Nos últimos anos, inúmeros estudos epidemiológicos evidenciaram a forte associação entre o carcinoma do colo uterino e a infecção por papilomavírus humano (HPV). Esta associação deriva do reconhecimento de que estes vírus codificam oncoproteínas, dentre as quais E6 e E7, que apresentam propriedades transformantes. O produto do gene E7 se liga ao produto do gene retinoblastoma que perde a sua função de regular negativamente o ciclo celular. O produto do gene E6 se liga ao produto do gene supressor de tumor p53 levando a sua degradação pela via de proteólise dependente de ubiquitina. O gene p53 é um supressor tumoral com função de regulação do ciclo celular que apresenta vários polimorfismos distintos em diversos grupos étnicos e tem sido amplamente estudado tanto em tecidos normais quanto em tecidos tumorais. O polimorfismo do códon 72 do gene i>p53 é o mais estudado e pode apresentar três alelos diferentes na população. Um alelo codifica arginina (Arg), um codifica prolina (Pro) e outro, raramente encontrado, codifica cisteína (Cys). Em 1993 foi iniciado um estudo epidemiológico da história natural da infecção por HPV e neoplasia da cérvice uterina em uma população feminina de baixa renda em São Paulo (Brasil), uma das áreas de maior risco em todo o mundo. O estudo focaliza a infecção persistente por tipos oncogênicos de HPV como evento precursor que leva à carcinogênese do colo do útero e visa entender os atributos da história natural da infecção viral e das doenças associadas ao colo uterino. Um dos objetivos deste estudo é avaliar se o polimorfismo do códon 72 do gene p53 pode, ou não, ser utilizado como marcador de predisposição ao câncer do colo do útero uma vez que um estudo inicial relatou que pacientes portando o genótipo p53Arg homozigoto seriam 7 vezes mais susceptíveis ao desenvolvimento de neoplasia da cérvice uterina que pacientes contendo o genótipo p53Pro e heterozigoto p53Pro/ Arg. Contudo, vários estudos posteriores contradizem e corroboram esses achados. O presente projeto teve como objetivos, portanto, verificar se o polimorfismo do códon 72 do gene p53 poderia estar associado a infecções persistentes por HPV e ao risco de neoplasia do colo do útero, além de comparar metodologias de detecção utilizadas por outros estudos, visando esclarecer se os motivos que levam à discordância dos resultados podem ser atribuídos a ocorrência de erros classificatórios metodológicos. Ao todo, sete metodologias de detecção foram comparadas. Apenas uma delas, PCR alelo-específica, apresentou resultado discordante das demais utilizadas. Coincidentemente, essa metodologia foi amplamente utilizada por muitos estudos que encontraram associações tanto positivas quanto negativas. Isso poderia nos dar indícios de que os erros classificatórios dependentes de metodologia poderiam influenciar os resultados de correlação entre o polimorfismo do códon 72 e o risco de neoplasia do colo do útero. As correlações observadas por este trabalho entre este polimorfismo do códon 72 e o risco de neoplasia do colo uterino não mostraram associação deste polimorfismo com o risco de infecções persistentes por HPV e as lesões precursoras do carcinoma do colo uterino. / In recent years, a number of epidemiological studies have pointed toward a strong association between cervical cancer and infection by Human Papillomavirus (HPV). This association derives from the discovery that these viruses code for oncoproteins, among them E6 and E7 that have transforming properties. The E7 gene product associates with the retinoblastoma gene product, causing the latter to lose its function as a negative regulator of the cell cycle. The E6 gene product interacts with the tumor suppressor p53 gene product, resulting in its degradation via ubiquitin dependent proteolysis. The p53 gene is a tumor suppressor that funcions in the regulation of the cell cycle. It presents a number of distinct polymorfisms in diverse ethnic groups, and has been widely studied, both in normal and tumor tissues. The polymorfism of codon 72 is the most studied, and may present three different alleles in the population. One allele codes for arginine (Arg), another codes for proline (Pro), and a third, rarely found, codes for cystein (Cys). In 1993 an epidemilogical study of the natural history of infection by HPV and its possible association with cervical neoplasia was initiated in a population of low income females in São Paulo, Brazil, one of the areas of greatest risk in the world. The study focuses on persistent infection by oncogenic types of HPV as a precursor to carcinogenesis of the cervix, and seeks to understand the attributes of the natural history of viral infection and of illnesses associated with the cervix. One of the objectives of the study is to evaluate if the polymorfisms of codon 72 of p53 can or not be used as a marker of predisposition to cervical cancer, given the finding in the initial study that patients who were homozygous for the p53Arg genotype were 7 times more susceptible to developing cervical neoplasias than those patients who were homozygous for p53Pro, or heterozygous p53 Pro/ Arg. Previous studies have been realized both supporting and disputing these findings. The current study had two main objectives: to verify if the polymorfism of p53 codon 72 could be associated with persistent infections of HPV and the risk of cervical neoplasia, as well as to compare methods of detection used by other studies, in an attempt to clarify if the discording results of past studies could be due to methodological classification errors. Seven detection methods were compared. Only one of these, allele specific PCR, presented discording results from the rest. Coincidentally, this method was widely used in a number of studies which found both positive and negative associations. This might indicate that the method-dependent classification errors could influence the results of correlation between codon 72 polymorphism and the risk of cervical neoplasia. The correlations observed by this study did not demonstrate an association between codon 72 polymorphism and the risk of persistent HPV infection and precursor lesions of cervical cancer.

