Dissertation (Ph.D.)--University of South Florida, 2009. / Title from PDF of title page. Document formatted into pages; contains 139 pages. Includes vita. Includes bibliographical references.

Objetivo: Determinar a correlação entre os níveis de PSA, escore Gleason e a estimativa de volume tumoral em fragmentos de biópsia de próstata em pacientes portadores de CaP. Material e Métodos: No período de 26 de abril a 15 de setembro de 2000 foram avaliados 64 pacientes submetidos à dosagem do PSA sérico e com biópsia transretal da próstata compatível com carcinoma. Os fragmentos biopsiados foram analisados quanto ao diagnóstico anatomo-patológico, graduação histológica pelo sistema Gleason e estimativa de volume tumoral através da determinação da proporção de carcinoma nos fragmentos obtidos na biópsia e medida do maior eixo tumoral. Resultados: Este estudo demonstrou a associação positiva entre estimativa de volume tumoral e níveis séricos de PSA. Entre as medidas de volume tumoral a correlação foi de maior magnitude quando se considera a proporção objetiva de carcinoma na amostra. Em relação ao escore Gleason, foi demonstrada associação significativa com níveis séricos de PSA (p<0,01) e com as medidas de volume tumoral (p<0,05). Conclusão:Existe correlação entre níveis séricos de PSA, escore Gleason e estimativa de volume tumoral em fragmentos de biópsia da próstata de pacientes com adenocarcinoma da próstata, porém o impacto dessa associação na determinação prognóstica desses pacientes permanece indeterminada. / Purpose: To determine the correlation between serum prostate specific antigen (PSA) levels, Gleason score and tumor volume in prostate needle biopsy cores in patients with prostate cancer. Materials and Methods: A total of 64 patients who underwent prostate biopsy between april 26th and September 15th 2000 had the histologic diagnosis of prostate cancer. Prostate needle biopsy specimens where examined for histologic diagnosis, Gleason score and tumor volume measure through the determination of the cancer ratio in the biopsy cores and by the linear measurement of the biggest tumor axle . Serum PSA levels obtained previously to the biopsy were also determined. Results: We found a positive correlation between tumor volume estimative and PSA serum levels. Considering the tumor volume measures, the cancer ratio in the biopsy cores was the independt measure wich had the strongest correlation. Considering Gleason score, a significant association with PSA serum levels was demonstrated (p<0,01) as well when associated to tumor volume measures, Gleason (p<0,05). Conclusions: There is correlation between PSA serum levels, Gleason score and tumor volume measures in prostate needle biopsy cores in men with prostate cancer, however the impact of this association in the prognostic determination of these patients remains unclear.

Objetivo: Determinar a correlação entre os níveis de PSA, escore Gleason e a estimativa de volume tumoral em fragmentos de biópsia de próstata em pacientes portadores de CaP. Material e Métodos: No período de 26 de abril a 15 de setembro de 2000 foram avaliados 64 pacientes submetidos à dosagem do PSA sérico e com biópsia transretal da próstata compatível com carcinoma. Os fragmentos biopsiados foram analisados quanto ao diagnóstico anatomo-patológico, graduação histológica pelo sistema Gleason e estimativa de volume tumoral através da determinação da proporção de carcinoma nos fragmentos obtidos na biópsia e medida do maior eixo tumoral. Resultados: Este estudo demonstrou a associação positiva entre estimativa de volume tumoral e níveis séricos de PSA. Entre as medidas de volume tumoral a correlação foi de maior magnitude quando se considera a proporção objetiva de carcinoma na amostra. Em relação ao escore Gleason, foi demonstrada associação significativa com níveis séricos de PSA (p<0,01) e com as medidas de volume tumoral (p<0,05). Conclusão:Existe correlação entre níveis séricos de PSA, escore Gleason e estimativa de volume tumoral em fragmentos de biópsia da próstata de pacientes com adenocarcinoma da próstata, porém o impacto dessa associação na determinação prognóstica desses pacientes permanece indeterminada. / Purpose: To determine the correlation between serum prostate specific antigen (PSA) levels, Gleason score and tumor volume in prostate needle biopsy cores in patients with prostate cancer. Materials and Methods: A total of 64 patients who underwent prostate biopsy between april 26th and September 15th 2000 had the histologic diagnosis of prostate cancer. Prostate needle biopsy specimens where examined for histologic diagnosis, Gleason score and tumor volume measure through the determination of the cancer ratio in the biopsy cores and by the linear measurement of the biggest tumor axle . Serum PSA levels obtained previously to the biopsy were also determined. Results: We found a positive correlation between tumor volume estimative and PSA serum levels. Considering the tumor volume measures, the cancer ratio in the biopsy cores was the independt measure wich had the strongest correlation. Considering Gleason score, a significant association with PSA serum levels was demonstrated (p<0,01) as well when associated to tumor volume measures, Gleason (p<0,05). Conclusions: There is correlation between PSA serum levels, Gleason score and tumor volume measures in prostate needle biopsy cores in men with prostate cancer, however the impact of this association in the prognostic determination of these patients remains unclear.

