No Brasil e no mundo a medicina nuclear vem ganhando destaque com as técnicas diagnósticas que permitem o estudo metabólico de doenças, alterando significativamente o gerenciamento dos pacientes. Essa tecnologia inovadora vem trazendo expectativas tanto para os setores especializados como para a sociedade. Nesse trabalho foi estudada a utilização do radiofármaco 18F-FDG na região metropolitana de São Paulo e nas áreas adjacentes, bem como a estrutura do mercado atual e das dificuldades a serem superadas com o aumento da demanda do 18F-FDG. A pesquisa contou com uma análise do mercado de radiofármacos internacional e das principais alterações que vem ocorrendo nessa área no Brasil nos últimos anos. Foram realizadas entrevistas com profissionais atuantes na área de medicina nuclear e coleta de dados através de questionário enviado para os centros consumidores do radiofármaco na região coberta pela pesquisa. As entrevistas expressaram as opiniões dos entrevistados sobre as transformações nesse setor e as tendências futuras e os dados coletados no questionário serviram de complementação a utilização do radiofármaco nos equipamentos do tipo Single Photon Emission Computed Tomography (SPECT), Positron Emission Tomography (PET) e Positron Emission Tomography / Computer Tomography (PET/CT). O maior uso do 18F-FDG tem sido para o diagnóstico oncológico nos equipamentos do tipo PET e PET/CT. Essa utilização deverá crescer nos próximos anos, podendo se expandir para outras especialidades como neurologia e cardiologia. Apesar de restrita atualmente as cidades de São Paulo e Rio de Janeiro deverá haver uma expansão dessa modalidade diagnóstica nos outros Estados do país que começam a estruturar produção do radioisótopo. A recente alteração na constituição que permite a produção e comercialização de radioisótopos de meia-vida curta também deverá aumentar o interesse da iniciativa privada nesse mercado, que internacionalmente possui projeções otimistas de crescimento. Existe também uma expectativa que a aprovação dos planos de saúde para a cobertura dos exames utilizando 18F-FDG no PET impulsione esse mercado ainda mais, repetindo a experiência internacional. Os recentes investimentos realizados pelo IPEN para aumentar a produção do 18F-FDG deverá garantir a oferta com confiabilidade, para a região Sudeste e Sul do país. / Nuclear Medicine in Brazil and worldwide has developed distinction with diagnosis techniques that allow metabolic research of the disease, changing in a significant fashion the patients outcome. This innovative technology leads expectations from specific fields up to society itself. This research studied the use of 18F-FDG radiopharmaceutical in the metropolitan region of São Paulo and adjacent areas, as well as the recent trade structure and the difficulties that should be overcome with the increase of the 18F-FDG demand. This research counted on the analysis of the international radiopharmaceutical trade and the main changes that have been happening in this area in Brazil during the past few years. Interviews were performed with professionals within the area of nuclear medicine and data has been collected through questionnaire sent to the consuming centers of the radiopharmaceutical in the region covered in this research. The interviews expressed the opinions of the interviewees concerning transformations in this field and future tendencies and the information obtained from the survey was the basis of complementation of the use of radiopharmaceutical on equipments such as Single Photon Emission Computed Tomography (SPECT), Positron Emission Tomography (PET) and Positron Emission Tomography / Computer Tomography (PET/CT). The major use of 18F-FDG has been used for oncology diagnosis with equipments such as PET and PEC/CT. This use shall grow in the next years, maybe expanding to other specialties such as neurology and cardiology. Although nowadays restricted to the cities of São Paulo and Rio de Janeiro, there is a possibility of expansion to other diagnosis modalities in other states of the country that are starting to structure the production of the radioisotope. The recent change in the constitution permitting the production and commerce of short half-life radioisotopes also contributes to the increase the interest of private funding of this sector in which internationally holds optimistic projections of increase. There is also the expectancy that approving health care plans coverage of these exams using 18F-FDG with PET to boast more this sector, repeating international experience. Recent investments made by IPEN to increase the production of 18F-FDG shall guarantee the offer of confidentiality for the Southeast and Southern regions of the country.

