Penile intraepithelial neoplasia: Distribution of subtypes, HPV genotypes and p16INK4a in 84 international cases.

There are few pathologic or molecular studies of penile precancerous lesions, and the majority refers to lesions associated with invasive carcinomas. Penile Intraepithelial Neoplasia (PeIN) is classified in two morphologically and distinctive molecular groups, non-HPV and HPV-related with special subtypes. The primary purpose of this international series was to classify PeIN morphologically, detect HPV genotypes and determine their distribution according to PeIN subtypes. A secondary aim was to evaluate the p16INK4a immunostaining as a possible HPV surrogate for high-risk HPV infection in penile precancerous lesions. Samples consisted of 84 PeIN cases, part of a retrospective cross-sectional analysis of 1095 penile carcinomas designed to estimate the HPV DNA prevalence in penile cancers using PCR and p16INK4a immunostaining. Penile Intraepithelial Neoplasia (PeIN) was classified in HPV-related (basaloid, warty-basaloid, warty, hybrid, and mixed subtypes) and non-HPV-related (differentiated), the former being the most frequent. PeIN subtypes were differentiated (non-HPV-related) and basaloid, warty-basaloid, warty, hybrid and mixed (HPV-related). Basaloid PeIN was the most commonly diagnosed subtype, and HPV16 was the most frequent HPV genotype detected. Warty-basaloid and warty PeIN showed a more heterogeneous genotypic composition. Most HPV genotypes were high-risk but low-risk HPV genotypes were also present in a few cases (4%). A single HPV genotype was detected in 82% of HPV positive cases. In contrast, multiple genotypes were detected in the remaining 18% of cases. The findings in this study support the paradigm that penile in situ neoplasia, like its invasive counterparts, is HPV dependent or independent and has distinctive morphological subtypes readily identified in routine practice. Considering that HPV16 is clearly the predominant type, and that the three available vaccines have HPV16, all of them will be suitable for vaccination programs; the price of the vaccines will be probably the main determinant to choose the vaccine.

Performance of an affordable urine self-sampling method for human papillomavirus detection in Mexican women.

INTRODUCTION: Urine self-sampling for human papillomavirus (HPV)-based cervical cancer screening is a non-invasive method that offers several logistical advantages and high acceptability, reducing barriers related to low screening coverage. This study developed and evaluated the performance of a low-cost urine self-sampling method for HPV-testing and explored the acceptability and feasibility of potential implementation of this alternative in routine screening. METHODS: A series of sequential laboratory assays examined the impact of several pre-analytical conditions for obtaining DNA from urine and subsequent HPV detection. Initially, we assessed the effect of ethylaminediaminetetraacetic acid (EDTA) as a DNA preservative examining several variables including EDTA concentration, specimen storage temperature, time between urine collection and DNA extraction, and first-morning micturition versus convenience sample collection. We further evaluated the agreement of HPV-testing between urine and clinician-collected cervical samples among 95 women. Finally, we explored the costs of self-sampling supplies as well as the acceptability and feasibility of urine self-sampling among women and healthcare workers. RESULTS: Our results revealed higher DNA concentrations were obtained when using a 40mM EDTA solution, storing specimens at 25°C and extracting DNA within 72 hrs. of urine collection, regardless of using first-morning micturition or a convenience sampling. We observed good agreement (Kappa = 0.72) between urine and clinician-collected cervical samples for HPV detection. Furthermore, urine self-sampling was an affordable method (USD 1.10), well accepted among cervical cancer screening users, healthcare workers, and decision-makers. CONCLUSION: These results suggest urine self-sampling is feasible and appropriate alternative for HPV-testing in HPV-based screening programs in lower-resource contexts.

HPV16 variants distribution in invasive cancers of the cervix, vulva, vagina, penis, and anus.

