Wim Quint

DDL Diagnostic Laboratory, Rijswijk, South Holland, Netherlands

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Publications (365)1700.12 Total impact

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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.
    International Journal of Cancer 06/2015; DOI:10.1002/ijc.29651
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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.
    Journal of Lower Genital Tract Disease 06/2015; DOI:10.1097/LGT.0000000000000124
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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.
    Modern Pathology 05/2015; DOI:10.1038/modpathol.2015.52
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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.
    Journal of Lower Genital Tract Disease 05/2015; DOI:10.1097/LGT.0000000000000114
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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.
    Vaccine 03/2015; 33(18). DOI:10.1016/j.vaccine.2015.03.015
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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.
    American Journal of Transplantation 02/2015; 15(3). DOI:10.1111/ajt.13053
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    ABSTRACT: Anal condylomata are common in HIV-positive individuals and among men who have sex with men (MSM). Generally attributable to infection by low-risk human papillomaviruses (HPVs), condylomata are considered benign low-grade Squamous Intraepithelial Lesions (SILs). However, anal condylomata have occasionally been linked to high-grade SIL and to oncogenic, high-risk HPVs. Here we describe the range of intraepithelial lesions and of the associated HPVs in heterosexual men/women and MSM. Perianal and anal condylomata were collected from 243 patients (56 heterosexual women, 61 heterosexual men and 126 MSM, including 41 HIV-positive MSM). We assessed lesion histology and HPV genotype. Prevalence estimates and Poisson models were used. Irrespective of HIV-infection status, MSM showed higher proportion of condylomata as high-grade SILs compared with heterosexual men/women. High-grade SILs were also more prevalent in anal than in perianal lesions in all patient groups. HIV-positive MSM exhibited increased prevalence ratio [4.6; 95% CI: 2.1-10.0] of perianal low-grade SILs containing only high-risk HPVs compared with HIV-negative MSM. In addition, more than 64% of anal SILs with a high-grade component, regardless of HIV infection, were exclusively associated with low-risk HPVs. In anal condylomata, both high-grade and low-grade SILs can be associated with high-risk and/or low-risk HPVs. Particularly, low-grade perianal SILs associated with high-risk HPVs were common in HIV-positive MSM, while presence of only low-risk HPVs in high-grade SILs were common in both MSM groups. Our findings sound a note of caution for the common clinical practice for the treatment of anal condylomata as benign lesions in MSM and HIV+ patients.
    Clinical Microbiology and Infection 02/2015; in press. DOI:10.1016/j.cmi.2015.02.009
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    ABSTRACT: To evaluate whether specific HPV genotypes or multiple HPV infection are associated with absence of cervical intraepithelial neoplasia (CIN) in the conization specimen.
    International Journal of Gynecology & Obstetrics 01/2015; 129(2). DOI:10.1016/j.ijgo.2014.11.009
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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; 10(1). DOI:10.4161/15592294.2014.990787
