Cancer is one of the major causes of worldwide mortality. Imaging plays a vital role in the staging, follow-up, and evaluation of therapeutic response in cancer patients. Whole-body (WB) magnetic resonance imaging (MRI), as a non-ionizing imaging technique, is a promising procedure to assess tumor spreading in a single examination. New MRI technological developments now enable the application of diffusion-weighted imaging (DWI) of the entire body. DWI reflects the random motion of water molecules and provides functional information of body tissues. DWI can be quantified with the use of the apparent diffusion coefficient (ADC). The aim of this dissertation was to demonstrate the value of WB MRI including DWI in cancer patients. WB MRI including DWI, 18F-NaF PET/CT, and bone scintigraphy was performed on 49 patients with newly diagnosed, high-risk prostate cancer, for the purpose of detecting bone metastases. WB DWI showed higher specificity, but lower sensitivity compared to 18F-NaF PET/CT. In addition, WB MRI including DWI, and CT of the chest and abdomen was performed in 23 patients with malignant melanoma. We concluded that WB MRI could not completely supplant CT for the staging of malignant melanoma, especially with respect to the detection of lesions in the chest region. In this study, WB MRI and DWI were able to detect more bone lesions compared to CT, and showed several lesions outside the CT field of view, reinforcing the advantage of whole-body examination. WB MRI, including DWI, was performed in 71 patients with testicular cancer. This modality demonstrated its feasibility for use in the follow-up of such patients. WB MRI, including DWI, and 18F-FDG PET-CT, were carried out in 50 patients with malignant lymphoma. Both these imaging modalities proved to be promising approaches for predicting clinical outcomes and discriminating between different subtypes of lymphomas. In conclusion, WB MRI, including DWI, is an evolving technique that is continuing to undergo technical refinement. Standardization of image acquisition and analysis will be invaluable, allowing for more accurate comparison between studies, and widespread application of this technique in clinical practice. Both WB MRI, including DWI and PET/CT, have their particular strengths and weaknesses in the evaluation of metastatic disease. DWI and PET/CT are different functional techniques, so that combinations of these techniques may provide complementary and more comprehensive information of tumor tissue.

Résumé : En imagerie médicale, il est courant d’associer plusieurs modalités afin de tirer profit des renseignements complémentaires qu’elles fournissent. Par exemple, la tomographie d’émission par positrons (TEP) peut être combinée à l’imagerie par résonance magnétique (IRM) pour obtenir à la fois des renseignements sur les processus biologiques et sur l’anatomie du sujet. Le but de ce projet est d’explorer les synergies entre l’IRM et la TEP dans le cadre d’analyses pharmacocinétiques. Plus spécifiquement, d’exploiter la haute résolution spatiale et les renseignements sur la perfusion et la perméabilité vasculaire fournis par l’IRM dynamique avec agent de contraste afin de mieux évaluer ces mêmes paramètres pour un radiotraceur TEP injecté peu de temps après. L’évaluation précise des paramètres de perfusion du radiotraceur devrait permettre de mieux quantifier le métabolisme et de distinguer l’accumulation spécifique et non spécifique. Les travaux ont porté sur deux radiotraceurs de TEP (18F-fluorodésoxyglucose [FDG] et 18F-fluoroéthyle-tyrosine [FET]) ainsi que sur un agent de contraste d’IRM (acide gadopentétique [Gd DTPA]) dans un modèle de glioblastome chez le rat. Les images ont été acquises séquentiellement, en IRM, puis en TEP, et des prélèvements sanguins ont été effectués afin d’obtenir une fonction d’entrée artérielle (AIF) pour chaque molécule. Par la suite, les images obtenues avec chaque modalité ont été recalées et l’analyse pharmacocinétique a été effectuée par régions d’intérêt (ROI) et par voxel. Pour le FDG, un modèle irréversible à 3 compartiments (2 tissus) a été utilisé conformément à la littérature. Pour la FET, il a été déterminé qu’un modèle irréversible à 2 tissus pouvait être appliqué au cerveau et à la tumeur, alors qu’un modèle