Objetivo: Determinar a correlação entre os níveis de PSA, escore Gleason e a estimativa de volume tumoral em fragmentos de biópsia de próstata em pacientes portadores de CaP. Material e Métodos: No período de 26 de abril a 15 de setembro de 2000 foram avaliados 64 pacientes submetidos à dosagem do PSA sérico e com biópsia transretal da próstata compatível com carcinoma. Os fragmentos biopsiados foram analisados quanto ao diagnóstico anatomo-patológico, graduação histológica pelo sistema Gleason e estimativa de volume tumoral através da determinação da proporção de carcinoma nos fragmentos obtidos na biópsia e medida do maior eixo tumoral. Resultados: Este estudo demonstrou a associação positiva entre estimativa de volume tumoral e níveis séricos de PSA. Entre as medidas de volume tumoral a correlação foi de maior magnitude quando se considera a proporção objetiva de carcinoma na amostra. Em relação ao escore Gleason, foi demonstrada associação significativa com níveis séricos de PSA (p<0,01) e com as medidas de volume tumoral (p<0,05). Conclusão:Existe correlação entre níveis séricos de PSA, escore Gleason e estimativa de volume tumoral em fragmentos de biópsia da próstata de pacientes com adenocarcinoma da próstata, porém o impacto dessa associação na determinação prognóstica desses pacientes permanece indeterminada. / Purpose: To determine the correlation between serum prostate specific antigen (PSA) levels, Gleason score and tumor volume in prostate needle biopsy cores in patients with prostate cancer. Materials and Methods: A total of 64 patients who underwent prostate biopsy between april 26th and September 15th 2000 had the histologic diagnosis of prostate cancer. Prostate needle biopsy specimens where examined for histologic diagnosis, Gleason score and tumor volume measure through the determination of the cancer ratio in the biopsy cores and by the linear measurement of the biggest tumor axle . Serum PSA levels obtained previously to the biopsy were also determined. Results: We found a positive correlation between tumor volume estimative and PSA serum levels. Considering the tumor volume measures, the cancer ratio in the biopsy cores was the independt measure wich had the strongest correlation. Considering Gleason score, a significant association with PSA serum levels was demonstrated (p<0,01) as well when associated to tumor volume measures, Gleason (p<0,05). Conclusions: There is correlation between PSA serum levels, Gleason score and tumor volume measures in prostate needle biopsy cores in men with prostate cancer, however the impact of this association in the prognostic determination of these patients remains unclear.

Orientador: Marilisa Berti de Azevedo Barros / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-17T02:24:18Z (GMT). No. of bitstreams: 1 Amorim_VivianMaeSchmidtLima_D.pdf: 1143037 bytes, checksum: 7b0304c669d1160e712a666b80ef0553 (MD5) Previous issue date: 2010 / Resumo: Justificativa: O câncer de mama, do colo de útero e de próstata são neoplasias importantes na incidência e na mortalidade no Brasil e são agravos que dispõem de métodos de rastreamento para detecção precoce oferecidos pelo Sistema Único de Saúde (SUS). Existe a necessidade de se identificar os grupos de mulheres e de homens que não realizam os exames de detecção precoce para esses agravos, como forma de implementar as estratégias para captação desses indivíduos visando minimizar as desigualdades sociais ainda existentes em relação ao acesso aos serviços de saúde. Objetivos: Analisar as práticas de detecção precoce para o câncer de mama, do colo uterino e de próstata, segundo características sociodemográficas, filiação a planos privados de saúde, morbidade e comportamentos relacionados à saúde. Material e Métodos: Estudo do tipo transversal, de base populacional, que teve como população de estudo todos os indivíduos do sexo feminino com idade de 20 a 69 anos residentes no município de Campinas, participantes do ISACAMP 2008/2009 e homens com idade superior a 50 anos residentes nos municípios de Campinas, Botucatu, Taboão da Serra, Embu e o distrito do Butantã em São Paulo, participantes do ISA-SP 2002/2003. Para a obtenção da amostra, os setores censitários dos municípios, foram agrupados em três estratos, segundo o percentual de chefes de família com nível universitário. Foram sorteados 10 setores censitários de cada estrato, e de cada setor censitário foram sorteados os domicílios e selecionados os indivíduos que seriam entrevistados, segundo os domínios de sexo e idade. As informações foram obtidas por meio de questionário estruturado em blocos temáticos, com a maioria das questões fechadas, aplicado diretamente à pessoa