RESUMEN
The association between an increased uptake of isoflavones and a reduced frequency of menopausal hot flushes was first described in 1992, based on a lower incidence of hot flushes in countries with a high consumption of soy. Since then, numerous clinical trials with various sources of isoflavones including soy and red clover have been presented, with practically all of the studies with adequate design delivering an outcome in favour of isoflavone supplementation. An in-depth risk assessment (EFSA 2015) concludes that the amply available human data does not indicate any suspected harmful effects from a potential interaction of isoflavones with hormone-sensitive tissues in the mammary gland, the uterus and the thyroid gland. Safety was ascertained with long-term intake of up to 150 mg isoflavones per day ingested for the duration of at least 3 years. Moreover, high isoflavone intake was found to have preventive effects with respect to breast cancer. Clinical findings indicate potential benefits of isoflavone exposure even during breast cancer treatment with tamoxifen or anastrozole.
Asunto(s)
Neoplasias de la Mama/prevención & control , Consenso , Glycine max , Sofocos/prevención & control , Isoflavonas/farmacología , Menopausia/efectos de los fármacos , Femenino , Humanos , Isoflavonas/administración & dosificación , Persona de Mediana EdadRESUMEN
OBJECTIVE: To evaluate the association between five interleukin-1 (IL-1) and -6 gene polymorphisms and risk of high grade cervical intraepithelial neoplasia (CIN 2-3). METHODS: This case-control study investigates five common IL-1 and IL-6 gene polymorphisms in 131 women with CIN 2-3 and 209 controls by pyrosequencing and polymerase chain reaction. Associations between gene polymorphisms and risk of CIN 2-3 are analysed by univariate and multivariable models. Their combined effect on the risk of CIN is evaluated by haplotype analysis. RESULTS: In a multivariable regression model IL1A -889 (odds ratio 0.3 [95% confidence interval 0.1-0.8], p=0.01) and smoking (4.0 [1.7-9.1], p=0.001) are independently associated with the risk of high grade CIN. Haplotype analysis does not reveal any high-risk combinations for the susceptibility of CIN. CONCLUSION: The single nucleotide polymorphism IL1A -889 is independently associated with risk of high grade CIN.
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Interleucina-1/genética , Interleucina-6/genética , Displasia del Cuello del Útero/genética , Neoplasias del Cuello Uterino/genética , Adulto , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Variación Genética , Haplotipos , Humanos , Polimorfismo de Nucleótido Simple , Neoplasias del Cuello Uterino/inmunología , Displasia del Cuello del Útero/inmunologíaRESUMEN
BACKGROUND: We describe transition probabilities for incident human papillomavirus (HPV) 16/18/31/33/35/45/52/58/59 infections and cervical intraepithelial neoplasia (CIN) 1 lesions. METHODS: Women ages 16 to 23 years underwent cytology and cervical swab PCR testing for HPV at approximately 6-month intervals for up to 4 years in the placebo arm of an HPV vaccine trial. The cumulative proportion of incident HPV infections with diagnosed CIN, clearing (infection undetectable), or persisting without CIN, were estimated. RESULTS: Most incident infections cleared, without detection of CIN, ranging at 36 months from 66.9% for HPV31 to 91.1% for HPV59. There was little variation in the 36-month proportion of incident HPV16, 18, and 31 infections followed by a CIN1 lesion positive for the relevant HPV type (range 16.7%-18.6%), with lower risks for HPV59 (6.4%) and HPV33 (2.9%). Thirty-six-month transition probabilities for CIN2 ranged across types from 2.2% to 9.1%; however, the number of events was generally too small for statistically significant differences to be seen across types for this endpoint, or CIN3. CONCLUSIONS: Some incident HPV types appear more likely to result in diagnosed CIN1 than others. The relative predominance of HPV16, vis-à-vis some other high-risk HPV types (e.g., HPV33) in prevalent CIN2/3, appears more directly associated with relatively greater frequency of incident HPV16 infections within the population, than a higher risk of infection progression to CIN2/3. IMPACT: Nearly all incident HPV infections either manifest as detectable CIN or become undetectable within 36 months. Some HPV types (e.g., 16 and 33) appear to have similar risk of CIN2/3 despite widely varied incidence.
