Wim Quint

DDL Diagnostic Laboratory, Rijswijk, South Holland, Netherlands

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Publications (354)1620.5 Total impact

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    Full-text · Dataset · Jan 2016
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    ABSTRACT: Background: We conducted a large international study to estimate fractions of head and neck cancers (HNCs) attributable to human papillomavirus (HPV-AFs) using six HPV-related biomarkers of viral detection, transcription, and cellular transformation. Methods: Formalin-fixed, paraffin-embedded cancer tissues of the oral cavity (OC), pharynx, and larynx were collected from pathology archives in 29 countries. All samples were subject to histopathological evaluation, DNA quality control, and HPVDNA detection. Samples containing HPV-DNA were further subject to HPV E6*I mRNA detection and to p16INK4a, pRb, p53, and Cyclin D1 immunohistochemistry. Final estimates of HPV-AFs were based on HPV-DNA, HPV E6*I mRNA, and/or p16INK4a results. Results: A total of 3680 samples yielded valid results: 1374 pharyngeal, 1264 OC, and 1042 laryngeal cancers. HPVAF estimates based on positivity for HPV-DNA, and for either HPV E6*I mRNA or p16INK4a, were 22.4%, 4.4%, and 3.5% for cancers of the oropharynx, OC, and larynx, respectively, and 18.5%, 3.0%, and 1.5% when requiring simultaneous positivity for all three markers. HPV16 was largely the most common type. Estimates of HPV-AF in the oropharynx were highest in South America, Central and Eastern Europe, and Northern Europe, and lowest in Southern Europe. Women showed higher HPV-AFs than men for cancers of the oropharynx in Europe and for the larynx in Central-South America. Conclusions: HPV contribution to HNCs is substantial but highly heterogeneous by cancer site, region, and sex. This study, the largest exploring HPV attribution in HNCs, confirms the important role of HPVs in oropharyngeal cancer and drastically downplays the previously reported involvement of HPVs in the other HNCs.
    Full-text · Article · Jan 2016 · Journal of the National Cancer Institute
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    ABSTRACT: Background: Invasive penile cancer is a rare disease with an approximately 22 000 cases per year. The incidence is higher in less developed countries, where penile cancer can account for up to 10% of cancers among men in some parts of Africa, South America, and Asia. Objective: To describe the human papillomavirus (HPV) DNA prevalence, HPV type distribution, and detection of markers of viral activity (ie, E6*I mRNA and p16INK4a) in a series of invasive penile cancers and penile high-grade squamous intraepithelial lesions (HGSILs) from 25 countries. A total of 85 penile HGSILs and 1010 penile invasive cancers diagnosed from 1983 to 2011 were included. Design, setting, and participants: After histopathologic evaluation of formalin-fixed paraffin-embedded samples, HPV DNA detection and genotyping were performed using the SPF-10/DEIA/LiPA25 system, v.1 (Laboratory Biomedical Products, Rijswijk, The Netherlands). HPV DNA-positive cases were additionally tested for oncogene E6*I mRNA and all cases for p16INK4a expression, a surrogate marker of oncogenic HPV activity. Outcome measurements and statistical analysis: HPV DNA prevalence and type distributions were estimated. Results and limitations: HPV DNA was detected in 33.1% of penile cancers (95% confidence interval [CI], 30.2-36.1) and in 87.1% of HGSILs (95% CI, 78.0-93.4). The warty-basaloid histologic subtype showed the highest HPV DNA prevalence. Among cancers, statistically significant differences in prevalence were observed only by geographic region and not by period or by age at diagnosis. HPV16 was the most frequent HPV type detected in both HPV-positive cancers (68.7%) and HGSILs (79.6%). HPV6 was the second most common type in invasive cancers (3.7%). The p16INK4a upregulation and mRNA detection in addition to HPV DNA positivity were observed in 69.3% of HGSILs, and at least one of these HPV activity markers was detected in 85.3% of cases. In penile cancers, these figures were 22.0% and 27.1%, respectively. Conclusions: About a third to a fourth of penile cancers were related to HPV when considering HPV DNA detection alone or adding an HPV activity marker, respectively. The observed HPV type distribution reinforces the potential benefit of current and new HPV vaccines in the reduction of HPV-related penile neoplastic lesions. Patient summary: About one-third to one-quarter of penile cancers were related to human papillomavirus (HPV). The observed HPV type distribution reinforces the potential benefit of current and new HPV vaccines to prevent HPV-related penile neoplastic lesions. About one-third to one-quarter of penile cancers were related to human papillomavirus (HPV) when considering HPV DNA detection alone or adding an HPV activity marker. The observed HPV type distribution reinforces the benefit of HPV vaccines in the reduction of HPV-related penile cancer.
