Chris J L M Meijer

VU University Medical Center, Amsterdamo, North Holland, Netherlands

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Publications (756)4192.28 Total impact

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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 05/2015; 136(10). DOI:10.1002/ijc.29290 · 5.01 Impact Factor
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    ABSTRACT: Enteropathy-Associated T-cell Lymphoma (EATL) is a rare intestinal non-Hodgkin lymphoma with a poor, though variable prognosis. The International Prognostic Index (IPI) and the prognostic index for peripheral T-cell lymphoma (PIT) have limited predictive value for outcome of EATL. The purpose of this study was to develop and validate a prognostic model for EATL, which can identify high risk patients who need more aggressive therapy. This retrospective multicenter study was based on 92 patients and included 45 patients diagnosed with EATL between 1999 and 2009 from the Netherlands and 47 patients from England and Scotland, diagnosed with EATL between 1994 and 1998. A new EATL prognostic index (EPI) was constructed using the RPART (recursive partitioning and regression trees) procedure. Validation was performed applying the bootstrap method. Three risk groups were distinguished (P<0.0001): a high risk group, characterized by the presence of B-symptoms (median overall survival (OS) of 2 months); an intermediate risk group, comprising patients without B-symptoms and an IPI score ≥ 2 (7 months); and a low risk group, representing patients without B-symptoms and an IPI score of 0-1 (34 months). Internal validation showed stability of statistical significance and prognostic discrimination. In contrast to the IPI and PIT, the EPI better classified patients in risk groups according to their clinical outcome. Our new validated prognostic model EPI accurately predicts survival outcome in EATL and may be used for patient selection for new therapeutic strategies and evaluation of clinical trials. Copyright © 2015, American Association for Cancer Research.
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    ABSTRACT: Primary human papillomavirus (HPV)-based cervical screening will be introduced in The Netherlands in 2016. We assessed the five-year cervical (pre)cancer risk of women with different combinations of HPV- and cytology test results. Special attention was paid to risks for cervical intraepithelial neoplasia grade 3 and 2 or more (CIN3+/2+) of HPV-positive women with a negative triage-test, since this determines the safety of a five year screenings interval for HPV-positive, triage test negative women. In addition, age-related effects were studied. 25,553 women were screened by HPV-testing and cytology in a screening-setting. Women were managed on presence of HPV and/or abnormal cytology. Five-year cumulative incidences for CIN3+/2+ were calculated. Five-year CIN3+(2+) risk was 10.0%(17.7%) among HPV-positive women. When stratified by cytology, the CIN3+(CIN2+) risk was 7.9%(12.9%) for women with normal cytology and 22.2%(45.3%) for women with equivocal or mildly abnormal (i.e. BMD) cytology. For HPV-negative women the five-year CIN3+(2+) risk was 0.09%(0.21%). Additional triage of HPV-positive women with normal cytology by repeat-cytology at 12 months showed a five-year CIN3+(2+) risk of 4.1%(7.0%). HPV-non16/18-positive women with normal cytology at baseline had comparable risks of 3.5%(7.9%). HPV-non 16/18-positive women with normal baseline cytology and normal repeat-cytology had a five-year CIN3+ risk of 0.42%. No age-related effects were detected. In conclusion, HPV-positive women with normal cytology and a negative triage test, either repeat-cytology after 12 months or baseline HPV 16/18 genotyping, develop a non-negligible CIN3+ risk over five years. Therefore, extension of the screening interval over five years only seems possible for HPV-screen negative women. Copyright © 2015, American Association for Cancer Research.