In recent years, the impressive progress performed in imaging, computational and technological fields have made possible the emergence of image-guided radiation therapy (IGRT) and adaptive radiation therapy (ART). The accuracy in radiation dose delivery reached by IMRT offers the possibility to increase locoregional dose-intensity, potentially overcoming the poor tumor control achieved by standard approaches. However, before implementing such a technique in clinical routine, a particular attention has to be paid at the target volumes definition and delineation procedures to avoid inadequate dosage to TVs/OARs. In head and neck squamous cell carcinoma (HNSCC), the GTV is typically defined on CT acquired prior to treatment. However, providing functional information about the tumor, FDG-PET might advantageously complete the classical CT-Scan to better define the TVs. Similarly, re-imaging the tumor with optimal imaging modality might account for the constantly changing anatomy and tumor shape occurring during the course of fractionated radiotherapy. Integrating this information into the treatment planning might ultimately lead to a much tighter dose distribution. From a methodological point of view, the delineation of TVs on anatomical or functional images is not a trivial task. Firstly, the poor soft tissue contrast provided by CT comes out of large interobserver variability in GTV delineation. In this regard, we showed that the use of consistent delineation guidelines significantly improved consistency between observers, either with CT and with MRI. Secondly, the intrinsic characteristics of PET images, including the blur effect and the high level of noise, make the detection of the tumor edges arduous. In this context, we developed specific image restoration tools, i.e. edge-preserving filters for denoising, and deconvolution algorithms for deblurring. This procedure restores the image quality, allowing the use of gradient-based segmentation techniques. This method was validated on phantom and patient images, and proved to be more accurate and reliable than threshold-based methods. Using these segmentation methods, we proved that GTVs significantly shrunk during radiotherapy in patients with HNSCC, whatever the imaging modality used (MRI, CT, FDG-PET). No clinically significant difference was found between CT and MRI, while FDG-PET provided significantly smaller volumes than those based on anatomical imaging. Refining the target volume delineation by means of functional and sequential imaging ultimately led to more optimal dose distribution to TVs with subsequent soft tissue sparing. In conclusion, we demonstrated that a multi-modality-based adaptive planning is feasible in HN tumors and potentially opens new avenues for dose escalation strategies. As a high level of accuracy is required by such approach, the delineation of TVs however requires a special care.

Thesis (M.A.)--Boston University / The standardized uptake value (SUV) is increasingly being used for diagnosis, staging, and monitoring disease in clinical oncology. Comparing tumor SUV to background SUV is an attractive way to minimize variability and ensure the quality of scans across different institutions. The liver has been identified as a potential source for background normalization, however no studies have compared the liver to other background sites for a variety of cancers. The purpose of this study was to evaluate the use of liver uptake for the standardization of FDG PET/CT imaging. Scans from 145 patients were prospectively reviewed under the supervision of a radiologist with board certification in nuclear medicine (R.M.S. , 3 years of experience). Liver SUV values were correlated to mediastinum SUV values in lung and breast cancer patients, and internal jugular vein (IJV) SUV values in head and neck cancer patients. The independent t-test was used to determine if there was a statistically significant affect of the amount of incubation time or use of intravenous contrast on the SUV. For the lung and breast cancer patients, a strong correlation was observed between the mediastinum SUVmean and liver SUVmean (r = 0.89), whereas for the head and neck cancer patients, a weaker correlation was observed between the IJV SUVmean and the liver SUVmean (r = 0.69). Neither the amount of incubation time nor the use of IV contrast demonstrated a significant affect on the SUV. We conclude that liver SUVmean may be used to standardize FOG PET/CT studies in cancers of the lung, breast and head and neck. However, additional studies in other cancers as well as the affects of age, gender, benign disease and use of chemotherapy are still desired before widespread adoption of this standard.

