Aspectos clínicos e epidemiológicos da infecção genital pelo Papilomavírus humano (HPV) em adolescentes da região metropolitana de Belém

A adolescência é um período de vida da mulher marcado por transformações biológicas e psicológicas que influenciam intensamente sua saúde futura. Essas mulheres são mais suscetíveis às DST. A infecção pelo HPV é uma das DST mais frequentes, sendo importante avaliar a sua prevalência, devido sua ligação com o câncer uterino. Este estudo avaliou a prevalência da infecção genital por HPV na população adolescente do sexo feminino em Belém. Estes dados foram correlacionados com fatores sócio demográficos, comportamentais e reprodutivos. Foi realizado um estudo transversal entre agosto de 2009 e agosto de 2011, com 134 mulheres entre 13 e 19 anos que procuraram a Unidade Materno-Infantil e Adolescente de Belém para exame de rastreamento do câncer do colo do útero. As pacientes selecionadas responderam a um questionário sobre os dados sócio demográficos, comportamentais e reprodutivos. Foi realizada coleta de material cervicovaginal para citologia convencional e escovado cervical para detecção de DNA-HPV por técnica da reação em cadeia de polimerase (PCR). A associação da infecção por HPV e fatores de risco selecionados foi avaliada por meio do teste do Qui-quadrado (χ²) e/ou exato de Fisher, todos com um nível alfa de significância de 0,05. A infecção genital pelo Papillomavirus humano apresentou a prevalência de 22%, sendo o HPV 58 o mais prevalente com 31% e o HPV 11 o menos comum com 3,4%. Entre as adolescentes 51,7% apresentaram infecção por outros tipos de HPV não incluídos na vacina quadrivalente (6, 11, 16 e 18), e 76,2% apresentavam infecção por pelo menos um tipo de HPV do grupo de alto risco. Foram encontradas alterações citológicas em 6,2% dos esfregaços cervicais. Os fatores de risco associados à infecção genital por HPV encontrados neste estudo foram escolaridade superior a oito anos, coitarca com idade maior que 14 anos, uso de anticoncepcional oral por mais de um ano, uso atual de anticoncepcional oral, gravidez com 14 anos ou menos e achado citológico anormal. Este estudo evidenciou o predomínio de HPV de alto risco não imunoprevenível nas amostras cervicais, demonstrando a necessidade de novas políticas de prevenção primária e secundária, que envolvam as adolescentes através de discussão e orientação motivando-as a participar ativamente na promoção da própria saúde.

Avaliação da instabilidade atlanto-axial em indivíduos com síndrome de Down por meio de radiografias da coluna cervical

O objetivo nesta pesquisa consiste em fazer um trabalho de prevenção junto às instituições APAE (Associação de Pais e Amigos de Excepcionais) e ASIN (Associação de síndrome de Down), ambas de São José dos Campos e ASPAD (Associação de Pais e Amigos de síndrome de Down) de Jacareí, orientando e avaliando sobre a presença ou não da instabilidade atlanto-axial (IAA), assim como verificar a prevalência dessa anormalidade nesses indivíduos. Foram convidados a participar do projeto todos os indivíduos das três instituições de assistência à SD, tendo formado uma amostra com 68 indivíduos, com idades entre 2 a 34 anos, sendo 39 do sexo masculino e 29 do feminino. Foram realizadas radiografias da coluna cervical nas posições de extensão, flexão e neutra, para as quais todos os responsáveis assinaram termo de consentimento. A verificação da IAA foi feita pela análise da distância atlanto-odontóide (DAO), utilizando o programa Radiocef, com uma ferramenta criada para isso. A DAO foi analisada nas três incidências, e era considerada a presença de IAA desde que o indivíduo apresentasse valores ?4,5mm em pelo menos uma dessas posições. Após a realização dos testes estatísticos e análise dos resultados, concluímos que a prevalência de IAA foi de 22,1% dos indivíduos, com valores DAO entre 4,5 e 8,83mm, tendo sido mais prevalente nos indivíduos do sexo masculino do que feminino, assim como nas crianças do que nos jovens e adultos. Foi possível verificar também que, a posição de flexão apresentou maior prevalência de IAA, mas que ela não deve sobrepor às posições de extensão e neutra, pois pode omitir casos ausentes em flexão, mas presentes nas outras posições. Dessa forma, foi realizado o trabalho de prevenção com a avaliação da IAA por meio da realização dos exames radiográficos em que os laudos... (Resumo completo, clicar acesso eletrônico abaixo)