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    ABSTRACT: Self-collected human papillomavirus (HPV) testing could reduce barriers to cervical cancer screening, with performance comparable to clinician-collected specimens. The ability of self-collected specimens to cross-sectionally and prospectively detect precursor lesions was investigated in an HPV vaccine randomized trial in Costa Rica. In the trial, 7466 women age 18 to 25 years received an HPV16/18 or control vaccine and were followed at least annually for four years. In this secondary analysis, we included all women who provided a self-collected cervicovaginal specimen six months after enrollment (5109 women = full analytical cohort). A subset (615 women = restricted cohort) also had clinician-collected specimens at the six-month postenrollment visit. High-grade squamous intraepithelial lesion or repeat low-grade squamous intraepithelial lesion prompted colposcopic referral throughout the study. HPV testing was performed with SPF10PCR/DEIA/LiPA25. Cross-sectional and prospective sensitivity, specificity, and predictive values were estimated. In the full cohort, one-time HPV testing on self-collected samples detected prevalent CIN2+ with a sensitivity of 88.7% (95% confidence interval [CI] =77.0% to 95.7%) and a specificity of 68.9% (95% CI = 67.6% to 70.1%). For predicting incident CIN2+ in the subsequent four years, sensitivity was 73.9% (95% CI = 65.8% to 81.0%) and specificity 69.4% (95% CI = 68.1% to 70.7%). In the restricted cohort, for incident CIN2+, self-collected HPV was much more sensitive than cytology (80.0% vs 10.0%); relative sensitivity was 0.1 (95% CI = 0.03% to 0.5%). Furthermore, three times more women with normal baseline cytology developed incident CIN2+ than those with negative self-collected HPV. Self-collected and clinician-collected HPV testing had comparable performance. Agreement between self- and clinician-collected samples was 89.7% (kappa = 0.78, McNemar χ2 = 0.62) for carcinogenic HPV types. Self-collected specimens can be used for HPV-based screening, providing sensitivity and specificity comparable with clinician-collected specimens and detecting disease earlier than cytology. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    JNCI Journal of the National Cancer Institute 01/2015; 107(1). DOI:10.1093/jnci/dju400
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    ABSTRACT: Efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infections with HPV in the PApilloma TRIal against Cancer In young Adults (PATRICIA; NCT00122681) was evaluated using a combination of the broad-spectrum L1-based SPF10 PCR-DEIA/LiPA25 system with type-specific PCRs for HPV-16 and 18. Broad-spectrum PCR assays may underestimate the presence of HPV genotypes present at relatively low concentrations in multiple infections, due to competition between genotypes. Therefore, samples were retrospectively re-analyzed using a testing algorithm incorporating SPF10 PCR-DEIA/LiPA25 plus a novel E6-based multiplex type-specific PCR and reverse hybridization assay (MPTS12 RHA), which permits detection of a panel of nine oncogenic HPV genotypes (types 16, 18, 31, 33, 35, 45, 52, 58 and 59). For vaccine HPV types 16 and 18, there was no major impact on estimates of vaccine efficacy (VE) for incident, 6-month or 12-month persistent infections when including MPTS12 RHA in the testing algorithm, versus the protocol-specified algorithm. However, the alternative testing algorithm showed greater sensitivity than the protocol-specified algorithm for detection of some non-vaccine oncogenic HPV types. More cases were gained in the control group than in the vaccine group, leading to higher point estimates of VE for 6-month and 12-month persistent infections for the non-vaccine oncogenic types included in the MPTS12 RHA assay (types 31, 33, 35, 45, 52, 58 and 59). This post-hoc analysis indicates that the per-protocol testing algorithm used in PATRICIA underestimated the VE against some non-vaccine oncogenic HPV types and that choice of HPV DNA testing methodology is important for the evaluation of VE in clinical trials. Copyright © 2014, American Society for Microbiology. All Rights Reserved.
