Chris J L M Meijer

Centro di Riferimento per l'Epidemiologia e la Prevenzione Oncologica in Piemonte, Torino, Piedmont, Italy

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Publications (624)3486.89 Total impact

  • M A Vink, J A Bogaards, C J L M Meijer, J Berkhof
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    ABSTRACT: Cytological screening has substantially decreased the cervical cancer incidence, but even better protection may be achieved by primary high-risk human papillomavirus (hrHPV) screening. In the Netherlands, five-yearly cytological screening for women aged 30-60 years will be replaced by primary hrHPV screening in 2016. The new screening guidelines involve an extension of the screening interval from 5 to 10 years for hrHPV-negative women aged 40 or 50 years. We investigated the impact of this program change on the lifetime cancer risks in women without an hrHPV infection at age 30, 35, 40, 45, or 50 years. The time to cancer was estimated using 14-year follow-up data from a population-based screening intervention trial and the nationwide database of histopathology reports. The new screening guidelines are expected to lead to a reduced cervical cancer risk for all age groups. The average risk reduction was 34% and was smallest (25%) among women aged 35 years. The impact of hrHPV screening on the cancer risk was sensitive to the duration from cervical intraepithelial neoplasia grade 2/3 (CIN2/3) to cancer; a small increase in the cancer risk was estimated for women aged 35 or 40 years in case a substantial proportion of CIN2/3 showed fast progression to cancer. Our results indicate that primary hrHPV screening with a 10-yearly interval for hrHPV-negative women of age 40 and beyond will lead to a further reduction in lifetime cancer risk compared to 5-yearly cytology, provided that precancerous lesions progress slowly to cancer. This article is protected by copyright. All rights reserved. Copyright © 2014 UICC.
    International Journal of Cancer 12/2014; · 6.20 Impact Factor
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    ABSTRACT: Background: The focus of testing the dynamic spectral imaging (DSI) colposcope has been on the technical characteristics and clinical performance. However, aspects from a patient's perspective are just as important. Methods: This study was designed as a substudy of the DSI validation study, a prospective comparative, multicenter clinical trial to assess the clinical performance of DSI colposcopy. All women included in this study were asked to complete two questionnaires: a patient characteristics questionnaire and a patient satisfaction questionnaire. Results: In the initial study a total of 239 women were included in the intention-to-treat cohort. Of these, 230 women (96.2%) completed both questionnaires. When assessing the women's preferences for some of the possible uses of DSI colposcopy, a high level of agreement was noted for all potential implementations. In general, women found the additional time DSI colposcopy took acceptable: just 15 women (6.5%) thought the time DSI colposcopy took made them feel uncomfortable. Furthermore, women ranked test accuracy as the most important characteristic, followed by (more) rapid testing and comfort. Quick notification of the results and costs were considered the least important characteristics. Conclusion: Women are willing to accept discomfort in the form of an additional or longer test if there is clinical benefit. © 2014 S. Karger AG, Basel.
    Gynecologic and Obstetric Investigation 11/2014; · 1.10 Impact Factor
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    ABSTRACT: Background Age- and type-specific hrHPV incidence estimates in screen-eligible women are relevant from a public health perspective because they provide an indication of the effect of vaccination on the occurrence of screen-positives in HPV-based screening. However, limited data from women over 25 years of age are available. Methods In 24,105 hrHPV-negative women participating in Dutch (POBASCAM) and Italian (NTCC) population-based randomized controlled screening trials the age- and type-specific distribution of incident hrHPV infections detected at the next screening round was assessed. HPV types were grouped into vaccine (bivalent: HPV16/18; polyvalent HPV16/18/31/33/45/52/58) and non-vaccine types. Results The incidence of screen-detected hrHPV among women aged 29-56 years was 2.54% (95% CI 2.30-2.78) in POBASCAM and 2.77% (2.36-3.19) in NTCC. In both studies, the incidence of bivalent, polyvalent, and non-polyvalent infections decreased with age (p-values < .0001). Among women with incident infection(s), vaccine-type positivity changed quadratically with age, in particular for the polyvalent vaccine (p-values: POBASCAM: bivalent 0.264, polyvalent 0.038; NTCC bivalent 0.039, polyvalent 0.005). However, over 20% and 50% of women with incident hrHPV were positive for respectively bivalent and polyvalent vaccine types in all ages in both studies. Conclusions We observed decreasing age trends of hrHPV vaccine and non-vaccine type incidences and age-related differences in the vaccine-type positivity among women with incident infections. Most importantly, hrHPV infections continued to be detected in all ages and the contribution of vaccine types remained substantial. Impact Our results indicate a considerable reduction of new hrHPV infections in vaccinated cohorts, ensuing revision of screening guidelines.
