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Background: Urocortin (UCN1) peptide shares structural and functional homology with corticotropin-releasing factor (CRF). UCN1 is significantly reduced in endometrial adenocarcinoma compared to healthy controls. However, there are no data which evaluate the effects of UCN1 in the endometrium, or how it is modulated. Methods: We used proliferation and transwell assays to determine the effect of UCN1 on the proliferation and migration of Ishikawa and HEC1A cells. We also determined the expression levels of UCN1 and its receptors produced by estrogen receptor agonists, and the effect of UCN1 on estrogen receptor expression, using quantitative polymerase chain reaction. Results: UCN1 suppressed cellular migration via CRF receptor 2 (CRFR2), as co-treatment with astressin-2B, a selective CRFR2 antagonist, reversed this effect. Activation of ERA reduced UCN1 expression, but only had a small effect on the expression of CRFR1. However, expression of CRFR2 was more notably reduced at both the mRNA and protein levels by activation of ERB. UCN1 in turn reduced both ERA and ERB expression, as assessed by real-time quantitative PCR. Conclusion: We demonstrate that UCN1 significantly suppresses the migration of endometrial cancer cells but has no effect on their proliferation. Thus, loss of UCN1 in endometrial cancer may promote invasion and metastatic spread. There is a complex relationship between the UCN1 system and estrogen receptors, which may provide insights into endometrial carcinogenesis, a disease known to be driven by estrogen excess.

Introduction: The NHS Cervical Screening Programme is now using human papillomavirus (HPV) testing as the primary test in six sentinel sites in England, with the intention of rolling this out across the whole of England. Previous research evaluating HPV testing in the cervical screening context suggests that an HPV-positive result may increase anxiety beyond that associated with abnormal cytology, but this has not been explored in the context of primary HPV testing. The main aim of this study is to explore the impact of the HPV primary screening programme on anxiety and distress. Methods and analysis: A cross-sectional betweengroups design (total N - 673) will be employed to assess the psychological impact of different HPV and cytology results at three time points: shortly after receiving the results, and 6 and 12 months later. Women will fall into one of six groups based on their screening results. The primary outcomes will be anxiety and general distress. Secondary outcomes will include understanding of screening results, perceived risk of cervical cancer, psychosexual functioning, intention to attend future screening and knowledge of HPV. General linear modelling will be used to test for differences between groups and changes over the three time points. Ethics and dissemination: Health Research Authority approval was received on 26 September 2016. Ethical approval was received from London-Surrey Borders NHS Research Ethics Committee on 30 August 2016. Section 251 approval was received from the Confidentiality Advisory Group on 24 August 2016. Results will be disseminated via peer-reviewed publication and presentation at national and international conferences.

We report final event-driven analysis data on the immunogenicity and efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in young women aged 15-25 years from the PApilloma TRIal against Cancer In young Adults (PATRICIA; NCT001226810). The total vaccinated cohort (TVC) included all randomised participants who received at least one vaccine dose (vaccine, n=9319; control, n=9325) at months 0, 1 and/or 6. The TVC-naïve (vaccine, n=5822; control, n=5819) had no evidence of high-risk HPV infection at baseline approximating adolescent girls targeted by most HPV vaccination programmes. Mean follow-up was approximately 39 months after the first vaccine dose in each cohort. At baseline, 26% of women in the TVC had evidence of past and/or current HPV-16/18 infection. HPV-16 and HPV-18 antibody titres post-vaccination tended to be higher among 15-17 year-olds than 18-25 year-olds. In the TVC, vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 1 or greater (CIN1+), CIN2+ and CIN3+ associated with HPV-16/18 was 55.5% (96.1% CI: 43.2, 65.3), 52.8% (37.5, 64.7) and 33.6% (-1.1, 56.9). VE against CIN1+, CIN2+ and CIN3+ irrespective of HPV DNA was 21.7% (10.7, 31.4), 30.4% (16.4, 42.1) and 33.4% (9.1, 51.5) and consistently significant only in 15-17 year-old women (27.4% [10.8, 40.9], 41.8% [22.3, 56.7] and 55.8% [19.2, 76.9]). In the TVC-naïve, VE against CIN1+, CIN2+ and CIN3+ associated with HPV-16/18 was 96.5% (89.0, 99.4), 98.4% (90.4, 100) and 100% (64.7, 100); and irrespective of HPV DNA was 50.1% (35.9, 61.4), 70.2% (54.7, 80.9) and 87.0% (54.9, 97.7). VE against 12-month persistent infection with HPV-16/18 was 89.9% (84.0, 94.0) and against HPV-31/33/45/51 was 49.0% (34.7, 60.3). In conclusion, vaccinating adolescents before sexual debut has a substantial impact on the overall incidence of high-grade cervical abnormalities, and catch-up vaccination up to 18 years of age is most likely effective. ispartof: Clinical and Vaccine Immunology vol:22 issue:4 pages:361-73 ispartof: location:United States status: published

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

Summary 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.

Background: Body mass index (BMI) is a risk factor for endometrial cancer. We quantified the risk and investigated whether the association differed by use of hormone replacement therapy (HRT), menopausal status, and histologic type. Methods: We searched MEDLINE and EMBASE (1966 to December 2009) to identify prospective studies of BMI and incident endometrial cancer. We did random-effects meta-analyses, meta-regressions, and generalized least square regressions for trend estimations assuming linear, and piecewise linear, relationships. Results: Twenty-four studies (17,710 cases) were analyzed; 9 studies contributed to analyses by HRT, menopausal status, or histologic type, all published since 2003. In the linear model, the overall risk ratio (RR) per 5 kg/m2 increase in BMI was 1.60 (95% CI, 1.52–1.68), P < 0.0001. In the piecewise model, RRs compared with a normal BMI were 1.22 (1.19–1.24), 2.09 (1.94–2.26), 4.36 (3.75–5.10), and 9.11 (7.26–11.51) for BMIs of 27, 32, 37, and 42 kg/m2, respectively. The association was stronger in never HRT users than in ever users: RRs were 1.90 (1.57–2.31) and 1.18 (95% CI, 1.06–1.31) with P for interaction ¼ 0.003. In the piecewise model, the RR in never users was 20.70 (8.28–51.84) at BMI 42 kg/m2, compared with never users at normal BMI. The association was not affected by menopausal status (P ¼ 0.34) or histologic type (P ¼ 0.26). Conclusions: HRT use modifies the BMI-endometrial cancer risk association. Impact: These findings support the hypothesis that hyperestrogenia is an important mechanism underlying the BMI-endometrial cancer association, whilst the presence of residual risk in HRT users points to the role of additional systems. Cancer Epidemiol Biomarkers Prev; 19(12); 3119–30.