Human papillomavirus (HPV) causes cervical, vulvar, and vaginal cancers, precancerous dysplasia, and genital warts. We report data for the longest efficacy evaluation to date of a prophylactic HPV vaccine. In total, 552 women (16 -23 years) were enrolled in a randomised, placebo-controlled study of a quadrivalent HPV 6/11/16/18 L1 virus-like-particle vaccine with vaccination at months 0, 2, and 6. At regular intervals through 3 years, subjects underwent gynaecologic examination, cervicovaginal sampling for HPV DNA, serum anti-HPV testing, and Pap testing, with follow-up biopsy as indicated. A subset of 241 subjects underwent two further years of follow-up. At 5 years post enrolment, the combined incidence of HPV 6/11/16/18-related persistent infection or disease was reduced in vaccine-recipients by 96% (two cases vaccine versus 46 placebo). There were no cases of HPV 6/11/16/18-related precancerous cervical dysplasia or genital warts in vaccine recipients, and six cases in placebo recipients (efficacy ¼ 100%; 95% CI:12 -100%). Through 5 years, vaccine-induced anti-HPV geometric mean titres remained at or above those following natural infection. In conclusion, a prophylactic quadrivalent HPV vaccine was effective through 5 years for prevention of persistent infection and disease caused by HPV 6/11/16/18. This duration supports vaccination of adolescents and young adults, which is expected to greatly reduce the burden of cervical and genital cancers, precancerous dysplasia, and genital warts.

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Objective To study the long term risk of invasive cancer of the cervix or vagina after treatment for cervical intraepithelial neoplasia grade 3. Design Prospective cohort study. Setting Swedish cancer registry. Participants All women in Sweden with severe dysplasia or cervical carcinoma in situ (equivalent to cervical intraepithelial neoplasia grade 3) treated during 1958-2002 (n=132 493) contributing 2 315 724 woman years. Main outcome measures Standardised incidence ratios with risk of cancer in the Swedish general female population as reference, and relative risks in multivariable log-linear regression model, with internal references. Results Women with previous cervical intraepithelial neoplasia grade 3 had an increased risk of invasive cervical cancer compared with the general female population (standardised incidence ratio 2.34, 95% confidence interval 2.18 to 2.50). The increased risk showed a decreasing trend with time since diagnosis for women treated later than 1970 but the risk was still increased after 25 years. An effect of age was found, with an accentuated increase in risk for women aged more than 50. The excess risk for cervical cancer associated with previous cervical intraepithelial neoplasia grade 3 has steadily increased since 1958. For vaginal cancer the standardised incidence ratio was 6.82 (5.61 to 8.21) but this decreased to 2.65 after 25 years. Adjustments in the multivariable log-linear regression model did not substantially alter these results. Conclusions Women previously treated for cervical intraepithelial neoplasia grade 3 are at an increased risk of developing invasive cervical cancer and vaginal cancer. This risk has increased since the 1960s and is accentuated in women aged more than 50. The risk is still increased 25 years after treatment.

Objective Proteomic analysis has previously shown that activin A, a member of the transforming growth factor β family, is produced by human articular cartilage. This study was undertaken to investigate whether activin A affects cartilage matrix catabolism and how its production is regulated. Methods The effect of exogenous activin A on interleukin‐1–induced aggrecanase‐generated neoepitope production was assessed by Western blotting, using medium from human cartilage explants. Levels of activin A production were determined by enzyme‐linked immunosorbent assay. For genes of interest, messenger RNA (mRNA) induction in cartilage explants or primary chondrocyte monolayers was assessed by reverse transcriptase–polymerase chain reaction. Activin A activity in cartilage explant medium was measured by incubating it with human dermal fibroblasts and determining the increase in phospho‐Smad2 by Western blotting. Results Activin A (1–10 ng/ml) suppressed aggrecanase‐mediated cleavage of aggrecan in human articular cartilage. Activin A mRNA and protein secretion were induced by dissection and culture of human or porcine articular cartilage. This activin A was biologically active. Its production was due to an active cellular process and was enhanced in osteoarthritic (OA) tissue. Activin A production on dissection was reduced by 80% by the fibroblast growth factor (FGF) receptor inhibitor PD173074 and by 70% by the IKK inhibitor BMS345541. Conclusion Activin A is potentially an anticatabolic molecule in articular cartilage. Its expression is induced by wounding in an FGF‐2– and NF‐κB–dependent manner. OA cartilage produced more activin A than did normal cartilage in vitro.

Although the vast majority of the women had experience of participating in the screening program, one in three of the women were unaware of which type of cancer she was being screened for and only half of the women were aware of the connection between dysplasia/cervix cancer and life-style factors. It is particularly important to provide better information about life-style factors in order to give women the opportunity of acting accordingly.