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    ABSTRACT: Primary testing for human papillomavirus (HPV) in cervical screening requires triage to differentiate women with transient infection from those with persistent infection who require more intensive management given their risk for cervical (pre)cancer. In this study, the clinical performance of a novel methylation marker FAM19A4 for the triage of high-risk (hr)HPV-positive women was evaluated. Using a training-validation set approach, we analyzed a FAM19A4 quantitative methylation-specific PCR (qMSP). The training set comprised hrHPV-positive cervical scrapes of 43 women with cervical intraepithelial neoplasia grade 3 or worse (CIN3+) and 135 women with <=CIN1. The validation set comprised hrHPV-positive cervical scrapes of 52 women with CIN2+, including 33 CIN3+, 19 CIN2, and 166 women with <=CIN1. The methylation threshold of FAM19A4 qMSP that gave rise to CIN3+ specificity of 70% in the training set was applied in the validation set. This resulted in CIN3+ sensitivity of 75.8% (95%CI: 61.1-90.4) at 67.0% (95%CI: 60.3-73.8) specificity. Next, the validated qMSP was applied to an independent series of hrHPV-positive cervical scrapes of 22 women with cervical cancer, 29 with advanced CIN2/3 (i.e., women with a known preceding hrHPV infection (PHI) lasting >=5 years as proxy of longer duration of lesion existence), and 19 with early CIN2/3 (i.e., PHI <5 years). All carcinomas (22/22) and advanced CIN2/3 lesions (29/29) were FAM19A4 methylation-positive, compared to 42.1% (8/19; 95%CI: 19.9-64.3) of early CIN2/3 lesions. In conclusion, FAM19A4 is an attractive triage marker for hrHPV-positive women, with a high reassurance for the detection of cervical carcinoma and advanced CIN2/3 lesions.
    Cancer prevention research (Philadelphia, Pa.). 10/2014;
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    ABSTRACT: Gene promoter hypermethylation is recognised as an essential early step in carcinogenesis, indicating important application areas for DNA methylation analysis in early cancer detection. The current study was set out to assess the performance of CADM1, MAL and miR124-2 methylation analysis in cervical scrapes for detection of cervical and endometrial cancer.