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Cuello del Útero/virología , Papillomaviridae/patogenicidad , Infecciones por Papillomavirus/epidemiología , Displasia del Cuello del Útero/epidemiología , Neoplasias del Cuello Uterino/epidemiología , Adolescente , Adulto , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Agencias Internacionales , Infecciones por Papillomavirus/virología , Vacunas contra Papillomavirus/uso terapéutico , Placebos , Prevalencia , Pronóstico , Factores de Riesgo , Tasa de Supervivencia , Neoplasias del Cuello Uterino/virología , Adulto Joven , Displasia del Cuello del Útero/virologíaRESUMEN
OBJECTIVES: To evaluate the prophylactic efficacy of the human papillomavirus (HPV) quadrivalent vaccine in preventing low grade cervical, vulvar, and vaginal intraepithelial neoplasias and anogenital warts (condyloma acuminata). DESIGN: Data from two international, double blind, placebo controlled, randomised efficacy trials of quadrivalent HPV vaccine (protocol 013 (FUTURE I) and protocol 015 (FUTURE II)). The trials were to be 4 years in length, and the results reported are from final study data of 42 months' follow-up. SETTING: Primary care centres and university or hospital associated health centres in 24 countries and territories around the world. PARTICIPANTS: 17 622 women aged 16-26 years enrolled between December 2001 and May 2003. Major exclusion criteria were lifetime number of sexual partners (>4), history of abnormal cervical smear test results, and pregnancy. INTERVENTION: Three doses of quadrivalent HPV vaccine (for serotypes 6, 11, 16, and 18) or placebo at day 1, month 2, and month 6. MAIN OUTCOME MEASURES: Vaccine efficacy against cervical, vulvar, and vaginal intraepithelial neoplasia grade I and condyloma in a per protocol susceptible population that included subjects who received all three vaccine doses, tested negative for the relevant vaccine HPV types at day 1 and remained negative through month 7, and had no major protocol violations. Intention to treat, generally HPV naive, and unrestricted susceptible populations were also studied. RESULTS: In the per protocol susceptible population, vaccine efficacy against lesions related to the HPV types in the vaccine was 96% for cervical intraepithelial neoplasia grade I (95% confidence interval 91% to 98%), 100% for both vulvar and vaginal intraepithelial neoplasia grade I (95% CIs 74% to 100%, 64% to 100% respectively), and 99% for condyloma (96% to 100%). Vaccine efficacy against any lesion (regardless of HPV type) in the generally naive population was 30% (17% to 41%), 75% (22% to 94%), and 48% (10% to 71%) for cervical, vulvar, and vaginal intraepithelial neoplasia grade I, respectively, and 83% (74% to 89%) for condyloma. CONCLUSIONS: Quadrivalent HPV vaccine provided sustained protection against low grade lesions attributable to vaccine HPV types (6, 11, 16, and 18) and a substantial reduction in the burden of these diseases through 42 months of follow-up. TRIAL REGISTRATIONS: NCT00092521 and NCT00092534.
Asunto(s)
Vacunas contra el Cáncer , Carcinoma in Situ/prevención & control , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus , Neoplasias Urogenitales/prevención & control , Displasia del Cuello del Útero/prevención & control , Adolescente , Adulto , Condiloma Acuminado/prevención & control , Método Doble Ciego , Femenino , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18 , Humanos , Resultado del Tratamiento , Neoplasias del Cuello Uterino/prevención & control , Neoplasias Vaginales/prevención & control , Neoplasias de la Vulva/prevención & control , Adulto JovenRESUMEN
BACKGROUND: We describe the incidence and duration of cervical human papillomavirus (HPV) infection episodes along with the risk of infection reappearance following a period of nondetection. METHODS: Women (1,788) ages 16 to 23 years underwent cytologic testing and PCR-based testing of cervical swab samples for HPV DNA (HPV-16/18/31/33/35/45/52/58/59) at approximately 6-month intervals for up to 4 years in the context of a phase 3 clinical trial (placebo arm). HPV type-specific incidence rates were estimated per 100 person-years. Duration of type-specific cervical infection episodes and risk of reappearance following a period of nondetection were estimated using Kaplan-Meier methods. RESULTS: HPV-16 exhibited the highest (5.9), and HPV-35 and HPV-33 exhibited the lowest (1.0) incidence rates per 100 person-years. Mean cervical infection durations ranged from 13 months for HPV-59 to 20 months for HPV-16 and 58 (with ongoing infections censored at the time of treatment, if done). The risk of cervical infection reappearance within approximately 3 years following a period of nondetection ranged from 0% to 16% across HPV types, with a mean of 8%. Limited evidence was found for a role of false-positive HPV tests, missed infections that were above the threshold for detection, or new acquisition of infection in accounting for patterns of infection reappearance. CONCLUSIONS: Incidence of high-risk cervical infection was observed to vary considerably more across HPV types than infection duration. A nontrivial proportion of women exhibited infection reappearance following a period of nondetection, with a potential explanation for many such events observed within this analysis being a return to detectable levels of a previously acquired infection. IMPACT: The risk of HPV infection reappearance following a period of nondetection has not been previously reported for individual HPV types, and this study finds that a nontrivial proportion of infected women exhibit reappearances. Future studies could ascertain subject-level factors that potentially modify the risk of infection reappearance.