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    ABSTRACT: The European Medicines Agency (EMA) recently approved two-dose immunization schedules for bivalent (HPV 16/18) and quadrivalent (HPV 6/11/16/18) human papillomavirus (HPV) vaccines in nine to fourteen and thirteen year-old-girls, respectively. Registration was based on trials comparing immunogenicity of two-dose schedules in girls 9-14 years to three-dose schedules in young women 15-26 years. We evaluate comparability of antibody levels between and within age groups and discuss potential implications for monitoring the effectiveness of HPV vaccination. A systematic literature search was performed for studies comparing immunogenicity of two-to three-dose schedules of HPV vaccination. We compared geometric mean concentrations (GMCs) of vaccine-type antibodies between different dosing schedules across different age groups. Meta-analysis was used to estimate pooled GMC ratios (bivalent vaccine) of two-compared with three--dose schedules within girls. For both vaccines, two-dose immunization of girls yielded non-inferior GMCs relative to a three-dose schedule in young women up to respectively 36 and 48 months follow-up. Pooled GMC ratios for the bivalent vaccine within girls showed the two-dose schedule becoming inferior to the three-dose schedule in girls for HPV 16 at approximately two years after the first dose. For the quadrivalent vaccine, antibody responses for HPV-18 became inferior from 18 months follow-up onwards when comparing the two-dose schedule three-dose with the two-dose schedule within in girls. Two-dose immunization of girls has non-inferior immunogenicity compared to a three-dose schedule among young women. However, non-inferior immunogenicity of two-compared with three-dose schedules within girls has not been shown at all time points. Due to this inconclusive evidence, implementation of two-dose HPV vaccination needs to be monitored closely. Copyright © 2015. Published by Elsevier Ltd.
    Journal of Infection 02/2015; DOI:10.1016/j.jinf.2015.02.005 · 4.02 Impact Factor
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    ABSTRACT: Triage of HPV screen-positive women is needed to identify those with underlying cervical intraepithelial neoplasia grade 2/3 or worse (CIN2/3+). Presently, cytology on a physician-taken cervical scrape is mostly accepted as triage test, but needs follow-up testing in order not to miss severe disease. Here, we evaluated the performance of combined cytology and bi-marker CADM1/MAL-methylation analysis as triage test on physician-taken cervical scrapes of HPV positive women. In this post-hoc analysis, we used 364 left-over HPV positive cytology triage samples of participants of a randomized controlled trial (PROHTECT-3: n=46,001) performed in population-based cervical screening. Study endpoints were CIN2+ and CIN3+ detection. Cytology testing with and without methylation marker analysis was evaluated with regard to sensitivity, specificity, positive and negative predictive value, and referral rate. Bi-marker CADM1/MAL-methylation positivity increased proportionally with severity of underlying lesions. Overall, cytology and bi-marker CADM1/MAL-methylation analysis yielded similar performances with regard to CIN3+ detection, yet in combination a significantly higher sensitivity for CIN3+ (88.7%) was obtained at a specificity of 53.6% and a colposcopy referral rate of 53.6%. The combined strategy detected all six cervical cancers, whereas triage by cytology alone failed to detect two of them. Cytology and bi-marker CADM1/MAL-methylation analysis perform complementary for CIN2+/CIN3+ detection when used as triage tool on cervical scrapes of HPV positive women. This approach not only results in a higher CIN3+ sensitivity than cytology triage with an acceptable referral rate, but also seems to reduce the risk of missing cervical cancers and advanced high-grade lesions. Copyright © 2015. Published by Elsevier Inc.
    Gynecologic Oncology 02/2015; DOI:10.1016/j.ygyno.2015.01.550 · 3.69 Impact Factor
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    ABSTRACT: Abstract High-risk human papillomavirus (hrHPV)-induced immortalization and malignant transformation are accompanied by DNA methylation of host genes. To determine when methylation is established during cell immortalization and whether it is hrHPV-type dependent, DNA methylation was studied in a large panel of HPVE6E7-immortalized keratinocyte cell lines. These cell lines displayed different growth behaviors, i.e., continuous growth versus crisis period prior to immortalization, reflecting differential immortalization capacities of the seven HPV-types (16/18/31/33/45/66/70) studied. In this study, cells were monitored for hypermethylation of 14 host genes (APC, CADM1, CYGB, FAM19A4, hTERT, miR124-1, miR124-2, miR124-3, MAL, PHACTR3, PRDM14, RASSF1A, ROBO3, and SFRP2) at 4 different stages during immortalization. A significant increase in overall methylation levels was seen with progression through each stage of immortalization. At stage 1 (pre-immortalization), a significant increase in methylation of hTERT, miR124-2, and PRDM14 was already apparent, which continued over time. Methylation of ROBO3 was significantly increased at stage 2 (early immortal), followed by CYGB (stage 3) and FAM19A4, MAL, PHACTR3, and SFRP2 (stage 4). Methylation patterns were mostly growth behavior independent. Yet, hTERT methylation levels were significantly increased in cells that just escaped from crisis. Bisulfite sequencing of hTERT confirmed increased methylation in immortal cells compared to controls, with the transcription core and known repressor sites remaining largely unmethylated. In conclusion, HPV-induced immortalization is associated with a sequential and progressive increase in promoter methylation of a subset of genes, which is mostly independent of the viral immortalization capacity.