    Journal of clinical pathology. 10/2014;
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    ABSTRACT: Primary human papillomavirus (HPV)-based screening results in a 2-5% lower specificity for cervical intraepithelial neoplasia grade 2 or worse (CIN2+) compared to Pap cytology. To identify HPV-positive women with CIN2+, we retrospectively evaluated the cross-sectional and longitudinal performance of p16/Ki-67 dual-stained cytology in HPV-positive women with normal cytology participating in population-based cervical screening.Conventional Pap cytology specimens of 847 of these women derived from the VUSA-Screen study were dual-stained for p16/Ki-67. Cross-sectional clinical performance in detecting CIN3 or worse (CIN3+), and CIN2+ was compared to that of baseline HPV genotyping. Moreover, 5-year cumulative incidence risks (CIR) for CIN3+ (CIN2+) were determined.The sensitivity of p16/Ki-67 dual-stained cytology for CIN3+ (CIN2+) was 73.3% (68.8%) with a specificity of 70.0% (72.8%). HPV16/18 genotyping showed a sensitivity for CIN3+ (CIN2+) of 46.7% (43.8%), with a specificity of 78.3% (79.4%). The 5-year CIR for CIN3+ in HPV-positive women with normal cytology was 6.9%. Testing these women with p16/Ki-67 dual-stained cytology resulted in a significantly lower CIN3+ 5-year CIR of 3.3% (p=0.017) in case of a negative test result. A negative HPV16/18 genotyping test result also led to a lower 5-year CIN3+ CIR of 3.6%.p16/Ki-67 dual-stained cytology detects more than 70% of underlying CIN3+ lesions in HPV-positive women with normal cytology at baseline and is therefore suitable for triaging these women to colposcopy. Furthermore, the CIN3+ 5-year CIR of 3.3% after a negative dual-stain result is significantly lower compared to the 5-year CIR of 6.9% in women without p16/Ki-67 dual-stained cytology triage. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 10/2014; · 6.20 Impact Factor
  • The Journal of infectious diseases. 09/2014;
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    ABSTRACT: Promoter methylation of the transcription factor PRDM14 (PRDI-BF1 and RIZ domain containing 14) represents a highly frequent event in human papillomavirus (HPV)-induced cervical cancers and cancer precursor lesions. Here, we aimed to assess the functional consequences of PRDM14 promoter methylation in HPV-induced carcinogenesis. PRDM14 promoter methylation, expression and consequences of ectopic PRDM14 expression were studied in HPV16-positive cervical and oral cancer cell lines (SiHa, CaSki and 93VU147T), Human Embryonic Kidney 293 (HEK293T) cells and primary human foreskin keratinocytes (HFK). PRDM14 mRNA expression was restricted to HEK293T and HFK cells, and could be upregulated in SiHa cells upon DNA methylation inhibition. Ectopic expression of PRDM14 in SiHa, CaSki and 93VU147T cells resulted in significantly more apoptotic cells, as measured by annexin V labelling, compared to HEK293T and HFK cells. MRNA profiling of 41 apoptosis regulators identified NOXA and PUMA as candidate target genes involved in PRDM14-mediated apoptosis induction. Full-length PRDM14 transactivated both NOXA and PUMA promoters. Transactivation was abolished upon deletion of the PRDM14 DNA binding domain. This suggests that NOXA and PUMA expression is directly regulated by PRDM14, which in case of NOXA was linked to a consensus PRDM14 binding motif in the promoter region. Taken together, these results suggest that PRDM14 acts as a regulator of NOXA and PUMA-mediated apoptosis induction, thereby providing evidence for a tumour suppressive role in HPV-induced carcinogenesis. The contribution of methylation-mediated gene silencing of PRDM14 to apoptosis evasion in HPV-positive cancer cells offers novel therapeutic options for HPV-induced cancers.
    Carcinogenesis 09/2014; · 5.64 Impact Factor
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    ABSTRACT: The LMNX Genotyping Kit HPV GP (LMNX) is based on the clinically validated GP5+/6+ PCR, with a genotyping read-out as an alternative for the more established enzyme immunoassay (EIA) detection of 14 targeted high-risk HPV types. LMNX is additionally provided with an internal control probe. Here, we present an analysis of the clinical performance of the LMNX using a sample panel and infrastructure provided by the international VALGENT (Validation of Genotyping Tests) project. This panel consisted of cervical specimens from approximately 1000 women attending routine screening, 'enriched' with 300 women with abnormal cytology. Cases were defined as women with CIN2+ (n=102) or CIN3+ (n=55) within 18 months. Controls were women who had normal cytology over two subsequent screening rounds at a three-year interval (n=746). The GP5+/6+-PCR EIA (EIA) was used as a comparator assay and showed a sensitivity of 94.1% and 98.2% for CIN2+ and CIN3+, respectively, with a clinical specificity of 92.4% among women aged ≥30 years. The LMNX demonstrated a clinical sensitivity of 96.1% for CIN2+ and of 98.2% for CIN3+, and a clinical specificity of 92.6% for women aged ≥30 years. The LMNX and EIA were in high agreement (Cohen's kappa= 0.969) for the detection of 14 hrHPVs in aggregate, and no significant difference was observed (McNemar's p=0.629). The LMNX internal control detected 0.6% inadequate specimens. Based on our study results, we consider the LMNX, similar as the EIA, useful for HPV-based cervical cancer screening.