Human papillomavirus (HPV)16 is the most oncogenic human papillomavirus, responsible for most papillomavirus-induced anogenital cancers. We have explored by sequencing and phylogenetic analysis the viral variant lineages present in 692 HPV16-monoinfected invasive anogenital cancers from Europe, Asia, and Central/South America. We have assessed the contribution of geography and anatomy to the differential prevalence of HPV16 variants and to the nonsynonymous E6 T350G polymorphism. Most (68%) of the variance in the distribution of HPV16 variants was accounted for by the differential abundance of the different viral lineages. The most prevalent variant (above 70% prevalence) in all regions and in all locations was HPV16_A1-3, except in Asia, where HPV16_A4 predominated in anal cancers. The differential prevalence of variants as a function of geographical origin explained 9% of the variance, and the differential prevalence of variants as a function of anatomical location accounted for less than 3% of the variance. Despite containing similar repertoires of HPV16 variants, we confirm the worldwide trend of cervical cancers being diagnosed significantly earlier than other anogenital cancers (early fifties vs. early sixties). Frequencies for alleles in the HPV16 E6 T350G polymorphism were similar across anogenital cancers from the same geographical origin. Interestingly, anogenital cancers from Central/South America displayed higher 350G allele frequencies also within HPV16_A1-3 lineage compared with Europe. Our results demonstrate ample variation in HPV16 variants prevalence in anogenital cancers, which is partly explained by the geographical origin of the sample and only marginally explained by the anatomical location of the lesion, suggesting that tissue specialization is not essential evolutionary forces shaping HPV16 diversity in anogenital cancers.

HPV vaccination impact on a cervical cancer screening program: methods of the FASTER-Tlalpan Study in Mexico.

OBJECTIVE: To outline the design of a clinical trial to evaluate the impact of HPV vaccination as part of a hrHPV-based primary screening program to extend screening intervals. MATERIALS AND METHODS: A total of 18,000 women aged 25-45 years, attending the regular cervical cancer-screening program in primary health care services in Tlalpan, Mexico City, will be invited to the study. Eligible participants will be assigned to one of three comparison groups: 1) HPV16/18 vaccine and hrHPV-based screening; 2) HPV6/11/16/18 vaccine and hrHPV-based screening; 3) Control group who will receive only hrHPV-based screening. Strict surveillance of hrHPV persistent infection and occurrence of precancerous lesions will be conducted to estimate safety profiles at different screening intervals; participants will undergo diagnosis confirmation and treatment as necessary. CONCLUSION: The FASTER-Tlalpan Study will provide insights into new approaches of cervical cancer prevention programs. It will offer valuable information on potential benefits of combining HPV vaccination and hrHPV-based screening to safety extend screening intervals.

HPV vaccination impact on a cervical cancer screening program: methods of the FASTER-Tlalpan Study in Mexico / Impacto de la vacunación de VPH en un programa de tamizaje de cáncer cervical: métodos del Estudio FASTER-Tlalpan en México

Abstract Objective: To outline the design of a clinical trial to evaluate the impact of HPV vaccination as part of a hrHPV-based primary screening program to extend screening intervals. Materials and methods: A total of 18,000 women aged 25-45 years, attending the regular cervical cancer-screening program in primary health care services in Tlalpan, Mexico City, will be invited to the study. Eligible participants will be assigned to one of three comparison groups: 1) HPV16/18 vaccine and hrHPV-based screening; 2) HPV6/11/16/18 vaccine and hrHPV-based screening; 3) Control group who will receive only hrHPV-based screening. Strict surveillance of hrHPV persistent infection and occurrence of precancerous lesions will be conducted to estimate safety profiles at different screening intervals; participants will undergo diagnosis confirmation and treatment as necessary. Conclusion: The FASTER-Tlalpan Study will provide insights into new approaches of cervical cancer prevention programs. It will offer valuable information on potential benefits of combining HPV vaccination and hrHPV-based screening to safety extend screening intervals.