by Chan Pui Chung, Denise. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2000. / Includes bibliographical references (leaves 119-135). / Abstracts in English and Chinese. / ACKNOWLEDGEMENTS --- p.i / ABSTRACT --- p.iii / ABSTRACT (CHINESE VERSION) --- p.v / TABLE OF CONTENTS --- p.vi / LIST OF TABLES --- p.x / LIST OF FIGURES --- p.xii / LIST OF ABBREVIATIONS --- p.xiv / Chapter CHAPTER 1 --- INTRODUCTION --- p.1 / Chapter 1.1 --- Biology of Human Papillomaviruses --- p.2 / Chapter 1.1.1 --- Taxonomy --- p.2 / Chapter 1.1.2 --- Genomic organisation --- p.2 / Chapter 1.1.3 --- "Types, subtypes and variants" --- p.4 / Chapter 1.2 --- Epidemiology of cervical cancers --- p.6 / Chapter 1.2.1 --- Incidence --- p.8 / Chapter 1.2.2 --- Cervical cancers screening programme --- p.10 / Chapter 1.3 --- Association between human papillomavirus and cervical cancers --- p.11 / Chapter 1.3.1 --- Infection --- p.11 / Chapter 1.3.2 --- Multistep pathogenesis of cervical cancers --- p.13 / Chapter 1.3.3 --- Geographical distribution --- p.14 / Chapter 1.3.4 --- Age distribution of HPV infection --- p.15 / Chapter 1.3.5 --- Oncogenic property of HPV --- p.15 / Chapter 1.3.6 --- Sequence variation --- p.20 / Chapter 1.4 --- Project design --- p.23 / Chapter CHAPTER 2 --- MATERIALS AND METHODS --- p.25 / Chapter 2.1 --- Evaluation of HPV DNA extraction methods for paraffin-embedded tissues --- p.26 / Chapter 2.1.1 --- Study population --- p.26 / Chapter 2.1.2 --- Paraffin-embedded tissue collection --- p.26 / Chapter 2.1.3 --- DNA extraction --- p.26 / Chapter 2.1.3.1 --- Phenol-chloroform extraction --- p.27 / Chapter 2.1.3.2 --- Microwave extraction --- p.28 / Chapter 2.1.3.3 --- QIAGEN spin column extraction --- p.28 / Chapter 2.1.4 --- PCR amplification --- p.29 / Chapter 2.1.4.1 --- PCR amplification for human beta-globin gene --- p.29 / Chapter 2.1.4.2 --- PCR amplification for HPV DNA --- p.30 / Chapter 2.1.5 --- Optimisation of PCRs --- p.30 / Chapter 2.1.5.1 --- Optimisation of beta-globin PCRs --- p.30 / Chapter 2.1.5.2 --- Optimisation of HPV PCRs --- p.31 / Chapter 2.1.5.3 --- Analytical sensitivity of PCRs --- p.31 / Chapter 2.1.5.3.1 --- Analytical sensitivity of beta-globin PCRs --- p.31 / Chapter 2.1.5.3.2 --- Analytical sensitivity of HPV PCRs --- p.32 / Chapter 2.1.5.4 --- Detection of PCR products --- p.32 / Chapter 2.1.6 --- PCR evaluation of DNA extraction methods --- p.33 / Chapter 2.1.6.1 --- Beta-globin PCRs --- p.33 / Chapter 2.1.6.2 --- HPV PCRs --- p.33 / Chapter 2.1.6.2.1 --- MY09/MY11 PCR --- p.33 / Chapter 2.1.6.2.2 --- GP5+/GP6+ PCR --- p.34 / Chapter 2.1.6.3 --- Detection of PCR products --- p.34 / Chapter 2.2 --- Prevalence and genotype distribution of HPV --- p.35 / Chapter 2.2.1 --- Study populations --- p.35 / Chapter 2.2.1.1 --- Women with normal cervices --- p.35 / Chapter 2.2.1.2 --- Women with abnormal cervical cytologies --- p.35 / Chapter 2.2.1.3 --- Women with cervical cancer --- p.35 / Chapter 2.2.2 --- Disease classification --- p.36 / Chapter 2.2.3 --- Specimen collection and preparation --- p.36 / Chapter 2.2.3.1 --- Cervical scrape collection --- p.36 / Chapter 2.2.3.1.1 --- DNA extraction --- p.37 / Chapter 2.2.4 --- HPV DNA detection --- p.37 / Chapter 2.2.4.1 --- MY09/MY11 PCR --- p.38 / Chapter 2.2.4.2 --- GP5+/GP6+ PCR --- p.38 / Chapter 2.2.4.3 --- Detection of PCR products --- p.38 / Chapter 2.2.5 --- HPV genotyping --- p.39 / Chapter 2.3 --- Sequence variation of HPV 16 E7 gene --- p.39 / Chapter 2.3.1 --- Study population --- p.39 / Chapter 2.3.2 --- Optimisation of HPV 16 E7 nested PCR --- p.40 / Chapter 2.3.3 --- HPV 16 E7 nested PCR --- p.41 / Chapter 2.3.3.1 --- Detection of PCR products --- p.42 / Chapter 2.3.4 --- Purification of nested PCR products --- p.42 / Chapter 2.3.5 --- Direct cycle sequencing --- p.42 / Chapter 2.3.5.1 --- Cycle sequencing reaction --- p.42 / Chapter 2.3.5.2 --- Purification of cycle sequencing products --- p.43 / Chapter 2.3.5.3 --- Electrophoresis on DNA sequencer --- p.43 / Chapter 2.3.6 --- Data analysis --- p.44 / Chapter 2.4 --- Statistical methods --- p.44 / Chapter CHAPTER 3 --- RESULTS --- p.45 / Chapter 3.1 --- Evaluation of HPV DNA extraction methods for paraffin-embedded tissues --- p.46 / Chapter 3.1.1 --- Optimised conditions for beta-globin PCRs --- p.46 / Chapter 3.1.2 --- Optimised conditions for HPV PCRs --- p.47 / Chapter 3.1.3 --- Analytical sensitivity of beta-globin and HPV PCRs --- p.48 / Chapter 3.1.4 --- PCR evaluation of DNA extraction methods --- p.48 / Chapter 3.1.4.1 --- PC03/PC07 PCRs --- p.48 / Chapter 3.1.4.2 --- Beta-GPl/Beta-GP2 PCRs --- p.49 / Chapter 3.1.4.3 --- HPV PCRs --- p.49 / Chapter 3.2 --- Prevalence and genotype distribution of HPV --- p.50 / Chapter 3.2.1 --- HPV detection --- p.50 / Chapter 3.2.2 --- HPV typing --- p.50 / Chapter 3.2.3 --- Women with normal cervices --- p.51 / Chapter 3.2.4 --- Women with abnormal cervical cytologies --- p.51 / Chapter 3.2.5 --- Women with cervical cancer --- p.53 / Chapter 3.3 --- Sequence variation of HPV 16 E7 gene --- p.54 / Chapter 3.3.1 --- Optimised conditions for HPV 16 E7 nested PCR --- p.54 / Chapter 3.3.2 --- HPV 16 E7 sequencing --- p.55 / Chapter 3.3.3 --- HPV 16 E7 variants --- p.55 / Chapter 3.3.4 --- Distribution of HPV 16 E7 variants --- p.56 / Chapter CHAPTER 4 --- DISCUSSION --- p.58 / Chapter 4.1 --- Evaluation of HPV DNA extraction methods for paraffin-embedded tissues --- p.59 / Chapter 4.1.1 --- PCR evaluation of DNA extraction methods --- p.59 / Chapter 4.2 --- Prevalence and genotype distribution of HPV --- p.61 / Chapter 4.2.1 --- Women with normal cervices --- p.61 / Chapter 4.2.2 --- Women with abnormal cervical cytologies --- p.62 / Chapter 4.2.3 --- Women with cervical cancer --- p.64 / Chapter 4.3 --- Sequence variation of HPV 16 E7 gene --- p.64 / Chapter CHAPTER 5 --- CONCLUSION --- p.69 / REFERENCES --- p.119

