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The human papillomavirus (HPV) is the etiologic agent of genital cancer, but alone it is incapable of inducing oncogenesis. Rather, progression to invasive lesions is associated with host immunity and interference in the process of cellular apoptosis. Among the several genes involved in cell death, theFAS gene appears to be an important factor. The aim of this study was to evaluate whether there is an association between polymorphisms of the FAS-670 gene promoter region and preinvasive and invasive lesions of the cervix. The FAS gene was evaluated for the presence of polymorphisms using polymerase chain reaction and restriction fragment length polymorphism techniques in 225 blood samples for the control group, as well as cervical tissue from patients with cervical intraepithelial neoplasia grade 3 (CIN 3; 75 cases) or invasive carcinoma (214 cases). The AG genotype of the FAS-670 gene promoter region was significantly more frequent in women with CIN 3, with an estimated risk of three times (OR = 3.0). No difference, however, was observed in the control group and women with cervical cancer. In women with cancer, the genotypes were similar in the different histological types and degree of tumor differentiation. Assessing allelic distribution (A or G), we observed no difference in frequency of genotypes in studied groups. These data suggest that polymorphism of the promoter region of the FAS-670 gene is associated with increased risk of CIN 3, but not for invasive cancer of the cervix.

CONTEXT AND OBJECTIVE: Epidemiology may help educators to face the challenge of establishing content guidelines for the curricula in medical schools. The aim was to develop learning objectives for a medical curriculum from an epidemiology database. DESIGN AND SETTING: Descriptive study assessing morbidity and mortality data, conducted in a private university in São Paulo. METHODS: An epidemiology database was used, with mortality and morbidity recorded as summaries of deaths and the World Health Organization's Disability-Adjusted Life Year (DALY). The scoring took into consideration probabilities for mortality and morbidity. RESULTS: The scoring presented a classification of health conditions to be used by a curriculum design committee, taking into consideration its highest and lowest quartiles, which corresponded respectively to the highest and lowest impact on morbidity and mortality. Data from three countries were used for international comparison and showed distinct results. The resulting scores indicated topics to be developed through educational taxonomy. CONCLUSION: The frequencies of the health conditions and their statistical treatment made it possible to identify topics that should be fully developed within medical education. The classification also suggested limits between topics that should be developed in depth, including knowledge and development of skills and attitudes, regarding topics that can be concisely presented at the level of knowledge. CONTEXTO E OBJETIVO: A epidemiologia pode auxiliar os educadores a enfrentar o desafio de estabelecer diretrizes para o conteúdo dos currículos em escolas médicas. O objetivo foi desenvolver objetivos de aprendizagem para um currículo médico por meio de um banco de dados epidemiológicos. TIPO DE ESTUDO E LOCAL: Estudo descritivo avaliando dados de morbidade e mortalidade, realizado por universidade particular em São Paulo. MÉTODOS: O banco de dados epidemiológicos com morbidade e mortalidade registrados como resumo de causas de morte e o Disability-Adjusted Life Year (DALY) da Organização Mundial de Saúde foi utilizado. A pontuação desenvolvida considerou probabilidades de mortalidade e morbidade. RESULTADOS: A pontuação apresenta uma classificação dessas condições de saúde para ser utilizada por uma comissão responsável pelo desenho curricular, considerando seus quartis superior e inferior, designando, respectivamente, maior e menor impacto na morbidade e mortalidade. Dados de três países foram utilizados para comparação internacional, mostrando resultados distintos. As pontuações resultantes indicaram temas a serem desenvolvidos pela taxonomia educacional. CONCLUSÃO: A frequência das condições de saúde e seu tratamento estatístico possibilitaram a identificação de temas que devem ser plenamente desenvolvidos em educação médica. A classificação sugere também limites entre tópicos que devem ser desenvolvidos em profundidade, incluindo o conhecimento e o desenvolvimento de habilidades e atitudes, a respeito de tópicos que podem ser concisamente apresentados ao nível de conhecimento.