Avaliação de concentração de citocinas no soro de pacientes portadoras de lesão intraepitelial escamosa de baixo grau, lesão intraepitelial escamosa de alto grau e carcinoma cervical invasor

A infecção genital por Papilomavírus Humano (HPV) é uma das doenças sexualmente transmissíveis (DST), de origem viral, mais prevalente no mundo. As lesões intraepiteliais escamosas de baixo grau (LIEBG) e de alto grau (LIEAG), assim como carcinoma cervical invasor (CCI), estão associadas à presença do HPV. A resposta imune tem papel importante na infecção pelo HPV na cérvice uterina, sendo as citocinas importantes reguladoras da transcrição viral. Avaliar a concentração de IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IFN-γ e TNF-α no soro de mulheres portadoras de LIEBG, LIEAG e CCI. Foram incluídas no estudo 40 mulheres com diagnóstico histopatológico de LIEBG (n=11), LIEAG (n=10), CCI (n=10) e 9 mulheres com suspeita de doença HPV induzida, mas sem alterações histopatológicas na biópsia do colo do útero (controle), atendidas no Ambulatório de Colposcopia da Faculdade de Medicina de Botucatu (UNESP) e no Ambulatório de Ginecologia Preventiva do Hospital Amaral Carvalho, Jaú, SP. O sangue periférico foi colhido por punção venosa e o soro armazenado até o processamento. A dosagem das citocinas no soro foi avaliada por ensaio imunoenzimático (ELISA). A pesquisa de HPV foi realizada empregando-se a técnica da reação em cadeia da polimerase (PCR). Os dados sócio-demográficos foram obtidos por entrevista no momento da consulta ginecológica. A mediana de idade das pacientes do grupo controle, LIEBG, LIEAG, e CCI foi de 38 (21-69), 32,5 (17-51), 39 (23-65) e 51,5 (29-72), respectivamente. Houve diferença estatisticamente significante de mediana de idade das pacientes do grupo CCI quando esta foi comparada com os demais grupos. Em relação às características das pacientes, 76% eram brancas, 68% relataram união estável, 31% concluíram o 2º grau, 42% eram fumantes, 37% das mulheres relataram 3 ou mais parceiros sexuais durante... (Resumo completo, clicar acesso eletrônico abaixo)

Prevalence of the germline TP53 p.R337H mutation in families with multiple cases of cancer

Germline mutations in TP53 gene are associated with Li-Fraumeni syndrome (LFS) and its variants Li-Fraumeni-like (LFL). They predispose carriers to a wide variety of early onset tumors. In Brazil, there is a high frequency of a germline mutation in this gene (NC_000017.9: c.1010G>A; p.R337H) in Southern and Southeastern regions, due to a founder effect. It is estimated to be present in 0,3% ofthe local population, but only few families have been detected. Due to this significant divergence, the purpose of this study was to verify the effectiveness of wider criteria for detection of these individuals. Herein, clinical criteria were established, DNA samples were collected, analyzed by Restriction Fragment Length Polymorphism (RFLP) and sequenced. Thus, assessing the prevalence of this mutation in families with multiple cases of cancer. Based on our proposed criteria, one out of 31 patients (3,22%) was found to carry p.R337H mutation. The patient developed ductal invasive breast cancer at age 47, invasive adenocarcinoma of the lung at age 48 and soft-tissue sarcoma at age 49. In addition, an extensive cancer family history was referred, atypical for LFS, including a case of Ewing’s sarcoma. These outcomes indicate that the proposed criteria may detect probable carriers who did not fit previous LFS criteria. Nevertheless, additional studies, which might include a larger number of families and more stringent parameters, will be useful to improve screening sensibility

