Thesis (Ph. D.)--University of Virginia, 2007. / Title from title page. Includes bibliographical references. Also available online through Digital Dissertations.

Thesis (D.Tech.: Radiography)-Dept. of Radiography, Durban Institute of Technology, 2006 xxiii, 166 leaves / The purpose of this study was to evaluate 99mTc- methoxyisobutylisonitrile (MIBI) imaging, in terms of sensitivity and specificity, for non invasively detecting extracutaneous involvement of Kaposi’s sarcoma (KS) and for differentiating pulmonary infection from malignancy in acquired immunodeficiency syndrome (AIDS) patients before and after treatment. Current investigations are invasive.

Made available in DSpace on 2015-09-25T12:21:41Z (GMT). No. of bitstreams: 0 Previous issue date: 2012-07-31 / Oral manifestations may represent the first clinical signs of HIV infection, being indicators of immunological compromise and of the disease progression. Thus, to investigate these expressions is crucial for the understanding of the epidemiology of AIDS. In this study, it was examined the prevalence of oral manifestations reported in patients with AIDS in the State of Paraíba and its associated factors, according to the Information System for Notifiable Diseases / SINAN, from 2000 to 2010. A quantitative cross-sectional epidemiological study was developed, using secondary data collected from the junction of SINAN W and Net from DST/AIDS program of Paraíba, in patients over 13 years old, who had a complete record of their case evolution. The sample census considered the inclusion criteria previously reported. Statistical analysis covered descriptive and analytical techniques, adopting a confidence interval of 95% and Pearson s chi-squared and prevalence ratio tests . The project was approved by the Ethics Committee of the State University of Paraiba, under CAAE 0404.0.133.000-10.For a total of 2.944 reported AIDS cases, occurred the record of 1009 oral manifestations for this disease, being 76.3% of Oral Candidiasis or Hairy Leukoplakia, 20% of Herpes Zoster and 3.7% of Kaposi's sarcoma. It was demonstrated a significant association between Oral Candidiasis or Hairy Leukoplakia and the variables years of research, macro-regions, years of education and evolution of cases, and it was found in the Herpes Zoster association between the variables years of research, age group and cases development (p <0.05 ). The largest number of oral manifestations identified for AIDS was established in the state capital, João Pessoa. According to the obtained results, the notification of oral manifestations of the disease under study has occurred in less than a half of the confirmed cases. / As manifestações orais podem representar os primeiros sinais clínicos da infecção por HIV, sendo indicadoras de comprometimento imunológico e do tempo de evolução da doença. Assim, investigar essas expressões é fundamental para o entendimento da epidemiologia da AIDS. Neste trabalho verificou-se a prevalência de manifestações orais notificadas em portadores de Aids no Estado da Paraíba e seus fatores associados, de acordo com o Sistema de Informação de Agravos de Notificação / SINAN, durante o período de 2000 a 2010. Desenvolveu-se um estudo epidemiológico transversal e quantitativo, utilizando dados secundários coletados a partir da junção do SINAN W e Net do programa do DST/AIDS da Paraíba, em pacientes maiores de 13 anos, que apresentavam o registro completo da evolução do caso. A amostragem censitária considerou os critérios de inclusão anteriormente relatados. O tratamento estatístico abrangeu técnicas descritivas e analíticas, adotando-se um intervalo de confiança de 95% e os testes Qui-quadrado de Person e Razão de Prevalência. O projeto foi aprovado pelo Comitê de Ética em Pesquisa da Universidade Estadual da Paraíba sob CAAE 0404.0.133.000-10. Para um total de 2944 casos notificados de AIDS ocorreu o registro de 1009 manifestações orais para essa doença, sendo 76,3% de Candidose oral ou Leucoplasia Pilosa, 20% de Herpes Zoster e 3,7% de Sarcoma de Kaposi. Demonstrou-se associação significativa entre a Candidose oral ou Leucoplasia Pilosa e as variáveis ano de investigação, macrorregião,grau de escolaridade e evolução dos casos e para o Herpes Zoster encontrou-se associação entre as variáveis ano de investigação, faixa etária e evolução dos casos (p < 0,05). O maior número de manifestações orais identificadas para a Aids ficou estabelecido na capital do Estado, a cidade de João Pessoa. De acordo com os resultados obtidos a notificação de manifestações orais para a doença em questão ocorreu em menos da metade dos casos confirmados da doença.