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Infecciones por Papillomavirus/epidemiología , Enfermedades del Cuello del Útero/epidemiología , Enfermedades del Cuello del Útero/virología , Adolescente , Ensayos Clínicos Fase III como Asunto , ADN Viral/análisis , Método Doble Ciego , Femenino , Humanos , Incidencia , Papillomaviridae/genética , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/prevención & control , Infecciones por Papillomavirus/virología , Reacción en Cadena de la Polimerasa , Prevalencia , Ensayos Clínicos Controlados Aleatorios como Asunto , Adulto JovenRESUMEN
BACKGROUND: The impact of the prophylactic vaccine against human papillomavirus (HPV) types 6, 11, 16, and 18 (HPV6/11/16/18) on all HPV-associated genital disease was investigated in a population that approximates sexually naive women in that they were "negative to 14 HPV types" and in a mixed population of HPV-exposed and -unexposed women (intention-to-treat group). METHODS: This analysis studied 17 622 women aged 15-26 years who were enrolled in one of two randomized, placebo-controlled, efficacy trials for the HPV6/11/16/18 vaccine (first patient on December 28, 2001, and studies completed July 31, 2007). Vaccine or placebo was given at day 1, month 2, and month 6. All women underwent cervicovaginal sampling and Papanicolaou (Pap) testing at day 1 and every 6-12 months thereafter. Outcomes were any cervical intraepithelial neoplasia; any external anogenital and vaginal lesions; Pap test abnormalities; and procedures such as colposcopy and definitive therapy. Absolute rates are expressed as women with endpoint per 100 person-years at risk. RESULTS: The average follow-up was 3.6 years (maximum of 4.9 years). In the population that was negative to 14 HPV types, vaccination was up to 100% effective in reducing the risk of HPV16/18-related high-grade cervical, vulvar, and vaginal lesions and of HPV6/11-related genital warts. In the intention-to-treat group, vaccination also statistically significantly reduced the risk of any high-grade cervical lesions (19.0% reduction; rate vaccine = 1.43, rate placebo = 1.76, difference = 0.33, 95% confidence interval [CI] = 0.13 to 0.54), vulvar and vaginal lesions (50.7% reduction; rate vaccine = 0.10, rate placebo = 0.20, difference = 0.10, 95% CI = 0.04 to 0.16), genital warts (62.0% reduction; rate vaccine = 0.44, rate placebo = 1.17, difference = 0.72, 95% CI = 0.58 to 0.87), Pap abnormalities (11.3% reduction; rate vaccine = 10.36, rate placebo = 11.68, difference = 1.32, 95% CI = 0.74 to 1.90), and cervical definitive therapy (23.0% reduction; rate vaccine = 1.97, rate placebo = 2.56, difference = 0.59, 95% CI = 0.35 to 0.83), irrespective of causal HPV type. CONCLUSIONS: High-coverage HPV vaccination programs among adolescents and young women may result in a rapid reduction of genital warts, cervical cytological abnormalities, and diagnostic and therapeutic procedures. In the longer term, substantial reductions in the rates of cervical, vulvar, and vaginal cancers may follow.
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Alphapapillomavirus/inmunología , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/administración & dosificación , Vacunas contra Papillomavirus/farmacología , Enfermedades de Transmisión Sexual/prevención & control , Infecciones Tumorales por Virus/prevención & control , Displasia del Cuello del Útero/prevención & control , Neoplasias del Cuello Uterino/prevención & control , Adolescente , Adulto , Femenino , Enfermedades de los Genitales Femeninos/prevención & control , Enfermedades de los Genitales Femeninos/virología , Salud Global , Papillomavirus Humano 11/inmunología , Papillomavirus Humano 16/inmunología , Papillomavirus Humano 18/inmunología , Papillomavirus Humano 6/inmunología , Humanos , Estimación de Kaplan-Meier , Prueba de Papanicolaou , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/virología , Parejas Sexuales , Enfermedades de Transmisión Sexual/epidemiología , Enfermedades de Transmisión Sexual/virología , Infecciones Tumorales por Virus/complicaciones , Infecciones Tumorales por Virus/epidemiología , Infecciones Tumorales por Virus/virología , Neoplasias del Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/virología , Frotis Vaginal , Adulto Joven , Displasia del Cuello del Útero/epidemiología , Displasia del Cuello del Útero/virologíaRESUMEN
OBJECTIVE: In the quadrivalent (types 6/11/16/18) HPV vaccine (GARDASIL/SILGARD) clinical program, 73% of women aged 16-26 were naïve to all vaccine HPV types. In these women, prophylactic administration of the vaccine was highly effective in preventing HPV 6/11/16/18-related cervical disease. Of the remaining women, 15% of had evidence of past infection with one or more vaccine HPV types (seropositive and DNA negative) at the time of enrollment. Here we present an analysis in this group of women to determine the efficacy of the HPV 6/11/16/18 vaccine against new cervical and external anogenital disease related to the same vaccine HPV type which had previously been cleared. Vaccine tolerability in this previously infected population was also assessed. METHODS: 18,174 women were enrolled into 3 clinical studies. The data presented comprise a subset of these subjects (n = 2,617) who were HPV seropositive and DNA negative at enrollment (for >or=1 vaccine type). In each study, subjects were randomized in a 1:1 ratio to receive HPV 6/11/16/18 vaccine or placebo at day 1, month 2 and month 6 (without knowledge of baseline HPV status). Procedures performed for efficacy data evaluation included detailed genital examination, Pap testing, and collection of cervicovaginal and external genital specimens. Analyses of efficacy were carried out in a population stratified by HPV serology and HPV DNA status at enrollment. RESULTS: Subjects were followed for an average of 40 months. Seven subjects in the placebo group developed cervical disease, and eight subjects developed external genital disease related to a vaccine HPV type they had previously encountered. No subject receiving HPV 6/11/16/18 vaccine developed disease to a vaccine HPV type to which they were seropositive and DNA negative at enrolment. CONCLUSIONS: These results suggest that natural HPV infection-elicited antibodies may not provide complete protection over time, however the immune response to the HPV 6/11/16/18 vaccine appears to prevent reinfection or reactivation of disease with vaccine HPV types. Vaccine-related adverse experiences were higher among subjects receiving vaccine, mostly due to increased injection site adverse experiences.
