Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2016-08-18T12:08:31Z No. of bitstreams: 2 Tese - José Eduardo Batista - 2014.pdf: 4845418 bytes, checksum: 4e199986cf3802d6ecf319c604412503 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2016-08-18T12:33:39Z (GMT) No. of bitstreams: 2 Tese - José Eduardo Batista - 2014.pdf: 4845418 bytes, checksum: 4e199986cf3802d6ecf319c604412503 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2016-08-18T12:33:39Z (GMT). No. of bitstreams: 2 Tese - José Eduardo Batista - 2014.pdf: 4845418 bytes, checksum: 4e199986cf3802d6ecf319c604412503 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2014-10-23 / Introduction: Genital infection by human papillomavirus (HPV) is considered the most common sexually transmitted infection in several countries. The prevalence of HPV genotypes in women with or without cytological abnormalities may vary according to the studied population and the region. Objective: To detect and identify specific HPV types correlating with sociodemographic/behavioral characteristics and cytological abnormalities present in cervical smears of Maroon women. Methods: This cross-sectional study included 353 maroon women users of the unified health System of the municipalities of Maranhão for screening of cervical cancer. The samples were analyzed for the presence of cytological abnormalities by conventional methods and tested for 37 HPV genotypes by polymerase chain reaction (PCR) with primers PGMY09/11 followed by reverse line blot hybridization performed with the Linear Array HPV Genotyping Test kit by Roche Molecular System®. The association of HPV types and cytological diagnosis was investigated according to the different age groups. Results: HPV infection was detected in 13% (46/353) of the cases. Infection types with high-risk HPV were more frequent (78,3 %, 36/46) than for low-risk HPV (21,7 %, 10/46). Genotypes 68 (24,2 % - 11 /46), 58 (19,8% - 9/46), 52 and 31 (10,8% - 5/46 each), and 62 (8,8% 4/46) were the most prevalent. Only 6,6% (3/46) of the cases were positive for HPV 61. The genotypes 73, 70, 54, 53, 45, IS39 and 18, individually represented 4,4% (2/46) of all cases. The CP6 -108, 84, 72, 71, 66, 59, 56, 55, 51, 39, 33 and 16 genotypes individually represented 2,2% (1/46) of the cases. In women without cytological abnormalities, viral infections, both simple and multiple, were detected in 10,7%(35/328) of the cases. For those diagnosed with an abnormality, the prevalence of HPV infection was 24,0% (1 /46), being higher in high grade squamous intraepithelial lesion (HSIL-75,0 %), followed by atypical squamous cells cannot exclude high-grade squamous intraepithelial lesions (ASC-H, 50%), low grade squamous intraepithelial lesions (LSIL-33,4 %) and atypical squamous cells of undetermined significance (ASC-US, 14,3%). The analysis showed a statistically significant association between HPV infection and the detection of cytologic abnormalities in the age groups between 31-40 years (OR = 7.40, 95 % CI :1.07 -51 ,19 , p = 0.03) and 51 to 60 years (OR = 20.4 , 95 % CI : 1.12 to 704.69, p = 0.03). None of the behavioral variables showed significant association with HPV infection, however the presence of this infection was positively associated with detection of cytologic abnormalities (OR=6,57: IC:2,772-15,606), p=0,001. Conclusion: It is possible that the results of this study are due to characteristics of the study population, geographically isolated, with conservative habits and sexual intercourse only between members of the Quilombo. This study with Maroon women allowed us to delineate the epidemiology of this HPV infection in populations living in Maranhão. / Introdução: A infecção do trato genital pelo Papilomavírus humano (HPV) é considerada a infecção sexualmente transmissível (IST) mais comum em diversos países. A prevalência dos genótipos do HPV em mulheres com ou sem anormalidades citológicas pode variar de acordo com a população e a região estudada. Objetivos: Detectar e identificar os tipos específicos de HPV e relacionar com características sociodemográficas/comportamentais e anormalidades citológicas presentes em esfregaços cervicais de mulheres quilombolas do Maranhão. Metodologia: Este estudo de corte transversal incluiu 353 mulheres quilombolas usuárias do Sistema Único de Saúde dos municípios do Maranhão para rastreamento do câncer do colo uterino. As amostras foram analisadas quanto à presença de anormalidades citológicas pelo método convencional e testadas para 37 genótipos de HPV por reação em cadeia da polimerase (PCR) com os iniciadores PGMY09/11, seguida de hibridização reversa em linhas através do Kit Linear Array HPV Genotyping Test (Roche Molecular System)®. A associação dos tipos de HPV e o diagnóstico citológico foi investigada de acordo com as diferentes faixas etárias. Resultados: A infecção pelo HPV foi detectada em 13% (46/353) das mulheres incluídas. Infecções por tipos de HPV de alto risco foram mais frequentes (78,3%; 36/46) do que por HPV de baixo risco (21,7%; 10/46). Os genótipos 68 (24,2% - 11/46); 58 (19,8% - 9/46); 52 e 31 (10,8% - 5/46 cada) e 62 (8,8% - 4/46) foram os mais prevalentes. Apenas 6,6% (3/46) dos casos foram positivos para o HPV 61. Os genótipos 73, 70, 54, 53, 45, IS39 e 18 representaram individualmente 4,4% (2/46) do total de casos. Os genótipos CP6-108, 84, 72, 71, 66, 59, 56, 55, 51, 39, 33, e 16 representaram individualmente 2,2% (1/46) do total de casos. Em mulheres que não apresentaram anormalidades citológicas, infecções virais, tanto simples quanto múltiplas, foram detectadas em 10,7%(35/328) dos casos. Considerando mulheres com diagnóstico de anormalidade citológica, a prevalência de infecção por HPV foi de 24,0% (11/46), sendo maior nos casos de lesão intraepitelial escamosa de alto grau (high grade squamous intaepithelial lesion)-HSIL-75,0%), seguida por mulheres com diagnóstico de células escamosas atípicas não podendo excluir alto grau (Atypical squamous cells cannot exclude high-grade squamous intraepithelial lesions) ASC-H- 50%), com lesão intraepitelial escamosa de baixo grau (low grade squamous intraepithelial lesion) LSIL- 33,4%) e com diagnóstico de células escamosas atípicas de significado indeterminado (atypical squamous cells of undetermined significance ASC-US (14,3%). Houve uma associação estatisticamente significativa entre a infecção por HPV e a detecção de anormalidades citológicas nas faixas etárias de 31 a 40 anos (OR = 7,40; 95% CI:1,07–51,19, p=0,03) e 51 a 60 anos (OR=20,4, 95%CI: 1,12-704,69; p = 0,03). Nenhuma das variáveis comportamentais analisadas mostrou associação significante com a infecção por HPV, contudo a presença desta infecção foi positivamente associada à detecção de anormalidades citológicas (OR=6,57: IC:2,772-15.606), p=0,001. Conclusão: É possível que os resultados deste estudo se devam às características da população estudada: isolada geograficamente, com hábitos conservadores e relações sexuais apenas entre membros do quilombo. Este estudo em mulheres quilombolas permitiu delinear a epidemiologia desta infecção por HPV em populações residentes no Maranhão.