    Journal of Clinical Microbiology 09/2014; · 4.07 Impact Factor
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    ABSTRACT: Methylation marker analysis using bi-marker panel MAL/miR-124-2 is a promising triage test for identifying cervical (pre)cancer in high-risk human papillomavirus (hrHPV) positive women. Bi-marker panel MAL/miR-124-2 can be applied directly on self-sampled cervico-vaginal material and its sensitivity is non-inferior to that of cytology, yet at the cost of more colposcopy referrals. Our objective was to increase specificity of MAL/miR-124-2 methylation analysis by varying the assay thresholds and adding HPV16/18 genotyping.
    Gynecologic oncology. 08/2014;
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    ABSTRACT: Primary screening for high-risk human papillomavirus (hrHPV) requires a triage protocol. Repeat cytology testing at baseline and after 6-12 months has emerged as a reasonable triage approach, but carries the risk of loss to follow-up. Repeat cytology testing may be omitted if cytology is supplemented with another, complementary triage test at baseline. In this study, the performance of combined triage by cytology and DNA methylation analysis was assessed. In hrHPV-positive cervical scrapes (n=250), cytology (threshold: atypical squamous cells of undetermined significance (ASCUS)), bi-marker CADM1/MAL methylation testing (at different assay thresholds) and combinations of both, were evaluated for endpoints cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and grade 3 or worse (CIN3+). At a predefined methylation threshold of 70% specificity for CIN3+, combined triage revealed a CIN3+ sensitivity of 86.8% (95% CI: 76.1-97.6) compared to 65.8% (95% CI: 50.7-80.9) for sole cytology triage testing. Corresponding CIN3+ specificity was 64.8% (95% CI: 58.1-71.5) for combined triage, and 78.6% (95% CI: 72.8-84.3) for sole cytology triage testing. For CIN2+, the sensitivity of combined triage testing was 84.5% (95% CI: 75.2-93.8) versus 65.5% (95% CI: 53.3-77.7) for sole cytology triage, with corresponding specificities of 69.9% (95% CI: 63.1-76.6) and 83.5% (95% CI: 78.0-89.0), respectively. In conclusion, combined triage reached substantially higher CIN2+/3+ sensitivities compared to sole cytology at a slight drop in specificity. Therefore, it is an attractive triage strategy for colposcopy of hrHPV-positive women with a high reassurance for cervical cancer and advanced CIN lesions.
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    ABSTRACT: We determined whether the participation rate for a brush-based cervicovaginal self-sampling device is non-inferior to the participation rate for a lavage-based one for testing for hrHPV (high-risk human papillomavirus). Additionally, positivity rates for hrHPV, the detection rates for cervical intraepithelial neoplasia grades 2 and 3 or worse (CIN2+/3+), and user comfort were compared. A total of 35,477 non-responders of the regular cervical screening programme aged 33-63 years were invited to participate. Eligible women (n=30,130) were randomly assigned to receive either a brush-based or a lavage-based device, and a questionnaire for reporting user convenience. Self-sampling responders testing hrHPV-positive were invited for a physician-taken sample for cytology; triage-positive women were referred for colposcopy. A total of 5218 women participated in the brush-based sampling group (34.6%) and 4809 women in the lavage-based group (31.9%), i.e. an absolute difference of 2.7% (95%CI 1.8-4.2). The hrHPV-positivity rates in the two groups were identical (8.3%, relative risk (RR) 0.99, 95%CI 0.87-1.13). The detection of CIN2+ and CIN3+ in the brush group (2.0% for CIN2+; 1.3% for CIN3+) was similar to that in the lavage group (1.9% for CIN2+; 1.0% for CIN3+) with a cumulative RR of 1.01, 95%CI 0.83-1.24 for CIN2+ and 1.25, 95%CI 0.92-1.70 for CIN3+. The two self-sampling devices performed similarly in user comfort. In conclusion, offering a brush-based device to non-responders is non-inferior to offering a lavage-based device in terms of participation. The two self-sampling methods are equally effective in detecting hrHPV, CIN2+/CIN3+ and are both well accepted. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 06/2014; · 6.20 Impact Factor
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    ABSTRACT: Infection of cervical epithelium with high-risk human papilloma virus (hrHPV) might result in productive or transforming cervical intraepithelial neoplasia (CIN) lesions, the morphology of which can overlap. In transforming CIN lesions, aberrations in host cell genes accumulate over time, which is necessary for the ultimate progression to cancer. On the basis of (epi)genetic changes, early and advanced transforming CIN lesions can be distinguished. This paves the way for new molecular tools for cervical screening, diagnosis and management of cervical cancer precursor lesions.