    Clinical and vaccine Immunology: CVI 12/2014; 22(2). DOI:10.1128/CVI.00457-14
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    ABSTRACT: Background Cervical cancer (CC) is caused by persistent infection with high-risk (HR) human papillomavirus (HPV) types. In Saudi Arabia which has a population of 6.5 million women over the age of 15 years, approximately 152 new cases of CC are diagnosed and 55 women die from the disease annually. Nevertheless current epidemiological data for HPV in this population are limited. This study evaluated the prevalence and type distribution of HPV and documented the awareness of HPV infection and health-related behavior among Saudi and non-Saudi women attending routine examination.Methods This was an observational, epidemiological cross-sectional study conducted between April 2010 and December 2011 at three hospitals in Saudi Arabia. Cervical samples from women aged ¿15 years, who were attending routine gynecological examinations were collected and tested for HPV-DNA by polymerase chain reaction and typed using the SPF10 DEIA/LiPA25 system. Two questionnaires on health-related behavior and awareness of HPV infection were completed.ResultsA total of 417 women, mean age (standard deviation) 41.9 (±10.4) years, were included in the final analysis, of whom 77% (321/417) were Saudi nationals. HPV-DNA was detected in 9.8% women (41/417, 95% confidence interval [CI]: 7.1-13.1). The prevalence of any HR-HPV by age was: 25¿34 years: 3.0%; 35¿44 years: 4.5%; 45¿54 years: 3.2%; >55 years: 10.9%. The most prevalent HR-HPV-types were: HPV-68/73 (5 cases); HPV-18 (4 cases); HPV-16 (3 cases). The most prevalent low risk (LR) types were HPV-6 (4 cases); HPV-42, HPV-53 and HPV-54 (2 cases each). The prevalence of HPV was higher among non-Saudi nationals vs. Saudi nationals (16.7% vs. 7.8%, P¿=¿0.0234). No statistically significant risk factors were identified: 32.2% (101/314) women were aware of HPV and 89.9% (285/317) showed an interest in HPV vaccination.Conclusion The overall prevalence of HPV was 9.8% in Saudi Arabia, but was higher in women over 55 years, as well as in non-Saudi nationals. These data provide a reference for public health authorities and may also help in determining future policies for the prevention of CC.Clinical trial registration NCT01213459.
    BMC Infectious Diseases 12/2014; 14(1):643. DOI:10.1186/s12879-014-0643-8
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    ABSTRACT: Persistent infection with high-risk (HR) human papillomavirus (HPV) causes cervical cancer, the fourth most frequent cancer in the Kingdom of Bahrain, with an annual incidence of four per 100,000 women. The aim of this study was to assess the prevalence and type distribution of HPV in Bahraini and non-Bahraini women attending routine screening. HPV prevalence was assessed by risk factors and age distribution. Health-related behaviors and HPV awareness were also studied. This observational study was conducted between October 2010 and November 2011 in the Kingdom of Bahrain (NCT01205412). Women aged either >=20 years attending out-patient health services for routine cervical screening or >=16 years attending post-natal check-ups were enrolled. Cervical samples were collected and tested for HPV-DNA by polymerase chain reaction and typed using the SPF10 DEIA/LiPA25 system. All women completed two questionnaires on health-related behavior (education level, age at first marriage, number of marital partners, parity and smoking status) and HPV infection awareness. HPV DNA was detected in 56 of the 571 women included in the final analysis (9.8%); 28 (4.9%), 15 (2.6%) and 13 (2.3%) women were infected with single, multiple and unidentifiable HPV types, respectively. The most prevalent HPV types among the HPV positive women were HR-HPV-52 in eight (1.4%), HR-HPV-16, -31 and -51 in six women each (1.1%); low-risk (LR)-HPV-6 in four (0.7%); and LR-HPV-70, -74 in three women each (0.5%). Co-infection with other HR-HPV types was observed in 50% HPV-16-positive women (with HPV-31, -45 and -56) and in both HPV-18-positive women (with HPV-52). None of the health-related risk factors studied were associated with any HR-HPV infection. More than half of women (68.7%) had never heard about HPV, but most women (91.3%) in our study were interested in HPV-vaccination. HPV prevalence in Bahraini women was 9.8%. The most frequently observed HPV types were HR-HPV-52, -16, -31 and -51 and LR-HPV-6, -70 and -74. These are useful baseline data for health authorities to determine the potential impact of preventive measures including the use of prophylactic vaccines to reduce the burden of cervical cancer.