Made available in DSpace on 2016-01-26T12:51:37Z (GMT). No. of bitstreams: 1 gustavohenriquedeoliveira_dissert.pdf: 1016056 bytes, checksum: b6eb4d4fc07821695de5cff5b5d6909b (MD5) Previous issue date: 2010-12-09 / To evaluate the importance of cervical gland area (CGA) to predict spontaneous preterm birth (SPB). Method: A prospective study was performed from October 2008 to September 2009 of 102 singleton pregnancies at 20 and 24 weeks. A transvaginal ultrasound during the routine morphological scan investigated: the cervical length, CGA, its thickness and signs of cervical funneling. A preterm birth is defined as one that occurs at less than 37 weeks gestation. Ultrasound and clinical variables were submitted to univariate analysis by calculations of descriptive statistics, the Student t-test, percentages, and two-dimensional associative arrays evaluated using the Fisher exact test and odds ratio. The level of significance was set at 5%. Results: Of the 102 patients, four were lost in the follow up and seven were excluded as delivery was induced prematurely; ten patients presented spontaneous preterm births and 81 at term. The mean maternal age was 28.8 years old (18-41 years) without significant difference between the spontaneous preterm birth and term groups. There were statistical differences in the mean (33.9 vs. 36.1 cm), median (33.5 vs. 37.0 cm) and spread (standard deviation: 9.6 vs. 7.0) of the cervical length between the two groups. Risk factors for SPB gave an odds ratio of 15.06. All patients presented a CGA with a mean thickness of 8.4 mm (5.1 to 15 mm SD: 3.1) for SPB and 8.9 mm (3.0 to 13.9 mm SD: 2.3) for term individuals. Conclusion: The results suggest that the presence or absence and thickness of CGA are not correlated to SPB even in clinically or ultrasonographically high-risk patients. Further studies are necessary to reevaluate the parameters used to predict SPB. / Avaliar a importância do eco glandular endocervical (EGE) na predição de parto prematuro espontâneo (PPE). Método: Estudo prospectivo de 102 gestações únicas, entre 20-24 semanas, de outubro/2008 a setembro/2009. Na ecografia morfológica, o exame transvaginal avaliou: comprimento do colo uterino, EGE, espessura e sinal do afunilamento. Foi considerado PPE interrupção antes de 37 semanas de gestação. As avaliações ultrassonográfica e clínica foram submetidas à análise univariada pelos cálculos de estatísticas descritivas, teste t de Student, distribuições percentuais, tabelas associativas para análises bidimensionais, teste exato de Fisher e odds ratio no nível de significância de 5%. Resultados: Das 102 pacientes, quatro perderam seguimento, sete foram excluídas por parto prematuro induzido, dez pacientes apresentaram PPE e 81 parto a termo (PT). A idade materna média foi de 28,8 anos (18-41 anos), sem diferença nos dois grupos (PPE e PT). No comprimento do colo observaram-se diferenças na média (33,9 x 36,1 cm), mediana (33,5 x 37,0 cm) e na dispersão (desvio padrão 9,6 x 7,0). Fatores de risco para PPE mostraram odds ratio de 15,06. Todas as pacientes apresentaram EGE, com espessura média de 8,4 mm (5,1 a 15 mm - desvio padrão 3,1) para PPE, e de 8,9 mm (3,0 a 13,9 mm - desvio padrão de 2,3) para PT. Conclusão: Os resultados indicam que a presença, ausência ou espessura do EGE não se correlacionou com PPE, mesmo naquelas pacientes com alto risco clínico e/ou ultrassonográfico de PPE. São necessárias novas pesquisas para reavaliação dos parâmetros indicadores de PPE.

Cervical cancer is an emerging public health problem in developing countries. Globally, it is the 3rd most common malignancy in women after breast and colorectal cancers and 4th most frequent cancer in women, with an estimated 570,000 new cases and 311,000 deaths in 2018. Cervical cancer screening in the developed countries is credited with the reductions in cervical cancer morbidity and mortality during the last 50 years. However, nearly 90% of cervical cancer deaths occur in less developed countries. Ghana has a cervical cancer rate of 26.4%. Further, it is the highest cancer incidence faced among women 25 to 44 years and has a mortality rate of 17.4% in this age group. Knowledge, culture, attitude, and beliefs are known to limit women's participation in Pap test screening programs. Guided by the health belief model, the purpose of this quantitative study was to examine how knowledge, attitude, culture, and religious beliefs affected intent to seek Pap test screening among adolescent girls in Accra, Ghana. A total of 155 participants ages 16 to 20 years completed a 30-item questionnaire. Descriptive frequencies were calculated. Correlation and Chi-square tests were also performed to assess associations with intent to screen with Pap test. Most girls (92%) had never heard about Pap test screening. There were statistically significant correlations between cervical cancer knowledge (p=0.032) and attitude (p=0.001) with intent to participate in Pap test screening. However, culture (p=0.049) and religious beliefs (p=0.529) were not significantly associated with screening intent. The implications for social change include informing practice and research on how cervical cancer prevention programs can be tailored to girls living in countries where different cultural and religious values are practiced.