Emerging evidence indicates that 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) are useful imaging modalities for evaluating tumor progression in transgenic mouse models of solid human cancers, but the potential of integrated FDG-PET/CT for assessing tumor development in genetically engineered mouse models of liquid human cancers - including neoplasms of immunoglobulin (Ig)-producing plasma cells - has not been established. Here we use a double-transgenic strain of laboratory mice, designated C.IL6Myc, that recapitulates key features of human plasma cell myeloma (a.k.a. multiple myeloma [MM]) to demonstrate that FDG-PET/CT affords a useful research tool for assessing plasma cell tumor (PCT) development in a serial, objective and, importantly, stage- and lesion-specific manner. Supported by serum biomarker analyses (Ig level, paraprotein) and histopathological findings in C.IL6Myc mice undergoing PCT development, the newly generated FDG-PET/CT data set demonstrates the potential of this imaging modality for preclinical basic and translational MM research. PET imaging of genetically engineered mice in which MM-like tumors arise predictably in an intact immunocompetent microenvironment may facilitate the design and testing of new approaches to the treatment and prevention of MM in humans.

Characterized by excessive myocardial glycogen deposition, cardiac hypertrophy, frequent cardiac arrhythmias and progressive conduction system disease, the PRKAG2 cardiac syndrome stems from a genetic mutation in the γ2-subunit of AMP-activated protein kinase (AMPK). Although functionally diverse, the main role of AMPK is to modulate cardiac metabolism in response to depleted ATP levels. A comprehensive study of the dysfunctional regulation of AMPK activity involved in the progression of the human PRKAG2 cardiac syndrome is hindered by the limitations of in vitro techniques. Positron emission tomography (PET) imaging with the glucose analogue, FDG, offers a quantitative assessment of myocardial glucose uptake non-invasively. The aim of this thesis was to determine the ability of FDG to detect changes in glucose uptake, storage and metabolism in the heart in relation to AMPK activity and provide insights into the mechanism of PRKAG2 cardiac hypertrophy. To achieve this aim, a transgenic AMPK γ2-subunit Arg302Gln mouse model was evaluated with small animal FDG PET with correlation to biochemical assays of cardiac AMPK activity and the glycogen metabolism pathway. Using the vena cava blood input function, FDG myocardial glucose uptake was reliably assessed in mice for the first time with Patlak modeling. Reduced FDG uptake in the Arg302Gln PRKAG2 mouse model suggested a feedback pathway reducing exogenous glucose uptake due to excessive intracellular glycogen stores. Despite an increase in FDG uptake in the skeletal muscle of the PRKAG2 mutant mice following insulin stimulation, there was no change in cardiac uptake, signifying myocardial insulin resistance. Increased reliance on glucose oxidation by TMZ inhibition of fatty acid oxidation reduced glycogen stores, restored cardiac function and eliminated ventricular preexcitation. The observed reduction in mouse myocardial FDG uptake mirrors the reduction previously observed in the human PRKAG2 patients. The potential now exists to evaluate both progression and therapeutic interventions for the PRKAG2 cardiac syndrome with the transgenic mouse model with translation to the affected patients using FDG cardiac imaging.