réversible à 2 tissus convenait aux muscles. La possibilité d’effectuer une conversion d’AIF (sanguine ou dérivée de l’image) entre le Gd DTPA et la FET, ou vice versa, a aussi été étudiée et s’est avérée faisable dans le cas des AIF sanguines obtenues à partir de l’artère caudale, comme c’est le cas pour le FDG. Finalement, l’analyse pharmacocinétique combinée IRM et TEP a relevé un lien entre la perfusion du Gd-DTPA et du FDG, ou de la FET, pour les muscles, mais elle a démontré des disparités importantes dans la tumeur. Ces résultats soulignent la complexité du microenvironnement tumoral (p. ex. coexistence de divers modes de transport pour une même molécule) et les nombreux défis rencontrées lors de sa caractérisation chez le petit animal. / Abstract : In medical imaging, different modalities are frequently combined in order to obtain complementary information. For example, positron emission tomography (PET) can be associated with magnetic resonance imaging (MRI) to derive both anatomical and biological information. This project explores the synergies between MRI and PET for pharmacokinetic modeling. Specifically, it exploits the high spatial resolution of MRI as well as the information about perfusion and vascular permeability derived from dynamic contrast-enhanced studies to better assess these parameters in a PET radiotracer injected shortly after the MRI examination. This more precise assessment of perfusion is thought to improve metabolism quantification for the radiotracer and to discriminate between its specific and non-specific accumulation. The present work focussed on 2 PET radiotracers, (18F-fluorodeoxyglucose [FDG] and 18F-fluoroethyltyrosine [FET]) as well as a MRI contrast agent (gadopentetic acid [Gd-DTPA]) applied to a rat glioblastoma model. Images were acquired using a sequential MRI-PET protocol and blood was drawn to derive the arterial input function (AIF) for each molecule. PET and MR images were subsequently registered and pharmacokinetic modeling was performed on regions of interest (ROI) or voxel-wise. For FDG, an irreversible 3 compartments (2-tissue) model was used in accordance to the literature. For FET, it was determined that an irreversible 2-tissue model is applicable for the brain and the tumor and a reversible 2-tissue model is preferred for the muscles. AIF (blood or image-derived) conversion between Gd-DTPA and FET, or vice versa, was also considered and proved feasible for the blood AIF derived from the caudal artery, similar to FDG. Finally, combined kinetic modeling for MRI and PET showed a relationship between the perfusion of FDG, or FET, and that of Gd-DTPA in muscle. Important disparities were noted for the tumor. These results illustrate the complexity of the tumor microenvironment (e.g. presence of various transport mechanisms for the same molecule) and the numerous challenges encountered during its characterization in small animals.

Positron emission tomography/computed tomography (PET/CT) is a method that quantitatively visualizes physiological processes. The most common indications for PET brain are early diagnosis of various dementia types with 18F-Fludeoxyglucose (18F-FDG). The hospital in Jonkoping installed a new PET/CT and brain examinations have not yet been performed. The aim of the study was to map how hospitals in Sweden performed seven selected brain examinations with PET/CT focusing on modality structure, examination method and reconstruction method, with a comparison of radiation dose between PET/CT and single photon emission computed tomography/CT (SPECT)/CT. Out of the nine university hospitals selected, two were excluded. The method was prospective with quantitative approach and data was collected through a protocol. Compilation was made on Excel and the statistics were processed using the Wilcoxon Signed Ranks Test. The result showed similarities, for example reconstruction method and differences, for example fasting time. Effective dose was higher on SPECT than PET in examination of Parkinson's disease, however no significant difference (p = 0,059) was detected. Higher effective doses on SPECT was due to longer half-lives and greater dosages of Ioflupane (123I-Datscan) than 18F-FDG. For further studies, more hospitals and parameters in the protocol can be included.