Background: Cervical cancer is the second most common cause of death from cancer among women in Kenya. Various international studies indicate that the knowledge level of cervical cancer and its predisposing and preventive measures is low among the nurses as well as general population. This study aimed to assess knowledge, practices and attitudes of nurses with regards to cervical cancer screening and preventive measures at two Nairobi hospitals in Kenya. Across-sectional quantitative descriptive study design was used. Convenience sampling method was applied and data were collected from respondents using self-administered questionnaire. About 114 nurses aged 18 years and above participated in the study. The study revealed that nurses have the information about cervical cancer, available screening tests and the purpose of screening. Nurses have the knowledge that cancer screening could detect this cancer at an early stage; however, uptake is low. Cervical screening services were hampered by barriers relating to health care institutions, nurses perception and fear of screening technique, embarrassment, stigma, social influence, financial costs and available sources of information / Health Studies / M.A. (Nursing Science)

Made available in DSpace on 2015-07-22T20:49:36Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-10-28 / Em 2002, o Estado de Mato Grosso aderiu à segunda fase de intensificação Programa Nacional de Controle do Câncer do Colo do Útero (PNCCU) como medida de enfrentamento das altas taxas da doença e de morte por neoplasia cervical. Com o objetivo de analisar os principais resultados do PNCCU, foi feito um estudo em duas partes. A primeira parte teve como objetivo levantar o perfil da doença e a cobertura do exame rastreamento pelo PNCCU no Estado. Os objetivos da segunda parte foram: analisar o seguimento clínico da população rastreada, analisar as diferentes características evolutivas da doença associadas aos fatores sócio-demográficos e clínicos, bem como analisar o risco de óbito e a taxa de sobrevida estratificada pelas variáveis sócio-demográficas e clínicas das mulheres que apresentaram carcinoma invasivo. Na primeira parte, foi utilizado estudo do tipo transversal e na segunda parte, foi realizado um estudo de coorte. O período do estudo compreendeu de 2002 a 2007 e abrangeu todos os municípios do Estado de Mato Grosso. A população estudada na primeira fase do estudo correspondeu todas as mulheres que fizeram o exame de rastreamento no ano de 2002. Na segunda parte do estudo, a população correspondeu a uma amostra aleatória representativa das mulheres que apresentaram alterações citológicas na primeira fase do estudo, totalizando 323 mulheres. A fonte de dados utilizada foi o sistema de informação oficial de saúde, dentre eles o SISCOLO, SIM, APAC, além de dados oficiais da Secretaria Estadual de Saúde/MT (SES/MT), dados disponíveis no site do INCA e do DATASUS e prontuários clínicos. Para análise estatística dos dados foram utilizadas técnicas descritivas e inferenciais. Na parte descritiva foram utilizados tabelas, gráficos e medidas de posição e de dispersão. Para avaliar a o risco de adoecer por carcinoma cervical invasor foi utilizado regressão logística univariada e multivariada. Para analisar a taxa de sobrevida global foi utilizado o estimador de Kaplan-Meier e para analisar os fatores prognósticos, foi utilizado o modelo de riscos proporcionais de Cox. Dentre os principais resultados, destaca-se que no período estudado, Mato Grosso apresentou taxas de incidência elevadas, acima da média nacional. Os dados do seguimento clínico mostraram os diferentes desfechos, dentre eles, destaca-se que: entre as 323 mulheres, 18 (6,2%) foram a óbito tendo o câncer do colo do útero como causa básica da morte. Foi analisado o risco de a doença evoluir para o carcinoma invasor, segundo as variáveis sócio-demográficas e clínicas, sendo que as variáveis: faixa etária, estado civil, tabagismo, menarca e município foram as que apresentaram forte associação com a doença na fase invasora. Já na análise de sobrevivência, a taxa de sobrevida global em 60 meses, estimada pelo método de Kaplan-Meier, foi de 66,7%. No modelo final de risco proporcional de Cox, as variáveis com maior risco de óbito foi o estágio avançado da doença e a raça/cor. Estes dados levam a concluir que a doença no Estado de Mato Grosso tem uma determinação social muito grande, considerando a dificuldade de acesso aos serviços de saúde da população desfavorecida pelas condições raciais, sócio-econômicas, e chegam aos serviços com a doença em fase adiantada, quando a chance de sobrevivência é muito pequena. Conclui-se que para o efetivo combate a doença são necessárias políticas governamentais, como o PNCCU, que garantam a universalidade da assistência, principalmente da população desfavorecida socialmente. / In 2002, the State joined the second phase of intensification of the National Program for the Control of Cervical Cancer (PNCCU) as a measure to deal with the high rates of the disease and of death by cervical neoplasia. With the aim of analyzing the main PNCCU results, a two-stage study was carried out. The first phase aimed at presenting the disease profile and the coverage of the screening exam by the PNCCU in the State. The aims of the second phase were to analyze the clinical follow-up of the population that was screened, analyze the different evolutionary characteristics of the disease associated to socio-demographic and clinic factors, as well as analyze the factors associated to death risk and the stratified survival rate by the socio-demographic and clinical variables of women that presented invasive carcinoma. In the first part, the cross-sectional study was used and a cohort study was used in the second phase. The period of study was from 2002 to 2007 and comprised all the municipalities of the State of Mato Grosso. The population studied in the first phase of the study was all the women who had undergone the screening test in 2002. The population used in the second phase of the study was a representative random sample of those that presented cytological alterations in the first phase of the study, a total of 323 women. The source of data used was the official health information system, among them the SISCOLO, SIM, APAC, and also the official data of the State Health Department/MT (SES/MT), data available in the INCA and DATASUS sites and medical records. For the statistical analysis of the data, descriptive and inferential techniques were used. In the descriptive part, tables, graphics and position and dispersion measures were used. In order to evaluate the risk of being sick due to invasive cervical carcinoma, the univariate and multivariate logistic regression analysis was used. The Kaplan-Meier estimator was used to analyze the survival rate and to analyze the prognostic factors, the Cox proportional hazards model was used. Among the main results it is highlighted that in 2002, Mato Grosso presented high incidence rates, above the national average. The data of the clinical follow up showed the different clinical outcomes, among the 323 women, 18 (6,2%) died having as the basic cause of death the cervical cancer. The risk of the disease developing into the invasive carcinoma was analyzed according