RESUMO Objetivos: identificar e correlacionar os achados epidemiolÃgicos, citolÃgicos, colposcÃpicos e histopatolÃgicos de um grupo de adolescentes com um grupo de mulheres adultas com suspeita de patologia cervical. Pacientes e mÃtodos: o estudo foi desenvolvido no perÃodo de janeiro de 2004 a setembro de 2006 na Maternidade Escola Assis Chateaubriand da Universidade Federal do CearÃ, Fortaleza-CearÃ. O desenho do estudo foi de caso-controle com um grupo de 104 adolescentes atà 19 anos e um grupo controle de 155 mulheres adultas com idade maior que 24 anos, ambos os grupos formados por pacientes que foram encaminhadas aos ambulatÃrios de patologia cervical por suspeita de lesÃo cervical. Todas as pacientes do estudo foram atendidas com preenchimento do formulÃrio padrÃo de atendimento dos ambulatÃrios de patologia cervical da MEAC com realizaÃÃo de colposcopia em todas as pacientes e biÃpsia quando necessÃrio. A partir dos dados coletados foram elaboradas planilhas no programa Microsoft Excel das quais foram elaboradas tabelas com anÃlise feita de forma descritiva e estudos estatÃsticos (teste exato de Fisher e teste de Mann-Whitney). Resultados: o uso de preservativo foi relatado por 32,5% das adolescentes que faziam uso de contracepÃÃo e 11,7% das adultas. A idade mÃdia da menarca no grupo de adolescentes foi de 11,93 e no grupo das adultas foi de 12,57. Quanto ao inÃcio da atividade sexual, as adolescentes tiveram a idade mÃdia de iniciaÃÃo sexual de 14,5 anos e as adultas de 18,5 anos. O resultado de HSIL na citologia foi observado em 10,7% do total de resultados de mulheres adultas e em nenhuma adolescente. A presenÃa de alteraÃÃes maiores ocorreu em 2,7% das colposcopias positivas das adolescentes e em 15,5% das adultas. Na comparaÃÃo da localizaÃÃo da JunÃÃo escamo-colunar entre os grupos se observa que as adolescentes tÃm em sua maioria a JEC localizada para fora do orifÃcio externo do colo uterino, num total de 77,2% dos casos e nas adultas a JEC teve essa localizaÃÃo em 38% dos casos. Em nenhum caso nas adolescentes a JEC se localizou dentro do canal, ocorrendo essa localizaÃÃo em 7,3% das adultas. Os casos com resultado histopatolÃgico de carcinoma foram trÃs, sendo todos no grupo das adultas, sendo uma com citologia normal com inflamatÃrio acentuado, uma com ASCUS e uma HSIL, quanto a colposcopia esses casos tiveram resultado de alteraÃÃes maiores (um caso) e miscelÃnea (dois casos). Todos os casos de alteraÃÃes maiores nas colposcopias que em sua maioria ocorreram no grupo das adultas tiveram histopatolÃgico positivo nos dois grupos. ConclusÃo: houve diferenÃa estatisticamente significativa entre os grupos em vÃrios aspectos, como o uso do preservativo que ocorreu mais no grupo das adolescentes, a idade mÃdia da menarca que foi menor no grupo das adolescentes, a presenÃa de HSIL na citologia que nÃo ocorreu no grupo das adolescentes, quanto a localizaÃÃo da JEC que na maioria das adolescentes ocorreu para fora do orifÃcio externo do colo uterino e a presenÃa de alteraÃÃes maiores na colposcopia que ocorreu mais no grupo das adultas. NÃo ocorreram casos de HSIL nas citologias das adolescentes, mas ocorreram dois casos de NIC 2/NIC trÃs no histopatolÃgico que foram subestimados pela citologia. A citologia subestimou todos os casos de carcinoma, sendo sua ocorrÃncia no grupo das adultas. / ABSTRACT Objectives: to identify and to correlate the epidemiological, cytological, colposcopic and histopathological findings from a group of adolescents with a group of adult women under suspicion of cervical pathology. Patients and methods: the study was developed from January 2004 to September 2006 at âMaternidade Escola Assis Chateaubriandâ (Assis Chateaubriand Maternity School Hospital) from the âUniversidade Federal do CearÃâ (Ceara Federal University), in Fortaleza â Ceara. The study was a case-control design that used subjects from a group of 104 adolescents younger than 19 years old and a control group of 155 adult women older than 24 years old, both groups were formed by patients who were referred to cervical pathology clinics under suspicion of cervical lesion. All the patients from the study had to fill in the standard treatment form from the cervical pathology clinics from the MEAC. It was done colposcopy in all the patients and biopsy when necessary. Spreadsheets in the Microsoft Excel were created with the data collected. The spreadsheets were developed with descriptive analysis and statistical study (Fisherâs exact test and Mann-Whitneyâs test). Results: condom use was reported by 32.5% of the adolescents who were using contraception and 11.7% of the adults. The mean age of menarche in the group of adolescents was 11.93 and in the group of adults was 12.57. The mean age at first sexual intercourse among the adolescents was 14.5 and among the adults was 18.5. The result of HSIL in the cytology was observed in 10.7 % of the adult women group and none in the adolescents. The presence of major changes occurred in 2.7% of the positive colposcopy of the adolescents and in 15.5% of the adults. Comparing the location of the squamocolumnar junction among the groups, it is observed in the adolescents group that the majority has it outside the external orifice of the cervix, in a total of 77.2% of the cases and in the adults group it had this location in 