In vivo evaluation of the genetic toxicity of Rubus niveus Thunb. (Rosaceae) extract and initial screening of its potential chemoprevention against doxorubicin-induced DNA damage

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Barriers related to non-adherence in a mammography breast-screening program during the implementation period in the interior of São Paulo State, Brazil

Mammography is the best exam for early diagnosis of breast cancer. Developing countries frequently have a low income of mammography and absence of organized screening. The knowledge of vulnerable population and strategies to increase adherence are important to improve the implementation of an organized breast-screening program. A mammography regional-screening program was implemented in a place around 54.238 women, aged 40-69 years old. It was proposed to perform biannual mammography free of cost for the women. We analyze the first 2 years of the implementation of the project. Mammography was realized in 17.964 women. 42.1% of the women hadn't done de mammography in their lives and these women were principally from low socio-economic status (OR=2.99), low education (OR=3.00). The best strategies to include these women were mobile unit (OR=1.43) and Family Health Program (OR=1.79). The incidence of early breast tumors before the project was 14.5%, a fact that changed to 43.2% in this phase. Multivariate analysis showed that the association of illiterate and the mobile unit achieve more women who had not performed mammography in their lives. The strategies to increase adherence to mammography must be multiple and a large organization is necessary to overpass the barriers related to system health and education.

The accuracy of pathological data for the prediction of insignificant prostate cancer

Introduction: The widespread screening programs prompted a decrease in prostate cancer stage at diagnosis, and active surveillance is an option for patients who may harbor clinically insignificant prostate cancer (IPC). Pathologists include the possibility of an IPC in their reports based on the Gleason score and tumor volume. This study determined the accuracy of pathological data in the identification of IPC in radical prostatectomy (RP) specimens. Materials and Methods: Of 592 radical prostatectomy specimens examined in our laboratory from 2001 to 2010, 20 patients harbored IPC and exhibited biopsy findings suggestive of IPC. These biopsy features served as the criteria to define patients with potentially insignificant tumor in this population. The results of the prostate biopsies and surgical specimens of the 592 patients were compared. Results: The twenty patients who had IPC in both biopsy and RP were considered real positive cases. All patients were divided into groups based on their diagnoses following RP: true positives (n = 20), false positives (n = 149), true negatives (n = 421), false negatives (n = 2). The accuracy of the pathological data alone for the prediction of IPC was 91.4%, the sensitivity was 91% and the specificity was 74%. Conclusion: The identification of IPC using pathological data exclusively is accurate, and pathologists should suggest this in their reports to aid surgeons, urologists and radiotherapists to decide the best treatment for their patients.

Longitudinal outcomes of high-risk human papillomavirus (HPV) infections as competing-risks events following cervical HPV test at baseline visit in the *NIS-LAMS** cohort

Background: The complex natural history of human papillomavirus (HPV) infections following a single HPV test can be modeled as competing-risks events (i.e., no-, transient- or persistent infection) in a longitudinal setting. The covariates associated with these compet ng events have not been previously assessed using competing-risks regression models. Objectives: To gain further insights in the outcomes of cervical HPV infections, we used univariate- and multivariate competing-risks regression models to assess the covariaies associated with these competing events. Study Design and Methods: Covariates associated with three competing outcomes (no-, transient- or persistent HR-HPV infection) were analysed in a sub-cohort of 1,865 women prospectively followed-up in the NIS (n = 3,187) and LAMS Study (n = 12,114). Results: In multivariate competing-risks models (with two other outcomes as competing events), permanently HR-HPV negative outcome was significantly predicted only by the clearance of ASCUS+Pap during FU, while three independent covariates predicted transient HR-HPV infections: i) number of recent (< 12 months) sexual partners (risk increased), ii) previous Pap screening history (protective), and history of previous CIN (increased risk). The two most powerful predictors of persistent HR-HPV infections were persistent ASCUS+Pap (risk increased), and previous Pap screening history (protective). In pair-wise comparisons, number of recent sexual partners and previous CIN history increase the probability of transient HR-HPV infection against the HR-HPV negative competing event, while previous Pap screening history is protective. Persistent ASCUS+Pap during FU and no previous Pap screening history are significantly associated with the persistent HR-HPV outcome (compared both with i) always negative, and ii) transient events), whereas multiparity is protective. Conclusions: Different covariates are associated with the three main outcomes of cervical HPV infections. The most significant covariates of each competing events are probably distinct enough to enable constructing of a risk-profile for each main outcome.