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Cuello del Útero/virología , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/inmunología , Vulva/virología , Adolescente , Adulto , Anticuerpos Antivirales/sangre , Cuello del Útero/citología , Cuello del Útero/patología , Femenino , Estudios de Seguimiento , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18 , Humanos , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/virología , Vacunas contra Papillomavirus/efectos adversos , Placebos/administración & dosificación , Vulva/patología , Adulto JovenRESUMEN
Quadrivalent human papillomavirus (HPV) vaccine has been shown to provide protection from HPV 6/11/16/18-related cervical, vaginal, and vulvar disease through 3 years. We provide an update on the efficacy of the quadrivalent HPV vaccine against high-grade cervical, vaginal, and vulvar lesions based on end-of-study data from three clinical trials. Additionally, we stratify vaccine efficacy by several baseline characteristics, including age, smoking status, and Papanicolaou (Pap) test results. A total of 18,174 females ages 16 to 26 years were randomized and allocated into one of three clinical trials (protocols 007, 013, and 015). Vaccine or placebo was given at baseline, month 2, and month 6. Pap testing was conducted at regular intervals. Cervical and anogenital swabs were collected for HPV DNA testing. Examination for the presence of vulvar and vaginal lesions was also done. Endpoints included high-grade cervical, vulvar, or vaginal lesions (CIN 2/3, VIN 2/3, or VaIN 2/3). Mean follow-up time was 42 months post dose 1. Vaccine efficacy against HPV 6/11/16/18-related high-grade cervical lesions in the per-protocol and intention-to-treat populations was 98.2% [95% confidence interval (95% CI), 93.3-99.8] and 51.5% (95% CI, 40.6-60.6), respectively. Vaccine efficacy against HPV 6/11/16/18-related high-grade vulvar and vaginal lesions in the per-protocol and intention-to-treat populations was 100.0% (95% CI, 82.6-100.0) and 79.0% (95% CI, 56.4-91.0), respectively. Efficacy in the intention-to-treat population tended to be lower in older women, women with more partners, and women with abnormal Pap test results. The efficacy of quadrivalent HPV vaccine against high-grade cervical and external anogenital neoplasia remains high through 42 months post vaccination.
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Vacunas contra el Cáncer/uso terapéutico , Vacunas contra Papillomavirus/uso terapéutico , Displasia del Cuello del Útero/prevención & control , Neoplasias del Cuello Uterino/prevención & control , Neoplasias del Cuello Uterino/virología , Adolescente , Adulto , Ensayos Clínicos Fase III como Asunto , Femenino , Enfermedades de los Genitales Femeninos/prevención & control , Enfermedades de los Genitales Femeninos/virología , Papillomavirus Humano 11 , Papillomavirus Humano 16 , Papillomavirus Humano 18 , Papillomavirus Humano 6 , Humanos , Estudios Multicéntricos como Asunto , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/prevención & control , Infecciones por Papillomavirus/virología , Ensayos Clínicos Controlados Aleatorios como Asunto , Adulto Joven , Displasia del Cuello del Útero/virologíaRESUMEN
OBJECTIVE: The Austrian Association for Gynecologic Oncology initiated in 1998 a prospective quality assurance program for patients with ovarian cancer. The aim of this study was to evaluate factors predicting overall survival especially under consideration of department volume. METHODS: All Austrian gynecological departments were invited to participate in the quality assurance program. A questionnaire was sent out that included birth date, histology, date of diagnosis, stage, and basic information on primary treatment. Description of comorbidity was not requested. Patient life status was assessed in a passive way. We did record linkage between each patient's name and birth date and the official mortality data set collected by Statistics Austria. No data were available on progression-free survival. Patients treated between January 1, 1999 and December 31, 2004 were included in the analysis. Mortality dates were available to December 31, 2006. Data were analyzed by means of classical statistical methods. Cut-off point for departments was 24 patients per year. RESULTS: A total of 1948 patients were evaluable. Approximately 75% of them were treated at institutions with fewer than 24 new patients per year. Patient characteristics were grossly similar for both department types. Multivariate analysis confirmed established prognostic factors such as International Federation of Gynecologists and Obstetricians (FIGO) stage, lymphadenectomy, age, grading, and residual disease. In addition, we found small departments (<24 patients per year) to have a negative effect on overall survival (hazards ratio, 1.38: 95% confidence interval, 1.2-1.7; and P < 0.001). CONCLUSIONS: The results indicate that in Austria, rules prescribing minimum department case load can further improve survival for patients with ovarian cancer.