Spontaneous regression of cervical intraepithelial neoplasia grade 2 (CIN2) lesions has been recognized since 1955, but predictors of this are poorly understood. Among the predictive markers studied, p16INK4ahas been suggested to be of some value in monitoring the diagnosis of CIN2. In this clinical trial, 90 Brazilian women, diagnosed to CIN2 and high-risk human papillomavirus infection, were randomized into two groups of equal size: 45 women whose lesions were excised and 45 women subjected to prospective follow-up at 3-month intervals at least for 1 year (mean 6.8 months). p16INK4aexpression was analyzed in paraffin-embedded sections using immunohistochemical staining. Among the 45 women in the follow-up group, 42% experienced spontaneous regression, 11% showed persistence, 22% progressed to CIN3, and 20% had partial regression to CIN1 or ASCUS (atypical squamous cell undetermined signifiance). p16INK4aexpression was detected in 68.9% of the patients. In univariate survival (Cox) analysis, no significant difference in regression was obtained between p16INK4a-negative and -positive CIN2 lesions (adjusted HR = 1.1; 95% CI 0.6–2.0). In conclusion, p16INK4aexpression could be useful in the diagnosis of CIN2. However, it failed to predict the outcome of CIN2. Because of its high spontaneous regression rate, follow-up could be considered as a management option of CIN2 in young and compliant women.

The p53 codon 72 polymorphism seems to be associated with HPV-carcinogenesis, although controversial data have been reported. A series of Brazilian women with cervix carcinomas were analyzed. Ninety-nine (67%) of 148 women were found to be homozygous (arg/arg) for the arginine polymorphism, and 49 (33%) were heterozygous (arg/pro). This polymorphism may be an important determinant of the risk for cervix cancer, but does not seem to be sufficient for carcinogenesis. Hospital Maternidade Leonor Mendes de Barros Oncologia Ginecológica Universidade Federal de São Paulo (UNIFESP) Laboratório de Ginecologia Molecular Universidade Estadual de Campinas Faculdade de Medicina Oncologia Ginecológica Universidade de São Paulo Departamento de Medicina Social Faculdade de Medicina de Ribeirão Preto Istituto Superiore di Sanità Laboratory of Epidemiology and Biostatistics Cytopathology Unit UNIFESP, Laboratório de Ginecologia Molecular SciELO

The c-myc protein is known to regulate the cell cycle, and its down-regulation can lead to cell death by apoptosis. The role of c-myc protein as an independent prognostic determinant in cervical cancer is controversial. In the present study, a cohort of 220 Brazilian women (mean age 53.4 years) with FIGO stage I, II and III (21, 28 and 51%, respectively) cervical squamous cell carcinomas was analyzed for c-myc protein expression using immunohistochemistry. The disease-free survival and relapse-rate were analyzed using univariate (Kaplan-Meier) survival analysis for 116 women who completed the standard FIGO treatment and were followed up for 5 years. Positive c-myc staining was detected in 40% of carcinomas, 29% being grade 1, 9% grade 2, and 2% grade 3. The distribution of positive c-myc according to FIGO stage was 19% (17 women) in stage I, 33% (29) in stage II, and 48% (43) in stage III of disease. During the 60-month follow-up, disease-free survival in univariate (Kaplan-Meier) survival analysis (116 women) was lower for women with c-myc-positive tumors, i.e., 60.5, 47.5 and 36.6% at 12, 36, and 60 months, respectively (not significant). The present data suggest that immunohistochemical demonstration of c-myc does not possess any prognostic value independent of FIGO stage, and as such is unlikely to be a useful prognostic marker in cervical squamous cell carcinoma.

Although human papillomavirus was identified as an aetiological factor in cervical cancer, the key human gene drivers of this disease remain unknown. Here we apply an unbiased approach integrating gene expression and chromosomal aberration data. In an independent group of patients, we reconstruct and validate a gene regulatory meta-network, and identify cell cycle and antiviral genes that constitute two major subnetworks upregulated in tumour samples. These genes are located within the same regions as chromosomal amplifications, most frequently on 3q. We propose a model in which selected chromosomal gains drive activation of antiviral genes contributing to episomal virus elimination, which synergizes with cell cycle dysregulation. These findings may help to explain the paradox of episomal human papillomavirus decline in women with invasive cancer who were previously unable to clear the virus.

To compare two management strategies for cervical intraepithelial neoplasia (CIN) 2, and evaluate reproducibility of the diagnosis.Ninety (90) women with biopsy-proven CIN2 diagnosed through the Brazilian public health service were randomly allocated into two groups: 45 in prospective follow-up without treatment, and 45 for radical loop electrosurgical excision procedure (LLETZ). As in the real-life situation, pathology-reviewed diagnoses and HPV genotypes were not available.Excision of the lesion proved to be more effective than prospective follow-up in reaching clearance of CIN2 (hazard ratio=3.66; 95% confidence interval 2.02-6.64). However, 44.1% of the lesions regressed without treatment during the 12-month follow-up.CIN2 lesions regress without treatment in one year, although an ablative procedure is more effective. However, excision of CIN2 may lead to additional morbidity and costs, and tailoring the management on an individual basis may result in better outcome. Misclassification of CIN2 is not a negligible problem.

