Wim Quint

King Faisal Specialist Hospital and Research Centre, Ar Riyāḑ, Ar Riyāḑ, Saudi Arabia

Are you Wim Quint?

Claim your profile

Publications (340)1560.37 Total impact

  • JNCI Journal of the National Cancer Institute 01/2016; 108(1):djv302. DOI:10.1093/jnci/djv302 · 12.58 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 12/2015; 137(12):2858-68. DOI:10.1002/ijc.29651 · 5.09 Impact Factor
  • [Show abstract] [Hide abstract]
    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.
    Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 11/2015; DOI:10.1016/j.jcv.2015.09.014 · 3.02 Impact Factor
  • [Show abstract] [Hide abstract]
    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.
    The American journal of surgical pathology 09/2015; 39(11). DOI:10.1097/PAS.0000000000000498 · 5.15 Impact Factor
  • [Show abstract] [Hide abstract]
    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.
    International Journal of Cancer 08/2015; DOI:10.1002/ijc.29824 · 5.09 Impact Factor
  • [Show abstract] [Hide abstract]
    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.
    International Journal of Cancer 08/2015; DOI:10.1002/ijc.29706 · 5.09 Impact Factor
  • [Show abstract] [Hide abstract]
    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.
    International Journal of Cancer 08/2015; DOI:10.1002/ijc.29722 · 5.09 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This is the author accepted manuscript. It is currently under an indefinite embargo pending publication of the final version.
  • [Show abstract] [Hide abstract]
    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; 19(4). DOI:10.1097/LGT.0000000000000124 · 1.99 Impact Factor
  • [Show abstract] [Hide abstract]
    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; 28(7). DOI:10.1038/modpathol.2015.52 · 6.19 Impact Factor
  • [Show abstract] [Hide abstract]
    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; 19(3). DOI:10.1097/LGT.0000000000000114 · 1.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 · 3.62 Impact Factor
  • [Show abstract] [Hide abstract]
    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 · 5.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 · 5.77 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective To evaluate whether specific HPV genotypes or multiple HPV infection are associated with absence of cervical intraepithelial neoplasia (CIN) in the conization specimen. Methods In a retrospective study, data were reviewed for women treated by conization at a center in Barcelona, Spain, between 2008 and 2011. Women whose pretreatment biopsy showed CIN2/3 with positive p16 staining but had no lesions in the conization specimen were included in the study group if material was sufficient for HPV genotyping. Age-matched control patients who had CIN2/3 in the conization specimen were selected. HPV genotyping was conducted on all histologic specimens. Results Both groups contained 43 patients. High-risk HPV genotypes were identified in the conization specimens of 14 (33%) women in the study group and of 42 (98%) in the control group (P < 0.001). HPV16/HPV18 was detected in the pretreatment biopsy samples of 27 (63%) women in the study group and 25 (58%) in the control group (P = 0.413). Multiple HPV infections were detected pretreatment in 8 (19%) women in the study group and 9 (21%) in the control group (P = 0.50). Conclusion No association was found between HPV genotype or multiple HPV infection and absence of lesion in the conization specimen. © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
    International Journal of Gynecology & Obstetrics 01/2015; 129(2). DOI:10.1016/j.ijgo.2014.11.009 · 1.54 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 · 4.78 Impact Factor
  • [Show abstract] [Hide abstract]
    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 · 12.58 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 · 2.47 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 · 2.61 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 · 3.36 Impact Factor

Publication Stats

14k Citations
1,560.37 Total Impact Points


  • 2014
    • King Faisal Specialist Hospital and Research Centre
      Ar Riyāḑ, Ar Riyāḑ, Saudi Arabia
  • 1995-2014
    • DDL Diagnostic Laboratory
      Rijswijk, South Holland, Netherlands
    • University of Groningen
      • Department of Obstetrics and Gynaecology
      Groningen, Groningen, Netherlands
  • 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 Cancer Institute (USA)
      • Division of Cancer Epidemiology and Genetics
      Bethesda, MD, United States
    • Karolinska Institutet
      Solna, Stockholm, Sweden
    • National Institutes of Health
      • Division of Cancer Epidemiology and Genetics
      베서스다, Maryland, United States
    • Università di Pisa
      Pisa, Tuscany, Italy
  • 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
    • Weill Cornell Medical College
      New York, New York, United States
    • Centre Hospitalier Universitaire Mont-Godinne
      Yvoir, Walloon Region, Belgium
  • 1999
    • University of Porto
      Oporto, Porto, Portugal
  • 1998-1999
    • University of Amsterdam
      • Department of Gastroenterology and Hepatology
      Amsterdamo, North Holland, Netherlands
  • 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
  • 1994
    • Gezond Amsterdam
      Amsterdamo, North Holland, Netherlands