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Ginecología/estadística & datos numéricos , Neoplasias Ováricas/mortalidad , Garantía de la Calidad de Atención de Salud/estadística & datos numéricos , Austria/epidemiología , Femenino , HumanosRESUMEN
BACKGROUND: We evaluated the impact of a quadrivalent human papillomavirus (HPV) vaccine on infection and cervical disease related to 10 nonvaccine HPV types (31, 33, 35, 39, 45, 51, 52, 56, 58, and 59) associated with >20% of cervical cancers. The population evaluated included HPV-naive women and women with preexisting HPV infection and/or HPV-related disease at enrollment. METHODS: Phase 3 efficacy studies enrolled 17,622 women aged 16-26 years. Subjects underwent cervicovaginal sampling and Pap testing on day 1 and then at 6-12-month intervals for up to 4 years. HPV typing was performed on samples from enrollment and follow-up visits, including samples obtained for diagnosis or treatment of HPV-related disease. All subjects who received 1 dose and returned for follow-up were included. RESULTS: Vaccination reduced the rate of HPV-31/33/45/52/58 infection by 17.7% (95% confidence interval [CI], 5.1% to 28.7%) and of cervical intraepithelial neoplasia (CIN) 1-3 or adenocarcinoma in situ (AIS) by 18.8% (95% CI, 7.4% to 28.9%). Vaccination also reduced the rate of HPV-31/58/59-related CIN1-3/AIS by 26.0% (95% CI, 6.7% to 41.4%), 28.1% (95% CI, 5.3% to 45.6%), and 37.6% (95% CI, 6.0% to 59.1%), respectively. Although a modest reduction in HPV-31/33/45/52/58-related CIN2 or worse was observed, the estimated reduction was not statistically significant. CONCLUSIONS: These cross-protection results complement the vaccine's prophylactic efficacy against disease associated with HPV-6, -11, -16, and -18. Long-term monitoring of vaccinated populations are needed to fully ascertain the population-based impact and public health significance of these findings. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00092521 , NCT00092534 , and NCT00092482.
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Alphapapillomavirus/inmunología , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus , Neoplasias del Cuello Uterino/prevención & control , Adenocarcinoma/prevención & control , Adenocarcinoma/virología , Adolescente , Adulto , Alphapapillomavirus/clasificación , Alphapapillomavirus/genética , Femenino , Humanos , Infecciones por Papillomavirus/virología , Neoplasias del Cuello Uterino/virología , Adulto Joven , Displasia del Cuello del Útero/prevención & control , Displasia del Cuello del Útero/virologíaRESUMEN
BACKGROUND: Human papillomavirus (HPV)-6/11/16/18 vaccine reduces the risk of HPV-6/11/16/18-related cervical intraepithelial neoplasia (CIN) 1-3 or adenocarcinoma in situ (AIS). Here, its impact on CIN1-3/AIS associated with nonvaccine oncogenic HPV types was evaluated. METHODS: We enrolled 17,622 women aged 16-26 years. All underwent cervicovaginal sampling and Pap testing at regular intervals for up to 4 years. HPV genotyping was performed for biopsy samples, and histological diagnoses were determined by a pathology panel. Analyses were conducted among subjects who were negative for 14 HPV types on day 1. Prespecified analyses included infection of 6 months' duration and CIN1-3/AIS due to the 2 and 5 most common HPV types in cervical cancer after HPV types 16 and 18, as well as all tested nonvaccine types. RESULTS: Vaccination reduced the incidence of HPV-31/45 infection by 40.3% (95% confidence interval [CI], 13.9% to 59.0%) and of CIN1-3/AIS by 43.6% (95% CI, 12.9% to 64.1%), respectively. The reduction in HPV-31/33/45/52/58 infection and CIN1-3/AIS was 25.0% (95% CI, 5.0% to 40.9%) and 29.2% (95% CI, 8.3% to 45.5%), respectively. Efficacy for CIN2-3/AIS associated with the 10 nonvaccine HPV types was 32.5% (95% CI, 6.0% to 51.9%). Reductions were most notable for HPV-31. CONCLUSIONS: HPV-6/11/16/18 vaccine reduced the risk of CIN2-3/AIS associated with nonvaccine types responsible for approximately 20% of cervical cancers. The clinical benefit of cross-protection is not expected to be fully additive to the efficacy already observed against HPV-6/11/16/18-related disease, because women may have >1 CIN lesion, each associated with a different HPV type. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00092521 , NCT00092534 , and NCT00092482.
Asunto(s)
Alphapapillomavirus/inmunología , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus , Adolescente , Adulto , Alphapapillomavirus/clasificación , Alphapapillomavirus/genética , Femenino , Humanos , Infecciones por Papillomavirus/virología , Neoplasias del Cuello Uterino/prevención & control , Neoplasias del Cuello Uterino/virología , Adulto JovenRESUMEN
The efficacy of the quadrivalent Human Papillomavirus (HPV) vaccine is thought to be mediated by humoral immunity. We evaluated the correlation between quadrivalent HPV vaccine-induced serum anti-HPV responses and efficacy. 17,622 women were vaccinated at day 1, and months 2 and 6. At day 1 and at 6-12 months intervals for up to 48 months, subjects underwent Papanicolaou and genital HPV testing. No immune correlate of protection could be found due to low number of cases. Although 40% of vaccine subjects were anti-HPV 18 seronegative at end-of-study, efficacy against HPV 18-related disease remained high (98.4%; 95% CI: 90.5-100.0) despite high attack rates in the placebo group. These results suggest vaccine-induced protection via immune memory, or lower than detectable HPV 18 antibody titers.