Resumen Objetivo: Describir los métodos de un ensayo clínico que permita evaluar el impacto de la incorporación de la vacunación contra VPH en el programa de detección oportuna de cáncer cervical con el fin de ampliar los intervalos de tamizaje. Material y métodos: Un total de 18 000 mujeres entre 25 y 45 años, usuarias del programa de detección oportuna de cáncer cervical de la Ciudad de México en Tlalpan, serán invitadas a participar en el estudio. Las mujeres elegibles serán aleatorizadas a uno de tres grupos de comparación: 1) Vacunación contra VPH16/18 y tamizaje con VPHar; 2) Vacunación contra VPH6/11/16/18 y tamizadas con VPHar; 3) Grupo control que será sólo tamizado con VPHar. Se llevará a cabo una estrecha vigilancia de la infección persistente de VPHar y de la ocurrencia de lesiones precancerosas, con el fin de estimar el perfil de seguridad de intervalos de tamizaje de distinta duración. Todas las participantes contarán con procedimientos de confirmación diagnóstica y tratamiento en caso necesario. Conclusión: El estudio FASTER-Tlalpan introducirá una nueva visión de la implementación de nuevos abordajes en la prevención de cáncer cervical. Ofrecerá información de los potenciales beneficios de la combinación de la vacunación contra VPH y el tamizaje basado en VPHar para extender los intervalos de tamizaje.

Secular trends of HPV genotypes in invasive cervical cancer in Cali, Colombia 1950-1999.

UNLABELLED: Aim To estimate relative contribution and time trends of HPV types in cervical cancer in Cali, Colombia over a 50 years' period. METHODS: Paraffin blocks of 736 cervical cancer histological confirmed cases were retrieved from the pathology laboratory at Hospital Universitario del Valle (Cali, Colombia) and HPV genotyped using SPF10-PCR/DEIA/LiPA25 (version 1) assay. Marginal effect of age and year of diagnosis in secular trends of HPV type prevalence among HPV+ cases were assessed by robust Poisson regression analysis. RESULTS: 64.7% (95%CI: 59.9-69.2) of squamous cell carcinomas (SCCs) were attributed to HPV 16 and 18, 78.2% (95%CI: 74-82) to HPV 16, 18, 31, 33 and 45 and 84.8% (95%CI: 81-88.1) to HPV 16, 18, 31, 33, 45, 52 and 58 while ninety-three percent of adenocarcinomas (ADCs) were attributed to HPV 16, 18 and 45 only. The prevalence of specific HPV types did not change over the 50-year period. A significant downward trend of prevalence ratios of HPV16 (​P=0.017) and α7 but HPV 18 (i.e., HPV 39, 45, 68, 70, ​P=0.024) with increasing age at diagnosis was observed. In contrast, the prevalence ratio to other HPV genotypes of α9 but HPV 16 genotypes (i.e., HPV 31, 33, 35, 52, 58, 67, ​P=0.002) increased with increasing age at diagnosis. CONCLUSION: No changes were observed in the relative contribution of HPV types in cervical cancer in Cali, Colombia during the 50 years. In this population, an HPV vaccine including the HPV 16, 18, 31, 33, 45, 52 and 58 genotypes may have the potential to prevent ∼85% and 93% of SCC and ADC cases respectively.

Work Outcome in Patients With Ankylosing Spondylitis: Results From a 12-Year Followup of an International Study.

OBJECTIVE: To understand the impact of ankylosing spondylitis (AS) on work disability (WD) over 12 years compared with the general population, and explore factors predicting adverse work outcome, defined as new partial WD or reduction in working hours. METHODS: Source of data was the Outcome Assessments in Ankylosing Spondylitis International Study, which includes patients from The Netherlands, France, and Belgium. Standardized WD rates over time compared to the general population were calculated using indirect standardization (Dutch patients only). Cox survival analyses identified baseline predictors as well as time-varying factors influencing adverse work outcome over 12 years. RESULTS: Of 215 patients, 55 (26%) were full WD at baseline and 139 (65%) were at risk for adverse work outcome during followup. When compared to the general population, WD over 12 years continued to be increased in Dutch men (incidence rate [IR] 2.9 [95% confidence interval (95% CI) 1.2, 4.6]), but less clearly for women (IR 1.2 [95% CI -0.4, 2.9]). Within the entire sample, baseline predictors of adverse work outcome over 12 years were residence in The Netherlands (versus France or Belgium) (hazard ratio [HR] 3.4 [95% CI 1.4, 8.4]) and worse Bath Ankylosing Spondylitis Functional Index (BASFI) (HR 1.2 [95% CI 1.0, 1.4]). Time-varying predictors over 12 years were residence in The Netherlands, uveitis, and either BASFI or Bath Ankylosing Spondylitis Disease Activity Index with age and inflammatory bowel disease. CONCLUSION: Although WD was already prevalent at inclusion in the cohort, a substantial proportion of patients incurred further adverse work outcome over 12 years. In addition to country of residence, uveitis, age, and self-reported physical function or disease activity predicted long-term adverse work outcome.

