[show abstract][hide abstract] ABSTRACT: Cytology is a widely used method of triaging women who test positive for human papillomavirus (HPV). However, self-sampled specimens, which can substantially increase participation in screening programmes, are not suitable for accurate cytological assessment. We investigated whether direct DNA methylation-based molecular triage on self-sampled cervicovaginal specimens was non-inferior to cytology triage on additional physician-collected cervical samples in the detection of cervical intraepithelial neoplasia grade 2 (CIN2) or worse in women who did not attend cervical screening programmes.
In this randomised controlled non-inferiority trial, we invited women (aged 33-63 years) registered as non-attendees of cervical screening in the Netherlands in 2007 to submit a self-collected cervicovaginal sample for HPV testing. Using a computer-generated sequence, we randomly allocated women who tested positive for high-risk hrHPV on a self-sample to either triage by cytology on an additional physician-taken smear or direct triage on the self-sample by methylation analysis of MAL and miR-124-2 genes (1:1; stratified by age and region, with block sizes by age group). Triage-positive women in either group were referred for colposcopy. The primary endpoint was detection of CIN2 or worse, analysed by intention to treat. The non-inferiority margin was 0·80. This study is registered in the Primary Trial Register of the Netherlands, number NTR6026.
We invited 46 001 women to participate, 12 819 of whom returned self-sampled material; 1038 samples tested positive for high-risk HPV. Between Nov 1, 2010, and Dec 31, 2011, after exclusion of women who were ineligible, we enrolled and randomly allocated 515 women to methylation triage and 509 to cytology triage. The detection of CIN2 or worse with methylation triage was non-inferior to that with cytology triage (90 [17%] of 515 women vs 75 [15%] of 509 women; relative risk 1·19, 95% CI 0·90-1·57). Referral for colposcopy was more common in the molecular group (284 [55%] women) than in the cytology group (149 [29%] women; p<0·0001). Mean time to CIN2 or worse diagnosis was shorter in the molecular triage group (96 days, range 44-101) than in the cytology triage group (158 days, 71-222; p=0·00084).
DNA methylation analysis of MAL and miR-124-2 genes on HPV-test-positive self-samples is non-inferior to cytology triage in the detection of CIN2 or worse, opening the way to full molecular screening.
Midden-West and Oost Screening Organisations and Stichting Achmea Gezondheidszorg.
The lancet oncology 02/2014; · 14.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background:Women with borderline/mildly dyskaryotic (BMD) cytology smears are currently followed up with repeat testing at 6 and 18 months. The objective of this study is to analyse the cross-sectional and longitudinal performance of p16/Ki-67 dual-stained cytology for the detection of cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) and CIN2+ in women with BMD, and to compare the results with baseline human papillomavirus (HPV) testing.Methods:Conventional Pap cytology specimens of 256 women with BMD were dual stained for p16/Ki-67 retrospectively, and compared with baseline HPV results and long-term follow-up results.Results:p16/Ki-67 dual-stained cytology showed a sensitivity of 100%, a specificity of 64.4% and a negative predictive value (NPV) of 100.% for CIN3+. Human papillomavirus testing demonstrated similar sensitivity (96.3%), and NPV (99.1%), but a significantly lower specificity (57.6%; P=0.024) for CIN3+. Sensitivity, specificity and NPV for CIN2+ of dual-stained cytology were 89.7%, 73.1% and 95.1%, respectively, which was similar when compared with HPV testing. Dual-stained cytology showed a significant lower referral rate than HPV testing (43.6% vs 49.1%; P=0.043). During long-term follow-up, no CIN3+ lesions developed in HPV-positive, dual-stained negative women.Conclusions:Comparable sensitivity and NPV of dual-stained cytology for CIN3+, combined with a significantly higher specificity, makes p16/Ki-67 dual-stained cytology a viable alternative to HPV testing for triaging BMD.British Journal of Cancer advance online publication, 11 February 2014; doi:10.1038/bjc.2014.34 www.bjcancer.com.