Accuracy of Screening for Potentially Malignant Disorders of the Oral Mucosa by Dentists in Primary Care

Purpose: To examine the accuracy of a screening programme for potentially malignant disorders of the oral mucosa by visual inspection in primary health care. Materials and Methods: The study was based on secondary data from the Primary Care Information System maintained by seven units of family health in Sao Paulo City managed by a non-governmental agency. The reference population was composed of 15,072 residents 50 years old or more of both genders. The study population comprised 2,980 individuals. During screening in community settings, the oral mucosa was examined by trained dentists and distributed into two categories: (a) screen negative (b) screen positive. All participants underwent comprehensive clinical exams by a general dental practitioner supervised by a specialist. Individual records were grouped in a working dataset. Point and 95% confidence interval estimates were calculated regarding measures of sensitivity (Se), specificity (Sp) and positive and negative predictive values (PPV and NPV, respectively). Results: 18.0% of the population was considered screen positive. A total of 133 lesions (4.5%) were identified and 8 cases of oral cancer were confirmed, which corresponded to a prevalence rate of 27 cases in 10,000 people, a much higher rate than expected. The measures found were Se: 91.7% (85.3-95.6), Sp: 85.4% (84.1-86.7), PPV: 22.7% (19.3-26.5), NPV: 99.5% (99.2-99.8). The visual screen presented high accuracy. Conclusion: The test presented high sensibility and specificity values. From a public health point of view, the high accuracy levels showed the importance of oral health teams on family health strategy for more comprehensive primary care. Targeting risk groups and delegating the screening to community health agents may improve PPV and coverage.

Differential Proteomic Analysis of Noncardia Gastric Cancer from Individuals of Northern Brazil

Gastric cancer is the second leading cause of cancer-related death worldwide. The identification of new cancer biomarkers is necessary to reduce the mortality rates through the development of new screening assays and early diagnosis, as well as new target therapies. In this study, we performed a proteomic analysis of noncardia gastric neoplasias of individuals from Northern Brazil. The proteins were analyzed by two-dimensional electrophoresis and mass spectrometry. For the identification of differentially expressed proteins, we used statistical tests with bootstrapping resampling to control the type I error in the multiple comparison analyses. We identified 111 proteins involved in gastric carcinogenesis. The computational analysis revealed several proteins involved in the energy production processes and reinforced the Warburg effect in gastric cancer. ENO1 and HSPB1 expression were further evaluated. ENO1 was selected due to its role in aerobic glycolysis that may contribute to the Warburg effect. Although we observed two up-regulated spots of ENO1 in the proteomic analysis, the mean expression of ENO1 was reduced in gastric tumors by western blot. However, mean ENO1 expression seems to increase in more invasive tumors. This lack of correlation between proteomic and western blot analyses may be due to the presence of other ENO1 spots that present a slightly reduced expression, but with a high impact in the mean protein expression. In neoplasias, HSPB1 is induced by cellular stress to protect cells against apoptosis. In the present study, HSPB1 presented an elevated protein and mRNA expression in a subset of gastric cancer samples. However, no association was observed between HSPB1 expression and clinicopathological characteristics. Here, we identified several possible biomarkers of gastric cancer in individuals from Northern Brazil. These biomarkers may be useful for the assessment of prognosis and stratification for therapy if validated in larger clinical study sets.