Efficacy of fewer than three doses of an HPV-16/18 AS04-adjuvanted vaccine: combined analysis of data from the Costa Rica Vaccine and PATRICIA Trials.

BACKGROUND: There is some evidence to suggest that one or two doses of the HPV vaccine provides similar protection to the three-dose regimen. The main aim of the study was to ascertain HPV-16/18 vaccine efficacy in both full and naive cohorts and to explore protection conferred against non-vaccine HPV types, by number of doses received. METHODS: Summary data from the Costa Rica Vaccine Trial (CVT; NCT00128661) and ~the PATRICIA trial (NCT001226810), two phase 3, double-blind, randomised controlled clinical trials of the HPV-16/18 AS04-adjuvanted vaccine in young women, were combined in a post-hoc analysis (GlaxoSmithKline [GSK] e-track number 202142) to investigate the efficacy of fewer than three doses of the HPV-16/18 vaccine after 4 years of follow-up. Women were randomly assigned to receive three doses of the HPV-16/18 vaccine or to a control vaccine; yet, some received fewer doses. After exclusion of women with less than 12 months of follow-up or those who were HPV-16/18 DNA-positive at enrolment (for the HPV-16/18 endpoint), we calculated vaccine efficacy against one-time detection of incident HPV infections after three, two, and one dose(s). The primary study endpoint was one-time detection of first incident HPV-16/18 infections accumulated during the follow-up phase. FINDINGS: We assessed vaccine efficacy against incident HPV-16/18 infection in the modified total vaccinated cohort (22 327 received three doses, 1185 two doses, 543 one dose). Vaccine efficacy against incident HPV-16/18 infections for three doses was 77·0% (95% CI 74·7-79·1), two doses was 76·0% (62·0-85·3), and one dose was 85·7% (70·7-93·7). Vaccine efficacy against incident HPV-31/33/45 infections for three doses was 59·7% (56·0-63·0), two doses was 37·7% (12·4-55·9), and one dose was 36·6% (-5·4 to 62·2). Vaccine efficacy against incident HPV-16/18 infection for two-dose women who received their second dose at 1 month was 75·3% (54·2-87·5) and 82·6% (42·3-96·1) for those who received the second dose at 6 months (CVT data only). Vaccine efficacy against HPV-31/33/45 for two-dose women who received their second dose at 6 months (68·1%, 27·0-87·0; CVT data only), but not those receiving it at one month (10·1%, -42·0 to 43·3), was similar to the three-dose group. INTERPRETATION: 4 years after vaccination of women aged 15-25 years, one and two doses of the HPV-16/18 vaccine seem to protect against cervical HPV-16/18 infections, similar to the protection provided by the three-dose schedule. Two doses separated by 6 months additionally provided some cross-protection. These data argue for a direct assessment of one-dose efficacy of the HPV-16/18 vaccine. FUNDING: US National Cancer Institute, National Institutes of Health Office of Research on Women's Health, and Ministry of Health of Costa Rica (CVT); GlaxoSmithKline Biologicals SA (PATRICIA).

Potential impact of a 9-valent HPV vaccine in HPV-related cervical disease in 4 emerging countries (Brazil, Mexico, India and China).