The present study assessed, in cervical carcinoma, expression levels of seven immune response genes and sought correlation to response to treatment. The expression levels of CD28, CTLA4, ICOS, ICOSL, CD80 and CD86 and granzyme B genes were assessed by real-time RT-PCR in pre-treatment tumor fragments. During the six-month follow-up after treatment, 8 patients presented tumor and 10 survived free of tumor. The only gene whose expression levels were higher in patients with poor outcome (p = 0.03) was granzyme B. Further evaluation, in adequately powered prospective studies is warranted to confirm the data and to translate this observation to the clinical setting.

O câncer de colo uterino é a maior causa de morte entre mulheres em todo o mundo, notadamente nos países em desenvolvimento. A Federação Internacional de Ginecologia e Obstetrícia preconiza o estadiamento durante o ato operatório, porém nos casos mais avançados a abordagem terapêutica não é cirúrgica. Nestes casos, o estadiamento, em geral, é feito com o exame clínico ginecológico e exames básicos de imagem. Entretanto, essa forma de abordagem não expressa a real extensão da doença e não inclui importantes fatores prognósticos como volume tumoral, invasão estromal e acometimento linfonodal. A ressonância magnética está sendo cada vez mais utilizada para este fim, pois nos estádios iniciais seu desempenho pode ser comparado aos achados intra-operatórios e nos estádios avançados se mostra superior em relação à avaliação clínica. A ressonância magnética apresenta excelente resolução para diversas densidades das estruturas pélvicas, não utiliza radiação ionizante, é confortável, melhora o estadiamento, permite a detecção precoce de recidiva e a identificação de fatores prognósticos fidedignos que contribuem na decisão e predição dos resultados terapêuticos, com excelente custo-efetividade. Este artigo tem como objetivo revisar os aspectos da ressonância magnética mais importantes no estadiamento desta doença. Cervical cancer is the worldwide leading cause of cancer-related death of women, especially in developing countries. The International Federation of Gynecology and Obstetrics recommends staging during surgery, however, surgical-pathologic staging would not be feasible in cases of more advanced cancers. Generally, in these cases, the staging is performed by means of clinical and gynecological examination and basic imaging studies. However, such an approach fails to demonstrate the actual extent of the disease, and does not include significant prognostic factors such as tumor volume, stromal invasion and lymph node involvement. Magnetic resonance imaging has increasingly been utilized in cervical cancer staging, since at early stages of the disease its performance may be compared to intraoperative findings and, at advanced stages, it shows to be superior to the clinical evaluation. Additionally, magnetic resonance imaging presents an excellent imaging resolution for the different densities of pelvic structures, does not require ionizing radiation, is comfortable for the patient, improves de staging, allowing the early detection of recurrence and the identification of reliable prognostic factors which contribute to the therapeutic decision making process and results prediction with an excellent cost-effectiveness. The present article is aimed at reviewing the most significant aspects of magnetic resonance imaging in the cervical cancer staging.

Recent data implicate that cytokine gene polymorphisms are important in pathogenesis of various neoplastic and nonneoplastic human diseases, and it was recently suggested that polymorphisms in interleukin (IL)-6 might increase the risk of gynecological malignancies, including cervical carcinomas. The aim of this case-control study is to compare the IL-6 polymorphisms in cervical cancer patients and healthy controls and to assess whether any of these polymorphisms would increase the risk of developing cervical cancer. The material in this case-control study consists of 56 patients with cervical carcinoma and 253 population-based control subjects, all ethnic Brazilian women. Control subjects were cancer-free women, following a negative cervical cytology and colposcopy. IL-6 genotyping was performed using a polymerase chain reaction-based restriction fragment length polymorphism. Distribution of the GG, GC, and CC genotypes in cases and controls was significantly different (P= 0.033). Compared with the GG genotype as reference, the adjusted odds ratio for the combined GC and CC genotypes in cancer patients was 1.90 (95% confidence interval, 1.1-3.4). These data suggest that women carrying at least one C genotype in their IL-6 promoter region (-174G-->C) are at higher risk of developing cervical cancer.