sorteada. O presente estudo incluiu 992 homens com 50 anos ou mais, 696 mulheres de 40 a 69 anos e 508 mulheres de 20 a 59 anos. Foram incluídos na análise dois grupos de variáveis: as independentes compostas por variáveis sociodemográficas, filiação a plano privado de saúde, comportamentos relacionados à saúde e estado da saúde e as dependentes, referentes à realização das práticas preventivas para a detecção do câncer de mama, do colo de útero e da próstata. Para as análises estatísticas foi utilizado os programas STATA 9 e STATA 11.0, que possibilitou levar em consideração as variáveis do plano de amostragem e o efeito de delineamento. As análises bivariadas incluíram estimativas de prevalência e intervalos confiança de 95% (IC) e modelos de regressão logística múltipla de Poisson. Resultados: O presente estudo verificou que 44,4% (IC 95%: 37,3-51,7) da população estudada dos homens de 50 anos ou mais, nunca haviam realizado exame preventivo para o câncer de próstata. Dos homens que referiram ter realizado exames de detecção do câncer de próstata (55,6%) o toque retal foi referido por 61,8%, o PSA por 73,2%, a ultra-sonografia por 28,2% e a biópsia por 7,3%. Dentre os homens que referiram ter realizado algum exame, 49,7% o haviam feito no ano que antecedeu a entrevista, 23% entre um a dois anos, 10% entre dois a três anos e 17% quatro anos ou mais antes da entrevista; Dos exames realizados, 41% foram financiados SUS. Os resultados da análise de regressão múltipla de Poisson apontam que a não realização dos exames preventivos para o câncer de próstata foi significativamente mais freqüente nos homens com menos de 70 anos, menor escolaridade, de menor renda familiar per capita, que não apresentam Diabetes Mellitus, que referiram algum tipo de deficiência visual e que não fizeram consulta odontológica no ano que antecedeu a entrevista. Em relação à realização da mamografia o presente estudo mostrou que das mulheres de 40 a 69 anos residentes no município de Campinas 47,7 % (IC95% 39,1-56,5) relataram filiação a planos privados de saúde e que 64,2% das mulheres realizaram a mamografia nos dois anos que antecederam a entrevista. O principal motivo apresentado para a realização da a mamografia foi realizá-la como procedimento de rotina sem a presença de queixas ou sintomas. Para as mulheres que nunca realizaram a mamografia o motivo mais alegado foi achar que a realização do exame não é um procedimento necessário s ser feito. Não ter o conhecimento do resultado do exame mostrou-se mais prevalente nas mulheres SUS dependente em relação as que têm plano privado de saúde. Das mamografias realizadas, 49,3 % foram financiadas pelo SUS e 50,7% pelos planos privados de saúde. A análise de regressão múltipla hierarquizada de Poisson revelou que persistiram significantes as variáveis: renda e plano privado de saúde, na 1ª etapa atividade física no lazer, diabetes mellitus e a consulta odontológica na 2ª etapa. Quanto a realização da citologia oncótica 46,4% (IC95% 34,1-59,2) das mulheres de 20 a 59 anos são filiadas a planos privados de saúde e que 86,2% (IC 95% 82,6-89,1) das mulheres entre 20 a 59 anos residentes no município de Campinas fizeram o exame nos últimos 3 anos, não sendo observada diferença na realização do Papanicolaou entre as mulheres que tem e as que não tem plano privado de saúde. Apenas 6,8% das mulheres entrevistadas referiram nunca ter realizado o Papanicolaou. O principal motivo alegado para a realização do exame foi fazê-lo como exame de rotina (92,8%). Já o principal motivo referido pelas mulheres que nunca fizeram o exame foi de acharem não ser um exame necessário. Quanto ao resultado do exame somente 4,5% não sabiam do resultado do último exame. Das citologias oncóticas realizadas, 55,7 % foram financiadas pelo SUS e 44,3% por planos privados de saúde. Não foi observada a associação entre as variáveis sócio-demográficas, de filiação a planos privados de saúde, de comportamento de saúde, morbidade e a realização da citologia oncótica nos três anos que antecederam a entrevista. Conclusão: Esse estudo mostrou importantes desigualdades socioeconômicas na realização do PSA, a presença da eqüidade na realização da citologia oncótica entre as mulheres de 20 a 59 anos residentes filiadas a planos privados de saúde e as SUS dependentes. Também apontou a existência de desigualdades, na realização da mamografia, entre das mulheres de 40 a 69 mostrando que as filiadas a planos privados de saúde realizam mais o exame do que as SUS dependentes. Quanto ao acesso na realização do Papanicolaou observou-se a existência da equidade apontando para a possibilidade de que o mesmo possa ocorrer em relação as outras praticas de