Bais, A.G.

Risk of recurrent high-grade cervical intraepithelial neoplasia after successful treatment: A long-term multi-cohort study (Article)

2011-05-01T00:00:00Z

Background: 15% of women treated for high-grade cervical intraepithelial neoplasia (CIN grade 2 or 3) develop residual or recurrent CIN grade 2 or 3 or cervical cancer, most of which are diagnosed within 2 years of treatment. To gain more insight into the long-term predictive value of different post-treatment strategies, we assessed the long-term cumulative risk of post-treatment CIN grade 2 or 3 or cancer and different follow-up algorithms to identify women at risk of residual or recurrent disease. Methods: Women who were included in three studies in the Netherlands and who were treated for CIN grade 2 or 3 between July, 1988, and November, 2004, were followed up by cytology and testing for high-risk human papillomavirus (hrHPV) at 6, 12, and 24 months after treatment, and subsequently received cytological screening every 5 years. The primary endpoint was the cumulative risk of post-treatment CIN grade 2 or higher by December, 2009. We also assessed the cumulative risk of CIN grade 2 or higher in women with three consecutive negative cytological smears and women with negative co-testing with cytology and hrHPV at months 6 and 24. This study is registered in the Dutch trial register, NTR1468. Findings: 435 women were included, 76 (17%) of whom developed post-treatment CIN grade 2 or higher, of which 39 were CIN grade 3 or higher. The 5-year risk of developing post-treatment CIN grade 2 or higher was 16·5% (95% CI 13·0-20·7) and the 10-year risk was 18·3% (13·8-24·0). The 5-year risk of developing post-treatment CIN grade 3 or higher was 8·6% (95% CI 6·0-12·1) and the 10-year risk was 9·2% (5·8-14·2). Women with three consecutive negative cytological smears had a CIN grade 2 or higher risk of 2·9% (95% CI 1·2-7·1) in the next 5 years and of 5·2% (2·1-12·4) in the next 10 years. The 5-year risk of CIN grade 3 or higher was 0·7% (95% CI 0·0-3·9) and the 10-year risk was 0·7% (0·0-6·3). Women with negative results for co-testing had a 5-year risk of CIN grade 2 or higher of 1·0% (95% CI 0·2-4·6) and a 10-year risk of 3·6% (1·1-10·7). The 5-year risk of CIN grade 3 or higher was 0·0% (95% CI 0·0-3·0) and the 10-year risk was 0·0% (0·0-5·3). Interpretation: The 5-year risk of post-treatment CIN grade 2 or higher in women with three consecutive negative cytological smears or negative co-testing for cytology and hrHPV at 6 and 24 months was similar to that of women with normal cytology in population-based screening and therefore justifies their return to regular screening. Funding: VU University Medical Center, Erasmus University Medical Center, Netherlands.

Post-treatment CIN: Randomised clinical trial using hrHPV testing for prediction of residual/recurrent disease (Article)

2009-02-15T00:00:00Z

We investigated in a randomised clinical trial whether addition of hrHPV testing (high-risk human papillomavirus) to cytological follow-up after treatment for high-grade CIN (cervical intraepithelial neoplasia 2/3) can lead to a better selection of women at risk for residual/recurrent CIN. We included 210 women with high-grade CIN undergoing treatment in outpatient clinics in The Netherlands. Follow-up was based on cytology alone and cytology combined with hrHPV detection. Our primary outcome measurement was improving specificity for residual/recurrent CIN after treatment. Secondary, we compared health-care costs and impact of individual hrHPV type on the risk of residual/recurrent CIN. Follow-up by abnormal cytology alone (6, 12 and 24 months after treatment according to the Dutch protocol) showed a lower specificity for detection of residual/recurrent CIN than follow-up by abnormal cytology and presence of hrHPV (80 vs. 91%, relative risk 0.87 (95% CI 0.77-0.99)). Both methods showed no significant difference in sensitivity ((86 vs. 100%) RR 0.86 (95% CI 0.63-1.16)). Comparing different post hoc modifications in the strategy of combined testing showed similar test characteristics when low-risk women (normal cytology and hrHPV negative at 6 months) omitted the 12 months visit (specificity 91%, p = 1.00 z = 0.00). Prediction of residual/recurrent CIN by typing of hrHPV could not be confirmed. Total health-care costs using cytology and hrHPV testing during follow-up decreased when low-risk women omit the 12 months visit. Follow-up after treatment for high-grade CIN can be improved by combining cytology with hrHPV testing. We advise combined cytology and hrHPV testing at 6, 12 and 24 months after treatment. Low-risk women may omit the 12 months visit, resulting in cost reduction.

Cytokine release in HR-HPV(+) women without and with cervical dysplasia (CIN II and III) or carcinoma, compared with HR-HPV(-) controls (Article)

2007-12-01T00:00:00Z

Aims. We investigated the effect of HR-HPV infection on the capacity of the cytokine network in whole blood cultures during carcinogenesis of cervical carcinoma. Methods. Thirty-nine women with moderate dysplasia, severe dysplasia, cervical carcinoma, or without dysplasia formed the study group. The control group consisted of 10 HR-HPV-negative women without CIN. Whole blood cultures were stimulated with phytohemagglutinin (PHA) and concentrations of tumour necrosis factor α (TNFα), interferon γ (IFNγ), interleukin 2 (IL-2), interleukin 12 (IL-12), interleukin 4 (IL-4), and interleukin 10 (IL-10) were determined by ELISAs. Results. A significant increase in cytokine release was detected in HR-HPV-positive women without dysplasia. In women with cervical cancer, release of IFNγ and IL-12 was of the same magnitude as in HR-HPV-positive women without clinical manifestations. Most Th1-type/Th2-type ratios decreased form CIN II to CIN III, and increased from CIN III to invasive carcinoma. Conclusions. (1) Infection with HR-HPV without expression of cervical dysplasia induces activation of the cytokine network. (2) Increases in ratios of Th1-type to Th2-type cytokines at the stage of cervical carcinoma were found by comparison with stage CIN III. (3) Significant changes in the kinetics of cytokine release to a Th2-type immune response in blood of women withcervical dysplasia occurred progressively from CIN II to CIN III. Copyright