BACKGROUND: We estimated the potential impact of an investigational 9-valent human papillomavirus (HPV) vaccine (HPVs 6/11/16/18/31/33/45/52/58) in HPV-related cervical disease in Brazil, Mexico, India and China, to help to formulate recommendations on cervical cancer prevention and control. METHODS: Estimations for invasive cervical cancer (ICC) were based on an international study including 1356 HPV-positive cases for the four countries altogether, and estimations for precancerous cervical lesions were extracted from a published meta-analysis including 6 025 HPV-positive women from the four mentioned countries. Globocan 2012 and 2012 World Population Prospects were used to estimate current and future projections of new ICC cases. RESULTS: Combined proportions of the 9 HPV types in ICC were 88.6% (95%CI: 85.2-91.3) in Brazil, 85.7% (82.3-88.8) in Mexico, 92.2% (87.9-95.3) in India and 97.3% (93.9-99.1) in China. The additional HPV 31/33/45/52/58 proportions were 18.8% (15.3-22.7) in Brazil, 17.6% (14.2-21.2) in Mexico, 11.3% (7.5-16.1) in India and 11.9% (7.5-17.2) in China. HPV6 and 11 single types were not identified in any of the samples. Proportion of the individual 7 high risk HPV types included in the vaccine varied by cytological and histological grades of HPV-positive precancerous cervical lesions. HPV 16 was the dominant type in all lesions, with contributions in low grade lesions ranging from 16.6%(14.3-19.2) in Mexico to 39.8% (30.0-50.2) in India, and contributions in high grade lesions ranging from 43.8% (36.3-51.4) in Mexico to 64.1% (60.6-67.5) in Brazil. After HPV 16, variations in other majors HPV types were observed by country, with an under representation of HPV 18 and 45 compared to ICC. CONCLUSION: The addition of HPVs 31/33/45/52/58 to HPV types included in current vaccines could increase the ICC preventable fraction in a range of 12 to 19% across the four countries, accounting the 9-types altogether 90% of ICC cases. Assuming the same degree of efficacy of current vaccines, the implementation of the 9-valent HPV vaccine in Brazil, Mexico, India and China would substantially impact on the reduction of the world cervical cancer burden.

Evaluación de la adherencia a las recomendaciones para disminuir el riesgo de Síndrome de Muerte Súbita del lactante / Adherence to recommendations to reduce the risk of Sudden infant Death Syndrome

Introduction: Recommendations for Sudden Infant Death Syndrome (SIDS) are available, although it is uncertain the degree of adherence to these measures. The aim of the study is to assess the adherence to recommendations to reduce the risk of SIDS, seeking factors associated to the noncompliance with these recommendations. Patients and Method: 468 infants were enrolled in two maternity hospitals, one public and one private. Postpartum and 4-month assessments were performed. A questionnaire was used adapting a model validated by the International Child Care Practices Study. Results: Adherence to obstetric recommendations was higher (75.4%) than to pediatric recommendations (53.3%). Regarding pediatric recommendations, a compliance decrease was detected after 4 months. Follow-ups showed decrease in breastfeeding (p < 0.001 84.9% vs 48.6%) and supine position (61.2% vs 21.2%, p < 0.001). Conclusions: The decreased adherence to recommendations for SIDS prevention was mainly observed in younger and less educated women, who were not in a relationship and living in poor housing quality and crowded environments.