to the socio-demographic and clinical variables, and the variables: age group, marital status, smoking history, menopause and municipality were those that presented a strong association with the disease in the invasive phase. However, in the survival analysis, the global survival rate in 60 months, estimated by the Kaplan-Meier method, was of 66,7%. In the final Cox proportional hazards model, the variables with higher death risk was the advanced stage of the disease and the race/color. These data lead to a conclusion that the disease in the State of Mato Grosso has a very large social determination, considering the difficulties in the access to the health services by the population affected by racial, socio-economic conditions that arrive in the health services with the disease in an advanced stage, when the survival probability is very small. The conclusion is that for the effective fight against the disease governmental policies such as the PNCCU are necessary, and that the universality of the assistance be guaranteed, mainly to the socially disadvantaged population. / TEDE / BV UNIFESP: Teses e dissertações

Nos últimos anos, inúmeros estudos epidemiológicos evidenciaram a forte associação entre o carcinoma do colo uterino e a infecção por papilomavírus humano (HPV). Esta associação deriva do reconhecimento de que estes vírus codificam oncoproteínas, dentre as quais E6 e E7, que apresentam propriedades transformantes. O produto do gene E7 se liga ao produto do gene retinoblastoma que perde a sua função de regular negativamente o ciclo celular. O produto do gene E6 se liga ao produto do gene supressor de tumor p53 levando a sua degradação pela via de proteólise dependente de ubiquitina. O gene p53 é um supressor tumoral com função de regulação do ciclo celular que apresenta vários polimorfismos distintos em diversos grupos étnicos e tem sido amplamente estudado tanto em tecidos normais quanto em tecidos tumorais. O polimorfismo do códon 72 do gene i>p53 é o mais estudado e pode apresentar três alelos diferentes na população. Um alelo codifica arginina (Arg), um codifica prolina (Pro) e outro, raramente encontrado, codifica cisteína (Cys). Em 1993 foi iniciado um estudo epidemiológico da história natural da infecção por HPV e neoplasia da cérvice uterina em uma população feminina de baixa renda em São Paulo (Brasil), uma das áreas de maior risco em todo o mundo. O estudo focaliza a infecção persistente por tipos oncogênicos de HPV como evento precursor que leva à carcinogênese do colo do útero e visa entender os atributos da história natural da infecção viral e das doenças associadas ao colo uterino. Um dos objetivos deste estudo é avaliar se o polimorfismo do códon 72 do gene p53 pode, ou não, ser utilizado como marcador de predisposição ao câncer do colo do útero uma vez que um estudo inicial relatou que pacientes portando o genótipo p53Arg homozigoto seriam 7 vezes mais susceptíveis ao desenvolvimento de neoplasia da cérvice uterina que pacientes contendo o genótipo p53Pro e heterozigoto p53Pro/ Arg. Contudo, vários estudos posteriores contradizem e corroboram esses achados. O presente projeto teve como objetivos, portanto, verificar se o polimorfismo do códon 72 do gene p53 poderia estar associado a infecções persistentes por HPV e ao risco de neoplasia do colo do útero, além de comparar metodologias de detecção utilizadas por outros estudos, visando esclarecer se os motivos que levam à discordância dos resultados podem ser atribuídos a ocorrência de erros classificatórios metodológicos. Ao todo, sete metodologias de detecção foram comparadas. Apenas uma delas, PCR alelo-específica, apresentou resultado discordante das demais utilizadas. Coincidentemente, essa metodologia foi amplamente utilizada por muitos estudos que encontraram associações tanto positivas quanto negativas. Isso poderia nos dar indícios de que os erros classificatórios dependentes de metodologia poderiam influenciar os resultados de correlação entre o polimorfismo do códon 72 e o risco de neoplasia do colo do útero. As correlações observadas por este trabalho entre este polimorfismo do códon 72 e o risco de neoplasia do colo uterino não mostraram associação deste polimorfismo com o risco de infecções persistentes por HPV e as lesões precursoras do carcinoma do colo uterino. / In recent years, a number of epidemiological studies have pointed toward a strong association between cervical cancer and infection by Human Papillomavirus (HPV). This association derives from the discovery that these viruses code for oncoproteins, among them E6 and E7 that have transforming properties. The E7 gene product associates with the retinoblastoma gene product, causing the latter to lose its function as a negative regulator of the cell cycle. The E6 gene product interacts with the tumor suppressor p53 gene product, resulting in its degradation via ubiquitin dependent proteolysis. The p53 gene is a tumor suppressor that funcions in the regulation of the cell cycle. It presents a number of distinct polymorfisms in diverse ethnic groups, and has been widely studied, both in normal and tumor tissues. The polymorfism of codon 72 is the most studied, and may present three different alleles in the population. One allele codes for arginine (Arg), another codes for proline (Pro), and a third, rarely found, codes for cystein (Cys). In 1993 an epidemilogical study of the natural history of infection by HPV and its possible association with cervical neoplasia was initiated in a population of low income females in São Paulo, Brazil, one of the areas of greatest risk in the world. The study focuses on persistent infection by oncogenic types of HPV as a precursor to carcinogenesis of the cervix, and seeks to understand the attributes of the natural history of viral infection and of illnesses associated with the cervix. One of the objectives of the study is to evaluate if the polymorfisms of codon 72 of p53 can or not be used as a marker of predisposition to cervical cancer, given the finding in the initial study that patients who were homozygous for the p53Arg genotype were 7 times more susceptible to developing cervical neoplasias than those patients who were homozygous for p53Pro, or heterozygous p53 Pro/ Arg. Previous studies have been realized both supporting and disputing these findings. The current study had two main objectives: to verify if the polymorfism of p53 codon 72 could be associated with persistent infections of HPV and the risk of cervical neoplasia, as well as to compare methods of detection used by other studies, in an attempt to clarify if the discording results of past studies could be due to methodological classification errors. Seven detection methods were compared. Only one of these, allele specific PCR, presented discording results from the rest. Coincidentally, this method was widely used in a number of studies which found both positive and negative associations. This might indicate that the method-dependent classification errors could influence the results of correlation between codon 72 polymorphism and the risk of cervical neoplasia. The correlations observed by this study did not demonstrate an association between codon 72 polymorphism and the risk of persistent HPV infection and precursor lesions of cervical cancer.