Submitted by Isaac Francisco de Souza Dias (isaac.souzadias@ufpe.br) on 2016-02-23T19:02:39Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) DISSERTAÇÃO Elaine Vasconcelos dos Santos.pdf: 5212230 bytes, checksum: 5466df96d7209befd8083f1fce37eff2 (MD5) / Made available in DSpace on 2016-02-23T19:02:39Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) DISSERTAÇÃO Elaine Vasconcelos dos Santos.pdf: 5212230 bytes, checksum: 5466df96d7209befd8083f1fce37eff2 (MD5) Previous issue date: 2015-01-23 / CNPQ / Radiofármacos são traçadores radioativos utilizados na Medicina Nuclear, compostos por um fármaco com afinidade por órgãos ou processos metabólicos específicos e um radionuclídeo. Enquanto retidos no corpo do paciente, podem ser detectados e mapeados fornecendo informações quanto à presença de patologias ou disfunções na área em estudo. Entre os mais utilizados se destacam os radiofármacos marcados com 99mTc e 18F. A cinética de distribuição destes compostos no organismo pode ser afetada em decorrência da influência de fatores ambientais na estabilidade do medicamento. Conforme a legislação sanitária brasileira, estudos de estabilidade devem ser conduzidos e um dos parâmetros a serem avaliados é a umidade relativa. O objetivo deste trabalho foi avaliar o efeito da umidade na estabilidade de radiofármacos marcados com 99mTc e 18F por meio de determinações periódicas da pureza radioquímica e do pH de amostras de Sestamibi-99mTc, ECD-99mTc e FDG-18F. As medições da pureza radioquímica foram feitas por meio de cromatografia em camada delgada utilizando as fases móveis e estacionárias descritas nas bulas dos medicamentos ou em compêndios oficiais. A medida do pH das amostras foi realizada utilizando-se papel indicador de pH. As amostras de radiofármacos marcados com 99mTc foram submetidas a umidades de 20% e 90% e analisadas ao longo de 24h. As amostras de FDG-18F foram submetidas a umidades de 20% a 90% e as análises foram conduzidas por 10 h. Os resultados obtidos para o radiofármaco Sestamibi-99mTc indicaram não haver influência da umidade relativa a que o medicamento foi submetido. Já os resultados obtidos para o ECD-99mTc mostram um perfil de decomposição radiolítica mais acelerado se comparado ao Sestamibi-99mTc, e sugerem a influência de umidades relativas altas (90%) na estabilidade do composto. As amostras de FDG-18F não apresentaram variação significativa dentro da faixa de valores de umidade testados, o radiofármaco manteve-se apto para uso durante todo o período de testes (10h). / Radiopharmaceuticals are radioactive tracers utilized in nuclear medicine and consist of a radionuclide labeled with a drug with affinity for specific organs or metabolic processes. Administered to the patients, radiopharmaceuticals can be detected and mapped providing information about diseases or disorders in the studied area. The most utilized radiopharmaceuticals for diagnostics purposes are those labeled with 99mTc e 18F. The distribution kinetics of those compounds in the body can be affected due to the influence of environmental factors (such as temperature) on the drug stability. According to Brazilian health legislation, stability studies should be conducted taking into account the influence of relative humidity, although there was not found evidences of such influence on radiopharmaceuticals stability. The objective of this study was to evaluate the influence of humidity on the stability of radiopharmaceuticals labeled with 99mTc and 18F through periodic determinations of the radiochemical purity and the pH on Sestamibi-99mTc, ECD- 99mTc and FDG-18F samples. Measurements of radiochemical purity were carried out by means of thin layer chromatography using the mobile and stationary phases described in official compendia or in accordance to the radiopharmaceutical producer instructions. The pH measurement was performed using pH indicator papers. Samples of radiopharmaceuticals labeled with 99mTc were submitted to humidity of 20% and 90% and tested during 24h. FDG-18F samples were submitted to humidity from 20% up to 90% and analyzes were conducted during 10 h. The results for Sestamibi-99mTc radiopharmaceutical indicated no influence of the relative humidity on this drug stability. The results obtained to ECD-99mTc samples showed a faster radiolytic decomposition profile compared to Sestamibi-99mTc, suggesting the influence of high relative humidity (90%) on the stability of this compound. The 18FFDG samples showed no significant variation on their radiochemical purity and pH within the range of humidity tested, remaining suitable for use the time period considered in this study (10h).