Pacientes com linfoma de Hodgkin (LH) tratados com poliquimioterpia com adriamicina, bleomicina, vincristina e doxorrubicina (ABVD) apresentam resposta terapêutica distinta. Para aprimorar a avaliação prognóstica e a abordagem terapêutica em LH objetivamos avaliar o valor prognóstico da PET-FDG após 2 ciclos de ABVD (PET2) em pacientes com LH. Foram incluídos nesse estudo prospectivo 115 pacientes com diagnóstico recente de LH no período de agosto de 2005 a dezembro de 2007. Os pacientes foram estadiados com exame clínico, laboratorial, tomografia computadorizada e PET-FDG (PET0). Todos os pacientes foram tratados com ABVD e aqueles com massa tumoral extensa foram tratados com radioterapia associada. Após dois ciclos de ABVD os pacientes foram submetidos a PET2. Nenhum tratamento foi alterado baseado na PET2. Foi avaliado o valor prognóstico dos fatores clínicos, Índice Prognóstico Internacional (IPI) e PET2 em relação à sobrevida livre de eventos (SLE) em três anos. Dos 104 pacientes que foram avaliados, 82 atingiram remissão completa e 22 pacientes apresentaram falha de tratamento durante a mediana de 36 meses de acompanhamento. A SG e SLE em três anos foi de 94,2% e 74,2% respectivamente. A SLE em três anos da PET2 positiva foi de 54,3%, enquanto da PET2 negativa foi de 90,5% (p< 0.001). Na análise de subgrupos de pacientes com estádio precoce, avançado, IPI baixo e alto risco, a PET2 também apresentou correlação estatisticamente significativa com o prognóstico. Concluímos que a PET2 é o melhor fator prognóstico independente na avaliação de pacientes com LH / Patients with Hodgkin lymphoma (HL) treated with poliquimioteraphy with adriamycin, bleomycin, vincristine and doxorubicin (ABVD) have distinct therapeutic response. In order to improve the prognostic assessment and therapeutic approach in HL we have evaluated the prognostic value of FDG-PET after 2 cycles of ABVD (PET2). Were included in this prospective study 115 patients with newly diagnosed LH in the period of August 2005 to December 2007. The patients were staged with physical examination, laboratory, CT and PET-FDG (PET0). All patients were treated with ABVD and those with extensive tumor were treated with radiotherapy associated. After two cycles of ABVD patients underwent PET2. No treatment was changed based on PET2. We assessed the prognostic value of clinical factors, international prognostic score (IPS) and PET2 in relation to event-free survival (EFS) in three years. Of the 104 patients who finalized the evaluation, 82 achieved complete remission and 22 patients experienced treatment failure during the median of 36 months of follow-up. The EFS at three years was 74.2%. EFS in three years of PET2 positive was 54.3%, while the PET2 negative was 90.5% (p <0.001). In subgroup analysis of patients with early stage, advanced, low and high risk IPS, PET2 also showed significant correlation with the prognosis. We conclude that the PET2 is the best independent prognostic factor in the evaluation of overall patients with LH, or in subgroups of early, advance; low and high risk of HL

Pacientes com linfoma de Hodgkin (LH) tratados com poliquimioterpia com adriamicina, bleomicina, vincristina e doxorrubicina (ABVD) apresentam resposta terapêutica distinta. Para aprimorar a avaliação prognóstica e a abordagem terapêutica em LH objetivamos avaliar o valor prognóstico da PET-FDG após 2 ciclos de ABVD (PET2) em pacientes com LH. Foram incluídos nesse estudo prospectivo 115 pacientes com diagnóstico recente de LH no período de agosto de 2005 a dezembro de 2007. Os pacientes foram estadiados com exame clínico, laboratorial, tomografia computadorizada e PET-FDG (PET0). Todos os pacientes foram tratados com ABVD e aqueles com massa tumoral extensa foram tratados com radioterapia associada. Após dois ciclos de ABVD os pacientes foram submetidos a PET2. Nenhum tratamento foi alterado baseado na PET2. Foi avaliado o valor prognóstico dos fatores clínicos, Índice Prognóstico Internacional (IPI) e PET2 em relação à sobrevida livre de eventos (SLE) em três anos. Dos 104 pacientes que foram avaliados, 82 atingiram remissão completa e 22 pacientes apresentaram falha de tratamento durante a mediana de 36 meses de acompanhamento. A SG e SLE em três anos foi de 94,2% e 74,2% respectivamente. A SLE em três anos da PET2 positiva foi