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Orientador: Luiz Carlos Zeferino Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas 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

La respuesta inmune es un elemento clave para la progresión o remisión de la infección por el Virus Papiloma Humano (VPH) en cérvix uterino. Este estudio tiene como objetivo la determinación de la frecuencia de Linfocitos T CD4+, CD8+ y Treg en biopsias de cérvix de pacientes que podrían tener una infección por VPH de alto riesgo (VPH-AR). Se evaluaron muestras de cérvix con diagnóstico histopatológico de neoplasia intraepitelial cervical (NIC), cervicitis crónica (Ccro) y sin alteraciones, las cuales se genotipificaron usando técnicas de reacción en cadena de polimerasa (PCR) convencional y Real-Time PCR (rtPCR); las poblaciones linfocitarias se marcaron por inmunohistoquímica para el reconocimiento de las poblaciones linfocitarias. Se evaluaron las características poblacionales (estado civil, edad e informe patológico) con respecto a la presencia de VPH. Se encontró una tendencia a que las mujeres solteras tengan más posibilidades de presentar dicha infección y alteraciones patológicas como NIC 1 y Ccro. Sin embargo, no se encontraron asociaciones estadísticamente significativas entre la edad y estado civil con la presencia o ausencia del VPH. También se evaluó la relación de linfocitos efectores (LT CD4, LT CD8) y linfocitos reguladores (LT reg) con respecto a la presencia de VPH. Existe una mayor cantidad de LT CD4 en biopsias positivas para VPH (p = 0.027), indicando una respuesta inmune activa, además en la evaluación de la frecuencia de LT CD4 e informe patológico se encontró mayor frecuencia en las biopsias con alguna alteración (NIC, Ccro). También se encontró una mayor presencia de LT CD8 en biopsias sin alteraciones (p = 0.04) comparadas a NIC o Ccro. No se encontró una diferencia establecida entre LT CD8, LT reg y la presencia del VPH. En conclusión el presente estudio indicó que en las etapas tempranas de la infección, donde aún las células no presentan cambios de alto nivel (NIC1), existe la presencia de células causantes de la fase efectora (LT CD4) de la respuesta inmune. En cambio no se pudo distinguir la fase reguladora ya que se evaluaron eventos tempranos de NIC.

El proyecto Hope utilizó los mensajes de texto como método de entrega de resultados de despistaje de VPH, el virus causante del cáncer de cuello uterino. El objetivo de este estudio es determinar las preferencias de las participantes de proyecto HOPE por un método de entrega de resultados y si esto está relacionado con su nivel de estudios, edad y uso de la tecnología. Para ello se seleccionó participantes del proyecto HOPE para poder hacerles una encuesta de 23 preguntas. De las 324 mujeres seleccionadas para la encuesta, 260 participaron. Ellas manifestaron su preferencia por la entrega de resultados mediante llamada telefónica. Si bien en el análisis multivariado varias variables resultaron asociadas a la preferencia de un método tecnológico para la entrega de resultados (whatsapp, email, llamada telefónica, mensaje de voz y mensaje de texto), solo el antecedente de uso de whatsapp en el último mes resultó asociado en el modelo multivariado, con una razón de prevalencia de 2.68 (IC95%: 1.82 – 3.95).

Submitted by Lígia Lavezo Ferreira null (ligialavezo@foa.unesp.br) on 2017-09-25T19:34:26Z No. of bitstreams: 1 TESE CORRIGIDA LÍGIA IMPRESSÃO.pdf: 2276410 bytes, checksum: 7a01cd5508f020f7688a503cb0fe116d (MD5) Approved for entry into archive by LUIZA DE MENEZES ROMANETTO (luizamenezes@reitoria.unesp.br) on 2017-09-29T19:28:09Z (GMT) No. of bitstreams: 1 ferreira_ll_dr_araca_par.pdf: 811024 bytes, checksum: f4e8ebcbb96f3bf29f3ef06ad79c7d67 (MD5) Made available in DSpace on 2017-09-29T19:28:09Z (GMT). No. of bitstreams: 1 ferreira_ll_dr_araca_par.pdf: 811024 bytes, checksum: f4e8ebcbb96f3bf29f3ef06ad79c7d67 (MD5) Previous issue date: 2017-08-28 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) O papilomavírus humano (HPV) subtipo 16 é um fator de risco para o desenvolvimento do carcinoma espinocelular (CEC) de orofaringe. No entanto, o papel do mesmo na carcinogênese oral, bem como a associação com as lesões potencialmente malignas, permanece controverso. O objetivo deste estudo foi comparar a prevalência do HPV-16, em amostras de tecido fresco, obtidas de 27 pacientes com CEC oral, 37 pacientes com leucoplasia bucal, 24 pacientes com líquen plano bucal (LPB) e 32 pacientes controle, correlacionando a presença do HPV com as variáveis clínico-patológicas em uma população da região noroeste do estado de São Paulo - Brasil. Realizouse a extração do DNA das amostras e a verificação da presença do HPV-16 por meio da Real-Time Polymerase Chain Reaction. Todas as amostras foram negativas para o HPV-16 nos quatro grupos estudados. Conclui-se que a ausência do HPV-16 nas amostras de CEC bucal, leucoplasia e LPB indica que a infecção pelo mesmo não é comum e não representa um fator de risco importante na carcinogênese oral na população da região noroeste do estado de São Paulo - Brasil. Human Papillomavirus (HPV), specially subtype 16, is a known risk factor for the oropharyngeal squamous cell carcinoma (SCC) development. However, HPV role in oral carcinogenesis, as well as in potentially malignant oral lesions remains controversial. The goal of the present study was to compare the HPV-16 prevalence, in fresh tissue samples obtained from 27 oral SCC patients, 34 oral leukoplakia (OL) patients, 24 oral lichen planus (OLP) patients and 32 control patients, correlating HPV presence with the clinicopathological variables in a population from northwest region of the Sao Paulo state - Brazil. DNA extraction was carried out and all samples were submitted to Real-Time PCR for HPV-16 DNA detection. We found that all fresh tissue samples of oral SCC, OL, OLP and oral normal mucosa were negative for HPV-16. We conclude that HPV-16 absence in oral SCC, OL and OLP samples indicates that its infection is uncommon and does not represent an important risk factor in oral carcinogenesis in the population from northwest region of the Sao Paulo state - Brazil.