saúde. Estratégias que garantam a equidade no acesso necessitam serem desenvolvidas com o objetivo de minimizar as desigualdades na realização da mamografia e do PSA e da integralidade das ações pertinentes às políticas nacionais da saúde do homem e da mulher / Abstract: Justification: Breast, uterine and prostate cancer are important malignancies in terms of incidence and mortality in Brazil. The Brazilian public healthcare system offers early detection methods for these conditions. There is need to identify groups of women and men who have not undergone early detection exams in order to implement strategies for reaching these individuals with the aim of minimizing existing social inequalities related to healthcare services. Objectives: The aim of the present study was to analyze early detection practices for breast, uterine and prostate cancer based on socio-demographic characteristics, affiliations with private health plans, morbidity and health-related behavior. Materials and Methods: A population-based cross-sectional study was carried out involving a study population of all females between 20 and 69 years of age in the city of Campinas (SP, Brazil) who participated in the ISACAMP 2008/2009 health survey and men aged 50 years or older residing in the cities of Campinas, Botucatu, Taboão da Serra and Embu and the district of Butantã in Sao Paulo (SP, Brazil) who participated in the ISA-SP 2002/2003 health survey. For the determination of the sample, the census sectors of the municipalities were grouped into three strata based on the percentage of heads of family with a university education. Ten census sectors of each stratum were selected by lots; residences were selected by lots from each census sector; and the individuals to be interviewed (based on gender and age) were then selected. The information was collected using a questionnaire structured in thematic blocks, with the majority of items closed questions, administered directly to the individual selected. The study involved 992 men aged 50 years or older, 696 women between 40 and 69 years of age and 508 women between 20 and 59 years of age. Two groups of variables were used in the analysis: independent variables, made up of socio-demographic variables, affiliations with private health plans, health-related behavior and health status; and dependent variables referring to preventive practices for the detection of breast, uterine and prostate cancer. The STATA 9 and STATA 11.0 programs were used for the statistical analysis, which allowed taking the sampling plan and design effect into consideration. The bivariate analyses included prevalence estimates and 95% confidence intervals (CI) as well as Poisson multiple logistic regression models. Results: A total of 44.4% (95% CI: 37.3-51.7) of population of males aged 50 years or older had never undergone a preventive prostate cancer exam. Among the men who reported having a prostate exam (55.6%), 61.8% reported undergoing the digital rectal exam, 73.2% reported undergoing the PSA exam, 28.2% reported undergoing ultrasonography and 7.3% reported undergoing biopsies. Among the men who reported undergoing an exam, 49.7% had done so in the year prior to the interview, 23% had done so one to two years earlier, 10% had done so two to three years earlier and 17% had done so four or more years prior to the interview. A total of 41% of the exams were financed by the Brazilian public healthcare system. The results of the Poisson multiple regression analysis revealed that the failure to undergo preventive prostate cancer exams was significantly more frequent among men under 70 years of age, those with less schooling, those with a lower household income, those without diabetes mellitus, those who reported some type of visual impairment and those Who had not visited the dentist in the previous year. With regard to mammography, among the female residents of the city of Campinas aged 40 to 69 years, 47.7% (95% CI: 39.1-56.5) reported affiliations with private health plans and 64.2% reported undergoing a mammogram in the two years prior to the interview. The main reason given for undergoing the exam was as a routine procedure, with no complaints or symptoms. Among the women who had never undergone a mammogram, the most reported reason was the belief that the exam is not a necessary procedure. A lack of knowledge regarding the results of the exam was more prevalent among those dependent on the public healthcare system in comparison to those with a private health plan. Among the mammograms performed, 49.3% were financed by the public healthcare system and 50.7% were financed by private plans. The following variables remained significant in the Poisson