The addition of an HPV test to the Pap test to screen women in their mid-30s for cervical cancer reduces the incidence of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected by subsequent screening examinations. (ClinicalTrials.gov number, NCT00479375 [ClinicalTrials.gov].).

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Nonadherence to screening intervals was the major reason for cervical cancer morbidity. The screening program was equally effective for women of all ages and was also effective against non-squamous cancers.

Primary HPV DNA-based screening with cytology triage and repeat HPV DNA testing of cytology-negative women appears to be the most feasible cervical screening strategy.

Objective To determine whether detection of invasive cervical cancer by screening results in better prognosis or merely increases the lead time until death.Design Nationwide population based cohort study. Setting Sweden.Participants All 1230 women with cervical cancer diagnosed during 1999-2001 in Sweden prospectively followed up for an average of 8.5 years.Main outcome measures Cure proportions and five year relative survival ratios, stratified by screening history, mode of detection, age, histopathological type, and FIGO (International Federation of Gynecology and Obstetrics) stage. ResultsIn the screening ages, the cure proportion for women with screen detected invasive cancer was 92% (95% confidence interval 75% to 98%) and for symptomatic women was 66% (62% to 70%), a statistically significant difference in cure of 26% (16% to 36%). Among symptomatic women, the cure proportion was significantly higher for those who had been screened according to recommendations (interval cancers) than among those overdue for screening: difference in cure 14% (95% confidence interval 6% to 23%). Cure proportions were similar for all histopathological types except small cell carcinomas and were closely related to FIGO stage. A significantly higher cure proportion for screen detected cancers remained after adjustment for stage at diagnosis (difference 15%, 7% to 22%).Conclusions Screening is associated with improved cure of cervical cancer. Confounding cannot be ruled out, but the effect was not attributable to lead time bias and was larger than what is reflected by down-staging. Evaluations of screening programmes should consider the assessment of cure proportions. IntroductionThe rationale of cervical screening is to reduce the incidence of cancer by the detection and treatment of precursors.1 2 A secondary aim is the early detection of invasive disease, which might improve the prognosis thereby also reducing mortality from the disease. Prognosis may depend on age, FIGO (International Federation of Gynecology and Obstetrics) stage, histopathological type, screening history, and mode of detection. 3 Thus cancers may be detected on the basis of either an abnormal screening test result or symptoms, and the women may also have been screened previously according to recommendations or not. The Swedish cervical screening programme carried out a nationwide audit of the screening history of all cases in the country and found that in addition to preventing cervical cancer, regular screening also detected invasive cervical cancers at earlier stages. In the nationwide Swedish audit 1 around 50% of women who were not screened according to recommendations were detected at FIGO stage II or higher, whereas among women participating in the screening programme most were at stages IA or IB (30% and 52%, respectively). For screen detected cancers the drift towards detection at early stages was even more apparent (47% of cancers were detected at stage IA and 46% at stage IB).However, the early detection of asymptomatic cancers is intuiti...

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Human papillomavirus (HPV) persistence is the major cause of cervical cancer, but most HPV infections will not persist and risk factors for HPV persistence are not well known. Chlamydia (C.) trachomatis infection seems to also be associated with cervical cancer. We investigated whether C. trachomatis infection is a risk factor for HPV persistence. In a cohort of 12,527 women participating in a population-based HPV screening trial in Sweden, 6,418 women completed testing for HPV DNA by general primer PCR and typing by reverse dot blot hybridization. On average 19 months later, 303 women that had been HPV-positive and had normal cytology at enrollment completed a new HPV test. Environmental exposures were assessed by an 87-item questionnaire. Previous sexually transmitted infections were also investigated by serology. At follow-up, 44% of the women were positive for the same type of HPV DNA as at enrollment. Persistence correlated with length of follow-up (p < 0.01) and condom use seemed to protect against HPV persistence (p < 0.05). The most significant risk factor for persistent presence of HPV DNA was self-reported history of previous C. trachomatis infection (relative risk in multivariate model = 2.09; 95% confidence interval = 1.05-4.18). We conclude that persistence of oncogenic HPV infections is more likely among women with a previous C. trachomatis infection. ' 2005 Wiley-Liss, Inc.Key words: HPV infection; HPV persistence; Chlamydia trachomatis; epidemiology Persistent oncogenic HPV infection is recognized as a necessary factor in development of high grade cervical intraepithelial neoplasia and invasive cervical cancer. 1 Genital infections with oncogenic HPV types are very common among sexually active women, but only a minority of infected women will have a persistent HPV infection. 2-4 Type-specific persistence of HPV (defined as repeated detectability of the same type of HPV DNA in serial samples) is a much stronger risk factor for high-grade CIN 5 and cervical cancer 6 than HPV infection per se.Chlamydia (C.) trachomatis has been found repeatedly to associate with cervical neoplasia and invasive cancer in cross-sectional case-control studies, 7,8 although the association has commonly been thought to be the result of confounding by HPV. During recent years, an association with C. trachomatis has also been found in several biobank-based longitudinal studies with invasive cervical cancer as endpoint. [9][10][11][12] The vexed question of whether the association could be due to confounding by HPV infection is, however, only possible to address in cohort studies comprising only HPV-infected women.A possible explanation for the association of C. trachomatis and cervical cancer might be that the C. trachomatis-induced inflammation results in an impaired ability to clear HPV infections.To investigate these issues, we carried out a prospective, population-based cohort study restricted to HPV-infected women with HPV persistence as the endpoint. Subjects and methods Study settingA population-based randomized mul...

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.