Orientadores: Luiz Carlos Zeferino, Silvia Helena Rabelo dos Santos. / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-21T17:32:08Z (GMT). No. of bitstreams: 1 CastroSobrinho_JucaraMariade_D.pdf: 1214452 bytes, checksum: db87fc4f5e35e2d9e1091af5b48fc8cf (MD5) Previous issue date: 2012 / Resumo: Objetivo: Analisar a associação entre a coinfecção por papilomavírus humano (HPV), Chlamydia trachomatis (CT), vaginose bacteriana (VB) e resposta inflamatória (RI) com a gravidade da neoplasia cervical. Sujeitos e métodos: Estudo experimental, de corte transversal, realizado em Campinas, São Paulo e em Goiânia, Goiás, Brasil. A casuística incluiu amostras biológicas de 290 mulheres consecutivas submetidas à excisão da zona de transformação (EZT) ou conização. Para o estudo que avaliou a coinfecção entre HPV e CT e a associação com gravidade da neoplasia cervical foram selecionadas 251 (86,6%) mulheres infectadas por HPV de alto risco (HR-HPV). A detecção de HPV foi realizada utilizando os primers PGMY09/11 e a genotipagem através de hibridização reversa em pontos. A detecção da CT foi realizada por polimerase chain reaction (PCR) empregando primers cujo alvo é uma região de plasmídio críptico, gerando um fragmento de aproximadamente 512 pares de base. Para o estudo que avaliou a VB e resposta inflamatória e a associação destas condições com a gravidade da neoplasia cervical foram selecionadas 211 mulheres infectadas por HR-HPV, com esfregaços cervicais disponíveis para as análises. A presença de 20% ou mais de células indicadoras no esfregaço cervical corado pelo método de Papanicolau foi considerada positiva para VB. A resposta inflamatória nos esfregaços cervicais foi avaliada pela contagem do número de neutrófilos. O encontro de 30 ou mais neutrófilos por campo microscópico, observado sob o aumento de 1000x, foi considerado como presença de resposta inflamatória. Resultados: A prevalência de CT em mulheres HPV positivas foi de 15,1% (38/251). Foi observada uma associação significativa em mulheres CT negativas, com 30 anos ou mais, e NIC 2 ou pior diagnóstico, mas esta associação não foi observada em mulheres CT positivas. Infecções por HPV 16 e/ou 18 foram detectadas em 50% das mulheres CT negativas com menos de 29 anos e que apresentavam NIC 2 ou pior diagnóstico, e em 19,5% das mulheres CT negativas com NIC 1 ou não neoplásico. Nestas mulheres, a associação entre HPV 16 e/ou 18 e NIC 2 ou pior diagnóstico foi significativa, mas esta associação não foi observada no grupo CT positivo. Resposta inflamatória e VB foram observadas em 43,5% e 46,2% dos esfregaços cervicais de mulheres com NIC 2. Resposta inflamatória e VB foram observados em 64,2% e 32,6% dos esfregaços cervicais de mulheres com diagnóstico histológico de NIC 3. Nestas mulheres, quando infectadas pelos tipos de HPV 16 e/ou 18, foram observadas resposta inflamatória e VB, respectivamente, em 43,1% e 20% dos casos. Resposta inflamatória apresentou associação estatisticamente significante com NIC 2 ou pior diagnóstico em mulheres infectadas pelos tipos de HPV 16 e/ou 18 (OR= 6,70; 95%IC:2,32-19,31) e por outros tipos de HPV (OR=4,90; 95%IC: 1,86-12,89). Associações significativas foram observadas em mulheres com VB e NIC 2 ou pior diagnóstico, infectadas pelos tipos de HPV 16 e/ou 18 (OR= 3,38; 95% IC :1,07-10,64) e por outros tipos de HPV (OR= 3,38; 95%IC: 1,15-10,01). Conclusões: A infecção por CT detectada por PCR não mostrou associação com o aumento do risco para NIC 2 ou pior diagnóstico em mulheres HPV positivas. Em mulheres CT negativas e com menos de 30 anos de idade, os tipos de HPV 16 e/ou 18 estão associados à NIC 2 ou pior diagnóstico, resultado não observado para as mulheres CT positivas. A VB e resposta inflamatória estão associadas à NIC 2 ou pior diagnóstico em mulheres HR-HPV positivas / Abstract: Objective: To analyze the association between co-infection Human Papillomavirus (HPV) and Chlamydia trachomatis (CT), bacterial vaginosis (BV) and inflammatory response with the severity of the cervical neoplasia. Subjects and methods: This is cross-sectional experimental study carried through in Campinas, São Paulo and in Goiânia, Goiás, Brazil. The casuistic included 290 consecutive women submitted a the Excision of the Transformation Zone or conization due CIN 2 and CIN 3. For the study that evaluated the association between HPV and CT and severity of cervical neoplasia were selected 251 women who were infected with high-risk HPV (HR-HPV). HPV detection .was performed by PCR using primers PGMY09/11 and genotyping by reverse lineblot hybridization assay. The detection of CT was performed by PCR. For the study that evaluated the association between BV and inflammatory response with the severity of cervical neoplasia were selected 211 women infected with HR-HPV with cervical smears available for analysis. The presence of 20% or more clue cells in cervical smears stained by the Papanicolaou method was considered positive for VB. Inflammatory response was assessed by counting the number of neutrophils. The finding of 30 or more neutrophils per field observed under 1000x magnification was taken as presence of inflammatory response. Results: The prevalence of CT in HPV positive women was 15.1% (38/251). Significant association was observed between women with 30 years or older and CIN 2 or worse diagnosis for those CT negative, but this association was not observed for those CT positive. HPV 16 and/or HPV 18 were detected in 50% of the women ? 