Submitted by Erika Demachki (erikademachki@gmail.com) on 2017-05-29T17:22:24Z No. of bitstreams: 2 Tese - Harley Fernandes Rodrigues - 2017.pdf: 14917308 bytes, checksum: 98bd396b4a6b5e7839b6b8ff0fd12102 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2017-05-30T10:44:17Z (GMT) No. of bitstreams: 2 Tese - Harley Fernandes Rodrigues - 2017.pdf: 14917308 bytes, checksum: 98bd396b4a6b5e7839b6b8ff0fd12102 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-05-30T10:44:17Z (GMT). No. of bitstreams: 2 Tese - Harley Fernandes Rodrigues - 2017.pdf: 14917308 bytes, checksum: 98bd396b4a6b5e7839b6b8ff0fd12102 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2017-04-19 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / Fundação de Amparo à Pesquisa do Estado de Goiás - FAPEG / In this thesis a methodology of real-time monitoring of magnetic hyperthermia (HM) in vivo was developed in the murine tumor model Sarcoma 180 using infrared thermography technique. Magnetic nanoparticles (NPM) consisted of Mn ferrites capable of generating heat at low magnetic field amplitude at the 300 kHz frequency within the safety limit determined by Atkinson. It has been shown that the apparent surface temperature value measured with the infrared camera underestimates the real skin temperature value of the mice if the camera objective does not form an angle 0 ° with the normal direction to the animal's skin in the region of interest on the tumor, with the error reaching more than 7.0 ° C (for 60 °). A new theoretical model to estimate the error in the temperature of curved surfaces was developed and proved valid even in the case where the surface temperature diverges significantly from the environment. Preclinical treatment results indicated a complete remission condition in animal that was submitted to 150 min of hyperthermia and other cases with partial remission, suggesting that biological response analyzes need to be done in a long time (> 60 days). Measurements of the intratumoral temperature monitored by three fiber-optic thermometers during the therapeutic procedure of HM with NPM indicated an inhomogeneous heat delivery within the tumor. Additionally, a new methodology for calculating the thermal dose (CEM43) evaluated at the surface, considering each pixel of the thermographic image as a thermometer in the tumor region, indicated that the value T10(t) of the temperature detected in vivo at the surface of the skin over subcutaneous tumors can report, with an error of the order of 5%, the mean intratumoral temperature value during the therapeutic procedure of HM. / Nesta tese foi desenvolvida uma metodologia de monitoramento em tempo real da hipertermia magnética (HM) in vivo no modelo tumoral murino Sarcoma 180 utilizando a técnica de termografia por infravermelho. As nanopartículas magnéticas (NPM) consistiam de ferritas de Mn capazes de gerar calor em baixa amplitude de campo magnético, na frequência de 300 kHz, dentro do limite de segurança determinado por Atkinson. Foi demonstrado que o valor da temperatura superficial aparente medido com a câmera de infravermelho subestima o valor da temperatura real da pele dos camundongos se a objetiva da câmera não formar um ângulo 0° com a direção normal à pele do animal na região de interesse sobre o tumor, podendo o erro chegar a mais do que 7,0 °C (para 60°). Um novo modelo teórico para estimar o erro na temperatura de superfícies curvas foi desenvolvido e se mostrou válido inclusive para o caso em que a temperatura superficial diverge significativamente da ambiente. Resultados pré-clínicos do tratamento indicaram uma situação de remissão completa em animal que passou por 150 min de hipertermia e outros casos com remissão parcial, sugerindo que análises de resposta biológica precisam ser feitas em longo tempo (> 60 dias). Medidas da temperatura intratumoral monitorada por três termômetros de fibra-óptica durante o procedimento terapêutico de HM com NPM indicaram uma entrega de calor não homogênea dentro do tumor. Adicionalmente, uma nova metodologia para o cálculo da dose térmica (CEM43) avaliada na superfície, considerando cada pixel da imagem termográfica como um termômetro na região do tumor, indicou que o valor de T10(t) da temperatura detectada in vivo na superfície da pele sobre tumores subcutâneos pode informar, com um erro da ordem de 5%, o valor da temperatura média intratumoral durante o procedimento terapêutico de HM.