The rapid progress in molecular biology has allowed the identification of the genes involved in different functions of normal cells and has also improved our understanding of the mechanisms of human carcinogenesis. The human papillomavirus (HPV) is a small double-stranded DNA tumor virus and its genes can manipulate cell cycle control to promote viral persistence and replication. The E6 and E7 proteins of high-risk HPV bind to cell cycle regulatory proteins and interfere with both G1/S and G2/M cell cycle checkpoints much more effectively than the low-risk HPV. The difference between the ability of low and high-risk HPV types to induce immortalization and transformation may well lie in their abilities to interact with the various cell cycle components, resulting in the loss of multiple cell cycle checkpoints, which are important in host genome fidelity, thus potentially resulting in accumulation of genetic abnormalities. Cervical cancer is one of the leading malignancies in women worldwide, with substantial morbidity and mortality. According to current concepts, HPV is recognized as the single most important causal agent in the pathogenesis of this cancer. HPV infection clearly precedes the development of malignancy, while being regularly associated with cervical cancer precursor lesions (all grades of squamous intraepithelial lesions). HPV-infected low-grade squamous intraepithelial lesion (SIL) has three possible outcomes: a) it may regress; b) it can persist; or c) it can make a clinical progression to in situ or invasive carcinoma. It has been well established by prospective cohort studies that the spontaneous regression rate increases in parallel with follow-up duration. In contrast, the clinical progression of lesions usually takes place quite rapidly, i.e. during the first two years from diagnosis. The mechanisms responsible for this divergent clinical behavior of HPV-associated squamous intraepithelial lesions are largely unknown, but currently under intense study in different laboratories worldwide. O rápido progresso dos estudos em biologia molecular permitiu identificar os genes envolvidos em diferentes funções celulares e também melhorou nossa compreensão sobre os mecanismos da carcinogênese humana. O papilomavírus humano (human papillomavirus, HPV) é um vírus de DNA e os seus genes podem manipular o controle do ciclo celular para promover a sua persistência e replicação. As proteínas E6 e E7 dos HPVs de alto risco oncogênico ligam-se às proteínas reguladoras do ciclo celular e interferem nas fases G1/S e G2/M mais efetivamente do que os HPVs de baixo risco. Os HPVs de baixo e alto risco diferem em sua capacidade de induzir imortalização e transformação celular bem como de interagir com os vários componentes de ciclo celular, o que resulta na perda de pontos de checagem do DNA, importantes para a manutenção do genoma do hospedeiro, e também resulta no acúmulo de anormalidades genéticas. O câncer de colo de útero é um dos principais cânceres genitais em mulheres em todo o mundo, com significativa morbidade e mortalidade. De acordo com conceitos atuais, o HPV é reconhecido como o agente causal mais importante na patogênese deste câncer. A infecção por HPV está associada a todas as lesões intra-epiteliais escamosas do colo do útero. A lesão intra-epitelial escamosa (squamous intraepithelial lesion, SIL) de baixo-grau tem três possíveis resultados: a) pode regredir; b) pode persistir ou c) pode progredir para câncer in situ ou invasivo. Estudos de coorte mostraram que a taxa de regressão espontânea destas lesões aumenta conforme o tempo de seguimento, em contraste com as lesões destinadas a progressão, que normalmente evoluem rapidamente, geralmente nos primeiros dois anos. Os mecanismos responsáveis pelo comportamento clínico da lesão intra-epitelial escamosa associada ao HPV ainda não são totalmente conhecidos, mas atualmente têm sido motivo de estudos em todo o mundo.