38% of the cases. In none of the cases among the adolescents the squamocolumnar junction was located inside the canal and among the adults in 7.3% of the cases it had this location. There were 3 cases with the histopathological result of carcinoma, all of them in the adults group, one of them with normal cytology with severe inflammatory process, one with ASCUS and one with HSIL. In relation of colposcopy, one case had major changes and in the other two cases the results were miscellaneous findings. In all the cases of major changes in the colposcopies which in the majority happened in the adults group had positive histopathological results in both groups. Conclusion: there were significant statistic differences among the groups in various aspects. As for the use of condom, it happened more often in the adolescents group. The mean age of menarche was lower in the adolescents group. The presence of HSIL in the cytology did not happen in the adolescents group. As for the location of the squamocolumnar junction, in the majority of the adolescents was outside the external orifice of the cervix. The presence of major changes in the colposcopy happened more in the group of adults. It did not happen cases of HSIL in the cytology of the adolescents but it happened two cases of NIC 2/NIC 3 in the histopathology, which were underestimated by the cytology. The cytology underestimated all the cases of carcinoma, which happened only in the adults group.

Introdução: O câncer de cabeça e pescoço vem aumentando sua incidência, sendo o quinto tipo de câncer mais comum e a sexta causa de morte por câncer no mundo, portanto é causa importante de morbimortalidade da população. O entendimento dos fatores de risco como tabagismo, etilismo e infecção pelo papilomavirus (HPV) é de fundamental importância, tanto para ações de prevenção e controle da doença, bem como avaliação de fatores prognósticos e terapêuticos. Objetivos: O presente estudo visa analisar as características clínicas, buscar o principal sítio anatômico tumoral e avaliar os fatores prognósticos entre os pacientes tabagistas ou não, e portadores ou não do HPV, que foram tratados cirurgicamente. Casuística e Métodos: Foram analisadas as variáveis clínicas e prognósticas dos grupos de pacientes tabagistas, não tabagistas, HPV negativo e HPV positivo. A amplificação do DNA viral, detecção e genotipagem do HPV se deu através da extração do DNA total a partir de blocos parafinados. Resultados: A amostra total foi composta por 399 pacientes, sendo que 266 eram tabagistas, 33 não tabagistas, e desses últimos, cinco eram HPV positivo. Houve diferença estatística em relação sexo, sendo que para o tabagista o predomínio foi do sexo masculino e para o HPV positivo foi o feminino. O paciente tabagista apresentou-se mais jovem (média 57,9 anos) que o não tabagista (média 64,1 anos). O sítio anatômico mais comum para os tabagistas foi a laringe e para o HPV positivo foi a cavidade oral e orofaringe. O tempo livre de doença foi de 63,6 meses para os tabagistas, 31,3 meses para os não tabagistas e 29,3 meses para os HPV positivo, havendo diferença quanto às curvas de sobrevidas livre da doença dos fumantes e não fumantes. Dos pacientes que foram á óbito pela neoplasia, o paciente HPV positivo foi o que apresentou menor tempo de sobrevida. Não houve diferença estatística entre os grupos quanto às curvas de sobrevidas global e da doença. Discussão: Apesar da literatura mostrar que o paciente não tabagista e o paciente HPV positivo geralmente serem mais jovens e apresentarem melhor prognóstico do que os típicos pacientes tabagistas, isso não foi observado nesse estudo, pois o paciente não tabagista apresentou-se com mais idade ao diagnóstico da doença e com pior prognóstico que o tabagista, e o paciente HPV positivo apresentouse com menor tempo até o óbito pela doença quando comparado ao paciente tabagista. Conclusões: O câncer nos pacientes tabagistas acometeu mais o sexo masculino, localizou-se principalmente na laringe e apresentou melhor prognóstico quando comparado aos não tabagistas. O câncer nos pacientes HPV positivo acometeu mais o sexo feminino e localização tumoral foi principalmente a cavidade oral e a orofaringe. / Introduction: Head and Neck cancer has been increasing its incidence, and it is the fifth most common type of cancer and the sixth leading cause of cancer death in the world, so it is an important cause of morbidity and mortality of the population. Understanding the risk factors such as smoking, alcohol use and papillomaviruses (HPV) infection is of fundamental importance, both for prevention and control of disease like for assessment of prognostic and therapeutic factors. Objectives: This study aims to analyze the clinical, seek the main site anatomical of the tumor and evaluate the prognostic factors among smokers or not, with the presence or absence of the HPV, which were surgically treated. Methods: The variables clinical and prognostic were analyzed in the groups of smokers, nonsmokers, HPV negative and HPV positive. The amplification of viral DNA, detection and genotyping of the HPV were made through the extraction of total DNA from paraffin blocks. Results: The total sample consisted of 399 patients, 266 were smokers, 33 nonsmokers, and this latter group had five patients HPV positive. There was statistical