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Study Question: Is the presence of human papillomavirus (HPV) in semen associated with impairment of semen quality?Summary Answer: In a large cohort of males seeking fertility evaluation, no associations were observed between seminal HPV presence and semen parameters.What Is Known Already: HPV is commonly detected in semen samples. Whether the presence of HPV is related to impairment of semen quality, remains unclear.Study Design, Size, Duration: This cross-sectional study included a cohort of 430 males.Participants/materials, Setting, Methods: Male partners in couples seeking fertility evaluation provided one semen sample per person. Semen samples were tested for HPV-DNA using GP5+/6+-PCR. Sperm concentration was counted and motility was assessed in a Makler counting chamber at a magnification of ×200. The presence of antisperm antibodies was assessed by a mixed agglutination reaction (MAR)-test.Main Results and the Role Of Chance: Overall HPV was detected in 14.9% (64/430) of semen samples, including 2.1% (9/430) that contained both high-risk (hr) HPV and low-risk (lr) HPV types, 8.8% (38/430) with exclusively hrHPV types and 4.0% (17/430) with exclusively lrHPV types. The presence of HPV in semen was not associated with the age of the participants, seminal pH, semen volume, total sperm count, sperm concentration, progressive motility or the presence of antisperm antibodies.Limitations, Reasons For Caution: This study did not observe an association between HPV presence in semen and impairment of semen quality. However, we cannot exclude an effect of seminal HPV on early embryo development and clinical reproductive outcomes.Wider Implications Of the Findings: As HPV is frequently present in semen, screening of donor semen for HPV should be considered to prevent iatrogenic cervical HPV infections in the recipient. However our findings do not support standardized HPV testing of semen in the diagnostic work-up of subfertile couples.Study Funding/competing Interests: This study was sponsored by an unrestricted grant of Stichting Researchfonds Pathology Amsterdam, the Netherlands. P.J.F.S. has been on the speakers bureau of Roche, Gen-Probe, Abbott, Qiagen and Seegene and has been a consultant for Crucell B.V. J.B. has been on the speakers bureau of Qiagen and has been a consultant for Roche, DDL Diagnostic Laboratory, GlaxoSmithKline and Merck. D.A.M.H. has been member of the scientific advisory boards of Amgen and Pfizer, and has been on the speakers bureau of Hologic/Gen-Probe. C.J.L.M.M. has been on the speakers bureau of GlaxoSmithKline, Qiagen, Merck, Roche, Menarini and Seegene, has served occasionally on the scientific advisory board of GlaxoSmithKline, Qiagen, Merck, Roche and Genticel, and has occasionally been a consultant for Qiagen. Formerly, C.J.L.M.M. was a minority shareholder of Delphi Biosciences, which bankrupted in 2014. C.J.L.M.M. is a minority shareholder of Diassay B.V. P.J.F.S., D.A.M.H. and C.J.L.M.M. have minority stake in Self-Screen B.V., a spin-off company of VU University Medical Center. R.L., M.G.D., P.G.A.H., D.T.M.P., and I.H. do not have any conflicts of interest to disclose.Trial Registration Number: Not applicable. [ABSTRACT FROM AUTHOR]

Rationale: Autofluorescence bronchoscopy (AFB) and computed tomography (CT) enable lung cancer (LC) detection at the early (pre-)invasive stage. However, LC risk in patients with preinvasive endobronchial lesions is unclear.Objectives: To assess LC incidence and identify potential risk determinants in patients with preinvasive lesions.Methods: In our tertiary care referral center, 164 subjects with preinvasive lesions were monitored up to 12.5 years by repeated AFB and CT. Occurrence of LC was monitored. Clinical management depended on histological grade, with cancer patients receiving standard care. Potential risk determinants (smoking status, baseline histology, cancer history, and chronic obstructive pulmonary disease [COPD] status) were evaluated in relation to cancer occurrence, event-free survival (EFS), and overall survival (OS).Measurements and Main Results: During surveillance (median of 30 mo, range 4-152) of 164 subjects with preinvasive lesions (80 high grade and 84 low grade at inclusion), 61 LCs were detected in 55 subjects (median time to event 16.5 mo). Twenty-three LCs (38%) were detected by CT, and 38 (62%) were detected by AFB. More cancers (36 of 61; 59%) developed from separate, rather than initial lesional sites. Subjects with high-grade lesions were more likely to be diagnosed with LC at the same or another site in the lungs than those with low-grade lesions (P = 0.03). Independent risk determinants for OS were previous curatively treated cancer and COPD (P ≤ 0.05).Conclusions: Presence of preinvasive lesions, especially high-grade lesions, may serve as LC risk markers. LCs occur both at preinvasive lesion sites and elsewhere in the bronchial epithelium or lung parenchyma. Prospective validation of biomarkers and randomized intervention studies are needed to determine optimal management strategies. [ABSTRACT FROM AUTHOR]

The article discusses a study which investigated the impact of human papillomavirus (HPV) testing on self collected cervicovaginal lavage specimens on compliance rate among women who do not attend cervical screening. The researchers enrolled 28,073 women aged 30 to 60 who were not attending the regular cervical screening programme in the Netherlands from December 2006 to December 2007. It was found that there was an increase in the coverage of screening programmes.

Background: Human papillomavirus (HPV) testing on self-collected samples is a potential alternative to HPV testing on clinician-collected samples, but non-inferiority of its clinical accuracy remains to be assessed in the regular screening population. The IMPROVE study was done to evaluate the clinical accuracy of primary HPV testing on self-collected samples within an organised screening setting.Methods: In this randomised, non-inferiority trial, women aged 29-61 years were invited to participate in the study as part of their regular screening invitation in the Netherlands. Women who provided informed consent were randomly allocated (1:1, with a block size of ten stratified by age) to one of two groups: a self-sampling group, in which women were requested to collect their own cervicovaginal sample using an Evalyn Brush (Rovers Medical Devices BV, Oss, Netherlands); or a clinician-based sampling group, in which samples were collected by a general practitioner with a Cervex-Brush (Rovers Medical Devices BV). All samples were tested for HPV using the clinically validated GP5+/6+ PCR enzyme immunoassay (Labo Biomedical Products BV, Rijswijk, Netherlands). HPV-positive women in both groups were retested with the other collection method and triaged by cytology and repeat cytology in accordance with current Dutch screening guidelines. Primary endpoints were detection of cervical intraepithelial neoplasia (CIN) of grade 2 or worse (CIN2+) and grade 3 or worse (CIN3+). Non-inferiority of HPV testing on self-collected versus clinician-collected samples was evaluated against a margin of 90% for the relative sensitivity and 98% for the relative specificity. This study is registered at the Dutch Trial register (NTR5078) and has been completed.Findings: Of the 187 473 women invited to participate, 8212 were randomly allocated to the self-sampling group and 8198 to the clinician-based sampling group. After exclusion of women who met the exclusion criteria or who did not return their sample, 7643 women were included in the self-sampling group and 6282 in the clinician-based sampling group. 569 (7·4%) self-collected samples and 451 (7·2%) clinician-collected samples tested positive for HPV (relative risk 1·04 [95% CI 0·92-1·17]). Median follow-up duration for HPV-positive women was 20 months (IQR 17-22). The CIN2+ sensitivity and specificity of HPV testing did not differ between self-sampling and clinician-based sampling (relative sensitivity 0·96 [0·90-1·03]; relative specificity 1·00 [0·99-1·01]). For the CIN3+ endpoint, relative sensitivity was 0·99 (0·91-1·08) and relative specificity was 1·00 (0·99-1·01).Interpretation: HPV testing done with a clinically validated PCR-based assay had similar accuracy on self-collected and clinician-collected samples in terms of the detection of CIN2+ or CIN3+ lesions. These findings suggest that HPV self-sampling could be used as a primary screening method in routine screening.Funding: Ministry of Health, Welfare, and Sport (Netherlands), and the European Commission. [ABSTRACT FROM AUTHOR]

DNA methylation analysis of cervical scrapes using FAM19A4 and mir124-2 genes has shown a good clinical performance in detecting cervical cancer and advanced CIN lesions in need of treatment in HPV-positive women. To date, longitudinal data on the cancer risk of methylation test-negative women are lacking. In our study, we assessed the longitudinal outcome of FAM19A4/mir124-2 methylation analysis in an HPV-positive screening cohort with 14 years of follow-up. Archived HPV-positive cervical scrapes of 1,040 women (age 29-61 years), who were enrolled in the POBASCAM screening trial (ISRCTN20781131) were tested for FAM19A4/mir124-2 methylation. By linkage with the nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA), 35 cervical cancers were identified during 14 years of follow-up comprising three screens (baseline, and after 5 and 10 years). The baseline scrape of 36.1% (n = 375) women tested positive for FAM19A4/mir124-2 methylation, including 24 women with cervical cancer in follow-up, and 30.6% (n = 318) had abnormal cytology (threshold borderline dyskaryosis or ASCUS), including 14 women with cervical cancer in follow-up. Within screening round capability of FAM19A4/mir124-2 methylation to detect cervical cancer was 100% (11/11, 95% CI: 71.5-100). Kaplan-Meier estimate of 14-year cumulative cervical cancer incidence was 1.7% (95% CI: 0.66-3.0) among baseline methylation-negative and 2.4% (95% CI: 1.4-3.6) among baseline cytology-negative women (risk difference: 0.71% [95% CI: 0.16-1.4]). In conclusion, a negative FAM19A4/mir124-2 methylation test provides a low cervical cancer risk in HPV-positive women of 30 years and older. FAM19A4/mir124-2 methylation testing merits consideration as an objective triage test in HPV-based cervical screening programs., (© 2018 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Women who test positive for a high-risk type of the human papillomavirus (HPV) require triage testing to identify those women with cervical intraepithelial neoplasia grade 3 or cancer (≥CIN3). Although Pap cytology is considered an attractive triage test, its applicability is hampered by its subjective nature. This study prospectively compared the clinical performance of p16/Ki-67 dual-stained cytology to that of Pap cytology, with or without HPV16/18 genotyping, in high-risk HPV-positive women visiting gynecologic outpatient clinics (n=446 and age 18-66 years). From all women, cervical scrapes (for Pap cytology, HPV16/18 genotyping, and p16/Ki-67 dual-stained cytology) and colposcopy-directed biopsies were obtained. The sensitivity of p16/Ki-67 dual-stained cytology for ≥CIN3 (93.8%) did neither differ significantly from that of Pap cytology (87.7%; ratio 1.07 and 95% confidence interval (CI): 0.97-1.18) nor from that of Pap cytology combined with HPV16/18 genotyping (95.1%; ratio 0.99 and 95% CI: 0.91-1.07). However, the specificity of p16/Ki-67 dual-stained cytology for ≥CIN3 (51.2%) was significantly higher than that of Pap cytology (44.9%; ratio 1.14 and 95% CI: 1.01-1.29) and Pap cytology combined with HPV16/18 genotyping (25.8%; ratio 1.99 and 95% CI: 1.68-2.35). After exclusion of women who had been referred because of abnormal Pap cytology, the specificity of p16/Ki-67 dual-stained cytology for ≥CIN3 (56.7%) remained the same, whereas that of Pap cytology (60.3%) increased substantially, resulting in a similar specificity of both assays (ratio 0.94 and 95% CI: 0.83-1.07) in this sub-cohort. In summary, p16/Ki-67 dual-stained cytology has a good clinical performance and is an interesting objective microscopy-based triage tool for high-risk HPV-positive women.

Primary human papillomavirus (HPV)-based cervical screening will be introduced in the Netherlands in 2016. We assessed the 5-year cervical (pre)cancer risk of women with different combinations of HPV and cytology test results. Special attention was paid to risks for cervical intraepithelial neoplasia grade 3 and 2 or more (CIN3+/2+) of HPV-positive women with a negative triage test, because this determines the safety of a 5-year screening interval for HPV-positive, triage test-negative women. In addition, age-related effects were studied. A total of 25,553 women were screened by HPV testing and cytology in a screening setting. Women were managed on the presence of HPV and/or abnormal cytology. Five-year cumulative incidences for CIN3+/2+ were calculated. Five-year CIN3+(2+) risk was 10.0% (17.7%) among HPV-positive women. When stratified by cytology, the CIN3+(CIN2+) risk was 7.9% (12.9%) for women with normal cytology and 22.2% (45.3%) for women with equivocal or mildly abnormal (i.e., BMD) cytology. For HPV-negative women, the 5-year CIN3+(2+) risk was 0.09% (0.21%). Additional triage of HPV-positive women with normal cytology by repeat cytology at 12 months showed a 5-year CIN3+(2+) risk of 4.1% (7.0%). HPV-non 16/18-positive women with normal cytology at baseline had comparable risks of 3.5% (7.9%). HPV-non 16/18-positive women with normal baseline cytology and normal repeat cytology had a 5-year CIN3+ risk of 0.42%. No age-related effects were detected. In conclusion, HPV-positive women with normal cytology and a negative triage test, either repeat cytology after 12 months or baseline HPV 16/18 genotyping, develop a non-negligible CIN3+ risk over 5 years. Therefore, extension of the screening interval over 5 years only seems possible for HPV screen-negative women., (©2015 American Association for Cancer Research.)

The effects of single or multiple concordant HPV infections at various anatomical sites on type-specific HPV seropositivity are currently unknown. In this cross-sectional study we assessed whether high-risk HPV infections at various anatomical sites (i.e., anal canal, penile shaft, and oral cavity), as well as concordant infections at multiple anatomical sites, were associated with type-specific seropositivity in HIV-positive and HIV-negative MSM. MSM aged ≥ 18 years were recruited in Amsterdam, the Netherlands (2010-2011). Baseline anal, penile, and oral samples were analyzed for HPV DNA and genotyped using a highly sensitive PCR and reverse line blot assay. Virus-like particle (VLP) based multiplex immunoassay was used to asses HPV-specific serum antibodies against L1 VLPs. The associations between HPV infections and type-specific seropositivity of seven high-risk HPV types (7-hrHPV: types 16, 18, 31, 33, 45, 52, 58) were estimated using logistic regression analyses with generalized estimating equations. We found that 86% of 306 HIV-positive MSM and 62% of 441 HIV-negative MSM were seropositive for at least one 7-hrHPV type. 69% of HIV-positive and 41% of HIV-negative MSM were infected with at least one 7-hrHPV type at the anus, penis, or oral cavity. In multivariable analyses, 7-hrHPV seropositivity was associated with type-specific anal (and not penile) 7-hrHPV infection, and did not significantly increase with a higher number of infected anatomical sites. Oral 7-hrHPV infection showed a positive, albeit non-significant, association with seropositivity. In conclusion, seropositivity among MSM appears to be largely associated with anal HPV infection, irrespective of additionally infected anatomical sites.

Background: Men who have sex with men (MSM), in particular HIV-infected MSM, are at increased risk for diseases related to human papilloma virus (HPV). Our goal was to assess the effect of HIV status on the presence of type-specific antibodies against seven high-risk HPV types in HPV-unvaccinated MSM. Moreover, we compared determinants of HPV seropositivity between HIV-negative and HIV-infected MSM., Methods: MSM ≥18 years of age were recruited from the Amsterdam Cohort Studies, a sexually transmitted infection clinic, and an HIV-treatment center in Amsterdam, the Netherlands. Participants completed a risk-factor questionnaire; serum samples were analyzed using a fluorescent bead-based multiplex assay., Results: MSM (n = 795) were recruited in 2010 to 2011; 758 MSM were included in this analysis. Median age was 40.1 years (interquartile range 34.8-47.5) and 308 MSM (40.6%) were HIV-infected. Seroprevalence of HPV-16 was 37.1% in HIV-negative and 62.7% in HIV-infected MSM (P < 0.001); seroprevalence of HPV-18 was 29.1% in HIV-negative MSM and 42.5% in HIV-infected MSM (P < 0.001). Similar patterns of seroprevalence were observed for HPV types 31, 33, 45, 52, and 58. In multivariable analyses, HPV seropositivity was associated with HIV infection [adjusted OR = 2.1; 95% confidence interval, 1.6-2.6]. In multivariable analyses stratified by HIV status, increasing age and number of lifetime male sex partners were significantly associated with HPV seropositivity in HIV-negative, but not HIV-infected MSM., Conclusions: Seroprevalence of high-risk HPV types is high among unvaccinated MSM., Impact: HIV infection is a strong and independent determinant for HPV seropositivity, which we hypothesize is because of increased persistence of HPV infection in HIV-infected MSM.

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 MSM., Design: Analysis of baseline data from a prospective cohort study., Methods: MSM aged 18 years or older were recruited from three 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 [short PCR fragment (SPF)10-PCR-DNA Enzyme Immuno Assay (DEIA)/LiPA25 system]., Results: In 2010-2011, 794 MSM were included, of whom 767 participants had sufficient data for analysis. Median age was 40.1 years [interquartile range (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., Conclusion: 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.

Human papillomavirus (HPV) infection has been etiologically linked to oropharyngeal squamous cell carcinoma (OPSCC). The prevalence of HPV-positive OPSCC varies between studies, ranging from 20 to 90%. This may be related to the lack of a standardized HPV detection assay as well as to the time period in which HPV prevalence is investigated, as rising incidence rates are reported over the last decades. Here, we validated our previously defined test algorithm for HPV detection in formalin-fixed paraffin-embedded (FFPE) tumor specimen consisting of p16(INK4A) immunostaining followed by high-risk HPV DNA detection by GP5+/6+ PCR on the positive cases (Smeets et al., Int J Cancer 2007;121:2465-72). In addition, we analyzed HPV prevalence rates in OPSCCs in the years 1990-2010. The test algorithm was validated on a consecutive series of 86 OPSCCs collected during 2008-2011, of which both fresh frozen and FFPE samples were available. We performed HPV-E6 RT-PCR on the frozen samples as gold standard and applied the algorithm to the corresponding FFPE samples. The test algorithm showed an accuracy of 98%. Using the validated algorithm, we determined the presence of an oncogenic HPV infection in 240 OPSCCs of patients diagnosed in the years 1990-2010 at our center. A significant increase in the proportion of HPV-positive samples was observed, from 5.1% in 1990 to 29.0% in 2010 (p = 0.001). In conclusion, we confirmed the accuracy of the test algorithm for HPV detection in FFPE tumor specimen and we found a significant increase in the prevalence of HPV in OPSCC over the last two decades at our center., (Copyright © 2012 UICC.)

Background: Self-sampling for high-risk human papillomavirus (hrHPV) testing is accepted by up to 30% of non-attendees to the regular cervical screening programme. Here, the yield of cervical intraepithelial neoplasia (CIN)2 or worse (≥ CIN2) and CIN3 or worse (≥ CIN3) of 15, 274 HPV self-sampling responders amongst non-attendees were compared to that of 176, 027 women participating in regular screening in the same period and in the same region. We also analysed which subpopulations amongst non-attendees are targeted by HPV self-sampling, and which characteristics relate to hrHPV prevalence and yield of ≥ CIN2/≥ CIN3., Method: Data from two consecutive self-sampling studies were pooled. ≥ CIN2/≥ CIN3 yields, screening history, age and ethnic status were retrieved from centralised pathology and screening databases, respectively. A logistic regression model was fitted to analyse method of invitation, ethnicity, age group, and screening history as predictors for response rate, hrHPV presence and ≥ CIN2/≥ CIN3 in non-attendees. For screening history analyses, women < 34 years were excluded since it was the first screening round in their life., Findings: ≥ CIN2/≥ CIN3 yields of HPV self-sampling responders were higher than those of screening participants (≥ CIN2: relative risk (RR) = 1.6, 95% confidence interval = 1.4-1.9; ≥ CIN3: RR = 1.8, 95%CI = 1.5-2.1 with relative risk values increasing with age (test of homogeneity:≥ CIN2: p = 0.04; ≥ CIN3: p=0.03). Native Dutch non-attendees responded better than immigrants (32% versus 22%, p<0.001) and those screened in the previous round revealed a higher response than underscreened (i.e. previous smear taken >7 years ago) or never screened (34% versus 25%, p<0.001) women. Strikingly, amongst under- and never screened women aged ≥ 39 years, never screened women responded better (25% versus 23%, p<0.001). ≥ CIN2 rates were higher amongst responding native Dutch women than immigrants (p<0.01), and higher in under-/never screened women than in women screened in the previous round (p<0.01)., Interpretation: Offering hrHPV self-sampling increases the efficacy of the screening programme by targeting a substantial portion of non-attendees of all ethnic groups who have not regularly been screened and are at highest risk of ≥ CIN2., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Human papillomavirus (HPV) testing is more sensitive for the detection of high-grade cervical lesions than is cytology, but detection of HPV by DNA screening in two screening rounds 5 years apart has not been assessed. The aim of this study was to assess whether HPV DNA testing in the first screen decreases detection of cervical intraepithelial neoplasia (CIN) grade 3 or worse, CIN grade 2 or worse, and cervical cancer in the second screening., Methods: In this randomised trial, women aged 29-56 years participating in the cervical screening programme in the Netherlands were randomly assigned to receive HPV DNA (GP5+/6+-PCR method) and cytology co-testing or cytology testing alone, from January, 1999, to September, 2002. Randomisation (in a 1:1 ratio) was done with computer-generated random numbers after the cervical specimen had been taken. At the second screening 5 years later, HPV DNA and cytology co-testing was done in both groups; researchers were masked to the patient's assignment. The primary endpoint was the number of CIN grade 3 or worse detected. Analysis was done by intention to screen. The trial is now finished and is registered, number ISRCTN20781131., Findings: 22,420 women were randomly assigned to the intervention group and 22 518 to the control group; 19 999 in the intervention group and 20,106 in the control group were eligible for analysis at the first screen. At the second screen, 19 579 women in the intervention group and 19,731 in the control group were eligible, of whom 16,750 and 16,743, respectively, attended the second screen. In the second round, CIN grade 3 or worse was less common in the intervention group than in the control group (88 of 19 579 in the intervention group vs 122 of 19,731 in the control group; relative risk 0·73, 95% CI 0·55-0·96; p=0·023). Cervical cancer was also less common in the intervention group than in the control group (four of 19 579 in the intervention group vs 14 of 19,731; 0·29, 0·10-0·87; p=0·031). In the baseline round, detection of CIN grade 3 or worse did not differ significantly between groups (171 of 19 999 vs 150 of 20,106; 1·15, 0·92-1·43; p=0·239) but was significantly more common in women with normal cytology (34 of 19,286 vs 12 of 19,373; 2·85, 1·47-5·49; p=0·001). Furthermore, significantly more cases of CIN grade 2 or worse were detected in the intervention group than in the control group (267 of 19 999 vs 215 of 20,106; 1·25, 1·05-1·50; p=0·015). In the second screen, fewer HPV16-positive CIN grade 3 or worse were detected in the intervention group than in the control group (17 of 9481 vs 35 of 9354; 0·48, 0·27-0·85; p=0·012); detection of non-HPV16-positive CIN grade 3 or worse did not differ between groups (25 of 9481 vs 25 of 9354; 0·99, 0·57-1·72; p=1·00). The cumulative detection of CIN grade 3 or worse and CIN grade 2 or worse did not differ significantly between study arms, neither for the whole study group (CIN grade 3 or worse: 259 of 19 999 vs 272 of 20,106; 0·96, 0·81-1·14, p=0·631; CIN grade 2 or worse: 427 of 19 999 vs 399 of 20,106; 1·08, 0·94-1·24; p=0·292), nor for subgroups of women invited for the first time (CIN grade 3 or worse in women aged 29-33 years: 102 of 3139 vs 105 of 3128; 0·97, 0·74-1·27; CIN grade 2 or worse in women aged 29-33 years: 153 of 3139 vs 151 of 3128; 1·01, 0·81-1·26; CIN grade 3 or worse in women aged 34-56 years: 157 of 16,860 vs 167 of 16 978; 0·95, 0·76-1·18; CIN grade 2 or worse in women aged 34-56 years: 274 of 16,860 vs 248 of 16 978; 1·11, 0·94-1·32)., Interpretation: Implementation of HPV DNA testing in cervical screening leads to earlier detection of clinically relevant CIN grade 2 or worse, which when adequately treated, improves protection against CIN grade 3 or worse and cervical cancer. Early detection of high-grade cervical legions caused by HPV16 was a major component of this benefit. Our results lend support to the use of HPV DNA testing for all women aged 29 years and older., Funding: Zorg Onderzoek Nederland (Netherlands Organisation for Health Research and Development)., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: To determine whether offering self sampling of cervicovaginal material for high risk human papillomavirus (HPV) testing is an effective screening method for women who do not attend regular cervical screening programmes., Design: Cohort study (the PROHTECT trial). Settings Noord-Holland and Flevoland regions of the Netherlands, December 2006 to December 2007, including 13 laboratories, gynaecologists, and more than 800 general practitioners., Participants: 28 073 women who had not responded to two invitations to the regular cervical screening programme: 27 792 women were assigned to the self sampling group and invited to submit a self collected cervicovaginal sample for HPV testing; 281 were assigned to the recall control group and received a second re-invitation for conventional cytology., Intervention: Women with a positive result on the high risk HPV test on their self sample material were referred to their general practitioner. Women with abnormal results on cytology were referred for colposcopy. Women with normal results on cytology were re-evaluated after one year by cytology and high risk HPV testing and referred for colposcopy if either result was positive., Main Outcome Measures: Attendance rate in both groups and yield of cervical intraepithelial neoplasia grade II/III or worse (>or=CIN II/>or=CIN III) in self sampling responders., Results: The compliance rate in the self sampling group was significantly higher than in the control group (crude 26.6% v 16.4%, P<0.001; adjusted 27.5% v 16.6%, P<0.001). The number of detected >or=CIN II and >or=CIN III lesions in self sampling responders was 99 (1.3%) and 76 (1.0%), respectively. Self sampling responders who had not participated in the previous round of screening (43%) had increased relative risks of >or=CIN II (2.04, 95% confidence interval 1.27 to 3.28) and >or=CIN III (2.28, 1.31 to 3.96) compared with self sampling women who had been screened in the previous round (57%)., Conclusions: Offering self sampling by sending a device for collecting cervicovaginal specimens for high risk HPV testing to women who did not attend regular screening is a feasible and effective method of increasing coverage in a screening programme. The response rate and the yield of high grade lesions support implementation of this method for such women. Trial registration ISRCTN45527158.

Objective: Because high-risk human papillomavirus (hrHPV) is the necessary factor in the development of high-grade cervical lesions, knowing the colposcopic differences between hrHPV-positive and hrHPV-negative lesions could be of value. We have evaluated whether there are colposcopic differences between lesions testing hrHPV-positive or hrHPV-negative., Materials and Methods: This study was conducted as a retrospective case-control study. We designed a scoring system for colposcopic criteria that might be of relevance to distinguish hrHPV-positive from hrHPV-negative lesions. Colposcopic images were analyzed from patients at the VU University Medical Center Amsterdam, the Netherlands, in whom a GP5+/6+ polymerase chain reaction hrHPV test had been performed within a month of the colposcopic examination (n = 507)., Results: Visibility of the transformation zone (corrected for age), a (very) coarse and irregular punctation pattern, and a large lesion (>25% of the visible cervix) were more often associated with a positive hrHPV test status (p =.001, odds ratio [OR] = 2.29, 95% CI = 1.41-3.73; p =.036, OR 2.37, 95% CI = 1.08-5.19; and p =.044, OR = 1.78, 95% CI = 1.08-2.94, respectively). After correction for histologic diagnosis, the difference between hrHPV-positive and hrHPV-negative lesions for visibility of the transformation zone and lesion size remained statistically significant (OR = 2.44, 95% CI = 1.35-4.41 and OR = 1.92, 95% CI = 1.04-3.54, respectively)., Conclusions: This study indicates that visibility of the transformation zone, (very) coarse punctation pattern, and larger lesion size were the main colposcopic features associated with a hrHPV-positive test status.

In The Netherlands, vaccination against HPV16/18 has been recommended for all 12-year-old girls. Because screening of vaccinated women remains important, we evaluated the model-based cost-effectiveness of cervical cancer screening strategies. We considered cytology and the HPV DNA test as primary screening instrument, varied the number of screening rounds from 7 to 4, and set the screening starting age at 30 and 35 years. Our model predicted reductions in cervical cancer mortality between 60 and 81% (from 199 deaths to 37-79) when adding screening to vaccination (assumptions for vaccination: 95% efficacy, 100% compliance, lifelong protection). Screening 5 times with HPV DNA (euro11,133/QALY) or 7 times with cytology (euro17,627/QALY) were scenarios with comparable costs and effects and incremental cost-effectiveness ratios below the threshold in The Netherlands (euro20,000 per QALY).

There is evidence that a subset of penile carcinomas is caused by infection with high-risk human papillomavirus (HPV). However, extensive studies on the possible influence of HPV infection on clinical outcome of penile cancer are lacking. This investigation is aimed to examine the prevalence of high-risk HPV in a large series of penile squamous-cell carcinomas (SCCs) and to determine the relationship between HPV and survival. Formalin-fixed, paraffin-embedded tumor specimens of 171 patients with penile carcinoma were tested for high-risk HPV DNA presence by GP5+/6+-PCR. The clinical course of the patients and the histopathological characteristics of the primary tumors were reviewed. High-risk HPV DNA was detected in 29% of the tumors, with HPV 16 being the predominant type, accounting for 76% of high-risk HPV containing SCCs. Disease-specific 5-year survival in the high-risk HPV-negative group and high-risk HPV-positive group was 78% and 93%, respectively (log rank test p = 0.03). In multivariate analysis, the HPV status was an independent predictor for disease-specific mortality (p = 0.01) with a hazard ratio of 0.14 (95% CI: 0.03-0.63). Our results indicate that the presence of high-risk HPV (29%) confers a survival advantage in patients with penile carcinoma., (Copyright 2006 Wiley-Liss, Inc.)

Introduction: High-risk human papillomavirus (hrHPV) DNA testing is an increasingly used instrument in cervical cancer prevention along cervical cytology. The inclusion of hrHPV testing in cervical screening requires efficient management as many hrHPV infections are transient. We investigated the potential value of hrHPV genotyping in normal and borderline/mildly dyskaryotic (BMD) smears., Materials and Methods: From a screening population of 44,102 women in the Netherlands, we included hrHPV-positive women with a normal or BMD smear. We assessed the type-specific 18-month risk of high-grade cervical intraepithelial neoplasia (CIN)., Results: In hrHPV-positive women, 18-month risk of CIN grade 3 or invasive cancer (> or =CIN3) was 6% [95% confidence interval (95% CI), 4-9] after normal cytology and 20% (95% CI, 16-25) after BMD. If positive for HPV16, > or =CIN3 risks were 14% (95% CI, 9-21) and 37% (95% CI, 28-48), respectively. In the subset of hrHPV-positive women without HPV16, HPV18 was associated with an increased risk of high-grade CIN after normal cytology and HPV31 and HPV33 were associated with an increased risk, particularly after BMD. HPV16 and HPV18 were also associated with an increased risk of high-grade CIN in women with an hrHPV-positive normal baseline smear and a repeat normal smear at 6 months., Discussion: HrHPV-positive women without type 16, 18, 31, or 33 had a relatively low risk of high-grade CIN. Among women with baseline normal cytology and among women with a baseline and repeat normal smear, HPV16/18-positive women showed an increased risk of high-grade CIN. This warrants more aggressive management of HPV16/18-positive women compared with other hrHPV-positive women.

High-risk human papillomavirus (hrHPV) types are causally related to cervical cancer and its high-grade precursor lesions. The risk posed by the different hrHPV types for the development of cervical intraepithelial neoplasia grade 2 or worse (> or =CIN2) needs to be established. Here, we present the hrHPV type-distribution in relation to cytology and histology for women participating in a cervical screening program. From 44,102 women who participated in a population-based cervical screening program in the Netherlands, 2,154 hrHPV GP5+/6+ PCR positive women were recruited to determine the distribution of 14 hrHPV types by reverse line blotting of GP5+/6+ PCR products. For each HPV type, associations with cytology and histologically confirmed > or =CIN2 were measured by odds ratios. HPV types 16 and 33 were more prevalent in women, amongst those containing a single hrHPV type, with moderate dyskaryosis or worse (>BMD) than in women with normal cytology, but only in case of underlying > or =CIN2 (OR 4.10, 95%CI 2.98-5.64 and OR 2.68, 95%CI 1.39-5.15, respectively). Similar results were obtained for women with double infections (OR 3.29, 95% CI 1.61-6.75 and OR 4.37, 95% CI 1.17-16.34). Coexisting types did not influence the prevalence of > or =CIN2 in HPV 16 or 33 positive women. The increased prevalence of type 16 and 33 in hrHPV positive women with > or =CIN2, compared to women with normal cytology, suggests that infection with these types confers an increased risk for development of > or =CIN2. Distinguishing these types may therefore have implications for future cervical screening strategies.

Human papillomavirus (HPV) infections and HPV-associated penile lesions are frequently found in male sexual partners of women with cervical intraepithelial neoplasia (CIN). To determine the significance of these findings, we studied the prevalence of HPV and HPV associated penile lesions in a male hospital population with non-STD complaints. Penoscopy was performed after application of acetic acid to identify flat lesions, papular lesions, condylomata acuminata and pearly penile papules (PPPs). Presence of HPV DNA in penile scrapes was tested by GP5+6+ PCR. In case of HPV 16 positivity, viral loads were quantified using a LightCycler based real-time PCR method. Comparing the non-STD male hospital population (n = 118) with the male sexual partners of women with CIN (n = 238), flat penile lesions were found in 14% vs. 60% and penile HPV in 25% vs. 59% of the men, respectively. We found that the presence of penile HPV and, in case of HPV 16 positivity, higher viral loads were associated with the presence of flat penile lesions. Amongst the HPV-positive men, flat penile lesions were more common and larger in size in male sexual partners of women with CIN than in the non-STD hospital population. HPV infections and HPV-associated flat penile lesions are commonly found in the non-STD male population. However, these lesions are less frequently present and smaller in size than in male sexual partners of women with CIN. Higher viral loads in penile scrapes of male sexual partners of women with CIN are reflected by a higher prevalence of flat penile lesions and a larger size of these lesions.

Women with persistent HPV infections have increased risk of progressive CIN lesions. Transmission of HPV between sexual partners might maintain viral infection and, consequently, may influence the clinical course of CIN. We investigated the effect of condom use on regression of CIN lesions and on clearance of HPV. Women with CIN and their male sexual partners were randomized for condom use (condom group n = 72 and noncondom group n = 76). They were conservatively managed and followed every 3-6 months by colposcopy, cytology and HPV testing by GP5+/6+ PCR. Baseline cervical biopsy specimens were taken. Median follow-up time for women was 15.2 months (range 3.0-85.4). Outcomes of interest were clinical regression of CIN at colposcopy and clearance of HPV. Outcomes were assessed in 64 women of the condom group and 61 women of the noncondom group. Women in the condom group showed a 2-year cumulative regression rate of 53% vs. 35% in the noncondom group (p = 0.03). The 2-year cumulative rates of HPV clearance were 23% vs. 4%, respectively (p = 0.02). Although lower regression rates were found if women were HPV-positive and had > or =CIN2 lesions at baseline, effects of condom use were found both in women with CIN1 and in women with > or =CIN2 lesions. Condom use promotes regression of CIN lesions and clearance of HPV., (Copyright 2003 Wiley-Liss, Inc.)