Introducción: Los marcadores p16 y Ki67 son útiles para determinar la evolución de la neoplásia intraepitelial cervical grado 2 o NIC 2. La detección de estos biomarcadores permite diferenciar entre la infección autolimitada por el virus del papiloma humano (VPH) y la trasformación celular inducida por células oncogénicas del VPH; sin embargo, es importante aportar evidencias de su capacidad predictiva. Metodología: Se realizó un estudio cuantitativo, observacional, descriptivo, retrospectivo de corte transversal en 54 biopsias con diagnostico histológico de NIC 2 del Centro Medico Oncomujer durante los años 2012 al 2015. Se utilizó el software SPSS 23.0 y Microsoft Excel 2010. Resultados: La frecuencia del biomarcador p16 en pacientes con NIC2 fue del 61,1% y del Ki67 fue de un 59% con un p0,05. Discusión: La asociación de las tinciones para los biomarcadores P16 y Ki67 mejoran la disquisición diagnóstica y permiten una mejor interpretación del riesgo de progresión según la literatura revisada en conformidad con el estudio. La positividad de ambas pruebas demostró un riesgo de progresión soportando la necesidad de manejo quirúrgico.

INTRODUÇÃO: A resposta imune pode ser um elemento chave para a progressão ou remissão da infecção pelo papilomavírus humano (HPV) no estroma da cérvice uterina. Este estudo objetivou quantificar no estroma cervical a presença de linfócitos T CD4, CD8 e células NK, por imunohistoquímica, em lesões de alto e baixo grau em pacientes infectadas por HPV MÉTODOS: Utilizou-se 56 amostras de biópsia da estroma cervical, sendo 43 amostras positivas para DNA de HPV de alto risco oncogênico e com diagnóstico histopatológico de neoplasia intraepitelial cervical (NIC) de alto e baixo grau, ou negativa para lesão intraepitelial e malignidade (NILM), e 13 amostras de pacientes negativas para DNA de HPV com diagnóstico histopatológico NILM RESULTADOS: Maior quantidade de linfócitos T CD4 foi observada em amostras NIC II/III, carcinoma e NILM (p=0,04) e naquelas cuja carga viral esteve entre 10 e 1,000 RLU/PCB. O predomínio de linfócitos T CD8 ocorreu em maior proporção nas amostras NIC II/III (p=0,02) e em amostras com carga viral entre 100 e 1.000 RLU/PCB. As células NK prevaleceram nas amostras com lesões de baixo grau e com baixa carga viral CONCLUSÕES: Este estudo comprovou que nas fases iniciais da infecção, onde não há ainda alterações celulares de alto grau, não temos a presença de células que possam desencadear a fase efetora da resposta imune. ABSTRACT - INTRODUCTION: Immune response might be a key element regarding the progression or regression of human papillomavirus (HPV) infection in the stroma of the uterine cervix. This study aimed to quantify the presence of CD4 and CD8 T lymphocytes and NK cells in the cervical stroma, by means of immunohistochemistry, in high and low grade lesions in patients infected by HPV.METHODS: Fifty-six biopsy samples from the uterine cervix were used. Forty-three samples were positive for oncogenic high-risk HPV DNA and had a histopathological diagnosis of high and low-grade cervical intraepithelial neoplasia (CIN) or negative for intraepithelial lesion and malignancy (NILM); while the other 13 samples were negative for HPV DNA with a histopathological diagnosis of NILM RESULTS: Higher quantities of CD4 T lymphocytes were observed in CIN II/III, carcinoma and NILM samples (p = 0.04) and in those in which the viral load was between 10 and 1.000 RLU/PCB. CD8 T lymphocytes were predominant in CIN II/III samples (p = 0.02) and also in samples with viral loads between 100 and 1,000 RLU/PCB. NK cells predominated in samples with low-grade lesions and low viral load. CONCLUSIONS: This study proved that in the initial stages of the infection, in which no high-grade cell abnormalities have yet occurred, no cells that might trigger the effector phase of the immune response.