difference regarding sex, for smokers the prevalence was male and for HPV positive was female. The smoker patient was younger (mean 57.9 years) than the non-smoker (mean 64.1 years). The most common anatomic site for the smokers was the larynx and for the HPV positive was the oral cavity and oropharynx. The diseasefree interval was 63.6 months for smokers, 31.3 months for nonsmokers and 29.3 months for HPV positive, with difference between free disease survival curves of the smokers and nonsmokers. Of the patients who died by disease, HPV positive patient showed the shorter survival. There was no statistical difference between the groups in terms of overall survival curves and of the disease. Discussion: Although the literature show that the nonsmoker patient and HPV positive patients are generally younger and present a better prognosis than the typical smokers, this was not observed in this study because the nonsmoker patient presented with more age at diagnosis of disease and a worse prognosis than the smoker, and the HPV positive patient presented with shorter survival of the disease when compared to smoking patients. Conclusions: The cancer in smokers affected more males, was located mainly in the larynx and showed better prognosis when compared to nonsmokers. The cancer in patients positive HPV affected more females and tumor location was mainly oral cavity and oropharynx.

Introdução: A relação causal entre infecção genital por papilomavirus humano (HPV) de alto risco e o câncer do colo uterino está bem estabelecida; porém, há controvérsias em diferentes populações quanto à prevalência e distribuição da infecção em relação à idade. Objetivos: Caracterizar, pela Captura Híbrida II (CHII), a prevalência da infecção genital por HPV de alto risco e sua estratificação por idade. Verificar a associação da infecção com fatores de risco, resultados da citologia oncológica (CO), da colposcopia e da biópsia cervical. Casuística e Métodos: Em estudo transversal estudou-se 2300 mulheres (15-65 anos) que buscaram rastreamento para o câncer cervical. Aplicou-se questionário epidemiológico e foi feita a coleta da CO e da CHII, no caso de alteração em destes exames ou ambos indicou-se colposcopia e, nos casos anormais, procedeu-se à biópsia cervical. Resultados: A prevalência da infecção genital por HPV de alto risco em toda amostra foi de 17,8%: 27% (<25 anos), 21% (25-34 anos), 12% (35-54 anos) e de 14% (55-65 anos). Participantes com maior número de parceiros sexuais durante a vida apresentaram uma maior chance de infecção, relacionamento estável, idade entre 30 a 54 anos e ser ex-fumante foram fatores associados à proteção da infecção. Encontrou-se 204 (8,8%) CO anormais e uma relação direta entre severidade do diagnostico citológico e infecção por HPV de alto risco, 14,3% em citologia normal, 78% em lesão escamosa de alto grau, 100% nos esfregaços compatíveis com carcinoma. Foram histologicamente confirmados: 10 casos de Neoplasia intra-cervical grau 2/3 (NIC2/3) entre as mulheres infectadas por HPV, com citologia normal; 4 NIC 2/3 e um carcinoma nas que apresentavam exclusivamente alteração citológica e 15 NIC 2/3 e 3 carcinomas em mulheres com ambos os testes positivos. Conclusão: A prevalência da infecção genital por HPV de alto risco foi alta, seguindo uma curva na qual se observou novo aumento da prevalência após os 55 anos. / The causal role of high risk human papillomavirus (HPV) infection and cervical cancer has been well documented. However HPV prevalence varies greatly across populations, as might the age distribution. Objective: We aimed to determine high risk HPV prevalence and its distribution by age groups. Risk factors, cytological, colposcopic and cervical biopsies results associated with high risk HPV infection in a sample of women who self referred for cervical cancer screening. Methods: In a cross sectional study we interviewed and obtained cervical specimens from a sample of randomized 2300 women (15-65 years). Specimens were tested for the presence of high risk HPV using Hybrid Capture II (HCII) and for cervical cytological abnormalities by Pap smears or liquid based cytology. Women, who had abnormal cytology or positive HCII, or both results, were referred to colposcopy examination. Whenever colposcopy revealed an abnormal pattern, a directed punch biopsy was taken. Results: Four hundred and eight (17.7%) study participants tested positive for high risk HPV types by HC2: 27% (<25 years), 21% (25-34 years), 12% (35-54 years) and 14% (55-65 years). The main risk factor for HPV infection was number of lifetime sexual partners; age at 30 to 54 years, women who live with a partner and former smokers were negative associated with high risk HPV infection. Two hundred four (8, 8%) women had cytological abnormalities. HC II positive was associated with cytology outcome (14, 3% in normal cytology, 78% in HSIL and 100% in cervical cancer). Cervical Intraepithelial Neoplasia grade 2/3 (CIN 2/3) were found in 10 HPV infected women with normal cytological results. Women with abnormal cytological results only had 4 CIN 2/3 and 1 carcinoma and women testing positive in both techniques had 15 CIN 2/3 and 3 carcinomas. Conclusions: High risk HPV prevalence was high in this sample and the prevalence age curve showed a second pick starting around 55 years old.

