Inmunoterapia para el tratamiento del cáncer de cabeza y cuello ¿dónde estamos y hacia dónde vamos? / Immunotherapy for the treatment of head and neck cancer: where are we and where are we going?

El cáncer de cabeza y cuello comprende a todos aquellos tumores que se desarrollan en el tracto aerodigestivo superior, una de las características de éstos es su diversidad, que no es solo desde el punto de vista histológico y etiológico, sino que incluyen diversas formas de presentación, progresión y enfoques terapéuticos. Son de causa multifactorial, siendo el alcohol y el tabaco los principales factores de riesgo asociados; en los últimos años se ha relacionado a ciertos virus con potencial oncogénico con la génesis tumoral, entre ellos al Virus del Papiloma Humano, lo que ha permitido modificar el sistema de estadificación tumor primario-nodos linfáticos cancerosos-metástasis (TNM); presentándolo ahora en dos grandes grupos acorde a la Proteína supresora de tumores P16: P16+ y P16-,los cuales tienen características y manejo diferente. En vista de la heterogeneidad de la enfermedad, son diversos los tratamientos que se ha empleados para el manejo de la misma, entre ellos cirugía, radioterapia, quimioterapia e/o inmunoterapia; ésta última terapéutica, está dirigida hacia la estimulación del sistema inmune del paciente con la finalidad de generar la destrucción de las células tumorales, se realizan previo a una intervención quirúrgica para reducir el tamaño del tumor. Una forma destacable, es la del bloqueo de puntos de control inmunitarios, especialmente hacia proteínas de control inmune moduladoras de respuesta de células T, como los anti-PD-1 y los anti-CTLA-4. La inmunoterapia cada vez va tomando más protagonismo en oncología, en especial las formas de evasión de las reacciones inmunitarias por parte de las células cancerígenas(AU)

Head and neck cancer includes all those tumors that develop in the upper aerodigestive tract, one of the characteristics of these is their heterogeneity, which is not only from the histological and etiological, but also include various forms of presentation, progression and therapeutic approaches.They have a multifactorial cause, with alcohol and tobacco being the main associated risk factors, however, in recent year scertain viruses with oncogenic potential have been linked to tumor genesis, including HPV, which has made it possible tomodify the TNM staging system; now presenting it in two large groups, P16+ and P16-, which have different characteristics and management. In view of the heterogeneity of the disease, there are various treatments that have been used to manageit, including surgery, radiotherapy, chemotherapy and/ orimmunotherapy which will be determined taking into account the location and tumor extension. The latter treatment, is aimedat stimulating the patient's immune system in order to generate the destruction of tumor cells, are performed prior to a surgical intervention to reduce the size of the tumor. A remarkable therapy is that of blocking immune checkpoints, especially anti-PD-1 and anti-CTLA. Immunotherapy is becoming more and more prominent, however, there is still much to discover, so we believe that we should continue investigating the ways of evasion of immune reactions by cancer cells(AU)

Percepción del riesgo de infección con virus del papiloma en jóvenes universitarios / Risk Perception about Papilloma Virus Infection in University Students

Introducción: El virus del papiloma humano es considerado la enfermedad de transmisión sexual de mayor prevalencia. El 50 por ciento de la población sexualmente activa ha tenido contacto con el virus alguna vez en su vida. Objetivo: Determinar el nivel de conocimientos y la percepción de riesgo que tiene la población universitaria de Machala acerca de la infección por virus del papiloma humano, sus aspectos generales, su transmisión y consecuencias. Métodos: Estudio transversal, cuantitativo, realizado con 239 estudiantes universitarios de uno y otro sexo. Fueron utilizadas: encuesta sobre el virus de papiloma humano en adultos, modificado con el Cuestionario de Vulnerabilidad al virus del Papiloma Humano. Resultados: Refirió que no había escuchado sobre el virus el 37,2 por ciento, principalmente estudiantes masculinos, se evidenciaron diferencias significativas (p = 0,000) en el conocimiento de la enfermedad de acuerdo al género. El 67,3 por ciento refirió nunca haber recibido charla educativa sobre el virus. La mayoría respondió adecuadamente a la forma de transmisión, que afecta a hombres como mujeres, las formas de protección, que provoca verrugas genitales, y la neoplasia del cuello uterino. Sin embargo, se encontró desconocimiento sobre la vacuna, la utilidad del Papanicolau, que esta enfermedad puede ser asintomática e incurable, y su relación con otras neoplasias. Conclusiones: La percepción de riesgo de los estudiantes fue muy baja en sentido general y más deficiente en hombres que en mujeres. En las comparaciones por sexo, se evidenció que aquellos estudiantes que recibieron charlas educativas por personal de la salud se asocian con un mejor conocimiento sobre el virus del papiloma humano(AU)

Introduction: The human papilloma virus is considered the most prevalent sexually transmitted disease. 50 percent of the sexually active population has had contact with the virus at some time in their lives. Objective: To determine the level of knowledge and risk perception of the university population of Machala about human papillomavirus infection, its general aspects, its transmission and consequences. Methods: A cross-sectional and quantitative study carried out with 239 university students of both sexes. We used a survey on human papillomavirus in adults, modified with the Human Papillomavirus Vulnerability Questionnaire. Results: 37.2 percent reported that they had not heard about the virus, mainly male students. There were significant differences (P=0.000) regarding the knowledge of the disease according to gender. 67.3 percent reported that they have never received an educational talk about the virus. Most of them responded adequately to the mode of transmission, that the virus affects men as well as women, the forms of protection, that it causes genital warts and neoplasia of the cervix. However, ignorance was found about the vaccine, the usefulness of the Pap smear test, that this disease can be asymptomatic and incurable, and its relationship with other neoplasms. Conclusions: The risk perception of the students was very low in general and more deficient in men than in women. In the comparisons by sex, it was evidenced that those students who received educational talks by the health personnel are associated with better knowledge about human papillomavirus(AU)

