Orientador: Fernando Cendes / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-22T17:03:57Z (GMT). No. of bitstreams: 1 Coan_AnaCarolina_D.pdf: 6791315 bytes, checksum: 88120ea79f2fe1f4f6c17ed50c0e32d1 (MD5) Previous issue date: 2013 / Resumo: Introdução: A epilepsia de lobo temporal mesial (ELTM) não é uma doença única, mas um conjunto de diferentes síndromes com etiologias diversas, que têm uma apresentação clínica e eletroencefalográfica comum. A compreensão dos diferentes tipos de ELTM é fundamental para o desenvolvimento de terapêuticas adequadas e individualizadas. Objetivo: Avaliar e comparar a ocorrência de alterações estruturais e funcionais na ELTM com (ELTM-EH) e sem (ELTM-NL) sinais de esclerose hipocampal (EH) nas imagens de ressonância magnética (RM) e relacionar essas alterações com a resposta ao tratamento. Métodos: Pacientes com diagnóstico de ELTM, e sem lesões estruturais exceto por sinais de EH, foram avaliados através de dados clínicos e por exames de RM de 3Tesla estruturais e funcionais. Os pacientes foram classificados em ELTM com (ELTM-EH) ou sem (ELTM-NL) sinais de EH através da quantificação de volume e sinal do hipocampo. Quantificação do volume da amígdala também foi realizada. Análise de volume da substância cinzenta (SC) cerebral foi realizada através da técnica de Morfometria Baseada em Voxel (VBM). Análise de alterações funcionais relacionadas às descargas epilépticas interictais (DEIs) foi realizada com o uso concomitante de EEG e RM funcional (EEG-RMf). Resultados: A quantificação de volume e sinal hipocampal nos exames de RM de 203 pacientes com ELTM aumentou em 28% a sensibilidade de detecção de sinas de EH em comparação com a análise visual. Subgrupos de pacientes com ELTM-EH e ELTM-NL e hipertrofia de amígdala foram observados. Após exclusão de pacientes com a lateralidade do foco epiléptico indefinida, 172 pacientes (122 ELTM-EH e 50 ELTM-NL) foram avaliados clinicamente e pela técnica de VBM. O grupo ELTM-NL apresentou idade de início de crises mais elevada e menor duração da epilepsia, além de antecedente familiar de epilepsia mais frequente do que ELTM-EH. ELTM-EH e ELTM-NL apresentaram atrofia de SC difusa, incluindo tálamos e córtex sensório motor bilaterais. Diferentemente do grupo ELTM-EH, os pacientes com ELTM-NL não apresentaram atrofia em regiões temporais e apresentaram atrofia pronunciada em córtex órbito-frontal ipsilateral ao foco epiléptico. A subdivisão dos grupos de acordo com a resposta à droga antiepiléptica (DAE) revelou atrofia de SC difusa em ELTM-EH benignos e refratários, a pesar do segundo grupo apresentar atrofia mais pronunciada principalmente em áreas sem conexões diretas com o hipocampo. Diferentemente, atrofia de SC foi observada apenas nos pacientes com ELTM-NL e crises refratárias. As redes neuronais funcionais relacionadas com as DEIs deferiram entre os grupos ELTM-EH e ELTM-NL e foram distintas das redes estruturais detectadas pelo VBM. Nos exames funcionais, em ambos os grupos, supressão da atividade em áreas da Default Mode Network foi observada concomitantemente às DEIs e esse padrão foi relacionado a melhor prognóstico cirúrgico em pacientes com crises refratárias. Conclusão: Alterações estruturais e funcionais são distintas em ELTM-EH e ELTM-NL. Diferentes redes neuronais estão relacionadas ao prognóstico clínico e cirúrgico na ELTM. Conhecimento detalhado das redes neuronais envolvidas nos diversos tipos de ELTM e da interação dinâmica entre elas deve contribuir para o aprimoramento do tratamento desses pacientes / Abstract: Introduction: Mesial temporal lobe epilepsy (MTLE) is not a single disease but a group of different diseases with distinct etiologies that share common clinical and EEG characteristics. Understanding the different types of MTLE is fundamental to the development of more appropriate and individualized therapies for ictal phenomena and comorbidities of each patient. Objective: To evaluate and compare the occurrence of structural and functional abnormalities of MTLE with (MTLE-HS) and without (MTLE-NL) signs of hippocampal sclerosis (HS) in magnetic resonance imaging (MRI) and to correlate these abnormalities with the response to treatment. Methods: Patients diagnosed with MTLE defined by clinical and electroencephalographic, and without structural lesions except for signs of HS were evaluated with clinical data and structural and functional 3T MRIs. Patients were classified as MTLE with (MTLE-HS) or without (TLE-NL) signs of HS by quantifying and hippocampal volume and signal. Amygdala volume quantification was also performed. Analysis of volume of brain gray matter (GM) of both groups was performed using the technique of voxel-based