CONTEXT: Adolescence and pregnancy are considered to be risk factors for human papillomavirus (HPV) infection. The relationship between this infection in the uterine cervix and oral HPV infection is controversial. CASE REPORT: This report describes a case of a pregnant 16-year-old adolescent who presented HPV infection in the uterine cervix and the mouth. Smears were collected from the cervix and the tongue/palate. Dental biofilm samples were also collected. The microarray technique was used to detect HPV. The HPV 56 subtype was observed in the cervical smear and HPV 6 in dental biofilm. CONCLUSION: In this pregnant adolescent, HPV infection was present in both the cervix and the mouth, but the HPV subtypes infecting these two areas were different. CONTEXTO: A adolescência e a gestação são consideradas fatores de risco para a infecção pelo papilomavírus humano (HPV). A relação entre essa infecção no colo do útero e na boca num mesmo paciente é controversa. RELATO DE CASO: Descrever o caso de uma adolescente grávida de 16 anos que apresentou a infecção pelo HPV no colo do útero e na boca. Esfregaços foram realizados no colo do útero e em língua/palato. Amostras de biofilme dental também foram coletadas. Para detectar o HPV, foi utilizada a técnica do microarranjo. O HPV 56 foi o subtipo encontrado no esfregaço cervical e o tipo HPV 6 no biofilme dental. CONCLUSÕES: Observamos, nessa adolescente grávida, a presença do HPV na boca e no colo do útero, mas os subtipos virais que infectavam essas duas regiões eram distintos.

To identify high-risk HPV genotypes in liquid-based cytology smears(SurePath®) with diagnosis of squamous atypia and squamous carcinoma. METHODS: This was a cross-sectional study using 165 liquid-based cytology with squamous atypia and 149 without atypia. HPV genotyping by real-time PCR was performed on this material. The material was processed by COBAS® 4800 System (Roche), which has three detection channels: HPV 16, HPV 18, and HPV HR (other twelve high-risk genotypes). RESULTS:We analyzed 75 cases of ASC-US, 62 LSIL, 8 ASC-H, 12 HSIL and 8 squamous carcinomas. The average age was 32.2 years in the group without atypia, 31.1 years for ASC-US and LSIL, 41.2 years for ASC-H and HSIL and 43.1 years for SCC. There were 112 positive cases for HPV (68%) in the group with atypia: 72% positive for HPV AR, 18% of HPV16 and 10% of HPV 18. Only in ASC-US group, HPV positive and negative frequency was similar (1:1). In the others, the amount of HPV positive cases surpassed negative ones. In the group of Cytology without atypia were found 40 positive cases for HPV (26%): 68% positive for HPV AR probe, 17% of HPV18 and 15% of HPV16. Detections by a single probe predominated in both groups (88% and 84%). In the group with atypia the most prevalent combination was HPV16 and HPV HR (57%); and in cases without atypia was HPV18 and HPV HR (68%) and there was a single positive case for three channels in this group. CONCLUSIONS: The prevalence of other 12 high-risk HPV genotypes (not 16 and 18), was frequent in cytology with and without squamous atypia, associated or not with genotypes 16 and 18. The connection of squamous atypia with HPV 16 and HPV HR was significant. The data obtained are in agreement with the literature regarding the existence of heterogeneity in the distribution of different genotypes and their most frequent association as the level of atypia. Identificar genótipos de HPV de alto risco em citologias em meio líquido com diagnóstico de atipias escamosas e carcinoma escamoso. MÉTODOS: Foi realizado estudo de corte transversal utilizando 165 citologias em meio líquido com atipias escamosas e 149 sem atipias. Nesse material foi realizado genotipagem do HPV por PCR em tempo real. O material foi processado pelo Sistema Cobas® 4800 (Roche), que apresenta três canais de detecção, para HPV 16, HPV 18, e HPV AR (outros doze genótipos de HPV de alto risco). RESULTADOS: Foram analisados 75 casos de ASC-US, 62 LSIL, 8 ASC-H, 12 HSIL e 8 carcinomas escamosos. A média etária foi de 32,2 anos no grupo sem atipias, 31,1 anos para ASC-US e LSIL, 41,2 anos para ASC-H e HSIL e 43,1 anos para CEC. Houve 112 casos positivos para HPV (68%) no grupo com atipias, sendo 72% de positividade para HPV AR, 18% de HPV 16 e 10% de HPV 18. Somente nos casos de ASC-US a frequência de HPV positivo e negativo foi semelhante (1:1). Nas demais, a quantidade de casos HPV positivo ultrapassou a de negativos. No grupo de citologias sem atipias, foram encontrados 40 casos positivos para HPV (26%), sendo 68% de positividade para a sonda HPV AR, 17% de HPV 18 e 15% de HPV16. Predominaram detecções por uma única sonda em ambos os grupos (88% e 84%). No grupo com atipias, a combinação mais presente foi HPV AR e 16 (57%); e nos casos sem atipias, foi HPV AR e 18 (68%) e houve um único caso positivo para os três canais neste grupo. CONCLUSÕES: A prevalência de outros 12 genótipos de alto risco de HPV (que não 16 e 18), foi frequente, em citologias com e sem atipias escamosas, associados ou não aos genótipos 16 e 18. A relação de atipias escamosas com HPV 16 e HPV AR foi significativa. Os dados obtidos estão em concordância com a literatura quanto à existência de uma heterogeneidade na distribuição dos diversos genótipos e sua associação mais frequente conforme o nível de atipia.

