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Department of Obstetrics and Gynaecology University of the Witwatersrand Johannesburg February 2015 A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Masters in Medicine, in the branch of Obstetrics and Gynaecology. / HIV accelerates the development of cervical cancer by up to15 years. South Africa is currently in the midst of an HIV epidemic. With limited facilities for colposcopy it is vital to identify risk factors within the HIV positive population resulting in positive margins after Large Loop Excision of the Transformation Zone (LLETZ) and persistence of cytological abnormalities on follow-up Pap smears. Objective: The primary objective was to determine the patient risk factors, pre and during colposcopy and LLETZ biopsy, which resulted in the histological involvement of margins of the LLETZ biopsy and persistent cervical dysplasia on follow-up Pap smears. Secondary objectives included determining follow up rate of patients at the clinic as well as the correlation between the original Pap smear cytology grade and the histological grade found on histology of the LLETZ biopsy. Methods: A retrospective review of the files of HIV seropositive patients was done at the colposcopy clinic at Charlotte Maxeke Johannesburg Academic Hospital after the roll out of antiretroviral treatment for the period 1 April 2004 to 31 October 2012. Patients with abnormal pap smears during this time were referred to the colposcopy clinic where a colposcopy and LLETZ biopsies were done. Demographic and clinical data in regards to age, gravidity, contraception, CD4 count, antiretroviral usage, and referral time was collected. Data from the clinical description of the colposcopy and histology of the LLETZ biopsy was also collected. Patients followed up again after 6 months when a repeat pap smear was done. The results of these Pap smears were also collected. Data was then analysed and variate and multivariate logistical regression was used to find statistically significant correlations. Results: A total of 480 files were found to have complete clinical records. One hundred and sixty eight (42.71%) patients had both endo and ectocervical margins clear. Predictive factors for the involvement of endocervical margins was the doctor performing the procedure (p-value <0.01) cytology of the original Pap smear (p value <0.01) and the grade of histological abnormality found at time of LLETZ (p-value <0.01). The statistically significant predictive factors for ectocervical margin involvement was the visualization of the transformation zone at colposcopy (p-value <0.01), the size of lesion found at colposcopy (p-value <0.01), the use of combined oral contraceptive pill (OCP) (p-value 0.02) and the histological grade of abnormality found on the LLETZ biopsy. Age, parity, CD4 count, use of antiretroviral drugs, length of time from Pap smear to colposcopy and use of contraception other than OCP were not found to be statistically significant in our sample population for the involvement of either endo or ectocervical margins. Statistically significant risk factors for the recurrence of intraepithelial lesions on follow up Pap smear was having both endo and ectocervical margin involvement on histology (p-value 0.01) The Ectocervical margin alone was found to have a p-value of <0.01. Abnormal cytology on follow up Pap smear was found in 58.69% of patients. The follow up rate at the clinic was 46.04%. Correlation of cytological grade and histological grade of cervical intraepithelial neoplasm in our sample population was found to be adequate (p-value <0.01). Conclusion: Incomplete incision of the intraepithelial lesion was found to be a significant risk factor for the recurrence of cytological abnormality in patients undergoing LLETZ biopsy. Identifying patients at increased risk for recurrence is important to ensure close follow up in this patient population.