morphometry (VBM). Analysis of functional changes related to interictal epileptic discharges (IED) in both groups was performed with concomitant use of EEG and functional MRI (EEG-fMRI). Results: The quantification of volume and hippocampal signal in MRI scans of 203 patients with MTLE increased in 28% the sensitivity of detecting signs of HS compared with the visual analysis. Subgroups of patients with MTLE-HS and MTLE-NL and amygdala hypertrophy were observed. After exclusion of patients with undefined or bilateral epileptic focus, a group of 172 patients (122 ELTM-HS and 50 ELTM-NL) were evaluated with VBM technique. Patients with MTLE-NL had higher age of epilepsy onset and shorter duration of epilepsy as well as more frequent family history of epilepsy than patients with MTLE-HS. MTLE-HS and MTLE-NL showed diffuse GM atrophy, including bilateral sensorimotor cortex and thalamus. Different from MTLE-HS group, patients with MTLE-NL showed no atrophy in mesial and neocortical temporal regions and had pronounced atrophy in the orbito-frontal cortex ipsilateral to the epileptic focus. The subdivision of the groups according to the response to antiepileptic drug (AED) revealed diffuse GM atrophy in both benign and refractory and MTLE-HS, despite the second group exhibit more pronounced atrophy specially in areas with no direct connections with the hippocampus. Differently, GM atrophy was observed only in patients with MTLE-NL and refractory seizures. The functional neuronal networks related to IED were different in MTLE-HS and MTLE-NL groups and were distinct from the structural networks detected by VBM technique. Functional analysis revealed in both groups suppression of activity in brain areas compatible with the Default Mode Network (DMN) concomitantly with IED and this pattern was related to better surgical outcome in patients with AED resistant seizures. Conclusion: Structural and functional networks abnormalities are distinct in MTLE-HS and MTLE-NL. Different neural networks are related to surgical and clinical prognosis in MTLE. Detailed knowledge of the neural networks involved in various types of MTLE and the dynamic interaction between them might contribute to improving the treatment of seizures and comorbidities in these patients / Doutorado / Neurociencias / Doutora em Fisiopatologia Médica

Orientador: Ricardo Della Coletta / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-23T10:39:52Z (GMT). No. of bitstreams: 1 Rodrigues_PriscilaCampioni_M.pdf: 27970537 bytes, checksum: eb1771ac3c81d257542caac03773b5c0 (MD5) Previous issue date: 2013 / Resumo: Embora várias características histopatológicas e moleculares tenham sido propostas como fatores prognósticos do carcinoma espinocelular (CEC) oral, nenhuma ainda é utilizada rotineiramente. Estudos prévios demonstraram que a presença de miofibroblastos no estroma de CECs orais é associada a um pior prognóstico e que pacientes jovens apresentam tumores com comportamento biológico distinto quando comparado ao de pacientes idosos. Os objetivos deste estudo foram 1) avaliar a influência das características demográficas, clínicas e histopatológicas no prognóstico dos CECs de língua, 2) avaliar a frequência de miofibroblastos em displasias orais (leve, moderada e severa), CECs (lesões bem diferenciadas e pobremente diferenciadas) e carcinomas verrucosos (uma variante bem diferenciada do CEC oral) e comparar a frequência destas células com hiperplasias fibrosas (HF) e 3) comparar a densidade de miofibroblastos entre CEC orais de pacientes jovens (<40 anos) e pacientes idosos (>45 anos). Para determinar a influência das características clínicas, demográficas e histopatológicas (risco histológico de Brandwein-Gensler) no prognóstico dos CECs de língua, um estudo retrospectivo com 202 pacientes foi realizado. A detecção de miofibroblastos foi realizada por reações de imuno-histoquímica para a isoforma ? da actina de músculo liso (?-SMA) em HFs com epitélio normal (n=29), displasias (n=69), CECs bem diferenciados (n=19), CECs pobremente diferenciados (n=18) e carcinomas verrucosos (n=8). A comparação entre CECs de pacientes jovens e de pacientes idosos foi realizada em um segundo grupo contendo 29 amostras pareadas para localização, estádio clínico e graduação histológica. A análise multivariada de Cox revelou que estádio T, estádio N e recorrência foram fatores independentes das sobrevidas global, específica e livre de doença para os pacientes com CEC de língua. O risco histológico não correlacionou com o prognóstico destes pacientes. HFs e displasias orais não apresentam miofibroblastos, enquanto que 62,2% dos CECs demonstraram miofibroblastos no estroma tumoral. A presença de miofibroblastos foi