de 54,3%, enquanto da PET2 negativa foi de 90,5% (p< 0.001). Na análise de subgrupos de pacientes com estádio precoce, avançado, IPI baixo e alto risco, a PET2 também apresentou correlação estatisticamente significativa com o prognóstico. Concluímos que a PET2 é o melhor fator prognóstico independente na avaliação de pacientes com LH / Patients with Hodgkin lymphoma (HL) treated with poliquimioteraphy with adriamycin, bleomycin, vincristine and doxorubicin (ABVD) have distinct therapeutic response. In order to improve the prognostic assessment and therapeutic approach in HL we have evaluated the prognostic value of FDG-PET after 2 cycles of ABVD (PET2). Were included in this prospective study 115 patients with newly diagnosed LH in the period of August 2005 to December 2007. The patients were staged with physical examination, laboratory, CT and PET-FDG (PET0). All patients were treated with ABVD and those with extensive tumor were treated with radiotherapy associated. After two cycles of ABVD patients underwent PET2. No treatment was changed based on PET2. We assessed the prognostic value of clinical factors, international prognostic score (IPS) and PET2 in relation to event-free survival (EFS) in three years. Of the 104 patients who finalized the evaluation, 82 achieved complete remission and 22 patients experienced treatment failure during the median of 36 months of follow-up. The EFS at three years was 74.2%. EFS in three years of PET2 positive was 54.3%, while the PET2 negative was 90.5% (p <0.001). In subgroup analysis of patients with early stage, advanced, low and high risk IPS, PET2 also showed significant correlation with the prognosis. We conclude that the PET2 is the best independent prognostic factor in the evaluation of overall patients with LH, or in subgroups of early, advance; low and high risk of HL

Rectal cancer is the eight most common cancer diagnosis in Sweden in both men and women, with almost 2000 new cases per year. Radiotherapy, which is an important treatment modality for rectal cancer, has evolved during the past decades. Diagnostic tools have also improved, allowing better staging and offering information used to make well-founded decisions in multidisciplinary team conferences. In a retrospective study (n=46) with locally advanced rectal cancer (LARC) patients, unfit for chemoradiotherapy, patients were treated with short-course radiotherapy. Delayed surgery was done when possible. Radical surgery was possible in 89% of the patients who underwent surgery (80%). Grade IV diarrhoea affected three elderly patients. Target radiation volume should be reduced in elderly or metastatic patients. In a prospective study (n=68) with LARC patients, magnetic resonance imaging (MRI) and 2-18F-fluoro-2-D-deoxyglucose (FDG) positron emission tomography (PET) were used to determine if FDG-PET could provide extra treatment information. Information from FDG-PET changed the stage of 10 patients. Delineation with FDG-PET generally resulted in smaller target volumes than MRI only. Seven of the most advanced LARC patients in the above cohort were used for a methodological study to determine if dose escalation to peripheral, non-resectable regions was feasible. Simultaneous integrated boost plans with photons and protons were evaluated. While toxicity was acceptable in five patients with both protons and photons, two patients with very large tumours had unacceptable risk for intestinal toxicity regardless of modality. In the interim analysis of the Stockholm III Trial (n=303, studying radiotherapy-fractionation and timing of surgery in relation to radiotherapy) compliance was acceptable and severe acute toxicity was infrequent, irrespective of fractionation. Short-course radiotherapy with immediate surgery tended to give more postoperative complications, but only if surgery was delayed more than 10 days after the start of radiotherapy. Quality-of-life in the Stockholm III Trial was studied before, during and shortly after treatment using the EORTC QLQ-C30 and CR38 questionnaires. Surgery accounted for more adverse effects than radiotherapy in all groups. Postoperatively, the poorest quality-of-life was seen in patients given short-course radiotherapy followed by immediate surgery. No postoperative differences were seen between the two groups with delayed surgery.