    Full-text · Article · Jan 2016 · European Urology

  • No preview · Article · Jan 2016 · JAIDS Journal of Acquired Immune Deficiency Syndromes
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    ABSTRACT: Objectives: To assess the feasibility of the Precursor-M methylation test as a triage marker on self-collected and hospital-collected samples amongst a hrHPV+ population in a resource limited setting. Methods: A total of 400 women were invited to participate through flyer recruitment in Abuja, Nigeria. After randomization, 200 were asked to self-collect and deposit cervical samples at designated collection points and 200 were invited to the hospital for a hospital-collected sample (HCS). A dry flocked swab was used in both groups. DNA was isolated with the nucliSENS easyMAG, tested with the GP5+/6+-PCR-EIA. A qPCR (RNaseP) to assess the level of DNA was performed. EIA+ samples with a Cq<28 (human genomic DNA concentration >1 ng/[mu]L) were tested with the Precursor-M methylation kit. Cut-offs for positivity were applied as described by the test manufacturer. Results: Samples from all 298 responding women (74.5% response) were included. The mean age of the women was 41.1 (SD 7.8, range 30-62). A total of 29 samples were found hrHPV+ by GP5+/6+; 28 (96.6%) contained enough DNA for Precursor-M testing (11 HCS, 17 self-samplers). 28.6% (8/28), including 3 HCS and 5 self-samplers, were methylation positive. Conclusions: The percentage of 28.6% methylation positive samples corresponds with previous findings (De Strooper et al, 2014). In order to assess the feasibility of methylation testing as a triage marker in the detection of high grade CIN lesions in an all-molecular screening setting, a follow-up study collecting a colposcopy directed biopsy will be performed. Results are expected by September 2015. Copyright
    No preview · Article · Jan 2016 · JAIDS Journal of Acquired Immune Deficiency Syndromes
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    ABSTRACT: : Establishment of molecular diagnostics for research requires high quality laboratory practices and validation of research methods by established laboratories. Amongst the objectives of the NIH funded H3Africa project at the African Collaborative Center for Microbiome and Genomics Research (ACCME), IHVN, Nigeria is molecular epidemiology of HPV infection. Methods: Staff from ACCME-IHVN were trained in HPV genotyping technology using the SPF10 PCR-DEIA-LiPA25, version 1 at the DDL Diagnostic Laboratory, Netherlands after which participants enrolled in the ACCME study of persistent HPV infection and cervical cancer in Nigeria were tested. Accuracy of results was ensured by sharing with collaborators at DDL for review before certification. A quality control panel of 18 positive samples and 10 negative samples were selected from a pool of 90 samples tested in Abuja were sent to DDL for re-testing. Results: The kappa statistic for agreement between detection of HPV genotypes by SPF10 DEiA in both laboratories was 0.85 (P < 0.001), 95% CI (0.66 to 1.05). All HPV negative sample results were concordant between both laboratories. Of the 18 samples used in the HPV Positive QC panel, 16 (88.8%) showed concordance of HPV genotypes, 1 (5.6%) showed compatibility for some but not all genotypes and 1 (5.6%) sample had discordant genotypes in both laboratories. Two of the 18 HPV positive samples in Nigeria tested negative at DDL. Of these 2, one was found positive for HPV 66 while the second sample had multiple HPV 45, 53, 70. Neither sample was genotyped for HPV at DDL. Of the 16 concordant HPV positive samples on DEIA, one sample was genotyped as type 52 in Nigeria but HPV X in Netherlands, while a second sample was genotyped as 40 in Nigeria but 40 and 58 in the Netherlands. Significance: The capacity of African scientists to conduct high throughput scientific research can be enhanced through training but also requires long term mentoring by international collaborating laboratories. Copyright