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Anticuerpos Antivirales/biosíntesis , Anticuerpos Antivirales/inmunología , Infecciones por Papillomavirus/inmunología , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/inmunología , Adolescente , Anticuerpos Antivirales/análisis , Condiloma Acuminado/epidemiología , Condiloma Acuminado/inmunología , Condiloma Acuminado/prevención & control , Femenino , Estudios de Seguimiento , Papillomavirus Humano 11/inmunología , Papillomavirus Humano 16/inmunología , Papillomavirus Humano 18/inmunología , Papillomavirus Humano 6/inmunología , Humanos , Esquemas de Inmunización , Prueba de Papanicolaou , Infecciones por Papillomavirus/patología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Vagina/patología , Frotis Vaginal , Vulva/patología , Adulto JovenRESUMEN
INTRODUCTION: Cervical cancer is the second most common cancer among women worldwide. In the absence of changing risk or intervention, it is projected that in comparison with 2002 there will be a 40% increase in the number of new cases of cervical cancer by 2020. HPV types 16 and 18 cause 70% of cervical cancers worldwide, 50% of high-grade cervical intraepithelial neoplasias and 25% of low-grade neoplasias. HPV types 6 and 11 are the causative agent of > 90% of genital warts. The aim of this study was to assess the baseline prevalence of infection with HPV 6, 11, 16 and 18 in young Austrian women. METHODS: Austrian females aged 16-24 (n = 123) were enrolled in a double-blind, placebo-controlled, randomized phase III trial of a quadrivalent HPV (types 6, 11, 16, 18) vaccine (FUTURE I, ClinicalTrials.gov number NCT00092521). Healthy women who were not pregnant and had no prior history of genital warts or abnormal results on cervical cytologic testing and had fewer than five lifetime sex partners were eligible for enrollment. The study sub-population was recruited primarily from university settings. RESULTS: Analysis of the sexual history of the Austrian subjects showed that 92.7% (114/123) were non-virgins and 46.3% were current smokers. At enrollment, 15 (13.5%) had positive serological or PCR tests for HPV 6, 11, 16 or 18. Serologically, 14 (12.3%) of women were positive to HPV 6, 11, 16 or 18: of these, 13 (11.4%) were positive for HPV 16, four (3.5%) were positive for HPV 18, and one (0.9%) for HPV 6. By PCR all were negative for HPV 6 and 11, whereas seven (6.1%) were positive for HPV 16 and one (0.9%) for HPV 18. Abnormal cytology was observed in 12 (10.3%) women. DISCUSSION: Although the prevalence of vaccine HPV types among young Austrian women with fewer than five lifetime sexual partners was lower than in international data, we observed a high prevalence of abnormal cytology and smoking. These data suggest that a substantial number of Austrian women are at risk for HPV-related disease.
Asunto(s)
Alphapapillomavirus/aislamiento & purificación , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/administración & dosificación , Fumar/epidemiología , Vacunación/estadística & datos numéricos , Adolescente , Adulto , Austria/epidemiología , Comorbilidad , Método Doble Ciego , Femenino , Papillomavirus Humano 11/aislamiento & purificación , Papillomavirus Humano 16/aislamiento & purificación , Papillomavirus Humano 18/aislamiento & purificación , Papillomavirus Humano 6/aislamiento & purificación , Humanos , Infecciones por Papillomavirus/microbiología , Prevalencia , Medición de Riesgo/métodos , Factores de Riesgo , Salud de la Mujer , Adulto JovenRESUMEN
BACKGROUND: Vulval and vaginal cancers among younger women are often related to infection with human papillomavirus (HPV). These cancers are preceded by high-grade vulval intraepithelial neoplasia (VIN2-3) and vaginal intraepithelial neoplasia (VaIN2-3). Our aim was to do a combined analysis of three randomised clinical trials to assess the effect of a prophylactic quadrivalent HPV vaccine on the incidence of these diseases. METHODS: 18 174 women (16-26 years) were enrolled and randomised to receive either quadrivalent HPV6/11/16/18 L1 virus-like-particle vaccine or placebo at day 1, and months 2 and 6. Individuals underwent detailed anogenital examination at day 1, 1 month after dose three, and at 6-12-month intervals for up to 48 months. Suspect genital lesions were biopsied and read by a panel of pathologists and vaccine HPV type-specific DNA testing was done. The primary endpoint was the combined incidence of VIN2-3 or VaIN2-3 associated with HPV16 or HPV18. Primary efficacy analyses were done in a per-protocol population. FINDINGS: The mean follow-up time was 3 years. Among women naive to HPV16 or HPV18 through 1 month after dose three (per-protocol population; vaccine n=7811; placebo n=7785), the vaccine was 100% effective (95% CI 72-100) against VIN2-3 or VaIN2-3 associated with HPV16 or HPV18. In the intention-to-treat population (which included 18 174 women who, at day 1, could have been infected with HPV16 or HPV18), vaccine efficacy against VIN2-3 or VaIN2-3 associated with HPV16 or HPV18 was 71% (37-88). The vaccine was 49% (18-69) effective against all VIN2-3 or VaIN2-3, irrespective of whether or not HPV DNA was detected in the lesion. The most common treatment-related adverse event was injection-site pain. INTERPRETATION: Prophylactic administration of quadrivalent HPV vaccine was effective in preventing high-grade vulval and vaginal lesions associated with HPV16 or HPV18 infection in women who were naive to these types before vaccination. With time, such vaccination could result in reduced rates of HPV-related vulval and vaginal cancers.