Frequência de neoplasia intraepitelial cervical e papilomavírus humano na região Sul do Brasil: um estudo retrospectivo / Frequency of cervical intraepithelial neoplasia and human papillomavirus in southern Brazil: a retrospective study

O artigo tem o objetivo de determinar a frequência de neoplasia intraepitelial cervical (NIC) e de papilomavírus humano (HPV) no Rio Grande do Sul (RS). Tratou-se de um estudo retrospectivo, em que se analisou a frequência de NIC e de HPV no RS durante o período de janeiro de 2015 a junho de 2018. Foram analisados 1.249 laudos histopatológicos de colo uterino, tendo sido possível observar na análise global que a maioria dos casos se manteve estável (183 casos), porém 107 progrediram em um nível. Dos 64 casos de NIC I em 2015, 12 apresentaram a presença de HPV; em 2016, 19 casos de NIC I, e todos com HPV; em 2017 teve uma diminuição de casos de NIC I mais HPV (12 casos). Até junho de 2018, apenas 2 casos de HPV foram registrados. Com este estudo, ficou evidente que, na população estudada, houve diminuição no número de casos de NIC (22%), o que pode estar relacionado a campanhas e incentivo aos cuidados com a saúde e prevenção.(AU)

The article aims to determine the frequency of cervical intraepithelial neoplasia (CIN) and human papillomavirus (HPV) in Rio Grande do Sul (RS). This was a retrospective study, in which the frequency of CIN and HPV in RS, from January 2015 to June 2018, was analyzed. 1,249 cases of histopathological reports of the cervix were analyzed, being It is possible to observe in the global analysis that the majority of cases remained stable (183 cases), but 107 progressed at one level. Of the 64 cases of CIN I in 2015, 12 presented the presence of HPV, in 2016, 19 cases of CIN I, and all with HPV, in 2017 there was a decrease in cases of CIN I plus HPV (12 cases). As of June 2018, only 2 cases of HPV have been reported. With this study it was evident that in the studied population there was a decrease in the number of CIN cases (22%), which may be related to campaigns and incentives to health care and prevention.(AU)

Papilomavírus humano: aspectos clínicos / Human papillomavirus: clinical aspects

A infecção pelo papilomavírus humano (HPV) é reconhecida como uma das principais causas de câncer relacionado à infecção em homens e mulheres. Embora a maioria das infecções pelo HPV seja assintomática e se resolva espontaneamente, a infecção persistente por tipos de HPV de alto risco pode levar a lesões precursoras e ao câncer. Em todo o mundo, a infecção pelo HPV causa até 4,5% (640.000 casos) de todos os casos novos de câncer mundial (8,6% mulheres; 0,9% homens), representando 29,5% de todos os cânceres relacionados com infecção. Os tipos de HPV de alto risco não são apenas responsáveis por praticamente todos os casos de câncer do colo do útero, mas também por uma fração dos cânceres de vulva, vagina, pênis, ânus e câncer de cabeça e pescoço. Além disso, o HPV também é a causa de verrugas anogenitais e papilomatose respiratória recorrente. Apesar da disponibilidade de múltiplas estratégias preventivas, o câncer relacionado ao HPV continua sendo uma das principais causas de morbimortalidade em muitas partes do mundo, principalmente nos países menos desenvolvidos.(AU)

ABSTRACTHuman papillomavirus (HPV) infection is recognized as one of the major causes of infection-related cancer in both men and women. Although most human papillomavirus (HPV) infections are asymptomatic and resolve spontaneously, persistent infection with high-risk HPV, may lead to precancerous lesions and cancer. Worldwide, HPV infection causes up to 4.5% (640,000 cases) of all new cancer cases worldwide (8.6% females; 0.9% males), representing 29.5% of all infection-related cancers. High-risk HPV types are not only responsible for virtually all cervical cancer cases but also for a fraction of cancers of the vulva, vagina, penis, anus, and head and neck cancers. Furthermore, HPV is also the cause of anogenital warts and recurrent respiratory papillomatosis. Despite the availability of multiple preventative strategies, HPV-related cancer remains a leading cause of morbimortality in many parts of the world, particularly in less developed countries.(AU)

Instruments for quality of life assessment in individuals with human papillomavirus / Instrumentos para evaluación de la calidad de vida en individuos con papillomavirus humano / Instrumentos para avaliação da qualidade de vida em indivíduos com papilomavírus humano

ABSTRACT Objective: To identify scientific evidence on quality of life measurement instruments used in individuals with infections caused by human papillomavirus. Method: This was an integrative review carried out from April 1995 to March 2017 in the LILACS, SciVerse Scopus, ISI Web of Science, CINAHL, and PubMed databases. The controlled descriptors adopted were: Infecções por Papilomavirus; Qualidade de Vida; Papillomavirus Infections; and Quality of Life. Results: Of the 416 articles found, 12 were selected. Thirteen different types of instruments to evaluate the quality of life of individuals with human papillomavirus were identified, in that nine were generic and four specific. Conclusion: Different generic and specific instruments were used to evaluate the quality of life of individuals with human papillomavirus, which means no consensus or preference among the studies was identified. However, a lack of use of specific instruments to evaluate this construct in this population was observed.

