O carcinoma da glândula tireoide é o câncer endócrino mais prevalente, com crescente incidência anual. Dentre as neoplasias tireóideas, o carcinoma papilífero é o mais frequente, representando 80 a 90% destes tumores. A despeito do excelente prognóstico de seus portadores e da baixa taxa de mortalidade, cerca de 5% a 20% dos indivíduos submetidos à tireoidectomia total desenvolverão recidiva regional e todavia não há consenso sobre os fatores preditivos de recidiva tumoral. MicroRNAs são pequenos RNAs endógenos, que não codificam proteínas, e que medeiam a regulação póstranscricional da expressão gênica ligando-se seletivamente aos RNAs mensageiros por pareamento de bases. A expressão dos microRNAs de uma forma controlada exerce papel importante em múltiplos processos fisiológicos. Em contrapartida, em câncer, níveis de microRNAs podem estar diminuídos ou aumentados e existem evidências de que microRNAs estão envolvidos no processo de metástase e recidiva. No presente estudo, investigamos se os níveis de miR-9, miR-10b, miR-21 e miR-146b são preditores de recidiva em carcinoma papilífero de tireoide. Utilizando amostras de carcinoma papilífero de tireoide fixadas em formalina e emblocadas em parafina, avaliamos a expressão de miR-9, miR-10b, miR-21 e miR-146b em amostras de tumor primário de 66 pacientes através da PCR em tempo real. Os pacientes foram reunidos em dois grupos: pacientes que apresentaram recidiva tumoral (n=19) e pacientes que não apresentaram recidiva tumoral (n=47). Todos os pacientes foram submetidos à tireoidectomia total e seguidos por um tempo mínimo de 120 meses para serem considerados livres de recidiva. Comparamos os grupos de pacientes com e sem recidiva tumoral em relação às variáveis idade, sexo, tamanho do tumor, riscos ATA e MSKCC-NY, estadiamento TNM, variante histológica do tumor, presença de multicentricidade, invasão vascular e perineural, extensão extra-tireóidea e metástases linfonodais cervicais. Análises univariadas e multivariadas foram realizadas utilizando-se os modelos de riscos proporcionais de Cox. Conforme análise univariada, tamanho do tumor primário (p=0,001) e extensão extra-tireóidea (p=0,027) estão associados à recidiva tumoral. Da mesma forma, pacientes em estadios mais avançados (III e IV) segundo TNM (p=0,001) ou classificados em grupos de risco mais elevados segundo ATA (p=0,025) também apresentam maior risco de evoluírem com recidiva da doença. Observamos níveis de expressão de mir- 9 e miR-21 significativamente inferiores nos indivíduos que apresentaram recidiva quando comparados aos que não apresentaram recidiva neoplásica (p<0,001 e p=0,001, respectivamente). Os resultados deste estudo demonstraram que expressão diminuída de miR-9 ou de miR-21 é fator prognóstico significativo para recidiva em indivíduos portadores de carcinoma papilífero de tireoide quando avaliados em amostras do tumor primário (RR = 1,48; 95% IC: 1,24-1,77 e RR = 1,52; 95% IC: 1,18-1,94; respectivamente), enquanto miR-10b e miR-146 não se mostraram diferentemente expressos entre os dois grupos. A análises multivariada envolvendo os níveis de expressão de miR-9 e mR-21 e parâmetros clínicos indica que os níveis de expressão destes microRNAs são fatores prognósticos independentes para pacientes com carcinoma papilífero de tireoide. Concluindo, nossos resultados sugerem que o nível de expressão de miR-9 e miR-21 poderia ser utilizado na prática clínica como biomarcador para avaliar o potencial para recidiva em carcinoma papilífero de tireoide / Thyroid cancer is the most prevalent endocrine neoplasm, and its annual incidence continues to rise. Papillary thyroid cancer is the most common histological type, accounting for 80-90% of all thyroid cancers. Despite its excellent prognosis and low mortality rates, regional recurrence is observed in 5-20% of patients and there is still no consensus concerning tumor recurrence predictive factors. MicroRNAs are endogenous small noncoding RNAs that mediate, post-transcriptionally, gene expression regulation. MicroRNAs selectively bind to mRNAs, playing important roles in multiple physiological processes. On the other hand, microRNAs levels may be down regulated or over expressed in cancer, and have been implicated in recurrence and metastasis-related processes. In the present study, we investigated whether miR-9, miR-10b, miR-21 and miR-146b expression levels could be predictive factors of papillary thyroid cancer recurrence. Using macrodissection followed by quantitative real-time PCR, we measured miR-9, miR-10b, miR-21 and miR- 146b expression levels in formalin-fixed, paraffin-embedded primary tumor samples from 66 patients with papillary thyroid cancer. Patients were categorized into two groups: the recurrent group (n=19) and the non-recurrent group (n=47). All patients underwent total thyroidectomy and were followed for at least 120 months after surgery to be considered recurrence-free. Both groups were compared for clinical and pathological characteristics, including age, gender, tumor