    Nature reviews. Cancer. 05/2014; 14(6):395-405.
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    ABSTRACT: Women treated for high-grade cervical disease (cervical intraepithelial neoplasia grade 2 or grade 3 [CIN 2/3]) face a significant risk of developing post-treatment disease. Therefore, in most European countries, they are monitored by cytologic testing at 6, 12, and 24 months after treatment. Although testing for high-risk types of the human papillomavirus (hrHPV) in the follow-up seems to be a valuable supplementary method, its use is not yet fully explored. Besides reviewing the literature, we completed a long-term follow-up study describing the cumulative risk for CIN 2/3 or cancer (CIN 2+) of different hrHPV and cytology test results after treatment. High-risk HPV testing improves the sensitivity to detect posttreatment CIN 2/3 (relative sensitivity = 1.15, 95% confidence interval [CI] = 1.06-1.25), but the highest sensitivity (95%, 95% CI = 91%-98%) is reached by performing cotesting (both cytology and hrHPV). The CIN 2+ risk after a single negative cotesting result taken 6 months after treatments was similar to the risk after 3 consecutive negative cytologic test results (5-y CIN 2+ risk being 3.0% [95% CI = 1.5%-6.1%] and 2.9% [95% CI = 1.2%-7.1%], respectively). Women who test negative for cotesting at both 6 and 24 months after treatment have a minimal risk of developing CIN 3+ in the next 5 years (0.0%, 95% CI = 0.0%-3.0%). We propose a new posttreatment surveillance protocol, consisting of combined testing with both cytology and hrHPV at 6 and 24 months after treatment. After 2 negative cotesting results, women should be retested after 5 years.
    Journal of Lower Genital Tract Disease 04/2014; · 1.21 Impact Factor
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    ABSTRACT: High attendance rates in cervical screening are essential for effective cancer prevention. Offering HPV-self-sampling to non-responders increases participation rates. The objectives of this study were to determine why non-responders do not attend regular screening, and why they do or do not participate when offered a self-sampling device. A questionnaire study was conducted in the Netherlands from October 2011 to December 2012. 35,477 non-responders were invited to participate in an HPV-self-sampling study; 5,347 women did opt-out. Finally, 30,130 women received a questionnaire and self-sampling device. The analysis was based on 9,484 returned questionnaires (31.5%) with a self-sample specimen, and 682 (2.3%) without. Among women who returned both, the main reason for non-attendance to cervical screening was that they forgot to schedule an appointment (3,068; 32.3%). The most important reason to use the self-sampling device was the opportunity to take a sample in their own time-setting (4,763; 50.2%). 30.9% of the women who did not use the self-sampling device preferred after all to have a cervical smear taken instead. Organisational barriers are the main reason for non-attendance in regular cervical screening. Important reasons for non-responders to the regular screening to use a self-sampling device are convenience and self-control.