Orientador: Luiz Carlos Zeferino / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-22T21:06:24Z (GMT). No. of bitstreams: 1 Vale_DiamaBhadraAndradePeixotodo_D.pdf: 2458866 bytes, checksum: 5cf40849bf3e978225063c3bfedc7aea (MD5) Previous issue date: 2013 / Resumo: INTRODUÇÃO: O exame citológico ainda é o método de rastreamento mais utilizado para a prevenção do câncer do colo do útero. Apesar da sua alta eficiência na prevenção do carcinoma escamoso invasivo, esses benefícios não são tão claros para as lesões escamosas em mulheres jovens e para o adenocarcinoma invasivo. Além disso, esse efeito protetor varia de acordo com o intervalo de realização dos controles. Uma vez que o teste de HPV não é recomendado para mulheres com menos de 30 anos de idade, a avaliação cuidadosa do desempenho do rastreamento neste grupo etário pode auxiliar os médicos a selecionar criteriosamente aquelas que irão ser encaminhadas para prosseguimento diagnóstico. OBJETIVO: Avaliar o impacto do rastreamento do câncer do colo do útero na prevalência dos resultados citológicos em função da idade da mulher e do intervalo entre os controles. MÉTODOS: Foi analisado o banco de dados de um laboratório central de citopatologia. O estudo incluiu 2.002.472 testes obtidos de mulheres previamente rastreadas e 217.826 testes obtidos de mulheres não previamente rastreadas. A Razão de Prevalência (RP) com um intervalo de confiança de 95% foi calculada para os resultados de testes de mulheres rastreadas em relação aos testes de mulheres não rastreadas, em função da idade. O laboratório utiliza o Sistema de Bethesda desde 1998, mas ainda subdivide o resultado Lesão Intraepitelial de Alto Grau (HSIL) em dois níveis: HSIL-CIN 2 e HSIL-CIN 3. RESULTADOS Para HSIL, a RP dos testes de mulheres rastreadas em relação aos testes de mulheres não rastreadas foi de 0,97 (0,83-1,13) em mulheres abaixo de 20 anos e 0,99 (0,86-1,14) para mulheres entre 20 e 24 anos, diminuindo significativamente em mulheres entre 25 e 29 anos (RP 0,63, 0,52-0,76). As RP para o carcinoma espinocelular (SCC), adenocarcinoma in situ (AIS) e adenocarcinoma invasivo apresentaram uma redução significativa em todos os grupos etários acima de 30 anos. Para o grupo etário 30 a 59 anos, a proteção conferida pelo rastreamento para SCC, AIS e adenocarcinoma invasivo foi de 83% ou mais, para intervalos de realização dos exames entre 1 e 5 anos. Para mais de cinco anos de intervalo, o efeito protetor oferecido para SCC foi de 50%. Nas mulheres não previamente rastreadas, a prevalência de lesões intraepiteliais de baixo grau (LSIL) e HSIL-CIN 2 diminuíram com a idade, enquanto que para HSIL-CIN 3 a prevalência aumentou. Ainda nesse grupo de testes, a prevalência de HSIL-CIN 2 foi maior do que a de HSIL-CIN 3 para mulheres de até 29 anos (RP = 4,73, 3,90-5,75) e mais baixa para os grupos de 30 a 49 anos (RP = 0,66, 0,50-0,87) e 50 anos ou mais (RP = 0.21,0.12-0.36). No grupo de testes de mulheres rastreadas, a prevalência de HSIL-CIN 2 foi maior nas faixas etárias até 29 anos (RP = 2,72, 2,49-2,97). CONCLUSÕES O rastreamento citológico reduziu a prevalência dos diagnósticos citológicos de HSIL, CEC, AIS e adenocarcinoma invasivo. Um intervalo de 3 anos para a realização dos controles foi apropriado para reduzir os resultados citológicos. O perfil da prevalência de HSIL-CIN 2 se assemelha ao padrão de prevalência de LSIL e foi mais prevalente do que HSIL-CIN 3 em mulheres jovens. O impacto do rastreamento foi menos evidente quando HSIL foi sugestivo de CIN 2. O rastreamento citológico em mulheres abaixo de 25 anos deve ser criteriosamente avaliado / Abstract: BACKGROUND Cervical cytology still is the cervical cancer screening test for women more used. Even though there is no doubt about the impact of cytology screening on invasive squamous cervical cancer, this issue is not as clear for squamous lesions on young women and for invasive adenocarcinoma. Moreover this protective effect varies according to interval tests. HPV testing is not recommended for women under age 30, and the carefully analysis of the performance of screening on this age group can help physicians to qualify their approach. OBJECTIVE To evaluate the impact of cervical cytology screening on the prevalence of cervical cytological results in women, as a function of age and the interval between tests. METHODS A central cytopathology laboratory database for cervical screening was analyzed. It included cytology screening data of 2.002.472 tests obtained from previously screened women and 217.826 tests from unscreened women. A prevalence ratio (PR) with a 95% confidence interval for screened women was calculated, in relation to unscreened women, as a function of age. The laboratory has been using the Bethesda System since 1998, but maintain the sub-categorization of HSIL in two levels: HSIL-CIN 2 and HSIL-CIN 3. RESULTS For high-grade squamous intraepithelial lesion (HSIL), the PR was 0.97 (0.83-1.13) for women aged 20 or younger and 0.99 (0.86-1.14) for women aged 20-24 years, decreasing significantly in women aged 25-29 years (PR 0.63, 0.52-0.76). The PR for squamous cell carcinoma (SCC), adenocarcinoma in situ (AIS) and invasive adenocarcinoma showed a significant reduction in all age groups over 30 