    No preview · Article · Jan 2016 · JAIDS Journal of Acquired Immune Deficiency Syndromes
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    ABSTRACT: Background: Previous Costa Rica Vaccine Trial (CVT) reports separately demonstrated vaccine efficacy against HPV16 and HPV18 (HPV16/18) infections at the cervical, anal, and oral regions; however, the combined overall multisite efficacy (protection at all three sites) and vaccine efficacy among women infected with HPV16 or HPV18 prior to vaccination are less known. Methods: Women age 18 to 25 years from the CVT were randomly assigned to the HPV16/18 vaccine (Cervarix) or a hepatitis A vaccine. Cervical, oral, and anal specimens were collected at the four-year follow-up visit from 4186 women. Multisite and single-site vaccine efficacies (VEs) and 95% confidence intervals (CIs) were computed for one-time detection of point prevalent HPV16/18 in the cervical, anal, and oral regions four years after vaccination. All statistical tests were two-sided. Results: The multisite woman-level vaccine efficacy was highest among “naïve” women (HPV16/18 seronegative and cervical HPV high-risk DNA negative at vaccination) (vaccine efficacy = 83.5%, 95% CI = 72.1% to 90.8%). Multisite woman-level vaccine efficacy was also demonstrated among women with evidence of a pre-enrollment HPV16 or HPV18 infection (seropositive for HPV16 and/or HPV18 but cervical HPV16/18 DNA negative at vaccination) (vaccine efficacy = 57.8%, 95% CI = 34.4% to 73.4%), but not in those with cervical HPV16 and/or HPV18 DNA at vaccination (anal/oral HPV16/18 VE = 25.3%, 95% CI = -40.4% to 61.1%). Concordant HPV16/18 infections at two or three sites were also less common in HPV16/18-infected women in the HPV vaccine vs control arm (7.4% vs 30.4%, P < .001). Conclusions: This study found high multisite vaccine efficacy among “naïve” women and also suggests the vaccine may provide protection against HPV16/18 infections at one or more anatomic sites among some women infected with these types prior to HPV16/18 vaccination.
    No preview · Article · Jan 2016 · JNCI Journal of the National Cancer Institute
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    ABSTRACT: Cervical glandular neoplasias (CGN) present a challenge for cervical cancer prevention due to their complex histopathology and difficulties in detecting pre-invasive stages with current screening practices. Reports of human papillomavirus (HPV) prevalence and type-distribution in CGN vary, providing uncertain evidence to support prophylactic vaccination and HPV screening. This study [108288/108290] assessed HPV prevalence and type-distribution in women diagnosed with cervical adenocarcinoma in situ (AIS, N=49), adenosquamous carcinoma (ASC, N=104), and various adenocarcinoma subtypes (ADC, N=461) from 17 European countries, using centralised pathology review and sensitive HPV testing. The highest HPV-positivity rates were observed in AIS (93.9%), ASC (85.6%) and usual-type ADC (90.4%), with much lower rates in rarer ADC subtypes (clear-cell: 27.6%; serous: 30.4%; endometrioid: 12.9%; gastric-type: 0%). The most common HPV types were restricted to HPV16/18/45, accounting for 98.3% of all HPV-positive ADC. There were variations in HPV prevalence and ADC type-distribution by country. Age at diagnosis differed by ADC subtype, with usual-type diagnosed in younger women (median: 43 years) compared to rarer subtypes (medians between 57-66 years). Moreover, HPV-positive ADC cases were younger than HPV-negative ADC. The six years difference in median age for women with AIS compared to those with usual-type ADC suggests that cytological screening for AIS may be sub-optimal. Since the great majority of CGN are HPV16/18/45-positive, the incorporation of prophylactic vaccination and HPV testing in cervical cancer screening are important prevention strategies. Our results suggest that special attention should be given to certain rarer ADC subtypes as most appear to be unrelated to HPV. This article is protected by copyright. All rights reserved. © 2015 UICC.