INTRODUCTION: Approximately 6 million couples in the United States experience infertility. Because few risk factors for infertility are known, identification of modifiable determinants is an important public health goal. Cervical intraepithelial neoplasia, CIN, occurs when the surface cells of the cervical tissue begin to change, and is caused by infection with a high-risk type of human Papillomavirus (HPV). CIN may affect the cervix’s immunological function, resulting in changes in mucus production, reduced protection against infections, and alterations in sperm transport through the cervical canal. CIN can also progress to invasive cervical cancer. There are four main CIN treatment procedures that aim to remove pre-cancerous cells from the cervix; loop excisions, commonly known as electrosurgical excision procedure (LEEP) or large loop excision of the transformative zone (LLETZ); cryosurgery; conization; and laser ablation. Because the goal of these procedures is to remove abnormal cells, healthy cervical cells may inadvertently be removed as well, leading to further changes in cervical mucus production, sperm motility, and reduced protection against infection. Because of the changes to the cervical tissue and its function, CIN and its surgical treatments may affect fecundability. METHODS: We analyzed data from Pregnancy Study Online (PRESTO), a preconception cohort of 5,594 North American pregnancy planners enrolled and followed between 2013 and 2018. At baseline, participants reported whether they had abnormal Pap tests and their age at their first abnormal Pap test, as well as cervical procedures and their age at the procedure. We estimated fecundability ratios (FR) and 95% confidence intervals (CI) using proportional probabilities models adjusted for sociodemographics, smoking, number of sexual partners, history of sexually transmitted infections/ pelvic inflammatory disease, and HPV vaccination. RESULTS: A history of abnormal Pap test, which we used as a proxy for cervical dysplasia, was positively associated with current and past smoking, gravidity, parity, irregular menses, number of sexual partners, history of chlamydia, genital warts and herpes, as well as a history of pelvic inflammatory disease. Of the women with an abnormal Pap test, the average age at first abnormal Pap test was 23.0 (std=4.5) years and the average number of abnormal Pap tests was 2.1 (std=1.7). We found little association overall between a history of abnormal Pap test and fecundability (FR=1.03, 95% CI: 0.96, 1.11). The results did not differ when the data were examined by number of abnormal Pap tests, or type of procedure. There was also little association between time since the diagnosis or procedure and pregnancy attempt and fecundability. There was however a slight decrease in fecundability within the first 2 years of diagnosis/ procedure, with FRs that tended to increase with increasing time since diagnosis/procedure. DISCUSSION: We found little association overall between a history of abnormal Pap test or cervical dysplasia, including excisional surgeries, and fecundability. These results are consistent with most other studies demonstrating no clear adverse effects of CIN and treatments. Recency of diagnosis or procedure did not appreciably affect these findings. Although we found a very slight decrease in fecundability within the first two years since diagnosis or procedure, fecundability became similar to that of undiagnosed/untreated women after 2 years, and then increased slightly. CONCLUSION: We found little association between a history of abnormal Pap and CIN treatments and fecundability. A major limitation of our study is that the data were self-reported, which may have resulted in non-differential exposure misclassification.

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / To systematically review all studies examining HPV vaccination acceptability among immigrant and ethnic minority parents and eligible individuals for cervical cancer prevention in the Unites states. MEDLINE/PubMed, Cumulative Index to Nursing and Allied Health Literature, EMBASE, and Cochrane database searches were conducted searching for English language, US‐based studies to examine immigrant and ethnic minority population’s acceptability of HPV vaccination. Thirteen of more than 3,098 potentially relevant articles were included in the final analysis. Results. Latinos were statistically more likely to accept vaccination for both their daughters and sons. Foreign‐born adult Latinas were more accepting of the vaccine than U.S.‐born Latinas after controlling for other variables. Overall African American and Asian American parents were less likely to accept HPV vaccination for their daughters than Hispanic and White parents. Of the African American parents who intended to vaccinate their children the majority were significantly non‐Baptist and had higher levels of education. The majority of Haitian immigrants intended to vaccinate daughters and the rest agreed that they would most likely have their daughters vaccinated if their daughters’ physicians recommended it. More research is needed, particularly in the context of health care provider HPV vaccination recommendation to immigrant and ethnic‐minority populations. Acceptance figures so far suggest that the vaccine is generally well received among Hispanic/Latin and Haitian immigrants, but details of ethnic variations among these groups and a qualitative understanding of lower rates of acceptability among African American and Asian American communities are still being awaited. Despite advances in cervical cancer screening rates in the US, cervical cancer remains disproportionately high among low‐income immigrant and minority women, making this subgroup particularly vulnerable to disparities in screening and its detection. The purpose of this study is to examine the qualitative aspects of institutional and community level interventions of Cervical Intraepithelial Neoplasia (CIN) within the immigrant and refugee populations and the use of HPV vaccination as a prevention method. Combinations of the following keywords/phrases will be used: CIN‐ Cervical Intraepithelial Neoplasia, Cervical diseases, Cervical dysplasia, Refugees, Pap smear, Cervical Cancer Screening, HPV‐ Human Papillomavirus, HPV vaccination, Ethnic minorities, Immigrants. Independent reviews of each article will be conducted to assess the study quality and confirm the accuracy, completeness, and consistency of the abstracted data.