significantemente mais frequente nos CECs pobremente diferenciados em comparação aos CECs bem diferenciados ou aos carcinomas verrucosos. Não houve diferença estatisticamente significante entre a densidade de miofibroblastos nos CECs de pacientes jovens e idosos. Os resultados deste estudo demonstram que as características clínicas são melhores fatores preditivos para o prognóstico do CEC de língua do que o risco histológico e que a presença de miofibroblastos não é associada com displasias orais, mas tumores pobremente diferenciados apresentam uma densidade significantemente maior que tumores bem diferenciados. O estudo revelou também que a presença de miofibroblastos no estroma dos CECs de língua não diferencia entre tumores em pacientes jovens e idosos / Abstract: Although several histopathological and molecular features have been proposed as prognostic factors of the oral squamous cell carcinoma (OSCC), any is routinely used. Previous studies have demonstrated that the presence of myofibroblasts in the stroma of the OSCC is associated with a worse prognosis and that young patients have tumors with a particular biological behavior when compared with older patients. The aims of this study were 1) to evaluate the influence of the demographics, clinical and histopathological features in the prognostic of SCC of tongue, 2) to determine the frequency of myofibroblasts in the oral dysplasias (mild, moderate and severe), OSCC (well differentiated and poorly differentiated) and verrucous carcinoma (a well differentiated variant of the OSCC) and compare the density of this cell with fibrous hyperplasias and 3) to compare the density of myofibroblasts among OSCC of young patients (< 40 years) and older patients (> 45 years). To determine the influence of the clinical, demographic and histopathological (histologic risk of Brandwein-Gensler) features in the prognostic of SCCs of tongue, a retrospective study was realized with 202 patients. Myofibroblasts were detected by immunohistochemical analysis of ? smooth muscle actin (?-SMA) in fibrous hyperplasia with normal epithelium (n=29), oral dysplasias (n=69), well differentiated OSCC (n=19), poorly differentiated OSCC (n=18) and verrrucous carcinoma (n=8). The comparison between OSCC affecting young patients and older patients was realized in a second group containing 29 samples paired to localization, clinical stage and histological differentiation. Cox multivariate analysis revealed that the T stage, N stage and recurrence were independent factors of overall survival, disease-especific survival and disease-free survival. The histologic risk was not correlated with the prognostic of the patients. Fibrous hyperplasia and oral dysplasias did not show myofibroblasts in the stroma. The presence of myofibroblasts was higher in the poorly differentiated OSCCs when compared with well differentiated OSCC or with verrucous carcinomas. No significant differences existed between the presence of stromal myofibroblasts of OSCC affecting young and old individuals. The results of this study demonstrated that the clinical features were best predictive factors to the SCC of tongue prognostic than the histologic risk, and the presence of myofibroblasts was not associated with the oral dyspasias. However the poorly differentiated tumors demonstrated a higher expression of myofibroblasts than well differentiated tumors. The study also revealed that the presence of myofibroblasts in the OSCC not show differences among young and older patients / Mestrado / Patologia / Mestra em Estomatopatologia

Orientador: Maurício Etchebehere / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-20T07:16:01Z (GMT). No. of bitstreams: 1 Mouraria_GuilhermeGrisi_M.pdf: 1020067 bytes, checksum: 911879a0f520b1816324bfcb8b9f71d7 (MD5) Previous issue date: 2012 / Resumo: O carcinoma de mama é a neoplasia mais frequente no mundo desenvolvido e a segunda mais frequente no Brasil. O diagnóstico tardio da doença é associado frequentemente com a presença de metástases ósseas. No esqueleto apendicular, o fêmur é o local mais acometido. As lesões femorais muitas vezes levam a fratura. Fatores prognósticos na mortalidade de pacientes com metástase óssea oriundas de neoplasias em geral estão relatados na literatura. Entretanto, não há relato específico de fatores prognósticos nas pacientes com metástases de neoplasia de mama no fêmur submetidas a tratamento cirúrgico. A determinação dos fatores prognósticos em portadores de metástase óssea auxilia na decisão terapêutica para cada paciente. O objetivo do estudo foi determinar os fatores clínicos e ortopédicos relacionados à mortalidade nesta coorte de pacientes. O estudo retrospectivo incluiu quarenta