    Full-text · Article · Dec 2015 · International Journal of Cancer
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    ABSTRACT: Background: Identification of human papillomavirus (HPV) DNA in cervical tissue is important for understanding cervical carcinogenesis and for evaluating cervical cancer prevention approaches. However, HPV genotyping using formalin-fixed, paraffin-embedded (FFPE) tissues is technically challenging. We evaluated the performance of four commonly used genotyping methods on FFPE cervical specimens conducted in different laboratories and compared to genotyping results from cytological samples. Methods: We included 60 pairs of exfoliated-cell and FFPE specimens from women with histologically confirmed cervical intraepithelial lesions grade 2 or 3. Cytology specimens were genotyped using the Linear Array assay. Four expert laboratories processed tissue specimens using different preparation methods and then genotyped the resultant sample preparations using four different HPV genotyping methods: SPF10-PCR DEIA LiPA25 (version 1), Inno-LiPA, Linear Array and the Onclarity assay. Percentage agreement, kappa statistics and McNemar's chi-square were calculated for each comparison of different methods and specimen types. Results: Overall agreement with respect to carcinogenic HPV status for FFPE samples between different methods was: 81.7, 86.7 and 91.7 % for Onclarity versus Inno-LiPA, Linear Array and SPF-LiPA25, respectively; 81.7 and 85.0 % for Linear Array versus Inno-LiPA and SPF-LiPA25, respectively; and 86.7 % for SPF-LiPA25 versus Inno-LiPA. Type-specific agreement was >88.3 % for all pair-wise comparisons. Comparisons with cytology specimens resulted in overall agreements from 80 to 95 % depending on the method and type-specific agreement was >90 % for most comparisons. Conclusions: Our data demonstrate that the four genotyping methods run by expert laboratories reliably detect HPV DNA in FFPE specimens with some variation in genotype-specific detection.
    Full-text · Article · Nov 2015 · BMC Infectious Diseases
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    ABSTRACT: Background: Testing for high-risk HPV is more effective in primary cervical cancer screening than the cytological examination of a Pap smear. Separate genotyping may be useful for triage in both HPV-based and cytology-based screening. Only clinically validated tests should be used in clinical practice. Objectives: VALGENT is a study framework for test comparison and validation of HPV assays in general and HPV genotyping tests in particular according to clinically relevant outcomes and for clinical applications endorsed by scientific evidence. Study design: VALGENT involves the collation of fresh or archived cervical cell specimen from women attending routine screening supplemented with cytologically abnormal samples. Multiple aliquots of residual material are sent from a central laboratory to participating laboratories for testing with novel HPV assays with limited, extended or full genotyping capacity. Outcomes are derived from screening and pathology registries. Each VALGENT panel includes an assay already validated for screening. A series of accuracy and concordance statistics were generated. Results: Currently, two VALGENT study rounds, originated from laboratories in Antwerp (Belgium) and Edinburgh (Scotland), were completed. Two new assays (G5+/6+ PCR-LMNX and Xpert HPV) were validated for screening by showing similar accuracy for cervical precancer as the standard comparator test. For two other tests (BD Onclarity, PapilloCheck) validation was confirmed. Inter-test agreement was high although certain type-specific discordances were observed which warrant further analysis. Conclusion: VALGENT extends current guidelines for high-risk HPV test validation in cervical cancer screening and has produced a large study resource for test comparison. More robust procedures of sample selection and handling and integration with the global WHO reference laboratory network focusing on analytical accuracy, may result in the generation of an international standard and a formalized system for clinical validation of HPV assays and quality control in HPV-based screening.