Type 1 and 2 Diabetes Mellitus are a growing health problem throughout the world. There is an increasing  need for methodologies, which are both reliable and non-invasive to measure the amount of insulin-producing tissue (Beta-cell mass, or BCM), as well as rapidly quantify changes in the BCM due to the onset of disease, beta-cell replacement therapy, or other treatments. Positron Emission Tomography (PET) is a non-invasive, quantitative functional imaging technique which can be used to study dynamical or static processes inside the body. In this thesis, we present a study protocol for in vivo imaging of the most common form of beta- cell replacement therapy; islet transplantation. Islets were labeled with the PET tracer, 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG), and administered intra-portally, while the recipient was monitored by PET/CT. The hepatic distribution of the islets was highly heterogeneous, and around 25% (human) or 50% (porcine) of the administered islets could not be found in the liver after completed transplantation, confirming previous reports of considerable cell injury during the procedure leading to low hepatic engraftment. Native BCM in the pancreas can potentially be quantified using a PET tracer with sufficiently high specificity, but the major obstacle is the relative low amounts of insulin producing tissue (only 1-2% of the pancreatic volume). Two tetrabenazine analogues, [18F]FE-(+)-DTBZ and [18F]FE-(+)-DTBZ-d4, are ligands to VMAT2, which is expressed in islet tissue. Both analogues were investigated and characterized as potential BCM imaging agents both in vitro and in vivo.  Both tracers exhibited high preferential binding to islet tissue compared to exocrine pancreatic tissue. However, the specificity was not high enough to overcome the obscuring exocrine signal in vivo (7-10% of the signal originating from specific islet tracer uptake). This thesis demonstrates that it is possible to quantitatively assess islet transplantation by PET imaging. In vivo determination of native pancreatic BCM is, in theory, possible with both [18F]FE-(+)-DTBZ and [18F]FE-(+)-DTBZ-d4, but tracer analogues with higher islet specificity is needed for quantification of smaller BCM changes with physiological impact.

No description available.

Although mammals are the most commonly utilized laboratory animal, laboratory animal medicine continually seeks to replace them with animals of lower phylogenic classification. Fish are becoming increasingly important as investigators seek alternative animal models for research. Fish can provide an economical and feasible alternative to typical mammalian models; moreover, many fish, which have comparatively short life spans, can easily reproduce in the laboratory. One key area of animal health research in which fish have been underutilized is the field of advanced imaging. Although many images of fish have been captured through the use of computed tomography (CT), radiography, and ultrasonography, these images have been primarily utilized for anatomical study. In addition, fish have never before been studied with positron emission tomography/ computed tomography (PET/CT). My objectives were to determine if these imaging techniques can be used to obtain physiological information from fish, therefore making it more likely that fish can be utilized as replacement animals using these new imaging techniques (CT, PET/CT). I performed two different types of studies to assess the potential application of advanced imaging techniques to fish. In the first experiment, microCT was used to characterize otolith deformity in vitamin C deficient captive-raised red drum and relate the deformity to behavioral and physiological changes. I found that the normal and abnormal fish had statistically significant differences in behavior, cortisol levels, and otolith volume and density. MicroCT assessment of abnormal fish revealed operculum abnormalities, malocclusions, and several types of otolith malformations. Therefore, the affected fish had not only an abnormal skeletal appearance but also significantly abnormal behavior and cortisol responses. In the second experiment, fluorodeoxyglucose-positron emission tomography/ computed tomography (FDG-PET/CT) was used to quantify glucose uptake in select organs prior to carcinogenesis studies in fish. The quantified glucose uptake was compared to published data on humans, mice, and dogs. Rapid, quantifiable glucose uptake was demonstrated, particularly in brain, kidneys, and liver in all imaged fish species. Glucose uptake in the major organ systems of fish was closer to that in humans than uptake in mice or dogs, indicating that fish may serve as an effective alternative animal model for tumor studies using this technology. Other applications for this technique in fish may include metabolism studies and screening for environmental carcinogenesis. I found that both microCT and PET/CT imaging provided useful and meaningful results. In addition, the use of non-invasive scanning allows for re-use of fish, thus reducing the number of animal models used in experiments. These experiments suggest that fish will be good replacement models for mammals using these advanced imaging techniques.