e um pacientes submetidos a tratamento cirúrgico da metástase femoral. Foram analisadas as seguintes variáveis: número e local das metástases ósseas e viscerais, presença de fratura patológica no fêmur, técnica cirúrgica empregada e exames laboratoriais (hematócrito, hemoglobina, ureia e creatinina). Tais fatores foram correlacionados com a mortalidade utilizando-se o método de COX de regressão logística multivariada e também a construção de curvas de mortalidade de Kaplan Meier testada pelo método de log-rank. O tempo de seguimento médio foi de 37 meses. Houve alta prevalência de múltiplas metástases associadas a fraturas patológicas no momento do ato cirúrgico. A mortalidade foi elevada e precoce. A localização subtrocantérica e distal, a presença de fratura, presença de anemia e alteração na função renal associaram-se a maior mortalidade. O tipo de implante, o número de metástase óssea e a presença de metástase em outros órgãos não influenciaram na mortalidade. Conclui-se que as lesões metastáticas no fêmur devem ser tratadas cirurgicamente o mais rapidamente possível, independentemente do implante utilizado, para evitar a fratura / Abstract: Breast carcinoma is a common malignancy in the developed world and in Brazil. Late diagnosis of the disease is frequently associated with bone metastasis. In the appendicular skeleton, the femur is most commonly affected. The lesions often lead to femoral fractures. Prognostic factors of mortality in patients with bone metastases originating from cancers in general have been reported. However, there is no specific report of prognostic factors in relation to breast cancer metastasis in the femur surgically treated. The determination of prognostic factors in patients with bone metastasis can assist in therapeutic decisions for each patient. The aim of this study was to determine clinical and orthopedic factors related to mortality in patients with breast cancer and metastases to the femur underwent surgical treatment. This was a retrospective cohort study and included 41 patients undergoing surgical treatment of femoral metastases. We analyzed the following variables: number and location of bone metastases, visceral metastases, presence of pathological fracture, fixation method, and laboratory tests. These factors were correlated with mortality using Cox multivariate logistic regression and Kaplan-Meier curves. The average follow-up was 37 months. There was a high prevalence of multiple metastases associated with pathological fractures at the time of surgery. Mortality was high and early. Subtrochanteric location, the presence of fractures, anemia, and alterations in renal function were associated with higher mortality. The fixation method (synthesis or prosthesis / endoprosthesis), the number of bone metastases, and the presence of metastasis in other organs did not affect mortality.Breast cancer with metastasis to the femur is an advanced disease with early mortality. Clinical and orthopedic factors should be considered as soon as possible when lesions occur, regardless of the type of implant used / Mestrado / Fisiopatologia Cirúrgica / Mestre em Ciências

Objetivo: A partir das medidas anatômicas isoladas (altura, diâmetro externo e interno) do BMI construir um novo índice prognóstico para a cirurgia de correção do Buraco Macular Idiopático (IPBM). Tipo de estudo: intervencional, série de casos. Pacientes e Métodos: Estudo realizado no Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo e no Instituto Suel Abujamra, São Paulo-SP, entre outubro de 2005 e outubro de 2007. Foram incluídos 36 olhos de 36 pacientes com BMI, que foram avaliados segundo as medidas apresentadas ao exame de TCO (Stratus - Zeiss, versão 4.01) antes da cirurgia do BMI. Utilizando o compasso do TCO, obteve-se a medida dos maiores diâmetros externo e interno e da altura dos BMI. Por meio dessas medidas, foi criado o IPBM. Após vitrectomia posterior com retirada de Membrana Limitante Interna (MLI), sem utilização de corantes, os pacientes foram acompanhados por seis meses. Após a cirurgia, os pacientes foram avaliados no primeiro e sétimo dias, duas semanas, um, três e seis meses. Ao final do seguimento, o IBPM e outras variáveis (sexo, idade, raça, estádio do BMI pela classificação biomicroscópica de Gass, tempo decorrido desde a piora da acuidade visual informada pelo paciente e a acuidade visual pré-operatória), foram correlacionadas com o resultado anatômico e a acuidade visual pós-operatória. Resultados: Vinte e nove (80,6%) dos 36 olhos com BMI obtiveram fechamento anatômico ao final de seis meses de acompanhamento (8,86 ± 4,23 meses). Dezenove (52,7%) dos BMI eram do estádio IV de Gass, com tempo de duração maior que