Several studies suggest that HPV testing is more sensitive than cytology in primary cervical screening. These studies had different designs and were reported in different ways. Individual patient data were collected for all European and North American studies in which cytology was routinely performed and HPV testing was included as an additional parallel test. More than 60,000 women were included. The sensitivity and specificity of HPV testing were compared with routine cytology, both overall and for ages <35, 35-49 and 501. The age-specific prevalence of high risk HPV (hr-HPV) was also analysed. HPV testing was substantially more sensitive in detecting CIN21 than cytology (96.1% vs. 53.0%) but less specific (90.7% vs. 96.3%). The sensitivity of HPV testing was similar in all studies carried out in different areas of Europe and North America, whereas the sensitivity of cytology was highly variable. HPV sensitivity was uniformly high at all ages, whereas the sensitivity of cytology was substantially better in women over the age of 50 than in younger women (79.3% vs. 59.6%). The specificity of both tests increased with age. Positivity rates for HPV testing in women without high-grade CIN were region dependent. These results support the use of HPV testing as the sole primary screening test, with cytology reserved for women who test HPV positive. Large demonstration projects are needed to fully evaluate this strategy. ' 2006 Wiley-Liss, Inc.Key words: HPV testing; cervical screening; sensitivity; specificity; primary screening Currently in Europe and North America, cervical cancer screening is based on exfoliative cytology performed at intervals ranging between 1 and 5 years. Although there has been a marked reduction in incidence and mortality rates of squamous cell carcinoma of the cervix in countries with established cytology screening programmes, 1-3 Sasieni et al. (1996) reported that 47% of women in the UK who developed stage 1B1 or worse invasive cervical cancer before the age of 70 had had an adequate previous screening history. 2 The weaknesses in cytology are 3-fold. First, results are dependent on the high quality sample being collected during examination. Second, the test requires the identification of morphological changes within cells, whose interpretation is highly subjective. Last, this method of screening is particularly repetitive, which can lead to a greater number of interpretive errors. False negative cytology has major medical, economic and legal implications, and this is reflected in high malpractice litigation costs in the US associated with misreading cervical smears.Interest in the use of HPV testing as a screening test is based on the finding that HPV DNA is present in almost all cervical cancers, 4 and the availability of easily performed tests, which have demonstrated higher sensitivity for high grade CIN (CIN21) than that achieved by cytology in several studies. This higher sensitivity offers several potential advantages, including reduced cancer rates and longer screening intervals, ...

Objective To obtain large scale and generalisable data on the long term predictive value of cytology and human papillomavirus (HPV) testing for development of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+). Design Multinational cohort study with joint database analysis. Setting Seven primary HPV screening studies in six European countries. Participants 24 295 women attending cervical screening enrolled into HPV screening trials who had at least one cervical cytology or histopathology examination during follow-up. Main outcome measure Long term cumulative incidence of CIN3+. Results The cumulative incidence rate of CIN3+ after six years was considerably lower among women negative for HPV at baseline (0.27%, 95% confidence interval 0.12% to 0.45%) than among women with negative results on cytology (0.97%, 0.53% to 1.34%)). By comparison, the cumulative incidence rate for women with negative cytology results at the most commonly recommended screening interval in Europe (three years) was 0.51% (0.23% to 0.77%). The cumulative incidence rate among women with negative cytology results who were positive for HPV increased continuously over time, reaching 10% at six years, whereas the rate among women with positive cytology results who were negative for HPV remained below 3%. Conclusions A consistently low six year cumulative incidence rate of CIN3+ among women negative for HPV suggests that cervical screening strategies in which women are screened for HPV every six years are safe and effective.

Multiciliated cells lining the surface of some vertebrate epithelia are essential for various physiological processes, such as airway cleansing. However, the mechanisms governing motile cilia biosynthesis remain poorly elucidated. We identify miR-449 microRNAs as evolutionarily conserved key regulators of vertebrate multiciliogenesis. In human airway epithelium and Xenopus laevis embryonic epidermis, miR-449 microRNAs strongly accumulated in multiciliated cells. In both models, we show that miR-449 microRNAs promote centriole multiplication and multiciliogenesis by directly repressing the Delta/Notch pathway. We established Notch1 and its ligand Delta-like 1(DLL1) as miR-449 bona fide targets. Human DLL1 and NOTCH1 protein levels were lower in multiciliated cells than in surrounding cells, decreased after miR-449 overexpression and increased after miR-449 inhibition. In frog, miR-449 silencing led to increased Dll1 expression. Consistently, overexpression of Dll1 mRNA lacking miR-449 target sites repressed multiciliogenesis, whereas both Dll1 and Notch1 knockdown rescued multiciliogenesis in miR-449-deficient cells. Antisense-mediated protection of miR-449-binding sites of endogenous human Notch1 or frog Dll1 strongly repressed multiciliogenesis. Our results unravel a conserved mechanism whereby Notch signalling must undergo miR-449-mediated inhibition to permit differentiation of ciliated cell progenitors.