Diss. (sammanfattning) Göteborg : Univ. , 2008. / Härtill 4 uppsatser.

Orientadores: Liliana Aparecida Lucci de Angelo Andrade, Konradin Metze / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-15T06:41:47Z (GMT). No. of bitstreams: 1 Triglia_RenatadeMarchi_D.pdf: 2275218 bytes, checksum: 3b9b61ceb5abbf3cd2002df7cf26737a (MD5) Previous issue date: 2010 / Resumo: As Neoplasias Intra-epiteliais Cervicais (NIC) são precursoras do carcinoma do colo uterino e, em sua maioria, causadas pelos vírus do Papiloma Humano (HPV) de alto risco oncogênico. A maior parte das NIC1 regride, mas cerca de 15% pode progredir e a integração viral ao genoma da célula tem papel importante neste evento. A hibridização in situ (HIS) detecta o tipo de vírus na lesão e, tem sido atribuído que o sinal difuso desta reação se relaciona à forma epissomal do vírus, enquanto o puntiforme representa o DNA viral integrado ao genoma. O Ki67, marcador de proliferação celular, tem sido usado na graduação das NIC e pode ser um adjuvante na avaliação do comportamento das NIC1. Métodos: 74 biópsias de NIC1 foram estudadas, cujas pacientes apresentaram no acompanhamento biópsias com diagnósticos variados: 19 de cervicite (regressão), 29 com manutenção de NIC1 e 26 com progressão para NIC 2-3. A primeira biópsia foi analisada pela reação de HIS para HPV de alto risco oncogênico (Genpoint®) e pela reação imunoistoquímica para Ki67. Na HIS foram avaliados o número e a distribuição das células nas camadas epiteliais (basal, intermédia ou superficial) e o tipo de sinal (puntiforme ou difuso). A análise do Ki67 foi realizada de 2 formas: a) leitura com avaliação subjetiva da expressão em diferentes níveis do epitélio (camadas basal e para-basal, até a metade e mais da metade da espessura epitelial), b) análise morfológica quantitativa por um programa de computador ("Sociology"), capaz de fazer muitas medidas, como densidade nuclear e relações de vizinhança entre os núcleos. Resultados: a idade da pacientes variou de 16 a 65 anos, sendo a média diferente entre os grupos com e sem progressão (31 e 26, respectivamente, p=0,02). A HIS foi positiva em 22 casos (30%), dos quais 8 progrediram e 14, não. Todos mostraram sinais puntiformes e difusos, entretanto sinal puntiforme na camada basal foi observado em 58,5% dos que progrediram e em apenas 4% dos casos sem progressão (p=0,05). A avaliação subjetiva do Ki67 demonstrou que o grupo que progrediu expressou positividade em mais da metade do epitélio (p=0.02). A análise morfológica quantitativa do Ki67 evidenciou os seguintes resultados significativos no grupo com regressão: menor densidade nuclear, menor quantidade de vizinhos e maior distância entre os núcleos vizinhos mais próximos (p=0,019; 0,008 e 0,02). As medidas da altura dos núcleos positivos no epitélio e da espessura epitelial não mostraram diferença. Conclusão: o sinal puntiforme da HIS na camada basal, a expressão do Ki67 em mais da metade do epitélio, avaliada subjetivamente, e a maior densidade de núcleos na análise morfológica quantitativa estão mais associados à manutenção e progressão das lesões de NIC1 / Abstract: Cervical Intraepithelial Neoplasias (CIN) are precursory lesions of the cervical carcinoma, and most of them are caused by high-risk Human Papillomavirus (HPV). The majority of CIN1 can regress, but around 15% progress, and viral integration has an important role in this event. Integration can be identified by In situ hybridization (ISH). Literature has considered a punctate signal in ISH as integrated HPV, and the diffuse signal as episomal virus. Ki67, a marker of cellular proliferation, can be useful in graduating CIN and evaluating CIN1 behavior. Methods: 74 CIN1 cases were studied and all patients had another biopsy in the follow-up which revealed: 19 without CIN (regression), 29 with maintenance of CIN1 diagnosis, and 26 that progressed to CIN2-3. ISH with Genpoint® for high risk HPV was evaluated according to the distribution of positive cells at different levels in squamous epithelium: basal, intermediate or superficial layers. The