    Preventive Medicine 04/2014; · 3.50 Impact Factor
  • The Lancet 04/2014; 383(9925):1295. · 39.21 Impact Factor
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    ABSTRACT: In view of possible type replacement upon introduction of human papillomavirus (HPV) vaccination, we aimed to explore patterns of type-specific clustering across populations with various background infection risks. A total of 3,874 women from 3 cross-sectional studies in the Netherlands (in 2007-2009) provided vaginal self-samples, which were tested for 25 HPV genotypes by a sensitive molecular assay (SPF10 line probe assay, DDL Diagnostic Laboratory, Voorburg, the Netherlands). The number of concurrent HPV infections per woman was studied by Poisson regression. Associations between HPV types were investigated by generalized estimating equation analyses. The prevalence of any HPV type was 14% in a population-based study, 54% in a chlamydia screening intervention study, and 73% in a study among attendees of sexually transmitted infection clinics. Overall, multiple HPV infections were detected in 26% of the women. The number of concurrent HPV infections conformed to an overdispersed Poisson distribution, even after correction for known risk factors. Types differed significantly in their tendencies to be involved in coinfections, but no evidence for particular type-type interactions was found. Moreover, the strongest associations were observed in the lowest-risk population and vice versa.We found no indications of pairwise interactions, but our findings do suggest that clustering differs among HPV types and varies across risk groups.
    American journal of epidemiology 04/2014; · 5.59 Impact Factor
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    ABSTRACT: We evaluated compliance with human papilloma virus (HPV) testing and risk-adapted patient pathways and monitored changes in high-grade cervical disease during long-term follow-up. Women aged >30 years attending routine screening for cervical cancer were managed according to results from first-round screening tests (cytology and high-risk HPV; Hybrid Capture 2). Between February 2006 and January 2011, 19,795/19,947 women agreed to participate, of whom 4067 proceeded to a second screening round 5 years after recruitment. Predefined endpoints were compliance, grade 3 cervical intraepithelial neoplasia or cancer (CIN3+), new HPV infection, HPV persistence, and abnormal smears in round 2. 765/19,795 women (3.9%) in round 1 and 41/4067 (1.0%) in round 2 were referred for colposcopy. Compliance rates with colposcopy were 93.1% and 92.7%, respectively, while histological assessment was performed in 680/712 (95.5%) and 36/38 (94.7%), respectively. CIN3+ rates were 172/19,795 (0.87%; 95% confidence intervals 0.7 to 1.0) in round 1 and 2/4064 (0.05%; 95% confidence intervals 0.006 to 0.2) in round 2; the difference was statistically significant (Fisher Exact test, P<0.001). After 5 years, the incidence of new HPV infection was 124/3906 (3.2%) and HPV persistence was observed in 22/161 (13.7%). Locally organised HPV/cytology co-testing is feasible and acceptable to women. Risk-adapted management rapidly detected a high rate of prevalent CIN3+ while the subsequent long-term risk of new high-grade cervical disease was surprisingly low. It remains unclear if this phenomenon is explained by CIN3 mostly occurring early in life or by modifying the natural course of HPV infection with colposcopy and histological assessment. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 02/2014; · 6.20 Impact Factor