British Journal of Cancer 02/2014; · 5.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: Cytology-based nation-wide cervical screening has led to a substantial reduction of the incidence of cervical cancer in western countries. However, the sensitivity of cytology for the detection of high-grade precursor lesions or cervical cancer is limited; therefore, repeated testing is necessary to achieve program effectiveness. Additionally, adenocarcinomas and its precursors are often missed by cytology. Consequently, there is a need for a better screening test. The insight that infection with high-risk human papillomavirus (hrHPV) is the causal agent of cervical cancer and its precursors has led to the development of molecular tests for the detection of hrHPV. Strong evidence now supports the use of hrHPV testing in the prevention of cervical cancer. In this review, we will discuss the arguments in favor of, and concerns on aspects of implementation of hrHPV testing in primary cervical cancer screening, such as the age to start hrHPV-based screening, ways to increase screening attendance, requirements for candidate hrHPV tests to be used, and triage algorithms for screen-positive women.
[show abstract][hide abstract] ABSTRACT: Methylation markers were studied for their suitability to triage human papillomavirus (HPV)-positive women by testing self-collected cervico-vaginal lavage specimens. For this purpose, we analyzed 355 hrHPV-positive self-collected specimens with three methylation markers, that is, CADM1-m18, MAL-m1 and miR-124-2 by quantitative methylation-specific PCR. The areas under the receiver-operating characteristic (ROC) curve for end-point cervical intraepithelial neoplasia grade 3 or worse (CIN3+) were 0.637 for CADM1-m18, 0.767 for MAL-m1 and 0.762 for miR-124-2. This indicates that CADM1-m18 is not suitable as single marker. By varying the thresholds of both markers in the bi-marker panels CADM1-m18/MAL-m1, CADM1-m18/miR-124-2 and MAL-m1/miR-124-2 upper and lower ROC curves were obtained, depicting the maximum and minimum CIN3+ sensitivity, respectively, at given specificity. For all these bi-marker combinations, the upper curves were similar. However, for the MAL-m1/miR-124-2 panel, the distance between upper and lower ROC curves was closest and this panel displayed the highest assay thresholds, indicating that this combination was most robust. At clinical specificities of 50 and 70%, the MAL-m1/miR-124-2 sensitivity for detection of CIN3+ ranged from 77.0 to 87.8% and from 64.9 to 71.6%, respectively. At 70% specificity thresholds no carcinomas were missed. By comparison, the CIN3+ sensitivity of HPV16/18 genotyping on the self-sampled lavage specimens was 58.1% (95%CI: 46.6-68.8) at a specificity of 87.7% (95%CI: 83.2-91.2). In conclusion, methylation analysis is a promising triage tool that in combination with HPV-DNA testing offers feasible, full molecular screening on self-collected cervico-vaginal lavage specimens.
International Journal of Cancer 01/2014; · 6.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background
In four randomised trials, human papillomavirus (HPV)-based screening for cervical cancer was compared with cytology-based cervical screening, and precursors of cancer were the endpoint in every trial. However, direct estimates are missing of the relative efficacy of HPV-based versus cytology-based screening for prevention of invasive cancer in women who undergo regular screening, of modifiers (eg, age) of this relative efficacy, and of the duration of protection. We did a follow-up study of the four randomised trials to investigate these outcomes.
176 464 women aged 20–64 years were randomly assigned to HPV-based (experimental arm) or cytology-based (control arm) screening in Sweden (Swedescreen), the Netherlands (POBASCAM), England (ARTISTIC), and Italy (NTCC). We followed up these women for a median of 6·5 years (1 214 415 person-years) and identified 107 invasive cervical carcinomas by linkage with screening, pathology, and cancer registries, by masked review of histological specimens, or from reports. Cumulative and study-adjusted rate ratios (experimental vs control) were calculated for incidence of invasive cervical carcinoma.
The rate ratio for invasive cervical carcinoma among all women from recruitment to end of follow-up was 0·60 (95% CI 0·40–0·89), with no heterogeneity between studies (p=0·52). Detection of invasive cervical carcinoma was similar between screening methods during the first 2·5 years of follow-up (0·79, 0·46–1·36) but was significantly lower in the experimental arm thereafter (0·45, 0·25–0·81). In women with a negative screening test at entry, the rate ratio was 0·30 (0·15–0·60). The cumulative incidence of invasive cervical carcinoma in women with negative entry tests was 4·6 per 105 (1·1–12·1) and 8·7 per 105 (3·3–18·6) at 3·5 and 5·5 years, respectively, in the experimental arm, and 15·4 per 105 (7·9–27·0) and 36·0 per 105 (23·2–53·5), respectively, in the control arm. Rate ratios did not differ by cancer stage, but were lower for adenocarcinoma (0·31, 0·14–0·69) than for squamous-cell carcinoma (0·78, 0·49–1·25). The rate ratio was lowest in women aged 30–34 years (0·36, 0·14–0·94).
HPV-based screening provides 60–70% greater protection against invasive cervical carcinomas compared with cytology. Data of large-scale randomised trials support initiation of HPV-based screening from age 30 years and extension of screening intervals to at least 5 years.
European Union, Belgian Foundation Against Cancer, KCE-Centre d'Expertise, IARC, The Netherlands Organisation for Health Research and Development, the Italian Ministry of Health.
[show abstract][hide abstract] ABSTRACT: Epidemiological studies identified 12 high-risk HPV (hrHPV) types and 8 probably/possibly hrHPV types which display different cancer risks. Functional studies on transforming properties of hrHPV are mainly limited to HPV16 and 18, which induce immortalization of human foreskin keratinocytes (HFKs) by successive bypass of two proliferative lifespan barriers, senescence and crisis. Here, we systematically compared the in vitro immortalization capacities as well as influences on p53, pRb, hTERT, growth behavior, and differentiation capacity of nine hrHPV types (HPV16/18/31/33/35/45/51/52/59), and two probably hrHPV types (HPV66/70). By retroviral transduction the respective E6E7 coding sequences were expressed in HFKs of two to three independent donors.Reduced p53 levels and low level hTERT expression in early passage cells, as seen in HPV16/31/33/35, and to a lesser extent HPV18 transduced HFKs, was associated with continuous growth and an increased immortalization capacity. Less frequent immortalization by HPV45/51 and immortalization by HPV66/70 was preceded by an intervening period of strongly reduced growth (crisis) without prior increase in hTERT expression. Immortalization by HPV59 was also preceded by a period crisis, despite the onset of low hTERT expression at early passage. HPV52 triggered an extended lifespan, but failed to induce immortality. Variations in p53 and pRb levels were not correlated to differences in alternative E6E7 mRNA splicing in all hrHPV transduced HFKs. On collagen rafts, transductants showed disturbed differentiation reminiscent of precancerous lesions.In conclusion, the in vitro oncogenic capacity differs between the established hrHPV types and both some established and probably hrHPV types display weak or moderate immortalization potential.
[show abstract][hide abstract] ABSTRACT: We recently identified a DNA copy number aberration (CNA)-based classifier, including changes at 3p26.3-p11.1, 3q26.2-29, and 6p25.3-24.3, as a risk predictor for cancer in individuals presenting with endobronchial squamous metaplasia. The current study was set out to validate the prediction accuracy of this classifier in an independent series of endobronchial squamous metaplastic and dysplastic lesions.The study included 36 high-risk subjects who had endobronchial lesions of various histological grades that were identified and biopsied by autofluorescence bronchoscopy and were subjected to arrayCGH in a nested case-control design. Of the 36 patients, 12 had a carcinoma in situ or invasive carcinoma at the same site at follow-up (median 11 months, range 4-24), while 24 controls remained cancer free (78 months, range 21-142).The previously defined CNA-based classifier demonstrated 92% (95% CI 77% to 98%) accuracy for cancer (in situ) prediction. All nine subjects with CNA-based classifier-positive endobronchial lesions at baseline experienced cancer outcome, whereas all 24 controls and 3 cases were classified as being low risk.In conclusion, CNAs prove to be a highly accurate biomarker for assessing the progression risk of endobronchial squamous metaplastic and dysplastic lesions. This classifier could assist in selecting subjects with endobronchial lesions who might benefit from more aggressive therapeutic intervention or surveillance.
[show abstract][hide abstract] ABSTRACT: There are very few data from men on the risk of HIV acquisition associated with penile human papillomavirus (HPV) infection and no data on the potential modifying effect of male circumcision. Therefore, this study evaluated whether HPV is independently associated with risk of HIV.
A cohort study of HPV natural history nested within a randomized control trial of male circumcision to reduce HIV incidence in Kisumu, Kenya.
Prospective data from 2519 men were analyzed using 6-month discrete-time Cox models to determine if HIV acquisition was higher among circumcised or uncircumcised men with HPV compared to HPV-uninfected men.
Risk of HIV acquisition was nonsignificantly increased among men with any HPV [adjusted hazard ratio (aHR) 1.72; 95% confidence interval (CI) 0.94-3.15] and high-risk HPV (aHR 1.92; 95% CI 0.96-3.87) compared to HPV-uninfected men, and estimates did not differ by circumcision status. Risk of HIV increased 27% with each additional HPV genotype infection (aHR 1.27; 95% CI 1.09-1.48). Men with persistent (aHR 3.27; 95% CI 1.59-6.72) or recently cleared (aHR 3.05; 95% CI 1.34-6.97) HPV had a higher risk of HIV acquisition than HPV-uninfected men.
Consistent with the findings in women, HPV infection, clearance, and persistence were associated with an increased risk of HIV acquisition in men. Given the high prevalence of HPV in populations at risk of HIV, consideration of HPV in future HIV-prevention studies and investigation into mechanisms through which HPV might facilitate HIV acquisition are needed.
AIDS (London, England) 10/2013; · 4.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: The APTIMA HPV assay is an FDA-approved assay to detect human papillomavirus (HPV) E6/E7 mRNA from 14 high-risk HPV types. This study evaluated the clinical performance of the APTIMA HPV assay for CIN2+ relative to the high-risk HPV GP5+6+-PCR in a cross-sectional clinical equivalence analysis using the non-inferiority score test on cervical samples from population-based screening, i.e., 69 cervical scrapings of women with CIN2+ and 843 of women without evidence of CIN2+. In addition, intra-laboratory reproducibility over time and inter-laboratory agreement of the APTIMA HPV assay were assessed on another set of 548 cervical samples. The APTIMA HPV assay showed a clinical sensitivity for CIN2+ of 94.2% (95% CI 85.5-97.8) and a clinical specificity for CIN2+ of 94.5% (95% CI 92.8-95.9). By comparison, these figures were 97.1% (67/69; 95% CI 89.1-99.3) and 93.6% (785/839; 95% CI 91.7-95.0), respectively, for GP5+/6+-PCR. Both clinical sensitivity and specificity of the APTIMA HPV assay were non-inferior to that of GP5+/6+-PCR (P=0.039 and P=0.00016, respectively). In addition, high reproducibility of the APTIMA HPV assay as reflected by intra-laboratory reproducibility over time of 96.0% (526/548; 95% CI 94.4-97.3, kappa 0.89) and inter-laboratory agreement of 96.7% (531/548; 95% CI: 95.4-98.1, kappa 0.91), respectively, was found. Altogether, these data show that the APTIMA HPV assay meets the cross-sectional clinical and reproducibility criteria of the international guidelines for HPV test requirements for cervical screening. Longitudinal data are needed to ensure long-term negative predictive value of this mRNA assay similar to validated HPV DNA tests.
Journal of clinical microbiology 08/2013; · 4.16 Impact Factor
[show abstract][hide abstract] ABSTRACT: Anal and penile high-risk human papillomavirus (HPV) infection is associated with anogenital cancer, which is especially common in HIV-infected MSM. We assessed HPV prevalence and determinants in MSM.
Analysis of baseline data from a prospective cohort study.
MSM aged at least 18 years were recruited in Amsterdam, the Netherlands. Participants completed risk-factor questionnaires. HPV DNA was analyzed in anal and penile shaft self-swabs and genotyped using a sensitive PCR and reverse line blot assay (SPF10-PCR-DEIA-LiPA25-system). Multivariable logistic regression analyses were performed to assess determinants of high-risk HPV infection.
MSM (n = 778) were recruited in 2010-2011, of whom 317 (41%) were HIV-infected. Prevalence of anal high-risk HPV infection was 45% in HIV-negative versus 65% in HIV-infected MSM (P <0.001). HPV-16 was the most frequently detected type and was more common in HIV-infected MSM (13% in HIV-negative and 22% in HIV-infected MSM; P = 0.001). Prevalence of penile high-risk HPV infection was 16% in HIV-negative and 32% in HIV-infected MSM (P <0.001). In multivariable analyses, HIV infection remained associated with anal [adjusted odds ratio (aOR) 2.2; 1.8-2.7] and penile (aOR 2.0; 1.4-2.9) high-risk HPV infection. Higher number of lifetime male sex partners was significantly associated with anal and penile high-risk HPV in HIV-negative, but not HIV-infected MSM. Receptive anal intercourse was associated with anal high-risk HPV in HIV-infected MSM.
Anal and penile high-risk HPV infections are very common in MSM. HIV infection is a strong and independent determinant for anal and penile high-risk HPV infection. Determinants for HPV infection appear to differ between HIV-negative and HIV-infected MSM.
AIDS (London, England) 08/2013; · 4.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: Little is known about the time span of progression from high-grade cervical intraepithelial neoplasia (CIN2/3) to invasive cervical cancer. Estimation of this duration from longitudinal studies is not permitted, as CIN2/3 should be treated when detected. Cross-sectional data on the age-specific incidence of detected CIN2/3 and cervical cancer cases are readily available in national registries, but these data are difficult to interpret because neither the moment of lesion development nor the onset of invasive cancer is observed. We developed a statistical model for estimating the duration of time between CIN2/3 and preclinical cancer using Dutch national registries for the years 2000-2005. Human papillomavirus (HPV) genotype data were used to separate CIN2/3 and cancer incidences to obtain estimates for HPV-16-positive and HPV-16-negative lesions. The median time from CIN2/3 to cancer was estimated to be 23.5 years (95% confidence interval: 20.8, 26.6), and 1.6% of the lesions progressed to cancer within 10 years. The median duration for HPV-16-positive lesions was similar, but 2.4% of the HPV-16-positive lesions progressed to cancer within 10 years, as compared with 0.6% for HPV-16-negative lesions. Estimated durations of time to cancer are essential for reassessment of the optimal screening interval in light of vaccination and novel screening tests.
American journal of epidemiology 07/2013; · 5.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: We compared the measurement of HPV-specific serum antibody levels with the virus-like- particle-multiplex immunoassay (MIA), competitive luminex immunoassay (cLIA), and glutathione-S-transferase (GST) L1-based MIA. Using a large panel of serum samples, these assays showed mutually good correlations for both naturally induced and vaccine-derived HPV-specific antibody levels. However, an adaptation of the GST-L1-based MIA resulted in an improved correlation with both cLIA and VLP-MIA.
Clinical and vaccine Immunology: CVI 06/2013; · 2.60 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background: High-risk Human Papillomavirus (hrHPV) testing has higher sensitivity but lower specificity than cytology for cervical (pre)-cancerous lesions. Therefore, triage of hrHPV positive women is needed in cervical cancer screening. Methods: A cohort of 1,100 hrHPV positive women, from a population-based screening trial (POBASCAM: n= 44,938, 29-61 years) was used to evaluate ten triage strategies, involving testing at baseline and six months with combinations of cytology, HPV16/18 genotyping and/or repeat hrHPV testing. Clinical end-point was cervical intra-epithelial neoplasia grade 3 or worse (CIN3+) detected within four years; results were adjusted for women not attending repeat testing. A triage strategy was considered acceptable, when the probability of no CIN3+ after negative triage (negative predictive value, NPV) was at least 98%, and the CIN3+ risk after positive triage (positive predictive value; PPV) was at least 20%. RESULTS : Triage at baseline with cytology only, yielded a NPV of 94.3% (95%CI: 92.0-96.0) and PPV of 39.7% (95%CI: 34.0-45.6). An increase in NPV, against a modest decrease in PPV, was obtained by triaging women with negative baseline cytology by repeat cytology (NPV 98.5%, PPV 34.0%) or by baseline HPV16/18 genotyping (NPV 98.8%, PPV 28.5%). Including both HPV16/18 genotyping at baseline and repeat cytology testing, provided a high NPV (99.6%) and a moderately high PPV (25.6%). Conclusions: Triaging hrHPV positive women by cytology at baseline and after 6-12 months, possibly in combination with baseline HPV16/18 genotyping, seems acceptable for cervical cancer screening. Impact: Implementable triage strategies are provided for primary hrHPV screening in an organized setting.
Cancer Epidemiology Biomarkers & Prevention 06/2013; · 4.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: Transformation of epithelial cells by high-risk human papillomavirus (hrHPV) types can lead to anogenital carcinomas, particularly cervical cancer, and oropharyngeal cancers. This process is associated with DNA methylation alterations often affecting tumor suppressor gene expression. This study aimed to comprehensively unravel genome-wide DNA methylation events linked to a transforming hrHPV-infection, which is driven by deregulated expression of the viral oncogenes E6 and E7 in dividing cells. Primary human keratinocytes transduced with HPV16E6E7 and their untransduced counterparts were subjected to methylation-specific digital karyotyping (MSDK) to screen for genome-wide DNA-methylation changes at different stages of HPV-induced transformation. Integration of the obtained methylation profiles with genome-wide gene expression patterns of cervical carcinomas identified 34 genes with increased methylation in HPV-transformed cells and reduced expression in cervical carcinomas. For 12 genes (CLIC3, CREB3L1, FAM19A4, LFNG, LHX1, MRC2, NKX2-8, NPTX-1, PHACTR3, PRDM14, SOST, and TNFSF13) specific methylation in HPV-containing cell lines was confirmed by semi-quantitative methylation specific PCR. Subsequent analysis of FAM19A4, LHX1, NKX2-8, NPTX-1, PHACTR3 and PRDM14 in cervical tissue specimens showed increasing methylation levels for all genes with disease progression. All six genes were frequently methylated in cervical carcinomas, with highest frequencies (up to 100%) seen for FAM19A4, PHACTR3, and PRDM14. Analysis of hrHPV-positive cervical scrapes revealed signifcantly increased methylation levels of the latter three genes in women with high-grade cervical disease compared to controls. In conclusion, MSDK analysis of HPV16 transduced keratinocytes at different stages of HPV-induced transformation resulted in the identification of novel DNA methylation events, involving FAM19A4, LHX1, NKX2-8, PHACTR3, and PRDM14 genres, in cervical carcinogenesis. These genes may provide promising triage markers to assess the presence of (pre)cancerous cervical lesions in hrHPV-positive women.
The Journal of Pathology 05/2013; · 7.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: This study showed that the Abbott RealTime High-Risk (HR) HPV assay fulfilled cross-sectional clinical equivalence and reproducibility criteria of international consensus guidelines , which indicates that this assay can be considered clinically validated for cervical cancer screening purposes.
Journal of clinical microbiology 05/2013; · 4.16 Impact Factor
[show abstract][hide abstract] ABSTRACT: OBJECTIVE:: Oral infection with human papillomavirus (HPV) is associated with a subset of head and neck cancers. We compared prevalence of, and risk factors for, oral HPV infection among HIV-negative and HIV-infected men who have sex with men (MSM). DESIGN:: Analysis of baseline data from a prospective cohort study. METHODS:: MSM aged ≥18 years were recruited from 3 study sites in Amsterdam, the Netherlands. Participants completed a self-administered risk-factor questionnaire. Oral-rinse and gargle specimens were analyzed for HPV DNA and genotyped using a highly sensitive PCR and reverse line blot assay (SPF10-PCR DEIA/LiPA25 system). RESULTS:: In 2010-11, 794 MSM were included, of whom 767 participants had sufficient data for analysis. Median age was 40.1 years (IQR 34.8-47.5) and 314 men were HIV-infected (40.9%). Any of 25 typable HPV types was present in 24.4% of all oral samples. Oncogenic HPV types were detected in 24.8% and 8.8% of oral samples from HIV-infected and HIV-negative MSM, respectively (P < 0.001). Of these high-risk types, HPV-16 was the most common (overall 3.4%). Oral infection with high-risk HPV was associated with HIV infection in multivariable analysis (P < 0.001). Increasing age was significantly associated with oral HPV infection in HIV-negative, but not in HIV-infected MSM. CONCLUSIONS:: Oral HPV infection is very common among MSM. HIV infection was independently associated with high-risk oral HPV infection, suggesting an important role of HIV in oral HPV infection.
AIDS (London, England) 04/2013; · 4.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: INTRODUCTION:: Infection with high-risk types of human papillomavirus (hrHPV) is associated with cervical, anogenital, and oropharyngeal cancers. Since a causal contribution of hrHPV infection to lung cancer (LC) is still a matter of debate, a comprehensive study was performed to delineate hrHPV involvement in LC, using a Dutch study population. METHODS:: Archival tissue specimens from 223 patients (145 men, 78 women, median age 65 years, range 27-87 years), who presented with cancer in the lungs, were subjected to GP5+/6+ polymerase chain reaction and p16 immunohistochemistry. The series included primary lung carcinomas of patients without a history of cancer (n = 175), primary lung carcinomas of patients with an unrelated cancer in the past (n = 36), and carcinomas with primary presentation in the lungs of which the origin (i.e., primary or metastasis) was equivocal at the time of diagnosis (n = 12). GP5+/6+ polymerase chain reaction/p16 double-positive carcinomas were subjected to HPV genotyping, HPVE7 transcript analysis, loss of heterozygosity analysis, and array-comparative genomic hybridization. RESULTS:: Whereas all primary lung carcinomas were hrHPV-negative (211 of 211, 100%), three hrHPV-positive equivocal carcinomas (3 of 12, 25%) were identified. These patients (1 male, 2 females) had a history of hrHPV-associated disease; one tonsillar and two cervical carcinomas. A clonal relationship between individual tumor pairs was supported by identical hrHPV genotype, pattern of p16 expression, HPVE7 mRNA expression, and genomic aberrations. CONCLUSIONS:: hrHPV presence in a tumor with primary presentation in the lungs signifies pulmonary metastasis from a primary hrHPV-positive cancer elsewhere in the body. No support was found for an attribution of hrHPV infection to the development of primary LC.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 04/2013; · 4.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: High-risk human papillomavirus (hrHPV) testing in cervical screening is usually performed on physician-taken cervical smears in liquid-based medium. However, solid-state specimen carriers allow easy, non-hazardous storage and transportation and might be suitable for self-collection by non-responders in screening and in low-resource settings. OBJECTIVES: We evaluated the adequacy of self-collected cervicovaginal (c/v) samples using a Viba-brush stored on an Indicating FTA-elute cartridge (FTA-based self-sampling) for hrHPV testing in women referred to a gynecology clinic due to an abnormal smear. STUDY DESIGN: 182 women accepted to self-collect a c/v sample. After self-sampling, a physician obtained a conventional liquid-based cervical smear. Finally, women were examined by colposcopy and a biopsy was taken when clinically indicated. Self-samples required only simple DNA elution, and DNA was extracted from physician-obtained samples. Both samples were tested for 14 hrHPVs by GP5+/6+-EIA-LQ Test and SPF10-DEIA-LiPA25. RESULTS: Both assays detected significantly more hrHPV in physician-collected specimens than in self-collected samples (75.3% and 67.6% by SPF10; 63.3% and 53.3% by GP5+/6+, respectively). The combination of physician-collected specimen and GP5+/6+ testing demonstrated the optimal balance in sensitivity (98.0%) and specificity (48.1%) for CIN2+ detection in this referral population. A test system of FTA-based self-collection and SPF10 hrHPV detection approached this sensitivity (95.9%) and specificity (42.9%). CONCLUSIONS: These results show that the clinical performance of hrHPV detection is determined by both the sample collection system and the test method. FTA-based self-collection with SPF10 testing might be valuable when a liquid-based medium cannot be used, but requires further investigation in screening populations.
Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 03/2013; · 3.12 Impact Factor