Objectives To investigate the role of human papillomavirus (HPV) in the development of cervical neoplasia in women with no previous cervical cytological abnormalities; whether the presence of virus DNA predicts development of squamous intraepithelial lesion; and whether the risk of incident squamous intraepithelial lesions differs with repeated detection of the same HPV type versus repeated detection of different types. Design Population based prospective cohort study. Setting General population in Copenhagen, Denmark. Participants 10 758 women aged 20-29 years followed up for development of cervical cytological abnormalities; 370 incident cases were detected (40 with atypical squamous cells of undetermined significance, 165 with low grade squamous intraepithelial lesions, 165 with high grade squamous intraepithelial lesions). Main outcome measures Results of cervical smear tests and cervical swabs at enrolment and at the second examination about two years later. Results Compared with women who were negative for human papillomavirus at enrolment, those with positive results had a significantly increased risk at follow up of having atypical cells (odds ratio 3.2, 95% confidence interval 1.3 to 7.9), low grade lesions (7.5, 4.8 to 11.7), or high grade lesions (25.8, 15.3 to 43.6). Similarly, women who were positive for HPV at the second examination had a strongly increased risk of low (34.3, 17.6 to 67.0) and high grade lesions (60.7, 25.5 to 144.0). For high grade lesions the risk was strongly increased if the same virus type was present at both examinations (813.0, 168.2 to 3229.2). Conclusions Infection with human papillomavirus precedes the development of low and high grade squamous intraepithelial lesions. For high grade lesions the risk is greatest in women positive for the same type of HPV on repeated testing.

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BACKGROUNDThe HER‐2 (Human Epidermal Growth factor receptor‐2, also known as c‐erb‐2/neu) protooncogene encodes a transmembrane receptor protein, Mr 185,000. Studies have shown that the HER‐2 oncogene is overexpressed in approximately 25–30% of ovarian carcinoma (OC) cases, but to the authors' knowledge, to date no consensus regarding overexpression and prognosis has been possible. The objective of the current study was first to analyze the presence of HER‐2 overexpression in tissue from Danish OC patients and correlate the distribution of HER‐2 overexpression with clinical and biochemical data and second to investigate the value of HER‐2 overexpression as a prognostic marker in OC and to compare this value with the prognostic value of other biochemical markers.METHODSThe study population was comprised of the first 181 patients diagnosed with epithelial OC who were included in the MALOVA study. The staining procedure for HER‐2 overexpression was performed using the p185 antibody.RESULTSHER‐2 overexpression was found in 95 of the 181 investigated cases (52.5%), in which 71 carcinomas (39.2%) were weakly positive (1+) and 24 carcinomas (13.3%) were moderately (2+) to intensely positive (3+). Increased HER‐2 expression was found to be correlated with reduced survival. Significant differences in survival between patients with (1+, 2+, and 3+) and those without HER‐2 overexpression were found for patients with International Federation of Gynecology and Obstetrics (FIGO) Stage I, Stage III, and Stage III/IV OC (Stage I: P = 0.021; Stage III: P = 0.0078; and Stage III/IV: P = 0.0054). Multivariate survival analyses including all 181 OC patients demonstrated that HER‐2 overexpression is a prognostic marker (P = 0.003) together with disease stage, serum tetranectin level, and patient age. For patients with Stage III OC, the only independent prognostic factors detected were HER‐2 overexpression (P = 0.009) and serum tetranectin level (P ≤ 0.0001).CONCLUSIONSThe results of the current study show that HER‐2 overexpression has prognostic value both in univariate and multivariate survival analyses. Therefore, the clinical relevance of this observation should be established conclusively by therapy that targets HER‐2 in a prospective Phase II clinical trial. Cancer 2003;98:66–73. © 2003 American Cancer Society.DOI 10.1002/cncr.11476