size, ATA and MSKCC-NY risk, TNM stage, multicentricity, vascular and perineural invasion, presence of cervical lymph node metastasis and histological type. Univariate and multivariate analysis were performed using the Cox proportional hazard analysis. Tumor size (p=0,001), extrathyroidal extension (p=0,027), higher risk ATA groups (p=0,025) and advanced TNM stages (p=0,001) were associated with recurrence. Expression levels of miR-9 and miR-21 were significantly lower in the recurrent group than in the nonrecurrent group (p<0,001 and p=0,001, respectively). MiR-9 and miR-21 expression levels were considered significant prognostic factors for recurrence in patients with papillary thyroid cancer (RR = 1,48; 95% CI: 1,24-1,77 and RR = 1,52; 95% CI: 1,18-1,94; respectively), but miR-10b and miR-146b were not. Multivariate analysis involving the expression levels of miR-9 and miR-21 and clinical parameters indicates that the expression levels are independent prognostic factor for papillary thyroid cancer patients. In conclusion, our results support the potential clinical value of miR-9 and miR-21 expression levels assessed in primary tumor samples as prognostic biomarkers for recurrence in papillary thyroid cancer

Orientador: José Francisco Comenalli Marques Júnior / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-21T08:08:20Z (GMT). No. of bitstreams: 1 Moraes_MaraCabral_M.pdf: 399240 bytes, checksum: bb189c0420b266a0b620156bd10cd435 (MD5) Previous issue date: 2012 / Resumo: INTRODUÇÃO: A ILD vem sendo utilizada como opção terapêutica para recaída de neoplasias hematológicas após transplante alogênico. Contudo, este procedimento não é isento de riscos e sua indicação deve ser criteriosa. Neste trabalho avaliamos a ILD quanto à eficácia da coleta; efeitos adversos para os doadores e pacientes e efeitos quanto à remissão da doença, redução de recaída e mortalidade. MÉTODOS: Foi realizado estudo retrospectivo dos pacientes (n=40) que receberam ILD, no Hemocentro da UNICAMP, de março 1995 a janeiro 2008, e dos respectivos doadores (n=40). As características dos pacientes, complicações e sobrevida foram comparadas a um grupo de pacientes (n=264) que realizou transplante alogênico e não recebeu ILD. RESULTADOS: As 54 coletas de linfócitos analisadas atingiram o alvo estabelecido de '10 POT. 7' CD3+/Kg receptor, sem nenhuma reação grave para os doadores. Não observamos diferença estatística na mortalidade (p= 0,85) ou incidência de DECHa (p=0,231) entre os grupos de pacientes. No entanto, as causas de óbito foram diferentes (p<0,001), com maior mortalidade por doença no grupo em estudo e por outras causas no grupo comparativo. A incidência de DECHc e remissão completa foram maiores no grupo comparativo (p<0,001), enquanto o tempo para o óbito foi maior no grupo em estudo (p=0,009). CONCLUSÕES: A coleta de linfócitos foi eficaz e segura para o doador. Para os pacientes a DECH se sobressaiu como efeito adverso, sem aumento após a ILD. Não foi observado aumento na remissão da doença ou queda na mortalidade após a ILD, contudo, o tempo para o óbito foi maior. Outros fatores e a heterogeneidade das amostras podem ter contribuído para os resultados encontrados / Abstract: BACKGROUND: Donor lymphocyte infusion (DLI) has been used as a therapeutic option for hematological recurrences after allogeneic transplantation. However, this procedure is not devoid of risks and its indication must be precise. In this article we assess DLI regarding collection efficacy; adverse effects in donors and patients and its impact on disease remission, recurrence induction and mortality. METHODS: A retrospective study of patients (n=40) who received DLI and their respective donors was performed at Hemocentro, UNICAMP, between March 1995 and January 2008. Patient characteristics, complications and survival were compared to a comparative group (n=264) consisting of patients who underwent allogeneic transplantation, but did not receive DLI. RESULTS: All the 54 lymphocyte collection procedures reviewed reached the set target of '10 POT. 7' CD3+/Kg receptor, with no serious adverse reactions to the donors. We did not observe statistical difference in mortality (p=0.85) nor in the incidence of acute GVHD (p=0.231) between the two patient groups. However, causes of death were statistically different (p<0.001), with a higher disease-related mortality rate in the study group and for other causes in the comparative group. Chronic GVHD incidence and complete remission were higher in the comparative group (p<0.001), while the overall survival was longer in the study group (p=0.008). CONCLUSIONS: Lymphocyte collection was efficient and safe to the donor. As for patients, GHVD was the most important side effect but did not have a higher incidence after DLI. We did not observe an increase in disease remission or decrease in mortality rate after DLI; however, overall survival was longer. Other factors and the sample heterogeneity might have contributed to the results observed / Mestrado / Clinica Medica / Mestra em Clínica Médica