29 years age with CIN 2 or worse diagnosis who were CT negative, and in 19.5% for those women with CIN 1 or no neoplastic in histological diagnostic. In these women the association between HPV 16 and/or 18 and CIN 2 or worse diagnosis was significative, but this association also was not observed considering the CT positive group. Inflammatory response and BV were observed in 5.5% and 16.7% of cervical smear of women with no neoplastic diagnosis and were observed in 22.9% and 12.5% of cervical smears of women with CIN 1 in histological diagnosis. Inflammatory response and BV were observed in 43.5% and 46.2% of cervical smears of women with CIN 2 in histological diagnosis. The BV prevalence was higher in cervical smears of women infected by the types 16 and/or 18 (25.6%) and inflammatory response was more observed in cervical smears of women infected by other HPV types (25.6%). Inflammatory response and BV were observed in 64.2% and 32.6% of cervical smears of women with CIN 3 in histological diagnosis and were more observed in cervical smears of women infected types 16 and/or 18 representing respectively 43.1% and 20.0% of cases. Inflammatory response and BV were more observed in cervical smears of women infected types 16 and/or 18 in women with invasive carcinoma, representing 27.2% and 18.2% of cases respectively. Inflammatory response was significantly associated with CIN 2 or worse diagnosis in women infeted by HPV16 and/or HPV 18 (OR= 6.70; 95%CI : 2.32-19.31) and HPV other types than HPV16 and/or18 (OR=4.90; 95%CI: 1.86-12.89). Significant associations with BV and CIN 2 or worse diagnosis were observed in women infected by HPV 16 and/or 18 (OR= 3.38; 95%C1:07-10.64) and HPV types other than HPV16 and/or 18 (OR=3.38; 95%CI: 1.15-10.01). Conclusions: CT infection detected by PCR, does not increase the risk for CIN 2 or worse diagnosis in HPV positive women. HPV 16 and/or HPV 18 types in young women are associated with CIN 2 or worse diagnosis, but without obvious association with CT. BV and inflammatory response are associated with CIN 2 or worse diagnosis in women HR-HPV positives women / Doutorado / Ciencias Biomedicas / Doutora em Tocoginecologia

Thesis (MCur)--University of Stellenbosch, 2011. / ENGLISH ABSTRACT: Title: Awareness, knowledge and experiences of women regarding cervical cancer in rural Kwa- Zulu-Natal, South Africa. Background: Cervical cancer has been identified as the second most common cancer in women and contributes to the high mortality rate in women. Among all cancers in women, cervical cancer is rated the second most common cancer in women worldwide. In poorly resourced settings, access to services offering cervical screening is still a challenge and it is estimated that more than 50% of women in developing countries have never had a single screening test for cervical abnormalities. Purpose: The purpose of this study was to assess women’s awareness, attitudes and experiences regarding cervical smear testing and for cervical cancer in rural KwaZulu-Natal and to better understand factors influencing access to and utilization of cervical cancer screening services by rural women. Methods: The method employed was a descriptive study using a questionnaire to collect quantitative data. The sample consisted of 69 women aged 30 years and above, was taken from women who were enrolled in the on-going Microbicide Clinical Trial and attending follow-up clinic visits between July and August 2009. The primary outcome measure for the analyses was who has been screened for cervical cancer and this was assessed from the previous history reports of the women. The secondary outcome measure was to investigate knowledge and perceptions regarding cervical cancer and screening. Socio-demographic factors associated with having been screened were also explored. Results: Out of 69 women, only N=13 (18.8%) reported ever screening for cervical cancer. More than half of women who had never screened reported lack of information as a barrier to screening N=50 (71.4%). Older women aged 35-45, 45 and above were less likely to screen compared to women aged 30 to 34 years of age (OR: 0.06). Having an educational background seemed to increase the likelihood to screen, twice if a woman had primary education (OR 2.0) and almost three times (OR 2.67) if a woman had a secondary or a higher education. More than half of the respondents considered themselves at risk for cervical cancer N=42 (60.8%) and almost all showed a willingness to screen in the future N=64 (93%). Conclusion: Most of the women in this study had never been screened for cervical cancer in their lifetime as reflected by n=55 (82%) while only n=14 (18%) ever screened for cervical cancer. The results of this study cannot be generalised to the population due to the small sample size. However, there is need to facilitate comprehensive health education and the implementation of cervical screening programmes to target women in rural communities to contribute to the success of the cervical screening programme. The results of this study showed that 60% of respondents were informed by health care professionals on cervical cancer screening. Health care workers also should play a vital role in educating communities on cervical cancer and on the benefits for cervical cancer screening, through reaching all patients who utilise health care services with cervical cancer information and also communities through outreach programmes. / AFRIKAANSE OPSOMMING: Titel: Vrouens se bewustheid, houding en ervarings van smeertoetse en servikale karsinoom in die landelike gebiede van KwaZulu-Natal Agtergrond: Servikale kanker is geïdentifiseer as die tweede mees algemene karsinoom in vrouens en dra by tot die hoë sterftesyfer in vrouens. Van al die tipes karsinoom wat by vrouens voorkom, is servikale karsinoom die tweede mees algemene karsinoom onder vrouens