    BMC Cancer 12/2014; 14(1):905. DOI:10.1186/1471-2407-14-905
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    ABSTRACT: Background Although adolescent girls are the main population for prophylactic human papillomavirus (HPV) vaccines, adult women who remain at risk of cervical cancer can also be vaccinated. We report data from the interim analysis of the ongoing VIVIANE study, the aim of which is to assess the efficacy, safety, and immunogenicity of the HPV 16/18 AS04-adjuvanted vaccine in adult women. Methods In this phase 3, multinational, double-blind, randomised controlled trial, we randomly assigned healthy women older than 25 years to the HPV 16/18 vaccine or control (1:1), via an internet-based system with an algorithm process that accounted for region, age stratum, baseline HPV DNA status, HPV 16/18 serostatus, and cytology. Enrolment was age-stratified, with about 45% of participants in each of the 26–35 and 36–45 years age strata and 10% in the 46 years and older stratum. Up to 15% of women in each age stratum could have a history of HPV infection or disease. The primary endpoint was vaccine efficacy against 6-month persistent infection or cervical intraepithelial neoplasia grade 1 or higher (CIN1+) associated with HPV 16/18. The primary analysis was done in the according-to-protocol cohort for efficacy, which consists of women who received all three vaccine or control doses, had negative or low-grade cytology at baseline, and had no history of HPV disease. Secondary analyses included vaccine efficacy against non-vaccine oncogenic HPV types. Mean follow-up time was 40·3 months. This study is registered with ClinicalTrials.gov, number NCT00294047. Findings The first participant was enrolled on Feb 16, 2006, and the last study visit for the present analysis took place on Dec 10, 2010; 5752 women were included in the total vaccinated cohort (n=2881 vaccine, n=2871 control), and 4505 in the according-to-protocol cohort for efficacy (n=2264 vaccine, n=2241 control). Vaccine efficacy against HPV 16/18-related 6-month persistent infection or CIN1+ was significant in all age groups combined (81·1%, 97·7% CI 52·1–94·0), in the 26–35 years age group (83·5%, 45·0–96·8), and in the 36–45 years age group (77·2%, 2·8–96·9); no cases were seen in women aged 46 years and older. Vaccine efficacy against atypical squamous cells of undetermined significance or greater associated with HPV 16/18 was also significant. We also noted significant cross-protective vaccine efficacy against 6-month persistent infection with HPV 31 (79·1%, 97·7% CI 27·6–95·9) and HPV 45 (76·9%, 18·5–95·6]) Serious adverse events occurred in 285 (10%) of 2881 women in the vaccine group and 267 (9%) of 2871 in the control group; five (<1%) and eight (<1%) of these events, respectively, were believed to be related to vaccination. Interpretation In women older than 25 years, the HPV 16/18 vaccine is efficacious against infections and cervical abnormalities associated with the vaccine types, as well as infections with the non-vaccine HPV types 31 and 45. Funding GlaxoSmithKline Biologicals SA.
    The Lancet 12/2014; DOI:10.1016/S0140-6736(14)60920-X
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    ABSTRACT: Two commercial HPV tests target the same 65bp fragment of the human papillomavirus genome (designated SPF10): the original HPV SPF10 PCR-DEIA-LiPA25 system, version 1, (LiPA25) and the INNO-LiPA HPV Genotyping Extra (INNO-LiPA). The original SPF10 LiPA25 system was designed to have high analytical sensitivity and applied in HPV vaccine and epidemiology studies worldwide. But due to apparent similarities, this test can be easily confused with INNO-LiPA, a more recent assay of which the intended use, i.e., epidemiological or clinical, is currently unclear. The aim was to compare the analytical sensitivity of SPF10 LiPA25 to that of INNO-LiPA on the level of general HPV detection and genotyping. HPV testing by both assays was performed on the same DNA isolated from cervical swab (n=370) and biopsy (n=42) specimens. In cervical swabs, SPF10 LiPA25 and INNO-LiPA identified 35.2% and 29.1% multiple infections, 52.4% and 51.4% single infections, and no HPV type in 12.4% and 19.5%, respectively. Genotyping results were 65% identical, 26% compatible and 9% discordant between both methods. SPF10 LiPA25 detected significantly more genotypes (p<0.001). The higher analytical sensitivity of SPF10 LiPA25 was confirmed by the MPTS123 genotyping assay. HPV positivity by the general probes in SPF10 DEIA was significantly higher (87.6%) than by those on INNO-LiPA (76.8%) (kappa=0.602, p<0.001). In cervical biopsies, SPF10 LiPA25 and INNO-LiPA identified 21.4% and 9.5% multiple types, 76.2% and 81.0% single types, and no type in 2.4% and 9.5%, respectively. Between both tests, the identification of genotypes was 76% identical, 14% compatible and 10% discordant. Overall, significantly more genotypes were detected by SPF10 LiPA25 (kappa =0.853, p=0.022). HPV positivity was higher by the SPF10 DEIA (97.6%) than by the INNO-LiPA strip (92.9%). These results demonstrate that SPF10 LiPA25 is more suitable for HPV genotyping in epidemiologic and vaccine-related studies, due to its higher analytical sensitivity. Copyright © 2014. Published by Elsevier B.V.