years. For the age group ranging from 30-59 years, protection conferred by screening for SCC, AIS and invasive adenocarcinoma was 83% or higher for screening intervals ranging from 1-5 years. For 5-year intervals or longer, the protective effect offered for SCC was 50%. For unscreened women, the prevalence of Low Grade Intraepithelial Lesions (LSIL) and HSIL-CIN 2 decreased with age, whereas HSIL-CIN 3 prevalence increased. The prevalence of HSIL-CIN 2 was higher than that of HSIL-CIN 3 for women up to 29 years (PR=4.73, 3.90-5.75) and lower for age groups 30-49 years (PR=0.66, 0.50-0.87) and 50 years or more (PR=0.21,0.12-0.36). For screened women, the prevalence of HSIL-CIN 2 was also higher in age groups up to 29 years (PR=2.72, 2.49-2.97). CONCLUSIONS Cytology screening reduced the prevalence of HSIL, SCC, AIS and invasive adenocarcinoma cytological results. A three-year interval was appropriate for the reduction of these lesions. HSIL-CIN 2 resembles the prevalence pattern of LSIL and was more prevalent than HSIL-CIN 3 in younger women. The impact of screening was less evident when HSIL is suggestive of CIN 2. Cervical cytology screening in women 25 or younger should be critically evaluated / Doutorado / Oncologia Ginecológica e Mamária / Doutora em Ciências da Saúde

Orientadores: Sophie Françoise Mauricette Derchain, Silvia Helena Rabelo dos Santos / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-23T16:29:09Z (GMT). No. of bitstreams: 1 Resende_LeandroSantosdeAraujo_M.pdf: 1302928 bytes, checksum: f506f4299bc449aaf95e8a2b34d89201 (MD5) Previous issue date: 2013 / Resumo: Introdução: O câncer do colo uterino é o terceiro tipo mais prevalente no mundo e representa a quarta causa de morte por câncer entre as mulheres. No Brasil, estima-se que 17,540 mulheres foram diagnosticadas com essa neoplasia no ano de 2012. A infecção persistente pelo Papillomavirus humano (HPV) de alto risco (hr-HPV) e é considerada fator causal e necessário para lesões precursoras e câncer invasor. Já foram identificados mais de 100 tipos de HPVs. Os HPVs 16 e 18 são reconhecidos, no mundo, como os maiores responsáveis pelo desenvolvimento dessa doença. Objetivos: Descrever a prevalência e a distribuição, por idade, de infecções simples e múltiplas por diferentes tipos de HPV em mulheres com lesões cervicais escamosas e glandulares. Sujeitos e métodos: 328 mulheres com lesões escamosas, ou glandulares intraepiteliais ou invasoras do colo uterino. Todas as amostras foram submetidas à genotipagem por hibridização reversa com sondas de 21 tipos de HPV de alto risco (hr-HPV) e 16 tipos de HPV de baixo risco (lr-HPV). A prevalência de infecções simples e múltiplas pelo HPV foi comparada de acordo com as faixas etárias. Resultados: 287 (87%) mulheres apresentaram infecção por pelo menos um tipo de HPV e 149 (52%) tinham infecção múltipla. O HPV16 foi o tipo de vírus mais prevalente na amostra, detectado em 142 casos (49% de todos os casos positivos para HPV), seguido dos outros tipos de HPV do grupo alfa-9: HPVs 58, 52, 31, 35 e 33. Infecção simples ou múltipla pelo HPV18 foi positiva em 23 casos (8% dos casos de infecção por HPV de alto risco). Praticamente todas as lesões glandulares foram associadas à infecção simples por HPVs 16 e 18. Infecções múltiplas foram, significativamente, mais prevalentes nas lesões escamosas do que nas glandulares pelos HPVs 16 e 18 (P=0,04 e 0,03, respectivamente). A prevalência de infecções múltiplas seguiu um modelo de distribuição bimodal, com pico em mulheres com menos de 29 anos e naquelas com idade entre 50 e 59 anos. Conclusão: Esta amostra sugere que a estratégia para prevenção de lesões pré-invasivas e invasivas, escamosas ou glandulares, deve ser direcionada para o HPV16 e alguns tipos virais do grupo alfa-9. Ficou claro, na amostra deste estudo, que em mulheres jovens, a prevenção de infecção pelo HPV deve cobrir os HPVs 16 e 18, principalmente / Abstract: Background: Cervical cancer ranks third in prevalence and fourth as cause of death in women worldwide. In Brazil, 17,540 women were diagnosed in 2012 with the disease. Persistent infection with high-risk HPV types is a necessary condition for the development of pre-invasive and invasive cervical neoplasia. Currently, over 100 HPV types have been identified, but HPV16 and 18 are recognized as the mayor culprits in cervical carcinogenesis. Objectives: to assess the relationships between single- (ST) and multiple-type (MT) HPV infection with patients' age and lesion pathological status. Materials and Methods: 328 patients with either squamous or glandular intraepithelial or invasive cervical lesion were selected. All subjects were tested for HPV genotypes with reverse hybridization for 21 high- (hr-HPV) and 16 low-risk (lr-HPV) probes. Prevalence of ST and MT HPV infections was compared across and age strata. Results: 287 (87%) women had at least one HPV type detected and 149 (52%) had MT infections. The most prevalent HPV type was HPV16, present in 142 cases (49% of all HPV-positive cases), followed by the alpha-9 group HPV58, 52, 31, 35 and 33, all of them from alpha-9 HPV group. ST or MT HPV18, single or in multiple infections occurred in 23 cases (8% of hr-HPV cases). Almost all glandular lesions were associated with HPV16 and 18 alone. Multiple infections were significantly more prevalent in squamous than in glandular lesion for HPV16 and 18 (P=0.04 and 0.03 respectively). The prevalence of MT infections followed a bimodal distribution; peaking in women younger 29 years and in those aged 50 to 59. Conclusions: our data indicate that prevention strategies for pre-invasive and invasive squamous lesions should be focused on HPV16 and a few alpha-9 HPV types. It is clear to us that in young women, prophylaxis must cover a large amalgam of HPV types beyond classic HPV16 and 18 / Mestrado / Oncologia Ginecológica e Mamária / Mestre em Ciências da Saúde