RESUMEN Objetivo: Identificar evidencias científicas sobre los instrumentos utilizados para medir la Calidad de Vida en individuos con infecciones causadas por Papillomavirus Humano. Método: Revisión integrativa realizada entre abril de 1995 y marzo de 2017, en las bases online LILACS, SciVerse Scopus, ISI Web of Science, CINAHL y PubMed. Los descriptores controlados adoptados fueron: "Infecções por Papillomavirus", "Qualidade de vida", "Papillomavirus Infections" y "Quality of Life". Resultados: Fueron hallados 416 artículos, de los que 12 resultaron seleccionados. Se identificaron 13 tipos diferentes de instrumentos para evaluar Calidad de Vida en personas con Papillomavirus Humano, nueve genéricos y cuatro específicos. Conclusión: Identificamos que son utilizados diferentes instrumentos, genéricos y específicos, para evaluar la Calidad de Vida de las personas con Papillomavirus Humano, sugiriendo inexistencia de consenso o preferencia entre los estudios identificados. No obstante, se observa la escasez del uso de instrumentos específicos para evaluación de dicho constructo en esta población.

RESUMO Objetivo: Identificar as evidências científicas acerca dos instrumentos utilizados para a mensuração da Qualidade de Vida em indivíduos com infecções causadas pelo Papilomavírus Humano. Método: Trata-se de uma revisão integrativa realizada no período de abril de 1995 a março/2017, nas bases de dados online LILACS, SciVerse Scopus, ISI Web of Science, CINAHL e PubMed. Os descritores controlados adotados foram: Infecções por Papillomavirus; Qualidade de Vida; Papillomavirus Infections e Quality of Life. Resultados: Foram encontrados 416 artigos, dos quais 12 foram selecionados. Identificaram-se 13 diferentes tipos de instrumentos para avaliar a Qualidade de Vida de pessoas com Papilomavírus Humano, nove genéricos e quatro específicos. Conclusão: Identificamos que diferentes instrumentos, genéricos e específicos, são utilizados para avaliar a Qualidade de Vida das pessoas com Papilomavírus Humano, sugerindo não haver consenso ou preferência entre os estudos identificados. Porém, observa-se a carência no uso de instrumentos específicos para avaliação desse construto nessa população.

Papilomavírus humano (HPV) / Human papillomavirus (HPV)

A infecção pelo papilomavírus humano (HPV) é muito prevalente e ocorre precocemente após o início da vida sexual. Dentre as patologias associadas, destaca-se o câncer do colo de útero, que, apesar dos programas de rastreamento, continua a acometer muitas mulheres relativamente jovens. O conhecimento da estrutura gênica de diferentes tipos de HPVs e a evolução tecnológica propiciaram o desenvolvimento de vacinas com a finalidade de impedir a infecção por tipos oncogênicos desse vírus. Desde 2007, elas já estão sendo aplicadas mundialmente e alguns resultados positivos já foram observados. A proposta deste artigo é descrever as vacinas contra HPV disponíveis no Brasil, as indicações de utilização, incluindo aquelas contempladas no PNI (Programa Nacional de Imunização) brasileiro, e os efeitos relacionados.(AU)

Lesão intraepitelial do colo uterino em adolescentes: como conduzir? / Intraepithelial lesions in adolescents: how to handle?

A atenção em saúde destinada a mulheres jovens, especialmente adolescentes, mostra-se um desafio, visto que, nesse grupo, apesar da maior incidência e prevalência de infecções genitais por HPV, há também maior probabilidade de regressão de lesões, com resolução espontânea na maioria das vezes. Frente a isto, surgem questionamentos quanto ao período ideal para início do rastreio do câncer de colo uterino e ao manejo das possíveis alterações citológicas. Em janeiro de 2016, o Instituto Nacional de Câncer (INCA) publicou a segunda edição, revisada e atualizada, das Diretrizes Brasileiras para Rastreamento do Câncer do Colo do Útero. Tal documento fornece as recomendações de rastreamento e seguimento para cada grupo de atipias citológicas, inclusive em populações especiais como adolescentes e gestantes. O presente artigo visa expor as recomendações no cuidado de adolescentes com citologia oncótica do colo uterino alterada, com base nas novas Diretrizes.(AU)

Health care for young women, especially adolescents, is challenging, since in this group, in spite of the higher incidence and prevalence of genital HPV infections, there is also a greater probability of regression of lesions, with spontaneous resolution in the majority of the times. Faced with this, questions arise regarding the ideal period for the beginning of cervical cancer screening and the management of possible cytologic alterations. In January 2016, the National Cancer Institute published the second, revised and updated edition of the Brazilian Guidelines for the Screening of Cervical Cancer. This document provides the recommendations for tracking and follow-up for each group of cytologic atypia, including in special populations such as adolescents and pregnant women. The present article aims to expose the recommendations in the care of adolescents with altered uterine cervical cytology, based on the new Guidelines.(AU)

Expresión de E-cadherina y células de Langerhans en verruga vulgar y papiloma bucal / Expression of E-cadherin and Langerhans cells in verruca vulgaris and oral papilloma

Introducción: la verruga vulgar y el papiloma bucal son lesiones provocadas por el virus papiloma humano se pueden encontrar presentes en la mayoría de las superfi cies cutáneas y mucosas, su comportamiento biológico es benigno. Las proteínas de adhesión como la E-cadherina, se encargan de mantener la organización y morfología celular, disminuyen su expresión epitelial en ciertas lesiones potencialmente cancerizables, y favorecen la migración e invasión celular ocasionando posiblesmetástasis. Las células de Langerhans, son células presentadoras deantígeno que activan el sistema inmunológico para proteger al organismocontra patógenos o sustancias extrañas. Objetivo: Determinar el grado de expresión de E-cadherina y de células de Langerhans en verruga vulgar y papiloma bucal. Material y métodos: Se realizó un estudio descriptivo y retrospectivo, en el cual se incluyeron 16 bloques con tejido incluido en parafi na con diagnóstico de verruga vulgar, ycuatro diagnosticados como papiloma bucal, todos los casos fueron corroborados con la tinción de hematoxilina y eosina. La determinacióndel grado de expresión de las células de Langerhans y E-cadherina se realizó por medio de la técnica de inmunohistoquímica, la valoraciónse llevó a cabo de manera semicuantitativa, y se realizó estadísticadescriptiva. Resultados: La expresión de E-cadherina en verruga vulgar fue intensa tanto en cantidad como intensidad, mientras que en papiloma bucal fue moderada también en ambos casos; las células de Langerhans mostraron una inmunotinción moderada en las lesiones de verruga vulgar en intensidad y cantidad; en el caso de papiloma bucal esta inmunotinción en intensidad y cantidad fue leve. . Conclusiones:Los resultados mostraron que las proteínas de adhesión E-cadherinano pierden su expresión en la verruga vulgar y papiloma bucal, lo cualconfi rma su benignidad...