This thesis examines the relation between classical and quantum mechanics from philosophical, mathematical and physical standpoints. It first presents arguments in support of "conjectural realism" in scientific theories distinguished by explicit contextual structure and empirical testability; and it analyses intertheoretic reduction in terms of weakly equivalent theories over a domain of applicability. Familiar formulations of classical and quantum mechanics are shown to follow from a general theory of mechanics based on pure states with an intrinsic probability structure. This theory is developed to the stage where theorems from quantum logic enable expression of the state geometry in Hilbert space. Quantum and classical mechanics are then elaborated and applied to subsystems and the measurement process. Consideration is also given to spacetime geometry and the constraints this places on the dynamics. Physics and Mathematics, it is argued, are growing apart; the inadequate treatment of approximations in general and localization in quantum mechanics in particular are seen as contributing factors. In the description of systems, the link between localization and lack of knowledge shows that quantum mechanics should reflect the domain of applicability. Restricting the class of states provides a means of achieving this goal. Localisation is then shown to have a mathematical expression in terms of compactness, which in tum is applied to yield a topological theory of bound and scattering states: Finally, the thesis questions the validity of "classical limits" and "quantisations" in intertheoretic reduction, and demonstrates that a widely accepted classical limit does not constitute a proof of reduction. It proposes a procedure for determining whether classical and quantum mechanics are weakly equivalent over a domain of applicability, and concludes that, in this restricted sense, classical mechanics reduces to quantum mechanics.

Abstract Primary intracerebral hemorrhage (pICH) is a severe, suddenly occurring disease involving high mortality and poor functional outcome. In the absence of curative treatment patient management is mainly supportive with the emphasis on preventing hematoma enlargement and complications. Better understanding of the factors predicting outcome are needed to define effective treatments. An unselected population-based registry study of 982 pICH patients admitted to Oulu University Hospital during the years 1993 to 2008 was conducted The study revealed that concomitant use of warfarin and serotonin-modulating antidepressants at the time of pICH increases the case fatality rate compared to patients with warfarin alone. An elevated C-reactive protein value on admission was an independent predictor of unfavorable outcome after pICH. This association was not explained by pre-existing heart disease, diabetes, severity of the bleeding, or infections. Patients undergoing surgical hematoma evacuation were observed to have improved 3-month survival compared to conservatively treated patients. Improved survival was noticed especially in patients with ≤70 years of age with ≥30ml supratentorial ICHs. Hematoma evacuation did not improve functional outcome. Earlier ischemic stroke was found to be an independent predictor of recurrent pICH. Diabetes seemed to increase and treated hypertension decrease the risk for fatal recurrence. Aspirin or serotonin-modulating antidepressants did not seem to increase the risk of recurrence. / Tiivistelmä Primääri aivoverenvuoto (pICH) on vakava, yhtäkkisesti alkava sairaus, johon liittyy korkea kuolleisuus ja vaikea vammautuminen. Parantavan hoidon puuttuessa on hoito lähinnä elintoimintoja tukevaa vuodon laajenemisen ja komplikaatioiden estämistä. Ennusteeseen vaikuttavien tekijöiden parempi tunteminen on ehto tehokkaiden hoitojen löytämiseksi. Väitöskirjatutkimustani varten kerättiin Oulun yliopistollisen sairaalan alueelta vuosien 1993-2008 aikana 982 aivoverenvuotoon sairastuneen potilaan väestöpohjainen aineisto. Tutkimus osoitti, että varfariinin ja selektiivisen serotoniinin takaisinoton estäjän (SSRI) yhteiskäyttö aivoverenvuodon aikana lisäsi kuolevuutta pelkkään varfariiniin nähden. Alkuvaiheen koholla oleva C-reaktiivinen proteiini oli itsenäinen aivoverenvuodon jälkeistä vammautuneisuutta ennustava tekijä. Yhteys ei selittynyt olemassa olevalla sydänsairaudella, diabeteksella, aivoverenvuodon vaikeudella tai infektioilla. Kirurginen aivoverenvuodon poistoleikkaus paransi kolmen kuukauden ennustetta verrattuna potilaisiin ilman leikkausta. Erityisesti leikkaus auttoi alle 70-vuotiaita potilaita, joilla oli yli 30 millilitran kokoinen pinnallisempi vuoto. Leikkaus ei parantanut fyysistä kuntoutumista. Aiempi sairastettu aivoinfarkti oli itsenäinen aivoverenvuodon uusiutumista ennustava tekijä. Diabetes saattaa lisätä ja hoidossa oleva verenpainetauti laskea riskiä tappavaan uusintavuotoon. Aspiriinin tai SSRI:n käyttö eivät lisänneet uusintavuodon riskiä.