We report final event-driven analysis data on the immunogenicity and efficacy of the human papillomavirus 16 and 18 ((HPV- 16/18) AS04-adjuvanted vaccine in young women aged 15 to 25 years from the PApilloma TRIal against Cancer In young Adults (PATRICIA). The total vaccinated cohort (TVC) included all randomized participants who received at least one vaccine dose (vaccine, n 9,319; control, n 9,325) at months 0, 1, and/or 6. The TVC-naive (vaccine, n 5,822; control, n 5,819) had no evidence of high-risk HPV infection at baseline, approximating adolescent girls targeted by most HPV vaccination programs. Mean follow-up was approximately 39 months after the first vaccine dose in each cohort. At baseline, 26% of women in the TVC had evidence of past and/or current HPV-16/18 infection. HPV-16 and HPV-18 antibody titers postvaccination tended to be higher among 15- to 17-year-olds than among 18- to 25-year-olds. In the TVC, vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 1 or greater (CIN1 ), CIN2 , and CIN3 associated with HPV-16/18 was 55.5% (96.1% confidence interval [CI], 43.2, 65.3), 52.8% (37.5, 64.7), and 33.6% ( 1.1, 56.9). VE against CIN1 , CIN2 , and CIN3 irrespective of HPV DNA was 21.7% (10.7, 31.4), 30.4% (16.4, 42.1), and 33.4% (9.1, 51.5) and was consistently significant only in 15- to 17-year-old women (27.4% [10.8, 40.9], 41.8% [22.3, 56.7], and 55.8% [19.2, 76.9]). In the TVC-naive, VE against CIN1 , CIN2 , and CIN3 associated with HPV-16/18 was 96.5% (89.0, 99.4), 98.4% (90.4, 100), and 100% (64.7, 100), and irrespective of HPV DNA it was 50.1% (35.9, 61.4), 70.2% (54.7, 80.9), and 87.0% (54.9, 97.7). VE against 12-month persistent infection with HPV-16/18 was 89.9% (84.0, 94.0), and that against HPV-31/33/45/51 was 49.0% (34.7, 60.3). In conclusion, vaccinating adolescents before sexual debut has a substantial impact on the overall incidence of high-grade cervical abnormalities, and catch-up vaccination up to 18 years of age is most likely effective. (This study has been registered at ClinicalTrials.gov under registration no. NCT001226810.)

The efficacy of the human papillomavirus type 16 (HPV-16)/HPV-18 AS04-adjuvanted vaccine against cervical infections with HPV in the Papilloma Trial against Cancer in Young Adults (PATRICIA) was evaluated using a combination of the broad-spectrum L1-based SPF10 PCR-DNA enzyme immunoassay (DEIA)/line probe assay (LiPA25) system with type-specific PCRs for HPV-16 and -18. Broad-spectrum PCR assays may underestimate the presence of HPV genotypes present at relatively low concentrations in multiple infections, due to competition between genotypes. Therefore, samples were retrospectively reanalyzed using a testing algorithm incorporating the SPF10 PCR-DEIA/LiPA25 plus a novel E6-based multiplex type-specific PCR and reverse hybridization assay (MPTS12 RHA), which permits detection of a panel of nine oncogenic HPV genotypes (types 16, 18, 31, 33, 35, 45, 52, 58, and 59). For the vaccine against HPV types 16 and 18, there was no major impact on estimates of vaccine efficacy (VE) for incident or 6-month or 12-month persistent infections when the MPTS12 RHA was included in the testing algorithm versus estimates with the protocol-specified algorithm. However, the alternative testing algorithm showed greater sensitivity than the protocol-specified algorithm for detection of some nonvaccine oncogenic HPV types. More cases were gained in the control group than in the vaccine group, leading to higher point estimates of VE for 6-month and 12-month persistent infections for the nonvaccine oncogenic types included in the MPTS12 RHA assay (types 31, 33, 35, 45, 52, 58, and 59). This post hoc analysis indicates that the per-protocol testing algorithm used in PATRICIA underestimated the VE against some nonvaccine oncogenic HPV types and that the choice of the HPV DNA testing methodology is important for the evaluation of VE in clinical trials. (This study has been registered at ClinicalTrials.gov under registration no. NCT00122681.).