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    ABSTRACT: Cytology is a widely used method of triaging women who test positive for human papillomavirus (HPV). However, self-sampled specimens, which can substantially increase participation in screening programmes, are not suitable for accurate cytological assessment. We investigated whether direct DNA methylation-based molecular triage on self-sampled cervicovaginal specimens was non-inferior to cytology triage on additional physician-collected cervical samples in the detection of cervical intraepithelial neoplasia grade 2 (CIN2) or worse in women who did not attend cervical screening programmes. In this randomised controlled non-inferiority trial, we invited women (aged 33-63 years) registered as non-attendees of cervical screening in the Netherlands in 2007 to submit a self-collected cervicovaginal sample for HPV testing. Using a computer-generated sequence, we randomly allocated women who tested positive for high-risk hrHPV on a self-sample to either triage by cytology on an additional physician-taken smear or direct triage on the self-sample by methylation analysis of MAL and miR-124-2 genes (1:1; stratified by age and region, with block sizes by age group). Triage-positive women in either group were referred for colposcopy. The primary endpoint was detection of CIN2 or worse, analysed by intention to treat. The non-inferiority margin was 0·80. This study is registered in the Primary Trial Register of the Netherlands, number NTR6026. We invited 46 001 women to participate, 12 819 of whom returned self-sampled material; 1038 samples tested positive for high-risk HPV. Between Nov 1, 2010, and Dec 31, 2011, after exclusion of women who were ineligible, we enrolled and randomly allocated 515 women to methylation triage and 509 to cytology triage. The detection of CIN2 or worse with methylation triage was non-inferior to that with cytology triage (90 [17%] of 515 women vs 75 [15%] of 509 women; relative risk 1·19, 95% CI 0·90-1·57). Referral for colposcopy was more common in the molecular group (284 [55%] women) than in the cytology group (149 [29%] women; p<0·0001). Mean time to CIN2 or worse diagnosis was shorter in the molecular triage group (96 days, range 44-101) than in the cytology triage group (158 days, 71-222; p=0·00084). DNA methylation analysis of MAL and miR-124-2 genes on HPV-test-positive self-samples is non-inferior to cytology triage in the detection of CIN2 or worse, opening the way to full molecular screening. Midden-West and Oost Screening Organisations and Stichting Achmea Gezondheidszorg.
    The Lancet Oncology 02/2014; · 25.12 Impact Factor
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    ABSTRACT: Background:Women with borderline/mildly dyskaryotic (BMD) cytology smears are currently followed up with repeat testing at 6 and 18 months. The objective of this study is to analyse the cross-sectional and longitudinal performance of p16/Ki-67 dual-stained cytology for the detection of cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) and CIN2+ in women with BMD, and to compare the results with baseline human papillomavirus (HPV) testing.Methods:Conventional Pap cytology specimens of 256 women with BMD were dual stained for p16/Ki-67 retrospectively, and compared with baseline HPV results and long-term follow-up results.Results:p16/Ki-67 dual-stained cytology showed a sensitivity of 100%, a specificity of 64.4% and a negative predictive value (NPV) of 100.% for CIN3+. Human papillomavirus testing demonstrated similar sensitivity (96.3%), and NPV (99.1%), but a significantly lower specificity (57.6%; P=0.024) for CIN3+. Sensitivity, specificity and NPV for CIN2+ of dual-stained cytology were 89.7%, 73.1% and 95.1%, respectively, which was similar when compared with HPV testing. Dual-stained cytology showed a significant lower referral rate than HPV testing (43.6% vs 49.1%; P=0.043). During long-term follow-up, no CIN3+ lesions developed in HPV-positive, dual-stained negative women.Conclusions:Comparable sensitivity and NPV of dual-stained cytology for CIN3+, combined with a significantly higher specificity, makes p16/Ki-67 dual-stained cytology a viable alternative to HPV testing for triaging BMD.British Journal of Cancer advance online publication, 11 February 2014; doi:10.1038/bjc.2014.34
    British Journal of Cancer 02/2014; 110(6):1579-1586. · 5.08 Impact Factor

Publication Stats

26k Citations
3,486.89 Total Impact Points


  • 2005–2014
    • Centro di Riferimento per l'Epidemiologia e la Prevenzione Oncologica in Piemonte
      Torino, Piedmont, Italy
  • 2002–2014
    • VU University Medical Center
      • • Department of Pathology
      • • Department of Epidemiology and Biostatistics