    Journal of Virological Methods 12/2014; 215-216. DOI:10.1016/j.jviromet.2014.11.008
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    ABSTRACT: Eight HPV types (HPV26, 53, 66, 67, 68, 70, 73 and 82) that are phylogenetically closely related to 12 WHO-defined high-risk (HR-)HPV have been rarely but consistently identified as single HPV infections in about 3% of cervical cancer (CxCa) tissues. Due to lack of biological data, these types are referred to as probable/possible (p)HR-HPV. To analyze their biological activity in direct comparison to HR-HPV types, we selected 55 formalin-fixed paraffin-embedded (FFPE) CxCa tissues harboring single pHR-HPV infections (2-13 cases per type) and 266 tissues harboring single HR-HPV (7-40 cases per type) from a worldwide, retrospective, cross-sectional study. Single HPV infection was verified by two genotyping methods. Presence of type-specific spliced E6*I mRNA transcripts and expression of cellular proteins indicative of HPV transformation were assessed in all cases. In 55 CxCa tissues with pHR-HPV, E6*I mRNA expression was 100%, high p16INK4a, 98%; low pRb, 96%; low CyD1, 93% and low p53, 84%. Compared to HPV16 tissues as a reference, individual frequencies of these five markers did not differ significantly, either for any of the eight pHR-HPV and the 11 other HR-types individually, or for the groups of pHR- and HR-types without HPV16. We conclude that the eight pHR-HPV types, when present as a single infection in CxCa, are biologically active and affect the same cellular pathways as any of the fully-recognized carcinogenic HR-HPV types. Therefore we have provided molecular evidence of carcinogenicity for types currently classified as probably/possibly carcinogenic. Although this evidence is crucial for HPV type carcinogenicity classification, per se it is not sufficient for inclusion of these HPV types into population-wide primary and secondary prevention programs. Such decisions have to include careful estimation of effectiveness and cost-benefit analyses.
    The Journal of Pathology 12/2014; 234(4). DOI:10.1002/path.4405
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    ABSTRACT: Human papillomavirus (HPV) is found in most women with high-grade cervical intraepithelial neoplasia (CIN) 2/3 in cervical cytology and biopsies. Multiple high-risk HPV (hrHPV) genotypes are present in 15% to 50% of cytology samples. We have shown by laser-capture microscopy (LCM)-polymerase chain reaction (PCR) that each lesion is associated with a single hrHPV type. Attribution of hrHPV types to CIN2/3 is important to understand the oncogenic role of different types and the limitations of cytologic typing. We studied hrHPV genotypes in 257 women with histologic CIN2/3 referred on the basis of abnormal cytology. HPV typing was done on cytology and CIN2/3 biopsies. If the whole-tissue section of the biopsy was positive for multiple hrHPV types, LCM-PCR was performed. We found 181 (70%) single and 71 (28%) multiple hrHPV infections in cytology, with 5 (2%) cases HPV-positive only on whole-tissue section PCR. Of cases with multiple cytologic hrHPV infections, 47/71 (66%) showed a single type in CIN2/3 lesions. In total, in 232 of 257 (90%) women with CIN2/3, a single hrHPV type caused CIN2/3. One was nonattributable on the LCM level. The remaining 24 women had 2 or more contiguous or separated lesions, each associated with a single hrHPV infection. The probability of HPV16 being present in CIN2/3, if detected in cytology, was 0.96 (95% confidence interval=0.90-0.98). LCM-PCR confirms that only 9% of histologic CIN2/3 is associated with multiple hrHPV types, much less than cytology would indicate, and each lesion was associated with a single hrHPV infection.