Human papillomavirus triage of women with persistent borderline or mildly dyskaryotic smears: Comparison of costs and side effects of three alternative strategies (Article)

2007-10-01T00:00:00Z

The conventional direct referral to colposcopy of persistent borderline or mildly dyskaryotic (BMD) smears in cervical cancer screening leads to considerable unnecessary referrals and associated anxiety and costs. This may be improved by including testing for oncogenic human papillomavirus (HPV) in the triage. We assessed costs and side effects (referrals, treatments and time in follow-up) for 3 possible HPV triage strategies (immediate HPV testing, a 6-month delay in HPV testing, a 2-stage combination of both) and compared them with the conventional strategy. The assessments are based on recent Dutch data from various national databases and trials. We estimated that the referral rate could be reduced by 49, 58 and 58% with immediate, delayed and 2-stage HPV testing, respectively. As a consequence, the average length of follow-up, as well as average costs, also decrease. Therefore, we advocate including HPV testing before referring to colposcopy. Among the 3 HPV strategies, analysis of additional aspects favors implementation of immediate HPV testing.

Risk reduction by HPV-Testing in Women with Premalignant Cervical Lesions: Studies of clinical management and observations on the immunological background (Doctoral Thesis)

2007-09-12T00:00:00Z

Chapters 2.1, 2.2 and 4 are preprints of articles accepted for publication in the International Journal of Cancer, Wiley Inc.

Human papillomavirus testing on self-sampled cervicovaginal brushes: An effective alternative to protect nonresponders in cervical screening programs (Article)

2007-04-01T00:00:00Z

Women not attending cervical screening programs are at increased risk of cervical cancer. We investigated in these nonresponders to what extent offering self-sampling devices for cervicovaginal brushes for high-risk human papillomavirus (hrHPV) testing would induce participation and, if so, what the yield of precursor (i.e. CIN2 or worse) lesions following self-sampling would be. In addition, we assessed screening history of participants and costs per detected high-grade CIN2 or worse ("CIN2+") lesion in comparison to the regular program in the Netherlands. Nonresponders received a device for hrHPV testing (self-sampling group, n = 2,546) or an extra recall for conventional cytology (control group, n = 284). The percentage of self-sampling responders were compared with responders in the recall group. hrHPV positive self-sampling responders were invited for cytology and colposcopy. CIN2+ yield and costs per detected C1N2+ were evaluated. Active response was higher in the self-sampling than in the control group (34.2 vs. 17.6%; p < 0.001). hrHPV positive self-sampling responders were less likely to have a prior screening history than screening participants (p < 0.001), indicating that they are regular nonresponders. hrHPV prevalence was similar (8.0 vs. 6.8%; p = 0.11), but CIN2+ yield was higher in self-sampling responders compared to screening participants (1.67 vs. 0.97%; OR = 2.93, 95% CI 1.48-5.80; p = 0.0013). Costs per CIN2+ lesion detected via self-sampling were in the same range as those calculated for conventional cytological screening (€8,836 vs. €7,599). Offering self-sampling for hrHPV testing in nonresponders is an attractive adjunct to effectively increase population coverage of screening without the adverse effect of markedly increased costs per detected CIN2+ lesion.

A shift to a peripheral Th2-type cytokine pattern during the carcinogenesis of cervical cancer becomes manifest in CIN III lesions (Article)

2005-01-01T00:00:00Z

BACKGROUND: A shifted balance between T helper 1 (Th1)-type and Th2-type cytokines has been hypothesised in cervical dysplasia. AIMS: To evaluate possible deregulation of the cytokine network by estimating the expression of peripheral cytokines in different stages of cervical disease and in relation to the presence or absence of high risk human papillomavirus (HR-HPV). METHODS: Twenty one HR-HPV positive women with high grade cervical intraepithelial neoplasia (CIN II-III) and 12 patients with invasive cervical carcinoma formed the study groups. Two control groups consisted of 10 HR-HPV positive and 11 HR-HPV negative women without CIN. Differences in leucocyte subgroups were evaluated by a differential leucocyte count. Plasma concentrations of tumour necrosis factor alpha (TNFalpha), TNFalpha receptors TNFRI and TNFRII, interferon gamma (IFNgamma), interleukin 2 (IL-2), IL-12, IL-4, and IL-10 were determined by enzyme linked immunosorbent assays. RESULTS: Leucocyte counts in patients with CIN III and carcinoma were significantly higher than in controls. Plasma IFNgamma concentrations were significantly lower in patients with CIN III and carcinoma than in women with CIN II or controls. Plasma concentrations of IL-12, IL-2, IL-4, and TNFalpha did not differ significantly between groups, but significantly lower plasma concentrations of TNFRII were found in CIN III and carcinoma compared with CIN II. IL-10 was detected with increased frequency in the plasma of patients with CIN III and carcinoma. CONCLUSIONS: These results indicate that a shift to a Th2-type cytokine pattern during the carcinogenesis of cervical cancer occurs in women with CIN III lesions.