      Amsterdamo, North Holland, Netherlands
    • Institut National de Recherche en Santé Publique
      Nouakchot, Nouakchott, Mauritania
    • Akademiska Sjukhuset
      Uppsala, Uppsala, Sweden
  • 1988–2014
    • VU University Amsterdam
      • • Department of Pathology
      • • Oral Pathology and Maxillofacial Surgery Section
      • • Department of Surgery
      • • Department of Obstetrics and Gynaecology
      Amsterdamo, North Holland, Netherlands
  • 2009–2013
    • DDL Diagnostic Laboratory
      Rijswijk, South Holland, Netherlands
  • 2003–2013
    • International Agency for Research on Cancer
      Lyons, Rhône-Alpes, France
    • Hannover Medical School
      Hanover, Lower Saxony, Germany
    • National Cancer Institute Thailand
      Krung Thep, Bangkok, Thailand
    • University of Buenos Aires
      Buenos Aires, Buenos Aires F.D., Argentina
    • National Cancer Center Korea
      Kōyō, Gyeonggi Province, South Korea
  • 2012
    • Reinier de Graaf Groep
      • Department of Gynecology and Obstetrics
      Delft, South Holland, Netherlands
  • 2008–2012
    • University Medical Center Utrecht
      • Department of Gynaecology
      Utrecht, Utrecht, Netherlands
    • Maria Sklodowska Curie Memorial Cancer Centre
      Gleiwitz, Silesian Voivodeship, Poland
    • Radboud University Medical Centre (Radboudumc)
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
    • Cancer Research UK
      Londinium, England, United Kingdom
  • 2007–2012
    • University of North Carolina at Chapel Hill
      • Department of Epidemiology
      Chapel Hill, NC, United States
  • 2005–2012
    • Erasmus MC
      • • Department of Obstetrics and Gynaecology
      • • Department of Pathology
      Rotterdam, South Holland, Netherlands
  • 1983–2012
    • University of Amsterdam
      • • Swammerdam Institute for Life Sciences
      • • Department of Pathology
      • • Department of Dermatology
      Amsterdamo, North Holland, Netherlands
  • 1970–2012
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • Department of Pathology
      Amsterdamo, North Holland, Netherlands
  • 2011
    • Johns Hopkins Bloomberg School of Public Health
      • Department of Epidemiology
      Baltimore, MD, United States
    • Queen Mary, University of London
      • Centre for Cancer Prevention
      London, ENG, United Kingdom
    • Shahid Beheshti University of Medical Sciences
      Teheran, Tehrān, Iran
  • 2005–2011
    • Institut National de Santé Publique du Québec (INSPQ)
      Québec, Quebec, Canada
  • 2002–2011
    • Institut Català d'Oncologia
      Barcino, Catalonia, Spain
  • 2010
    • KIST Medical College
      Lalitpur, Central Region, Nepal
  • 2005–2009
    • Erasmus Universiteit Rotterdam
      • Department of Obstetrics and Gynaecology
      Rotterdam, South Holland, Netherlands
  • 1979–2009
    • Leiden University Medical Centre
      • • Department of Dermatology
      • • Department of Pathology
      Leiden, South Holland, Netherlands
  • 2006–2007
    • Netherlands Cancer Institute
      • Department of Pathology
      Amsterdam, North Holland, Netherlands
    • Belgian Scientific Institute for Public Health
      Bruxelles, Brussels Capital Region, Belgium
    • Rijnstate Hospital
      Arnheim, Gelderland, Netherlands
  • 2003–2007
    • Albert Schweitzer Ziekenhuis
      Dordt, South Holland, Netherlands
  • 2004–2005
    • Leiden University
      Leyden, South Holland, Netherlands
    • University of Ibadan
      • College of Medicine
      Ibadan, Oyo State, Nigeria
  • 1998–2005
    • Danish Cancer Society
      København, Capital Region, Denmark
    • Institut National d'Oncologie, Rabat
      Rabat, Rabat-Salé-Zemmour-Zaër, Morocco
  • 2001
    • Vanderbilt University
      Nashville, Michigan, United States
    • Instituto Nacional de Salud Pública
      • The Center for Population Health Research
      Cuernavaca, Morelos, Mexico
  • 2000
    • Freie Universität Berlin
      Berlín, Berlin, Germany
  • 1993
    • Utrecht University
      Utrecht, Utrecht, Netherlands
  • 1985
    • University of the Free State
      Bloemfontein, Free State, South Africa