pattern of ISH reaction was classified as diffuse or punctate. Ki67 analysis was performed by 2 different ways: a) interpretation with subjective estimation of the immunostaining in different epithelium levels (basal and parabasal layers, until a half and more than a half of the epithelium thickness); b) quantitative morphological analysis by a software ("Sociology"), capable of performing many measurements, as nuclear density and neighborhood relations among the nuclei. Results: the age varied from 16 to 65 and mean age without progression was 26 and 31 for progression (p=0.02). ISH was positive in 30% (22 cases: 8 with lesion progression and 14 without). All cases showed punctate and diffuse signals, but punctate were observed in 58.5% with progression and only in 4% without (p=0.05). Ki67 subjective analysis revealed that group with progression expressed positive nuclei in more than a half of the epithelium thickness (p=0.02). In the regression group, Ki67 quantitative morphological analysis showed smaller nuclei density, a lower quantity of positive cells and a longer distance between neighbor cells when compared to the others (p=0,019; 0,008 e 0,02). The height of Ki67 positive nuclei and the epithelial thickness were not different among the 3 groups. Conclusion: an ISH punctate signal in the basal layer, Ki67 expression in more than a half of epithelium thickness and the nuclear Ki67 density evaluated quantitatively can be related to CIN1 maintenance and progression / Doutorado / Anatomia Patologica / Doutor em Ciências Médicas

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

O câncer cervical é o segundo câncer mais comum entre as mulheres em todo o mundo. A infecção por Papilomavirus (HPV) do tipo oncogênico é causa necessária. Estudos internacionais sugerem importante papel de carotenóides e tocoferóis séricos e dietéticos na redução do risco para lesões precursoras, mas os resultados dos estudos prévios são inconsistentes. Indivíduos e métodos: O presente estudo de casos e controles de base hospitalar conduzido na cidade de São Paulo analisou a associação entre concentrações séricas de carotenóides (licopeno, &#946;-caroteno), tocoferóis (&#945;- e &#947;-), consumo alimentar e casos incidentes, com confirmação histopatológica, de neoplasia intraepitelial cervical (NIC) graus 1,2,3 e câncer cervical. O estudo incluiu 453 mulheres do grupo controle (sem lesões de colo uterino) e 4 grupos de casos (NIC1, n=140; NIC2, n=126; NIC3, n=231; câncer cervical, n=108) recrutadas em dois hospitais públicos de referência entre 2003 e 2005. Resultados. A concentração sérica de licopeno foi inversamente associada à NIC1, NIC3 e câncer cervical com os seguintes Odds Ratio (OR) (intervalo de confiança de 95%), respectivamente: 0,53 (0,27-1,00; p de tendência=0,05); 0,48 (0,22-1,04; p de tendência=0,05) e 0,18 (0,06-0,52; p de tendência=0,002) quando comparado o maior com o menor tercil após ajuste por variáveis de confusão e grupos de HPV. O maior tercil de &#946;-caroteno sérico foi inversamente associado ao câncer quando comparado ao menor: OR ajustado = 0,36 (0,13-1,03: p de tendência=0,04). Maiores concentrações de &#945;- e &#947;-tocoferóis foram inversamente associadas a NIC3 com redução do risco em 50%, após ajuste por covariáveis e HPV. Maior tercil de consumo do grupo de folhas verde-escuras, legumes e frutas de cor alaranjada ou amarela escura foi inversamente associado ao risco para NIC3: OR ajustado comparado ao menor foi 0,52 (0,27-1,00; p de tendência=0,05). Conclusão: Os resultados do presente estudo sugerem que maiores concentrações séricas de antioxidantes e o consumo de alimentos ricos em carotenóides podem reduzir o risco para NIC3 e câncer cervical em mulheres brasileiras. / Cervical cancer is the second most common cancer in women worldwide. Human papillomavirus (HPV) infection has been recognized to be a necessary cause for cervical cancer. Serum concentrations and dietary carotenoids and tocopherols have been associated with the risk for cervical dysplasia, but results from previous studies