OBJETIVO : Analisar o conhecimento de homens e mulheres acerca do HPV e das vacinas e sua intenção de serem vacinados e de vacinarem seus filhos adolescentes. MÉTODOS : Estudo descritivo, de corte transversal, com 286 mulheres (18 a 49 anos) e 252 homens (18 a 60 anos), usuários de cinco unidades básicas de saúde e duas policlínicas do Sistema Único de Saúde, em Campinas, SP, em 2011. Foi realizada entrevista estruturada. Realizou-se análise bivariada e regressão de Poisson para identificar variáveis associadas ao conhecimento sobre HPV e vacinas e à intenção de vacinação. RESULTADOS : Quase 40,0% dos entrevistados referiram ter ouvido falar do HPV e 28,9% mencionaram informações adequadas; a principal fonte de informação foi a mídia (41,7%); 8,6% tinham ouvido falar das vacinas. Depois de informados da existência das vacinas, cerca de 94,0% dos participantes disseram que se vacinariam e/ou vacinariam filhos adolescentes se as vacinas estivessem disponíveis na rede pública de saúde. Escolaridade > 8 anos e ser do sexo feminino estiveram independentemente associados a ter ouvido falar do HPV e das vacinas e a ter conhecimento adequado sobre o vírus. Maior idade associou-se a ter ouvido falar das vacinas. Não houve variáveis associadas à intenção de vacinação. CONCLUSÕES : Os resultados reforçam a necessidade de haver intervenções educativas na população para prover informação adequada sobre o HPV e sobre medidas de prevenção. Objetivo : Analizar el conocimiento de hombres y mujeres sobre el VPH y de las vacunas y su intención de ser vacunados y de vacunar sus hijos adolescentes. Métodos : Estudio descriptivo, de corte transversal, con 286 mujeres (18 a 49 años) y 252 hombres (18 a 60 años), usuarios de cinco unidades básicas de salud y dos policlínicas del Sistema Único de Salud, en Campinas, SP – Brasil, en 2011. Se realizó entrevista estructurada. Se utilizó el análisis bivariado y regresión de Poisson para identificar variables asociadas al conocimiento sobre VPH y vacunas y la intención de vacunación. Resultados : Casi el 40,0% de los entrevistados mencionaron haber oído hablar del VPH y 28,9% relataron informaciones adecuadas; la principal fuente de información fueron los medios de comunicación (41,7%); 8,6% habían oído hablar de las vacunas. Después de informados de la existencia de las vacunas, cerca de 94,0% de los participantes dijeron que se vacunarían y/o vacunarían hijos adolescentes si las vacunas estaban disponibles en la red pública de salud. Escolaridad > 8 años y ser del sexo femenino estuvieron independientemente asociados al haber oído hablar del VPH y de las vacunas y tener conocimiento adecuado sobre el virus Mayor edad se asoció al haber oído hablar de vacunas. No hubo variables asociadas a la intención de vacunación. Conclusiones : Los resultados refuerzan la necesidad de haber intenciones educativas en la población para proveer información adecuada sobre el VPH y sobre medidas de prevención OBJECTIVE : To investigate knowledge of HPV and HPV vaccines in men and women, users of the Brazilian Unified Health System, and the intention to get themselves and their teenage children vaccinated. METHODS : A descriptive, cross-sectional study with 286 women (18-49 years old) and 252 men (18-60 years old), users of five primary health units and two polyclinics in Campinas, SP, Southeastern Brazil, was carried out. Participants were interviewed in 2011 using a structured questionnaire. Bivariate and Poisson regression analysis were performed to identify variables associated with knowledge of HPV and HPV vaccines, and participants vaccination intentions. RESULTS : Almost 40.0% of the participants reported having heard of HPV and 28.9% mentioned adequate information. The main information source was the media (41.7%). Only 8.6% of the participants had heard of the HPV vaccines. Once the participants were informed of the existence of HPV vaccines about 94% of them said they would get vaccinated and/or vaccinate their teenage children, if the vaccines were available in the public health system. Schooling of over 8 years and being female were the variables independently associated with having heard of HPV, the vaccines and having adequate knowledge of the virus. Advanced age was associated with having heard of HPV vaccines. There were no variables associated with the vaccination intentions. CONCLUSIONS : These results reinforce the need for educational activities that provide the population with adequate information on HPV and preventive measures.

Background. We examined risk of newly detected human papillomavirus (HPV) infection and cervical abnormalities in relation to HPV type 16/18 antibody levels at enrollment in PATRICIA (Papilloma Trial Against Cancer in Young Adults; NCT00122681). Methods. Using Poisson regression, we compared risk of newly detected infection and cervical abnormalities associated with HPV-16/18 between seronegative vs seropositive women (15–25 years) in the control arm (DNA negative at baseline for the corresponding HPV type [HPV-16: n = 8193; HPV-18: n = 8463]). Results. High titers of naturally acquired HPV-16 antibodies and/or linear trend for increasing antibody levels were significantly associated with lower risk of incident and persistent infection, atypical squamous cells of undetermined significance or greater (ASCUS+), and cervical intraepithelial neoplasia grades 1/2 or greater (CIN1+, CIN2+). For HPV-18, although seropositivity was associated with lower risk of ASCUS+ and CIN1+, no association between naturally acquired antibodies and infection was demonstrated. Naturally acquired HPV-16 antibody levels of 371 (95% confidence interval [CI], 242–794), 204 (95% CI, 129–480), and 480 (95% CI, 250–5756) EU/mL were associated with 90% reduction of incident infection, 6-month persistent infection, and ASCUS+, respectively. Conclusions. Naturally acquired antibodies to HPV-16, and to a lesser extent HPV-18, are associated with some reduced risk of subsequent infection and cervical abnormalities associated with the same HPV type.