um ano em 21 pacientes (58,3%). A AV LogMAR corrigida pré-operatória média foi de 1,10 (0,60 a 1,62) e a pós-operatória média foi de 0,69 (0,0 a 1,60). A média de melhora da AV foi de 3,94 linhas. Em relação ao fechamento anatômico, não houve significância em relação ao tempo de história da doença entre os grupos aberto (grupo 1) e fechado (grupo 2) (Teste t-Student, p=0,072). O diâmetro da base interna foi maior no grupo 1 em relação ao grupo 2 (Teste t-Student, p=0,007). Na análise do índice IPBM, houve diferença significativa entre o grupo 1 (média 0,49) e o grupo 2 (média 0,91). (Teste t-Student, p< 0,001) A análise de regressão logística apontou que BMIs com IPBM maior que 0,53 apresentam chance de fechamento anatômico 9,6 vezes maior (Odds Ratio= 9,6, p = 0,018). Pacientes com IPBM > 0,53 apresentaram AV pós-operatória ao final do sexto mês significativamente melhor do que pacientes com IPBM < 0,53 (Mann-Whitney, p=0,005). O ganho percentual da AV foi de 41,93% nos pacientes com IBPM>0,53, quando comparado com os 7,14% do grupo com IPBM <0,53 (p=0,002). No que diz respeito à AV final LogMAR, todas as variáveis estudadas anteriormente foram submetidas ao teste de correlação de Pearson. Observou-se que o IPBM tem uma correlação negativa significante com a AV, e foi selecionado juntamente com a AV pré-operatória através de regressão linear como os melhores preditores de AV final (p<0,001 e p=0,005, respectivamente). O modelo aponta que 58,4% da AV pós-operatória está sendo explicada pelo IPBM e AV pré-operatória. Conclusões: Foi construído um novo índice Prognóstico do Buraco Macular Idiopático (IPBM) representado pela razão altura / diâmetro interno do BMI. Verificou-se que o IPBM pode ser utilizado como fator prognóstico de fechamento anatômico do BMI. O IPBM e a AV pré-operatória foram os fatores prognósticos com melhor relação para a AV no sexto mês após o tratamento cirúrgico do BMI. / Purpose: To create a new prognostic index for IMH surgery based on anatomical values of IMH height, external and internal diameters (MHPI). Type of Study: Prospective, interventional, case of series. Patients and Methods: 36 eyes with IMH of 36 patients followed at Hospital das Clinicas, University of São Paulo Medical School (HC-FMUSP) and Suel Abujamra Institute (ISA), São Paulo-SP, between October 2006 and October 2007, were included. IMH OCT measurements were obtained before surgery (Stratus - Zeiss version 4.01) Values of the larger external and internal diameters, and the IMH height were obtained using the OCT compass. The prognostic index of IMH (MHPI) was defined as the index height / internal base. MHPI was defined by using those OCT measurements. Patients underwent pars plana vitrectomy with ILM peeling without dye and were followed by 6 months. Patients were seen at days 1, 7, 14, and months 1, 2, 3, and 6 after surgery. At the end of the follow-up period, MHPI and, other variables (sex, age, ethnic group, stage of IMH following the biomicroscopic classification of Gass, the time of visual loss reported by the patient, and pre surgical visual acuity) were correlated with anatomical results and post-surgical visual acuity. Results: Twenty nine eyes (80.6%) of thirty six patients with IMH had anatomical closure at the end of the six-month follow-up (8.86 ± 4.23 months). Nineteen (52.7%) IMH were stage IV of Gass with more than one year duration in twenty one patients. Pre-surgical medium LogMAR VA was 1.10 (0.60 to 1.62) and post-surgical was 0.69 (0.0 to 1.60). Medium VA improvement was 3.94 lines. The internal base diameter (BINT) was larger in group 1 than in group 2 (t-Student Test, p=0.373). MHPI analisys showed significant difference between group 1 (average 0.49) and group 2 (average 0.91) (t-Student Test, p> 0.001). Logistical regression showed that IMH with MHPI higher than 0.53 present 9.6 times more risk of failure than those with MHPI lower than 0.53 (Mann-Whitney, p=0.005). The percentage gain of VA was 41.93% in patients with MHPI > 0.53, and 7.14% in patients with MHPI lower than 0.53 (p=0.002). In regards to the final LogMAR VA, all studied variables above submitted to Pearson correlation test. MHPI is inversely correlated with VA by linear regression with gradient procedure as best predictor of final VA (p< 0.001 and p= 0.005 respectively). The sample shows that 58.4% of post-surgery VA is being explained by the MHPI and pre-surgery VA. Conclusions: A new prognostic index for IMH surgery was defined as IMH height/internal diameter. We concluded that MHPI may be used as a prognostic factor for IMH anatomical closure after surgical treatment. MHPI and preoperatory VA were the best correlated prognostic factors for 6-month VA.