Introduction: verruca vulgaris and oral papilloma are lesions causedby the human papillomavirus. They can be found on most skin and mucosalsurfaces, and their biological behavior is benign. Adhesion proteinssuch as E-cadherins are responsible for maintaining cell morphologyand organization; they decrease the expression in certain potentiallycancerous epithelial lesions and promote cell migration and invasion,causing possible metastasis. Langerhans cells are antigen-presentingcells that activate the immune system to protect the body againstpathogens or foreign substances. Objective: To determine the degreeof expression of E-cadherin and Langerhans cells in verruca vulgarisand oral papilloma. Material and methods: We performed a descriptiveand retrospective study involving 16 paraffi n-embedded tissue blocksof diagnosed cases of verruca vulgaris and 4 paraffi n-embedded tissueblocks identifi ed as oral papilloma. The diagnosis was previouslyconfi rmed by hematoxylin and eosin staining. The degree of expressionof Langerhans cells and E-Cadherin was determined by immunohistochemistry,while the evaluation was carried out semiquantitatively,with descriptive statistics being performed. Results: The expression ofE-cadherin in verruca vulgaris was strong in terms of both quantityand intensity, whereas in the case of oral papilloma it was moderatefor both. Langerhans cells showed moderate immunostaining for bothintensity and quantity in verruca vulgaris-type lesions, while for oralpapilloma, the immunostaining was also mild in both cases. Conclusions:The results suggest that the expression of E-cadherin adhesionproteins does not diminish in verruca vulgaris and oral papilloma,which confi rms their benignity...

Populosis bowenoide en pene. Dos casos con buena respuesta a crioterapia / Bowenoid populosis in penis. Two cases with good response to cryotherapy

La papulosis bowenoide es un carcinoma espinocelular in situ de bajo grado que se observa mayormente en genitales. El agente etiológico es el virus del papiloma humano. Existen múltiples opciones terapéuticas médicas y quirúrgicas pero debería ser tratado de forma conservadora. Presentamos dos casos de papulosis bowenoide tratados exitosamente con crioterapia (AU)

Bowenoid papulosis is a low grade squamous cell in situ carcinoma. It is usually seen in genitals. Etiologic agent is the human papilloma virus. There are many treatments available but it should be treated conservatively. Two cases of bowenoid papulosis with good response to cryotherapy are reported (AU)

Oropharyngeal cancer: an emergent disease? / Cáncer de orofaringe: ¿una enfermedad emergente?

Abstract Oropharyngeal cancer incidence has recently increased, thereby attracting public attention. Akin to other malignancies of the upper aerodigestive tract, it has been attributed to the carcinogenic effects of tobacco and alcohol use. However, recent evidence shows that a substantial increase in the disease is attributable to the effects of human papillomavirus (HPV). Marked progress has been made in relation to the knowledge of molecular and genetic mechanisms involved in the genesis and progression of these cancers. This has led to the development of new and promising therapies of a more specific and less toxic nature that have prolonged life and improved its quality. However, these therapies have failed to significantly increase the proportion of patients who are cured. To decrease the mortality associated with these neoplasms, it is necessary to adopt public health measures aimed at prevention and early diagnosis.

Resumen El cáncer de orofarínge recientemente ha incrementado su incidencia, por lo que ha atraído la atención pública. Como en otras neoplasias malignas de las vías aerodigestivas superiores se atribuye a los efectos carcinogénicos del tabaco y alcohol, sin embargo evidencia reciente señala un incremento substancial atribuible a los efectos del virus del papiloma humano. Mucho se ha avanzado en relación a los conocimientos de los mecanismos moleculares y genéticos implicados en la génesis y progresión de estas neoplasias, lo que ha conducido al desarrollo de nuevas y prometedoras terapias, mas especificas y menos tóxicas, que han prolongado la vida y mejorado su calidad, pero no han logrado incrementar significativamente la proporción de pacientes curados. Si se desea abatir la mortalidad por estas neoplasias es necesario emprender medidas de salud publica dirigidas a su prevención y diagnóstico temprano.

CCR2 and CCR5 genes polymorphisms in women with cervical lesions from Pernambuco, Northeast Region of Brazil: a case-control study

Polymorphisms in chemokine receptors play an important role in the progression of cervical intraepithelial neoplasia (CIN) to cervical cancer (CC). Our study examined the association of CCR2-64I (rs1799864) andCCR5-Δ32 (rs333) polymorphisms with susceptibility to develop cervical lesion (CIN and CC) in a Brazilian population. The genotyping of 139 women with cervical lesions and 151 women without cervical lesions for the CCR2-64I and CCR5-Δ32 polymorphisms were performed using polymerase chain reaction-restriction fragment length polymorphism. The individuals carrying heterozygous or homozygous genotypes (GA+AA) for CCR2-64I polymorphisms seem to be at lower risk for cervical lesion [odds ratio (OR) = 0.37, p = 0.0008)]. The same was observed for the A allele (OR = 0.39, p = 0.0002), while no association was detected (p > 0.05) with CCR5-Δ32 polymorphism. Regarding the human papillomavirus (HPV) type, patients carrying the CCR2-64Ipolymorphism were protected against infection by HPV type 16 (OR = 0.35, p = 0.0184). In summary, our study showed a protective effect ofCCR2-64I rs1799864 polymorphism against the development of cervical lesions (CIN and CC) and in the susceptibility of HPV 16 infection.