Strategies and results of the oral cancer prevention campaign among the elderly in Sao Paulo, Brazil, 2001 to 2009

Objective. To describe the strategies and results obtained by the early diagnosis and prevention of an oral cancer campaign targeting the population aged 60 years or older developed since 2001 in the state of Sao Paulo. Methods. The main strategies used to develop the campaign were described based on the review of documents issued by the Health Ministry, National Cancer Institute, Sao Paulo State Health Department, Oncocentro Foundation of Sao Paulo, Sao Paulo City Health Department, School of Public Health at the University of Sao Paulo (USP), and Santa Marcelina Health Care Center. The impact of the campaign on the incidence of new cases of oral cancer in the target population was evaluated. Results. In 2001, 90 886 elderly were examined vs. 629 613 in 2009. The following strategies were identified: training of professionals, development of printed materials to guide municipal governments in developing the campaign and using standardized codes and criteria, guidelines for data consolidation, establishment of patient referral flows, practical training with a specialist at the basic health care unit after the follow-up examination of individuals presenting changes in soft tissues, and increase in the number of oral diagnosis services. Between 2005 and 2009, there was a significant reduction in the rate of confirmed cases of oral cancer per 100 000 individuals examined, from 20.89 to 11.12 (P = 0.00003). Conclusions. The campaign was beneficial to the oral health of the elderly and could be extended to include other age groups and regions of the country. It may also provide a basis for the development of oral cancer prevention actions in other countries, as long as local characteristics are taken into account.

ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making

Colorectal cancer (CRC) is the most common tumour type in both sexes combined in Western countries. Although screening programmes including the implementation of faecal occult blood test and colonoscopy might be able to reduce mortality by removing precursor lesions and by making diagnosis at an earlier stage, the burden of disease and mortality is still high. Improvement of diagnostic and treatment options increased staging accuracy, functional outcome for early stages as well as survival. Although high quality surgery is still the mainstay of curative treatment, the management of CRC must be a multi-modal approach performed by an experienced multi-disciplinary expert team. Optimal choice of the individual treatment modality according to disease localization and extent, tumour biology and patient factors is able to maintain quality of life, enables long-term survival and even cure in selected patients by a combination of chemotherapy and surgery. Treatment decisions must be based on the available evidence, which has been the basis for this consensus conference-based guideline delivering a clear proposal for diagnostic and treatment measures in each stage of rectal and colon cancer and the individual clinical situations. This ESMO guideline is recommended to be used as the basis for treatment and management decisions.

The influence of human papillomavirus type and HIV status on the lymphomononuclear cell profile in patients with cervical intraepithelial lesions of different severity

Abstract Background Immunological alterations are implicated in the increased prevalence of high-grade squamous intraepithelial lesions (HG-SIL) and persistent human papillomavirus (HPV) infection. This study evaluated the expression of CD4, CD8, CD25 (IL-2Rα) and CD28 antigens from SIL biopsies, stratified by HIV status and HPV-type. Biopsies specimens from 82 (35 HIV+) women with a normal cervix, low-grade (LG-SIL) or high-grade lesions (HG-SIL) were studied. CD molecule expression was evaluated by immunohistochemistry and HPV detection/typing performed using PCR techniques. Results CD4 stromal staining was increased in patients with HPV18. Women with HPV16 infection showed decreased: a) CD8 and CD25 stromal staining, b) CD25 staining in LG-SIL epithelium and in HG-SIL stroma. In HIV- women samples, CD28 epithelial staining and CD8 stromal staining surrounding metaplastic epithelium were less intense and even absent, as compared to HIV+ women. Both epithelial and stromal CD8 staining was more intense in the HG-SIL/HIV+ group than in the HG-SIL/HIV- group. Positive correlations were observed between CD4/CD25, CD4/CD28 and CD25/CD28 in the stroma and CD25/CD28 in the epithelium. Conclusion HIV status and HPV-type may influence the lymphomononuclear cell profile present in the spectrum of cervical lesions. The knowledge of the infiltrating cell profile in cervical tumours may help the development of specific anti-tumoural strategies.

