinicians and researchers may formulate more accurate prognostic information and develop treatments targeting hypoxic cells. Renal cell carcinoma (RCC) is a tumour resistant to radiation and chemotherapy that is yet to have its oxygen status investigated. / Although the “gold standard” of oxygen tension measurement is the Polarographic Oxygen Sensor (POS or Eppendorf pO2 histograph), non-invasive means of measuring oxygen status via imaging, immunohistochemistry or serum tumour markers are more practical. As highlighted by Menon and Fraker, it is imperative that reliable, globally usable, and technically simplistic methods be developed to yield a consistent, comprehensive, and reliable profile of tumour oxygenation. Until newer more reliable techniques are developed, existing independent techniques or appropriate combinations of techniques should be optimized and validated using known endpoints in tumour oxygenation status and/or treatment outcomes.17 / Hanahan and Weinberg 18 surmised that the field of cancer research has largely been guided by a reductionist focus on cancer cells and the genes within them- a focus that has produced an extraordinary body of knowledge. Looking forward in time, they believe that progress in cancer research would come from regarding tumours as complex tissues in which mutant cancer cells have conscripted and subverted normal cell types (endothelial cells, immune cells, fibroblasts) to serve as active collaborators in their neoplastic agenda. The interactions between the genetically altered malignant cells and these supporting coconspirators will prove critical to understanding cancer pathogenesis and to the development of novel, effective therapies.18 / Essentially, the background outlined here not only highlights the core aim of this thesis: to better understand the oxygen status of renal cell carcinoma and the relationship of this to angiogenesis so that better targeted therapies may be pursued in the future; but it also places this research in the context of the future proposed by Hanahan and Weinberg,18 by clearly focusing on collaborators in the neoplastic agenda, rather than just tumour cells themselves, to better understand RCC.

<p>Positron Emission Tomography (PET) has gained an important roll in clinical for diagnosis, staging and prognosis of a range of cancer types. Utilization of PET for monitoring and evaluation of cancer treatment is an attractive but almost new concept. The proper choice of PET-tracer as a biomarker for treatment follow-up is crucial. The important characteristic for a suitable tracer is its ability to reflect the response to a treatment at an early stage, before any morphologically changes occurs. It would be an advantage to screen a battery of PET tracers in a preclinical model and introduce a few potential tracers in clinical trial. </p><p>The most conventional pre-clinical approach in PET-oncology utilizes xenografts in mice or rats and requires a large number of subjects. It would be a great advantage to introduce a less demanding but still reliable preclinical method for a more efficient planning of studies in animal model and then in human trials. </p><p>The Multicellular Tumour Spheroid (MTS) system represents an intermediary level between cells growing as monolayer and solid tumours in experimental animals or patients. It mimics the growth of naturally occurring human tumours before neovascularization and appears to be more informative than monolayer and more economical and more ethical than animal models.</p><p>The aim of this work was to establish, refine and evaluate the application of MTS model as a preclinical approach in PET oncology. The vision was to introduce a preclinical method to probe and select PET tracer for treatment monitoring of anticancer drugs, which can hopefully be applied for optimization in breast cancer treatment.</p><p>In this thesis, a number of basic experiments were performed to explore the character of 2-[fluorine-18]-fluoro-2-deoxy-d-glucose (FDG) uptake in MTS. FDG as the most established PET tracer was an obvious initial option for the evaluation of the model. For further assess-ment, we studied effects on FDG uptake in MTS treated with five routinely used chemother-apy agents. For association of PET tracer uptake to size change of MTS, we developed a reliable and user-friendly method for size determination of MTS. The next step was to apply the MTS model to screen PET tracers for analysis of early response of chemotherapy in breast cancer. Finally the method was utilized for translational imaging exemplified with a new chemotherapy agent.</p><p>The results were encouraging and the MTS model was introduced and evaluated as a preclini-cal tool in PET oncology. The method was implicated to in vitro quickly assess a therapy profile of existing and newly developed anticancer drugs in order to investigate the effects of candidate drugs on tumour-growth, selection of appropriate PET tracer for treatment monitor-ing and finally understanding relation between growth inhibition and biomarkers as part of translational imaging activities.</p>