hierarchal multiple regression analysis: income and private health plan in the 1st step; and physical leisure activity, diabetes mellitus and dental appointment in the 2nd step. Regarding cancer cytology, 46.4% (95% CI: 34.1-59.2) of the women affiliated to private health plans between 20 and 59 years of age and 86.2% (95% CI: 82.6-89.1) of those between 20 and 59 years of age residing in the city of Campinas had taken the exam in the previous three years, with no significant difference in having undergone a Papanicolaou test between women with and without a private health plan. Only 6.8% of the women interviewed reported never having taken this exam. The main reason given for taking the test was as a routine exam (92.8%). The main reason given by the women who had never taken the test was the belief that it was unnecessary. Only 4.5% did not know the result of their last Papanicolaou test. A total of 55.7% of the cancer cytology exams were financed by the public healthcare system and 44.3% were financed by private plans. No associations were found between the socio-demographic variables, affiliation with private health plans, health-related behavior, morbidity and having undergone a cancer cytology exam in the three years prior to the interview. Conclusion: The present study demonstrated important socioeconomic inequalities with regard to having undergone a PSA exam as well as equity regarding having undergone cancer cytology exams among women between 20 and 59 years of age either affiliated to private health plans or dependent on the public healthcare system. Inequalities were detected in having undergone mammography among women aged 40 to 69 years, demonstrating that those affiliated to private health plans underwent the exam more than those dependent on the public healthcare system. Equity was found with regard to the Papanicolaou test, indicating the possibility that the same could also occur with other health practices. Strategies that ensure equity in relation to access to health services need to be drafted in order to minimize inequalities regarding mammography and the PSA test as well as the promotion of integral actions that are relevant to national health policies for men and women / Doutorado / Epidemiologia / Doutor em Saude Coletiva

Abstract Human prostate-specific antigen (hPSA, KLK3) and glandular kallikrein 2 (hK2, KLK2), two members of a large human tissue kallikrein enzyme family, were produced as recombinant mature proteins for the first time and characterized. Furthermore, their association with prostate cancer was studied. Both proteins were produced with baculovirus expression vector system in pilot-scale using bioreactors. Recombinant hPSA was either active with chymotrypsin-like activity or inactive with incorrect processing of N-terminus. The molecular weight of active recombinant hPSA was 31 kD and it formed stable complexes with serine protease inhibitors, α1-antichymotrypsin (ACT) and α2-macroglobulin (2αM). Two polymorphic forms of KLK2, Arg226hK2 and Trp226hK2, were found. The recombinant Arg226hK2 had trypsin-like activity, while recombinant Trp226hK2 was inactive. The Arg226hK2 was labile with low production yields. The molecular weights of hK2 polymorphic forms were 33 kD. hPSA isoforms secreted by prostate cancer cells, LNCaP, were isolated and characterized. These proteins were N-terminally heterogeneous: 10-60% of LNCaP-PSAs were correctly processed. Molecular modeling suggested that the additions or deletions of two or four N-terminal amino acids could affect the three-dimensional structure and reduce the activity of LNCaP-PSA. Active isoforms had chymotrypsin-like activity and formed stable complexes with ACT and 2αM. The expression of hPSA and hK2 was studied with in situ hybridization and immunohistochemistry techniques in benign and cancerous prostate tissue. hK2 mRNA was expressed at a significantly higher level in prostate cancer tissue than in benign prostate tissue (P &lt; 0.0005). The hPSA mRNA expression levels were reversed (P = 0.06). In benign tissue, the mean level of hK2 mRNA was 82% of the respective value of hPSA (P &lt; 0.003), whereas in tumor tissue the mean hK2 expression level was 21% higher than that of hPSA (P &lt; 0.01). The results at protein level supported the mRNA findings. There was a correlation between hPSA and hK2 mRNA levels in both benign (r = 0.735; P &lt; 0.01) and malignant (r = 0.767; P &lt; 0.01) prostate tissue. It was shown with competitively differential PCR that the KLK2 gene was amplified in prostate tumor tissue, while the KLK3 gene was not. These results suggest that hK2 and hPSA have a diverse value in the diagnosis of prostate cancer.