Submitted by Renorbio (renorbioba@ufba.br) on 2017-07-06T14:52:02Z No. of bitstreams: 1 DEFINIÇÃO DE PROTOCOLOS DE PET-CT (defesa) (FINAL-crip).pdf: 2587129 bytes, checksum: ee0e1f775d6ec22cc7dc9aead962cb89 (MD5) / Approved for entry into archive by Uillis de Assis Santos (uillis.assis@ufba.br) on 2017-07-06T15:21:56Z (GMT) No. of bitstreams: 1 DEFINIÇÃO DE PROTOCOLOS DE PET-CT (defesa) (FINAL-crip).pdf: 2587129 bytes, checksum: ee0e1f775d6ec22cc7dc9aead962cb89 (MD5) / Made available in DSpace on 2017-07-06T15:21:56Z (GMT). No. of bitstreams: 1 DEFINIÇÃO DE PROTOCOLOS DE PET-CT (defesa) (FINAL-crip).pdf: 2587129 bytes, checksum: ee0e1f775d6ec22cc7dc9aead962cb89 (MD5) / A crescente disponibilidade de equipamentos de alta performance, software de reconstrução e métodos quantitativos tem proporcionado novas oportunidades para a melhoria das imagens e gestão dos pacientes. A busca por estratégias eficazes de redução da dose, sem comprometer o diagnóstico, tem se tornado uma parte essencial para otimização de protocolos. Este estudo descreve um método para se obter alta qualidade das imagens clínicas com aquisições de PET/CT com FDG-F18 relacionando a geometria do paciente, regime de dose, protocolos de aquisição de imagens e técnicas de processamento. Dados de aquisição de 58 indivíduos adultos de ambos os sexos foram avaliados retrospectivamente. Imagens do fígado foram adquiridas em modo-lista durante 360 s em um equipamento de PET/CT de alto desempenho. As imagens foram reconstruídas com intervalo de 30s. Foram avaliadas as relações entre os diferentes parâmetros indivíduo-dependentes, qualidade dos dados e da imagem. A taxa de ruído equivalente e o coeficiente de variação foram utilizados como métricas. Com base nas relações mais fortes entre estes parâmetros, foram identificados protocolos de aquisição otimizados e regimes de administração de atividade para diferentes métodos de reconstrução. Foi encontrada a relação mais forte da qualidade dos dados entre NECR e a massa corpórea, sendo o aumento da massa corpórea capaz de causar uma redução exponencial do NECR (R² = 0,72). Encontramos também uma relação entre qualidade de imagem e massa corpórea (R² = 0,82 para reconstruções OSEM3D e R² = 0,86 nas reconstruções PSF, p <0,001). Se um regime linear dose é utilizado, aumentando FDG- F18 proporcionalmente a massa, a qualidade da imagem degrada com o aumento da massa corpórea do paciente quando um mesmo tempo de aquisição é usado. A adoção de protocolos diferentes para três faixas de massa corporal (<60 kg, 60-90 kg, > 90 kg) na rotina clínica permite melhor qualidade de imagem com tanto PSF e métodos de reconstrução OSEM3D. Em conclusão, foi demonstrada neste estudo uma metodologia para determinar o tempo de aquisição das imagens, a partir da atividade de FDG-F18 administrada, a fim de obter imagens de alto padrão de qualidade. Este método oferece uma oportunidade para se realizar procedimentos de PET/CT mais custo-eficazes e com redução da dose de radiação. / The increasing availability of high performance equipment, reconstruction software and quantitative methods have provided new opportunities to improve image capturing and management of patients. Currently, new and effective strategies that reduce dose exposure, yet do not compromise diagnostics are underway and have become essential to protocol optimization. This study describes a method to achieve consistent clinical image quality in 18F-FDG scans accounting for patient habitus, dose regimen, image acquisition and processing techniques. Data was acquired from 58 adults, male and female, which were evaluated retrospectively. Images of the liver were acquired in list-mode during 360 s on a high-performance PET/CT scanner. The scans were reconstructed at incremental 30 s intervals and correlations between different patient-dependent parameters (PDP) and image and data quality were evaluated. Patient Noise Equivalent Count Rate (NECR) and coefficient of variation (CV) were used as metrics in our analysis. Based on the strongest PDP correlations, optimized acquisition protocols and dose regimens were identified for different reconstruction methods. Results: The strongest correlation of patient data quality was found between NECR per unit activity (NECRN) and body mass (BM): increasing BM causes NECRN to decrease exponentially (R² = 0.72). Patient body mass was also found to be the strongest PDP determinant of image quality (R² = 0.82 in OSEM3D and R² = 0.86 in PSF, p < 0.001). If a linear dose regimen is used, increasing 18F-FDG proportionally to BM, image quality degrades with increasing patient body mass when standard acquisition time is used. The adoption of different schemes for three body mass ranges (< 60 kg, 60–90 kg, > 90 kg) in clinical routine allows improved image quality with both PSF and OSEM3D reconstruction methods. In conclusion, this study has demonstrated a methodology for determining the time of image acquisition from FDG- F18 activity administered in order to obtain high quality standard images. The proposed methodology may be used by PET/CT centers to develop protocols to standardize PET/CT imaging procedures, and achieve better patient management and cost-effective operations and at a reduced radiation dose.