Cervical cancer is the second most common cancer in women worldwide. The principal cause of cervical cancer is infection with human papillomavirus (HPV). HPV-16 is a high-risk virus and it is responsible for a high portion of all HPV-caused cancers. The HPV-16 genome consists of early and late genes. The virus initially infects basal cells of the cervix epithelium and in these cells early genes are expressed, whilst late genes, L1 and L2, are only expressed in the upper cell layers of the epithelium. Proteins encoded by the late genes are highly immunogenic, thus it is speculated that expression of the late genes earlier in the virus life cycle could lead to clearance of the virus due to interference of the immune system.     The aim of this study was to treat reporter cell lines with three different small molecule drugs to see if they had the ability to induce HPV-16 late gene expression. The reporter cell lines used in this study had been previously created by transfecting HeLa-cells with plasmids representing the HPV-16 genome. In these plasmids, L1 is replaced with a CAT reporter gene that encodes the CAT protein, which can be easily quantified using a sandwich ELISA.     Upon treating the reporter cell lines with TPA, a significant induction of late gene expression was detected. Furthermore, treatment with valproic acid showed some induction of late gene expression. In conclusion, TPA and valproic acid was deemed to have potential to act as a candidate drugs for treatment of HPV infections.

Chaque année 610 000 cancers sont diagnostiqués dans le monde induits par une infection à papillomavirus humains à haut-risque (HPV-HR). Bien que les carcinomes des voies aéro-digestives supérieures (VADS) soient principalement associés à une forte consommation de tabac et d’alcool, 20 à 25% sont causés par une infection à HPV, particulièrement l’HPV de type 16. Les patients HPV positifs présentent un meilleur survi global, pourtant ils sont diagnostiqués avec plus de métastases à distance que les patients HPV négatifs. Au travers d’une étude sur des lignées cellulaires dérivées des VADS, nous avons montré que toutes les lignées cellulaires HPV+ présentaient une intégration du génome d’HPV au sein du génome cellulaire, avec des profils d’intégration différents. Les lignées pouvant être utilisées comme modèles caractéristiques des tumeurs HPV+ et HPV- sont respectivement les lignées UPCI:SCC090 et FaDu. La première par ses capacités migratoire et proliférative et la seconde par sa faible agressivité et une mutation du gène cellulaire p53. Dans une étude portant sur une série rétrospective de cancers de l’oropharynx éligible à une résection chirurgicale, 6 cancers sur 40 soit 15% présentaient une infection à HPV16 active (expression de l’ARNm E6*I). Nous avons étudié les marqueurs de TEM dans ces cancers oropharyngés en fonction du statut HPV. Nous avons retrouvé une perte plus importante du marqueur épithélial cadhérine-E au sein du groupe HPV+, associée à une moins bonne survie globale.Au total, nous montrons que le statut HPV et les marqueurs de TEM semblent être deux facteurs indépendants, qui peuvent se combiner pour définir des niveaux pronostiques différents. / Each year, 610,000 cancers are diagnosed worldwide attributed to high risk human papillomavirus (HR-HPV) infection. Although head and neck squamous cell carcinoma (HNSCC) is mainly associated with tobacco and/or alcohol consumption, 20 to 25% are caused by HPV infection, particularly HPV type 16. Although patients with HPV+ tumors present a better overall survival, they are diagnosed with more lymph node metastasis than HPV-negative patients.Through a study of HNSCC derived cell lines, we showed that all HPV-positives cell lines harbored HPV genome integration through host genome, with different integration profiles. Cell lines identified as good HPV+ and HPV- tumors models are UPCI:SCC090 and FaDu respectively. The first one by its migratory and proliferative properties, the second through its poor aggressiveness and mutation of p53 cellular gene.In a study on a retrospective series of oropharyngeal carcinomas with surgical resection, 6 out of 40 cancers shown HPV16 active infection (expressing E6*I mRNA). We studied epithelial-to-mesenchymal transition (EMT) markers on this oropharyngeal cancers, according to HPV status. We found a larger loss of epithelial marker E-cadherin in HPV+ group and loss of this marker is associated with a worse overall survival.We showed that HPV and EMT status seem to be two independent factors that could combine differently to define different prognostic levels.