Introducción: Existen recomendaciones preventivas en el Sindrome de Muerte Súbita del lactante (SMSL), aunque es incierto el grado de adherencia a dichas medidas. El objetivo del estudio fue evaluar la adherencia a las recomendaciones para disminuir el riesgo de SMSL, buscando factores asociados al no cumplimiento de dichas recomendaciones. Pacientes y Método: Se incluyeron 468 recién nacidos de dos maternidades, pública y privada. Se efectuó una evaluación posparto y a los 4 meses de la adherencia a las recomendaciones. Se utilizó un cuestionario adaptando un modelo de encuesta validado por el International Child Care Practices Study Resultados: La adherencia a las recomendaciones obstétricas fue mayor (75,4%) que a las recomendaciones pediátricas (53,3%). A su vez en las recomendaciones pediátricas se evidenció una caída del cumplimiento de las recomendaciones a los 4 meses. Al seguimiento se observó reducción de lactancia (84,9% vs 48,6%; p < 0,001) y de posición supina (61,2% vs 21,2%; p < 0,001). Conclusiones: La disminución de la adherencia a las recomendaciones para la prevención del SMSL se observó principalmente en las mujeres de menor edad y menor nivel educativo, no estar en pareja, mala calidad habitacional y presencia de numerosos convivientes.

Time trends of human papillomavirus types in invasive cervical cancer, from 1940 to 2007.

Contribution over time of human papillomavirus (HPV) types in human cancers has been poorly documented. Such data is fundamental to measure current HPV vaccines impact in the years to come. We estimated the HPV type-specific distribution in a large international series of invasive cervical cancer (ICC) over 70 years prior to vaccination. Paraffin embedded ICC cases diagnosed between 1940 and 2007 were retrieved from eleven countries in Central-South America, Asia and Europe. Included countries reported to have low-medium cervical cancer screening uptake. Information on age at and year of diagnosis was collected from medical records. After histological confirmation, HPV DNA detection was performed by SPF-10/DEIA/LiPA25 (version1). Logistic regression models were used for estimating the adjusted relative contributions (RC) of HPV16 and of HPV18 over time. Among 4,771 HPV DNA positive ICC cases, HPV16 and HPV18 were the two most common HPVs in all the decades with no statistically significant variations of their adjusted-RC from 1940-59 to 2000-07 (HPV16-from 61.5 to 62.1%, and HPV18-from 6.9 to 7.2%). As well, the RC of other HPV types did not varied over time. In the stratified analysis by histology, HPV16 adjusted-RC significantly increased across decades in adenocarcinomas. Regarding age, cases associated to either HPV16, 18 or 45 were younger than those with other HPV types in all the evaluated decades. The observed stability on the HPV type distribution predicts a high and stable impact of HPV vaccination in reducing the cervical cancer burden in future vaccinated generations.

[Adherence to recommendations to reduce the risk of Sudden infant Death Syndrome]. / Evaluación de la adherencia a las recomendaciones para disminuir el riesgo de Síndrome de Muerte Súbita del lactante.

INTRODUCTION: Recommendations for Sudden Infant Death Syndrome (SIDS) are available, although it is uncertain the degree of adherence to these measures. The aim of the study is to assess the adherence to recommendations to reduce the risk of SIDS, seeking factors associated to the noncompliance with these recommendations. PATIENTS AND METHOD: 468 infants were enrolled in two maternity hospitals, one public and one private. Postpartum and 4-month assessments were performed. A questionnaire was used adapting a model validated by the International Child Care Practices Study. RESULTS: Adherence to obstetric recommendations was higher (75.4%) than to pediatric recommendations (53.3%). Regarding pediatric recommendations, a compliance decrease was detected after 4 months. Follow-ups showed decrease in breastfeeding (p < 0.001 84.9% vs 48.6%) and supine position (61.2% vs 21.2%, p < 0.001). CONCLUSIONS: The decreased adherence to recommendations for SIDS prevention was mainly observed in younger and less educated women, who were not in a relationship and living in poor housing quality and crowded environments.

Male circumcision and prevalence of genital human papillomavirus infection in men: a multinational study.