Orientador: Miriam Dambros Lorenzetti / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-28T00:11:28Z (GMT). No. of bitstreams: 1 Souza_FelipeGoncalvesSchrodere_M.pdf: 1431848 bytes, checksum: df85a182625e0c75b33faa908d302d6c (MD5) Previous issue date: 2015 / Resumo: Introdução: A neoplasia de próstata é a segunda mais prevalente entre os homens, com estimativa de cerca de 68 mil casos novos no Brasil em 2014. Além disso, é a segunda causa de morte no sexo masculino por neoplasias. O câncer de próstata raramente causa sintomas em seus estágios iniciais, por isso existe a necessidade do diagnóstico precoce. Atualmente a forma de rastreamento desta neoplasia ainda é controverso, porém quando realizado, baseia-se em exame digital retal da próstata e na mensuração sérica dos níveis do PSA. Estudos de rastreamento populacional mostraram uma diminuição de 41% no casos de neoplasia avançada de próstata e risco de diagnóstico de câncer 46% maior, quando comparados a grupos não submetidos a rastreamento. O PSA não é câncer específico, então, os refinamentos do PSA (relação do PSA livre/total, densidade do PSA e velocidade do PSA) aparecem como métodos para melhorar sua especificidade, na tentativa de diminuir o número de biópsias desnecessárias. Quando existe suspeita diagnóstica, é indicada uma biópsia guiada por ultrassonografia transretal, procedimento que não é isento de complicações, principalmente as infecciosas. Objetivos: Avaliar a positividade para adenocarcinoma de próstata em biópsias guiadas por ultrassonografia transretal, e estratificá-la de acordo com a idade, com o valor do PSA total, com a densidade do PSA e com a relação entre a fração livre do PSA e o PSA total. Materiais e Métodos: Analisamos retrospectivamente os resultados obtidos no serviço de urologia do Hospital Municipal Dr. Mário Gatti com relação à positividade das biópsias estratificadas pela idade, PSA total, percentual da fração livre do PSA e densidade do PSA, comparando-os com os dados descritos na literatura. Resultados: Foram realizadas 314 biópsias no período de janeiro de 2011 à novembro de 2012. A média de idade dos pacientes foi de 65,2 (± 8,32) anos e a positividade foi de 44,9%. A positividade das biópsias foi maior com o aumento da idade (p<0,001), com o aumento do PSA (p<0,001), com o aumento da densidade (p<0,001) e com a diminuição da relação do PSA (p=0,002) Conclusão: A neoplasia prostática correlacionou-se significativamente com o aumento da idade, do PSA total, da densidade do PSA, e com a diminuição da relação entre o PSA livre sobre o PSA total / Abstract: Introduction: Prostate neoplasia is the second most prevalent neoplasia in men and about 68 thousand new cases were estimated in 2014 in Brazil. In addition, it is the second most common cause of cancer related death in men. Prostate cancer rarely causes symptoms at an early stage, hence the need of an early diagnosis. Although there is still no consensus about how to screen this neoplasia, it is done through digital rectal examination and measurement of PSA levels. Population screening trials showed a decrease of 41% in new cases of advanced prostate neoplasia. The risk of a cancer diagnosis increased 46% when compared to the group who was not screened. PSA is not cancer specific. Therefore, PSA features (relation between free PSA and total PSA, PSA density, PSA velocity) are used to increase its specificity, attempting to reduce the number of unnecessary biopsies. Once there is a cancer suspicion, a biopsy guided by transrectal ultrasonography is indicated, which is not a complication free procedure, mainly infection. Objective: to assess the positiveness of prostatic adenocarcinoma in transrectal ultrasonography guided biopsies and to evaluate it according to age, total PSA value, PSA density, and the relation between free PSA and total PSA. Materials and Methods: This is a retrospective study with patients who underwent prostatic biopsy guided by transrectal ultrasonography done by the urology team from Hospital Municipal Dr. Mário Gatti. Collected data included patient¿s age, total PSA value, PSA density and the relation between free PSA and total PSA. Results: 314 prostatic biopsies guided by transrectal ultrasonography were analyzed between January 2011 and November 2012. Patient¿s mean age was 65.2 (+/-8.32) years. A positive biopsy to adenocarcinoma was found in 44.9% of the patients. The number of positive biopsies was higher among older patients (p<0.001). It was also higher the higher the PSA (p<0.001) and the higher the PSA density (p<0.001). It was inversely related to PSA relation (p=0.002). Conclusion: There is a direct correlation between prostatic neoplasia and age, value of PSA and PSA density. Additionally, prostatic neoplasia is inversely proportional to the relation of free PSA over total PSA / Mestrado / Fisiopatologia Cirúrgica / Mestre em Ciências da Cirurgia