Introduction The progression of human papillomavirus (HPV) infection in the anogenital tract has been associated with the involvement of cells with regulatory properties. Evidence has shown that glucocorticoid-induced tumor necrosis factor receptor (GITR) is an important surface molecule for the characterization of these cells and proposes that GITR ligand may constitute a rational treatment for many cancer types. We aimed to detect the presence of GITR and CD25 in cervical stroma cells with and without pathological changes or HPV infection to better understand the immune response in the infected tissue microenvironment. Methods We subjected 49 paraffin-embedded cervical tissue samples to HPV DNA detection and histopathological analysis, and subsequently immunohistochemistry to detect GITR and CD25 in lymphocytes. Results We observed that 76.9% of all samples with high GITR expression were HPV-positive regardless of histopathological findings. High GITR expression (77.8%) was predominant in samples with ≥1,000 RLU/PCB. Of the HPV-positive samples negative for intraepithelial lesion and malignancy, 62.5% had high GITR expression. High GITR expression was observed in both carcinoma and high-grade squamous intraepithelial lesion (HSIL) samples (p = 0.16). CD25 was present in great quantities in all samples. Conclusions The predominance of high GITR expression in samples with high viral load that were classified as HSIL and carcinoma suggests that GITR+ cells can exhibit regulatory properties and may contribute to the progression of HPV-induced cervical neoplasia, emphasizing the importance of GITR as a potential target for immune therapy of cervical cancer and as a disease evolution biomarker.

Introdução: A incidência do carcinoma epidermóide de orofaringe (CEO) aumentou em todo o mundo nos últimos 30 anos. Estudos identificaram o papiloma vírus humano (HPV) como um fator de risco para essa neoplasia. Objetivos: O objetivo do presente estudo foi verificar a frequência do HPV em pacientes com CEO e em pacientes sem neoplasia maligna e avaliar a existência de uma diferença estatisticamente significativa na frequência do HPV entre os dois grupos. O objetivo secundário foi estudar a correlação entre a infecção pelo HPV e a localização do tumor na orofaringe, o estadiamento clínico e o grau de diferenciação tumoral. Métodos: Foi realizado um estudo de caso-controle com 59 pacientes com CEO e 54 pacientes sem neoplasia, no qual foram analisados os blocos de parafina contendo material tumoral e tecido não neoplásico. Foram analisadas respectivamente a frequência do HPV e sua atividade viral utilizando a técnica de hibridização in situ cromogênica (CISH) para HPV de baixo risco (BR) e alto risco (AR) e a expressão imunoistoquímica da proteína P16. Resultados: A frequência do HPV foi maior no grupo caso em comparação ao grupo controle quando utilizamos a expressão imunoistoquímica da proteína P16 como método de detecção isolado (OR=10,3; P0,20). Conclusão: Utilizando-se a técnica de imunoistoquímica para P16 isolada ou combinada com a técnica de CISH, observou-se uma maior positividade para o HPV no grupo de pacientes com CEO. A localização do tumor na orofaringe, o estadiamento clínico e o grau de diferenciação tumoral não tiveram correlação com a positividade para o HPV. Introduction: The incidence of oropharyngeal squamous cell carcinoma (OSCC) has increased worldwide over the last 30 years. Studies have identified human papillomavirus (HPV) infection as a risk factor for OSCC. Objectives: To compare the frequency of HPV infection in patients with OSCC and patients with benign oral or oropharyngeal disease and ascertain whether a statistically significant difference in HPV frequency exists between these two groups. As a secondary objective, to assess potential correlations between HPV positivity, anatomic site of OSCC, tumor staging, and degree of tumor differentiation. Methods: Case-control study. The sample comprised 59 patients with OSCC and 54 non-OSCC controls who underwent surgery for benign oral or oropharyngeal conditions. Paraffin-embedded specimens from cases and controls were tested for HPV positivity by chromogenic in situ hybridization (CISH) for low-risk (LR) and high-risk (HR) HPV, and HPV activity was assessed by P16 immunohistochemistry (IHC). Results: The frequency of HPV positivity was higher in the case group than in the control group when assessed by P16 IHC alone (OR=10.3, P0.20). Conclusion: Using a P16 IHC assay alone or combined with CISH, the authors showed a higher rate of HPV positivity among patients with OSCC, as compared with patients with benign disease. Tumor site within the oropharynx, tumor stage, and degree of differentiation did not correlate with HPV positivity.