BACKGROUND: Accumulated evidence from epidemiological studies and more recently from randomized controlled trials suggests that male circumcision (MC) may substantially protect against genital HPV infection in men. The purpose of this study was to assess the association between MC and genital HPV infection in men in a large multinational study. METHODS: A total of 4072 healthy men ages 18-70 years were enrolled in a study conducted in Brazil, Mexico, and the United States. Enrollment samples combining exfoliated cells from the coronal sulcus, glans penis, shaft, and scrotum were analyzed for the presence and genotyping of HPV DNA by PCR and linear array methods. Prevalence ratios (PR) were used to estimate associations between MC and HPV detection adjusting for potential confounders. RESULTS: MC was not associated with overall prevalence of any HPV, oncogenic HPV types or unclassified HPV types. However, MC was negatively associated with non-oncogenic HPV infections (PR 0.85, 95% confident interval: 0.76-0.95), in particular for HPV types 11, 40, 61, 71, and 81. HPV 16, 51, 62, and 84 were the most frequently identified genotypes regardless of MC status. CONCLUSIONS: This study shows no overall association between MC and genital HPV infections in men, except for certain non-oncogenic HPV types for which a weak association was found. However, the lack of association with MC might be due to the lack of anatomic site specific HPV data, for example the glans penis, the area expected to be most likely protected by MC.

Epidemiologic profile, sexual history, pathologic features, and human papillomavirus status of 103 patients with penile carcinoma.

PURPOSE: The incidence of penile cancer is four times higher in Paraguay than in the United States or Europe. There are no adequate scientific explanations for this geographical variation. The goal of this study was to evaluate the interplay among risk factors, morphology of the primary tumor, and HPV status. METHODS: Information on socioeconomic status, education level, habits, and sexual history was obtained in 103 Paraguayan patients with penile cancer. All patients were then treated by surgery, and specimens were evaluated histopathologically. RESULTS: Patients usually dwelled in rural/suburban areas (82%), lived in poverty (75%), had a low education level (91%), and were heavy smokers (76%). Phimosis (57%), moderate/poor hygienic habits (90%), and history of sexually transmitted diseases (74%) were frequently found. Patients with >10 lifetime female partners had an odds ratio of 3.8 (95% CI 1.1, 12.6; P-trend = .03) for presenting HPV-positive tumors when compared to patients with <6 partners. However, this trend was not significant when the number of sexual partners was adjusted for age of first coitus and antecedents of sexually transmitted diseases. HPV-related tumors (found in 36% of the samples) were characterized by a warty and/or basaloid morphology and high histological grade in most cases. CONCLUSIONS: In our series, patients with penile cancer presented a distinctive epidemiologic and pathologic profile. These data might help explaining the geographical differences in incidence and aid in the design of strategies for cancer control in Paraguay.

Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial.

BACKGROUND: Cervical intraepithelial neoplasia grade 2 or greater (CIN2+) is the surrogate endpoint used in licensure trials of human papillomavirus (HPV) vaccines. Vaccine efficacy against CIN3+, the immediate precursor to invasive cervical cancer, is more difficult to measure because of its lower incidence, but provides the most stringent evidence of potential cancer prevention. We report vaccine efficacy against CIN3+ and adenocarcinoma in situ (AIS) in the end-of-study analysis of PATRICIA (PApilloma TRIal against Cancer In young Adults). METHODS: Healthy women aged 15-25 years with no more than six lifetime sexual partners were included in PATRICIA, irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to receive an HPV-16/18 AS04-adjuvanted vaccine or a control hepatitis A vaccine via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The patients and study investigators were masked to allocated vaccine. The primary endpoint of PATRICIA has been reported previously. In the present end-of-study analysis, we focus on CIN3+ and AIS in the populations of most clinical interest, the total vaccinated cohort (TVC) and the TVC-naive. The TVC comprised all women who received at least one vaccine dose, approximating catch-up populations and including sexually active women (vaccine n=9319; control=9325). The TVC-naive comprised women with no evidence of oncogenic HPV infection at baseline, approximating early adolescent HPV exposure (vaccine n=5824; control=5820). This study is registered with ClinicalTrials.gov, number NCT00122681. FINDINGS: Vaccine efficacy against CIN3+ associated with HPV-16/18 was 100% (95% CI 85·5-100) in the TVC-naive and 45·7% (22·9-62·2) in the TVC. Vaccine efficacy against all CIN3+ (irrespective of HPV type in the lesion and including lesions with no HPV DNA detected) was 93·2% (78·9-98·7) in the TVC-naive and 45·6% (28·8-58·7) in the TVC. In the TVC-naive, vaccine efficacy against all CIN3+ was higher than 90% in all age groups. In the TVC, vaccine efficacy against all CIN3+ and CIN3+ associated with HPV-16/18 was highest in the 15-17 year age group and progressively decreased in the 18-20 year and 21-25 year age groups. Vaccine efficacy against all AIS was 100% (31·0-100) and 76·9% (16·0-95·8) in the TVC-naive and TVC, respectively. Serious adverse events occurred in 835 (9·0%) and 829 (8·9%) women in the vaccine and control groups, respectively; only ten events (0·1%) and five events (0·1%), respectively, were considered to be related to vaccination. INTERPRETATION: PATRICIA end-of-study results show excellent vaccine efficacy against CIN3+ and AIS irrespective of HPV DNA in the lesion. Population-based vaccination that incorporates the HPV-16/18 vaccine and high coverage of early adolescents might have the potential to substantially reduce the incidence of cervical cancer. FUNDING: GlaxoSmithKline Biologicals.