Abstract The purpose of this study was to evaluate the effect of antibiotic treatment and surgery on acute otitis media (AOM), and to evaluate quality of life (QoL) among children with AOM and their parents. To evaluate the effectiveness of antibiotics, a total of 82 children with AOM were randomized for antibiotic or placebo treatment for 7 days. The duration of middle ear effusion was measured by daily tympanometry screenings at home over 2 weeks. Duration was also measured at clinical visits, including at entry, after 3 days, after 7 days, and then weekly until both ears were healthy according to pneumatic otoscopy or otomicroscopy, or for a maximum of 2 months. Among the group receiving antibiotics, middle ear effusion disappeared 2.0 weeks earlier than among those receiving placebo (P&lt;0.02). On day 14, 69% of children in the antibiotic group and 38% in the placebo group had normal tympanometry findings (P=0.02). On day 60, 5% of children in the antibiotic group and 24% in the placebo group had persistent middle ear effusion (P=0.01). The effect of surgery was assessed by randomly assigning 300 children with recurrent AOM, aged 10 months to 2 years, into 3 groups: 1. to receive ventilation tubes (VTs), 2. to receive VTs and adenoidectomy and 3. non-surgery. Follow-up of children occurred at clinical visits every 4 months for a 1-year period. If children suffered from upper respiratory symptoms or their parents suspected AOM during this period they were encouraged to receive additional follow-up care. Intervention was considered unsuccessful if a child had 2 AOM episodes in 2 months, 3 episodes in 6 months or persistent effusion lasting for 2 months. Intervention failed in 34% of children in the non-surgery group, 21% in the VT group (P=0.04 compared to non-surgery) and 16% in the group with VT and adenoidectomy (P=0.004 compared to non-surgery). QoL was assessed among 159 children participating in the study on the effect of surgery in children with recurrent AOM. We used disease-specific (Otitis Media-6) and generic instruments (Child Health Questionnaire-50) to measure QoL among children with AOM and their parents, and the effect of surgery on QoL. Children with AOM and their parents had a significantly poorer QoL than healthy children. QoL improved significantly at 1-year follow-up, but it did not reach the level observed in healthy children. Surgery did not have any additional impact on QoL. / Tiivistelmä Työn tavoitteena oli tutkia antibiootin ja kirurgian vaikutusta äkilliseen välikorvatulehdukseen sekä tutkia välikorvatulehduksia sairastavien lasten ja heidän vanhempiensa elämänlaatua. 82 äkillistä välikorvatulehdusta sairastavaa lasta satunnaistettiin saamaan joko antibiootti- tai lumelääkettä. Välikorvaeritteen poistumista seurattiin kotona päivittäisillä tympanometriamittauksilla kahden viikon ajan. Seurantakäynnit olivat yhden, kolmen ja seitsemän päivän kuluttua sekä viikoittain, kunnes korvat oli todettu terveiksi pneumaattisella otoskoopilla tai korvamikroskoopilla tai kahden kuukauden seuranta-aika päättyi. Välikorvaerite poistui kaksi viikkoa aikaisemmin antibiootti- kuin lumelääkkeellä (P&lt;0.02). Tympanometria normalisoitui kahden viikon kuluttua 69 %:lla antibioottiryhmästä ja 38 %:lla lumelääkeryhmästä (P=0.02). 60 päivän kuluttua välikorvaeritettä oli 5 %:lla antibioottiryhmästä ja 24 %:lla lumelääkeryhmästä (P=0.02). Kirurgian vaikuttavuutta toistuviin äkillisiin välikorvatulehduksiin tutkittiin satunnaistamalla 300 10–24 kk:n ikäistä lasta saamaan ilmastointiputket tai sekä ilmastointiputket että kitarisanpoisto tai ei kumpaakaan. Seurantakäynnit olivat neljän kuukauden välein vuoden ajan tai aina kun lapset sairastuivat ylähengitystietulehdukseen tai vanhemmat epäilivät välikorvatulehdusta. Interventio katsottiin epäonnistuneeksi (äkillisiä välikorvatulehduksia 2 / 2 kk, 3 / 6 kk tai jatkuva erite 2 kk) 34 %:lla ilman kirurgiaa hoidetuista lapsista, 21 %:lla ilmastointiputkiryhmän lapsista (P=0.04 verrattuna ilman kirurgiaa hoidettuihin) ja 16 %:lla lapsista, joille tehtiin sekä kitarisan poisto että asetettiin ilmastointiputket (P=0.004 verrattuna ilman kirurgiaa hoidettuihin). Elämänlaadun, äkillisen välikorvatulehduksen sekä siihen liittyvän kirurgian välistä yhteyttä selvitettiin 159 lapsella, jotka osallistuivat kirurgian vaikuttavuutta selvittävään tutkimukseen. Elämänlaatua mitattiin sekä tautikohtaisilla (Otitis Media-6) että yleistä elämänlaatua (Child Health Questionnaire-50) mittaavilla kyselylomakkeilla. Äkillistä välikorvatulehdusta sairastavilla lapsilla ja heidän vanhemmillaan oli merkittävästi huonompi elämänlaatu kuin terveillä. Elämänlaatu parani merkittävästi vuoden seuranta-aikana, mutta ei saavuttanut terveiden tasoa. Kirurgia ei tuonut mitään lisähyötyä elämänlaatuun.