Asunto(s)
Papillomaviridae/inmunología , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus , Displasia del Cuello del Útero/prevención & control , Neoplasias del Cuello Uterino/prevención & control , Adolescente , Adulto , Femenino , Humanos , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
OBJECTIVE: To review clinical studies assessing the effect of phytoestrogen supplementation on the signs and symptoms of the climacteric syndrome and on the incidence of breast cancer, cardiovascular disease, and skeletal fractures. DESIGN: Literature research using PubMed and the Cochrane controlled trials register. SETTING: None. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): None. RESULT(S): Six systematic reviews and meta-analyses of 25 randomized, controlled trials (RCTs) assessing the use of phytoestrogens for the treatment of the climacteric syndrome were identified. Systematic reviews of RCTs show contradictory results, and meta-analyses demonstrate no statistically significant reduction of vasomotor symptoms for phytoestrogens. Individual RCTs report significant reductions in vasomotor symptoms for red clover and soy phytoestrogens. In selected patient populations, such as in women with early natural postmenopause and mild to moderate vasomotor symptoms, a systematic review of five RCTs found a significant reduction of hot flashes in five out of five RCTs. Twenty-two case-control and cohort studies examined the incidence of breast cancer among women with and without a diet high in phytoestrogens. A meta-analysis of 21 studies found a significantly reduced incidence of breast cancer among past phytoestrogen users. RCTs document beneficial effects of phytoestrogens on surrogate parameters such as bone mineral density, vasodilation, platelet aggregation, insulin resistance, and serum concentrations of triglycerides, high-density lipoprotein, and low-density lipoprotein. None of the available RCTs documents a protective effect of phytoestrogens for the clinical end points of breast cancer, bone fracture, or cardiovascular events. CONCLUSION(S): Based on the available evidence, phytoestrogens should only be used in selected women, i.e., those presenting with mild to moderate vasomotor symptoms in early natural postmenopause. None of the compounds investigated so far have been proven to protect against breast cancer, bone fracture, or cardiovascular disease.
Asunto(s)
Neoplasias de la Mama/prevención & control , Menopausia/efectos de los fármacos , Fitoestrógenos/uso terapéutico , Estudios de Cohortes , Estrógenos/sangre , Femenino , Humanos , Isoflavonas/uso terapéutico , Persona de Mediana Edad , Extractos Vegetales/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: A phase 3 trial was conducted to evaluate the efficacy of a prophylactic quadrivalent vaccine in preventing anogenital diseases associated with human papillomavirus (HPV) types 6, 11, 16, and 18. METHODS: In this randomized, placebo-controlled, double-blind trial involving 5455 women between the ages of 16 and 24 years, we assigned 2723 women to receive vaccine and 2732 to receive placebo at day 1, month 2, and month 6. The coprimary composite end points were the incidence of genital warts, vulvar or vaginal intraepithelial neoplasia, or cancer and the incidence of cervical intraepithelial neoplasia, adenocarcinoma in situ, or cancer associated with HPV type 6, 11, 16, or 18. Data for the primary analysis were collected for a per-protocol susceptible population of women who had no virologic evidence of HPV type 6, 11, 16, or 18 through 1 month after administration of the third dose. RESULTS: The women were followed for an average of 3 years after administration of the first dose. In the per-protocol population, those followed for vulvar, vaginal, or perianal disease included 2261 women (83%) in the vaccine group and 2279 (83%) in the placebo group. Those followed for cervical disease included 2241 women (82%) in the vaccine group and 2258 (83%) in the placebo group. Vaccine efficacy was 100% for each of the coprimary end points. In an intention-to-treat analysis, including those with prevalent infection or disease caused by vaccine-type and non-vaccine-type HPV, vaccination reduced the rate of any vulvar or vaginal perianal lesions regardless of the causal HPV type by 34% (95% confidence interval [CI], 15 to 49), and the rate of cervical lesions regardless of the causal HPV type by 20% (95% CI, 8 to 31). CONCLUSIONS: The quadrivalent vaccine significantly reduced the incidence of HPV-associated anogenital diseases in young women. (ClinicalTrials.gov number, NCT00092521 [ClinicalTrials.gov].).
Asunto(s)
Alphapapillomavirus , Carcinoma in Situ/prevención & control , Condiloma Acuminado/prevención & control , Neoplasias de los Genitales Femeninos/prevención & control , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus , Adenocarcinoma/prevención & control , Adolescente , Adulto , Alphapapillomavirus/genética , Alphapapillomavirus/aislamiento & purificación , Carcinoma in Situ/epidemiología , Condiloma Acuminado/epidemiología , ADN Viral/sangre , Método Doble Ciego , Femenino , Estudios de Seguimiento , Neoplasias de los Genitales Femeninos/epidemiología , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18 , Humanos , Vacunas contra Papillomavirus/efectos adversosRESUMEN
The incorporation of multiple antigens into a single human papillomavirus (HPV) vaccine may induce immune interference. To evaluate whether interference occurs when HPV type 16 (HPV16) virus-like particles are combined in a multivalent vaccine, we conducted a study to evaluate anti-HPV16 responses among subjects receiving three-dose regimens of either a monovalent HPV16 vaccine or a quadrivalent HPV (types 6, 11, 16, and 18) vaccine.