Cross-protective efficacy of HPV-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by non-vaccine oncogenic HPV types: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial.

BACKGROUND: We evaluated the efficacy of the human papillomavirus HPV-16/18 AS04-adjuvanted vaccine against non-vaccine oncogenic HPV types in the end-of-study analysis after 4 years of follow-up in PATRICIA (PApilloma TRIal against Cancer In young Adults). METHODS: Healthy women aged 15-25 years with no more than six lifetime sexual partners were included in PATRICIA irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to HPV-16/18 vaccine or a control hepatitis A vaccine, via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The study was double-blind. The primary endpoint of PATRICIA has been reported previously; the present analysis evaluates cross-protective vaccine efficacy against non-vaccine oncogenic HPV types in the end-of-study analysis. Analyses were done for three cohorts: the according-to-protocol cohort for efficacy (ATP-E; vaccine n=8067, control n=8047), total vaccinated HPV-naive cohort (TVC-naive; no evidence of infection with 14 oncogenic HPV types at baseline, approximating young adolescents before sexual debut; vaccine n=5824, control n=5820), and the total vaccinated cohort (TVC; all women who received at least one vaccine dose, approximating catch-up populations that include sexually active women; vaccine n=9319, control=9325). Vaccine efficacy was evaluated against 6-month persistent infection, cervical intraepithelial neoplasia grade 2 or greater (CIN2+) associated with 12 non-vaccine HPV types (individually or as composite endpoints), and CIN3+ associated with the composite of 12 non-vaccine HPV types. This study is registered with ClinicalTrials.gov, number NCT00122681. FINDINGS: Consistent vaccine efficacy against persistent infection and CIN2+ (with or without HPV-16/18 co-infection) was seen across cohorts for HPV-33, HPV-31, HPV-45, and HPV-51. In the most conservative analysis of vaccine efficacy against CIN2+, where all cases co-infected with HPV-16/18 were removed, vaccine efficacy was noted for HPV-33 in all cohorts, and for HPV-31 in the ATP-E and TVC-naive. Vaccine efficacy against CIN2+ associated with the composite of 12 non-vaccine HPV types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), with or without HPV-16/18 co-infection, was 46·8% (95% CI 30·7-59·4) in the ATP-E, 56·2% (37·2-69·9) in the TVC-naive, and 34·2% (20·4-45·8) in the TVC. Corresponding values for CIN3+ were 73·8% (48·3-87·9), 91·4% (65·0-99·0), and 47·5% (22·8-64·8). INTERPRETATION: Data from the end-of-study analysis of PATRICIA show cross-protective efficacy of the HPV-16/18 vaccine against four oncogenic non-vaccine HPV types-HPV-33, HPV-31, HPV-45, and HPV-51-in different trial cohorts representing diverse groups of women. FUNDING: GlaxoSmithKline Biologicals.