La mammite clinique (MC) est l'une des maladies les plus fréquentes et plus coûteuses touchant les vaches laitièrs. Un des L'aspect frustrant de la MC est sa récurrence. Il n’existe actuellement aucune étude exhaustive sur le risque de récurrence de la MC, les facteurs de risque de cas répétés de MC et ses impacts. Cependant, la récurrence de la MC chez les vaches laitières a été abordée dans de nombreuses études indépendantes. Par conséquent, un examen de portée a été effectué afin de développer des connaissances sur le risque de récurrence de la MC, ses facteurs de risque et ses impacts négatifs. Deux bases de données (PubMed et CAB Abstracts) et une plate-forme de recherche (Web of Science) ont été utilisées pour récupérer de nombreuses publications scientifiques pertinentes publiées en anglais et français après 1989. Cinquante-sept articles ont été sélectionnés pour la synthèse qualitative. Trente-trois, 19 et 37 études choisies inclurent respectivement des descriptions et des données sur les cas récurrents de MC, ses impacts négatifs et ses facteurs de risque. Ensuite, une méta-analyse et une méta-régression ont été effectuées pour calculer le rapport de risque (RR), permettant de comparer le risque de MC chez les vaches ayant subi un cas de MC dans une lactation donnée par rapport au risque de MC chez les vaches en santé. Le nombre total de lactations suivies et le nombre de lactations avec ≤ 1 et ≤ 2 cas de MC ont été rapportés dans neuf études et cette information a été utilisée dans la méta-analyse. Ces neuf études ont ensuite été séparées en deux groupes selon le temps minimum entre deux cas pour considérer qu'un cas subséquent est un nouveau cas ; ceux avec des échéances de 24 heures et de ≥ 5 jours entre deux cas de MC, considérant la prochaine occurrence de MC comme étant un nouveau cas de MC. Pour les études avec d'un délai minimum de seulement 24 heures, les vaches ayant déjà subi un cas de MC dans une lactation donnée avaient un RR de 1,5 fois plus élevé pour une MC récurrente comparativement aux vaches en santé. Cependant, pour les études demandantdes délais ≥ 5 jours entre deux cas de MC, le risque de cas répétés de MC n’était pas différent chez les vaches ayant déjà subi un cas de MC dans une lactation donnée comparativement aux vaches en santé (RR : 0,99, IC à 95 % : 0,86 et 1,1). Dans cette étude, la diminution de la production laitière et le risque accru de décès et de réforme ont été identifiés comme étant des impacts négatifs importants de la MC récurrente. Les vaches laitières âgées, les vaches laitières à haute production laitière et le manque de guérison bactériologique à la suite d’un premier cas de MC ont été identifiés comme étant les plus importants facteurs de risque de la MC récurrente. Une meilleure compréhension concernant les caractéristiques des vaches et des agents pathogènes associés à la récurrence des événements de MC pourrait éventuellement aider à contrôler ces événements récurrents, à réduire les coûts associés et à diminuer les quantités d'antibiotiques utilisées dans les fermes laitières. De plus, l'acquisition de ces connaissances pourrait également être utile pour prédire la probabilité d'un événement récurrent de MC et pourrait par conséquent être utile pour développer des outils servant à formuler les décisions de gestion des producteurs laitiers concernant la MC. / Clinical mastitis (CM) is one of the most common and most costly diseases of dairy cows in dairy herds. A frustrating aspect of CM is its recurrent nature. Currently, no study has reported in an exhaustive and comprehensive manner information about risk of recurrent CM, risk factors for CM recurrence and its impacts. However, the information about CM recurrence in dairy cows were investigated in many, but disconnected studies. Therefore, a scoping review was conducted to synthesize knowledge on risk of recurrent CM, its risk factors, and negative impacts. Two databases (PubMed and CAB Abstracts), and one search platform (Web of Science) were searched to identify relevant English or French scientific literature published after 1989. Fifty-seven articles were selected for qualitative synthesis. Description of recurrent CM, its negative impacts, and risk factors were reported in 33, 19, and 37 selected studies, respectively. Then, meta-analysis and meta-regression analysis were applied to compute risk ratio (RR) comparing risk of CM in cows that experienced one CM case in the current lactation to risk of CM of healthy cows. The total number of lactations followed and the number of lactations with ≤ 1 and ≤ 2 CM cases were reported in nine studies and the information was used in meta-analysis. These nine studies were then separated into two groups based on recurrent CM definition; those requiring only 24 h and those requiring ≥ 5 d between two CM cases to consider a CM case as a new CM event. For studies requiring only 24 h, cows that already had one CM case in the current lactation had a 1.5 times higher RR for recurrent CM than healthy cows. However, for studies using ≥ 5 d between two CM cases, risk of repeated cases of CM was not different in cows that suffered one CM case in a given lactation as compared with healthy cows (RR: 0.99; 95% CI: 0.86, 1.1). In this study, milk yield reduction and increased risk of mortality and culling were identified as important negative impacts of recurrent CM. Moreover, the most important CM recurrence risk factors were older dairy cow, high-producing dairy cow, and not having cure of treatment following initial CM case. A better understanding of the cow’s, pathogens’ and herd’s characteristics associated with recurrent CM events may possibly help controlling these recurrent events, decrease the associated costs as well as reduce amounts of antibiotics used on dairy farms. Moreover, these knowledges may be also useful in predicting the probability of a repeated CM event and could, therefore, be used to develop tools to inform dairy producer’s CM-related management decisions.