La dérégulation de l’expression des microARN peut induire des cancers. De plus, ils jouent un rôle crucial dans la pathogénèse et la survie des virus. L’herpès virus humain de type 8 (HHV-8 ou KSHV) est l’agent étiologique du sarcome de Kaposi et est impliqué dans la génération de lymphomes agressifs de type B. De manière intéressante, le génome ce virus code 12 pré-miARN localisés dans la région de latence et exprimés sur un même pri-miARN. Les miARN du KSHV sont importants pour le maintien de la latence, l’inhibition de l’apoptose ou encore la régulation du cycle cellulaire de l’hôte. Nous nous intéressons à leur expression et leur régulation durant l’infection virale. Nous avons résolu la structure secondaire de l’ARN codant ces miARN afin d’identifier les critères structuraux responsables de leur accumulation différentielle. Nous avons initié une analyse cinétique de la première étape de maturation et enfin nous essayons d’identifier des co-facteurs modulant leur expression. / It is now well known that modulation of microRNAs expression is linked to the development of cancers. Moreover, they play a crucial role in the pathogenesis and the survival of some viruses. Kaposi’s sarcoma associated herpes virus (KSHV) is the etiologic agent of Kaposi’s sarcoma and is involved in human aggressive B lymphomas generation. Its genome encodes 12 precursor miRNAs that are clustered in a latency region and expressed on a single long primary transcript. KSHV miRNAs are important to maintain the virus latency and to regulate or inhibit the host cell cycle or apoptosis, respectively. Therefore, understanding the regulation of KSHV miRNA accumulation is of prime importance. In this respect, we resolved the secondary structure of them iRNA cluster to identify structural criteria responsible of their differential accumulation. In addition, we started to analyse the mechanism of their maturation by kinetics studies. Finally we tried to identify some cofactors of miRNA expression.

Introduction: Little is known about the aetiology of cancer in teenagers and young adults (TYA) aged 15-24 years, although in England, cancer is the most common cause of disease-related mortality in this age group. The most common cancers at this age are lymphomas, central nervous system (CNS) tumours and germ cell tumours (GCT). The commonest carcinomas seen at older ages including lung, breast, large bowel and prostate account for only 3-4% of TYA cancers. In this thesis I describe the incidence patterns of selected cancers in TYA and the variation seen with geography, time and in population subgroups. The focus is on CNS tumours, GCT and bone tumours as they either peak in incidence in TYA and/or contribute disproportionately to cancer related mortality in TYA. This will allow formulation of hypotheses regarding aetiology of cancer in this age group which can then be tested by further research. Methods: For the majority of the analysis, anonymised national cancer registration data from England on individual patients of all ages with newly diagnosed cancer between 1979 and 2003 were used. To contrast the incidence patterns in England with that of India, data from five Indian urban population based cancer registries were used for part of the analysis. Age, sex, site and histology specific incidence rates were calculated and expressed per million person years. All rates, where appropriate, were adjusted to the world standard population using direct methods. To explore the link of growth with development of osteosarcoma and Ewing sarcoma, a random-effects meta-analysis was undertaken on studies which investigated an association of these tumours with height at diagnosis. Results: The incidence of cancer in TYA overall in England exceeded that of India. This was also true for most individual sites including epithelial cancers of lung, colon/rectum, breast, ovary and cervix, and non-epithelial cancers including melanoma, Hodgkin lymphoma and testicular cancer. Notable exceptions to this pattern were cancers of the mouth, gall bladder and stomach (females only) where incidence was higher in India. In England, CNS tumours in TYA were a composite of pilocytic astrocytomas and embryonal tumours (representing