were not consistent. Subjects and methods: In this hospital-based case-control study conducted in São Paulo city, Brazil, we evaluated the association of serum carotenoids (&#946;-carotene, lycopene), tocopherols (&#945;- and &#947;-), and dietary intakes with the risk of incident histologically confirmed cervical intraepithelial neoplasia (CIN) grades 1, 2, 3, and cervical cancer. The sample included 453 controls and four groups of cases (CIN1, n= 140; CIN2, n= 126; CIN3, n= 231; invasive cancer, n=108) recruited from two major public hospital-based clinics between 2003 and 2005. Results. Concentrations of serum lycopene were negatively associated with CIN1, CIN3 and cancer, with odds ratio (OR) (95% confidence interval) for the highest compared with the lowest tertile of 0.53 (0.27-1.00, p trend=0.05) for CIN1, 0.48 (0.22-1.04, p trend=0.05) for CIN2 and 0.18 (0.06-0.52, p trend= 0.002) for cervical cancer adjusted for confounding variables and HPV status. The adjusted OR for cancer of the highest versus the lowest tertile of serum &#946;-carotene was 0.36 (0.13-1.03, p trend= 0.04). Increasing concentrations of serum &#945;- and &#947;-tocopherols were associated with 50% decreasing risk of CIN3, for the women in the highest compared with the lowest quartile after adjusting for confounding variables and HPV. Increased dietary intakes of dark green and deep yellow vegetables and fruits were inversely associated with CIN3 among women in the highest compared to the lowest tertile (adjusted OR= 0.52, 95%CI = 0.27-1.00; p trend=0.05). Conclusion: These results support the evidence that high serum levels of antioxidants as well as dietary intakes may reduce the risk for CIN3 and invasive cancer in Brazilian women.

O câncer cervical é o segundo câncer mais comum entre as mulheres em todo o mundo. A infecção por Papilomavirus (HPV) do tipo oncogênico é causa necessária. Estudos internacionais sugerem importante papel de carotenóides e tocoferóis séricos e dietéticos na redução do risco para lesões precursoras, mas os resultados dos estudos prévios são inconsistentes. Indivíduos e métodos: O presente estudo de casos e controles de base hospitalar conduzido na cidade de São Paulo analisou a associação entre concentrações séricas de carotenóides (licopeno, &#946;-caroteno), tocoferóis (&#945;- e &#947;-), consumo alimentar e casos incidentes, com confirmação histopatológica, de neoplasia intraepitelial cervical (NIC) graus 1,2,3 e câncer cervical. O estudo incluiu 453 mulheres do grupo controle (sem lesões de colo uterino) e 4 grupos de casos (NIC1, n=140; NIC2, n=126; NIC3, n=231; câncer cervical, n=108) recrutadas em dois hospitais públicos de referência entre 2003 e 2005. Resultados. A concentração sérica de licopeno foi inversamente associada à NIC1, NIC3 e câncer cervical com os seguintes Odds Ratio (OR) (intervalo de confiança de 95%), respectivamente: 0,53 (0,27-1,00; p de tendência=0,05); 0,48 (0,22-1,04; p de tendência=0,05) e 0,18 (0,06-0,52; p de tendência=0,002) quando comparado o maior com o menor tercil após ajuste por variáveis de confusão e grupos de HPV. O maior tercil de &#946;-caroteno sérico foi inversamente associado ao câncer quando comparado ao menor: OR ajustado = 0,36 (0,13-1,03: p de tendência=0,04). Maiores concentrações de &#945;- e &#947;-tocoferóis foram inversamente associadas a NIC3 com redução do risco em 50%, após ajuste por covariáveis e HPV. Maior tercil de consumo do grupo de folhas verde-escuras, legumes e frutas de cor alaranjada ou amarela escura foi inversamente associado ao risco para NIC3: OR ajustado comparado ao menor foi 0,52 (0,27-1,00; p de tendência=0,05). Conclusão: Os resultados do presente estudo sugerem que maiores concentrações séricas de antioxidantes e o consumo de alimentos ricos em carotenóides podem reduzir o risco para NIC3 e câncer cervical em mulheres brasileiras. / Cervical cancer is the second most common cancer in women worldwide. Human papillomavirus (HPV) infection has been recognized to be a necessary cause for cervical cancer. Serum concentrations and dietary