    Epigenetics: official journal of the DNA Methylation Society 01/2015; DOI:10.4161/15592294.2014.990787 · 5.11 Impact Factor
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    ABSTRACT: Background Our aim was to compare the 12-month incidence and clearance of oral high-risk HPV infection between HIV-infected men who have sex with men (MSM) and HIV-negative MSM.MethodsMSM aged 18 years or older were recruited in Amsterdam, the Netherlands. Questionnaire data and oral-rinse and gargle samples were collected at baseline, and after 6 and 12 months. HPV DNA was genotyped using the SPF10-PCR & DEIA-LiPA25 system (version 1). Determinants of oral HPV incidence and clearance were explored using Cox and logistic regression analyses respectively.Results433 HIV-negative and 290 HIV-infected MSM were included in these analyses. The median follow-up time per participant was 12 months (range 3¿15). During follow-up, 114 incident oral high-risk HPV infections were observed. The incidence rate of HPV-16 was 3.5/1000 person-months (PM) in HIV-infected and 0.9/1000 PM in HIV-negative MSM (IRR 4.1; 95%CI 1.3-13.2). The incidence rates of other high-risk HPV types ranged between 1.3-3.5/1000 PM in HIV-infected and 0.0-1.1/1000 PM in HIV-negative MSM. In multivariable analyses, HIV infection (adjusted hazard ratio [aHR] 3.8; 95%CI 2.3-6.2) and a higher number of recent oral sex partners (aHR 2.4 for ¿8 partners compared to ¿2; 95%CI 1.4-4.2) were associated with HPV incidence. Of the 111 baseline oral high-risk infections, 59 (53.2%) were cleared. In multivariable analyses, only a higher number of recent oral sex partners was associated with HPV clearance (adjusted odds ratio 3.4 for ¿8 compared to ¿2 partners; 95%CI 1.3-9.0).Conclusions The incidence rate of oral high-risk HPV infection was higher in HIV-infected MSM and in those with a higher number of recent oral sex partners. Just over half of the oral high-risk HPV infections at baseline were cleared after 12 months, with a higher likelihood of clearance among MSM reporting higher numbers of recent oral sex partners, but no difference by HIV status.
    BMC Infectious Diseases 12/2014; 14(1):3845. DOI:10.1186/s12879-014-0668-z · 2.56 Impact Factor
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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; DOI:10.1002/ijc.29381 · 5.01 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; DOI:10.1159/000367921 · 1.25 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.
    Cancer Epidemiology Biomarkers & Prevention 10/2014; DOI:10.1158/1055-9965.EPI-14-0628 · 4.32 Impact Factor
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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 10/2014; DOI:10.1158/1940-6207.CAPR-14-0237 · 5.27 Impact Factor
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    ABSTRACT: Aims 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. Methods A series of cervical scrapes of women with cervical (n=79) or endometrial (n=21) cancer, cervical intraepithelial neoplasia grade 3 (CIN3) (n=16) or CIN2 (n=32), and women without evidence of CIN2 or worse (n=120) were assessed for methylation of CADM1, MAL and miR124-2. Methylation analysis was done by the PreCursor-M assay, a multiplex quantitative methylation-specific PCR. Results All samples of women with cervical cancer (79/79, 100%), independent of the histotype, and 76% (16/21; 95% CI 58.0% to 94.4%) of women with endometrial cancer scored positive for DNA methylation for at least one of the three genes. In women without cancer, methylation frequencies increased significantly with severity of disease from 19.2% (23/120; 95% CI 12.1% to 26.2%) in women without CIN2 or worse to 37.5% (12/32; 95% CI 20.7% to 54.3%) and 68.8% (11/16; 95% CI 46.0% to 91.5%) in women with CIN2 and CIN3, respectively. Overall methylation positivity and the number of methylated genes increased proportionally to the lesion severity. Conclusions DNA methylation analysis of CADM1, MAL and miR124- 2 in cervical scrapes consistently detects cervical cancer and the majority of CIN3 lesions, and has the capacity to broaden its use on cervical scrapes through the detection of a substantial subset of endometrial carcinomas.