Abstract Malignant tissue growth induces marked biochemical and structural changes in the extracellular matrix of the tumour and its surrounding tissues. In the present study, we evaluated the prognostic value of the serum concentration of the markers of synthesis of type I collagen (PICP, PINP) and type III collagen (PIIINP) as well as the marker of type I collagen degradation (ICTP) and compared them with the conventional indicators of prognosis (clinical stage, grade of differentiation, histological subtype, residual tumour load and the age of the patient). The prognostic value of peritoneal cytological findings at operation was an additional object in our studies. High preoperative serum ICTP (>5.6μg/L) and PIIINP (>3.2μg/L) concentrations and a low PICP:PINP ratio (>2) correlated with poor prognosis in ovarian carcinoma in univariate analysis and in multivariate analysis when each variable was analyzed separately with the conventional factors. However, ICTP concentration was the only prognostic variable in multivariate analysis including PIIINP, PINP, ICTP and CA125. When analyzed with conventional prognostic factors (clinical stage, grade, residual tumour, presence of ascites, histology), clinical stage and ICTP were independent indicators of prognosis. In addition, malignant cells in the peritoneal fluid aspirate at primary operation, grade and the age of the patient predicted poor prognosis in multivariate analysis. Postoperative serum ICTP concentration 9-months after the operation was the strongest prognostic factor as compared to the preoperative ICTP and CA125 values and clinical variables. These results indicate that serum collagen metabolites, especially ICTP, are indicators of prognosis in epithelial ovarian cancer. The present ICTP-test does not detect the degradation products of immature type I collagen, the dominating form in ovarian cancer tissue. Therefore, the excess ICTP in invasive ovarian cancer might originate through the degradation of trivalently matured collagens in non-malignant tissues surrounding the malignancy. ICTP may thus be an indicator of invasive properties of the tumor and its determination opens up new perspective to predict the clinical outcome of ovarian cancer.

Introduction: Les données des analyses génomiques des tumeurs de vessie ont défini des sous-groupes qui présentent une agressivité et une réponse à la chimiothérapie différents. Notre but était d’identifier des marqueurs moléculaires prédictifs de l'évolution tumorale.Matériels et méthodes: Les ADNs de 54 tumeur solides et de 50 échantillons d’ urines de patients avec une tumeur de vessie ont été hybridés sur la puce CGH (Comparative Genomic Hybridization) BCA-oligo. Des TMAs (Tissue Micro Array) de 140 tissus paraffinés de tumeurs primitives et métastatiques, ont été analysés en immunohistochimie pour les marqueurs impliqués dans: stabilité de l’ADN, prolifération cellulaire et définition de sous-groupe basal ou luminal. Des corrélations avec les données cliniques ont été recherchées à tous les niveaux d’analyse.Résultats: Le nombre d'altérations chromosomiques augmentait significativement avec le stade tumoral. La distribution de ces altérations était cohérente entre les ADNs extraits de tissu tumoral et de prélèvements urinaires. Si aucun marqueur immunohistochimique ne permettait de différencier les patients métastatiques ou non, des profils de marquage similaires ont été observés entre tumeurs primitives et métastases. La présence d'emboles tumoraux lymphatiques était prédictive du statut métastatique. Conclusion: l’utilisation dans la pratique clinique de la puce BCA-oligo pour prédire une évolution d'une tumeur de vessie vers un stade ou un grade plus élevé peut être envisagée, et réalisée sur un simple prélèvement urinaire. La recherche systématique d’emboles lymphatiques sur tumeurs primitives peut être utilisée pour prédire une évolution métastatique. / Introduction: Recent data from genomic analysis of bladder tumors have identified subgroups with different aggressiveness patterns and chemotherapy response profiles. The aim of our study was to identify molecular markers that can be used in clinical practice, to predict the evolution of these tumors in order to personalize their management.Materials and Methods: DNAs extracted from 54 solid tumors and 50 urine samples from patients with bladder cancer were hybridized on the BCA-oligo CGH (Comparative Genome Hybridization) chip. TMAs (Tissue Micro Array) from 140 paraffine-embedded tissues of primary and metastatic tumors, were analyzed in immunohistochemistry with antibodies directed against proteins involved in DNA stability, cell proliferation and the definition of basal or luminal subgroup. Correlations with clinical data were sought at all levels of analysis.Results: The number of chromosomal alterations increased significantly with the tumor stage. In addition, the distribution of these alterations was consistent between the DNAs extracted from tumor tissue and those from urinary samples. If no immunohistochemical marker differentiated between metastatic and non-metastatic patients, similar labeling patterns were observed between primary tumors and metastases. Notably, the presence of lymphatic emboli was predictive of metastatic status.Conclusion: The use in clinical practice of the BCA-oligo chip to predict a progression of a bladder tumor to a higher stage or grade may be considered. This analysis is feasible on urine sample. The systematic search for lymphatic emboli on primary tumors can be used in clinical practice to predict a metastatic evolution.