Prophylactic human papillomavirus (HPV) vaccines are now available and vaccination programs are being widely implemented, targeting adolescent girls prior to sexual debut. Since the risk of HPV exposure persists throughout a woman's sexual life, the duration of protection provided by vaccination is critical to the overall vaccine effectiveness. We report the long-term efficacy and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine (Cervarix (®) ) up to 8.4 y after the first vaccine dose. In an initial placebo-controlled study performed in US, Canada and Brazil, women aged 15-25 y with normal cervical cytology, HPV-16/18 seronegative by ELISA, DNA-negative for 14 oncogenic HPV types by PCR, received either the HPV-16/18 vaccine or placebo (n = 1,113). Subjects were followed up to 6.4 y after the first dose (n = 776). We report an additional 2-y follow-up for women enrolled from the Brazilian centers from the initial study (n = 436). During the current follow-up study (HPV-023, NCT00518336), no new infection or lesions associated with HPV-16/18 occurred in the vaccine group. Vaccine efficacy over the entire follow-up (up to 8.4 y) was 95.1% (84.6, 99.0) for incident infection, 100% (79.8, 100) for 6-mo persistent infection, 100% (56.1, 100) for 12-mo persistent infection and 100% (0, 100) for CIN2+ associated with HPV-16/18. All women in the vaccine group remained seropositive to both HPV-16/18, with antibody titers for total and neutralizing antibodies remaining several-folds above natural infection levels. The safety profile was clinically acceptable for both vaccine and control groups. This is, to date, the longest follow-up study for a licensed cervical cancer vaccine.

CONTEXT: Highly active antiretroviral therapy (HAART) has turned human immunodeficiency virus (HIV) infection into a chronic condition, and this has led to increased incidence of anal dysplasia among HIV-positive patients. Routine anal evaluation including the anal canal and perianal area is recommended for this population, especially for patients infected by oncogenic human papillomavirus (HPV) types. CASE REPORT: A 54-year-old homosexual HIV-positive man presented with a six-year history of recurrent perianal and anal warts. He had previously undergone incomplete surgical excision and fulguration in another institution on two occasions. He had been using HAART over the past two years. He presented some condylomatous spreading lesions occupying part of the anal canal and the perianal skin, and also a well-demarcated slightly painful perianal plaque of dimensions 1.0 x 1.0 cm. Both anal canal Pap smears and biopsies guided by high-resolution anoscopy revealed high-grade squamous intraepithelial lesion. Biopsies of the border of the perianal plaque also revealed high-grade squamous intraepithelial lesion. HPV DNA testing of the anus detected the presence of HPV-16 type. The patient underwent local full-thickness excision of the lesion. Histological analysis on the excised tissue revealed high-grade squamous intraepithelial lesion with one focus of microinvasive squamous cell cancer measuring 1 mm. No lymph vessel or perineural invasion was detected. The patient showed pathological evidence of recurrent anal and perianal high-grade squamous intraepithelial lesions at the sixth-month follow-up and required further ablation of those lesions. However no invasive squamous cell carcinoma recurrence has been detected so far. CONTEXTO: A terapia anti-retroviral altamente ativa tornou a infecção pelo HIV uma condição crônica, levando a um aumento na incidência de pacientes HIV-positivos com displasia anal. A avaliação anal rotineira incluindo a região anal e perianal é recomendada nessa população, especialmente nos doentes infectados por tipos oncogênicos do HPV. RELATO DE CASO: Um homem homossexual HIV-positivo de 54 anos foi encaminhado para avaliação de condilomas anais e perianais recorrentes há seis anos. Referia duas ressecções cirúrgicas incompletas em outro serviço. Encontrava-se em uso de medicação anti-retroviral altamente ativa há dois anos. Ao exame proctológico, apresentava algumas lesões condilomatosas no canal anal e na região perianal, assim como uma placa bem delimitada de 1,0 por 1,0 cm levemente dolorosa na região perianal. Ambos esfregaço do canal anal e biópsia guiada por anoscopia de alta resolução revelaram lesão escamosa intraepitelial de alto grau. Uma biópsia da borda da placa perianal também diagnosticou lesão escamosa intraepitelial de alto grau. A pesquisa de DNA de HPV do canal anal detectou a presença do HPV tipo 16. O paciente foi submetido à excisão local profunda da lesão. O estudo anatomopatológico revelou lesão escamosa intra-epitelial de alto grau com um foco de 1 mm de carcinoma epidermóide microinvasivo, sem invasão perineural ou linfo-vascular. O paciente apresentou recorrência de lesão escamosa intra-epitelial de alto grau no canal anal e na região perianal confirmadas por biópsias no sexto mês pós-operatório, necessitando ablação. Entretanto, até o momento não apresentou recorrência do carcinoma epidermóide invasivo.