    Journal of Clinical Pathology 10/2014; 67(12). DOI:10.1136/jclinpath-2014-202616 · 2.55 Impact Factor
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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; DOI:10.1093/carcin/bgu197 · 5.27 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 09/2014; 135(6). DOI:10.1002/ijc.28783 · 5.01 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; 58(11). DOI:10.1128/JCM.01962-14 · 4.23 Impact Factor
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    ABSTRACT: Objective To compare the clinical performance of the PapilloCheck assay (Greiner Bio-One, Germany) with that of the clinically validated high-risk HPV GP5+/6+-PCR according to the international guidelines for HPV test requirements for cervical screening (Meijer et al., IJC., 2009). Methods 1,437 cervical scrapings of women without evidence CIN2+ and 192 of women with CIN3+, originating from a population-based screening cohort (POBASCAM) were tested with both PapilloCheck and the GP5+/6+-PCR. In addition, intra-laboratory reproducibility over time and inter-laboratory agreement of the PapilloCheck assay were assessed on another set of 550 cervical samples. Clinical sensitivity and specificity values of the PapilloCheck assay were compared with those of GP5+/6+-PCR by non-inferiority score testing using previously defined thresholds for non-inferiority, i.e., relative sensitivity for CIN2+ >90% and relative specificity for CIN2+ >98%. For intraand inter-laboratory agreement a lower confidence bound not less than 87 % was used as threshold. Conclusions When restricting PapilloCheck analysis to the 14 hrHPV types targeted by GP5+/6+-PCR the clinical sensitivity and specificity were 95.8 % (95 % CI 92.8–98.8) and 96.7 % (95 % CI 95.7–97.7), respectively. By comparison, these figures were 96.4 % (95 % CI : 93.9–98.9) and 97.7 % (95 % CI : 96.9–98.5), respectively, for GP5+6+-PCR. Both the clinical sensitivity and specificity of PapilloCheck were non-inferior to that of GP5+/6+-PCR (non-inferiority score test ; P < 0.0001 and P = 0.007, respectively). High reproducibility values for HPV-positivity were obtained for both the intra-laboratory reproducibility overtime (97.6 % ; 95 % CI 96.3 %–98.6 % ; kappa value 0.941) as well as the inter-laboratory agreement (94.0 % ; 95 % CI 92.1 %–95.7 % ; kappa 0.842). Thus, when only the 14 hrHPV types targeted by the GP5+/6+-PCR are considered, PapilloCheck fulfils the crosssectional clinical and reproducibility criteria of the international guidelines for HPV test requirements for cervical screening and can be considered clinically validated.