    No preview · Article · Nov 2015 · Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology
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    ABSTRACT: Grading cervical intraepithelial neoplasia (CIN) determines clinical management of women after abnormal cytology with potential for overdiagnosis and overtreatment. We studied a novel biomarker of human papillomavirus (HPV) life-cycle completion (panHPVE4), in combination with the minichromosome maintenance (MCM) protein cell-cycle marker and the p16 transformation marker, to improve CIN diagnosis and categorization. Scoring these biomarkers alongside CIN grading by 3 pathologists was performed on 114 cervical specimens with high-risk (HR) HPV. Interobserver agreement for histopathology was moderate (κ=0.43 for CIN1/negative, 0.54 for CIN2/≤CIN1, and 0.36 for CIN3). Agreement was good or excellent for biomarker scoring (E4: κ=0.896; 95% confidence interval [CI]: 0.763-0.969; p16: κ=0.798; 95% CI: 0.712-0.884; MCM: κ=0.894; 95% CI: NC (this quantity cannot be calculated). Biomarker expression was studied by immunofluorescence and immunohistochemistry and was correlated with 104 final CIN diagnoses after histologic review. All 25 histologically negative specimens were p16 and panHPVE4 negative, although 9 were MCM-positive. There were variable extents of p16 positivity in 11/11 CIN1 and extensive panHPVE4 staining in 9/11. Ten CIN2 lesions expressed panHPVE4 and p16, and 13 CIN2 expressed only p16. CIN3 showed extensive p16 positivity with no/minimal panHPVE4 staining. PanHPVE4, unlike MCM, distinguished CIN1 from negative. PanHPVE4 with p16 separated CIN2/3 showing only expression of p16, indicating transforming HR-HPV E7 expression, from CIN1/2 showing completion of HR-HPV life cycle by E4 expression and variable p16 expression. PanHPVE4 and p16 staining are complementary markers that could provide simple, reliable support for diagnosing CIN. Their value in distinguishing CIN1/2 that supports HR-HPV life-cycle completion (and which might ultimately regress) from purely transforming CIN2/3 needing treatment warrants further research.
    No preview · Article · Sep 2015 · The American journal of surgical pathology
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    ABSTRACT: Recently, DNA methylation analysis of FAM19A4 in cervical scrapes has been shown to adequately detect high-grade cervical intraepithelial neoplasia and cervical cancer (≥CIN3) in high-risk HPV (hrHPV)-positive women. Here, we compared the clinical performance of FAM19A4 methylation analysis to cytology and HPV16/18 genotyping, separately and in combination, for ≥CIN3 detection in hrHPV-positive women participating in a prospective observational multi-center cohort study. The study population comprised hrHPV-positive women aged 18-66 years, visiting a gynecological outpatient clinic. From these women, cervical scrapes and colposcopy-directed biopsies (for histological confirmation) were obtained. Cervical scrapes were analyzed for FAM19A4 gene promoter methylation, cytology and HPV16/18 genotyping. Methylation analysis was performed by quantitative methylation-specific PCR (qMSP). Sensitivities and specificities for ≥CIN3 were compared between tests. Stratified analyses were performed for variables that potentially influence marker performance. Of all 508 hrHPV-positive women, the sensitivities for ≥CIN3 of cytology, FAM19A4 methylation analysis, and cytology combined with HPV16/18 genotyping were 85.6%, 75.6% and 92.2%, respectively, with corresponding specificities of 49.8%, 71.1%, and 29.4%, respectively. Both sensitivity and specificity of FAM19A4 methylation analysis were associated with age (p≤0.001 each). In women ≥30 years (n=287), ≥CIN3 sensitivity of FAM19A4 methylation analysis was 88.3% (95%CI:80.2-96.5) which was non-inferior to that of cytology [85.5% (95%CI:76.0-94.0)], at a significantly higher specificity [62.1% (95%CI:55.8-68.4) compared to 47.6% (95%CI:41.1-54.1)]. In conclusion, among hrHPV-positive women from an outpatient population aged ≥30 years, methylation analysis of FAM19A4 is an attractive marker for the identification of women with ≥CIN3. This article is protected by copyright. All rights reserved. © 2014 Wiley Periodicals, Inc.
    No preview · Article · Aug 2015 · International Journal of Cancer
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    ABSTRACT: Recent studies have shown that CADM1/MAL methylation levels in cervical scrapes increase with severity and duration of the underlying cervical intraepithelial neoplasia (CIN) lesion. Multiple lesions of different histological grades and duration are frequently present on the cervix. To gain more insight into the possible epigenetic heterogeneity and its consequences for the methylation status in cervical scrapes, we performed an exploratory study of CADM1/MAL methylation in different grades of CIN lesions present in women with multiple cervical biopsies. CADM1-M18 and MAL-M1 methylation was assessed using a standardised, multiplex, quantitative methylation specific PCR on 178 biopsies with various grades of CIN in 65 women, and in their corresponding cervical scrapes. CADM1/MAL methylation positivity increased with disease severity, from 5.5% in normal biopsies to 63.3% and 100% in biopsies with CIN3 and cervical cancer, respectively. In the majority (8/9) of women where besides a CIN2/3 lesion a biopsy from normal cervical tissue was present, the CIN2/3 biopsy was CADM1/MAL methylation positive and the normal biopsy was CADM1/MAL methylation negative. A good concordance (78%) was found between CADM1/MAL methylation results on the scrapes and the biopsy with the worst diagnosis, particularly between samples of women with CIN3 and cervical cancer (92% and 100% concordance, respectively). Thus, in women with multiple cervical biopsies, CADM1/MAL methylation increases with severity of the lesion and is lesion-specific. CADM1/MAL methylation status in cervical scrapes appears to be representative of the worst underlying lesion, particularly for CIN3 and cervical cancer.