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Formación de Anticuerpos/inmunología , Papillomavirus Humano 16/inmunología , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/clasificación , Vacunas contra Papillomavirus/inmunología , Adolescente , Adulto , Anticuerpos Antivirales/biosíntesis , Método Doble Ciego , Femenino , Humanos , Vacunas contra Papillomavirus/administración & dosificaciónRESUMEN
Cell migration is essential in many diverse processes ranging from embryonic development to wound healing and immune response. Cancer cells have recently been shown to utilize chemoattraction mechanisms mediated by chemokines and their respective receptors, e.g., the CXCL12/CXCR4 pathway normally found in leukocytes. Here we show that Slit2, a secreted protein signaling through the Roundabout (Robo) receptor as a chemorepellent in axon guidance and neuronal migration, acts as a potent chemoattractant for breast cancer cells. Comparing cell lines specifically metastasizing to either brain or bone, we found significant differences in their responses to CXCL12 and Slit2 treatments, suggesting a role for Slit/Robo signaling in brain metastasis.
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Neoplasias Encefálicas/secundario , Neoplasias de la Mama/patología , Péptidos y Proteínas de Señalización Intercelular/fisiología , Proteínas del Tejido Nervioso/fisiología , Línea Celular Tumoral , Movimiento Celular , Quimiocina CXCL12/fisiología , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Metaloproteinasa 9 de la Matriz/genética , Proteínas del Tejido Nervioso/genética , ARN Mensajero/análisis , Receptores CXCR4/genética , Receptores Inmunológicos/genética , Receptores Inmunológicos/fisiología , Proteínas RoundaboutRESUMEN
MTA1 was reported as a metastasis-associated gene. Tumors with higher MTA1 mRNA level were shown to have higher rates of invasion and lymph node metastasis and tended to have higher rates of vascular involvement. The majority of invasive breast carcinomas were demonstrated to overexpress MTA1 compared to surrounding normal tissues. MTA1 was also found to be more expressed in metastatic breast cancer cell lines than in nonmetastatic ones. Originally we were interested in analyzing factors differently expressed in invasive and noninvasive breast cancer cell lines. Therefore we analyzed expression of MTA1 together with several other genes in correlation with cell invasiveness in 25 breast epithelial cell lines. Furthermore, we analyzed it in 90 primary breast tumor tissues and examined its correlation with expression of estrogen receptor, progesterone receptor, plasminogen activator inhibitor-1, E-cadherin, histopathological data, disease-free survival, and overall survival. Our results demonstrated that MTA1 expression was significantly higher in noninvasive cell lines than in invasive ones. It also correlated positively with expression of noninvasive factors and reverse correlated with invasive factors in both cell lines and tumor tissues.
Asunto(s)
Neoplasias de la Mama/metabolismo , Histona Desacetilasas/biosíntesis , Proteínas Represoras/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Cadherinas/biosíntesis , Cadherinas/genética , Línea Celular Tumoral , Femenino , Expresión Génica , Histona Desacetilasas/genética , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Inhibidor 1 de Activador Plasminogénico/biosíntesis , Inhibidor 1 de Activador Plasminogénico/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Receptores de Estrógenos/biosíntesis , Receptores de Estrógenos/genética , Receptores de Progesterona/biosíntesis , Receptores de Progesterona/genética , Proteínas Represoras/genética , TransactivadoresRESUMEN
PURPOSE: Kruppel-like factor (KLF5) is a cell growth mediator in various epithelial cells. Higher KLF5 increases cell growth rate and leads to transformed phenotypes. Because tumor cell proliferation is tightly associated with tumor progression, and consequently, with survival of cancer patients, we wanted to examine the prognostic value of KLF5 gene expression for patients with breast cancer. EXPERIMENTAL DESIGN: The gene expression levels of KLF5, ER, PR, HER2, and MKI67 were quantified in the tumor tissues of 90 patients with breast cancer and correlated with disease-free survival and overall survival of the patients. The correlations of gene expression between KLF5 and ER, PR, HER2, and MKI67 were analyzed. In addition, KLF5 expression was also compared with clinical data and age of patients. RESULTS: Statistically significant correlations were found between gene expression of KLF5 and both disease-free survival (univariate analysis) and overall survival (univariate and multivariate analysis). Patients with higher KLF5 expression had shorter disease-free survival and overall survival time, whereas patients with lower KLF5 expression had better survival. Moreover, KLF5 was also found to be positively correlated with HER2 and MKI67, and negatively correlated with age of the patients at diagnosis. CONCLUSION: The gene expression of KLF5 is directly correlated with cell proliferation in vivo and is a prognostic factor for patients with breast cancer. Patients with higher KLF5 expression have shorter disease-free survival and overall survival than patients with lower KLF5 expression. In addition, KLF5 has higher expression in patients ages 50 years old.