Ces travaux de thèse s'inscrivent dans le contexte de la prédiction de la récidive en radiothérapie du cancer de l'utérus. L'objectif était d'analyser les images de tomographie par émission de positons (TEP) au 18F-fluorodésoxyglucose (18F-FDG) en vue d'en extraire des paramètres quantitatifs statistiquement corrélés aux événements de récidive. Six études ont été réalisées afin de répondre aux différentes problématiques soulevées par l'analyse des images 18F-FDG TEP telles que la présence d'artefact, l'isolation du métabolisme tumoral ou l'évaluation du signal en cours de traitement. Les études statistiques ont porté sur l'analyse de paramètres reflétant l'intensité, la forme et la texture du métabolisme tumoral avant, et en cours de traitement. À l'issue de ces travaux, le volume métabolique tumoral pré-thérapeutique ainsi que la glycolyse totale de la lésion per-thérapeutique apparaissent comme les paramètres les plus prometteurs pour la prédiction de récidive de cancers du col de l'utérus. De plus, il apparaît que la combinaison de ces paramètres avec d'autres caractéristiques de texture ou de forme, à l'aide de modèles statistiques d'apprentissage supervisé ou de modèles de régression plus classiques, ont permis d'augmenter la prédiction des événements de récidive. / This thesis deals with the issue of predicting the recurrence within the context of cervical cancer radiotherapy. The objective was to analyze positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) to extract quantitative parameters that could show statistical correlation with tumor recurrence. Six study were performed to address 18F-FDG PET imaging issues such as the presence of bladder uptake artifacts, tumor segmentation impact, as well as the analysis of tumor evolution along the treatment. Statistical analyses were performed among parameters reflecting intensity, shape and texture of the tumor metabolism before, and during treatment. Results show that the pre-treatment metabolic tumor volume and the per-treatment total lesion glycolysis are the most promising parameters for cervical cancer recurrence prediction. In addition, combinations of these parameters with shape descriptors and texture features, using machine-learning methods or regression models, are able to increase the prediction capability.