    American Journal of Surgical Pathology 10/2014; 39(4). DOI:10.1097/PAS.0000000000000342
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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
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    ABSTRACT: Objective It has been suggested that colposcopy can miss a significant percentage of high-grade cervical intraepithelial neoplasia (CIN2 +). Improved disease ascertainment was evaluated by taking multiple lesion-directed biopsies. Methods In a cross-sectional multicentre study in the Netherlands and Spain, 610 women referred to colposcopy following abnormal cervical cytology results were included. Multiple directed biopsies were collected from lesions and ranked according to impression. A non-directed biopsy of normal-appearing tissue was added if fewer than four biopsies were collected. We evaluated the additional CIN2 + yield for one and two directed biopsies. Colposcopic images were reviewed for quality control. Results In women with at least two lesion-directed biopsies the yield for CIN2 + increased from 51.7% (95%CI; 45.7-57.7) for one directed biopsy to 60.4% (95%CI; 54.4-66.2, p < 0.001) for two biopsies. The highest CIN2 + yield was observed in women who were HPV16-positive, had high-grade squamous intraepithelial lesion (HSIL) cytology, and high-grade colposcopy impression. The yield increased from 83.1% (95%CI; 71.5-90.5) with one directed biopsy to 93.2% (95%CI; 83.8-97.3) with two directed biopsies. Only 4.5% additional CIN2 + were detected in biopsies not targeting abnormal areas on the cervix. Conclusions A second lesion-directed biopsy is associated with a significant increase in CIN2 + detection. Performing a second lesion-directed biopsy and using a low threshold for abnormality of any acetowhitening should become the standard clinical practice of colposcopy.
    Gynecologic Oncology 09/2014; 135(2). DOI:10.1016/j.ygyno.2014.08.040
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    ABSTRACT: HPV infection is a necessary cause for cervical cancer, and it is also causally linked with a range of different attributable fractions to other anogenital and head and neck cancers. The highest HPV DNA involvement in cancers other than cervix has been described in anal cancer (88.3%), followed by vaginal cancers (74.3%), peneal (33.0%) and vulvar (28.6). In high grade pre-neoplastic lesions from vulvar, vaginal, peneal and anal sites a very high HPV DNA detection rate is observed (over 85%). Agreement with biomarkers measuring the viral transforming activity is not 100%. The contribution of these additional markers is not well established when global estimates of HPV-attributable fractions (AF) in human cancer are provided. Objectives To evaluate the contribution of HPV type specific DNA, p16INK4a and type specific mRNA E6*I in anogenital cancers derived from a large repository of parafin-embedded specimens. Methods HPV DNA (SPF-10/LiPA25), p16INK4a and type specific mRNA E6*I are being evaluated in cancer and precancerous lesions of the vulva, vagina, anus and penis. The HPV contribution is estimated by considering different scenarios of biomarkers positivity and correcting for sensitivity drops. Preliminary results p16INK4a positivity among HPV DNA positive cases was 98% in cervical cancer; 95% in anal cancer; 87% in cancer of the vagina; 83% in cancer of the vulva; and 70% in peneal cancer. The HPV contribution varies depending on the markers used e.g. in vulva cancer contribution would range from 29.4% if considering a positive staining with p16INK4a, 27% with HPV DNA or 22% both combined. The meaning of discrepant results between biomarkers is still subject of discussion. Comprehensive analyses on HPV DNA, p16INK4a and mRNA E6*I in anogenital locations will be provided. Discussion The best approach to estimate HPV contribution in a given tumor has relied mainly on the viral DNA detection. A better understanding of the additional information obtained by other markers like p16INK4a or mRNA may refine our estimates of HPV contribution in related cancers at the population level.