Estudou-se a prevalência do papilomavírus humano (HPV) em 228 mulheres portadoras de lesões em cérvice uterina, atendidas no Instituto Ofir Loiola, em Belém, Pará, no período de março de 1992 a maio de 1996. As pacientes foram submetidas à biópsia de colo uterino, sendo o material encaminhado para histopatologia e pesquisa de HPV por PCR e hibridização por dot-blot. Distribuíram-se as participantes em três grupos, conforme diagnóstico histopatológico. O grupo A constituiu-se de 155 mulheres com carcinoma epidermóide invasor ou com adenocarcinoma, o grupo B de 54 portadoras de neoplasia intra-epitelial cervical grau II ou III, e o grupo C de 19 pacientes com cervicite crônica. Observaram-se prevalências de HPV em 70,3%, 63,0% e 36,8% das mulheres dos grupamentos A, B e C, respectivamente, sendo o HPV 16 registrado em 60,4% das amostras positivas do grupo A e 54,5% daquelas do grupo B. Os tipos 16, 18 e 33 representaram 71,4% dos detectados no grupo C. It was studied the prevalence of human papillomavirus (HPV) among 228 women with lesions of uterine cervix attending the Ofir Loiola Institute, in Belem, Para, from March 1992 to May 1996. Histopathological examination was performed with all cervical biopsy samples obtained from these patients. In addition, specimens were analysed by both polimerase chain reaction and dot-blot hybridization to detect HPV DNA. The patients were assigned to three groups, according to the diagnosis made by histopathology, as follows: A, including 155 women suffering from invasive epidermoid carcinoma or adenocarcinoma; B, 54 patients having either cervical intraepithelial neoplasia grade II or III; and C, involving 19 women with chronic cervicitis. The prevalence rates of HPV in groups A, B and C were 70.3%, 63% and 36.8% respectively. HPV 16 accounted for 60.4% and 54.5% of types identified in groups A and B, respectively. Altogether HPV types 16, 18 and 33 were detected in 71.4% of positive patients belonging to group C.

RESUMEN: Se revisa la patogénesis del condiloma y el cáncer inducidos por los papilomavirus (PVH), que puede resumirse así: a través de microheridas en el epitelio, el virus infecta las células basa les y en el proceso de cicatrización se activa la proliferación celular con lo que se permite iniciar el ciclo de replicación viral; el producto del gen viral E7 se une a la proteína celular Rb, liberando el factor E2F que induce a la célula a entrar en el ciclo de división. El estado proliferativo debería ser contrarrestado por una respuesta apoptótica que es mediada, en este tipo de células, por la proteína p53. El gen viral E6 inactiva esta proteína con lo que se permite la aparición del condiloma por desequilibrio entre la proliferación y la apoptosis. En el contexto de una replicación celular activa e incontrolada y con la proteína p53 inactivada para cumplir sus funciones proapoptóticas y reparadoras, es muy alta la probabilidad de aparición de una célula maligna. Este panorama se hace más complejo cuando los virus, eventualmente, se integran al genoma celular (10 que es más frecuente en el PVH tipo 18). En este caso el gen regulador E2 se inactiva y consecuentemente aumentan las proteínas E6 y E7. ABSTRACT: A review is presented on the pathogenesis of condiloma and cancer induced by papillomavirus infection: through minimal epithelial wounds these viruses reach basal cells; cell proliferation is activated in the healing process thereby allowing the viral replication cycle to take place. The product of viral gen E7 joins Rb cell protein releasing the factor (E2F) that induces cell division. Proliferation should be opposed by apoptosis mediated by cell protein p53 but viral gen E6 inactivates the latter leading to an imbalance between cell division and death. With the occurrence of active, uncontrolled cell division the likelihood of malignancy development becomes high.

Objective: To identify human papillomavirus type 16 (HPV16) E6 and L1 molecular variants infecting Guarani Indian women settled in Misiones, Argentina, a region with a high prevalence of cervical cancer. Some intratypic molecular variants of HPV16 have been associated with greater oncogenic risk, but their implication in the etiology of cervical cancer is still uncertain. Methods: Seventy HPV16 positive cervical samples from Guarani Indian women settled in two different areas of Misiones, Argentina, (34 from the northern area and 36 from the central area), were analyzed. Thirty-seven had normal cytology, 18 had a low-grade squamous intraepithelial lesion (LGSIL), and 15 a high-grade squamous intraepithelial lesion (HGSIL). HPV16 E6 and L1 molecular variants were identified by PCR, followed by dot blot hybridization with 23 and 12 biotinylated oligonucleotide probes, respectively. Results: The frequency of HPV16 variants over the Guarani population was 51% EP (European prototype), 32% E-350G, 9% Af1-a (African 1), 4% E-6862C, 3% Af2-a, and 1% AA-a (Asian-American). The distribution of variants was not homogeneous in the two areas under analysis, with the northern area being more diverse showing 74% of European variants, white the central area presented exclusively E variants. No statistically significant association was found between any particular variant and grade of cervical lesion. Conclusion: This study reports for the first time HPV16 E6 and L1 molecular variants infecting women from an aboriginal community inhabiting a rainforest region of South America. The presence of E class variants could be attributed primarily to contacts with the Spanish conquerors, and Af variants from African slaves introduced later in the South American continent. Fil: Tonon, Sergio Andrés. Universidad Nacional de Misiones. Laboratorio de Biologia Molecular Aplicada; Argentina. Fil: Basiletti, Jorge. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas. Servicio Virus Oncogénicos; Argentina. Fil: Badano, Inés. Universidad Nacional de Misiones. Laboratorio de Biologia Molecular Aplicada; Argentina. Fil: Alonio, Lidia Virginia. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas. Servicio Virus Oncogénicos; Argentina. Fil: Villa, Luisa Lina. Ludwig Institute for Cancer Research. Virology Department; Brasil. Fil: Teyssie, Angelica Rita. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas. Servicio Virus Oncogénicos; Argentina. Fil: Picconi, María Alejandra. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas. Servicio Virus Oncogénicos; Argentina.