O objetivo do presente estudo foi avaliar a estabilidade das alterações cefalométricas dentoesqueléticas e do perfil tegumentar obtidas durante a correção da má oclusão de Classe II divisão 1, com o aparelho Herbst com cantiléver seguido do aparelho fixo, 11 anos após o término de tratamento. O grupo tratado foi composto por 13 pacientes (3 feminino; 10 masculino) com idade média inicial de 12,87 anos os quais foram avaliados em três estágios: inicial (T1), final (T2), e pós-tratamento em longo prazo (T3). O grupo controle foi composto por 15 indivíduos (5 feminino; 10 masculino) com oclusão normal e idade média compatível com a do grupo tratado. A análise de variância para medidas repetidas (ANOVA), seguida por testes de Tukey (p<0,05) foram utilizadas para comparação intragrupo entre os três estágios. A comparação intergrupos das alterações no período pós-tratamento em longo prazo (T3-T2) e alterações do crescimento normal em um período comparável foram realizadas por meio do teste t (p<0,05). A maior parte das alterações dentoesqueléticas e dos tecidos tegumentares obtidas durante o tratamento se mantiveram estáveis em longo prazo. No entanto, a sobremordida demonstrou recidiva significativa, enquanto o lábio inferior tornou-se mais retrusivo em relação ao grupo controle. Apesar de alterações sutis terem ocorrido na sobremordida e na posição do lábio inferior em longo prazo, essas podem ser consideradas de menor relevância clínica. O tratamento da Classe II com Herbst com cantiléver seguido de aparelho fixo demonstrou estabilidade em longo prazo. / The aim of this study was to assess the stability of the dentoskeletal and soft-tissue cephalometric changes obtained during Class II division 1 malocclusion correction with the Cantilever Bite Jumper (CBJ), followed by fixed appliances, 11 years after treatment. The treatment group comprised 13 patients (3 female; 10 male) with an initial mean age of 12.87 years who were evaluated in three stages: initial (T1), final (T2), and long-term posttreatment (T3). The control group comprised 15 subjects (5 female; 10 male) with normal occlusion and compatible mean age with the treated group. Repeated measures analysis of variance (ANOVA), followed by Tukey tests (p<0.05) were used for intratreatment comparisons among the three stages. Intergroup comparisons of long-term posttreatment changes (T3-T2) and normal growth changes in a comparable period were performed with t tests (p<0.05). Most of dentoskeletal and soft-tissue changes obtained during treatment remained stable in the long-term. However, overbite demonstrated significant relapse while lower lip become more retrusive in relation to control group. Although mild changes have occured in overbite and lower lip position in the long-term, these can be considered of less clinical relevance. Treatment of Class II with Cantilever Bite Jumper followed by fixed appliances showed long-term stability.

Introduction: The aim of this study was to evaluate the influence of different upper retainers in speech, through Perceptual Auditory Analysis by the laypersons and acoustic analysis. Methods: Eighteen volunteers were selected to use four types of upper retainers: conventional Wrap-Around (CWA), modified horseshoe Wrap-Around (HWA), modified anterior hole Wrap-Around (AHWA) and vacuum-formed (VF). They were used for 21 days each, with intervals of 7 days without use among them. Speech evaluation was performed in vocal excerpts recordings made before installation of the retainers (T0), immediately after the installation of each retainer (T1), and 21 days after the installation (T2). The Perceptual Auditory Analysis of laypersons was performed by means of the visual analogue scale of 100 mm, while the acoustic analysis consisted of the mean diadochokinesia (DDK) rate evaluation, as well as the formant frequencies F1 and F2 of the fricative consonants. One-way ANOVA and two-way ANOVA were used. Results: In the Perceptual Auditory Analysis of laypersons, there was a worsening in the values of T0 to T1 in all the retainers, but only for CWA and VF the values were statistically lower. In T2 the values increased, but for the VF the value still remained statistically lower than T0 while for the AHWA the difference of T0 for T2 was practically null. There were no changes in DDK values. For the formant frequencies, in general way there was a difference from T0 to T1 and a little difference from T0 to T2, whereas in the comparison among the devices the CWA presented greater changes in the F1 formants of some consonants, whereas AHWA presented lower values, with the others devices showing intermediate values. Conclusions: In both types of analysis (subjective and objective), there was a change in speech after the installation of each retainer, with an improvement after 21 days of use. The laypersons considered larger speech disorders involving VF, and smaller ones involving AHWA. For the acoustic analysis, the changes were greater for CWA, whereas for AHWA there were lower changes. / Introdução: O objetivo deste estudo foi avaliar a influência de diferentes contenções superiores na fala, através de análise perceptiva auditiva por leigos e análise acústica. Métodos: Dezoito voluntários foram selecionados para utilizar quatro tipos de contenções superiores, sendo elas: placa Wrap-Around convencional (WAC), Wrap- Around modificada em formato de ferradura (WAF) Wrap-Around modificada com orifício anterior (WAO) e contenção termoplástica transparente (CTT). Elas foram usadas por 21 dias cada, com intervalos de 7 dias sem utilização entre elas. A avaliação da fala foi realizada em gravações de trechos vocais realizadas antes da instalação das contenções (T0), imediatamente após a instalação de cada contenção (T1), assim como após 21 dias de uso destas (T2). A análise perceptiva auditiva dos leigos foi realizada através da escala visual analógica de 100 mm, enquanto a análise acústica consistiu na avaliação da média da taxa de diadococinesia (DDC), bem como a frequência dos formantes F1 e F2 das consoantes fricativas. Os testes ANOVA a um critério e ANOVA a dois critérios foram utilizados. Resultados: Na análise perceptiva auditiva dos leigos houve uma piora nos valores de T0 para T1 em todas as contenções, mas somente para WAC e CTT os valores foram estatisticamente menores. Em T2 os valores voltaram a aumentar, mas para CTT ainda houve um valor estatisticamente menor do que T0 enquanto para WAO a diferença de T0 para T2 foi praticamente nula. Não houve alterações nos valores da DDC. Para os formantes, de uma maneira geral houve uma diferença de T0 para T1 e pouca diferença de T0 para T2, enquanto na comparação entre os aparelhos a WAC apresentou alterações maiores nos formantes F1 de algumas consoantes, enquanto WAO apresentou valores menores, e os demais dispositivos valores intermediários. Conclusões: Nos dois tipos de análise (subjetiva e objetiva) houve alteração na fala após a instalação de cada contenção, havendo uma melhora após 21 dias de uso. Os leigos consideraram maiores as alterações da fala envolvendo a CTT, e menores envolvendo WAO. Para a análise acústica os valores foram piores para WAC, enquanto para WAO as alterações foram menores.