Prevalence of the BRCA1 founder mutation c.5266dupin Brazilian individuals at-risk for the hereditary breast and ovarian cancer syndrome

About 5-10% of breast and ovarian carcinomas are hereditary and most of these result from germline mutations in the BRCA1 and BRCA2 genes. In women of Ashkenazi Jewish ascendance, up to 30% of breast and ovarian carcinomas may be attributable to mutations in these genes, where 3 founder mutations, c.68_69del (185delAG) and c.5266dup (5382insC) in BRCA1 and c.5946del (6174delT) in BRCA2, are commonly encountered. It has been suggested by some authors that screening for founder mutations should be undertaken in all Brazilian women with breast cancer. Thus, the goal of this study was to determine the prevalence of three founder mutations, commonly identified in Ashkenazi individuals in a sample of non-Ashkenazi cancer-affected Brazilian women with clearly defined risk factors for hereditary breast and ovarian cancer (HBOC) syndrome. Among 137 unrelated Brazilian women from HBOC families, the BRCA1c.5266dup mutation was identified in seven individuals (5%). This prevalence is similar to that encountered in non-Ashkenazi HBOC families in other populations. However, among patients with bilateral breast cancer, the frequency of c.5266dup was significantly higher when compared to patients with unilateral breast tumors (12.1% vs 1.2%, p = 0.023). The BRCA1 c.68_69del and BRCA2 c.5946del mutations did not occur in this sample. We conclude that screening non-Ashkenazi breast cancer-affected women from the ethnically heterogeneous Brazilian populations for the BRCA1 c.68_69del and BRCA2 c.5946del is not justified, and that screening for BRCA1c.5266dup should be considered in high risk patients, given its prevalence as a single mutation. In high-risk patients, a negative screening result should always be followed by comprehensive BRCA gene testing. The finding of a significantly higher frequency of BRCA1 c.5266dup in women with bilateral breast cancer, as well as existence of other as yet unidentified founder mutations in this population, should be further assessed in a larger well characterized high-risk cohort.

Anticancer drug screening from images of zebrafish embryogenesis

During the previous 10 years, global R&D expenditure in the pharmaceuticals and biotechnology sector has steadily increased, without a corresponding increase in output of new medicines. To address this situation, the biopharmaceutical industry's greatest need is to predict the failures at the earliest possible stage of the drug development process. A major key to reducing failures in drug screenings is the development and use of preclinical models that are more predictive of efficacy and safety in clinical trials. Further, relevant animal models are needed to allow a wider testing of novel hypotheses. Key to this is the developing, refining, and validating of complex animal models that directly link therapeutic targets to the phenotype of disease, allowing earlier prediction of human response to medicines and identification of safety biomarkers. Morehover, well-designed animal studies are essential to bridge the gap between test in cell cultures and people. Zebrafish is emerging, complementary to other models, as a powerful system for cancer studies and drugs discovery. We aim to investigate this research area designing a new preclinical cancer model based on the in vivo imaging of zebrafish embryogenesis. Technological advances in imaging have made it feasible to acquire nondestructive in vivo images of fluorescently labeled structures, such as cell nuclei and membranes, throughout early Zebrafishsh embryogenesis. This In vivo image-based investigation provides measurements for a large number of features at cellular level and events including nuclei movements, cells counting, and mitosis detection, thereby enabling the estimation of more significant parameters such as proliferation rate, highly relevant for investigating anticancer drug effects. In this work, we designed a standardized procedure for accessing drug activity at the cellular level in live zebrafish embryos. The procedure includes methodologies and tools that combine imaging and fully automated measurements of embryonic cell proliferation rate. We achieved proliferation rate estimation through the automatic classification and density measurement of epithelial enveloping layer and deep layer cells. Automatic embryonic cells classification provides the bases to measure the variability of relevant parameters, such as cell density, in different classes of cells and is finalized to the estimation of efficacy and selectivity of anticancer drugs. Through these methodologies we were able to evaluate and to measure in vivo the therapeutic potential and overall toxicity of Dbait and Irinotecan anticancer molecules. Results achieved on these anticancer molecules are presented and discussed; furthermore, extensive accuracy measurements are provided to investigate the robustness of the proposed procedure. Altogether, these observations indicate that zebrafish embryo can be a useful and cost-effective alternative to some mammalian models for the preclinical test of anticancer drugs and it might also provides, in the near future, opportunities to accelerate the process of drug discovery.