    Revue Francophone des Laboratoires 09/2014; 2014(465):12–13. DOI:10.1016/S1773-035X(14)72669-3

Publication Stats

13k Citations
1,700.12 Total Impact Points


  • 1995–2015
    • DDL Diagnostic Laboratory
      Rijswijk, South Holland, Netherlands
  • 2014
    • King Faisal Specialist Hospital and Research Centre
      Ar Riyāḑ, Ar Riyāḑ, Saudi Arabia
    • Arabian Gulf University
      Al Manāmah, Manama, Bahrain
  • 2007–2014
    • National Cancer Institute (USA)
      • Division of Cancer Epidemiology and Genetics
      베서스다, Maryland, United States
    • Università di Pisa
      Pisa, Tuscany, Italy
    • Karolinska Institutet
      Solna, Stockholm, Sweden
  • 2013
    • IDIBELL Bellvitge Biomedical Research Institute
      Barcino, Catalonia, Spain
  • 2007–2013
    • National Institutes of Health
      • Division of Cancer Epidemiology and Genetics
      Maryland, United States
  • 1997–2013
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • Academic Medical Center
      Amsterdamo, North Holland, Netherlands
  • 2012
    • London Research Institute
      Londinium, England, United Kingdom
  • 2010–2012
    • Radboud University Medical Centre (Radboudumc)
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
  • 2006–2011
    • Leiden University Medical Centre
      • • Department of Public Health and Primary care
      • • Department of Medical Microbiology
      Leyden, South Holland, Netherlands
  • 2009
    • VU University Medical Center
      • Department of Pathology
      Amsterdam, North Holland, Netherlands
  • 2008
    • Makerere University
      Kampala, Central Region, Uganda
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 1997–2005
    • Slotervaartziekenhuis
      Amsterdamo, North Holland, Netherlands
  • 2004
    • National Cancer Center Korea
      Kōyō, Gyeonggi Province, South Korea
  • 1999–2004
    • Reinier de Graaf Groep
      Delft, South Holland, Netherlands
  • 2001
    • Cornell University
      Итак, New York, United States
    • Centre Hospitalier Universitaire Mont-Godinne
      Yvoir, Walloon Region, Belgium
  • 2000
    • University Medical Center Utrecht
      Utrecht, Utrecht, Netherlands
  • 1998–1999
    • University of Amsterdam
      • Department of Gastroenterology and Hepatology
      Amsterdamo, North Holland, Netherlands
    • University of Porto
      Oporto, Porto, Portugal
    • St Anna Ziekenhuis
      Гельдроп, North Brabant, Netherlands
  • 1988–1999
    • Radboud University Nijmegen
      • Department of Medical Microbiology
      Nymegen, Gelderland, Netherlands
    • Netherlands Cancer Institute
      • Division of Molecular Genetics
      Amsterdam, North Holland, Netherlands
  • 1990–1998
    • Erasmus Universiteit Rotterdam
      • • Department of Public Health (MGZ)
      • • Department of Dermatology
      • • Department of Virology
      Rotterdam, South Holland, Netherlands
  • 1996
    • Het Oogziekenhuis Rotterdam
      Rotterdam, South Holland, Netherlands
  • 1994–1996
    • University of Antwerp
      Antwerpen, Flanders, Belgium
    • Centraalbureau voor Schimmelcultures
      Utrecht, Utrecht, Netherlands
  • 1992–1994
    • Gezond Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 1993
    • Université Libre de Bruxelles
      • Laboratory of Microbiology
      Brussels, BRU, Belgium