    No preview · Article · Aug 2015 · International Journal of Cancer
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    ABSTRACT: Human Papillomavirus (HPV) is reported in 60-100% of cervical adenocarcinoma (CADC) globally. We investigated this relationship in a hospital-based survey in China. 718 CADC samples from nine Chinese regions were analysed. Expert pathologists reviewed cases with p16 and progesterone receptor immunostaining. Cases were tested for HPV using whole-tissue sections (WTS) and laser-capture microdissection. All cases were HPV-tested by L1 based broad-spectrum SPF10 -DEIA-LiPA25 PCR. Negative cases were tested for DNA adequacy and with E6 oncogene, type-specific HPV PCRs. Using WTS-PCR CADC showed overall 75% HPV-positivity (33-100% for different histological types). LCM-PCR showed that none of minimal deviation or serous CADC, and <10% of all clear cell and endometrioid CADC were HPV-positive in tumour cells. Usual and adenosquamous CADC showed a single HPV genotype in 60 and 78% cases. In some cases, HPV was found in adjacent cervix but not in tumour. HPV 16, 18 and 45 accounted for 90% of HPV in tumour cells. Patients with HPV-positive tumours were on average 6 years younger and presented at a lower clinicopathological stage as compared to patients with HPV-negative cancers. CADC is diverse pathologically and in HPV status. Special histopathological tumor subtypes may develop through different cellular and molecular pathways. Between 20 and 40% usual and adenosquamous types, in particular these diagnosed in older women and at advanced FIGO stages, are not driven by oncogenic HPV. In these cases HPV may not be involved in carcinogenisis or maybe lost during tumour progression. © 2015 UICC.
    No preview · Article · Aug 2015 · International Journal of Cancer
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    ABSTRACT: This is the author accepted manuscript. It is currently under an indefinite embargo pending publication of the final version.
    No preview · Article · Jun 2015
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    ABSTRACT: Performing endocervical curettage (ECC) at colposcopy may increase the yield of cervical intraepithelial neoplasia grade 2 (CIN2) or worse (CIN2+) compared to biopsies alone. The additional benefit of ECC in detecting CIN2+ was studied in women with lesion-targeted biopsies (low-grade or worse impression) and women with biopsies of normal-appearing cervix (less than low-grade impression). In this subanalysis of a multicenter study, 126 women referred to colposcopy who had an ECC were included. Multiple directed biopsies were taken from lesions, and a nontargeted biopsy was added if fewer than 4 biopsies were collected. Risk strata of CIN2+ were evaluated based on cytology and colposcopic appearance to identify women for whom ECC would be most valuable. The CIN2+ yield of ECC in addition to biopsies was 15 (11.9%) of 126. In women with lesion-targeted biopsies and ECC, the CIN2+ yield of targeted biopsies was 34 (51.5%) of 66, the yield of additional nontargeted biopsies was 1 (1.5%) of 66, and the additional CIN2+ yield of ECC was 5 (7.6%) of 66. The yield in women with nontargeted biopsies only and ECC was 5 (8.3%) 60, and the additional yield for ECC was 10 (16.7%) of 60. Endocervical curettage did not find disease in women with atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion. In women with less than low-grade impression and especially those with unsatisfactory colposcopy, the yield of CIN2+ was higher for ECC compared to nontargeted biopsies. The highest yield of CIN2+ from ECC was observed in women with high-grade squamous intraepithelial lesion and less than low-grade impression, suggesting that disease is higher up in the endocervix in this group.