Abstract Breast carcinoma is the most common malignancy in females in western countries. Classical prognostic factors such as the size of a primary tumor and the presence or absence of axillary lymph node metastases, malignancy grade and hormone receptor status reflect the subsequent risk of disease recurrence after primary therapy and the need for adjuvant therapies. However, most breast carcinomas are detected in the early stage of the disease and the value of these classical prognostic factors is limited. There is also a great need to find new factors predicting the clinical efficacy of the anticancer drugs available. In this thesis tumor suppressor gene p53, oncogene c-erbB-2 and matrix metalloproteinase-9 were evaluated for their prognostic relevance in breast carcinoma patients treated in Oulu University Hospital, and matrix metalloproteinase-9 was also analyzed in women with premalignant lesions in the breast tissue in order to examine its role in breast carcinogenesis. Histological analyses were carried out from formalin-fixed, paraffin-embedded primary tumor specimens and p53, c-erbB-2 and matrix metalloproteinase-9 (MMP-9) statuses were systematically analyzed by immunohistochemistry. P53 expression correlated with disease-free survival and overall survival in patients with early-stage breast carcinoma, regardless of adjuvant antiestrogen therapy. The co-expression of p53 and c-erbB-2 characterizes a tumor type with a clinically aggressive course of breast carcinoma. The clinical efficacy of anthracyline-based chemotherapy in metastatic carcinoma might be limited in patients with p53 expression in a primary tumor. When postmenopausal patients with lymph node metastases and receiving adjuvant antiestrogen therapy were examined, MMP-9 expression indicated a slightly greater risk of breast carcinoma recurrence in patients with estrogen receptor negative tumors. Hyperplastic breast tissue and invasive breast carcinoma lesions expressed some MMP-9 immunopositivity. However, the strongest positivity was seen in ductal carcinoma in situ samples, suggesting that MMP-9 participates in breast carcinogenesis in the preinvasive phase.

Population development of Pardubice's region from year 2006 and prognosis by year 2041 Abstract This diploma thesis sets up main task in evaluation of population development in municipalities with extended powers in the Pardubice region between 2006 and 2015. In the frame of this development are process of mortality, fertility, nuptality, divorce rate, induced abortion rate and rate of natural increase and net migration at the level of district and administrative municipalities with extended powers (ORP) using the following indicators: life expectancy at birth, infant mortality rate, total fertility rate, the general marriage rate, the general rate of divorce, abortion-livebirth ratio, crude rate of natural change and the crude rate of net migration. The next section deals with a cluster analysis, which aims to show the typology of the Pardubice region by district based on the above variables. The second objective of this work is to forecast the population in the Pardubice region by the year 2041. The forecast also includes educational structure and development of households.

Abstract Squamous cell carcinoma (SCC) of the mobile tongue is the most common type of cancer of the oral cavity, accounting for 30-40% of oral cancers. It behaves aggressively and almost half of the affected patients still die of the disease despite great advances in its medical and surgical care. Ameloblastomas are the most common clinically significant type of odontogenic tumors, constituting approximately 1% of all cysts and tumors of the jaw. They are benign but locally invasive tumors with a strong tendency to recur after surgery. Ameloblastic carcinoma combines the histological features of ameloblastoma with cytologic atypia irrespective of the presence or absence of metastasis. The effectiveness of tight junction proteins (claudins 1, 4, 5, 7 and occludin) and cancer-associated fibroblasts (CAFs) as prognostic markers in OTSCC and as markers of malignancy in ameloblastomas was studied. Abundance of CAFs and Claudin 7 derangement was found to be associated with poor disease-specific survival in oral (mobile) tongue cancer. Appearance of CAFs within the epithelial islands of ameloblastoma was found to be a marker of malignancy in the tumor. The prognostic predictability of CAF density, Ki-67 (cell proliferation marker), maspin (tumor suppressor marker) and tumor DNA content (tumor ploidy using image cytometry) in tongue cancers was also tested. CAF density was the only marker strongly predictive of prognosis. In ameloblastomas, α-SMA (for CAFs), Ki-67, epithelial membrane antigen (EMA) and DNA content (using image and flow cytometry) were assessed as markers of ameloblastic carcinoma. Only α-SMA was able to predict ameloblastic carcinoma when found in the epithelial islands. In conclusion, staining for α-SMA and claudin 7 seems to be beneficial for prognostication in tongue cancer, while α-SMA staining may be beneficial in differentiating ameloblastoma from ameloblastic carcinoma.