Positron emission tomography (PET) tracer 3-fluoro-3-deoxythymidine (FLT) is used for imaging tumor proliferation. Prior to this work, human equilibrative nucleoside transporter 1 (hENT1) was the only known human nucleoside transporter (hNT) capable of FLT transport. The aim of this research was to determine if other hNTs, including hENT2, human concentrative nucleoside transporter 1 (hCNT1), hCNT2 and hCNT3, were capable/important of/for FLT transport in mammalian cells. Transport assays performed in Xenopus laevis oocytes producing recombinant hNTs demonstrated that hENT1/2 and hCNT1/3 were capable of FLT transport. FLT uptake assays with or without hENT1 inhibitor nitrobenzylmercaptopurine ribonucleoside (NBMPR) in various cultured cancer cell lines demonstrated that hENT1 was responsible for the majority of mediated FLT uptake in all tested cell lines, suggesting that hENT1 was important for FLT uptake. The in vivo role of hENT1 in FLT uptake was determined by performing [18F]FLT PET on wild-type and ENT1 knockout mice. One hour after [18F]FLT injection, ENT1 knockout mice displayed significantly reduced [18F]FLT accumulation in the blood, heart, brain, kidney, liver, and lungs compared to wild-type mice. Interestingly, ENT1 knockout mice displayed increased [18F]FLT accumulation in the bone marrow and spleen which both have high CNT expression, suggesting that loss of ENT1 significantly alters FLT biodistribution in mice. hENT1 is a predictive marker of gemcitabine response in pancreatic cancers. Since FLT uptake and gemcitabine toxicity are dependent on hENT1, FLT uptake may predict gemcitabine response in pancreatic cancers. To test this hypothesis, six different pancreatic cancer cell lines were analyzed for FLT uptake and gemcitabine toxicity. hENT1/2 inhibition in cells decreased FLT uptake and gemcitabine sensitivity. In five of six cell lines, a positive correlation was observed between FLT uptake and gemcitabine toxicity, suggesting that FLT PET may be clinically useful for predicting gemcitabine response in pancreatic cancers. The results from this research suggest that hNTs, especially hENT1, are important for FLT uptake in mammalian cells and that FLT uptake can predict gemcitabine response in most cultured pancreatic cancer cells. The results warrant FLT PET clinical trials in pancreatic cancer patients to determine the potential of FLT PET in predicting gemcitabine response.

Positron Emission Tomography (PET) has gained an important roll in clinical for diagnosis, staging and prognosis of a range of cancer types. Utilization of PET for monitoring and evaluation of cancer treatment is an attractive but almost new concept. The proper choice of PET-tracer as a biomarker for treatment follow-up is crucial. The important characteristic for a suitable tracer is its ability to reflect the response to a treatment at an early stage, before any morphologically changes occurs. It would be an advantage to screen a battery of PET tracers in a preclinical model and introduce a few potential tracers in clinical trial. The most conventional pre-clinical approach in PET-oncology utilizes xenografts in mice or rats and requires a large number of subjects. It would be a great advantage to introduce a less demanding but still reliable preclinical method for a more efficient planning of studies in animal model and then in human trials. The Multicellular Tumour Spheroid (MTS) system represents an intermediary level between cells growing as monolayer and solid tumours in experimental animals or patients. It mimics the growth of naturally occurring human tumours before neovascularization and appears to be more informative than monolayer and more economical and more ethical than animal models. The aim of this work was to establish, refine and evaluate the application of MTS model as a preclinical approach in PET oncology. The vision was to introduce a preclinical method to probe and select PET tracer for treatment monitoring of anticancer drugs, which can hopefully be applied for optimization in breast cancer treatment. In this thesis, a number of basic experiments were performed to explore the character of 2-[fluorine-18]-fluoro-2-deoxy-d-glucose (FDG) uptake in MTS. FDG as the most established PET tracer was an obvious initial option for the evaluation of the model. For further assess-ment, we studied effects on FDG uptake in MTS treated with five routinely used chemother-apy agents. For association of PET tracer uptake to size change of MTS, we developed a reliable and user-friendly method for size determination of MTS. The next step was to apply the MTS model to screen PET tracers for analysis of early response of chemotherapy in breast cancer. Finally the method was utilized for translational imaging exemplified with a new chemotherapy agent. The results were encouraging and the MTS model was introduced and evaluated as a preclini-cal tool in PET oncology. The method was implicated to in vitro quickly assess a therapy profile of existing and newly developed anticancer drugs in order to investigate the effects of candidate drugs on tumour-growth, selection of appropriate PET tracer for treatment monitor-ing and finally understanding relation between growth inhibition and biomarkers as part of translational imaging activities.