    No preview · Article · Jun 2015 · Journal of Lower Genital Tract Disease
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    ABSTRACT: High-risk human papillomavirus (HPV) types cause cervical lesions of varying severity, ranging from transient productive infections to high-grade neoplasia. Disease stratification requires the examination of lesional pathology, and possibly also the detection of biomarkers. P16(INK4a) and MCM are established surrogates of high-risk HPV E6/E7 activity, and can be extensively expressed in high-grade lesions. Here we have combined these two cellular biomarkers with detection of the abundant HPV-encoded E4 protein in order to identify both productive and transforming lesions. This approach has allowed us to distinguish true papillomavirus infections from similar pathologies, and has allowed us to divide the heterogeneous CIN2 category into those that are CIN1-like and express E4, and those that more closely resemble nonproductive CIN3. To achieve this, 530 lesional areas were evaluated according to standard pathology criteria and by using a multiple staining approach that allows us to superimpose biomarker patterns either singly or in combination onto an annotated hematoxylin and eosin (H&E) image. Conventional grading of neoplasia was established by review panel, and compared directly with the composite molecular pathology visualized on the same tissue section. The detection of E4 coincided with the onset of vacuolation, becoming abundant in koilocytes as the MCM marker declined and cells lost their defined nuclear margins as visualized by standard H&E staining. Of the dual marker approaches, p16(INK4a) and E4 appeared most promising, with E4 generally identifying areas of low-grade disease even when p16(INK4a) was present. Extensive p16(INK4a) expression usually coincided with an absence of E4 expression or its focal retention in sporadic cells within the lesion. Our results suggest that a straightforward molecular evaluation of HPV life-cycle deregulation in cervical neoplasia may help improve disease stratification, and that this can be achieved using complementary molecular biomarker pairs such as MCM/E4 or, more promisingly, p16(INK4a)/E4 as an adjunct to conventional pathology.Modern Pathology advance online publication, 8 May 2015; doi:10.1038/modpathol.2015.52.
    No preview · Article · May 2015 · Modern Pathology
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    ABSTRACT: To study diagnostic and therapeutic strategies, outcomes, and follow-up in a large series of women with adenocarcinoma in situ (AIS) of the uterine cervix and investigate if human papillomavirus (HPV) typing among women with negative cytology reports would have helped with early AIS detection. Records of 132 AIS cases diagnosed between 1989 and 2012 were retrieved. Clinical and pathological data were reviewed and analyzed. Mean age at diagnosis was 37 years. Seventy-two percent (n = 95) of all patients were asymptomatic; diagnosis was established using cytology and biopsy. Primary treatment for 124 patents was cold knife cone or loop electrosurgical excision procedure (LEEP). Positive margins were found in 18% of those women treated with CKC versus 40% in those treated with LEEP. The mean follow-up time was 62 months (range, 2-217 months; median, 46 months). Three recurrences were found after conservative treatment in 86 patients. High-risk HPV (hrHPV) positivity was detected in 115 (96%) of 120 patients, with HPV-18 being the most commonly occurring subtype (51%). There is a small risk of relapse after conservative therapy with cold knife cone or LEEP when resection margins are negative in women with AIS. Patients should be given the options of hysterectomy or conservative therapy with strict follow-up.