Abstract Pulmonary adenocarcinoma is the most common and most heterogeneous form of lung cancer, and its histological and biological diversity is well recognized. On its publication in 2011, the IASLC/ATS/ERS lung adenocarcinoma classification drew attention to the prognostic value of adenocarcinoma subtypes, and it has been anticipated to provide a novel architecture based grading system. The prognostic role of other tumor-associated features in lung adenocarcinoma is less established. MUC1 overexpression has been demonstrated in many carcinomas, and in lung adenocarcinoma, depolarized MUC1 expression has been associated with poor outcome. The role of MUC4 in lung cancer, however, is somewhat conflicting. Moreover, there is no published data on either MUC1 or MUC4 expression with regard to the different subtypes of lung adenocarcinoma. This study aimed to investigate the correlation between the IASLC/ATS/ERS classification, prognosis, and clinical characteristics in a series of 112 surgically resected lung adenocarcinoma patients. The analysis of tumor architecture aimed also at the discovery of new morphological biomarkers for lung cancer. Additionally, the study focused on the expression of MUC1, MUC4, and EGFR in lung adenocarcinoma, evaluating their relationship with tumor architecture, patient outcome, and smoking. The study applied the methods of light microscopy, immunohistochemistry, and cell culture with experimental cigarette smoke exposure combined with real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and immunoelectron microscopy. The study demonstrated that the prognostic value of the current adenocarcinoma classification is not limited to predominant growth patterns as a more favorable clinical outcome was associated with minor lepidic pattern. Significant associations were observed between adenocarcinoma subtypes and smoking history. Classic histological features of malignancy correlated with tumor architecture and survival, further confirming the prognostic value of semiquantitative growth pattern analysis and identifying potential prognostic biomarkers such as mitotic activity and tumor necrosis. Depolarized MUC1 expression correlated with histology and patient outcome, and moreover, with smoking both in vivo and in vitro, suggesting a pathogenetic relationship between cigarette smoke exposure and MUC1 in lung adenocarcinoma. / Tiivistelmä Keuhkon adenokarsinooma on maailmanlaajuisesti yleisin ja monella tapaa monimuotoisin keuhkosyöpätyyppi. Vuonna 2011 uusi kansainvälinen keuhkosyöpäluokitus nosti esille adenokarsinooman histologisten alatyyppien ennustemerkityksen, ja luokituksen on odotettu muodostavan pohjan uudelle kasvutapoihin perustuvalle gradeerausmenetelmälle. Kasvaimen muiden histopatologisten piirteiden ennusteellinen merkitys keuhkon adenokarsinoomassa on vähemmän tunnettu. MUC1-proteiinin yli-ilmentymistä on kuvattu monissa karsinoomatyypeissä, ja keuhkon adenokarsinoomassa MUC1:n poikkeava eli depolarisoitunut ilmentyminen on liitetty huonoon ennusteeseen. MUC4:n merkitys keuhkosyövässä on puolestaan ristiriitainen. Toisaalta MUC1- tai MUC4-ilmentymistä ei ole tutkittu tarkemmin keuhkon adenokarsinooman eri alatyypeissä. Väitöskirjatutkimuksessa pyrittiin selvittämään uuden adenokarsinoomaluokituksen yhteyttä ennusteeseen ja muihin kliinisiin muuttujiin aineistossa, joka käsitti 112 Oulun yliopistosairaalassa leikkaushoidettua keuhkon adenokarsinoomapotilasta. Kasvainten histopatologisten ominaispiirteiden kartoittamisen toivottiin tuovan ilmi myös uusia morfologisia ennustetekijöitä. Lisäksi tutkimus keskittyi MUC1-, MUC4- ja EGFR-proteiinien ilmentymiseen keuhkon adenokarsinoomassa, arvioiden niiden suhdetta kasvaimen histologiaan, potilaiden ennusteeseen ja tupakointihistoriaan. Tutkimusmenetelminä käytettiin valomikroskopiaa, immunohistokemiaa sekä kokeellista tupakka-altistusta soluviljelymallissa yhdistettynä kvantitatiiviseen reaaliaikaiseen käänteistranskriptiopolymeraasiketjureaktio-tekniikkaan (RT-qPCR) ja immunoelektronimikroskopiaan. Tutkimus osoitti, ettei nykyisen adenokarsinoomaluokituksen ennustearvo rajoitu hallitseviin kasvutapoihin, vaan myös väistyvä lepidinen kasvutapa vaikutti ennusteeseen suotuisasti. Keuhkon adenokarsinooman alatyyppien ja tupakoinnin välillä todettiin merkittävä yhteys. Pahanlaatuisten kasvainten klassiset histologiset piirteet liittyivät adenokarsinooman kasvutapoihin ja ennusteeseen korostaen semikvantitatiivisen kasvutapa-analyysin ennustemerkitystä ja tarjoten myös mahdollisia uusia ennustetekijöitä. Depolarisoituneen MUC1:n ilmentyminen liittyi histologiaan, ennusteeseen ja erityisesti tupakka-altistukseen sekä in vivo että in vitro. Tämä löydös viittaa mahdolliseen patogeneettiseen yhteyteen tupakoinnin ja MUC1:n välillä.