wêreldwyd. Die beskikbaarheid van dienste wat servikale smeer toetsing bied, is nog steeds ’n uitdaging in arm gebiede en daar word geskat dat meer as 50 % van vrouens in ontwikkelende lande nog nooit ’n toets vir enige servikale abnormaliteite gehad het nie. Doel: Die doel van hierdie studie was om vrouens se bewustheid, houding en ervarings van servikale smeer toetsing en van servikale karsinoom in die plattelandse gebiede van KwaZulu-Natal te toets en om ’n beter begrip te kry van faktore wat ’n invloed het op toegang tot en gebruik van servikalesmeer toetsing by vrouens in landelike areas. Metode: Die metode wat gebruik is, is ’n beskrywende studie waarin gebruik gemaak is van vraelyste om kwantitatiewe data te versamel. Die monster het bestaand uit 69 vrouens, ouderdom 30 jaar en ouer, wat deelnemers was aan die “Microbicide Kliniese Navorsingsprojek” en wat opvolgbesoeke by klinieke gehad het tussen Julie en Augustus 2008. Die primêre bevinding, wie al ooit vir servikale karsinoom getoets is, is bereik deur die inligting in die laboratorium verslae van die vroue na te gaan. Die sekondêre bevinding was om die deelnemers se kennis en persepsies aangaande servikale karsinoom te toets. Sosio-demografiese faktore wat verband hou met of deelnemers ooit getoets is, is ook ondersoek. Resultate: Van die 69 vrouens, het slegs N=13 (18.8 %) gerapporteer dat hulle ooit getoets is vir servikale kasinoom. Meer as die helfte van die vrouens wat ooit getoets is vir servikale karsinoom het gerapporteer dat ’n gebrek aan inligting ’n weerhoudende faktor was tot die toetse, N=50 (71.4%). Ouer vrouens tussen die ouderdom van 35 – 45, 45 en ouer was minder bereid om te toets in vergelyking met vrouens tussen die ouderdom van 30 tot 34 (OR: 0.06). Dit blyk asof skoolonderrig die kanse op toetsing verhoog, vrouens met primêre skoolopleiding se kanse dat hulle getoets is, is twee keer groter (OR 2.0) en amper drie keer meer (OR 2.67) as ’n vrou sekondêre onderrig of hoër onderrig ontvang het. Meer as die helfte van die respondente dink hulle loop ’n risiko om servikale kanker te kry N=42 (60.8%) en feitlik almal was bereid om hulle te laat toets in die toekoms N=64 (93 %). Bevinding: Die meeste vroue in hierdie studie n=55 (82%) was nog nooit in hul leeftyd getoets vir servikale karsinoom nie terwyl slegs n=14 (18%) ooit getoets was vir servikale karsinoom. Die resultate van hierdie studie kan nie veralgemeen word nie, aangesien die navorsingspopulasie as gevolg van die klein steekproef te klein was. Nietemin is daar ‘n behoefte vir die fasilitering van omvattende gesondheidsopvoeding en die implementering van servikalesmeer toetsing programme. Die resultate van hierdie studie het aangedui dat 60% van die respondente deur professionele gesondheids werkers ingelig is met betrekking tot servikalesmeer toetsing. Gesondheidswerkers behoort ‘n vitale rol te speel in die opvoeding van gemeenskappe in verband met servikale karsinoom en die voordele van hiervan deur alle pasiente wat gesondheidsdienste benut in te lig omtrent servikale karsinoom en ook deur middel van gemeenskaps-uitreikings programme.

Les papillomavirus humains (VPHs) sont reconnus comme les agents étiologiques du cancer du col de l’utérus. Notre étude a pour but de décrire le polymorphisme de la région régulatrice virale (LCR) et du gène E6 du VPH52 chez 216 femmes canadiennes avec différents grades de lésion du col et d’établir s’il existe une association entre les variantes décrites et la présence de lésions intraépithéliales de haut-grade (CIN2,3) du col de l’utérus ou de cancer invasif. L’âge (OR 1.1, 95% CI 1.02-1.17, p=0.005) fut significativement associé à la présence de cancer invasif. Une variante de la région régulatrice virale, MTL-52-LCR-02, présentant une substitution nucléotidique au niveau du nucléotide 7436, fut aussi associée à la présence de cancer du col de l’utérus (p=0.015). Dans une analyse multivariée, après ajustement pour l’âge, l’ethnicité et le site de recrutement, une délétion au niveau du nucléotide 7695 (OR 5.7, 95% CI 1.2-27.9) ainsi qu’une substitution au niveau du nucléotide 7744 (OR 8.3, 95% CI 1.1-61.0) du LCR, et la variante K93R de la protéine E6 (OR 9.5, 95% CI 1.3-68.9) furent associées de façon significative avec la présence de CIN2,3. Ainsi, le polymorphisme du LCR et du gène E6 du VPH52 est associé avec la présence de CIN2,3 et probablement avec celle d’un cancer invasif. / Human papillomaviruses (HPVs) are the main etiological agents of cervical cancer. Our study aims to describe HPV52 polymorphism in the long control region (LCR) and in the E6 gene, and to investigate the association between LCR and E6 polymorphism and high-grade cervical intraepithelial neoplasia (CIN2,3) or invasive cervical cancer in 216 canadian women with various grades of cervical disease. Age was significantly associated with cervical cancer (OR 1.1, 95% CI 1.02-1.17, p=0.005). The MTL-52-LCR-02 variant, with a nucleotide substitution in the LCR at position 7436, was also associated with cervical cancer. MTL-52-LCR-02 has been identified in 28.6% of women with cervical cancer and in 0.0% of women without cervical cancer or CIN2,3 (p=0.015). In a multivariate analysis, after adjusting for age, ethnicity, detection of HPV16 or 18, and study site, a deletion at nucleotide position 7695 (OR 5.7, 95% CI 1.2-27.9), a variation at nucleotide position 7744 (OR 8.3, 95% CI 1.-61.0) in the LCR and the K93R variant of the protein E6 (OR 9.5, 95% CI 1.3-68.9) were associated with CIN2,3. This study confirms that HPV52 polymorphism in the LCR and in the E6 gene is associated with risk of development of CIN2,3 and possibly invasive cancer of the uterine cervix.