    Full-text · Article · May 2015 · Journal of Lower Genital Tract Disease
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    ABSTRACT: The Costa Rica Vaccine Trial (CVT) was a randomized clinical trial conducted between 2004 and 2010, which randomized 7466 women aged 18 to 25 to receive the bivalent HPV-16/18 vaccine or control Hepatitis-A vaccine. Participants were followed for 4 years with cross-over vaccination at the study end. In 2010 the long term follow-up (LTFU) study was initiated to evaluate the 10-year impact of HPV-16/18 vaccination, determinants of the immune response, and HPV natural history in a vaccinated population. Herein, the rationale, design and methods of the LTFU study are described, which actively follows CVT participants in the HPV-arm 6 additional years at biennial intervals (3 additional study visits for 10 years of total follow-up), or more often if clinically indicated. According to the initial commitment, women in the Hepatitis-A arm were offered HPV vaccination at cross-over; they were followed 2 additional years and exited from the study. 92% of eligible CVT women accepted participation in LTFU. To provide underlying rates of HPV acquisition and cervical disease among unvaccinated women to compare with the HPV-arm during LTFU, a new unvaccinated control group (UCG) of women who are beyond the age generally recommended for routine vaccination was enrolled, and will be followed by cervical cancer screening over 6 years. To form the UCG, 5000 women were selected from a local census, of whom 2836 women (61% of eligible women) agreed to participate. Over 90% of participants complied with an interview, blood and cervical specimen collection. Evaluation of comparability between the original (Hepatitis-A arm of CVT) and new (UCG) control groups showed that women's characteristics, as well as their predicted future risk for cervical HPV acquisition, were similar, thus validating use of the UCG. LTFU is poised to comprehensively address many important questions related to long-term effects of prophylactic HPV vaccines. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Mar 2015 · Vaccine
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    ABSTRACT: Immunosuppressive treatment of organ transplant recipients is associated with an increase in the occurrence of human papillomavirus (HPV) related anogenital (pre)malignancies. This cohort study investigated the genotype-specific prevalence of HPV infections in a large cohort of female renal transplant recipients (RTRs). Participants self-collected a cervicovaginal sample for detection and genotyping of HPV. Besides, they completed a questionnaire regarding sociodemographic variables, medical data and sexual behavior. Anogenital screening was offered to all HPV-positive participants. A total number of 218 female RTRs was included. The prevalence of mucosal HPV infections was 27.1% and 17.4% for high risk HPV in particular. The studied cohort showed a broad range of HPV genotypes and multiple HPV genotypes were found in 27.1% of HPV-positive patients. Seven participants were identified with occult premalignant anogenital lesions. In conclusion, this study shows a high point-prevalence of HPV in female RTRs (age-matched West-European general population: 9-10%) with a shift in the distribution of genotypes as compared with the general population. Moreover, a substantial number of patients with occult premalignancies was identified. The introduction of self-sampling for HPV positivity can help in early detection of (pre)malignant anogenital lesions in this vulnerable population. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.
    No preview · Article · Feb 2015 · American Journal of Transplantation

Publication Stats

15k Citations
1,620.50 Total Impact Points


  • 2006-2016
    • DDL Diagnostic Laboratory
      Rijswijk, South Holland, Netherlands
  • 2014
    • King Faisal Specialist Hospital and Research Centre
      Ar Riyāḑ, Ar Riyāḑ, Saudi Arabia
  • 2006-2011
    • Leiden University Medical Centre
      • • Department of Public Health and Primary care
      • • Department of Dermatology
      • • Department of Medical Microbiology
      Leyden, South Holland, Netherlands
  • 2010
    • Radboud University Medical Centre (Radboudumc)
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
  • 2008
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2007
    • National Institutes of Health
      • Division of Cancer Epidemiology and Genetics
      베서스다, Maryland, United States
    • Università di Pisa
      Pisa, Tuscany, Italy
    • Karolinska Institutet
      Solna, Stockholm, Sweden
  • 2005
    • Slotervaartziekenhuis
      Amsterdamo, North Holland, Netherlands
  • 1998-2004
    • Reinier de Graaf Groep
      Delft, South Holland, Netherlands
  • 1997-2003
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • Academic Medical Center
      Amsterdamo, North Holland, Netherlands
  • 2001
    • Cornell University
      Итак, New York, United States
    • Centre Hospitalier Universitaire Mont-Godinne
      Yvoir, Walloon Region, Belgium
    • Weill Cornell Medical College
      New York, New York, United States
  • 1998-1999
    • University of Amsterdam
      • Department of Gastroenterology and Hepatology
      Amsterdamo, North Holland, Netherlands
    • University of Porto
      Oporto, Porto, Portugal
  • 1988-1999
    • Radboud University Nijmegen
      • Department of Medical Microbiology
      Nymegen, Gelderland, Netherlands
  • 1990-1998
    • Erasmus Universiteit Rotterdam
      • • Department of Public Health (MGZ)
      • • Department of Virology
      Rotterdam, South Holland, Netherlands
  • 1995
    • University of Groningen
      • Department of Obstetrics and Gynaecology
      Groningen, Groningen, Netherlands
  • 1994
    • Gezond Amsterdam
      Amsterdamo, North Holland, Netherlands