Prostate cancer (CaP) is the second leading cause of cancer related deaths in men in the United States. Currently, androgen depletion is an essential strategy for CaP combined with surgery, chemotherapy and radiation. Hormone independent cancer stem cells escaping conventional therapy present a major therapeutic challenge. The available treatment regimens for hormone resistant CaP are only palliative and marginally increase survival. Therefore, novel strategies to eradicate CaP including stem cells are imperative. Oncolytic virus (OV) therapy is a novel approach that overcomes the limitations posed by radiation and chemotherapy. Oncolytic virotherapy of cancer is based on the use of replication competent, tumor selective viruses with limited toxicity. Newcastle Disease Virus (NDV), an avian paramyxovirus, is a safe and promising OV successfully used in many clinical trials. NDV is inherently tumor selective and cytotoxic but replication restricted in normal cells. But, systemically delivered NDV fails to reach solid tumors in therapeutic concentrations and also spreads poorly within the tumors due to barriers including complement, innate immunity and extracellular matrix. Overcoming these hurdles is paramount to realize the exceptional oncolytic efficacy of NDV. Therefore, we engineered the fusion (F) glycoprotein of NDV and generated a recombinant NDV (rNDV) cleavable exclusively by prostate specific antigen (PSA). The rNDV replicated efficiently and specifically only in prostate cancer (CaP) cells but failed to replicate in the absence of PSA. Further, PSA-cleavable rNDV caused specific lysis of androgen independent and dependent/responsive CaP cells with a mean effective concentration (EC50) ranging from 0.01 to 0.1 multiplicity of infection (MOI). PSA retargeted rNDV efficiently lysed three-dimensional prostaspheres, suggesting efficacy in vivo. Also, PSA-cleavable NDV failed to replicate in chicken embryos, indicating absence of pathogenicity to its natural host, chickens. Prostaspheres generated from DU-145 CaP cell line derived xenografts showed self-renewal, proliferative and clonogenic potential in vitro, and exhibited increased tumorigenicity in vivo. Embryonic stem and progenitor cell markers like Nanog, Nestin and CD44 were overexpressed in spheres as compared to the cell line suggesting prostaspheres comprise tumor-initiating cells from CaP. Xenograft and cell line derived prostaspheres were permissive for rNDV replication, when the fusion protein was activated by exogenous PSA. The EC50 against tumor initiating cells was 0.11-0.14 MOI, suggesting an excellent therapeutic margin for in vivo studies. PSA retargeting is likely to enhance the therapeutic index of rNDV owing to tumor restricted replication and enhanced fusogenicity. Our results suggest PSA retargeted rNDV selectively replicates and lyse PSA producing CaP cells including tumor-initiating cells and is a promising candidate for immediate Phase I/II clinical trials. / Ph. D.

This thesis investigates two questions: the methodological strengths and weaknesses of meta-analysis and the diagnostic performance of the Stockholm3 test for clinically significant prostate cancer. Through a systematic review and meta-analysis, we explore the robustness and limitations of meta-analysis, focusing on aspects such as bias assessment, heterogeneity, and the impact of the file-drawer problem. Applying these methods, we evaluate the Stockholm3 test’s performance, comparing it to the conventional Prostate-Specific Antigen (PSA) test. Our analysis synthesizes data from four studies consisting of 6 497 men, indicating that the Stockholm3 test offers improved diagnostic accuracy, with a higher pooled Area Under the Curve (AUC), in turn suggesting better identification of clinically significant prostate cancer. Nonetheless, the study also reveals challenges within the practice of meta-analysis, including variation among study methodologies and the presence of bias. These findings highlight the dual purpose of the research: demonstrating the utility and drawbacks of meta-analysis and validating the Stockholm3 test’s potential as a diagnostic tool. The conclusions drawn emphasize the need for continued research to enhance both meta-analytic methods and the clinical applicability of the Stockholm3 test in broader populations.