tail end of childhood CNS tumours), pituitary tumours, nerve sheath tumours, high grade astrocytomas and meningiomas (representing early-onset of CNS tumours that peak in incidence in the 6th and 7th decade of life), and of CNS GCTs, pleomorphic xanthoastrocytomas and neurocytomas which show a peak incidence in TYA. Irrespective of site or histology, GCT in England showed a peak in incidence between ages of 10 to 39 years which was more marked in males. This however varied by site and the peak incidence was seen at 10 to 14 years in the CNS, 15 to 19 years in ovary, 25 to 29 in mediastinum & thorax and abdomen & pelvis, and 30 to 34 years in testicular tumours. Osteosarcoma and Ewing sarcoma were the predominant bone tumours in TYA in England and showed a distinct peak of incidence at 10 to 14 years age in females and a larger peak at 15 to 19 years age in males. The peak incidence of osteosarcoma of long bones of the lower limb was six times more than that at any other site while the peak incidence of Ewing sarcomas located in the bones of the central axis exceeded those in long bones of the lower limb. The average height of patients with osteosarcoma at diagnosis was found to be significantly above the average height of the reference population, at the 95% level. The association of greater height at diagnosis with Ewing sarcoma was also significant at the 95% level but much weaker. Conclusion: In this thesis I have explored the epidemiology of cancer in TYA using some of the established methodologies which have previously been used in advancing our knowledge of childhood and older adult cancers. These studies provide some clues to aetiology. Variation in environmental exposures and lifestyle factors between England and India can explain the majority of the differences in incidence patterns observed. Genetic predisposition to cancer along with carcinogen exposure could lead to early onset of some cancers generally seen in older adults. Regardless of site, the similarity in age-incidence patterns of GCT, suggests a common initiation of these tumours in embryonic/foetal life with variable rates of tumour progression as a result of local factors or events during postnatal and pubertal period. The incidence patterns of osteosarcoma along with the strong and consistent association with a greater height at diagnosis indicate that bone growth is important in the development of this tumour while different biological pathways which may be unrelated to growth could also be relevant for Ewing sarcoma.

Introducción: El Sarcoma de Kaposi (SK) es una enfermedad neoplásica por Herpesvirus 8 en sinergia con el VIH. En la actualidad, no existe tratamiento con evidencia científica que respalde su efectividad y disminución de mortalidad. Objetivo: Evaluar si el uso del tratamiento oncológico disminuye la mortalidad a tres años de inicio de TARV de los pacientes con VIH y SK. Materiales y métodos: Un estudio transversal analítico se realizó en tres hospitales nacionales entre el 2008 y 2018. Los pacientes con SK se dividieron entre aquellos que recibieron TARV y aquellos que recibieron TARV con tratamiento oncológico. La historia clínica y la ficha TARV fueron revisadas. Resultados: La media poblacional fue de 45,02 años para los pacientes de bajo riesgo (DE:12,56). En el análisis bivariado se encontró asociación significativa entre mortalidad y abandono del TARV (p=0,046). No se identificó asociación significativa de la mortalidad al momento de elegir tratamiento oncológico más TARV o TARV solo como tratamiento inicial (PR: 0,92; IC 95% 0,326;2,575). En el modelo ajustado no se observa asociación significativa entre las variables Evento de Muerte y Tratamiento. Conclusiones: El tratamiento oncológico no disminuye la mortalidad a tres años de inicio de TARV de los pacientes con VIH y SK. Existe aumento de mortalidad en pacientes con VIH y SK que abandonan TARV. El Estadiaje de SK, Rango de CD4 Inicial, Orientación Sexual, entre otros, no resultaron influyentes en la mortalidad. Fallecieron 27,9 % de pacientes con VIH y SK durante el periodo de estudio. Existen diversos factores aumentan la incidencia de VIH y SK. / Introduction: Kaposi's Sarcoma (KS) is a neoplastic disease