Prevalence of genital human papillomavirus among rural and urban populations in southern Yunnan province, China

This study was designed to investigate and compare the HPV prevalence, genotypes distribution and associated risk factors in rural and urban women living in Xishuang Banna district, in the province of Yunnan. A total of 177 and 190 women from rural and urban areas were engaged, respectively. HPV DNA was amplified using the L1 consensus primers system (MY09/11 and GP5/6) and HPV GenoArray test was conducted for genotyping. Proportions were compared by chi-square test, and logistic regression was used to evaluate risk factors. A total of 54 women were positive for HPV DNA. Among rural women, 23 women were positive for HPV infection, of which 21 showed a single infection and 2 had a multiple infection. HPV-16 (10/23) was the most prevalent genotype followed by HPV-52 (5/23), and HPV-58 (5/23). Urban women had a higher infection rate for overall HPV (31/54) and for multiple genotype infection (8/31). HPV-52 (9/31) was the most prevalent genotype followed by HPV-39 (7/31) and HPV-68 (5/31). The age-specific HPV prevalence was also different between rural and urban women. In urban area, women with age <35 years had the highest HPV prevalence, which declined thereafter as age advanced. However, in rural women the highest HPV prevalence was observed in an older age group (>56 years). Ethnicity, smoking and parity were significantly associated with HPV infection among urban women. Our study demonstrates that HPV prevalence and genotype distribution varies among women from rural and urban areas in the south of Yunnan.

Efeito da infecção por HPV nas vias de sinalização por toll like receptors / Effects of HPV infection on TLR signaling pathway

As oncoproteínas E6 e E7 do Papilomavírus Humano (HPV) estão envolvidas na desregulação do sistema imune inato, provocando alterações na expressão dos receptores do tipo Toll (TLR). Considerando-se a função da via de sinalização iniciada por TLR, haveria uma vantagem para o vírus capaz de manipular a resposta desta via de modo que possa persistir nas células sem ser detectado pelo sistema imune ou ainda modulando essa resposta e criando um ambiente mais propício à manutenção da infecção. No entanto, muitos dos mecanismos que levam à eliminação da infecção ou persistência do HPV ainda são pouco conhecidos. O objetivo principal desse trabalho é investigar o papel das vias de TLR no processo de carcinogênese mediado por HPV. Inicialmente, foi analisada a expressão de genes da via de TLR em linhagens de tumores cervicais e em células expressando as oncoproteínas virais. Foram identificados vários genes diferencialmente expressos entre linhagens de células tumorais e queratinócitos normais, incluindo moléculas adaptadoras da via de TLR e genes associados à via da MAP quinase, ativação de NFkappaB e resposta imune antiviral. Cerca de 90% destes genes foram regulados negativamente. Entre eles, destacamos HMGB1, que apesar de possuir menos RNAm nas células tumorais possui um nível proteico muito maior, além de ter-se mostrado de grande importância para a viabilidade e proliferação das células tumorais, conforme demonstrado através de experimentos de supressão gênica. Em conjunto, os nossos dados indicam que E6 e E7 de HPVs de alto risco inibem proteínas da via de sinalização de TLR

Previous studies have shown that E6 and E7 HPV oncoproteins are involved in innate immune system dysregulation, causing alterations on Toll-like receptors (TLR) expression. Considering TLR pathway function, it would be advantageous for a virus to manipulate the response of this pathway so it can persist in cells without being detected by the immune system or to modulate this response to create a better environment for persistence of infection. However, many of the mechanisms leading to HPV infection clearance or persistence are still unknown and matter of active investigation. We analyzed in cervical cancer cell lines expression of genes from TLR pathway; several were differentially expressed between tumor cells lines and normal keratinocytes, including TLR adaptors molecules and genes associated with MAP kinase pathway, NFkappaB activation and antiviral immune response. About 90% of these genes were down regulated. Among them, we selected HMGB1 for further characterization due to its interference with tumor cell viability and proliferation. Altogether, our data indicate that high risk HPV E6 and E7 can inhibit TLR signaling pathway

Vias de transdução de sinal e polimorfismo de Toll-like Receptors na carcinogenese por HPV / Toll-like Receptors signaling pathway and polymorphism on the HPV carcinogenesis

Seres humanos dependem incessantemente de um sistema de reconhecimento efetivo contra infecções para sobreviver. Dentre as diversas proteínas que compõem a resposta imune inata estão os receptores do tipo Toll (TLR Toll-like Receptors), que possuem a função de reconhecer padrões moleculares associados a patógenos e dar início a uma resposta imune adequada. O carcinoma do colo uterino é uma das principais causas de morte de mulheres por câncer mundialmente, sendo o terceiro tipo de câncer mais comum entre mulheres. Este tipo de neoplasia é vinculada etiologicamente à infecção pelo Papilomavírus humano (HPV). Dentre as principais proteínas virais, E6 e E7 são responsáveis pela manipulação dos processos celulares para promover ciclo viral, sendo essenciais no processo de transformação celular. Nesse contexto, o objetivo deste trabalho foi investigar a importância da via de sinalização de TLRs sobre a infecção por HPV. O polimorfismo rs5743836, na região promotora de TLR9, capaz de alterar a expressão deste receptor, foi estudado quanto à influência sobre a história natural da infecção por HPV em uma coorte de mulheres brasileiras; nenhuma associação relevante foi encontrada, indicando que este polimorfismo não interfere significativamente na resposta à infecção e risco de desenvolvimento de lesões no colo do útero causadas por HPV. Proteínas componentes da via de TLRs demonstraram serem alvos de interação com E6 de HPV16; dentre elas, o notável adaptador MyD88 e IKKε, enzima ativadora de importantes transfatores do sistema imune. Estas interações foram aqui estudadas. A interação de E6 com MyD88 resultou em estabilização da proteína viral, o que parece não depender do sítio LxxLL presente em MyD88, como ocorre com outros parceiros moleculares de E6. O sítio de interação de E6 com IKKε coincide com a região onde se localiza o sítio catalítico desta enzima, sugerindo a ação de E6 na ativação de proteínas alvo de IKKε. Esta interação foi observada em queratinócitos, células alvo das infecções por HPV. A produção de citocinas foi afetada por E6 de HPV16, resultando num aumento da quantidade de IL-8 e IL-6; a indução desta citocina poderia ser explicada pela ativação de IKKε. Estes resultados apontam para a capacidade do HPV16 de interferir com o sistema imune, contribuindo para o processo de carcinogênese

Humans constantly rely on an effective recognition system against infections in order to survive. Among various proteins that compose the innate immune response, Toll-like Receptors (TLRs) have the role to recognize pathogen associated molecular patterns and initiate a proper immune response. The cervical cancer is one of the main causes of women death worldwide, being the third most common cancer type among women. This type of neoplasia is etiologically associated with the Human papillomavirus (HPV) infection. E6 and E7, two main viral proteins, are responsible for manipulating the cellular processes to promote the virus' life-cycle, being essential to the cellular transformation process. In the context, the objective of this work was to investigate the relevance of the TLR signaling pathway on the HPV infection. The rs5743836 polymorphism, in the TLR9 promoter region, capable of altering this receptor's expression, was studied regarding its influence on the natural history of HPV infection in a Brazilian women cohort; no relevant association was found, indicating that this polymorphism does not interfere significantly in the infection response and risk of developing cervix lesions caused by HPV. Component proteins of TLR pathway were shown to be interaction targets of HPV16 E6; among them, the notable adaptor MyD88 and IKKε, enzyme that activates important immune system transfactors. These interactions were studied in this work. The interaction of E6 with MyD88 resulted in the stabilization of the viral protein, which seems independent of the LxxLL site present on MyD88, as in other E6 molecular partners. The interaction site on IKK with E6 matches with the region containing the enzyme's catalytic site, suggesting an influence of E6 in the activation of IKKε target proteins. This interaction was observed in keratinocytes, natural targets of HPV infections. The cytokines production was altered by HPV16 E6, resulting in an increase of IL-8 and IL-6 concentration; the induction of the latter could be explained by the activation of IKKε. These results point to the ability of HPV16 of interfering with the immune system, contributing to the carcinogenesis process

Virus papiloma humano en cáncer oral y orofaríngeo: revisión de la literatura / Human papilloma virus in oral and oropharyngeal cancer: review of the literature

Estudios recientes demuestran una realidad prácticamente ineludible que manifiesta que el Virus Papiloma Humano (VPH) puede estar asociado al desarrollo del Carcinoma de Células Escamosas en cavidad oral y orofarínge. Desde el descubrimiento en 1974 por parte de zur Hausen et al., quienes ayudaron a definir el mecanismo por medio del cual el VPH provoca la transformación del queratinocito normal a un estado maligno, han sido numerosos los estudios que han descrito la presencia del VPH en carcinomas de cabeza y cuello, específicamente en cavidad oral y orofarínge. La detección del virus en estos carcinomas podría tener implicaciones clínicas importantes en el pronóstico y tratamiento de estos tumores, con resultados más favorables para el paciente; así mismo, justificar planes de prevención orientados al diagnóstico temprano y a la protección específica contra el VPH. Actualmente están en desarrollo terapias experimentales mínimamente invasivas que potencian el sistema inmunitario para atacar estos tumores, sin embargo, aún no están aprobadas para su uso general. En Chile todavía no existen estudios que describan la situación actual del VPH con respecto al Carcinoma de Células Escamosas en cavidad oral y orofarínge que pudieran orientar al sistema de salud con respecto a la prevención y tratamiento de este tipo de cáncer. En esta revisión presentamos los principales aspectos que relacionan al virus con este tipo de carcinoma. Se revisaron artículos indexados en inglés (Pubmed, Scopus, Cochrane Library, Google Scholar) y español (SciELO, Google Scholar), con el objetivo de brindar al Odontólogo general y especialistas una información actualizada sobre este tema, tanto desde su epidemiología como desde los mecanismos de acción carcinogénica del virus, técnicas de diagnóstico avanzadas, además, formas de prevención y estado del arte en materia de tratamiento.

Recent studies indicate what has become a nearly inescapable reality in that Human Papilloma Virus can be associated to the development of Oral and Oropharyngeal Squamous Cell Carcinoma. Since the discovery of zur Hausen et al. that helped define the mechanism by which HPV causes normal keratinocyte transformation to a malignant state, there have been numerous studies that have described the presence of HPV in head and neck carcinomas, specifically in oral cavity and oropharynx. The detection of the virus in these carcinomas may have important clinical implications in the prognosis and treatment of these tumors with more favorable patient outcomes; likewise, justify prevention plans aimed at early diagnosis and specific protection against HPV. Currently minimally invasive experimental therapies that boost the immune system to attack these tumors are in development, however, they are not yet approved for general use. In Chile there are no studies that describe the current situation with regard to HPV Squamous Cell Carcinoma in oral cavity and oropharynx that may guide the health system regarding the prevention and treatment of this cancer. In this review we present the principal aspects that associate the virus with this type of oral and oropharyngeal carcinoma. We reviewed indexed articles in English (Pubmed, Scopus, Cochrane Library, Google Scholar) and Spanish (SciELO, Google Scholar), with the objective to provide Dental Surgeons and specialists the most updated information about this subject. The review was developed considering the epidemiology as well as the carcinogenic mechanisms of the virus, advanced diagnostic techniques, ways of prevention and state of the art in treatment matters.

Diagnóstico molecular do papilomavírus humano por captura híbrida e reação em cadeia da polimerase / Molecular diagnosis of human papillomavirus in hybrid capture and polymerase chain reaction

A infecção pelo papilomavírus humano (HPV) é extremamente comum e está associada a várias condições clínicas, que variam de infecções assintomáticas a doenças benignas e malignas da mucosa genital, como as verrugas genitais, a neoplasia intraepitelial cervical e o câncer do colo do útero. O objetivo deste estudo foi apresentar as técnicas de biologia molecular por captura híbrida (CH) e reação em cadeia da polimerase (PCR), utilizadas no diagnóstico do HPV e suas aplicações. Métodos mais precisos, quando aplicados em situações especiais, principalmente no caso de divergência entre outros métodos diagnósticos, podem ser aplicados às políticas de saúde pública, visando diminuir a mortalidade causada pelo câncer do colo do útero em consequência do HPV.(AU)

HPV infection is extremely common and is associated with various clinical conditions, ranging from asymptomatic infections to benign and malignant diseases of the genital mucosa, such as genital warts, cervical intraepithelial neoplasia and cervical cancer. The aim of this study was to present the techniques of molecular biology by hybrid capture and PCR, used in the diagnosis of HPV and its applications. More accurate methods when applied in special situations, especially in the case of divergence between other diagnostic methods can be applied to public health policies in order to reduce mortality caused by cervical cancer because of HPV.(AU)

Papilomavírus humano: biologia viral e carcinogênese / Papillomavirus human: viral biology and carcinogenesis

O Papilomavírus humano (HPV) exerce um papel central na carcinogênese do colo uterino. Os mecanismos utilizados pelos HPVs de alto risco para influenciar o ciclo de divisão celular, levando-o à sua desregulação e, consequentemente, para a progressão de lesões, incluem fatores inerentes ao vírus e à sua inter-relação com a célula hospedeira. Tais interferências no metabolismo celular poderão causar modificações morfológicas e funcionais, promovendo o aparecimento de neoplasias. Compreendendo a importância do conhecimento dos processos biológicos e moleculares utilizados pelo HPV na carcinogênese para o diagnóstico precoce e na avaliação prognóstica da doença, o objetivo deste trabalho foi buscar na literatura científica a relação da biologia viral do HPV com o desenvolvimento do câncer de colo útero e novas descobertas.(AU)

The Human papillomavirus (HPV) plays a central role in carcinogenesis of the cervix. The mechanisms used by high-risk HPVs to influence the cell division cycle taking it to its deregulation and consequently for progression of lesions include factors related to the virus and its interrelationship with the host cell. Changes in cellular metabolism can cause morphological and functional changes, promoting the appearance of tumors. Understanding the importance of knowledge of the biological and molecular processes used by HPV in carcinogenesis for early diagnosis and prognostic evaluation of the disease, the objective was to search the scientific literature regarding the HPV?s viral biology to the development of cervical cancer and new discoveries.(AU)

Prevalência de alterações citológicas anais em pacientes com citologia cervical anormal / Prevalence of cytological anal abnormalities in patients with abnormal cervical cytology

A incidência do carcinoma escamoso anal vem crescendo expressivamente. Principal fator associado a ele é o Papiloma Vírus Humano (HPV). Estudos epidemiológicos mostram fases pré-clínicas antes do início do câncer anal. Esse trabalho visou a estimar a prevalência de alterações citológicas anais em pacientes com citologia cervical anormal e sem lesão macroscópica HPV induzida na região anal. Foram selecionadas 70 mulheres com citologia cervical alterada, soronegativas para o Vírus da Imunodeficiência Humana (HIV) e sem lesão perianal macroscópica pelo HPV. As pacientes foram submetidas a um questionário e foram realizadas coletas de captura híbrida anal e cervical, bem como de uma amostra de citologia oncológica cervical e duas amostras anais. A prevalência das alterações citológicas anais encontrada foi de 71,4%, sendo que 57,1% apresentaram captura híbrida anal positiva. A prevalência de captura híbrida anal positiva para HPV de alto risco oncogênico em paciente com citologia cervical de atipia escamosa de significado indeterminado, provavelmente não neoplásico (ASC-US) e de lesão intraepitelial escamosa de baixo grau (LSIL) foi de 27,1% e, em pacientes com citologia cervical de atipia escamosa de significado indeterminado, não podendo excluir lesão intraepitelial de alto grau (ASC-H), lesão intraepitelial escamosa de alto grau (HSIL), e carcinoma epidermóide do colo do útero foi de 30%. Pacientes com captura cervical positiva tiveram 4 vezes mais chance de apresentar captura anal positiva (OR=4; p=0,018). Concluímos haver alta prevalência citológica anal alterada na população estudada. O risco de contaminação anal é significativo nas pacientes com HPV de alto poder oncogênico em cérvice, portanto todas as pacientes com citologia cervical anormal merecem investigação anal, independente da gravidade do laudo citológico

The incidence of anal squamous cell carcinoma has been growing significantly. The main risk factor associated with this injurie is the Human Papilloma Virus (HPV). As studies have shown preclinical stages before the onset of anal cancer. This study aimed to estimate the prevalence of anal cytological abnormalities in patients with abnormal cervical cytology and without macroscopic HPV induced lesions in the anal region. The sample consisted of 70 women with abnormal cervical cytology, seronegative for human immunodeficiency virus (HIV) and without macroscopic anal lesions. Patients answered a questionnaire a were submited to collection of anal and cervical hybrid capture assay and collection of a sample of cervical cytology of two anal samples. Prevalence of anal cytological abnormalities found in patients with cervical cytological abormalities without macroscopic anal lesions was 71.4% and 57.1% of patients showed positive anal capture. Prevalence of positive hybrid capture to oncogenic anal HPV in patients with cervical cytology of atypical squamous cells of undetermined significance (ASC-US) and of low grade squamous intraepithelial lesion (LSIL) was 27.1%. Prevalence in patients with cervical cytology of atypical squamous cells – cannot exclude (ASC-H), high grade squamous intraepithelial lesion (HSIL) and squamous cell carcinoma of the uterine cervix in situ or were 30%. Patients with positive cervical capture were 4 times more likely to present positive anal capture (OR=4, p=0.018). In conclusion, we found a high prevalence of anal cytology abnormalities in this population. The risk of anal contamination is significant in patients with oncogenic HPV in cervix, so all patients with abnormal cervical cytology deserve anal investigation, regardless of the severity of cytological report

Prevalência da infecção pelo HPV em cânceres não anogenitais: uma revisão sistemática / Prevalence of HPV infection in non-anogenital cancers: a systematic review

O papilomavírus humano (HPV), uma das infecções sexualmente transmissíveis mais comuns no mundo, tem um papel estabelecido na patogênese de cânceres genitais, bem como no câncer anal. Essa infecção também foi implicada na oncogênese de outros cânceres, como os de cabeça e pescoço. Existem evidências do aumento de incidência dos cânceres de orofaringe associados à infecção pelo HPV. Além disso, parece haver melhor prognóstico desses cânceres associados ao HPV, comparados aos não associados. Por outro lado, existem também alusões na literatura à associação da infecção pelo HPV a outros tipos de cânceres, como os cânceres de esôfago, de bexiga, de pulmão e de mama. Essas informações têm aplicação potencial para eventuais programas de triagem em subgrupos de risco. Atualmente, a vacinação contra o HPV, aprovada para a prevenção do câncer do colo uterino, poderia ter papel potencial na prevenção de outros cânceres associados a essa infecção. Além disso, há interesse no desenvolvimento de tratamentos especificamente dirigidos ao subgrupo de cânceres associados ao HPV. Nesta revisão, foi discutido o possível papel da infecção pelo HPV em cânceres não anogenitais.(AU)

Human papillomavirus (HPV), one of the most common sexually infection transmitted worldwide, has an established role in the pathogenesis of genital and anal malignancies. The HPV has also been implicated in the oncogenesis of other cancers, including head and neck malignancies. There are evidences that the increase of oropharyngeal cancer?s incidence is associated with HPV infection. Besides, these cancers, which are associated to HPV, show improved outcomes compared of those not associated with HPV infection. On the other hand, there are also references regarding the association of HPV infection with other cancers, as the esophagus, bladder, lung and breast cancers. This information has potential implications for the eventual screening of high-risk groups. While HPV vaccination is currently approved for the prevention of cervical cancers, it also has potential in the prevention of all HPV-associated malignancies. Moreover, there is interest in designing treatments specifically for this HPV-positive subgroup. In this review, the role of HPV in non-anogenital cancers was discussed.(AU)

Lesión intraepitelial cervical en adolescentes / cervical intraepithelial lesion teen

Objetivo: Evaluar las lesiones intraepiteliales cervicales en pacientes adolescentes que acuden a la consulta del Servicio de Ginecología de la Maternidad “Concepción Palacios”. Métodos: Estudio prospectivo, descriptivo, transversal. Se incluyeron 76 pacientes adolescentes en edades comprendidas entre los 10 y 19 años que hubiesen iniciado relaciones sexuales, con hallazgos citológicos y/o histológicos de patología cervical, a las cuales se les tomó muestra para determinar ácido desoxirribonucleico de virus de papiloma humano por reacción en cadena de polimerasa, se realizó colposcopia y de presentar cambios, se tomó biopsia. Se registraron factores de riesgo a partir de la historia clínica. Resultados: La edad promedio fue 17 ± 1 años, el inicio de las relaciones sexuales fue 15 ± 1 años, el número de parejas sexuales tuvo una mediana de 2. En 41 pacientes se encontró un solo tipo viral (53,9 %), el más frecuente fue el tipo 6 (43,1 %). El hallazgo citológico más frecuente fue lesión intraepitelial cervical de bajo grado con 52 pacientes. El epitelio acetoblanco plano se presentó en 32 pacientes, en 57 casos (75 %) las lesiones fueron exocervicales. El diagnóstico histológico más frecuente fue neoplasia intraepitelial 1 (77,6 %). Conclusiones: El tipo viral más frecuente fue el tipo 6, el alcohol fue el factor de riesgo con importancia estadística.

Objective: To evaluate cervical intraepithelial lesions in adolescent patients attending the Gynecology Service Consultation to the Concepción Palacios Maternity Hospital. Methods: Prospective, descriptive, transversal. 76 patients were included, adolescents aged between 10 and 19 who had initiated sex with cytologic findings and/or histological cervical pathology, to which sample was taken to determine deoxyribonucleic acid from human papilloma virus by reaction polymerase chain. We practice colposcopy and biopsy was taken, when it was necessary. The risk factors were registration for the medical history. Results: The mean age was 17 ± 1 years, the onset of sexual intercourse was 15 ± 1 years, the number of sexual partners had a median of 2. In 41 patients there was a single viral type (53.9 %), the most frequent was type 6 (43.1 %). The most common cytologic finding was cervical intraepithelial lesion low grade with 52 patients. Flat acetowhite epithelium occurred in 32 patients, 57 cases (75 %) were ectocervical lesions. The most frequent histological diagnosis was intraepithelial neoplasia I (77.6 %). Conclusions: The most frequent viral type was type 6, the alcohol was the risk factor with statistical significance.