carotenoids and tocopherols have been associated with the risk for cervical dysplasia, but results from previous studies were not consistent. Subjects and methods: In this hospital-based case-control study conducted in São Paulo city, Brazil, we evaluated the association of serum carotenoids (&#946;-carotene, lycopene), tocopherols (&#945;- and &#947;-), and dietary intakes with the risk of incident histologically confirmed cervical intraepithelial neoplasia (CIN) grades 1, 2, 3, and cervical cancer. The sample included 453 controls and four groups of cases (CIN1, n= 140; CIN2, n= 126; CIN3, n= 231; invasive cancer, n=108) recruited from two major public hospital-based clinics between 2003 and 2005. Results. Concentrations of serum lycopene were negatively associated with CIN1, CIN3 and cancer, with odds ratio (OR) (95% confidence interval) for the highest compared with the lowest tertile of 0.53 (0.27-1.00, p trend=0.05) for CIN1, 0.48 (0.22-1.04, p trend=0.05) for CIN2 and 0.18 (0.06-0.52, p trend= 0.002) for cervical cancer adjusted for confounding variables and HPV status. The adjusted OR for cancer of the highest versus the lowest tertile of serum &#946;-carotene was 0.36 (0.13-1.03, p trend= 0.04). Increasing concentrations of serum &#945;- and &#947;-tocopherols were associated with 50% decreasing risk of CIN3, for the women in the highest compared with the lowest quartile after adjusting for confounding variables and HPV. Increased dietary intakes of dark green and deep yellow vegetables and fruits were inversely associated with CIN3 among women in the highest compared to the lowest tertile (adjusted OR= 0.52, 95%CI = 0.27-1.00; p trend=0.05). Conclusion: These results support the evidence that high serum levels of antioxidants as well as dietary intakes may reduce the risk for CIN3 and invasive cancer in Brazilian women.

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2016-04-15T12:35:53Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Trabalho e Artigo. BIBLIOTECA.pdf: 1144641 bytes, checksum: 49381fb9cd2af1b7f9dccd4c30011139 (MD5) / Made available in DSpace on 2016-04-15T12:35:53Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Trabalho e Artigo. BIBLIOTECA.pdf: 1144641 bytes, checksum: 49381fb9cd2af1b7f9dccd4c30011139 (MD5) Previous issue date: 2015-09-11 / CAPEs / O câncer de colo uterino é o terceiro câncer mais comum em mulheres. A infecção e persistência do papilomavirus humano (HPV) tem papel fundamental no surgimento e evolução das lesões cervicais, promovendo alterações no ciclo celular e proliferação celular descontrolada através das oncoproteínas E6 e E7. Entretanto, fazem-se necessários diversos outros fatores para o desenvolvimento de neoplasias. Entre estes, encontram-se as metaloproteinases de matriz (MMP), endopeptidases capazes de digerir matriz extracelular, membrana basal e induzir fatores de crescimento, que participam dos processos de invasão, metástase, angiogênese e recidiva tumorais. Em lesões neoplásicas, a síntese de MMPs encontra-se aumentada. Sua atividade normalmente é contrarregulada por inibidores endógenos, sendo muito comum que haja desequilíbrio nesta relação em lesões tumorais. A despeito de muito estudo sobre sua relação com o câncer cervical, sabe-se pouco sobre o papel das MMPs e seus inibidores na progressão de lesões cervicais causadas por HPV. Este estudo procura correlacionar a expressão de TIMP2 e RECK às lesões cervicais causadas por HPV. Foram utilizadas 115 amostras teciduais, obtidas por conização de lesões cervicais uterinas entre 2011 e 2015 no Hospital das Clínicas de Recife, nas quais foi realizado estudo histopatológico e imunohistoquímico. Foi observada reatividade fraca no citoplasma de células do tecido escamoso de 28,5% dos controles, sem nenhuma lâmina demonstrar reatividade moderada ou forte. Quanto ao núcleo, a quase totalidade das amostras não apresentou TIMP-2, enquanto 28,5% dos controles o fez. No epitélio glandular nenhuma amostra do Grupo Controle, NIC I ou NIC II foi positiva para TIMP2 no citoplasma e núcleo. Das amostras de NIC III, 