Oral human papillomavirus (HPV) infection and its association with head and neck cancers (HNCs) have been established by many studies. The characteristics of HPV-associated HNCs are distinguishable from those of non HPV-associated HNCs. HPV-associated HNCs are related to sexual behaviour, particularly the lifetime number of oral sex partners. The oral and oropharyngeal HPV epidemiology in South African men has not yet been researched. The objective of this study was to determine the oral and oropharyngeal HPV strain prevalence and associated factors in a selected male population in Pretoria, South Africa. Male factory workers were recruited on a voluntary basis to be part of this study. Oral rinse and gargle samples were tested for 37 HPV types using the HPV linear array genotyping kit (Roche Molecular System). A questionnaire was utilised to obtain information regarding age, medical conditions, substance and alcohol use and sexual behaviour. HIV testing was optional. The HPV prevalence was 5.6% among the men (n=125) aged 17-64 years. High risk HPV (hrHPV) types 16 and 68 were found in two men. Amongst the majority of the participants oral sex seemed to be an uncommon practice however, those participants with hrHPV did practice oral sex. A statistically significant association between HPV infection and an increased number of sexual partners (p=0.027) was seen but not between substance use, HIVstatus or clinical mucosal pathology. Considering the oral and oropharyngeal HPV prevalence found in this study compared to those reported in other countries. It is therefore proposed that a larger nationwide study be conducted to give a more representative view of the burden of oral and oropharyngeal HPV infection in South Africa. / Dissertation (MSc)--University of Pretoria, 2014. / lk2014 / Community Dentistry / MSc / Unrestricted

Human papillomaviruses (HPV) are double-stranded, DNA, epitheliotropic viruses that infect skin and mucosal membranes. Over 200 types of HPV have been identified and classified into alpha (α), beta (β), gamma (γ), mu (µ), and nu (ν) genera. HPV in the genus α mainly infect mucosal membranes, cause the majority of the ano-genital cancers, and are widely studied. However, epidemiology of HPV in the other genera, which mainly infect skin, is poorly understood. Few studies have reported the seroprevalence of cutaneous HPV among healthy individuals, and to date, no study has prospectively examined the association between cutaneous HPV seropositivity and development of external genital lesions (EGLs) in men. The objectives of this study were to estimate the seroprevalence of cutaneous HPV types and investigate factors associated with the seropositivity, and evaluate the association between seropositivity to cutaneous HPV types and the risk of development of EGLs. Several studies have reported the seroprevalence of mucosal HPV types (6, 11, 16 and 18) in the 4-valent HPV vaccine among men. However, few studies have reported the seroprevalence of the five additional HPV types (31, 33, 45, 52 and 58) in the recently approved 9-valent HPV (9vHPV) vaccine specifically among men across a broad age range. Baseline data on seroprevalence prior to vaccine introduction and dissemination are needed to establish the effectiveness of vaccines over time. Also, this study estimated the seroprevalence of 9vHPV vaccine types and investigated factors associated with the seropositivity among men residing in Brazil, Mexico, and the United States (U.S.). To estimate the seroprevalence of cutaneous HPV types and 9vHPV vaccine types, 600 men were randomly selected from the HPV Infection in Men (HIM) Study. To examine the association between seropositivity to cutaneous HPV types and development of EGLs, a case-control study of 163 incident EGL cases and 352 EGL-free controls nested in the HIM cohort was conducted. Cases were ascertained through visual inspection at each of up to 10 biannual clinical visits, confirmed through biopsy, and categorized into condyloma, suggestive of condyloma, penile intraepithelial neoplasia (PeIN) and other EGLs. Archived serum specimens were tested for antibodies against 14 cutaneous HPV types, β types (5, 8, 12, 14, 17, 22, 23, 24, 38 and 47), α type 27, γ type 4, µ type1 and ν type 41, and 9vHP types (6, 11, 16, 18, 31, 33, 45, 52 and 58) using a glutathione S-transferase (GST) L1-based multiplex serology assay. Socio-demographic and sexual behavior data were collected through a questionnaire. Binomial proportions were used to estimate seroprevalence, and logistic regression was used to examine factors associated with seropositivity. Overall, seroprevalence of ≥1 cutaneous HPV types was 65.4%, 1≥ β-HPV types was 39.0%, α-HPV 27 was 8.9%, γ-HPV 4 was 30.9%, µ-HPV 1 was 28.6%, and ν-HPV 41was 9.4%. Higher educational attainment was significantly associated with seropositivity to ≥1 cutaneous HPV types (adjusted odds ratio [AOR] 1.75 for ≥16 years of education vs. ≤12 years of education, 95% confidence interval [CI] 1.08-2.83), and seropositivity of ≥1 β-HPV types was significantly associated with increasing age (AOR 1.72 for men aged 31-44 years vs. men aged 18-30 years, 95% CI: 1.12–2.63,). Country of residence, circumcision status, and lifetime number of male anal sex partners were other factors significantly associated with various type-specific cutaneous HPV seropositivity. No statistically significant association was observed between grouped or individual cutaneous HPV seropositivity and the risk of development of EGLs across all pathological diagnoses. The seroprevalence of grouped and individual cutaneous HPV types was similar across different EGL categories and controls, with the most frequent types being ɤ-HPV 4, µ-HPV 1, and β-HPV 8. The seroprevalence of ≥1 9vHPV vaccine types was 28.3%, ≥1 high-risk types was 14.0%, five additional high-risk types was 11.2%, and low-risk types (6/11) was 17.4%. Compared to men with no male anal sex partners, men with ≥2 partners were two times more likely to be seropositive for grouped 9vHPV vaccine types, ≥1 high-risk types and ≥1 low-risk types, in addition to individual HPV types 6, 16, 33, and 58, with AORs ranging from 2.19 to 7.36. Older age, current smoking, and being single were other factors significantly positively associated with different grouped and type-specific seropositivity. In conclusion, our data show that exposure to cutaneous HPV was common in men although different risk factors were independently associated with grouped and type-specific cutaneous HPV seropositivity. It appears that exposure to cutaneous HPV is not likely to increase the risk of EGLs among men. Similarly, exposure to 9vHPV vaccine types was also common in men and seropositivity to 9vHPV vaccine types was positively associated with older age and lifetime number male anal sex partners.