O câncer de próstata é o quinto tipo mais comum de câncer no mundo e o mais comum em homens. Fatores clínicos e anatomopatológicos atualmente usados na clínica não são capazes de distinguir entre a doença indolente e a agressiva. Existe uma grande necessidade de novos marcadores de prognóstico, a fim de melhorar o gerenciamento clínico de pacientes de câncer de próstata. Além das anormalidades em genes codificadores de proteínas, alterações em RNAs não codificadores (ncRNAs) contribuem para a patogênese do câncer e, portanto, representam outra fonte potencial de biomarcadores de câncer de próstata. Entretanto, até o momento, poucos estudos de perfis de expressão de ncRNAs foram publicados. Este projeto teve como principal objetivo identificar perfis de expressão de genes codificadores e não codificadores de proteína correlacionados com recorrência de tumor de próstata, a fim de gerar um perfil prognóstico com potencial uso como biomarcadores e elucidar o possível papel de ncRNAs no desenvolvimento do câncer. Para isso, foram analisados os perfis de expressão de genes codificadores e não codificadores de proteína de um conjunto de 42 amostras de tecido tumoral de câncer de próstata de pacientes de amostras de pacientes submetidos à prostatectomia radical, com longo acompanhamento clínico (cinco anos) e conhecida evolução da doença Nós utilizamos microarranjos por nós desenhados e fabricados pela Agilent sob encomenda, interrogando aproximadamente 18.709 transcritos não codificadores longos (>500 nt), sem evidência de splicing, que mapeiam em regiões intrônicas dentro de 5.660 loci genômicos. Os dados de expressão foram extraídos de cada arranjo, normalizados entre todas as 42 amostras de pacientes. Usando uma estratégia de múltipla amostragem, foi identificado um perfil de expressão de mau prognóstico, contendo 51 transcritos intrônicos não codificadores de proteína. O perfil prognóstico de ncRNAs foi aplicado a um conjunto teste independente de 22 pacientes, classificando corretamente 82% das amostras. Uma análise de Kaplan-Meier dos pacientes do conjunto teste indicou que as curvas de sobrevida dos grupos de alto e baixo risco foram significativamente distintas (Log-rank test p = 0,0009; Hazard ratio = 23,4, 95% CI = 3,62 a 151,2), confirmando assim que este classificador é útil para identificar pacientes com alto risco de recorrência. Além disso, estas descobertas indicam um potencial papel destes RNAs intrônicos não codificadores na progressão do tumor de próstata e apontam para os RNAs intrônicos como potenciais novos marcadores de câncer / Prostate cancer is the fifth most common type of cancer in the world, and the most common in men. Clinical and anatomo-pathological factors currently used in clinic are not able to distinguish between the indolent and the aggressive disease. There is a major need of new prognostic makers in order to improve the clinical management of prostate cancer patients. Apart from abnormalities in protein-coding genes, changes in non-coding RNAs (ncRNAs) contribute to the pathogenesis of cancer and thus represent another potential source of prostate cancer biomarkers. However, few studies of expression profiles of ncRNAs have been published. This project aimed to identify expression profiles of protein-coding and non-coding genes correlated to prostate cancer biochemical recurrence. For this, we analyzed the expression profile of 42 prostate cancer samples from patients undergoing radical prostatectomy, with long follow-up (five years), and know disease outcome. We used a custom microarray designed by us and printed by Agilent, that probes 18,709 long (>500 nt) ncRNAs mapping to intronic regions within 5,660 genomic loci. The expression data were extracted from each array and normalized across all 42 samples. Using a multiple random sampling validation strategy, we identified an expression profile of poor prognosis, comprising 51 ncRNAs. The prognostic profile of ncRNAs was applied to an independent test set of 22 patients, correctly classifying 82% of the samples. A Kaplan-Meier analysis of the test set of patients indicated that the survival curves of high and low risk groups were significantly different (Log-rank test p = 0.0009, Hazard ratio = 23.4, 95% CI = 3.62 to 151.2) thus confirming that this classifier is useful for identifying patients at high risk of recurrence. Furthermore, these findings indicate a potential role of these intronic non-coding RNAs in the progression of prostate tumors and points to the intronic ncRNAs as potential new markers of cancer.