Objective . The prognostic value of p53 codon72 polymorphism was analyzed in Brazilian women with cervical cancer. Methods . The present study consists of 148 women diagnosed and treated for invasive cervical carcinoma (FIGO stages Ib–IIIb) between 1992 and 2002. Demonstration of p53 polymorphism was performed in DNA extracted from paraffin-embedded sections using the polymerase chain reaction (PCR). Results . Among the 148 women, arg/arg was found in 99 (67%) and, arg/pro in 49 (33%). The overall survival (OS) curves (univariate) were different between arg/arg and arg/pro patients ( P = 0.01). There was slightly increased risk of death for arg/arg patients (crude HR 2.2 CI 95% 1.2–4.0), which was not confounded by FIGO stages (adjusted HR 2.4 CI 95% 1.3–4.3). For disease-free survival (DFS), two situations were considered: (1) 124 women who received any treatment, and (2) 118 who received FIGO-recommended treatment. In the first group, 59% of arg/arg patients presented recurrence as compared to 32% in the arg/pro group ( P = 0.02), whereas in the second group, 61% of the arg/arg and 34% arg/pro showed recurrence ( P = 0.04). The risk of recurrence adjusted by FIGO stage for the 124 patients was 2.4 (CI 95% 1.0–3.7) and for the 118 it was 1.9 (CI 95% 1.0–3.4). These adjusted models showed no confounding and no interaction. Conclusions . Despite the prognostic significance of p53 polymorphism in univariate survival analysis, there was no or only marginal evidence on the independent prognostic value of p53arg/arg in multivariate analysis. The more ominous prognosis of the homozygous (arg/arg) patients was explained by the primary treatment, independent on the FIGO stage.

O câncer de colo uterino apresenta alta mortalidade no Brasil, apesar dos programas para rastreamento. O objetivo deste estudo, de corte transversal, foi analisar conhecimento, atitude e prática do exame de Papanicolaou e entender a não adesão das mulheres a este exame. Foram entrevistadas 138 mulheres: noventa com neoplasia intra-epitelial de alto grau e 48 com câncer invasivo de colo uterino. As mulheres com câncer invasivo tiveram prática mais inadequada do exame. No entanto, independente do diagnóstico, mais de 80% delas referiram desmotivação/vergonha, 60% relataram que os médicos não examinavam e, cerca de 50% apontaram o tempo de espera para a consulta e a demora no agendamento como dificuldades para serem atendidas. Em geral, a prática do exame dependeu da iniciativa do médico e a periodicidade da coleta foi determinada pela procura de consulta devido a sintomas. As mulheres com 56 anos ou mais mostraram maior inadequação no conhecimento, na atitude e na prática. No entanto, aquelas com maior escolaridade conheciam melhor o exame. A maior idade e a menor escolaridade podem estar associados a não adesão das mulheres ao exame, porém as dificuldades sociais e econômicas para conseguir atendimento em saúde precisam ser consideradas para aumentar a prática do exame. Despite screening programs, Brazil has a high cervical cancer mortality rate. The objective of this cross-sectional study was to analyze knowledge, attitudes, and practices related to the Pap smear and to understand why women fail to submit to this screening test. A structured questionnaire was used to interview 138 women: 90 with high grade intraepithelial neoplasia and 48 with invasive cervical cancer. Inadequate practices were more frequent among women with invasive cancer. In terms of difficulties in obtaining medical care, more than 80% of women reported lack of motivation, 60% reported that physicians failed to conduct a complete physical examination, and some 50% reported that physicians' schedules were busy. Having a Pap smear usually depended on a physician's request and the woman being symptomatic. Women over than 56 years old showed more frequent inadequate knowledge, attitudes and practices. However, those with more schooling were more knowledgeable of the Pap smear procedure. Age and less schooling could be barriers against women participating in screening programs, but socioeconomic problems must also be considered for improving practices related to the Pap smear.

Objetivo: analisar os niveis dos esteroides sexuais endogenos e gonadotrofinas em mulheres com e sem câncer de endometrio. Metodos: foi realizado estudo clinico-comparativo com 20 mulheres na pos-menopausa com câncer de endometrio e 20 mulheres na pos-menopausa, sem câncer de endometrio. A idade, o tempo de menopausa e o indice de massa corporea foram utilizados como variaveis de emparelhamento. Os niveis plasmaticos dos esteroides sexuais endogenos foram medidos por metodos de radioimunoensaio e imunoenzimatico. Para analise estatistica utilizamos o teste "t" de Student. Resultados: os niveis de androstenediona (A), testosterona total (t) e testosterona livre (TL) foram mais elevados nas mulheres com câncer de endometrio e os niveis de hormonio luteinizante (LH) foram significativamente menores nessas mulheres. Tambem observamos que a razao (E1/A) mostrou valores significativamente menores no grupo de mulheres com câncer, ao passo que a razao (E2/E1) nao apresentou diferencas nos dois grupos. Conclusoes: destacamos a potencialidade dos esteroides sexuais e gonadotrofinas na genese do adenocarcinoma de endometrio em mulheres na pos-menopausa.