6% demonstraram positividade no citoplasma. Os resultados de RECK no citoplasma do epitélio escamoso mostraram que a expressão de RECK no citoplasma de células epiteliais escamosas é significativamente maior quanto maior o grau de lesão do tecido, exceto no CC, onde a expressão é menor que a das lesões NIC III (p = 0,019). Os resultados demonstraram que a expressão nuclear de RECK em células epiteliais escamosas é significativamente menor nos tecidos displásicos (p < 0,001). Nas análises de citoplasma do epitélio glandular , nenhuma amostra do Grupo Controle, NIC I e NIC II foi positiva, havendo 3,6% de positividade nas lesões de NIC III, todas com reatividade fraca ou moderada, e 10% de positividade moderada nas amostras de CC. Nenhuma das amostras apresentou positividade nuclear. Os resultados obtidos demonstram menor expressão nuclear de TIMP2 e RECK na presença de displasia e maior expressão citoplasmática de RECK nas células escamosas. Esta foi maior quanto mais alto o grau de displasia, mas foi menor nas amostras de carcinoma do que nas de NIC III. Conclui-se que os inibidores de MMPs podem ter utilidade como marcadores imunohistológicos nas lesões cervicais, sendo necessários mais estudos para sua validação prática. / Cervical cancer is the third most common cancer in women. The infection and persistence of human papillomavirus (HPV) plays a key role in the emergence and evolution of cervical lesions, promoting changes in the cell cycle and uncontrolled cell proliferation through the oncoproteins E6 and E7. However, make up several other factors required for the development of malignancies. Among these are the matrix metalloproteinases (MMPs), endopeptidases capable of digesting the extracellular matrix, basement membrane and induce growth factors, that participate in the processes of invasion, metastasis, angiogenesis and tumor recurrence. In neoplastic lesions, MMPs synthesis is increased. Its activity is usually contrarregulada by endogenous inhibitors, being very common there is imbalance in this relationship in tumor lesions. Despite much study on its relationship with cervical cancer, little is known about the role of MMPs and their inhibitors in the progression of cervical lesions caused by HPV. This study tries to correlate the expression of RECK and TIMP2 the cervical lesions caused by HPV. 115 tissue samples were used, obtained by conization to uterine cervical lesions between 2011 and 2015 at the Hospital das Clinicas of Recife, in which was conducted histopathological and immunohistochemical study. Weak reactivity was observed in the cytoplasm of the squamous tissue cells of 28.5% of controls, with no slide show moderate or strong reactivity. As for the core, almost all of the samples showed no TIMP-2, while 28.5% of controls did. Glandular epithelium in any sample of the control group, CIN I or CIN II was positive for TIMP2 in the cytoplasm and nucleus. Samples of CIN III, 6% showed positivity in the cytoplasm. The results of RECK in the cytoplasm of squamous epithelium showed that RECK expression in the cytoplasm of squamous epithelial cells is significantly higher the higher the degree of tissue injury, except DC, where expression is lower than that of CIN III lesions (p = 0.019). The results showed that nuclear RECK expression in squamous epithelial cells is significantly lower in dysplastic tissues (p <0.001). In the cytoplasm analysis of glandular epithelium, no sample of the control group, CIN I and CIN II was positive, with 3.6% of positivity in CIN III lesions, all with low or moderate reactivity, and 10% moderate positivity in the samples DC. None of the samples showed nuclear positivity. The results showed lower nuclear expression TIMP2 and RECK in the presence of dysplasia and increased cytoplasmic expression of RECK in squamous cells. This was greater the higher the degree of dysplasia, but was lower in carcinoma samples than in CIN III. We conclude that MMP inhibitors may have utility as immunohistological markers in cervical lesions, more research is needed to validate your practice.