O câncer de próstata (CaP) é a segunda causa mais comum de câncer em homens. De acordo com o INCA, no Brasil, em 2016, estimam-se aproximadamente 61.200 novos casos de câncer de próstata. Objetivo: Identificar as características demográficas e epidemiológicas, bem como dados do estadiamento tumoral dos pacientes com CaP atendidos na Unidade de Oncologia do Hospital Marcio Cunha na cidade de Ipatinga-MG nos anos de 2012, 2013 e 2014. Metodologia: Trata-se de um estudo retrospectivo e descritivo onde foram analisados 668 prontuários de pacientes, com registro do diagnóstico anatomopatológico, atendidos nos anos de 2012, 2013 e 2014, conforme lista fornecida pela instituição, com diagnóstico de CaP cadastrados com CID-10 - C 61. As variáveis analisadas foram: procedência, ano do diagnóstico, faixa etária, raça autodeclarada, fatores de risco como tabagismo, etilismo, história familiar de CaP, PSA total ao diagnóstico, tipo histológico da biópsia, score de Gleason da biópsia, tipo histológico da peça cirúrgica, score de Gleason da peça cirúrgica. Os dados foram analisados empregando-se estatística descritiva e inferencial, utilizando o software SPSS, versão 19.0. Resultados: A maior incidência de casos de CaP foram provenientes das cidades mais populosas da microrregião de saúde analisada e faixa etária mais prevalente foi entre 61 e 80 anos com prevalência em pardos e brancos e com histórico familiar de 17,2% de parentes de primeiro grau; com o pai em 37,3%, o irmão em 60,8% e filho em 1,9%. Apenas 165 (25,9 %) eram fumantes e 20,8% etilistas. Os níveis de PSA ficaram entre 4,1ng/ e 10ng/ml (49,5%) e quanto maior a faixa etária maiores os valores do PSA. Pacientes pardos apresentaram PSA total mais elevado. Ao avaliarmos se existia relação entre os níveis de PSA total com fatores de risco como tabagismo, etilismo e histórico familiar, somente houve relação estatisticamente significativa com o etilismo. Houve concordância do score de Gleason entre biópsia e peça cirúrgica em 70%, subgraduação em 18,7% e supergraduação em 11,3%. Comparando a idade dos pacientes com Score de Gleason, quanto maior a idade do paciente maior foi o Score de Gleason do material obtido pela biópsia via transretal Pacientes tabagistas e etilistas apresentaram Score de Gleason da peça cirúrgica mais elevados. Conclusão: A concordância entre o Score de Gleason da biópsia e o Score de Gleason da peça cirúrgica foi de 70%; etilistas apresentaram PSA mais elevados; quanto maior foi a faixa etária, mais indiferenciado foi o tumor ( biópsia); pacientes tabagistas e etilistas apresentaram tumores mais indiferenciados na peça cirúrgica; este é o primeiro estudo epidemiológico de CaP desenvolvido na região do Vale do Aço, a caracterização sócio demográfica e as associações aqui encontradas podem contribuir com programas para desenvolver ações de controle do CaP nesta região. / Prostate cancer (PCa) is the second most common cause of cancer in men. According to INCA, in Brazil, in 2016, approximately 61,200 new cases of prostate cancer are estimated. Objective: To identify the demographic and epidemiological characteristics, as well as data on the tumor staging of patients with PCa treated at the Oncology Unit of Hospital Marcio Cunha in the city of Ipatinga-MG in the years of 2012, 2013 and 2014. Methodology: This is a retrospective and descriptive study where 668 patients\' records, with a diagnosis of pathological diagnosis, were analyzed in the years 2012, 2013 and 2014, according to the list provided by the institution, with a diagnosis of PCa registered with ICD-10-C 61. The analyzed variables were: origin, year of diagnosis, age group, self-reported race, risk factors such as smoking, alcoholism, family history of PCa, total PSA at diagnosis, histological type of biopsy, Gleason score of biopsy, histological type of the surgical specimen, Gleason score of the surgical specimen. Data were analyzed using descriptive and inferential statistics, using SPSS software, version 19.0. Results: The highest incidence of PCa cases came from the most populated cities of the analyzed health micro-region and the most prevalent age group was between 61 and 80 years old, with prevalence in brown and whites and with a family history of 17.2% of first-degree relatives degree; With father in 37.3%, brother in 60.8% and son in 1.9%. Only 165 (25.9%) were smokers and 20.8% were alcoholics. PSA levels ranged from 4.1ng / e to 10ng / ml (49.5%) and the higher the age group the higher the PSA values. Brown patients had higher total PSA. When we evaluated whether there was a relationship between total PSA levels and risk factors such as smoking, alcohol consumption and family history, there was only a statistically significant relationship with alcohol consumption. There was concordance of the Gleason score between biopsy and surgical specimen in 70%, subgrade in 18.7% and overdose in 11.3%. Comparing the age of patients with Gleason score, the greater the patient\'s age, the greater the Gleason score of the material obtained by the transrectal biopsy. Smokers and alcoholists presented the highest Gleason score of the surgical specimen. Conclusion: The agreement between the Gleason score of the biopsy and the Gleason score of the surgical specimen was 70%; Higher PSA levels; The longer the age group, the more undifferentiated was the tumor (biopsy); Smokers and alcoholics presented more undifferentiated tumors in the surgical specimen; This is the first epidemiological study of PCa developed in the Vale do Aço region, the socio-demographic characterization and the associations found here can contribute with programs to develop actions of control of PCa in this region.