Characterized by excessive myocardial glycogen deposition, cardiac hypertrophy, frequent cardiac arrhythmias and progressive conduction system disease, the PRKAG2 cardiac syndrome stems from a genetic mutation in the γ2-subunit of AMP-activated protein kinase (AMPK). Although functionally diverse, the main role of AMPK is to modulate cardiac metabolism in response to depleted ATP levels. A comprehensive study of the dysfunctional regulation of AMPK activity involved in the progression of the human PRKAG2 cardiac syndrome is hindered by the limitations of in vitro techniques. Positron emission tomography (PET) imaging with the glucose analogue, FDG, offers a quantitative assessment of myocardial glucose uptake non-invasively. The aim of this thesis was to determine the ability of FDG to detect changes in glucose uptake, storage and metabolism in the heart in relation to AMPK activity and provide insights into the mechanism of PRKAG2 cardiac hypertrophy. To achieve this aim, a transgenic AMPK γ2-subunit Arg302Gln mouse model was evaluated with small animal FDG PET with correlation to biochemical assays of cardiac AMPK activity and the glycogen metabolism pathway. Using the vena cava blood input function, FDG myocardial glucose uptake was reliably assessed in mice for the first time with Patlak modeling. Reduced FDG uptake in the Arg302Gln PRKAG2 mouse model suggested a feedback pathway reducing exogenous glucose uptake due to excessive intracellular glycogen stores. Despite an increase in FDG uptake in the skeletal muscle of the PRKAG2 mutant mice following insulin stimulation, there was no change in cardiac uptake, signifying myocardial insulin resistance. Increased reliance on glucose oxidation by TMZ inhibition of fatty acid oxidation reduced glycogen stores, restored cardiac function and eliminated ventricular preexcitation. The observed reduction in mouse myocardial FDG uptake mirrors the reduction previously observed in the human PRKAG2 patients. The potential now exists to evaluate both progression and therapeutic interventions for the PRKAG2 cardiac syndrome with the transgenic mouse model with translation to the affected patients using FDG cardiac imaging.

The aim of this thesis was to develop and validate prognostic and predictive biomarkers in order to better identify among patients with metastatic colorectal cancer those at high-risk of early death or progression. The interest in developing such biomarkers is that their subsequent use in clinical practice would avoid exposing a patient for months to the toxic side effects of ineffective and expensive treatments, and thus to limit the financial impact of these treatments on our healthcare systems.The projects carried out in the framework of this thesis have shown that:The biomarker WB-MATV (metabolically active tumor volume of the whole body) measured before the start of the last line treatment has a high prognostic value, higher than the general clinical parameters commonly used. This biomarker was then validated in first line treatment and was shown to have a high prognostic value, also higher than the general clinical parameters.The biomarker cfDNA (circulating DNA) also representing the tumor load was then investigated to assess its value added to the previously validated WB-MATV. We showed that the presence of high levels of cfDNA before starting the last-line treatment is significantly associated with poor prognosis and that these two biomarkers are prognostically complementary, each providing an added value.The biomarker of early metabolic response to last line treatment has a high negative predictive value (95%). This biomarker was then validated as a predictive biomarker independent of WB-MATV and clinical factors in first-line treatment setting.In conclusion, the results of this thesis strongly support the clinical use of these prognostic and predictive biomarkers in patients with metastatic colorectal cancer. Allowing a more accurate stratification of patients, the use of the combination of these biomarkers should become an essential tool to help oncologists in tailoring therapeutic strategies according to the patients’ individual risk. / Doctorat en Sciences médicales (Médecine) / info:eu-repo/semantics/nonPublished

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18853号 / 医博第3964号 / 新制||医||1007(附属図書館) / 31804 / 京都大学大学院医学研究科医学専攻 / (主査)教授 山田 泰広, 教授 武田 俊一, 教授 野田 亮 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20252号 / 医博第4211号 / 新制||医||1020(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 三森 経世, 教授 伊達 洋至, 教授 竹内 理 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM