Identifying Populations Most Susceptible To Get Benefit From Broadening The Scope For Prevention Of Cervical Cancer: Example From Uruguay

Objectives: To identify factors associated with high-risk human papillomavirus (HPV) infection and high grade squamous intraepithelial lesion (HSIL) among a high-risk group of HPV-unvaccinated women in Montevideo. Methods: Participants completed a questionnaire on socio-demographics, sexual behavior and gynecological history and received a gynecological examination. HPV DNA was detected by PCR using MY09/11 primers. Logistic regression analyses were performed to identify factors associated with high-risk HPV infection and HSIL. Results: A total of 469 women with HPV DNA and cytological results completed the questionnaire. Among women older than 30 years, those with high number of sexual partners and regular housing conditions were more likely to be positive for high-risk HPV infection (adjusted OR: 2.94, 95% CI: 1.01-8.51 and 2.68, 95% CI: 1.01-7.21, respectively). A marginally non-statistically significant association between getting a HSIL and having a high number of sexual partners was also observed (adjusted OR: 3.22, 95% CI: 0.97-10.75). Conclusions: In an era of development of new strategies for accelerating the reduction of cervical cancer incidence and mortality, our results may contribute to identify populations most susceptible to get benefit from broadening the scope for prevention of cervical cancer and could be used with other triage strategies

Competing mortality in oropharyngeal carcinoma according to HPV status

Purpose or Objective:The objective of the present study is to assess differences in the competing causes of death in oropharyngeal carcinoma (OPC) patients as a function of the HPV status

Might Oral Human Papillomavirus (HPV) Infection in Healthy Individuals Explain Differences in HPV-Attributable Fractions in Oropharyngeal Cancer? A Systematic Review and Meta-analysis

Background. Differences in oral human papillomavirus (HPV) prevalence and contrasts in HPV-attributable fractions (AFs) in oropharyngeal cancer (OPC) have not been evaluated in depth. Methods. A systematic review was performed to identify studies in which at least 50 healthy individuals were tested for oral HPV infection. Information on sex, age, tobacco/alcohol consumption, sex practices, specimen collection, HPV detection, and population type was extracted. Prevalences were pooled using random-effects models for meta-analyses of binomial data. Correlations were assessed by the Spearman test. Results. Forty-eight reports comprising 28 544 individuals fulfilled inclusion criteria. Global oral HPV prevalence was 4.9%. Estimates were highest in Europe, although regional differences were not statistically significant. HPV16 prevalence was 1.0% globally, and regional differences became statistically significant. A lifetime history of >6 sex partners showed a higher risk of oral HPV infection. The age-specific HPV distribution revealed a prevalence of >= 5% over 40 years of age and a lower prevalence at younger ages. There was no association between oral HPV prevalence and HPV-AFs or age-standardized rates (ASRs) of OPC, genital HPV in healthy women, or tobacco use. Conclusions. Differences in HPV-AFs or ASRs of OPC cannot be explained by differences in the prevalence of oral HPV infection across healthy populations. Consistent research on determinants of oral HPV prevalence, acquisition, clearance, and persistence is warranted

Human papillomavirus in premalignant oral lesions: no evidence of association in a Spanish cohort

Background: human papillomavirus (HPV) is the cause of a fraction of head and neck squamous cell carcinoma. Although this relation is well-known, it is still not clear the role of HPV in premalignant oral lesions such as oral lichen planus (OLP) and dysplasia. We aimed to evaluate the HPV-DNA prevalence and type distribution in a set of oral biopsies obtained from patients diagnosed with OLP and dysplasia, as well as the role of HPV in these lesions. Methods: a retrospective cohort of all premalignant oral lesions consecutively diagnosed from March 30th 1995 to May 21st 2014 at Hospital of Bellvitge and Odontological University Hospital of Bellvitge was identified and classified in four groups: OLP (groups 1 and 2) and dysplasias (groups 3 and 4) that progressed or not to invasive cancer during follow-up. A random selection targeting 25 cases was aimed to be performed for each group. All selected cases were subjected to pathological evaluation, DNA quality control and HPV-DNA detection. HPV-DNA positive samples were further subject to p16INK4a analysis. Results: a total of 83 cases yielded a valid HPV-DNA result. From those, 7 and 34 cases were OLP that progressed or not to invasive cancer during follow-up, whereas 24 and 18 cases were displasias that progressed or not to invasive cancer during follow-up, respectively. HPV-DNA was detected in 4 samples (3 dysplastic lesions and 1 OLP). Two samples were HPV16 positive (2%), 1 sample HPV18 positive (1%) and 1 sample (1%) was HPV indeterminate. Two out of four HPV-DNA positive cases had high p16INK4a expression and none of the HPV positive cases progressed to invasive cancer during long-term follow-up. CONCLUSIONS: We found a low HPV-DNA attributable fraction in premalignant lesions of the oral cavity, suggesting that HPV is unlikely to play a significant role in oral carcinogenesis in our setting

Human Papillomavirus and factors associated with recurrence in sinonasal inverted papillomas from Poland and Spain

Sinonasal inverted papilloma (SNIP) is a benign but locally aggressive tumor that has a tendency for recurrence and malignant transformation. The role of human papillomavirus (HPV) in SNIP is controversial. To determine the HPV-DNA prevalence and type distribution in SNIP in two different geographic areas and assess the association between SNIP recurrence and HPV infection, as well as additional potential etiologic factors. Two retrospective cohorts of SNIP patients from Poland and Spain were evaluated. Demographic, tobacco/alcohol use, clinical, and follow-up data were collected. All samples were subject to histopathologic evaluation, DNA quality control, and HPV-DNA detection by PCR. HPV-DNA positive samples and a random sample of HPV-DNA negative cases were further subject to p16INK4a analysis. Proportional-hazards models were used to evaluate the risk of recurrence by selected variables. Seventy-nine SNIP patients (46 from Spain diagnosed between 1995 and 2014, and 33 from Poland diagnosed between 2012 and 2017) were included in the study. HPV-DNA was detected in four patients (5.1%), two from each region, and all four were positive for the HPV11 subtype. Seventeen patients (21.5%) experienced recurrence, with a median time to recurrence of 14 months. No association was identified between lesional HPV-DNA positivity, toxic habits, Krouse stage, or malignant transformation and a higher risk of recurrence. The low prevalence of HPV-DNA in SNIPs suggests that HPV is not a main etiology for development of these lesions. With a lack of association between the evaluated factors and recurrence, further research with larger number of patients and additional biomarkers is warranted to further understand predisposing risk factors

Distinctive Expression and Amplification of Genes at 11q13 in Relation to HPV Status with Impact on Survival in Head and Neck Cancer Patients

Clear differences have been established between head and neck squamous cell carcinomas (HNSCC) depending on human papillomavirus (HPV) infection status. This study specifically investigated the status of the CTTN, CCND1 and ANO1 genes mapping at the 11q13 amplicon in relation to the HPV status in HNSCC patients. CTTN, CCND1 and ANO1 protein expression and gene amplification were respectively analyzed by immunohistochemistry and real-time PCR in a homogeneous cohort of 392 surgically treated HNSCC patients. The results were further confirmed using an independent cohort of 279 HNSCC patients from The Cancer Genome Atlas (TCGA). The impact on patient survival was also evaluated. CTTN, CCND1 and ANO1 gene amplification and protein expression were frequent in HPV-negative tumors, while absent or rare in HPV-positive tumors. Using an independent validation cohort of 279 HNSCC patients, we consistently found that these three genes were frequently co-amplified (28%) and overexpressed (39-46%) in HPV-negative tumors, whereas almost absent in HPV-positive tumors. Remarkably, these alterations (in particular CTTN and ANO1 overexpression) were associated with poor prognosis. Taken together, the distinctive expression and amplification of these genes could cooperatively contribute to the differences in prognosis and clinical outcome between HPV-positive and HPV-negative tumors. These findings could serve as the basis to design more personalized therapeutic strategies for HNSCC patients

Síntesis estereoselectiva de cis-decahidroquinolinas: intermedios avanzados para el acceso a las lepadinas

[spa] Las lepadinas son alcaloides de origen marino de interesantes propiedades farmacológicas aislados entre 1991 y 2002 de los ascidios tunicados "Clavelina lepadiformis", "Didemnum" y "Aplidium Tabascum". Su estructura se caracteriza por contener un esqueleto cis-decahidroquinolínico trisustituido con un grupo metilo en C-2, un grupo hidroxilo libre o esterificado en C-3 y una cadena lateral en C-5. En la presente Tesis Doctoral se han estudiado tres estrategias sintéticas diferentes para la síntesis de cis-decahidroquinolinas enantiopuras, que pudiesen ser utilizadas como intermedios avanzados en la síntesis de lepadinas: - Aminociclaciones de 3-aminociclohexenonas - Reacciones de expansión de ciclo en octahidroindoles - Aminociclaciones de 4-(3-aminoalquil)dihidroanisoles Con estas metodologías se han aislado y caracterizado dieciocho nuevas cis-decahidroquinolinas, algunas de ellas plausibles intermedios para el acceso a las lepadinas. En la primera aproximación se han obtenido decahidroquinolinas 2-metil, 3-hidroxi, 5-butil trisustituidas enantiopuras a partir de 2-(3-aminoalquil)ciclohexenonas, a través de un proceso one-pot de reducción del doble enlace de la enona, doble desbenzilación de la función amina terciaria y aminociclación reductiva intramolecular. Si bien la estereoquímica obtenida no es la adecuada para la síntesis de lepadinas la metodología desarrollada puede ser aplicable a la síntesis de otros alcaloides tales como trans-195A o 5-epi-trans-243A y alcaloides relacionados aislados de la piel de anfibios. Para la obtención de las ciclohexenonas precursoras de la aminociclación se llevó a cabo la adición del derivado lítico del acetal de la 2-bromociclohexenona sobre los epóxidos (1S) y (1R)-[1'(S)-(Dibenzilamino)etil]oxirano en presencia de trifluoruro de boro eterado, obteniendo los productos deseados con buenos rendimientos. No se hallaba descrito en la literatura el ataque de derivados líticos sobre este tipo de epóxidos, de manera que estos resultados constituyen un nuevo procedimiento de obtención de alfa-alquil, beta-aminoalcoholes. En la segunda aproximación se han obtenido decahidroquinolinas 3-hidroxisustituidas por expansión de ciclo de octahidroindoles 2-hidroximetilsustituidos en condiciones termodinamicas, y decahidroquinolinas 2-metil,3-hidroxidisustituidas por expansión de ciclo de octahidroindoles 2-(1-hidroxietil)sustituidos en condiciones cinéticas. La reacción de expansión de ciclo sobre octahidroindoles no se hallaba descrita previamente en la literatura. Asimismo, se ha llevado a cabo un estudio de la mayor estabilidad de los octahidroindoles explorados en este trabajo frente a las correspondientes decahidroquinolinas. Algunos de los productos obtenidos pueden aplicarse a la síntesis de las lepadinas F y G y del alcaloide pandolina. En la tercera aproximación se han obtenido decahidroquinolinas 2-metil,3-hidroxidisustituidas enantiopuras por aminociclación de 4-(3-aminoalquil)dihidroanisoles provenientes de la reducción de Birch de homotiraminas. Este tipo de reacciones solo se hallaba descrita para la obtención de decahidroquinolonas no sustituidas en su versión racémica. Para la preparación de los aminoalcoholes de partida se han llevado a cabo tres metodologías sintéticas diferentes. Los productos de ciclación obtenidos mediante esta aproximación contienen la estereoquímica y funcionalización adecuadas para ser utilizados como intermedios avanzados en las síntesis de las lepadinas A, B, C, F y G, siendos estas dos últimas las de mayor interés al ser las únicas de su família que no han sido todavía sintetizadas.[eng] "Stereoselective synthesis of cis-decahydroquinolines. Advanced intermediates for the access to lepadin alkaloids". cis-Decahydroquinolines constitute the azabicyclic skeleton of natural products such as lepadins and several amphibian alkaloids, as well as some pharmacologically interesting synthetic compounds. Moreover, this heterocyclic motif occurs as a subunit of other azapolycyclic compounds (gephyrotoxins, cylindricines, and pseudoaspidopermidine and pandoline alkaloids). The extensive … [+]occurrence of this azabicyclic ring has stimulated the implementation of new procedures to gain acces to functionalized enantiopure cis-decahydroquinolines that can be used as advanced intermediates in the synthesis of compounds embodying this skeleton type. The development of novel procedures to gain acces to functionalized enantiopure cis-decahydroquinolines was studied in this work, with the ultimate aim of using these compounds as intermediates in the synthesis of natural products embodying this structural motif. Three general methods were explored: Route 1) Aminocyclization of 2-(3-aminoalkyl)cyclohexenones. Route 2) Ring expansion of functionalized octahydroindoles Route 3) Birch reduction followed by aminocyclization of homotyramines. In the first study we obtained decahydroquinolines by aminocyclization of cyclohexenones, via a one-pot reduction of the double bond, double debenzylation and intramolecular reductive amination process. The required starting cyclohexenones were obtained by the coupling reaction between aryllithium derivatives and -aminoalkylepoxides in the presence of boron trifluoride etherate, constituting a new synthetic procedure to achieve enantiopure syn and anti -aminoalcohols. The developed methodology is directly applicable to the synthesis of some alkaloids such as trans-195A and 5-epi-trans-243A. In the second study we investigated the ring expansion rearrangement of octahydroindoles, a type of reaction which was unprecedented. The obtained products could be used as advanced intermediates in the synthesis of the alkaloid pandoline. Finally, in the third study we obtained stereoselectively cis-decahydroquinolines from Birch reduction of homotyramineswith a syn--aminoalcohol unit followed by acid treatment of formed dihydroanisol derivatives. The stereoselectively of the process was determined by the functionality present on the oxigenated side chain. The major product contains four stereogenic centers with the same relative configuration as that of lepadins F and G, so it can be considered as advanced intermediate for the synthesis of this natural products