    Revue Francophone des Laboratoires 09/2014; 2014(465):11. DOI:10.1016/S1773-035X(14)72665-6
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    ABSTRACT: Methylation markers were studied for their suitability to triage human papillomavirus (HPV)-positive women by testing self-collected cervico-vaginal lavage specimens. For this purpose, we analyzed 355 hrHPV-positive self-collected specimens with three methylation markers, that is, CADM1-m18, MAL-m1 and miR-124-2 by quantitative methylation-specific PCR. The areas under the receiver-operating characteristic (ROC) curve for end-point cervical intraepithelial neoplasia grade 3 or worse (CIN3+) were 0.637 for CADM1-m18, 0.767 for MAL-m1 and 0.762 for miR-124-2. This indicates that CADM1-m18 is not suitable as single marker. By varying the thresholds of both markers in the bi-marker panels CADM1-m18/MAL-m1, CADM1-m18/miR-124-2 and MAL-m1/miR-124-2 upper and lower ROC curves were obtained, depicting the maximum and minimum CIN3+ sensitivity, respectively, at given specificity. For all these bi-marker combinations, the upper curves were similar. However, for the MAL-m1/miR-124-2 panel, the distance between upper and lower ROC curves was closest and this panel displayed the highest assay thresholds, indicating that this combination was most robust. At clinical specificities of 50 and 70%, the MAL-m1/miR-124-2 sensitivity for detection of CIN3+ ranged from 77.0 to 87.8% and from 64.9 to 71.6%, respectively. At 70% specificity thresholds no carcinomas were missed. By comparison, the CIN3+ sensitivity of HPV16/18 genotyping on the self-sampled lavage specimens was 58.1% (95%CI: 46.6-68.8) at a specificity of 87.7% (95%CI: 83.2-91.2). In conclusion, methylation analysis is a promising triage tool that in combination with HPV-DNA testing offers feasible, full molecular screening on self-collected cervico-vaginal lavage specimens.
    International Journal of Cancer 08/2014; 135(4). DOI:10.1002/ijc.28723 · 5.01 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; 135(1). DOI:10.1016/j.ygyno.2014.08.003 · 3.69 Impact Factor
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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.
    Cancer Epidemiology Biomarkers & Prevention 06/2014; 23(9). DOI:10.1158/1055-9965.EPI-14-0347 · 4.32 Impact Factor

Publication Stats

37k Citations
4,192.28 Total Impact Points

Institutions

  • 2001–2015
    • VU University Medical Center
      • Department of Pathology
      Amsterdamo, North Holland, Netherlands
    • Vanderbilt University
      Nashville, Michigan, United States
    • Instituto Nacional de Salud Pública
      • The Center for Population Health Research
      Cuernavaca, Morelos, Mexico
  • 1999–2014
    • VU University Amsterdam
      • Department of Pathology
      Amsterdamo, North Holland, Netherlands
  • 2013
    • National Institute for Public Health and the Environment (RIVM)
      • Laboratory for Infectious Diseases and Perinatal Screening
      Utrecht, Provincie Utrecht, Netherlands
  • 2008–2012
    • University Medical Center Utrecht
      • Department of Gynaecology
      Utrecht, Utrecht, Netherlands
    • Radboud University Medical Centre (Radboudumc)
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
  • 1983–2012
    • University of Amsterdam
      • • Department of Pathology
      • • Department of Obstetrics and Gynaecology
      • • 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
  • 1975–2008
    • Leiden University Medical Centre
      • • Department of Dermatology
      • • Department of Pathology
      Leiden, South Holland, Netherlands
  • 2007
    • University of North Carolina at Chapel Hill
      • Department of Epidemiology
      Chapel Hill, NC, United States
  • 2005–2007
    • Erasmus Universiteit Rotterdam
      • Department of Obstetrics and Gynaecology
      Rotterdam, South Holland, Netherlands
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
  • 1996–2007
    • Netherlands Cancer Institute
      • Department of Pathology
      Amsterdam, North Holland, Netherlands
  • 1998–2005
    • Danish Cancer Society
      København, Capital Region, Denmark
    • Philippine General Hospital
      Manila, National Capital Region, Philippines
  • 2003–2004
    • International Agency for Research on Cancer
      • Section of Cancer Information
      Lyons, Rhône-Alpes, France
    • Institut Català d'Oncologia
      Barcino, Catalonia, Spain
    • University of Buenos Aires
      Buenos Aires, Buenos Aires F.D., Argentina
    • Hannover Medical School
      Hanover, Lower Saxony, Germany
  • 2002
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 1993
    • Utrecht University
      • Department of Dermatology and Allergology
      Utrecht, Utrecht, Netherlands
  • 1980–1981
    • Leiden University
      Leyden, South Holland, Netherlands