caused by Herpesvirus 8 in synergy with HIV. Currently, there is no treatment with scientific evidence to support its effectiveness and decrease in mortality. Objective: Assess whether the use of cancer treatment reduces mortality three years after starting ART in patients with HIV and KS. Materials and methods: An analytical cross-sectional study was conducted in three national hospitals between 2008 and 2018. KS patients were divided between those who received ART and those who received ART with cancer treatment. The clinical history and the ART file were reviewed. Results: The population mean was 45,02 years for low-risk patients (SD: 12,56). In the bivariate analysis, a significant association was found between mortality and abandonment of ART (p=0,046). No significant association was identified between mortality and initial treatment, be it cancer treatment plus ART or ART alone (PR: 0,92; 95% CI 0,326;2,575). In the adjusted model, no significant association was observed between the variables Death Event and Treatment. Conclusions: Cancer treatment does not reduce mortality three years after starting ART in patients with HIV and KS. There is an increase in mortality in patients with HIV and KS who abandon ART. KS Staging, Initial CD4 Range, Sexual Orientation, among others, were not influential in mortality. 27.9% of patients with HIV and KS died during the study period. There are several factors that increase the incidence of HIV and KS. / Tesis

Background: Pulmonary artery sarcoma is a rare tumor with a poor prognosis. Case Report: We report the case of a 64-year-old man with an intimal pulmonary artery sarcoma presenting with severe high oxygen flow-demanding dyspnea and weight loss of 12 kg in the last 6 months. On echocardiography, right heart insufficiency, markedly elevated right ventricular pressure, a pressure gradient along the right outflow tract, and a tumor mass adherent to the wall of the truncus pulmonalis were detected. The tentative diagnosis by echocardiographic findings was pulmonary artery sarcoma. Computed tomography of the thorax and 18-fluorodeoxyglucose positron emission tomography showed an advanced local tumor manifestation. Surgical resection of the tumor to improve hemodynamics confirmed the diagnosis. Conclusions: Pulmonary artery sarcoma should be considered as a rare differential diagnosis in patients with dyspnea due to right heart failure, particular in the case of additional weight loss, and echocardiographic examination is a useful first diagnostic approach in establishing the diagnosis. / Hintergrund: Das Pulmonalarteriensarkom ist eine seltene Erkrankung mit einer schlechten Prognose. Fallbericht: Wir berichten über einen 64-jährigen Mann mit einem intimalen Pulmonalarteriensarkom, der sich mit starker Luftnot trotz hoher Sauerstoffsubstitution und einem Gewichtsverlust von 12 kg in den letzten 6 Monaten vorstellte. Echokardiographisch fielen eine Rechtsherzinsuffizienz, ein deutlich erhöhter rechtsventrikulärer Druck, ein Druckgradient über dem rechten Ausflusstrakt und eine Tumormasse im Bereich des Trunkus pulmonalis mit Kontakt zur Gefäßwand auf. Die mittels Echokardiographie erhobene Verdachtsdiagnose lautete Pulmonalarteriensarkom. Die Computertomographie des Thorax und die 18-Flur-Desoxyglukose-Positron-Emissionstomographie erbrachten den Befund eines lokal fortgeschrittenen Tumors. Die chirurgische Resektion des Tumors, die zur Verbesserung der Hämodynamik durchgeführt wurde, bestätigte die Diagnose. Schlussfolgerungen: Das Pulmonalarteriensarkom sollte differenzialdiagnostisch als eine seltene Ursache der Luftnot im Rahmen einer Rechtsherzinsuffizienz, insbesondere bei zusätzlichem Gewichtsverlust, in Erwägung gezogen werden. Die Echokardiographie stellt eine wertvolle initiale Untersuchungsmethode bei der Diagnosestellung dar. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Objective: In this study, 22 cases of locally recurrent urological malignant fibrous histiocytoma were reviewed considering therapeutic options, follow-up and prognosis. Patients and Methods: In the available literature on this topic we identified 19 cases of locally recurrent genitourinary malignant fibrous histiocytoma. Three additional cases are discussed, primarily arising from the kidney, the bladder and the paratesticular region. Results: The prognosis of locally recurrent urological malignant fibrous histiocytoma was found to be extraordinarily poor. Only 2 of 22 patients have survived for longer than 3.5 years. One of them reported herein is still alive 10 years after extensive lymphatic spread accompanying the first local recurrence. In this case, late local recurrence occurred after an 8-year interval free of disease. Conclusion: Malignant fibrous histiocytoma is an unusual urological malignancy with a high rate of local recurrence. The latter is frequently accompanied by metastatic disease and unrelenting progression. Despite the poor prognosis early detection of local failure and aggressive salvage therapy might offer the chance of long-term survival in selected cases. Close and life-long follow-up is advisable for patients once treated for recurrent urological malignant fibrous histiocytoma. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Au moins 60% des patients atteints de cancer vont recevoir de la radiothérapie (RT). L’efficacité de la radiothérapie dans le traitement du cancer est limitée par le phénomène de radiorésistance des cellules cancéreuses et par la toxicité des radiations sur les tissus sains. La découverte de nouveaux agents radiosensibilisants et radioprotecteurs permettrait de surmonter ces difficultés. Les modèles cellulaires 3D tels que les sphéroïdes, émergent motivés par le besoin de modèles précliniques plus proches des tumeurs in vivo. L’objectif du projet est d’optimiser un système microfluidique pour tester facilement et à faible coût des agents thérapeutiques avec la RT sur des sphéroïdes dans un contexte de repositionnement. Le système microfluidique développé permet la formation de 336 sphéroïdes homogènes en deux jours avec intervention minimale de l’utilisateur. Les sphéroïdes sont répartis dans 16 chambres de culture séparées par un système de valve magnétique pour éviter des effets bystander entre sphéroïdes irradiés et non-irradiés. Une nouvelle technique d’irradiation a été développée permettant d’exposer un système à 4 doses de radiation différentes. En tout, 4 doses de radiation et 4 concentrations d’agents thérapeutiques peuvent être testées par système. En utilisant cette approche, l’efficacité de trois agents avec la RT a été évaluée avec des tests de survie clonogénique. Nous avons démontré que le Talazoparib, un inhibiteur de PARP, radiosensibilise les cellules de sarcome de tissus mous (STS) cultivés en sphéroïdes à 2 Gy. Le système développé permet d’évaluer le potentiel d’agents thérapeutiques avec la RT et contribue à l’adoption des sphéroïdes comme modèle préclinique. / At least 60% of cancer patients will receive radiotherapy (RT) as part of their treatment. The efficacy of radiotherapy in the treatment of cancer is limited by the phenomenon of radioresistance of cancer cells and by the toxicity of radiation on healthy tissues. The discovery of new radiosensitizers and radioprotectors is essential to overcome these challenges. 3D cellular models such as spheroids emerge motivated by the need for better preclinical models. The objective of the project was to optimize a microfluidic system for easy, fast and low-cost testing of therapeutic agents with RT on spheroids. The developed microfluidic system allows the formation of 336 homogeneous spheroids in two days with minimal user intervention. The spheroids are distributed in 16 culture chambers separated by a magnetic valve system to avoid bystander effects between irradiated and unirradiated spheroids. A new irradiation technique has been developed to expose a system with 4 different radiation doses. In total, 4 radiation doses and 4 concentrations of therapeutic agents can be tested per system. Using this approach, the efficacy of three agents with RT was evaluated with clonogenic assays. Radiosensitizing properties of Talazoparib, a PARP inhibitor, on soft tissue sarcoma (STS) cells cultured as spheroids at 2 Gy were demonstrated. The developed system enables the evaluation of therapeutic agents with RT and contributes to the wide adoption of spheroids as a preclinical model.