Because the information advance in technology, the social welfare gradually increase, creates the government expenditure to increase, the finance is difficult. In 2000, the government had announced private participation public construction law, positively impelling the private organization participation public construction, and used the resources, the technology, the efficiency to lighten the government serious financial burden, and created the vigorous folk commercial vitality. The high tech health center is medical industry extending, and is one kind of important tool to impel the preventive medicine. Although it has used the massive medicine theory and the technology, it has not involved the treatment behavior and the medicine prescription. However, it still located in the medical scope, must controlled by the government health organization. At present, the health center has two kinds of managements, one is attached in the hospital, and the other picks the independent form. This case belongs to former. The rehabilitation, operation and transfer on the positron emission tomography center of Kaohsiung Veterans General Hospital bases on the law of private participation public construction. The rehabilitation and operation periods amounts to 11 years. Kaohsiung Veterans General Hospital should suggest that specialized organization or by itself to handle the feasibility and earlier scheme before R.O.T. proposals. If the earlier scheme checks to pass, Veterans General Hospital has to proceed following system of preposition and commercial attraction. Bases on the market analysis, we find that five hospitals have been established positron emission tomography equipment in the area of Kaohsiung and Pingtung. At present, the market supplies increase much, and potential market demands develop slowly. Under these factors disturbance about global budget payment system or hospital excellent project, it inevitably will have the influence on the investment will of industry. Moreover, the condition of industrial and marketable environment, like the supply source of positron medicine FDG, the degree of market development, the medical standard of teams, will be the essential topics. From financial assessment, we find that the private organization participates in the business of the positron emission tomography center of Kaohsiung Veterans General Hospital by the R.O.T. form, Kaohsiung Veterans General Hospital could gain considerable premium, the management efficiency, the higher reputation, and provide the precise health examines. The franchised corporation also could gain required return. The bank financing gets safety. Therefore, the contract about the private participation in the positron emission tomography center of Kaohsiung Veterans General Hospital resembles reasonable. By the sensitivity analysis, we find that the key factors in turn as follows: Revenue, operating cost, operating expenses, initial investment, and financing interest rate. Revenue at their own expense affects this case much higher than customers. Health insurance revenue is regulated by the global budget payment system, we find that pay point is more sensitive than pay value per point, and the franchised corporation must spend more resources to develop the market about non-insurance revenue. The R.O.T. on the positron emission tomography center of Kaohsiung Veterans General Hospital belongs to successful case, its main points including: First, we can use R.O.T. business model to break these constraint of laws and regulations, effectively promote the management elasticity and the overall achievements. Second, the party of the public in the plan and operating stage assigns professionals and continues to participate in the coordination and the management, which is helpful to the project implemented. Third, with the lower premium threshold and the higher surveillance standard, this is helpful to the quality control. Finally, by financial assessment, we can control risk management in advance.

At the Gesellschaft für Schwerionenforschung in Darmstadt a therapy unit for heavy ion cancer treatment has been established in collaboration with the Deutsches Krebsforschungszentrum Heidelberg, the Radiologische Universitätsklinik Heidelberg and the Forschungszentrum Rossendorf. For quality assurance the dual-head positron camera BASTEI (Beta Activity meaSurements at the Therapy with Energetic Ions) has been integrated into this facility. It measures ß+-activity distributions generated via nuclear fragmentation reactions within the target volume. BASTEI has about 4 million coincidence channels. The emission data are acquired in a 3D regime and stored in a list mode data format. Typically counting statstics is two to three orders of magnitude lower than those of typical PET-scans in nuclear medicine. Two iterative 3D reconstruction algorithms based on ISRA (Image Space Reconstruction Algorithm) and MLEM (Maximum Likelihood Expectation Maximization), respectively, have been adapted to this imaging geometry. The major advantage of the developed approaches are run-time Monte-Carlo simulations which are used to calculate the transition matrix. The influences of detector sensitivity variations, randoms, activity from outside of the field of view and attenuation are corrected for the individual coincidence channels. Performance studies show, that the implementation based on MLEM is the algorithm of merit. Since 1997 it has been applied sucessfully to patient data. The localization of distal and lateral gradients of the ß+-activity distribution is guaranteed in the longitudinal sections. Out of the longitudinal sections the lateral gradients of the ß+-activity distribution should be interpreted using a priori knowledge.

The criteria for diagnosing Alzheimer’s disease (AD) have recently been revised to include the use of biomarkers for the in vivo presence of β-amyloid, one of the neuropathological hallmarks of AD. Examples of such biomarkers are positron emission tomography (PET) β-amyloid specific ligands, including [18F]flutemetamol. The aim of this thesis was to characterize the binding properties of [18F]flutemetamol from a tracer kinetic perspective as well as by validating binding measures through comparison with tissue pathology assessments. The applicability of previously developed kinetic models of tracer binding for voxel-based analysis was examined and compared to arterial input compartment modelling, the “gold standard” for PET quantification. Several voxel-based methods were found to exhibit high correlations with compartment modelling, including the semi-quantitative standardized uptake value ratio (SUVR). The kinetic components of [18F]flutemetamol uptake were also investigated without model assumptions using the data driven method spectral analysis, with binding to β-amyloid shown to relate to a slow kinetic component. The same component was also found to predominate in the uptake of white matter, known to be free of β-amyloid accumulation. White matter uptake was however possible to separate from β-amyloid binding based on the relative contribution of the slow component to the total volume of distribution. Uptake of [18F]flutemetamol as quantified using SUVR or assessed visually was found to correlate well with tissue pathology assessments. Classifying the brains of 68 deceased subjects who had undergone [18F]flutemetamol PET scanning ante mortem, based on the spatial distribution of β-amyloid according to pre-defined phases, revealed that abnormal uptake patterns of [18F]flutemetamol were only certain to be found in the last phase of β-amyloid accumulation. In the same cohort however, [18F]flutemetamol was also shown to accurately distinguish between subjects with AD and non-AD dementia. While this supports the use of [18F]flutemetamol in clinical settings for ruling out AD, the association of abnormal [18F]flutemetamol uptake to late phases of β-amyloid accumulation may limit the detection of early accumulation and pre-clinical stages of AD. It remains to be investigated whether application of voxel-based methods and slow component filtering may increase sensitivity, particularly in the context of clinical trials.

In 3D positron emission tomography the scatter effect is a significant physical factor degrading image quality. The advancements in computing that occurred the last decades al lowed us to simulate the scatter coincidences fast and ef ficiently. The main concern now is how accurately do we simulate the scatter events. The scope of this project is the implementation and the evaluation of a scatter simulation algorithm that would be able to simulate the scat ter ef fect more precisely than the existing ones. One way to simulate the scatter distribut ion is with an algorithm, first published by Watson and Ollinger, that is based on the Klein-Nishina formula. These methods have been implemented taking into account only the single scatter events (where a photon scatters once in the at tenuation medium). Multiple scatter is generally taken into account by some scaling or filtering procedure. Their main advantages are short computational time and relatively good precision compared to previous more heuristical methods. Although these single scatter algorithms have been effective there are cases where their results are not that accurate. For low energy thresholds and large at tenuation mediums multiple scatter is increased. Given that a significant percentage of people are over -weight (thus the at tenuation medium has large volume) we should consider introducing multiple scatter events in our simulations. Moreover, the distribut ion of all scatter events is broader than the one of single scatter events therefore even if the single scatter distribution is scaled it will not match the total scatter one. In previous work by C. Tsoumpas et al, a new scatter simulation algorithm was developed that attempts to approximate the total scatter distribution by taking into account the case where the one annihilated photon is scattered twice and the case where both annihilated photons are scattered once. These two cases describe the double scatter events and by introducing them into our scatter simulation algorithm we aim to obtain a better approximation of the total scatter distribution. In this thesis we have improved this double scatter simulation algorithm in two important ways. When both annihilated photons scatter they acquire a favourable polarization direction with respect to each other and this influences thei r detect ion probabilities, especially when low energy photons are detected. In the algorithm that we implemented we considered this effect by using the polarized Klein-Nishina formula for this case. In addition, we investigated and validated the need to introduce extra solid angle factors in the implementation. The whole implementation is based on the STIR library (Software for Tomographic Image Reconstruction) written in the C++ programming language. Scatter events can also be simulated by Monte Carlo simulation packages such as SimSET. SimSET is a public domain package designed to simulate positron emission tomography (PET) (and Single Photon Emission Tomography) and was used extensively in this project. Monte Carlo packages because of their ability to exclude any unknown physical parameter they can simulate physical processes like the ones that take place in PET very accurately. Thus they were essential for the evaluation of our scatter correction algorithm. The reason why Monte Carlo packages are not used inclinical practice instead of the model-based methods is that they demand a large computational time. Besides Monte Carlo packages we also per formed a series of experimental scans in order to evaluate our scatter simulation algorithm. The tomograph used for the experiments was the ECAT 962 used in a 3D mode. / -

Objective: To characterize the association between longitudinal changes in fasting serum glucose and changes in flourodeoxyglucose Positron Emission Tomography (FDG PET) measurements of regional cerebral metabolic rate for glucose (rCMRgl) in brain regions preferentially affected by Alzheimer's disease (AD). A secondary objective was to investigate whether higher fasting serum glucose levels are associated with lower rCMRgl in younger adults within these same AD relevant brain areas. Methods: For the primary study, baseline, interim, and 4.4 ± 1.0-year follow-up fasting serum glucose and PET CMRgl were analyzed in 80 cognitively unimpaired, non-diabetic, 61.5 ± 5 year-old persons with a first-degree family history of AD, including 38 carriers and 42 non-carriers of the apolipoprotein E (APOE) ε 4 allele. An automated brain-mapping algorithm was used to characterize associations between changes in fasting serum glucose levels and changes in rCMRgl. Longitudinal changes in fasting serum glucose levels and their correlation with changes in six pre-selected neuropsychological test measures of memory, attention and processing speed were also assessed with linear regression. The secondary study included a cross sectional sample of 31 cognitively unimpaired, non-diabetic participants, 31.2 ±5.4 years of age. General linear model-based voxel-wise analyses were performed to examine the correlation between fasting serum glucose and rCMRgl. Results: In the primary study of older adults, average fasting serum glucose levels increased over longitudinal measurement, and changes in these levels were inversely associated with longitudinal CMRgl changes in the vicinity of brain regions preferentially affected by AD (p<0.05, corrected for multiple comparisons). Fasting serum glucose was also inversely associated with performance on a measure of visuospatial memory (p<0.05, corrected for multiple comparisons). In the younger sample, fasting serum glucose levels were inversely associated with rCMRgl in left frontal pole and right primary visual cortex regions (p<.05, corrected for multiple comparisons).Conclusions: In older adults, fasting serum glucose increases across time and is inversely related to rCMRgl in AD relevant regions and to visual memory test scores. This relationship between serum glucose and regional brain metabolism may begin in metabolically sensitive areas at a younger age.

The prospects for enhanced Positron Emission Tomography imaging using liquid xenon (LXe) gamma ray detectors had been examined. Monte-Carlo simulations using GEANT4 were performed and the results were used to study the expected performance of a small animal PET scanner in comparison with a simulated conventional small animal scanner (LSO Focus 120). A NEMA-like cylinder phantom and an image contrast phantom were simulated with both scanners to compare performance characteristics. A Compton reconstruction algorithm was developed for the LXe scanner, and its performance and limitations studied.